3Rs implementation in veterinary vaccine batch-release testing: Current state-of-the-art and future opportunities. A webinar and workshop report.

Regulatory authorities require veterinary batch-release testing to confirm vaccine potency and safety, but these tests have traditionally relied on large numbers of laboratory animals. Advances in vaccine research and development offer increasing opportunities to replace in vivo testing, and some stakeholders have made significant progress in incorporating 3Rs elements in quality control strategies. A three-part event series entitled "3Rs Implementation in Veterinary Vaccine Batch-Release Testing: Current state-of-the-art and future opportunities" was jointly organized by the Animal-Free Safety Assessment Collaboration, HealthforAnimals, and the International Alliance of Biological Standardization. Two webinars and a workshop aimed to outline the state-of-the-art non-animal approaches for veterinary batch-release testing. The events included information on the state of the deletion of obsolete safety testing and the current initiatives implemented by European, North American, and Asian-Pacific stakeholders on 3Rs implementation and regulatory acceptance. The events contributed to a better understanding of the barriers to 3Rs implementation. Participants highlighted the need for open communication, continued collaboration between stakeholders, and international harmonization of regulatory requirements to help accelerate acceptance. Despite the challenges, the countries represented at this three-part event have shared their commitments to advancing the acceptance of alternative methods.

Component Rotation in Well-Functioning, Gap Balanced Total Knee Arthroplasty Without Navigation.

BACKGROUND: Malalignment of total knee arthroplasty (TKA) components is a potential cause of clinical failure following TKA. Since the goal of a gap balancing (GB) technique is equal flexion and extension gaps secondary to soft-tissue balancing, and not necessarily component alignment, variation in component placement may exist. Our purpose was (1) to evaluate precision of component alignment in well-functioning GB TKAs performed without the aid of navigation using computed tomographic evaluation and (2) to determine any relationship between femoral version and/or tibial torsion and TKA component positioning. METHODS: There were 93 well-functioning TKAs performed with an extension gap first GB technique with a minimum 2-year follow-up evaluated using computed tomography to assess component rotational alignment, as well as osseous femoral version and tibial torsion. Femoral and tibial rotational alignment was assessed by previously described methods. RESULTS: The mean Knee Society Score was 185.7 ± 21.7. The mean range of motion was 128.5 ± 7.8°. Femoral posterocondylar axis (relative to the transepicondylar axis) values ranged from -8.3 to 4.1° with a mean of -0.78 ± 2.7° (internal rotation). Mean tibial rotation was 17.2 ± 7.9° internal rotation relative to the tibial tubercle. No correlation was found between native femoral version and femoral component rotational alignment (Pearson's correlation coefficient, r, 0.007). Weak correlation was found between native tibial torsion and tibial component alignment (r = 0.24). CONCLUSION: Despite being only a secondary objective with the GB technique, most components evaluated were within the desired range of rotation. Alignment was not influenced by native osseous rotational geometry. LEVEL OF EVIDENCE: Level III, Retrospective Cohort Study.

Use of Fractional Exhaled Nitric Oxide to Guide the Treatment of Asthma: An Official American Thoracic Society Clinical Practice Guideline.

Background: The fractional exhaled nitric oxide (FENO) test is a point-of-care test that is used in the assessment of asthma. Objective: To provide evidence-based clinical guidance on whether FENO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered. Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FENO. The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidence-based answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations. Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FENO-based care. In patients with asthma in whom treatment is being considered, we suggest that FENO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice. Conclusions: Clinicians should consider this recommendation to measure FENO in patients with asthma in whom treatment is being considered based on current best available evidence.

Alpha-Defensin Offers Limited Utility in Routine Workup of Periprosthetic Joint Infection.

