Laser Capture Microscopy RNA Sequencing for Topological Mapping of Synovial Pathology During Rheumatoid Arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is an autoimmune disease in which the joint lining or synovium becomes highly inflamed and majorly contributes to disease progression. Understanding pathogenic processes in RA synovium is critical for identifying therapeutic targets. We performed laser capture microscopy (LCM) followed by RNA sequencing (LCM-RNAseq) to study regional transcriptomes throughout RA synovium. METHODS: Synovial lining, sublining, and vessel samples were captured by LCM from seven patients with RA and seven patients with osteoarthritis (OA). RNAseq was performed on RNA extracted from captured tissue. Principal component analysis was performed on the sample set by disease state. Differential expression analysis was performed between disease states based on log2 fold change and q value parameters. Pathway analysis was performed using the Reactome Pathway Database on differentially expressed genes among disease states. Significantly enriched pathways in each synovial region were selected based on the false discovery rate. RESULTS: RA and OA transcriptomes were distinguishable by principal component analysis. Pairwise comparisons of synovial lining, sublining, and vessel samples between RA and OA revealed substantial differences in transcriptional patterns throughout the synovium. Hierarchical clustering of pathways based on significance revealed a pattern of association between biologic function and synovial topology. Analysis of pathways uniquely enriched in each region revealed distinct phenotypic abnormalities. As examples, RA lining samples were marked by anomalous immune cell signaling, RA sublining samples were marked by aberrant cell cycle, and RA vessel samples were marked by alterations in heme scavenging. CONCLUSION: LCM-RNAseq confirms reported transcriptional differences between the RA synovium and the OA synovium and provides evidence supporting a relationship between synovial topology and molecular anomalies in RA.

Longitudinal Associations Between Symptoms of ADHD and Life Success: From Emerging Adulthood to Early Middle Adulthood.

OBJECTIVE: To expand on current adult ADHD literature by investigating the stability of ADHD symptomatology (i.e., inattention and hyperactivity-impulsivity) across a 15-year period (from emerging adulthood to early middle adulthood) and the relative contributions of ADHD symptomatology to life success. METHOD: A sample of 320 post-secondary students was initially assessed for ADHD symptomatology using the Conners' Adult ADHD Rating Scale (CAARS). Fifteen years later, participants were re-assessed using the CAARS and several measures of life success (e.g., relationship satisfaction, career satisfaction, and stress levels). RESULTS: Inattention and hyperactivity-impulsivity symptoms showed strong stability across the 15-year period. Additionally, inattention symptoms during emerging adulthood and early middle adulthood were consistently associated with poorer life success (i.e., lower relationship and career satisfaction), particularly for men. Associations for hyperactivity-impulsivity symptoms were less consistent. CONCLUSION: ADHD symptomatology can be conceptualized as a stable, dimensional trait across adulthood, with important impacts on life success.

A nondepleting anti-CD19 antibody impairs B cell function and inhibits autoimmune diseases.

B cells contribute to multiple aspects of autoimmune disorders, and B cell-targeting therapies, including B cell depletion, have been proven to be efficacious in treatment of multiple autoimmune diseases. However, the development of novel therapies targeting B cells with higher efficacy and a nondepleting mechanism of action is highly desirable. Here we describe a nondepleting, high-affinity anti-human CD19 antibody LY3541860 that exhibits potent B cell inhibitory activities. LY3541860 inhibits B cell activation, proliferation, and differentiation of primary human B cells with high potency. LY3541860 also inhibits human B cell activities in vivo in humanized mice. Similarly, our potent anti-mCD19 antibody also demonstrates improved efficacy over CD20 B cell depletion therapy in multiple B cell-dependent autoimmune disease models. Our data indicate that anti-CD19 antibody is a highly potent B cell inhibitor that may have potential to demonstrate improved efficacy over currently available B cell-targeting therapies in treatment of autoimmune conditions without causing B cell depletion.

