Neurogenesis-dependent remodeling of hippocampal circuits reduces PTSD-like behaviors in adult mice.

Post-traumatic stress disorder (PTSD) is a hypermnesic condition that develops in a subset of individuals following exposure to severe trauma. PTSD symptoms are debilitating, and include increased anxiety, abnormal threat generalization, and impaired extinction. In developing treatment strategies for PTSD, preclinical studies in rodents have largely focused on interventions that target post-encoding memory processes such as reconsolidation and extinction. Instead, here we focus on forgetting, another post-encoding process that regulates memory expression. Using a double trauma murine model for PTSD, we asked whether promoting neurogenesis-mediated forgetting can weaken trauma memories and associated PTSD-relevant behavioral phenotypes. In the double trauma paradigm, consecutive aversive experiences lead to a constellation of behavioral phenotypes associated with PTSD including increases in anxiety-like behavior, abnormal threat generalization, and deficient extinction. We found that post-training interventions that elevate hippocampal neurogenesis weakened the original trauma memory and decreased these PTSD-relevant phenotypes. These effects were observed using multiple methods to manipulate hippocampal neurogenesis, including interventions restricted to neural progenitor cells that selectively promoted integration of adult-generated granule cells into hippocampal circuits. The same interventions also weakened cocaine place preference memories, suggesting that promoting hippocampal neurogenesis may represent a broadly useful approach in hypermnesic conditions such as PTSD and substance abuse disorders.

Quantifying Patient Expectations for Total Knee Arthroplasty: Expectations for Improvement are Greater than MCID.

INTRODUCTION: Achieving a minimal clinically important difference (MCID) in patient-reported outcomes (PROs) following total knee arthroplasty (TKA) is common, yet up to 20% patient dissatisfaction persists. Unmet expectations may explain post-TKA dissatisfaction. No prior studies have quantified patient expectations using the same PRO metric as used for MCID to allow direct comparison. METHODS: This was a prospective study of patients undergoing TKA with five fellowship-trained arthroplasty surgeons at one academic center. Baseline Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) and Pain Interference (PI) domains were assessed. Expected PROMIS scores were determined by asking patients to indicate the outcomes they were expecting at 12 months postoperatively. Predicted scores were generated from a predictive model validated in the Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement (FORCE-TJR) dataset. T-tests were used to compare baseline, expected, and predicted PROMIS scores. Expected scores were compared to PROMIS MCID values obtained from the literature. Regression models were used to identify patient characteristics associated with high expectations. RESULTS: There were 93 patients included. Mean age was 67 years (range, 30 to 85) and 55% were women. Mean baseline PROMIS PF and PI was 34.4+/-6.7 and 62.2+/-6.4, respectively. Patients expected significant improvement for PF of 1.9 times the MCID (MCID = 11.3; mean expected improvement = 21.6, 95% CI [confidence interval] 19.6 to 23.5, P < 0.001) and for PI of 2.3 times the MCID (MCID=8.9; mean expected improvement=20.6, 95%CI 19.1-22.2, P < 0.001). Predicted scores were significantly lower than expected scores (mean difference = 9.5, 95% CI 7.7 to 11.3, P < 0.001). No unique patient characteristics were associated with high expectations (P > 0.05). CONCLUSION: To our knowledge, this study is the first to quantify preoperative patient expectations using the same metric as MCID to allow for direct comparison. Patient expectations for improvement following TKA are ∼2x greater than MCID and are significantly greater than predicted outcome scores. This discrepancy challenges currently accepted standards of success after TKA and indicates a need for improved expectation setting prior to surgery.

Diagnosis and Management of Longitudinal Erythronychia: A Clinical Review by an Expert Panel.

Longitudinal erythronychia (LE) is defined as a longitudinal red band of the nail(s) and is classified as localized (involvement of one nail) or polydactylous (involvement of more than one nail). The differential diagnosis is distinct for these classifications. The etiologies of localized longitudinal erythronychia (LLE) are most frequently benign subungual neoplasms, and less often malignancies. Polydactylous longitudinal erythronychia (PLE) is typically secondary to regional or systemic diseases, including lichen planus and Darier disease. LE is a common, but underrecognized clinical finding. Increased dermatologist awareness of the clinical characteristics and differential diagnosis for LE is necessary given the possibility for malignancy and associated systemic disease. In this clinical review, the clinical features, differential diagnosis, evaluation, and management of LE are described.

Clinical, onychoscopic, nail clipping, and histopathological findings of malignant onychopapilloma.

