A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family.

Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKR-P1 (NK1.1) receptors. This murine cytomegalovirus (MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a "polar claw" mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay.

Clinical features, future cardiac events, and prognostic factors following percutaneous coronary intervention in young female patients.

BACKGROUND: The proportion of young females among the patients who undergo percutaneous coronary intervention (PCI) is relatively small, and information on their clinical characteristics is limited. This study investigated the clinical characteristics and prognostic factors for future cardiac events in young females who underwent PCI. METHODS: This multicenter observational study included 187 consecutive female patients aged < 60 years who underwent PCI in seven hospitals. The primary composite endpoint was the incidence of cardiac death, nonfatal myocardial infarction, and target vessel revascularization. RESULTS: The mean patient age was 52.1 ± 6.1 years and 89 (47.6%) had diabetes, and renal dysfunction (an estimated glomerular filtration rate < 60 mL/min/1.73 m2) was observed in 38 (20.3%). During a median follow-up of 3.3 years, the primary endpoint occurred in 28 patients. The Cox proportional hazards models showed that renal dysfunction was an independent predictor for the primary endpoint (hazard ratio 3.04, 95% confidence interval 1.25-7.40, p = 0.01), as well as multivessel disease (hazard ratio 2.79, 95% confidence interval 1.12-6.93, p = 0.03). Patients with renal dysfunction had a significantly higher risk for the primary endpoint than those without renal dysfunction. CONCLUSIONS: Renal dysfunction was strongly associated with future cardiac events in young females who underwent PCI.

Editorial Commentary: Diverse Factors Affect Measurement of Patella Alta: Trochlear Morphology and Sagittal Knee Balance Represent Defining Factors of Patellofemoral Stability.

Patella alta is a known risk factor for patellar instability, contributing to increased length changes of the medial patellofemoral complex, and associated with high rates of failure after medial patellofemoral complex reconstruction. Distalization through tibial tuberosity osteotomy (TTO) is a surgical option to address patella alta during patellar stabilization surgery. However, distalization has been shown to have greater complication rates than other types of TTO, and therefore precise indications through proper assessments of patellar height are needed. The Caton-Deschamps index is a commonly used measurement and is independent of patellar tendon length, allowing for assessment of patellar height before and after distalizing TTO. Additional options that may offer this ability are femoral-based measurements such as the patellotrochlear index and sagittal patellar engagement, which also do not rely on the position of the tubercle and may better represent the functional engagement of the patellofemoral joint. However, femoral-based measurements depend on trochlear morphology; theoretically, an advantage of femoral-based measurements is that they may reflect the functional engagement of the patella within the trochlea. However, in knowing the common relation between patella alta and trochlear dysplasia, the question becomes whether an overlap between the patella and a dysplastic proximal trochlea on a sagittal measurement truly represents functional engagement and stability of the patellofemoral joint. Measurement of patella alta and determining indications for distalization can be influenced by measurement techniques including magnetic resonance imaging versus radiography, tibial- versus femoral-based measurements, and positional and morphologic considerations. Increased understanding of trochlear morphology and sagittal knee balance as they relate to patella alta will be important for defining the factors that affect patellofemoral stability.

Sagittal tibial tuberosity to trochlear groove distance measurements may reflect patellofemoral contact pressures.

Tibial tubercle to trochlear groove (TTTG) distance is a commonly utilized measurement in the assessment of knees with patellar instability, representing malalignment in the form of tuberosity lateralization relative to the trochlear groove. More recently, the concept of the anteroposterior TTTG (AP-TTTG), renamed as the sagittal TTTG (sTTTG), has been studied as a measurement to assess the relationship between the two structures in a different direction, potentially representing patellofemoral contact pressures through its assessment in the sagittal plane. As we incorporate this measurement to capture how our surgical procedures can offload the joint and 'correct' the sTTTG distance, the utility of this measurement as a proxy for patellofemoral contact pressures will continue to grow, allowing us to better consider joint preservation in addition to stability in the management of patellar instability.