Endometriosis and adenomyosis: shared pathophysiology.

Endometriosis and adenomyosis are closely related disorders. Their pathophysiologies are extremely similar. Both tissues originate from the eutopically located intracavitary endometrium. Oligoclones of endometrial glandular epithelial cells with somatic mutations and attached stromal cells may give rise to endometriosis if they travel to peritoneal surfaces or the ovary via retrograde menstruation and/or may be entrapped in the myometrium to give rise to adenomyosis. In both instances, the endometrial cell populations possess survival and growth capabilities conferred by somatic epithelial mutations and epigenetic abnormalities in stromal cells. Activating mutations of KRAS are the most commonly found genetic variant in endometriotic epithelial cells, whereas the adenomyotic epithelial cells almost exclusively bear KRAS mutations. Epigenetic abnormalities in the stromal cells of endometriosis and adenomyosis are very similar and involve an abnormal expression pattern of nuclear receptors, including the steroid receptors. These epigenetic defects give rise to excessive local estrogen biosynthesis by aromatase and abnormal estrogen action via estrogen receptor-ß. Deficient progesterone receptor expression results in progesterone resistance in both endometriosis and adenomyosis.

Development of a charged model of the SARS-CoV-2 viral surface.

A recent study provided experimental evidence of inactivation of viral activity after radio-frequency (RF) exposures in the 6-12 GHz band that was hypothesized to be caused by vibrations of an acoustic dipole mode in the virus that excited the viral membrane to failure. Here, we develop an atomic-scale molecular dynamics (MD) model of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral surface to estimate the electric fields necessary to rupture the viral membrane via dipole shaking of the virus. We computed the absorption spectrum of the system via unbiased MD simulations and found no particular strong absorption in the GHz band. We investigated the mechanical resiliency of the viral membrane by introducing uniaxial strains in the system and observed no pore formation in the membrane for strains up to 50%. Because the computed absorption spectrum was found to be essentially flat, and the strain required to break the viral membrane was >0.5, the field strength associated with rupture of the virus was greater than the dielectric breakdown value of air. Thus, RF disinfection of enveloped viruses would occur only once sufficient heat was transferred to the virus via a thermal mechanism and not by direct action (shaking) of the RF field oscillations on the viral membrane.

EVL and MIM/MTSS1 regulate actin cytoskeletal remodeling to promote dendritic filopodia in neurons.

Dendritic spines are the postsynaptic compartment of a neuronal synapse and are critical for synaptic connectivity and plasticity. A developmental precursor to dendritic spines, dendritic filopodia (DF), facilitate synapse formation by sampling the environment for suitable axon partners during neurodevelopment and learning. Despite the significance of the actin cytoskeleton in driving these dynamic protrusions, the actin elongation factors involved are not well characterized. We identified the Ena/VASP protein EVL as uniquely required for the morphogenesis and dynamics of DF. Using a combination of genetic and optogenetic manipulations, we demonstrated that EVL promotes protrusive motility through membrane-direct actin polymerization at DF tips. EVL forms a complex at nascent protrusions and DF tips with MIM/MTSS1, an I-BAR protein important for the initiation of DF. We proposed a model in which EVL cooperates with MIM to coalesce and elongate branched actin filaments, establishing the dynamic lamellipodia-like architecture of DF.

Surgical Deroofing for Hidradenitis Suppurativa.

Hidradenitis suppurativa can present in varying degrees of severity; management often poses a challenge for primary care physicians and dermatologists. Deroofing is a surgical technique that has shown superiority over standard excision. We describe the deroofing procedure and review clinical data to provide instruction and support its use.

Retrospective Review of Arthroplasty Radiographs: How to Define an Adequate Radiograph.