BACKGROUND: Alpha-defensin (AD) is a synovial biomarker included as a minor criterion in the scoring system for diagnosing periprosthetic joint infection (PJI). The purpose of this study is to study the impact of AD on diagnosis and management of PJI. METHODS: Synovial fluid from 522 patients after total knee and hip arthroplasty was retrospective reviewed. Synovial white blood cell count, percentage of neutrophils, and culture from the AD immunoassay laboratory were reviewed with serum erythrocyte sedimentation rate and C-reactive protein values from our institution. A modified version of the 2018 scoring system for diagnosis of PJI was used, only scoring white blood cell count, percentage of neutrophils, erythrocyte sedimentation rate, and C-reactive protein. AD was then analyzed with these scores to determine if AD changed diagnostic findings or clinical management. RESULTS: Eight-two patients were categorized as "infected" (score ≥6), of which 76 patients had positive AD. Of the 6 "infected" patients with negative AD, 2 had positive cultures (Staphylococcus epidermidis). Two-hundred thirteen patients were diagnosed as "possibly infected" (score 2-5). Fourteen of these patients had positive AD, of which 5 had positive cultures assisting with the diagnosis. The AD test changed the diagnosis from "possibly infected" to "infected" in 8 patients (1.5%) but only altered treatment plan in 6 patients (1.1%). A score <2 (not infected) was calculated in 227 patients with no patients having positive AD. CONCLUSION: AD may be beneficial in some cases where laboratory values are otherwise equivocal; however, its routine use for the diagnosis of PJI may not be warranted.

A Prophylactic Tibial Stem Reduces Rates of Early Aseptic Loosening in Patients with Severe Preoperative Varus Deformity in Primary Total Knee Arthroplasty.

BACKGROUND: Patients with a preoperative varus deformity >8 degrees are at increased risk of aseptic loosening after total knee arthroplasty. This study analyzes the effect of a tibial stem on the rate of aseptic loosening in patients with a severe preoperative varus deformity. METHODS: Patients with a preoperative varus deformity of >8 degrees and 2-year minimum follow-up with a stemmed tibial component (n = 67) were matched 1:2 to patients with a similar preoperative varus deformity with a standard tibial component (n = 134). Radiolucent lines were measured on the tibia at 6 weeks, 1 year, and 2 years postoperatively using the Knee Society Radiographic Evaluation System. Failure was defined as revision due to aseptic loosening of the tibial component. Outcomes were evaluated using Student's t-tests and log-rank tests. RESULTS: Patients with tibial stems had greater preoperative deformity (12.9 vs 11.3 degrees, P = .004). There was no difference in postoperative alignment (1.7 vs 2.1 degrees varus, P = .25) or tibial component angle (1.8 vs 2.1 degrees varus, P = .33). Patients with stems were more likely to have more constraint (44.8% vs 1.5%, P < .001). Progression of radiolucent lines >2 mm was observed in 17.6% (23/134) vs 5.97% (4/67) of patients in the stem group (P = .03). Rates of aseptic loosening were lower in the stem group (0% vs 5.15%, P = .05). CONCLUSION: Despite worse preoperative deformity and higher utilization of constraint, tibial stem use in patients with severe preoperative varus deformity resulted in lower rates of aseptic loosening. Prophylactic use of stems in these patients may help increase implant survival.

Alpha-Defensin Is Not Superior to Traditional Diagnostic Methods for Detection of Periprosthetic Joint Infection in Total Hip Arthroplasty and Total Knee Arthroplasty Patients.

BACKGROUND: Synovial fluid alpha-defensin (AD) may improve diagnostic accuracy of periprosthetic joint infection (PJI) following total knee (TKA) and hip (THA) arthroplasty but is only available as send-out test. This study evaluated laboratory result accuracy between send-out test vs hospital labs and if AD made a difference in treatment plan. METHODS: A retrospective review was performed of 152 consecutive patients with a TKA or THA joint aspiration for painful or clinically concerning joint. Synovial fluid was sent to our institution (hospital-based labs, HBL) and send-out immunoassay laboratory (Synovasure). Patients were scored with specific criteria from validated scoring system for PJI using HBL and Synovasure results. The score with and without AD test was compared to determine if AD impacted patient management. RESULTS: Overall, there was strong agreement between institutions for PJI diagnosis (Cohen's kappa score 0.96). Twenty-nine patients had PJI diagnosis (score ≥6), of which 28 (97%) had positive AD with 1 false-negative result. Sixty-three patients had inconclusive score (between 2 and 5) and 60 patients had negative PJI diagnosis (score ≤1). Of these patients, 5 underwent surgery for infection. Two patients had surgery for positive AD, 2 for positive culture, and 1 because of elevated HBL results. The AD test changed the PJI diagnosis and influenced decision for surgery in only 1.3% (2/152) of patients. CONCLUSION: Minimal differences were found in laboratory values between institutions. The addition of AD may be useful in cases of equivocal laboratory results but does not appear to be necessary for routine diagnosis of PJI after TKA/THA. LEVEL EVIDENCE: Level III.