Telemedicine After COVID-19: Incorporating Virtual Visits Into Your Practice.

The use of telemedicine services within orthopaedics increased rapidly as a result of the COVID-19 pandemic. Telemedicine may improve access to care and save time and money for patients and clinicians; however, limitations such as technical issues and limited physical examination may reduce its widespread adoption. Virtual visits generally produce equivalent satisfaction and clinical outcomes compared with those performed in person. Although telemedicine has served many different roles within orthopaedic practices, its main utility is for patients who have to travel significant distances and for visits that do not require physical examination to determine a treatment plan. Several regulations govern the use of telemedicine. Most notably, clinicians must be licensed to practice medicine in the state in which the patient is located during the appointment. Although compliance issues remain a potential source of legal issues, experts cite misdiagnosis from limited physical examination as the most likely reason for medical liability. Clinicians should be familiar with techniques for virtual physical examination and should provide instruction to patients before the visit to optimize data obtained.

Establishment of a Monoclonal Antibody against Human NTCP That Blocks Hepatitis B Virus Infection.

Hepatitis B virus (HBV) infects 240 million people worldwide. Current therapy profoundly suppresses HBV replication but requires long-term maintenance therapy. Therefore, there is still a medical need for an efficient HBV cure. HBV enters host cells by binding via the preS1 domain of the viral L protein to the Na+/taurocholate cotransporting polypeptide (NTCP). Thus, NTCP should be a key target for the development of anti-HBV therapeutics. Indeed, myrcludex B, a synthetic form of the myristoylated preS1 peptide, effectively reduces HBV/hepatitis D virus (HDV) infection and has been approved as Hepcludex in Europe for the treatment of patients with chronic HDV infection. We established a monoclonal antibody (MAb), N6HB426-20, that recognizes the extracellular domain of human NTCP and blocks HBV entry in vitro into human liver cells but has much less of an inhibitory effect on bile acid uptake. In vivo, administration of the N6HB426-20 MAb prevented HBV viremia for an extended period of time after HBV inoculation in a mouse model system without strongly inhibiting bile acid absorption. Among the extracellular loops (ECLs) of NTCP, regions of amino acids (aa) 84 to 87 in ECL1 and aa 157 to 165 near ECL2 of transmembrane domain 5 are critically important for HBV/HDV infection. Epitope mapping and the three-dimensional (3D) model of the NTCP structure suggested that the N6HB426-20 MAb may recognize aa 276/277 at the tip of ECL4 and interfere with binding of HBV to the region from aa 84 to 87. In summary, we identified an in vivo neutralizing NTCP-targeting antibody capable of preventing HBV infection. Further improvements in efficacy of this drug will pave the way for its clinical applications. IMPORTANCE A number of entry inhibitors are being developed to enhance the treatment of HBV patients with oral nucleoside/nucleotide analogues (NA). To amplify the effectiveness of NA therapy, several efforts have been made to develop therapeutic MAbs with neutralizing activity against HBs antigens. However, the neutralizing effect of these MAbs may be muted by a large excess of HBsAg-positive noninfectious particles in the blood of infected patients. The advantage of NTCP-targeted HBV entry inhibitors is that they remain effective regardless of viral genotype, viral mutations, and the presence of subviral particles. Although N6HB426-20 requires a higher dose than myrcludex to obtain equivalent suppression of HBV in a model mouse system, it maintained the inhibitory effect for a long time postadministration in proportion to the half-life of an IgG MAb. We believe that further improvements will make this antibody a promising treatment option for patients with chronic hepatitis B.

Electrospray mass spectrometry method to prevent the reduction of hexavalent to pentavalent chromium.

RATIONALE: Electrospray mass spectrometry (ESI-MS) is one of the most effective methods for assessing the state of metals in solution. For ions with a redox potential close to ~0.55 V, such as Cr6+ , reduction of the metal in solution occurs in the ESI-MS system. In our studies, it was observed that [HCrO4 ]- undergoes reduction, resulting in the formation of [CrO3 ]- . The precise mechanism remains ambiguous. The reduction of hexavalent chromium to pentavalent chromium is supported by Frost diagrams, reinforcing our confidence in the validity of the ESI-MS measurement method. The reduction mechanism in ESI-MS was clarified, and a system was devised to eliminate electron donation during the reduction of Cr6+ in solution. METHODS: To determine the state of Cr6+ by ESI-MS, CrO3 in solid form was dissolved in ultrapure water to prepare a solution of 500 × 10-6  mol/L (µM) concentration. The pH was adjusted to 4.0, 5.3, 6.3, 8.2 and 9.1 and subsequently measured. CrO3 solutions with various concentrations of 10, 100 and 500 µM were prepared and adjusted to a pH of ~7 using tetramethylammonium hydroxide to measure Cr6+ under different conditions. RESULTS: Cr6+ in solution was soluble and existed as an oxoacid with a negative charge independent of pH. Cr6+ was stable over a wide pH range at various concentrations. The ESI-MS method determined the negative ion [HCrO4 ]- as the stable ion, but [CrO3 ]- was also present as a byproduct. Therefore, we were interested in the presence of other species, such as [CrO3 ]- , which could have formed owing to the reduction of Cr6+ . CONCLUSIONS: In ESI-MS system, it undergoes reduction to form [CrO3 ]- . The high flow rate of ultrapure water in pump insulated the acceptance of electrons by Cr6+ preventing its reduction. Further in-depth ESI-MS studies could explain the complex formation and behavior of Cr6+ in aqueous solution.

Long-term outcomes of percutaneous revascularization for internal mammary artery-left anterior descending artery bypass failure.

Despite the excellent long-term results of internal mammary artery (IMA)-left anterior descending (LAD) bypass, percutaneous revascularization of IMA is sometimes required for IMA-LAD bypass failure. However, its clinical outcomes have not been fully elucidated. The aim of this study was to investigate the long-term clinical outcomes, including target lesion revascularization (TLR) following contemporary percutaneous revascularization of failed IMA bypass graft. We examined data of 59 patients who had undergone percutaneous revascularization of IMA due to IMA-LAD bypass failure at nine hospitals. Patients with IMA graft used for Y-composite graft or sequential bypass graft were excluded. The incidence of TLR was primarily examined, whereas other clinical outcomes including cardiac death, myocardial infarction, and target vessel revascularization were also evaluated. Mean age of the enrolled patients was 67.4 ± 11.3 years, and 74.6% were men. Forty patients (67.8%) had anastomotic lesions, and 17 (28.8%) underwent revascularization within three months after bypass surgery. Procedural success was achieved in 55 (93.2%) patients. Stent implantation was performed in 13 patients (22.0%). During a median follow-up of 1401 days (interquartile range, 282-2521 days), TLR was required in six patients (8.5% at 1, 3, and 5 years). Patients who underwent percutaneous revascularization within 3 months after surgery tended to have a higher incidence of TLR. Clinical outcomes of IMA revascularization for IMA-LAD bypass failure were acceptable.

Editorial Commentary: The Medial Patellofemoral Complex Is Composed of the Medial Patellofemoral Ligament and the Medial Quadriceps Tendon-Femoral Ligament: Do We Need to Reconstruct Both?

The medial patellofemoral ligament (MPFL) has been known as the primary soft-tissue restraint to lateral patellar translation. More recent anatomic studies have identified additional fibers that extend to the quadriceps tendon (medial quadriceps tendon-femoral ligament [MQTFL]), leading to the use of the term "medial patellofemoral complex" (MPFC) to describe the broad and variable attachment of this complex on the patella and quadriceps tendon. Whereas many techniques and outcomes of traditional MPFL reconstruction have been described, fewer reports exist on anatomic MPFC reconstruction to recreate both bundles of this complex. To date, the specific biomechanical roles of, and indications for, reconstruction of the MPFL versus MQTFL fibers have not been defined. One primary benefit of MQTFL reconstruction has been to avoid the risk of patella fracture, which is not obviated in the setting of concurrent patellar fixation when reconstructing both components of the MPFC. The risks and benefits comparing fixation on the patella, quadriceps tendon, or both with anatomic double-bundle reconstruction remain to be determined. Additional studies are needed to understand the differences between reconstructing the proximal and distal fibers of the MPFC with regard to graft length changes and femoral attachment sites, in order to optimally recreate the function of each graft bundle in the surgical treatment of patellar instability.

Medial Patellofemoral Reconstruction Techniques for Patellar Instability.

The medial patellofemoral complex (MPFC) is the term used to describe the primary soft tissue stabilizer of the patella, which consists of fibers that attach to the patella (medial patellofemoral ligament, or MPFL), and the quadriceps tendon (medial quadriceps tendon femoral ligament, or MQTFL). Despite the variability of its attachment on the extensor mechanism, the midpoint of this complex is consistently at the junction of the medial quadriceps tendon with the articular surface of the patella, indicating that either patellar or quadriceps tendon fixation can be used for anatomic reconstruction. Multiple techniques exist to reconstruct the MPFC, including graft fixation on the patella, quadriceps tendon, or both structures. Various techniques using several graft types and fixation devices have all reported good outcomes. Regardless of the location of fixation on the extensor mechanism, elements critical to the success of the procedure include anatomic femoral tunnel placement, avoiding placing undue tension on the graft, and addressing concurrent morphological risk factors when present. This infographic reviews the anatomy and techniques for the reconstruction of the MPFC, including graft configuration, type, and fixation, while addressing common pearls and pitfalls in the surgical treatment of patellar instability.

Location and Progression of Chondral Injuries at the Time of Revision ACL Surgery Varies by Sex.

PURPOSE: To quantify progression of chondral and meniscal injuries between primary and revision anterior cruciate ligament (ACL) surgery. METHODS: Patients who underwent both index and revision ACL reconstruction between 2000 and 2020 at our institution were identified, and dates of injury and surgery, demographics, and clinical data were obtained from operative reports. Outerbridge grade was recorded in each compartment, along with presence and location of meniscal injury. The frequency of each injury between first and second cases was calculated. Differences in injury and progression were compared over time as well as between patient sex and age. RESULTS: The study included 189 patients (96 female, 93 male). Age at first surgery was 31.7 ± 13.2 years. Mean time to second injury was 3.3 ± 3.0 years. In total, 116 patients had a new or previous chondral injury (odds ratio, 1.6; 95% CI, 1.2-2.1). The medial femoral condyle (31%) and the patella (21%) accounted for the highest proportion of new injury to articular surfaces, whereas new injury to menisci was comparable between the medial (25%) and lateral (23%) meniscus. At the time of revision ACL reconstruction, females had a high prevalence of chondral injuries to the lateral compartment, whereas males had a high prevalence of chondral injury to the medial femoral condyle. The prevalence of new chondral injuries was comparable between sexes, with males having a slightly higher proportion. While time between surgeries, sex, and age had graphical evidence of moderating risk, the effects were small and imprecise. CONCLUSIONS: Revision ACL reconstruction carried a 1.6 increase in the odds for new or progressive chondral lesions in our cohort. At the time of revision, females had a relatively higher proportion of lateral-sided chondral injuries, whereas males had a relatively higher proportion of medial femoral condyle injuries. The greatest increase in the prevalence of new and progressive lesions was observed in the medial femoral condyle and trochlea. This progression appeared to be moderated by time between surgeries, patient sex, and age; however, the differences were small and imprecise. STUDY DESIGN: Level IV, therapeutic case series.

Radiographic Landmark Measurements for the Femoral Footprint of the Medial Patellofemoral Complex May Be Affected by Visible Femoral Shaft Length on Lateral Knee Radiographs.

PURPOSE: To assess the effect of visible femoral shaft length on the accuracy of radiographic landmarks of the medial patellofemoral complex (MPFC). METHODS: In 9 cadaveric knees, the MPFC footprint was exposed on the medial femur, and its proximal and distal boundaries were marked. Lateral fluoroscopic images of the knee were assessed in 1-cm length increments, beginning 1 cm proximal to the medial condyle and continuing proximally to 8 cm. The MPFC midpoint was described on each image relative to the posterior cortical line of the femur and a line perpendicular to this line through the proximal margin of the medial condyle. In addition, the MPFC midpoint was assessed relative to a line from the proximal posterior cortex to the midpoint of Blumensaat line. RESULTS: Using the posterior cortical line as a reference, the MPFC radiographic landmark moved anteriorly with decreasing visible femoral shaft on radiographs, particularly at 4 cm and less. However, no proximal-distal change was noted. Linear regression analysis demonstrated a relationship between visible femoral shaft and MPFC position on radiographs (R = 0.461, R2 = 0.212, B = -0.636, P < .001). For every centimeter decrease in the visible femoral shaft, the radiographic MPFC footprint moved anteriorly by 0.636 mm. Receiver operating characteristic curve analysis revealed that a minimum of 4 cm of femoral shaft on lateral radiographs is required for accurate MPFC footprint localization (area under the curve = 0.80; sensitivity = 76.7%; specificity = 69.0%; P < .001). In contrast, no anterior-posterior change was seen when referencing a line from the proximal posterior cortex to the midpoint of Blumensaat line. CONCLUSIONS: When using the posterior cortical line to identify the midpoint of the MPFC, at least 4 cm of femoral shaft should be visible for accurate assessment. If less than 4 cm of shaft is visible, a line through the midpoint of Blumensaat line and the proximal posterior cortex can be used as an alternative method to estimate the position of the femoral footprint. CLINICAL RELEVANCE: As fluoroscopy is frequently used intraoperatively for MPFC reconstruction, our findings may serve as a guide when assessing femoral tunnel placement on fluoroscopy.

When the Physician Becomes the Patient: Considerations for Work, Life, and Leadership.

Most orthopaedic surgeons are unprepared for serious medical illnesses. In such cases, the unique work-related and personal considerations for orthopaedic surgeons affect their career, their practice partners, and their patients. Planning together as an orthopaedic business organization for such issues can provide a framework to better navigate these difficult situations. Understanding the considerations and stressors from the individual's perspective can help provide the appropriate level of support while maintaining privacy. Throughout these considerations, open communication regarding expectations and concerns and expressions of empathy are the cornerstones of dealing with physician illness. Being a physician-patient adds complexity to an already difficult and stressful profession. Further dialogue regarding the physician-patient experience can help increase awareness of this issue and allow organizations to create a structure to best manage this almost inevitable occurrence.

Increased Interleukin-36ß Expression Promotes Angiogenesis in Japanese Atopic Dermatitis.

While atopic dermatitis (AD) is considered as a T helper 2 (Th2)-centered disease, an increase in other types of inflammatory cytokines is also noted in AD and they may also contribute to the development of the disease. Recently, the efficacy of an anti-IL-36 receptor antibody in AD was demonstrated in a clinical trial. Although there have been several reports on IL-36α and IL-36γ expression and function in AD, IL-36ß has been barely studied. In this report, we examined IL-36ß expression and function using clinical samples of AD and the epidermal keratinocyte cell line, HaCaT cells. We demonstrated that IL-36ß expression in epidermal keratinocytes was increased in AD lesional skin compared to healthy skin. IL-36ß promoted vascular endothelial growth factor A production in HaCaT keratinocytes through phosphorylation of extracellular signal-regulated kinases 1 and 2. In addition, IL-36ß up-regulated placental growth factor mRNA expression in HaCaT keratinocytes. IL-36ß expression levels in epidermal keratinocytes were correlated with the number of dermal vessels in AD skin. These results suggest that IL-36ß may play an important role for angiogenesis in lesional skin of AD and that IL-36ß can be a therapeutic target in AD.