Introduction Adequacy of postoperative hip and knee radiographs has a direct impact on its interpretation. We undertook a quality improvement project by creating local standards to meet the arthroplasty team expectations for a satisfactory radiograph. The purposes of the study are 1. Assessment of the adequacy of radiographs according to defined criteria, and 2. Correlation of system and patient factors with inadequate radiographs. Methods Stage I: We conducted a single centre, retrospective audit to check the adequacy of a postoperative radiography following a total hip or knee replacement. A total of 100 radiographs were assessed against the nine criteria laid out with the consensus of orthopaedic surgeons and radiologists. Stage II: We created a quality improvement proforma for use in the radiology department. We re-assessed 100 radiographs during the second cycle against the nine criteria to check the adequacy of hip and knee arthroplasty radiographs, Results Stage I: Of 100 radiographs, 51 were from the knee and 49 from the hip arthroplasty group. Sixty-nine radiographs were adequate considering overall criteria, and 31 radiographs were inadequate. The inadequacy in radiographs was related to the visibility of prosthesis, cement or relevant anatomy. Stage II: We created a quality improvement performa for use in radiology department, highlighting the nine initial criteria. One hundred radiographs of hip and knee arthroplasty were re-assessed. Overall, 84 radiographs fulfilled the criteria of being adequate. Conclusion Adequacy of knee and hip arthroplasty radiographs is essential in picking up pathologies that can be missed otherwise. We present simple criteria to improve the adequacy of x-ray and prevent repetition of radiographs.

The impact of clinical risk conditions on influenza and pneumonia diagnoses in England: a nationally representative retrospective cohort study, 2010-2019.

The impact of influenza and pneumonia on individuals in clinical risk groups in England has not previously been well characterized. Using nationally representative linked databases (Clinical Practice Research Database (CPRD), Hospital Episode Statistics (HES) and Office for National Statistics (ONS)), we conducted a retrospective cohort study among adults (≥ 18 years) during the 2010/2011-2019/2020 influenza seasons to estimate the incidence of influenza- and pneumonia-diagnosed medical events (general practitioner (GP) diagnoses, hospitalisations and deaths), stratified by age and risk conditions. The study population included a seasonal average of 7.2 million individuals; approximately 32% had ≥1 risk condition, 42% of whom received seasonal influenza vaccines. Medical event incidence rates increased with age, with ~1% of adults aged ≥75 years hospitalized for influenza/pneumonia annually. Among individuals with vs. without risk conditions, GP diagnoses occurred 2-5-fold more frequently and hospitalisations were 7-10-fold more common. Among those with obesity, respiratory, kidney or cardiovascular disorders, hospitalisation were 5-40-fold more common than in individuals with no risk conditions. Though these findings likely underestimate the full burden of influenza, they emphasize the concentration of disease burden in specific age and risk groups and support existing recommendations for influenza vaccination.

Optic Perineuritis Presenting as the Initial Manifestation of Central Nervous System Involvement in Rai Stage 0 Chronic Lymphocytic Leukemia.

BACKGROUND: To describe the first case of optic perineuritis because of meningeal involvement of early stage chronic lymphocytic leukemia (CLL). METHODS: A case report and review of the literature. RESULTS: A case of unilateral optic neuropathy associated with enhancement of the optic nerve sheath is described in a patient with a prior 2-year history of Rai Stage 0 CLL. Lumbar puncture revealed a lymphocytic pleocytosis. Cerebrospinal fluid flow cytometry revealed a monoclonal expansion of CD5+ B cells compatible with CLL, matching the flow cytometry characteristics of his peripheral blood. CONCLUSIONS: Optic perineuritis is often initially diagnosed as optic neuritis, yet the 2 have different etiologies and follow a different clinical course. Orbital MRI with contrast structurally separates the 2, revealing a characteristic pattern of peripheral optic nerve sheath rather than primary optic nerve enhancement. Etiologies of optic perineuritis are varied and include inflammatory, infectious, neoplastic, and toxic entities. Central nervous system (CNS) involvement by chronic lymphocytic leukemia is unusual, but cranial nerve and meningeal involvement have been reported. This case adds central nervous system chronic lymphocytic leukemia to the list of differential diagnostic possibilities for optic perineuritis. It also alerts clinicians to consider optic perineuritis as a potential presenting feature of CNS involvement in otherwise asymptomatic and stable CLL.