This report describes the clinical, onychoscopic, nail clipping, and histopathologic features of a malignant onychopapilloma. A 71-year-old male presented to our outpatient clinic for a stable, asymptomatic lesion on his left middle finger that had been present for 2 years. Prior nail clipping histopathology showed nail plate thinning with subungual abnormal onychocytes. Clinical examination revealed a 2-mm-wide streak of longitudinal xanthonychia extending to the proximal nail fold, with distal hyperkeratosis and onycholysis. Onychoscopy showed irregular longitudinal nail plate ridging with scattered punctate hemorrhagic foci. An excisional nail unit biopsy demonstrated cellular atypia of the nail bed epithelium, matrix metaplasia, longitudinal abnormal onychocytes, increased Ki-67 staining, and negative HPV immunoperoxidase staining, confirming the diagnosis of malignant onychopapilloma.

Scores predicting atrial fibrillation after mitral valve surgery: Do we need a more specific score?

Background: Atrial fibrillation after cardiac surgery (POAF) is associated with increased morbidity and mortality. Several scores were used to predict POAF, with variable results. Thus, this study assessed the performance of several scoring systems to predict POAF after mitral valve surgery. Additionally, we identified the risk factors for POAF in those patients. Methods: This retrospective cohort included 1381 recruited from 2009 to 2021. The patients underwent mitral valve surgery, and POAF occurred in 233 (16.87%) patients. The performance of CHADS2, CHA2DS2-VASc, POAF, EuroSCORE II, and HATCH scores was evaluated. Results: The median age was higher in patients who developed POAF (60 vs. 54 years; p < .001). CHA2-DS2-VASc, POAF, EuroSCORE II, and HATCH scores significantly predicted POAF, with areas under the curve of the receiver operator curve (AUCROC) of 0.56, 0.61, 0.58, and 0.54, respectively. We identified age > 58 years, body mass index > 28 kg/m2, creatinine clearance < 90 mL/min, reoperative surgery, and preoperative inotropic and intra-aortic balloon pump use as predictors of POAF. We constructed a score from these variables (PSCC-AF). A score > 2 significantly predicted POAF (p < .001). The AUCROC of this score was 0.67, which was significantly higher than the AUCROC of the POAF score (p = .009). Conclusion: POAF after mitral valve surgery can be predicted based on preoperative patient characteristics. The new PSCC-AF score significantly predicted POAF after mitral valve surgery and can serve as a bedside diagnostic tool for POAF risk screening. Further studies are needed to validate the PSCC-AF-mitral score externally.

Assessing Healthcare Simulation Facilitation: A Scoping Review of Available Tools, Validity Evidence, and Context Suitability for Faculty Development in Low-Resource Settings.

SUMMARY STATEMENT: Assessment tools support simulation facilitation skill development by guiding practice, structuring feedback, and promoting reflective learning among educators. This scoping review followed a systematic process to identify facilitation assessment tools used in postlicensure healthcare simulation. Secondary objectives included mapping of the validity evidence to support their use and a critical appraisal of their suitability for simulation faculty development in low-resource settings. Database searching, gray literature searching, and stakeholder engagement identified 11,568 sources for screening, of which 72 met criteria for full text review. Thirty sources met inclusion; 16 unique tools were identified. Tools exclusively originated from simulation practice in high-resource settings and predominantly focused on debriefing. Many tools have limited validity evidence supporting their use. In particular, the validity evidence supporting the extrapolation and implications of assessment is lacking. No current tool has high context suitability for use in low-resource settings.

Onychomycosis.

This Patient Page describes the risk factors, clinical features, diagnosis, and treatment of onychomycosis.

Bisbiguanide analogs induce mitochondrial stress to inhibit lung cancer cell invasion.

Targeting cancer metabolism to limit cellular energy and metabolite production is an attractive therapeutic approach. Here, we developed analogs of the bisbiguanide, alexidine, to target lung cancer cell metabolism and assess a structure-activity relationship (SAR). The SAR led to the identification of two analogs, AX-4 and AX-7, that limit cell growth via G1/G0 cell-cycle arrest and are tolerated in vivo with favorable pharmacokinetics. Mechanistic evaluation revealed that AX-4 and AX-7 induce potent mitochondrial defects; mitochondrial cristae were deformed and the mitochondrial membrane potential was depolarized. Additionally, cell metabolism was rewired, as indicated by reduced oxygen consumption and mitochondrial ATP production, with an increase in extracellular lactate. Importantly, AX-4 and AX-7 impacted overall cell behavior, as these compounds reduced collective cell invasion. Taken together, our study establishes a class of bisbiguanides as effective mitochondria and cell invasion disrupters, and proposes bisbiguanides as promising approaches to limiting cancer metastasis.