A call for collaboration and consensus on training for endotracheal intubation in the medical intensive care unit.

Endotracheal intubation (EI) is a potentially lifesaving but high-risk procedure in critically ill patients. While the ACGME mandates that trainees in pulmonary and critical care medicine (PCCM) achieve competence in this procedure, there is wide variation in EI training across the USA. One study suggests that 40% of the US PCCM trainees feel they would not be proficient in EI upon graduation. This article presents a review of the EI training literature; the recommendations of a national group of PCCM, anesthesiology, emergency medicine, and pediatric experts; and a call for further research, collaboration, and consensus guidelines.

Patient Perception Regarding Potential Effectiveness of Cannabis for Pain Management.

BACKGROUND: Self-reported cannabis use has increased since its recent legalization in many states. The primary objective of this study is to describe patients' beliefs regarding the potential effectiveness of cannabis and gauge patient acceptance of these compounds if prescribed by a physician. METHODS: Five hundred fifty-five consecutive new patients in a total joint arthroplasty (TJA) practice completed a questionnaire at their new patient or preoperative encounter. Questions regarding their beliefs about the potential effectiveness of cannabis for pain management were presented to the patient. Each question was scored in accordance to the agreement of the patient. Data were also collected on patient demographics, and current cannabis, tobacco, and/or alcohol use. RESULTS: Current cannabis use was reported in 20.2% (112/555) of respondents. Patients were interested in using cannabis if prescribed by a physician for acute (75.3%, 418/515) and chronic (74.4%, 415/555) pain. Seventy-seven percent (428/555) of patients believe (strongly agree or agree) that cannabis should be legalized for medical use, whereas only 39% (217/555) strongly agree or agree that cannabis should be legalized for recreational use. Patients strongly agree or agree that cannabis can help with sleep or anxiety, 44.9% (249/555) and 49.4% (274/555) respectively. Most patients had never smoked (53%, 294/555) and drink one or less alcoholic beverage per week (52.1%, 299/555). CONCLUSION: Patients believe that cannabis may be helpful for pain management after TJA and are willing to use if prescribed by their orthopedic provider. Further research is warranted to determine if cannabis is a helpful adjunct to pain management in this patient population.

Siblings of adults with intellectual and developmental disabilities: Their knowledge and perspectives on guardianship and its alternatives.

BACKGROUND: Siblings of adults with intellectual and developmental disabilities (IDD) often support their brothers and sisters through caregiving and guardianship. METHODS: In this qualitative study, the knowledge and views of 10 adult siblings were explored. RESULTS & CONCLUSIONS: The tripartite impact of limited knowledge of guardianship and alternatives, the viewpoint of full guardianship as necessary and the desired/anticipated roles of siblings combined to create the Sibling Reciprocal Effect (SRE). The present authors define SRE as the phenomenon of siblings to recognize the applicability of complementary forms of guardianship for other adults with IDD, but fail to see the advantage of available decision-making alternatives with their own brothers/sisters. Instead, siblings defer to full guardianship as the preferred mechanism for decision making. Implications for practitioners include informing families of the full range of options for supporting persons with IDD in decision making. Future research suggestions include examining the elements of the SRE and siblings' knowledge regarding guardianship and the alternatives.

DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression.