Augmentation of the Esophageal Sphincter Using LINX.

Gastroesophageal reflux disease (GERD) is the retrograde flow of gastric contents into the distal esophagus and may be treated medically or surgically. Magnetic sphincter augmentation surgery using LINX has recently demonstrated comparable results to Nissen fundoplication. We aimed to evaluate preoperative patient risk factors that were associated with LINX removal rates or postoperative EGD with dilation rates (POEGDD). This is a single institution retrospective review of patients undergoing LINX between 2015 and 2021. One hundred and twelve patients were reviewed, 106 included within the study; those excluded had prior foregut surgery or device fracture. Variables including age, sex, BMI, size of device, DeMeester score, manometry, GERD Health-Related Quality of Life (GERD HRQL) questionnaires, POEGDD, and removal rates were recorded. Comparing removal and dilation status, the chi-square or Fisher's exact test and the Mann-Whitney U test were used to analyze categorical and continuous variables, respectively. A P < .05 was considered to be statistically significant. Eleven LINX devices were removed (10%); of these, 9 (81%) underwent POEGDD (P = .0023). There was no difference in DeMeester scores, size of device, or BMI in patients requiring LINX removal compared to those not removed or POEGDD rates. Patients who required LINX removal had higher GERD HRQL scores both preoperatively (median 34 vs 28) and postoperatively at all visits compared to those patients who did not undergo removal (P = .032). Manometry and DeMeester scores were not associated with LINX removal suggesting a less invasive GERD HRQL questionnaire may be a better predictor of patients who will succeed with LINX surgery.

Increases in Student Knowledge and Protective Behaviors Following Enhanced Supports for Sexual Health Education in a Large, Urban School District.

PURPOSE: School-based sexual health education (SHE) can teach students critical knowledge and skills. For effective SHE, school districts can offer support, including strong curricula and professional development. This study assessed changes in students' sexual health knowledge and sexual behaviors following implementation of enhanced support for SHE delivery in one school district. METHODS: Sexual health knowledge was assessed at the beginning and end of middle and high school health education classes in a large, urban district (n = 7,555 students). Sexual behaviors were assessed using Youth Risk Behavior Survey data from the district (2015 and 2017) and state (2017). Analyses explored differences in behavior from 2015 (n = 2,596) to 2017 (n = 3,371) among intervention district students and compared intervention district students (n = 3,371) to other students in the same state (n = 1,978). RESULTS: Hierarchical linear model regression analyses revealed significant knowledge gains among students. Logistic regression results revealed that among students in the intervention district, 6 of 16 examined behaviors moved in the intended direction from 2015 to 2017; 1 moved in the unintended direction. Logistic regression results of 2017 data revealed that in comparison of intervention district students to other students in the state, intervention district students had significantly higher odds of reporting condom use at last sex (adjusted odds ratio [AOR] = 1.36, 95% confidence interval [CI] = 1.07-1.72) and significantly lower odds of reporting having had sex with 4+ persons (AOR = .72, 95% CI = .55-.94) or alcohol or drug use before last sex (AOR = .63, 95% CI = .42-.94). CONCLUSIONS: Findings suggest potential effects of the district's SHE in increasing knowledge and improving behaviors and experiences among youth.

ADHD and Academic Success in University Students: The Important Role of Impaired Attention.