Subpopulation commensalism promotes Rac1-dependent invasion of single cells via laminin-332.

Phenotypic heterogeneity poses a significant hurdle for cancer treatment but is under-characterized in the context of tumor invasion. Amidst the range of phenotypic heterogeneity across solid tumor types, collectively invading cells and single cells have been extensively characterized as independent modes of invasion, but their intercellular interactions have rarely been explored. Here, we isolated collectively invading cells and single cells from the heterogeneous 4T1 cell line and observed extensive transcriptional and epigenetic diversity across these subpopulations. By integrating these datasets, we identified laminin-332 as a protein complex exclusively secreted by collectively invading cells. Live-cell imaging revealed that laminin-332 derived from collectively invading cells increased the velocity and directionality of single cells. Despite collectively invading and single cells having similar expression of the integrin α6ß4 dimer, single cells demonstrated higher Rac1 activation upon laminin-332 binding to integrin α6ß4. This mechanism suggests a novel commensal relationship between collectively invading and single cells, wherein collectively invading cells promote the invasive potential of single cells through a laminin-332/Rac1 axis.

Peptidoglycan in osteoarthritis synovial tissue is associated with joint inflammation.

OBJECTIVES: Peptidoglycan (PG) is an arthritogenic bacterial cell wall component whose role in human osteoarthritis is poorly understood. The purpose of this study was to determine if PG is present in synovial tissue of osteoarthritis patients at the time of primary total knee arthroplasty (TKA), and if its presence is associated with inflammation and patient reported outcomes. METHODS: Intraoperative synovial tissue and synovial fluid samples were obtained from 56 patients undergoing primary TKA, none of whom had history of infection. PG in synovial tissue was detected by immunohistochemistry (IHC) and immunofluorescence microscopy (IFM). Synovial tissue inflammation and fibrosis were assessed by histopathology and synovial fluid cytokine quantification. Primary human fibroblasts isolated from arthritis synovial tissue were stimulated with PG to determine inflammatory cytokine response. RESULTS: A total of 33/56 (59%) of primary TKA synovial tissue samples were positive for PG by IHC, and PG staining colocalized with markers of synovial macrophages and fibroblasts by IFM. Synovial tissue inflammation and elevated IL-6 in synovial fluid positively correlated with PG positivity. Primary human fibroblasts stimulated with PG secreted high levels of IL-6, consistent with ex vivo findings. Interestingly, we observed a significant inverse correlation between PG and age at time of TKA, indicating younger age at time of TKA was associated with higher PG levels. CONCLUSION: Peptidoglycan is commonly found in synovial tissue from patients undergoing TKA. Our data indicate that PG may play an important role in inflammatory synovitis, particularly in patients who undergo TKA at a relatively younger age.

Excitability mediates allocation of pre-configured ensembles to a hippocampal engram supporting contextual conditioned threat in mice.

Little is understood about how engrams, sparse groups of neurons that store memories, are formed endogenously. Here, we combined calcium imaging, activity tagging, and optogenetics to examine the role of neuronal excitability and pre-existing functional connectivity on the allocation of mouse cornu ammonis area 1 (CA1) hippocampal neurons to an engram ensemble supporting a contextual threat memory. Engram neurons (high activity during recall or TRAP2-tagged during training) were more active than non-engram neurons 3 h (but not 24 h to 5 days) before training. Consistent with this, optogenetically inhibiting scFLARE2-tagged neurons active in homecage 3 h, but not 24 h, before conditioning disrupted memory retrieval, indicating that neurons with higher pre-training excitability were allocated to the engram. We also observed stable pre-configured functionally connected sub-ensembles of neurons whose activity cycled over days. Sub-ensembles that were more active before training were allocated to the engram, and their functional connectivity increased at training. Therefore, both neuronal excitability and pre-configured functional connectivity mediate allocation to an engram ensemble.

Age-Based Heuristics Bias Treatment of Displaced Femoral Neck Fractures in the Elderly.

Background: Surgeons performing arthroplasty for femoral neck fractures may rely on mental shortcuts (heuristics) when choosing total hip arthroplasty (THA) vs hemiarthroplasty (HA). We sought to quantify the extent to which age-based heuristics drive decision-making. Methods: We identified all Medicare beneficiaries from 2017-2018 with femoral neck fractures who underwent THA or HA. We compared the likelihood of THA vs HA among patients admitted within 4 weeks before vs 4 weeks after their birthday for each age under the hypothesis that these cohorts would be similar except for numerical age. We controlled for race/ethnicity, sex, comorbidities, poverty status, and hospital census region in a multivariable regression that included facility-level cluster effects. We generated predicted/adjusted probabilities for THA vs HA for different age transition points. Results: Thirteen thousand three hundred sixty-six elderly patients were included. One thousand eight hundred sixty-five (14%) received THA and 11,501 (86%) received HA. The likelihood of THA decreased from 50.3% among patients almost 67 to 8% among those ≥85 (P < .001). We found significant decreases in likelihood of THA across age transitions. The largest decrement was at age transition 69 (THA likelihood 28.7% for newly 69 vs 43.3% for almost 69, 33.7% relative change). Female gender, Black race, higher comorbidity burden, and lower socioeconomic status were also associated with a lower likelihood of THA. Conclusions: Our data demonstrate that patient age transitions seem to influence the choice of THA vs HA. Further research is needed to develop data-driven surgical decision aids for this population.

Mitigating mutual coupling effects on circular polarization for improved bandwidth in MIMO systems: A novel approach.

An improved mutual coupling compensation in circularly polarized (CP) multi-input multi-output (MIMO) dielectric resonator antenna (DRA) is presented in this paper. Using trimming approach, the mutual coupling (MC) between closely spaced DRA units at 0.3λ has been significantly reduced while axial ratio performance has been maintained. Mutual coupling reduction is obtained by trimming the DRA to ensure low mutual coupling below -20dB. The exclusive features of the proposed MIMO DRA include wide impedance matching bandwidth (BW), triple band circular polarization, and suppressed MC between the radiating elements. The impedance bandwidth matches perfectly with a triple band's 3 dB axial ratio (AR). It is designed with characteristic mode analysis with good agreement of the measurement that has been obtained. Using the probe feed method, the DRA and patch strip are coupled together to allow bandwidth widening of the pro-posed DRA. An impedance bandwidth of 34% at a lower frequency to around 2% at a higher frequency was achieved in all resonance frequencies. Thus, we refer to our newly designed DRA as a proposed method for effectively reducing the mutual coupling between DRAs. Additionally, the 3 dB AR bandwidth matched at 3.3 GHz, 4.6 GHz, and 6.3 GHz with a percentage of 11.66%, 3.04%, and 2.22% obtained at the three different frequencies. Note that the proposed DRA exhibits low mutual coupling (below -20 dB) at the targeted frequencies, which is suitable for better signal reception for MIMO applications. By computing, the metrics envelop correlation coefficient, diversity gain, channel capacity loss, and total active reflection coefficient, the MIMO performance of the proposed antenna is verified. The experiments show a close result between simulated and computed validation of the proposed DRA.

Corrigendum: Maternal serum iron status, hepcidin and interleukin-6 levels in women with preeclampsia.

[This corrects the article DOI: 10.3389/fphys.2023.1049994.].

Imageless robotic total knee arthroplasty determines similar coronal plane alignment of the knee (CPAK) parameters to long leg radiographs.

BACKGROUND: The coronal plane alignment of the knee (CPAK) classification was first developed using long leg radiographs (LLR) and has since been reported using image-based and imageless robotic total knee arthroplasty (TKA) systems. However, the correspondence between imageless robotics and LLR-derived CPAK parameters has yet to be investigated. This study therefore examined the differences in CPAK parameters determined with LLR and imageless robotic navigation using either generic or optimized cartilage wear assumptions. METHODS: Medial proximal tibial angle (MPTA) and lateral distal femoral angle (LDFA) were determined from the intraoperative registration data of 61 imageless robotic TKAs using either a generic 2 mm literature-based wear assumption (Navlit) or an optimized wear assumption (Navopt) found using an error minimization algorithm. MPTA and LDFA were also measured from preoperative LLR by two observers and intraclass correlation coefficients (ICCs) were calculated. MPTA, LDFA, joint line obliquity (JLO), and arithmetic hip-knee-ankle angle (aHKA) were compared between the robotic and the average LLR measurements over the two observers. RESULTS: ICCs between observers for LLR were over 0.95 for MPTA, LDFA, JLO, and aHKA, indicating excellent agreement. Mean CPAK differences were not significant between LLR and Navlit (all differences within 0.6°, P > 0.1) or Navopt (all within 0.1°, P > 0.83). Mean absolute errors (MAE) between LLR and Navlit were: LDFA = 1.4°, MPTA = 2.0°, JLO = 2.1°, and aHKA = 2.7°. Compared to LLR, the generic wear classified 88% and the optimized wear classified 94% of knees within one CPAK group. Bland-Altman comparisons reported good agreement for LLR vs. Navlit and Navopt, with > 95% and > 91.8% of measurements within the limits of agreement across all CPAK parameters, respectively. CONCLUSIONS: Imageless robotic navigation data can be used to calculate CPAK parameters for arthritic knees undergoing TKA with good agreement to LLR. Generic wear assumptions determined MPTA and LDFA with MAE within 2° and optimizing wear assumptions showed negligible improvement.

Racial and Ethnic Minorities Underrepresented in Pain Management Guidelines for Total Joint Arthroplasty: A Meta-analysis.

BACKGROUND: Total joint arthroplasty aims to improve quality of life and functional outcomes for all patients, primarily by reducing their pain. This goal requires clinical practice guidelines (CPGs) that equitably represent and enroll patients from all racial/ethnic groups. To our knowledge, there has been no formal evaluation of the racial/ethnic composition of the patient population in the studies that informed the leading CPGs on the topic of pain management after arthroplasty surgery. QUESTIONS/PURPOSES: Using papers included in the 2021 Anesthesia and Analgesia in Total Joint Arthroplasty Clinical Practice Guidelines and comparing them with US National census data, we asked: (1) What is the representation of racial/ethnic groups in randomized controlled trials compared with their representation in the US national population? (2) Is there a relationship between the reporting of racial/ethnic groups and year of data collection/publication, location of study, funding source, or guideline section? METHODS: Participant demographic data (study year published, study type, guideline section, year of data collection, study site, study funding, study size, gender, age, and race/ethnicity) were collected from articles cited by this guideline. Studies were included if they were full text, were primary research articles conducted primarily within the United States, and if they reported racial and ethnic characteristics of the participants. The exclusion criteria included duplicate articles, articles that included the same participant population (only the latest dated article was included), and the following article types: systematic reviews, nonsystematic reviews, terminology reports, professional guidelines, expert opinions, population-based studies, surgical trials, retrospective cohort observational studies, prospective cohort observational studies, cost-effectiveness studies, and meta-analyses. Eighty-two percent (223 of 271) of articles met inclusion criteria. Our original literature search yielded 27 papers reporting the race/ethnicity of participants, including 24 US-based studies and three studies conducted in other countries; only US-based studies were utilized as the focus of this study. We defined race/ethnicity reporting as the listing of participants' race or ethnicity in the body, tables, figures, or supplemental data of a study. National census information from 2000 to 2019 was then used to generate a representation quotient (RQ), which compared the representation of racial/ethnic groups within study populations to their respective demographic representation in the national population. An RQ value greater than 1 indicates an overrepresented group and an RQ value less than 1 indicates an underrepresented group, relative to the US population. Primary outcome measures of RQ value versus time of publication for each racial/ethnic group were evaluated with linear regression analysis, and race reporting and manuscript parameters were analyzed with chi-square analyses. RESULTS: Two US-based studies reported race and ethnicity independently. Among the 24 US-based studies reporting race/ethnicity, the overall RQ was 0.70 for Black participants, 0.09 for Hispanic participants, 0.1 for American Indian/Alaska Natives, 0 for Native Hawaiian/Pacific Islanders, 0.08 for Asian participants, and 1.37 for White participants, meaning White participants were overrepresented by 37%, Black participants were underrepresented by 30%, Hispanic participants were underrepresented by 91%, Asian participants were underrepresented by 92%, American Indian/Alaska Natives were 90% underrepresented, and Native Hawaiian Pacific Islanders were virtually not represented compared with the US national population. On chi-square analysis, there were differences between race/ethnicity reporting among studies with academic, industry, and dual-supported funding sources (χ2 = 7.449; p = 0.02). Differences were also found between race/ethnicity reporting among US-based and non-US-based studies (χ2 = 36.506; p < 0.001), with 93% (25 of 27) of US-based studies reporting race as opposed to only 7% (2 of 27) of non-US-based studies. Finally, there was no relationship between race/ethnicity reporting and the year of data collection or guideline section referenced. CONCLUSION: The 2021 Anesthesia and Analgesia in Total Joint Arthroplasty Clinical Practice Guidelines provide evidence-based recommendations that reflect the current standards in orthopaedic surgery, but the studies upon which they are based overwhelmingly underenroll and underreport racial/ethnic minorities relative to their proportions in the US population. As these factors impact analgesic administration, their continued neglect may perpetuate inequities in outcomes after TJA. CLINICAL RELEVANCE: Our study demonstrates that all non-White racial/ethnic groups were underrepresented relative to their proportion of the US population in the 2021 Anesthesia and Analgesia in Total Joint Arthroplasty Clinical Practice Guidelines, underscoring a weakness in the orthopaedic surgery evidence base and questioning the overall external validity and generalizability of these combined CPGs. An effort should be made to equitably enroll and report outcomes for all racial/ethnic groups in any updated CPGs.