Phosphorylation of ribosomal protein L13a is essential for translational repression of inflammatory genes by the interferon (IFN)-gamma-activated inhibitor of translation (GAIT) complex. Here we show that IFN-gamma activates a kinase cascade in which death-associated protein kinase-1 (DAPK) activates zipper-interacting protein kinase (ZIPK), culminating in L13a phosphorylation on Ser(77), L13a release from the ribosome, and translational silencing of GAIT element-bearing target mRNAs. Remarkably, both kinase mRNAs contain functional 3'UTR GAIT elements, and thus the same inhibitory pathway activated by the kinases is co-opted to suppress their expression. Inhibition of DAPK and ZIPK facilitates cell restoration to the basal state and allows renewed induction of GAIT target transcripts by repeated stimulation. Thus, the DAPK-ZIPK-L13a axis forms a unique regulatory module that first represses, then repermits inflammatory gene expression. We propose that the module presents an important checkpoint in the macrophage "resolution of inflammation" program, and that pathway defects may contribute to chronic inflammatory disorders.

High Incidence of Recurrent Patellofemoral Crepitus in Total Knee Arthroplasty Patients Following Arthroscopic Debridement.

Background: Patellofemoral crepitus is an unfavorable complication following total knee arthroplasty (TKA) with a posterior-stabilized (PS) implant. The purpose of this study was to study patellar crepitus recurrence and reoperation rates following arthroscopic debridement in patients with a PS-TKA. Methods: Our institution database was used to identify patients with a PS-TKA who underwent arthroscopic debridement for patellofemoral crepitus at our institution. Patients must have had a resurfaced patella and minimum 2 years clinical follow-up from the arthroscopic debridement to be included in the study. Recurrence of patellar crepitus, subsequent operations, and any adverse events were documented. Results: We identified 35 patients who met inclusion criteria with an average follow-up of 8.0 years (range 2.1 to 18.4 years) from their arthroscopic debridement. Nineteen patients (54.3%) had history of a nonarthroplasty knee surgery prior to their TKA. The mean time interval between TKA and arthroscopic debridement for patellar crepitus was 1.6 years (range 0.2 to 5.0 years). Overall, 16 patients (45.7%) developed recurrent crepitus (8 asymptomatic and 8 symptomatic). Six of the symptomatic patients (17.1% of the entire cohort) underwent a repeat surgery for recurrent patellofemoral crepitus. Of theses 6 patients, 3 developed recurrent crepitus but only 1 patient had a third surgical procedure. No postoperative complications were noted following any surgical procedure. The mean knee range of motion following arthroscopic debridement did not change (126.9° preoperatively vs 127.0° postoperatively). Conclusions: Patients experienced high rates of recurrent patellofemoral crepitus following arthroscopic debridement. One-sixth of the patient cohort required a second surgical intervention for recurrent crepitus.

Expression of phosphorylated signal transducer and activator of transcription 5 is associated with an increased risk of death in acute myeloid leukemia.

BACKGROUND: Constitutive activation of STAT5 (by phosphorylation) has been identified in a number of malignancies, including acute myeloid leukemia (AML). OBJECTIVES: We investigated whether the level of phosphorylated STAT5 (pSTAT5) expression correlates with clinical outcome in AML. METHODS: Adult patients with newly diagnosed AML receiving induction chemotherapy and with an available diagnostic bone marrow were evaluated. RESULTS: Forty-two percent of patients had pSTAT5 expression >0 on immunohistochemical analysis of fixed bone marrow core biopsies. In multivariable analyses, controlling for age, history of antecedent hematologic disorder, cytogenetic risk, and WBC at diagnosis, pSTAT5 expression was significantly associated with an increased risk of death (HR 1.96, 95% CI 1.19-3.23, P = 0.008) and of relapse after achieving complete remission (HR 2.31, 95% CI 1.16-4.63, P = 0.018). CONCLUSIONS: Validation of pSTAT5's prognostic value requires additional study in a larger group of uniformly treated patients. However, our data suggests that targeting this signaling pathway in AML may improve the outcome of patients.

Self-regulation of time: The importance of time estimation accuracy.

Time management is one central aspect of students' self-regulated learning. In addition, biased time estimation seems to be central to students' self-regulation of their time. In this study, we explored college students' time estimation bias. In addition, we were interested in whether the activation of task beliefs influenced students' time estimation bias and how specific beliefs about task difficulty influence time estimation bias. Findings suggested that students tended to demonstrate bias in their estimations of the time their academic tasks would take. Additionally, the activation of task beliefs did not influence students' time estimation accuracy. Finally, both prior task difficulty and anticipated difficulty influenced students' time estimation bias. These findings highlight the complexity of students' time estimation bias and point to the opportunities for future directions.