Educational challenges for 22q11.2 deletion syndrome in Japan: Findings from a mixed methods survey.

BACKGROUND: The 22q11.2 deletion syndrome (22q11DS) is characterised by a changing pattern of overlapping intellectual, physical, and mental disabilities along the course of one's life. However, the impact of overlapping disorders (multimorbidity) on educational challenges remains unclear. METHOD: A survey was conducted with 88 caregivers of individuals with 22q11DS. A quantitative analysis of educational challenges and support needs divided into age groups (7-12, 13-15, 16-18, and 19 years and over) and a qualitative analysis of the free-text items in the questionnaire was conducted. RESULTS: Caregivers were more interested in comprehensive developmental support when their children were younger, and the emphasis shifted to concerns regarding environments that matched individual characteristics at older ages. Furthermore, when there are multiple disabilities or disorders, support is concentrated on the more obvious disabilities, and the lack of support for the less superficially obvious disabilities associated with multiple difficulties, including mental health problems, can be a challenge for people with 22q11DS and their families. CONCLUSIONS: This study suggests a need for increased focus on multimorbidity and associated disabilities in school education that are difficult to observe because of their mildness or borderline levels if present alone.

Bim establishes the B-cell repertoire from early to late in the immune response.

In T cell-dependent antibody responses, some of the activated B cells differentiate along extrafollicular pathways into low-affinity memory and plasma cells, whereas others are involved in subsequent germinal center (GC) formation in follicular pathways, in which somatic hypermutation and affinity maturation occur. The present study demonstrated that Bim, a proapoptotic BH3-only member of the Bcl-2 family, contributes to the establishment of the B-cell repertoire from early to late stages of immune responses to T cell-dependent antigens. Extrafollicular plasma cells grew in the spleen during the early immune response, but their numbers rapidly declined with the appearance of GC-derived progeny in wild-type mice. By contrast, conditional Bim deficiency in B cells resulted in expansion of extrafollicular IgG1+ antibody-forming cells (AFCs) and this expansion was sustained during the late response, which hampered the formation of GC-derived high-affinity plasma cells in the spleen. Approximately 10% of AFCs in mutant mice contained mutated VH genes; thus, Bim deficiency appears not to impede the selection of high-affinity AFC precursor cells. These results suggest that Bim contributes to the replacement of low-affinity antibody by high-affinity antibody as the immune response progresses.

Medical, welfare, and educational challenges and psychological distress in parents caring for an individual with 22q11.2 deletion syndrome: A cross-sectional survey in Japan.

Parents of children with 22q11.2 deletion syndrome (22q11DS) experience distress not only due to multimorbidity in the patients, but also due to professionals' lack of understanding about 22q11DS and insufficient support systems. This study investigated relationships between medical, welfare, and educational challenges and parental psychological distress. A cross-sectional survey was conducted on primary caregivers of children with 22q11DS. Participants included 125 parents (114 mothers, 91.2%; average age = 44.3 years) who reported their challenges, psychological distress, and child's comorbidities of 22q11DS. Results showed that the difficulty in going to multiple medical institutions (ß = 0.181, p < 0.05) and lack of understanding by welfare staff and insufficient welfare support systems for 22q11DS (ß = 0.220-0.316, all p < 0.05) were associated with parental psychological distress, even after adjusting for child's comorbidities. In the subsample of parents whose child attended an educational institution, inadequate management in classroom and mismatch between service and users in educational settings were associated with psychological distress (ß = 0.222-0.296, all p < 0.05). This study reveals the importance of assessing not only severity of comorbidities in 22q11DS, but also the medical, welfare, and educational challenges for parental mental health.

Tetramer Immunization and Selection Followed by CELLISA Screening to Generate Monoclonal Antibodies against the Mouse Cytomegalovirus m12 Immunoevasin.

The generation of reliable mAb of unique and desired specificities serves as a valuable technology to study protein expression and function. However, standard approaches to mAb generation usually involve large-scale protein purification and intensive screening. In this study, we describe an optimized high-throughput proof-of-principle method for the expanded generation, enrichment, and screening of mouse hybridomas secreting mAb specific for a protein of interest. Briefly, we demonstrate that small amounts of a biotinylated protein of interest can be used to generate tetramers for use as prime-boost immunogens, followed by selective enrichment of Ag-specific B cells by magnetic sorting using the same tetramers prior to hybridoma generation. This serves two purposes: 1) to effectively expand both low- and high-affinity B cells specific for the antigenic bait during immunization and 2) to minimize subsequent laborious hybridoma efforts by positive selection of Ag-specific, Ab-secreting cells prior to hybridoma fusion and validation screening. Finally, we employ a rapid and inexpensive screening technology, CELLISA, a high-throughput validation method that uses a chimeric Ag fused to the CD3ζ signaling domain expressed on enzyme-generating reporter cells; these reporters can detect specific mAb in hybridoma supernatants via plate-bound Ab-capture arrays, thereby easing screening. Using this strategy, we generated and characterized novel mouse mAb specific for a viral immunoevasin, the mouse CMV m12 protein, and suggest that these mAb may protect mice from CMV infection via passive immunity.

What Is the Clinical Benefit of Common Orthopaedic Procedures as Assessed by the PROMIS Versus Other Validated Outcomes Tools?

BACKGROUND: Patient-reported outcome measures (PROMs), including the Patient-reported Outcomes Measurement Information System (PROMIS), are increasingly used to measure healthcare value. The minimum clinically important difference (MCID) is a metric that helps clinicians determine whether a statistically detectable improvement in a PROM after surgical care is likely to be large enough to be important to a patient or to justify an intervention that carries risk and cost. There are two major categories of MCID calculation methods, anchor-based and distribution-based. This variability, coupled with heterogeneous surgical cohorts used for existing MCID values, limits their application to clinical care. QUESTIONS/PURPOSES: In our study, we sought (1) to determine MCID thresholds and attainment percentages for PROMIS after common orthopaedic procedures using distribution-based methods, (2) to use anchor-based MCID values from published studies as a comparison, and (3) to compare MCID attainment percentages using PROMIS scores to other validated outcomes tools such as the Hip Disability and Osteoarthritis Outcome Score (HOOS) and Knee Disability and Osteoarthritis Outcome Score (KOOS). METHODS: This was a retrospective study at two academic medical centers and three community hospitals. The inclusion criteria for this study were patients who were age 18 years or older and who underwent elective THA for osteoarthritis, TKA for osteoarthritis, one-level posterior lumbar fusion for lumbar spinal stenosis or spondylolisthesis, anatomic total shoulder arthroplasty or reverse total shoulder arthroplasty for glenohumeral arthritis or rotator cuff arthropathy, arthroscopic anterior cruciate ligament reconstruction, arthroscopic partial meniscectomy, or arthroscopic rotator cuff repair. This yielded 14,003 patients. Patients undergoing revision operations or surgery for nondegenerative pathologies and patients without preoperative PROMs assessments were excluded, leaving 9925 patients who completed preoperative PROMIS assessments and 9478 who completed other preoperative validated outcomes tools (HOOS, KOOS, numerical rating scale for leg pain, numerical rating scale for back pain, and QuickDASH). Approximately 66% (6529 of 9925) of patients had postoperative PROMIS scores (Physical Function, Mental Health, Pain Intensity, Pain Interference, and Upper Extremity) and were included for analysis. PROMIS scores are population normalized with a mean score of 50 ± 10, with most scores falling between 30 to 70. Approximately 74% (7007 of 9478) of patients had postoperative historical assessment scores and were included for analysis. The proportion who reached the MCID was calculated for each procedure cohort at 6 months of follow-up using distribution-based MCID methods, which included a fraction of the SD (1/2 or 1/3 SD) and minimum detectable change (MDC) using statistical significance (such as the MDC 90 from p < 0.1). Previously published anchor-based MCID thresholds from similar procedure cohorts and analogous PROMs were used to calculate the proportion reaching MCID. RESULTS: Within a given distribution-based method, MCID thresholds for PROMIS assessments were similar across multiple procedures. The MCID threshold ranged between 3.4 and 4.5 points across all procedures using the 1/2 SD method. Except for meniscectomy (3.5 points), the anchor-based PROMIS MCID thresholds (range 4.5 to 8.1 points) were higher than the SD distribution-based MCID values (2.3 to 4.5 points). The difference in MCID thresholds based on the calculation method led to a similar trend in MCID attainment. Using THA as an example, MCID attainment using PROMIS was achieved by 76% of patients using an anchor-based threshold of 7.9 points. However, 82% of THA patients attained MCID using the MDC 95 method (6.1 points), and 88% reached MCID using the 1/2 SD method (3.9 points). Using the HOOS metric (scaled from 0 to 100), 86% of THA patients reached the anchor-based MCID threshold (17.5 points). However, 91% of THA patients attained the MCID using the MDC 90 method (12.5 points), and 93% reached MCID using the 1/2 SD method (8.4 points). In general, the proportion of patients reaching MCID was lower for PROMIS than for other validated outcomes tools; for example, with the 1/2 SD method, 72% of patients who underwent arthroscopic partial meniscectomy reached the MCID on PROMIS Physical Function compared with 86% on KOOS. CONCLUSION: MCID calculations can provide clinical correlation for PROM scores interpretation. The PROMIS form is increasingly used because of its generalizability across diagnoses. However, we found lower proportions of MCID attainment using PROMIS scores compared with historical PROMs. By using historical proportions of attainment on common orthopaedic procedures and a spectrum of MCID calculation techniques, the PROMIS MCID benchmarks are realizable for common orthopaedic procedures. For clinical practices that routinely collect PROMIS scores in the clinical setting, these results can be used by individual surgeons to evaluate personal practice trends and by healthcare systems to quantify whether clinical care initiatives result in meaningful differences. Furthermore, these MCID thresholds can be used by researchers conducting retrospective outcomes research with PROMIS. LEVEL OF EVIDENCE: Level III, therapeutic study.

An exploration of person-centred approach in end-of-life care policies in England and Japan.

BACKGROUND: Increasing evidence has suggested that a person-centred approach (PCA) is beneficial not only for improving care outcomes but also for mitigating the pressure on public health systems. However, policy implementation gaps have prevented the translation of this complex framework into useful practical, ethical and moral stances for end-of-life care (EOLC). This article aims to explore the meaning and implications of person-centredness in EOLC policy discourses. METHODS: By perceiving policy documents as a medium embodied with socio-political and cultural norms, we analysed how PCA in EOLC is constructed within specific socio-cultural contexts and the implications of these contexts on resultant care. Focusing on England and Japan, we conducted a critical policy analysis to examine and compare key policy and legal documents released between 2000 and 2019 in these two post-industrial and socio-culturally distinctive countries. RESULTS: Our analysis found that the PCA is mobilised in policy discourses primarily through three interconnected dimensions: individual, relational and existential. While acknowledging that both countries have developed varied policy and legal mechanisms to emphasise holistic and integrated care with respect to these three dimensions, we also identified significant gaps in the pol icies both within and between England and Japan. They include ambiguity in defining patients' best interests, fragmented support for social and family care and the neglect of existential needs. CONCLUSIONS: This cross-cultural analysis has revealed the complex nature of discourses around PCA in English and Japanese EOLC policies, which often concentrate on the multifaceted aspects of experiences as one approaches the end of life. Despite this, we argue that a more holistic construction of PCA is needed in EOLC policies not only in England and Japan but also more broadly, to encapsulate the richness of end-of-life experiences.