OBJECTIVE: To improve on several methodological issues regarding current literature investigating the relationship between ADHD symptomatology and academic success in adults and examine the relative contributions of specific dimensions of ADHD symptomatology (i.e., inattention, hyperactivity, and impulsivity) to post-secondary academic success. METHOD: A large sample of 3,688 post-secondary students were examined using a longitudinal design. The Conners' Adult ADHD Rating Scale (CAARS) was used to assess adult ADHD symptoms and academic success was assessed using students' official academic records (e.g., final GPAs and degree completion status). RESULTS: Students with greater inattention symptomatology at the start of their academic program showed consistently poorer long-term academic success (i.e., lower GPAs, higher dropout rates), regardless of gender. CONCLUSION: Inattention symptoms are the primary driver of the relationship between ADHD symptomatology and academic underachievement in adults. Post-secondary education institutions should target and prioritize educational programming for inattention symptoms of ADHD in at-risk post-secondary students.

Differences in kinematics and driver performance in elite female and male golfers.

The aim of this study was to compare swing kinematic differences between women and men and investigate which variables predict clubhead speed (CHS) and carry distance (CD) whilst accounting for individual variation. METHODS: Swing kinematics and driver performance data were collected on 20 (10 women) elite golfers (HCP 0.7 ± 1.4). We used Bayesian T-test for between sex comparison of swing kinematics and Bayesian Analysis of covariance (ANCOVA) to produce general linear models for CHS and carry distance for elite female and male golfers separately. RESULTS: There was strong evidence that the driver performance variables CHS and CD were decreased in women compared to men, and two kinematic variables; time to arm peak speed downswing and angular wrist peak speed were slower in women. The ANCOVAs identified very strong to overwhelming evidence that participant as a fixed factor was a determinant of CHS for both women and men but was not a determinant of CD. CONCLUSION: when looking to enhance driver performance among high-level golfers, coaches should be aware that variables that determine CHS and CD differ among women and men and if the aim is to improve CHS coaches should not forget the importance of individual swing characteristics.

Influenza vaccine uptake among at-risk adults (aged 16-64 years) in the UK: a retrospective database analysis.

BACKGROUND: In the UK, annual influenza vaccination is currently recommended for adults aged 16-64 years who are in a clinical at-risk group. Despite recommendations, rates of vaccine uptake in the UK have historically been low and below national and international targets. This study aims to analyse vaccine uptake among adults in clinical at-risk groups from the 2015-2016 influenza season to the present. METHODS: A retrospective analysis of influenza vaccine coverage in the UK was conducted using data extracted from publicly available sources. Clinically at-risk individuals (as defined by Public Health England), including pregnant women, aged 16-64 years, were included in this study. RESULTS: Influenza vaccination coverage rates across the UK in adults aged 16-64 years in a clinical at-risk group have been consistently low over the past 5 years, with only 48.0, 42.4, 44.1 and 52.4% of eligible patients in England, Scotland, Wales and Northern Ireland receiving their annual influenza vaccination during the 2018-2019 influenza season. Influenza vaccine coverage was lowest in patients with morbid obesity and highest in patients with diabetes in 2018-2019. Coverage rates were below current national ambitions of ≥75% in all clinical risk groups. In these clinical at-risk groups, influenza vaccine coverage decreased between 2015 and 2019, and there was considerable regional variation. CONCLUSIONS: Uptake of the influenza vaccine by adults aged 16-64 years in a clinical at-risk group was substantially below the national ambitions. As a result, many individuals in the UK remain at high risk of developing severe influenza or complications. Given that people who are vulnerable to COVID-19 are also at increased risk of complications from influenza, during the 2020-2021 season, there is a heightened need for healthcare professionals across the UK to address suboptimal vaccine uptake, particularly in at-risk patients. Healthcare professionals and policymakers should consider measures targeted at increasing access to and awareness of the clinical benefits of the influenza vaccine.

Continuous transversus abdominis plane blocks in patients undergoing minimally invasive colorectal surgery: a randomized pilot study.