Corrigendum: Self-regulation of time: The importance of time estimation accuracy.

[This corrects the article DOI: 10.3389/fpsyg.2022.925812.].

Use of Cannabis Does Not Decrease Opioid Consumption in Patients Who Underwent Total Joint Arthroplasty.

Background: The primary purpose of this study was to determine if cannabis use decreases narcotic consumption in patients undergoing total joint arthroplasty (TJA). Material and methods: Forty-six patients undergoing a primary unilateral TJA, who self-reported the use of cannabis, were prospectively enrolled and completed this study between July 2015 and November 2019. This cohort was prospectively matched to patients who did not report cannabis use. Morphine equivalents (MEs) were averaged and recorded at 1 and 2 weeks postoperatively. Secondary outcomes and complications were recorded and reported. Results: There were no differences noted in ME during the hospitalization between the user (78.7 ± 58.5) and nonusers (70.4 ± 46.3), P = .455. ME daily average did not differ between the cohorts (user [36.8 ± 30.7] and nonuser [31.7 ± 25.6] at 1 week (P = .389) or user [22.5 ± 26.3] and nonusers [15.9 ± 18.3] at 2 weeks, P = .164, postoperatively). The total ME at 2 weeks did not differ between the user and nonuser groups (415 ± 375 vs 333 ± 275, P = .235). Pain scores at 1 week were significantly higher in patients who used cannabis (4.1 ± 1.9 vs 3.4 ± 1.6, P = .05). No differences in pain were noted during the patient's hospitalization or at 2- (P = .071) or 6-week (P = .111) follow-up. No differences in secondary outcomes or complications were noted. Conclusion: We were unable to show a decrease in narcotic consumption in patients who use cannabis undergoing primary unilateral joint replacement. These findings do not support the routine use of cannabis to decrease or supplement narcotic use after primary TJA. Level of evidence: Level II therapeutic.

A back table ultraviolet light decreases environmental contamination during operative cases.

BACKGROUND: The purpose of this study is to assess the impact of a germicidal ultraviolet light-emitting diode (LED) on the contamination level of a back table in the operating room (OR) during total joint arthroplasty procedures. METHODS: Eight Tryptic Soy Agar petri plates were placed on a table located near the operative field and exposed to air. One plate was removed on the hour over an 8-hour time span. The back table had either an UV-LED for disinfection or a sham UV-LED. This process was repeated in 12 different ORs (6 with UV light, 6 with sham device). The plates were then incubated for 48 hours at 36°C ± 1°C . Colony forming units (CFU) were recorded 24 and 48 hours after incubation. RESULTS: There was a statistically significant difference in total CFUs between the intervention vs sham at 24-hours (27 vs 95, P = .0001) and 48-hours (38 vs 122, P < .0001). The multivariate analysis revealed that the 24-hour and 48-hour count, the predictors UV light (P = .002) and hour of plate removal (P = .050) were statistically significantly associated with CFU counts. Together, the predictor variables explained 15.8% and 23.0% of the variance in CFU counts at 24- and 48-hours, respectively. CONCLUSIONS: A back table UV-LED may decrease environmental contamination near the operative field. This has potential to lead to a decrease in joint infection.

Effectiveness of Manual Terminal Cleaning Varies on High-Touch Surfaces Near the Operative Field.

Background: Periprosthetic joint infection may result from pathogen to patient transmission within the environment. The purpose of this study is to evaluate the contamination level of selected high-touch surfaces in the operating room (OR) using a blacklight fluorescent marking system after a manual terminal clean. Methods: Prior to the manual terminal clean, 16 high-touch surfaces were marked using a blacklight fluorescent gel. The marked areas were assessed the next morning for thoroughness of cleaning. Surfaces were categorized based on the average percent of the marks removed as "clean" (>75%), "partially clean" (26%-74%), or poorly cleaned (<25%). This process was repeated randomly 12 times. Terminal cleaning was done in the standard fashion, and the perioperative team was unaware of the initiation of this study. Results: A total of 936 marks were analyzed. There was a significant difference in the number of marks completely clean (29.1%, 272/936) vs marks that were not touched (40.8%, 382/936), P < .001. Only the OR back table (75%) had a rating of clean. Partially clean areas included Mayfield table (72%), overhead lights (70.1%), infusion pump (61.1%), clock reset button (58.3%), table remote control (50%), tourniquet machine (50%), and the OR table (33.3%). Poorly cleaned surfaces included anesthesia medication cart (21.8%), door handles (20.8%), phone (16.7%), electrocautery unit (16.7%), foot pedal (16.7%), anesthesia cart (16.2%), nurses' station (14.1%), and supply cabinet doors (6%). Conclusions: Effectiveness of manual terminal cleaning varied greatly across surfaces. In general, surfaces further from the operative field were less likely to have markings removed.

Bronchoscopy Teaching Without a Gold Standard: Attending Pulmonologists' Assessment of Learners, Supervisory Styles, and Variation in Practice.

BACKGROUND: Despite the growing role of simulation in procedural teaching, bronchoscopy training largely is experiential and occurs during patient care. The Accreditation Council for Graduate Medical Education sets a target of 100 bronchoscopies to be performed during pulmonary fellowship. Attending physicians must balance fellow autonomy with patient safety during these clinical teaching experiences. Few data on best practices for bronchoscopy teaching exist, and a better understanding of how bronchoscopy currently is supervised could allow for improvement in bronchoscopy teaching. RESEARCH QUESTION: How do attending bronchoscopists supervise bronchoscopy, and in particular, how do attendings balance fellow autonomy with patient safety? STUDY DESIGN AND METHODS: This was a focused ethnography conducted at a single center using audio recording of dialog between attendings and fellows during bronchoscopies, supplemented by observation of nonverbal teaching. Interviews with attending bronchoscopists and limited interviews of fellows also were recorded. Interviews were transcribed verbatim before analysis. We used constant comparative analysis to analyze data and qualitative research software to support data organization and thematic analysis. Education researchers from outside of pulmonary critical care joined the team to minimize bias. RESULTS: We observed seven attending bronchoscopists supervising eight bronchoscopies. We noted distinct teaching behaviors, classified into themes, which then were grouped into four supervisory styles of modelling, coaching, scaffolding, and fading. Observation and interviews illuminated that assessing fellow skill was one tool used to choose a style, and attendings moved between styles. Attendings accepted some, but not all, variation in both performing and supervising bronchoscopy. INTERPRETATION: Attending pulmonologists used a range of teaching microskills as they moved between different supervisory styles and selectively accepted variation in practice. These distinct approaches may create well-rounded bronchoscopists by the end of fellowship training and should be studied further.

Virtual Procedural Supervision During the COVID-19 Pandemic: A Novel Pilot for Supervising Invasive Bedside Procedures in the ICU.

The ability to perform invasive bedside procedures (IBPs) safely and efficiently is a core skill set within critical care medicine. Fellowship training provides a pivotal time for learners to attain baseline proficiency in such procedures to decrease patient complications. The coronavirus disease 2019 pandemic has posed distinct challenges to the traditional model of teaching and supervising IBPs in the intensive care unit, including stewardship of personal protective equipment and limiting health care worker exposure to persons with coronavirus disease 2019. To address these challenges, we piloted a novel method of IBP supervision and teaching using a virtual monitoring system. In this virtual procedural supervision model, the supervising teacher is located outside the patient room, limiting personal protective equipment use and health care worker exposure. An audiovisual monitoring system allowed communication between the teacher and the learner as well as supervisor visualization of the procedural encounter. Virtual supervision was used for central line placement and bronchoscopy in the medical intensive care unit with no complications or instances of the supervisor needing to enter the patient room. Success was felt to depend on camera positioning and preprocedure planning and to be best for advanced learners who would not require tactile feedback. Upper level learners appreciated autonomy granted by this process. Virtual IBP supervision is felt to be a useful tool in specific situations. As with any tool, there are notable strengths and limitations. Success is felt to be optimized when attention is paid to procedural teaching best practices, learner selection, and technological logistics.