PURPOSE: Transversus abdominis plane (TAP) blocks are used in an attempt to decrease narcotic use and its subsequent consequences. The primary goal of this study was to see if TAP blocks decreased narcotic use in patients undergoing minimally invasive colorectal surgery. METHODS: A randomized pilot study was conducted. The amount of narcotic used examined in morphine milligram equivalents (MME) was collected for the first 4 post-operative days (PODs). Demographic data, length of stay (LOS), readmission rate, and 90-day mortality was also examined. Statistical analysis of the data was performed with a p < 0.05 determined to be significant. RESULTS: Eighty-eight patients were included. Forty-seven were randomized to the TAP group and 41 to the no TAP group. There was no difference in age, race, gender, indication for operation, or Charlson Comorbidity Index (p > 0.05). The median MME for each POD was similar for POD 1 (22.5 vs 37.5; p = 0.054), POD 3 (15 vs 22.5; p = 0.48), and POD 4 (22.5 vs 10.5; p = 0.42) on bivariate analysis. On POD 2, the TAP group had significantly less narcotic intake than the no TAP group (17.5 vs 30; p = 0.047). However, on multivariate analysis when controlling for other variables, there was no statistical difference between the groups. Median LOS was 3 days for both groups. Readmissions, post-operative complications, and mortality were also similar between the two groups (p > 0.05). CONCLUSION: Our findings indicate that continuous TAP blocks do not decrease the amount of MME used during the first 4 post-operative days compared to patient receiving traditional pain control measures.

Is Perceived Autonomy Support Provided by a Coach Related to the Intention of Injury Preventative Behavior Among National and International Level Golfers?

The successful implementation of injury prevention programs is reliant on athletes and coaches accepting, adopting, and complying with behaviors that reduce injury risk. Exploring factors, such as motivation and planned behavior, that might increase the frequency of these behaviors warrants investigation. The aim of the study was to investigate the complex interaction between perceived autonomy support, self-determined motivation, planned behavior, and how this relates to golfers self-reported intention injury preventative behavior. A total of 60 golfers completed questions on psychological measures of perceived autonomy support from coaches, autonomous motivation, and intentions of injury preventative behavior. A neural network model analysis was performed to investigate the strength of connection between covariates and construct a network structure. Analysis of results was performed by assessing edge strengths and node centrality to guide inference of the network topology. The most central node was autonomous regulation and the results showed one cluster comprising positive interactions between perceived autonomy support, effort of injury preventative behavior, and frequency of injury preventative behavior. When aiming to encourage injury preventative behavior, coaches should consider giving feedback that supports autonomous motivation since it is positively associated with effort and frequency of injury preventative behavior among high-level golfers. Injury prevention programs should include strategies to improve the athlete's autonomous motivation to carry out preventive activities.

A bifactor analysis of the 20-item Toronto Alexithymia Scale: Further support for a general alexithymia factor.

The 20-Item Toronto Alexithymia Scale (TAS-20) is the most widely used measure to assess the personality construct of alexithymia and is composed of three-factor analytically derived subscales. These subscales measure and represent three critical, theoretically based facets of alexithymia. The subscales are distinct, yet highly interrelated and only as a collective body do they reflect adequately the alexithymia construct. Although different studies using both university student and community samples suggest that TAS-20 total scores are largely reflective of variation on a single construct, and that subscale scores do not provide unique and reliable information beyond total scores, many users of the scale frequently continue to employ and even rely more heavily on subscale scores rather than total scale scores when interpreting research study outcomes. Our goal in this study is to provide clinicians and researchers with replicable psychometric information for the TAS-20 estimated from bifactor modeling in an attempt to provide further support for using total rather than subscale scores. In general, our findings were consistent with previous studies indicating that TAS-20 total scores can be considered indicative of a single construct. The replication of these earlier results from previous investigations provides additional support for the use of a total TAS-20 score and questions the utility of using TAS-20 subscale scores. Based on these results, we recommend that researchers and clinicians use a single total TAS-20 score and not subscale scores. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Soluble α-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia.

Parkinson's disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn-antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1ß (IL-1ß) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-ß peptide (Aß) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia.