Association of Unmet Social Needs With Level of Capability in People With Persistent Knee Pain.

BACKGROUND: Musculoskeletal providers are increasingly recognizing the importance of social factors and their association with health outcomes as they aim to develop more comprehensive models of care delivery. Such factors may account for some of the unexplained variation between pathophysiology and level of pain intensity and incapability experienced by people with common conditions, such as persistent nontraumatic knee pain secondary to osteoarthritis (OA). Although the association of one's social position (for example, income, employment, or education) with levels of pain and capability are often assessed in OA research, the relationship between aspects of social context (or unmet social needs) and such symptomatic and functional outcomes in persistent knee pain are less clear. QUESTIONS/PURPOSES: (1) Are unmet social needs associated with the level of capability in patients experiencing persistently painful nontraumatic knee conditions, accounting for sociodemographic factors? (2) Do unmet health-related social needs correlate with self-reported quality of life? METHODS: We performed a prospective, cross-sectional study between January 2021 and August 2021 at a university academic medical center providing comprehensive care for patients with persistent lower extremity joint pain secondary to nontraumatic conditions such as age-related knee OA. A final 125 patients were included (mean age 62 ± 10 years, 65% [81 of 125] women, 47% [59 of 125] identifying as White race, 36% [45 of 125] as Hispanic or Latino, and 48% [60 of 125] with safety-net insurance or Medicaid). We measured patient-reported outcomes of knee capability (Knee injury and Osteoarthritis Outcome Score for Joint Replacement), quality of life (Patient-Reported Outcome Measure Information System [PROMIS] Global Physical Health and PROMIS Global Mental Health), and unmet social needs (Accountable Health Communities Health-Related Social Needs Survey, accounting for insufficiencies related to housing, food, transportation, utilities, and interpersonal violence), as well as demographic factors. RESULTS: After controlling for demographic factors such as insurance status, education attained, and household income, we found that reduced knee-specific capability was moderately associated with experiencing unmet social needs (including food insecurity, housing instability, transportation needs, utility needs, or interpersonal safety) (standardized beta regression coefficient [ß] = -4.8 [95% confidence interval -7.9 to -1.7]; p = 0.002 and substantially associated with unemployment (ß = -13 [95% CI -23 to -3.8]; p = 0.006); better knee-specific capability was substantially associated with having Medicare insurance (ß = 12 [95% CI 0.78 to 23]; p = 0.04). After accounting for factors such as insurance status, education attained, and household income, we found that older age was associated with better general mental health (ß = 0.20 [95% CI 0.0031 to 0.39]; p = 0.047) and with better physical health (ß = 0.004 [95% CI 0.0001 to 0.008]; p = 0.04), but effect sizes were small to negligible, respectively. CONCLUSION: There is an association of unmet social needs with level of capability and unemployment in patients with persistent nontraumatic knee pain. This finding signals a need for comprehensive care delivery for patients with persistent knee pain that screens for and responds to potentially modifiable social risk factors, including those based on one's social circumstances and context, to achieve better outcomes. LEVEL OF EVIDENCE: Level II, prognostic study.

Variability in Pain Management Practices for Pediatric Anterior Cruciate Ligament Reconstruction.

BACKGROUND: The opioid epidemic in the United States is a public health crisis. Pediatric orthopaedic surgeons must balance adequate pain management with minimizing the risk of opioid misuse or dependence. There is limited data available to guide pain management for anterior cruciate ligament reconstruction (ACLR) in the pediatric population. The purpose of this study was to survey current pain management practices for ACLR among pediatric orthopaedic surgeons. METHODS: A cross-sectional survey study was conducted, in which orthopaedic surgeons were asked about their pain management practices for pediatric ACLR. The voluntary survey was sent to members of the Pediatric Orthopaedic Society of North America. Inclusion criteria required that the surgeon perform anterior cruciate ligament repair or reconstruction on patients under age 18. Responses were anonymous and consisted of surgeon demographics, training, practice, and pain management strategies. Survey data were assessed using descriptive statistics. RESULTS: Of 64 included responses, the average age of the survey respondent was 48.9 years, 84.4% were males, and 31.3% practiced in the southern region of the United States. Preoperative analgesia was utilized by 39.1%, 90.6% utilized perioperative blocks, and 89.1% prescribed opioid medication postoperatively. For scheduled non-narcotic medications postoperatively 82.8% routinely advocated and 93.8% recommended cryotherapy postoperatively.Acetaminophen was the most used preoperative medication (31.3%), the most common perioperative block was an adductor canal block (81.0%), and the most common postoperative analgesic medication was ibuprofen (60.9%). Prior training or experience was more frequently reported than published research as a primary factor influencing pain management protocols. CONCLUSIONS: Substantial variability exists in pain management practices in pediatric ACLR. There is a need for more evidence-based practice guidelines regarding pain management. LEVEL OF EVIDENCE: Level V.

The Interobserver Reliability of Grading of Distal Radius Volar Plate Prominence.

PURPOSE: The 3-category rating of volar plate prominence in relation to the most volar edge of the distal radius (the watershed line) on lateral radiographs was reliable among a small group of surgeons and associated with the probability of flexor tendon irritation and potential rupture. Classifications are often less reliable when tested among a large group of practicing surgeons in different environments. METHODS: In this survey-based experiment, an international group of 115 fracture and upper extremity surgeons viewed 1 of 4 sets of 24 lateral radiographs (96 unique lateral radiographs) of patients with distal radius fractures who underwent volar plating in the practice of a single surgeon using 2 types of plates. Surgeons were asked to rate the following metrics: (1) the grade of plate prominence according to Soong, (2) whether the plate was more prominent than the watershed line, (3) whether the plate was separate from the bone distally, and (4) whether there is more than 5° of dorsal angulation of the distal radius articular surface. RESULTS: The interobserver agreement of the classification was "fair" (κ = 0.32; 95% confidence interval [CI] = 0.27-0.36), and grading was more reliable among surgeons who do not supervise trainees. Volar prominence was less reliable (κ = 0.034; 95% CI = 0.013-0.055) than plate separation from bone (κ = 0.50; 95% CI = 0.42-0.59) and more than 5° of dorsal angulation (κ = 0.42; 95% CI = 0.35-0.48). CONCLUSIONS: Among a large number of international practicing surgeons, the classification of volar plate prominence in 3 categories was fair. CLINICAL RELEVANCE: The diagnosis of plate prominence might develop toward criteria with moderate reliability, such as separation of the plate from the bone and residual angulation of the distal radius.

Early Sport Specialization and Past Injury in Competitive Youth Rock Climbers.

INTRODUCTION: Sport specialization has been shown to have negative effects on athletes but has not been studied within rock climbing. This study seeks to evaluate the proportion and impact of specialization in pediatric climbers. METHODS: Climbers (ages 8-18 y) were recruited from throughout the United States to complete a 1-time survey regarding climbing experience, training patterns, and injury history. The main outcome of proportion of climbers suffering an injury was assessed within the last 12 mo and within their entire climbing experience (defined as "lifetime" injury). Early specialization was defined as exclusive participation in climbing, with training for >8 mo‧y-1, prior to age 12 y (late specialization if after age 12 y). RESULTS: Participants (n=111, 14±3 y [mean±SD], 69 females) were high-level climbers. Fifty-five percent of participants specialized in climbing, and 69% of those specialized early. Hand and ankle injuries occurred most commonly. Seventy-eight percent of late specialized climbers had a lifetime injury. Late specialized climbers were 1.6 times (95% CI: 1.1-2.3) more likely than early specialized climbers to have had a lifetime injury and 1.8 times (95% CI: 1.1-2.8) more likely to have had an injury in the last 12 mo. No difference in overuse injuries was found between specialization groups. CONCLUSIONS: Early specialization is common among youth climbers but was not associated with an increase in injuries. Late specialization was associated with a higher likelihood of having had a climbing injury in the last 12 mo and during an entire climbing career.

Melanoma cells can be eliminated by sialylated CD43 × CD3 bispecific T cell engager formats in vitro and in vivo.

Targeted cancer therapy with monoclonal antibodies has proven successful for different cancer types but is limited by the availability of suitable antibody targets. CD43s, a unique sialylated form of CD43 expressed by hematologic malignancies, is a recently identified target and antibodies interacting with CD43s may have therapeutic potential against acute myeloid leukemia (AML) and myelodysplastic syndrome. CD43s is recognized by the human antibody AT1413, that was derived from a high-risk AML patient who successfully cleared leukemia after allogeneic stem cell transplantation. Here we observed that AT1413 binds also to certain non-hematopoietic tumor cells, particularly melanoma and breast cancer. AT1413 immune precipitated CD43s from melanoma cells confirming that it recognizes the same target on melanoma as on AML. AT1413 induced antibody-dependent cellular cytotoxicity against short-term cultured patient-derived melanoma samples. However, AT1413 was unable to affect the growth of melanoma cells in vivo. To increase the efficacy of AT1413 as a therapeutic antibody, we generated two different formats of bispecific T-cell engaging antibodies (TCEs): one binding bivalently (bTCE) and the other monovalently (knob-in-hole; KiH) to both CD43s and CD3ε. In vitro, these TCEs redirected T-cell cytotoxicity against melanoma cells with differences in potencies. To investigate their effects in vivo, we grafted mice that harbor a human immune system with the melanoma cell line A375. Treatment with both AT1413 bTCE and AT1413 KiH significantly reduced tumor outgrowth in these mice. These data indicate a broad therapeutic potential of AT1413 that includes AML and CD43s-expressing solid tumors that originate from CD43-negative tissues.

Time Refraction of Spin Waves.

We present an experimental study of time refraction of spin waves (SWs) propagating in microscopic waveguides under the influence of time-varying magnetic fields. Using space- and time-resolved Brillouin light scattering microscopy, we demonstrate that the broken translational symmetry along the time coordinate results in a loss of energy conservation for SWs and thus allows for a broadband and controllable shift of the SW frequency. With an integrated design of SW waveguide and microscopic current line for the generation of strong, nanosecond-long, magnetic field pulses, a conversion efficiency up to 39% of the carrier SW frequency is achieved, significantly larger compared to photonic systems. Given the strength of the magnetic field pulses and its strong impact on the SW dispersion relation, the effect of time refraction can be quantified on a length scale comparable to the SW wavelength. Furthermore, we utilize time refraction to excite SW bursts with pulse durations in the nanosecond range and a frequency shift depending on the pulse polarity.

The Association of α Angle on Disease Severity in Adolescent Femoroacetabular Impingement.

BACKGROUND: Femoroacetabular Impingement (FAI) is a common cause of hip pain in adolescent patients. Clinical exam and radiographic markers, such as α angle and lateral center edge angle (LCEA), are commonly used to aid in the diagnosis of this condition. The purpose of this study was to correlate preoperative α angle and LCEA with preoperative symptoms, intraoperative findings, and preoperative and postoperative patient reported outcomes (PROs) in the adolescent patient. METHODS: A retrospective analysis of prospectively collected data was conducted for all patients who underwent operative intervention for FAI at an academic institution over an 11-year period. Preoperative imaging was obtained and measured for LCEA and α angle. PROs (modified Harris Hip Score, Hip Disability and Osteoarthritis Outcome Score, and UCLA score) were collected preoperatively, as well as 1, 2, and 5 years postoperatively. Operative intervention was either open surgical hip dislocation or arthroscopic, and intraoperative disease was graded using the Beck Classification system. Patients with minimum 1-year follow-up were included in statistical analysis. RESULTS: There were 86 hips (64 female hips) included with an average age of 16.3 years (range, 10.4 to 20.5 y), with an average of 37 months of follow-up. There was no correlation between severity of preoperative symptoms or difference between pre and postoperative PROs for both α angle and LCEA. Overall, significant improvement was noted in modified Harris Hip Score, Hip Disability and Osteoarthritis Outcome Score, and UCLA Score (P<0.001 for each). Independent of preoperative symptoms, increased α angle correlated with more severe intraoperative labral disease (P<0.001), and longer length of labral tear (Corr 0.295, P<0.01). Femoral head and acetabular articular cartilage damage did not correlate with α angle or LCEA, nor did overall severity of disease. CONCLUSIONS: In adolescent patients with FAI, increased α angle was found to significantly correlate with labral pathology, including increased length of tear and severity of disease, irrespective of preoperative symptoms or postoperative patient reported outcomes. LEVEL OF EVIDENCE: Level III-retrospective.

Hybrid-ALPPS followed by Ante Situm with Cardiopulmonary Bypass: Rapid Liver Augmentation and Complex Surgery.

BACKGROUND: Tumors invading the inferior vena cava (IVC) and hepatic veins pose a challenge for surgeons. Hannoun et al.1 were able to show that the resection of these tumors can be done under hypothermia in the Ante-Situm position. Additionally, not only the localization of the tumor but the remaining volume of the remnant liver (FLR) needs to be considered. Schnitzbauer et al.2 were able to induce massive liver hypertrophy in a short period, combining an in-situ split with a portal vein ligation (ALPPS). As this controversial technique has evolved, a safe ALPPS can be performed nowadays.3 To our knowledge, this is the first case that combines a laparoscopic partial ALPPS with an extended resection requiring cardiopulmonary bypass (CPB). METHODS: A 58-year-old female presented with a known chronic hepatitis C suffered from a pulmonary embolism, caused by a large, central hepatocellular carcinoma (HCC) with invasion of the suprahepatic IVC and continuous growth into the right atrium (RA). Due to the small FLR, we performed a laparoscopic hybrid-partial-ALPPS with an embolization of the right portal vein. We were able to remove the mass with an Ante-Situm position and resection of the RA under CPB. RESULTS: The postoperative course was complicated by posthepatic liver failure and bleeding. However, after 28 days the patient was discharged in a good medical condition. CONCLUSIONS: Although tumors invading the suprahepatic IVC and RA pose a surgical challenge, patients can be treated adequately with multidisciplinary management. Advanced HCCs have high recurrence rates; however, a R0 resection might improve overall survival. Wakayma et al. showed in their retrospective study with 13 patients a median survival of 30.8 months when a complete resection was performed.4 Our patient had a disease-free survival of 11 months and is still alive after 24 months. Taking the complexity of the operation and the oncological prospect with a probable recurrence into account, indication for surgery needs to be considered on an individual basis.

Dietary intake of advanced glycation end products (AGEs) and changes in body weight in European adults.

PURPOSE: Advanced glycation end products (AGEs) can be formed in foods by the reaction of reducing sugars with proteins, and have been shown to induce insulin resistance and obesity in experimental studies. We examined the association between dietary AGEs intake and changes in body weight in adults over an average of 5 years of follow-up. METHODS: A total of 255,170 participants aged 25-70 years were recruited in ten European countries (1992-2000) in the PANACEA study (Physical Activity, Nutrition, Alcohol, Cessation of smoking, Eating out of home in relation to Anthropometry), a sub-cohort of the EPIC (European Prospective Investigation into Cancer and Nutrition). Body weight was measured at recruitment and self-reported between 2 and 11 years later depending on the study center. A reference database for AGEs was used containing UPLC-MS/MS-measured Nε-(carboxymethyl)-lysine (CML), Nε-(1-carboxyethyl)-lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) in 200 common European foods. This reference database was matched to foods and decomposed recipes obtained from country-specific validated dietary questionnaires in EPIC and intake levels of CEL, CML, and MG-H1 were estimated. Associations between dietary AGEs intake and body weight change were estimated separately for each of the three AGEs using multilevel mixed linear regression models with center as random effect and dietary AGEs intake and relevant confounders as fixed effects. RESULTS: A one-SD increment in CEL intake was associated with 0.111 kg (95% CI 0.087-0.135) additional weight gain over 5 years. The corresponding additional weight gain for CML and MG-H1 was 0.065 kg (0.041-0.089) and 0.034 kg (0.012, 0.057), respectively. The top six food groups contributing to AGEs intake, with varying proportions across the AGEs, were cereals/cereal products, meat/processed meat, cakes/biscuits, dairy, sugar and confectionary, and fish/shellfish. CONCLUSION: In this study of European adults, higher intakes of AGEs were associated with marginally greater weight gain over an average of 5 years of follow-up.

Flashbulb memory recall in healthy adults - a functional magnetic resonance imaging study.

The present study investigated neural activations related to flashbulb memory (FM) recall and examined whether the amygdala and hippocampus are involved in FM recall. 20 healthy adults completed a block design with an FM-condition, where the reception events for a number of potential FM events had to be recalled, and a control condition (FMC) comprising reception events lacking FM characteristics. A definition naming task was used as an implicit baseline. The individual emotional reaction to the FM events (EMO) and self-rated retrieval success were included in the SPM model as modulating parameters. The main contrast of interest were FM > FMC and activations associated with EMO. ROI-analyses on mesiotemporal regions were performed. FM > FMC yielded activations in line with the autobiographical memory network, with mostly left sided-activations. EMO was associated with a more bilateral activation pattern. ROI-analysis revealed activations for EMO in the right amygdala and HATA. FM > FMC was associated with right hippocampal activations. The present findings are compatible with previous research into autobiographical memory, but also show activations for FM recall different from ordinary, not highly emotional autobiographical memories, as EMO is associated with a more bilateral network. Moreover, the amygdala seems to be involved in FM recall.

Narrowing geographic inequality in life expectancy in Brazil: a multilevel analysis between 1991 and 2010.

OBJECTIVES: To analyze the geographic inequalities in life expectancy (LE) and the probability of survival up to 40 and 60 years in Brazil between 1991 and 2010, to partition the variance of these indicators by including municipalities, states, and macroregions in the analysis, and to test the association between municipal socio-economic and health services indicators with life expectancy. STUDY DESIGN: Multilevel analysis. METHODS: Census data from 1991, 2000, and 2010 were used to calculate the outcomes and the socio-economic variables. Municipalities were separated into centiles according to their values in each outcome. Absolute and relative differences were calculated for each year. Multilevel linear regression models were performed, taking into account three levels: regions, states, and municipalities. Municipal socio-economic and health services variables were included in the model with the 2010 data. RESULTS: All 5545 Brazilian counties showed improvement in the three indicators, but the magnitude varied significantly across the country. The highest gains in LE were observed in the North and Northeast regions. The gap in LE between the 1st and 99th percentile decreased from 19.6 years to 12.2 years. The relative difference also fell, from 1.37 to 1.18. Most counties' socio-economic and health services indicators were associated with the outcomes and explained 86.7%, 31.2%, and 32.4% of the variation in LE attributable to regions, states, and counties, respectively. CONCLUSIONS: The average life expectancy increased between 1991 and 2010. Concomitantly, a reduction in geographic disparities was observed. The counties' socio-economic and health services variables explained much of the variation of the outcomes in 2010.

The Use of Psychological Patient Reported Outcome Measures to Identify Adolescent Athletes at Risk for Prolonged Recovery Following an ACL Reconstruction.

BACKGROUND: Psychological response to injury and the recovery process impact return to play and can put an athlete at risk for prolonged recovery. The purpose of this study was to investigate the psychological changes that occur surrounding an anterior cruciate ligament (ACL) reconstruction utilizing a set of patient reported outcomes measures (PROMs) that focus on psychological factors. METHODS: Consecutive patients undergoing a primary ACL reconstruction, ages 12 to 18, were recruited. Patients were included if they verbalized a desire to return to the same sport and a baseline Tegner of >6. Functional and psychological PROMs were administered preoperatively, 6 months, and 1 year postoperatively. A Y-Balance Test was utilized to assess for clearance. RESULTS: Of the 68 participants, 36 were female (52.9%) and 32 male, with a mean age of 14.5 years. On average, participants were cleared to return to sport 259.1 days postoperatively. Of the measures given preoperatively, only the Athletic Coping Skills Inventory-28 (ACSI)-28 correlated with delayed recovery time (rs=-0.291, P=0.04). Lower baseline ACSI-28 subscale scores in coachability (rs=-0.298, P=0.03) and Coping with Adversity (rs=-0.341, P=0.01) were correlated with delayed recovery. Participants that took longer than average to recover scored significantly lower on the ACSI-28 preoperatively than those with a shorter recovery time (62.04 vs. 54.8, P<0.01). Participants that scored <58 on their preoperative ACSI-28 took 2 months longer to recover than participants who scored ≥58 (9.6 vs. 7.65 mo, P<0.01). At 6 months postoperatively, higher ACSI-28 subscale Concentration (rs=-0.357, P<0.01) and Peaking Under Pressure (rs=-0.274, P=0.04) scores correlated with shorter recovery time. CONCLUSIONS: The ACSI-28 significantly correlated with recovery time following ACL reconstruction. A baseline score of 58 may be a valuable cutoff to identify youth athletes at risk for prolonged recovery. LEVEL OF EVIDENCE: Level II-prospective study.

Excitation of Whispering Gallery Magnons in a Magnetic Vortex.

We present the generation of whispering gallery magnons with unprecedented high wave vectors via nonlinear 3-magnon scattering in a µm-sized magnetic Ni_{81}Fe_{19} disc which is in the vortex state. These modes exhibit a strong localization at the perimeter of the disc and practically zero amplitude in an extended area around the vortex core. They originate from the splitting of the fundamental radial magnon modes, which can be resonantly excited in a vortex texture by an out-of-plane microwave field. We shed light on the basics of this nonlinear scattering mechanism from an experimental and theoretical point of view. Using Brillouin light scattering microscopy, we investigated the frequency and power dependence of the 3-magnon splitting. The spatially resolved mode profiles give evidence for the localization at the boundaries of the disc and allow for a direct determination of the modes wave number.

Cross-disorder risk gene CACNA1C differentially modulates susceptibility to psychiatric disorders during development and adulthood.

Single-nucleotide polymorphisms (SNPs) in CACNA1C, the α1C subunit of the voltage-gated L-type calcium channel Cav1.2, rank among the most consistent and replicable genetics findings in psychiatry and have been associated with schizophrenia, bipolar disorder and major depression. However, genetic variants of complex diseases often only confer a marginal increase in disease risk, which is additionally influenced by the environment. Here we show that embryonic deletion of Cacna1c in forebrain glutamatergic neurons promotes the manifestation of endophenotypes related to psychiatric disorders including cognitive decline, impaired synaptic plasticity, reduced sociability, hyperactivity and increased anxiety. Additional analyses revealed that depletion of Cacna1c during embryonic development also increases the susceptibility to chronic stress, which suggest that Cav1.2 interacts with the environment to shape disease vulnerability. Remarkably, this was not observed when Cacna1c was deleted in glutamatergic neurons during adulthood, where the later deletion even improved cognitive flexibility, strengthened synaptic plasticity and induced stress resilience. In a parallel gene × environment design in humans, we additionally demonstrate that SNPs in CACNA1C significantly interact with adverse life events to alter the risk to develop symptoms of psychiatric disorders. Overall, our results further validate Cacna1c as a cross-disorder risk gene in mice and humans, and additionally suggest a differential role for Cav1.2 during development and adulthood in shaping cognition, sociability, emotional behavior and stress susceptibility. This may prompt the consideration for pharmacological manipulation of Cav1.2 in neuropsychiatric disorders with developmental and/or stress-related origins.

Broadly Reactive Anti-Respiratory Syncytial Virus G Antibodies from Exposed Individuals Effectively Inhibit Infection of Primary Airway Epithelial Cells.

Respiratory syncytial virus (RSV) causes severe respiratory disease in young children. Antibodies specific for the RSV prefusion F protein have guided RSV vaccine research, and in human serum, these antibodies contribute to >90% of the neutralization response; however, detailed insight into the composition of the human B cell repertoire against RSV is still largely unknown. In order to study the B cell repertoire of three healthy donors for specificity against RSV, CD27+ memory B cells were isolated and immortalized using BCL6 and Bcl-xL. Of the circulating memory B cells, 0.35% recognized RSV-A2-infected cells, of which 59% were IgA-expressing cells and 41% were IgG-expressing cells. When we generated monoclonal B cells selected for high binding to RSV-infected cells, 44.5% of IgG-expressing B cells and 56% of IgA-expressing B cells reacted to the F protein, while, unexpectedly, 41.5% of IgG-expressing B cells and 44% of IgA expressing B cells reacted to the G protein. Analysis of the G-specific antibodies revealed that 4 different domains on the G protein were recognized. These epitopes predicted cross-reactivity between RSV strain A (RSV-A) and RSV-B and matched the potency of antibodies to neutralize RSV in HEp-2 cells and in primary epithelial cell cultures. G-specific antibodies were also able to induce antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis of RSV-A2-infected cells. However, these processes did not seem to depend on a specific epitope. In conclusion, healthy adults harbor a diverse repertoire of RSV glycoprotein-specific antibodies with a broad range of effector functions that likely play an important role in antiviral immunity.IMPORTANCE Human RSV remains the most common cause of severe lower respiratory tract disease in premature babies, young infants, the elderly, and immunocompromised patients and plays an important role in asthma exacerbations. In developing countries, RSV lower respiratory tract disease has a high mortality. Without an effective vaccine, only passive immunization with palivizumab is approved for prophylactic treatment. However, highly potent RSV-specific monoclonal antibodies could potentially serve as a therapeutic treatment and contribute to disease control and mortality reduction. In addition, these antibodies could guide further vaccine development. In this study, we isolated and characterized several novel antibodies directed at the RSV G protein. This information can add to our understanding and treatment of RSV disease.

Forebrain glutamatergic, but not GABAergic, neurons mediate anxiogenic effects of the glucocorticoid receptor.

Anxiety disorders constitute a major disease and social burden worldwide; however, many questions concerning the underlying molecular mechanisms still remain open. Besides the involvement of the major excitatory (glutamate) and inhibitory (gamma aminobutyric acid (GABA)) neurotransmitter circuits in anxiety disorders, the stress system has been directly implicated in the pathophysiology of these complex mental illnesses. The glucocorticoid receptor (GR) is the major receptor for the stress hormone cortisol (corticosterone in rodents) and is widely expressed in excitatory and inhibitory neurons, as well as in glial cells. However, currently it is unknown which of these cell populations mediate GR actions that eventually regulate fear- and anxiety-related behaviors. In order to address this question, we generated mice lacking the receptor specifically in forebrain glutamatergic or GABAergic neurons by breeding GRflox/flox mice to Nex-Cre or Dlx5/6-Cre mice, respectively. GR deletion specifically in glutamatergic, but not in GABAergic, neurons induced hypothalamic-pituitary-adrenal axis hyperactivity and reduced fear- and anxiety-related behavior. This was paralleled by reduced GR-dependent electrophysiological responses in the basolateral amygdala (BLA). Importantly, viral-mediated GR deletion additionally showed that fear expression, but not anxiety, is regulated by GRs in glutamatergic neurons of the BLA. This suggests that pathological anxiety likely results from altered GR signaling in glutamatergic circuits of several forebrain regions, while modulation of fear-related behavior can largely be ascribed to GR signaling in glutamatergic neurons of the BLA. Collectively, our results reveal a major contribution of GRs in the brain's key excitatory, but not inhibitory, neurotransmitter system in the regulation of fear and anxiety behaviors, which is crucial to our understanding of the molecular mechanisms underlying anxiety disorders.

FKBP51 inhibits GSK3ß and augments the effects of distinct psychotropic medications.

Psychotropic medications target glycogen synthase kinase 3ß (GSK3ß), but the functional integration with other factors relevant for drug efficacy is poorly understood. We discovered that the suggested psychiatric risk factor FK506 binding protein 51 (FKBP51) increases phosphorylation of GSK3ß at serine 9 (pGSK3ß(S9)). FKBP51 associates with GSK3ß mainly through its FK1 domain; furthermore, it also changes GSK3ß's heterocomplex assembly by associating with the phosphatase PP2A and the kinase cyclin-dependent kinase 5. FKBP51 acts through GSK3ß on the downstream targets Tau, ß-catenin and T-cell factor/lymphoid enhancing factor (TCF/LEF). Lithium and the antidepressant (AD) paroxetine (PAR) functionally synergize with FKBP51, as revealed by reporter gene and protein association analyses. Deletion of FKBP51 blunted the PAR- or lithium-induced increase in pGSK3ß(S9) in cells and mice and attenuated the behavioral effects of lithium treatment. Clinical improvement in depressive patients was predicted by baseline GSK3ß pathway activity and by pGSK3ß(S9) reactivity to ex vivo treatment of peripheral blood mononuclear lymphocytes with lithium or PAR. In sum, FKBP51-directed GSK3ß activity contributes to the action of psychotropic medications. Components of the FKBP51-GSK3ß pathway may be useful as biomarkers predicting AD response and as targets for the development of novel ADs.

Human Memory B Cells Producing Potent Cross-Neutralizing Antibodies against Human Parechovirus: Implications for Prevalence, Treatment, and Diagnosis.

UNLABELLED: The family Picornaviridae is a large and diverse group of positive-sense RNA viruses, including human enteroviruses (EVs) and human parechoviruses (HPeVs). The human immune response against EVs and HPeVs is thought to be mainly humoral, and an insufficient neutralizing antibody (Ab) response during infection is a risk factor and can ultimately be life threatening. The accessibility of different antigenic sites and observed cross-reactivity make HPeVs a good target for development of therapeutic human monoclonal antibodies (MAbs). In this study, we generated two different human MAbs specific for HPeV by screening culture supernatants of Ab-producing human B cell cultures for direct neutralization of HPeV1. Both MAbs showed HPeV1-specific neutralization as well as neutralization of HPeV2. One antibody, AM18, cross-neutralized HPeV4, -5, and -6 and coxsackievirus A9 (CV-A9). VP1 capsid protein-specific assays confirmed that AM18 bound VP1 of HPeV1, -2, and -4 with high affinity (11.5 pM). In contrast, the HPeV1-specific MAb AM28, which neutralized HPeV1 even more efficiently than did AM18, showed no cross-reactivity with HPeV3 to -6 or other EVs and did not bind any of the capsid proteins, suggesting that AM28 is specific for a conformation-dependent, nonlinear epitope on the virus. The discovery of MAbs that are cross-reactive between HPeVs may help development of HPeV treatment options with antibodies and vaccine design based on epitopes recognized by these antibodies. IMPORTANCE: HPeV infections are widespread among young children and adults, causing a broad range of disease. Infections can be severe and life threatening, while no antiviral treatment is available. Given that the absence of neutralizing Abs is a risk factor for severe disease in infants, treatment of picornavirus infections with MAbs would be a therapeutic option. To study antibody neutralization of HPeV in more detail, we generated two different HPeV1-specific human MAbs. Both MAbs show HPeV1-specific neutralization and cross-neutralized HPeV2. One MAb also cross-neutralized other HPeVs. Surprisingly, this MAb also neutralized CV-A9. These MAbs provide a unique tool for further research and for the diagnosis (antigen detection) and possible treatment of HPeV infections.

SLC6A15, a novel stress vulnerability candidate, modulates anxiety and depressive-like behavior: involvement of the glutamatergic system.

Major depression is a multifactorial disease, involving both environmental and genetic risk factors. Recently, SLC6A15 - a neutral amino acid transporter mainly expressed in neurons - was proposed as a new candidate gene for major depression and stress vulnerability. Risk allele carriers for a single nucleotide polymorphism (SNP) in a SLC6A15 regulatory region display altered hippocampal volume, glutamate levels, and hypothalamus-pituitary-adrenal axis activity, all markers associated with major depression. Despite this genetic link between SLC6A15 and depression, its functional role with regard to the development and maintenance of depressive disorder is still unclear. The aim of the current study was therefore to characterize the role of mouse slc6a15 in modulating brain function and behavior, especially in relation to stress as a key risk factor for the development of mood disorders. We investigated the effects of slc6a15 manipulation using two mouse models, a conventional slc6a15 knock-out mouse line (SLC-KO) and a virus-mediated hippocampal slc6a15 overexpression (SLC-OE) model. Mice were tested under basal conditions and following chronic social stress. We found that SLC-KO animals displayed a similar behavioral profile to wild-type littermates (SLC-WT) under basal conditions. Interestingly, following chronic social stress SLC-KO animals showed lower levels of anxiety- and depressive-like behavior compared to stressed WT littermates. In support of these findings, SLC-OE animals displayed increased anxiety-like behavior already under basal condition. We also provide evidence that GluR1 expression in the dentate gyrus, but not GluR2 or NR1, are regulated by slc6a15 expression, and may contribute to the difference in stress responsiveness observed between SLC-KO and SLC-WT animals. Taken together, our data demonstrate that slc6a15 plays a role in modulating emotional behavior, possibly mediated by its impact on glutamatergic neurotransmission.

Linear and non-linear heart rate metrics for the assessment of anaesthetists' workload during general anaesthesia.

BACKGROUND: Excessive workload may impact the anaesthetists' ability to adequately process information during clinical practice in the operation room and may result in inaccurate situational awareness and performance. This exploratory study investigated heart rate (HR), linear and non-linear heart rate variability (HRV) metrics and subjective ratings scales for the assessment of workload associated with the anaesthesia stages induction, maintenance and emergence. METHODS: HR and HRV metrics were calculated based on five min segments from each of the three anaesthesia stages. The area under the receiver operating characteristics curve (AUC) of the investigated metrics was calculated to assess their ability to discriminate between the stages of anaesthesia. Additionally, a multiparametric approach based on logistic regression models was performed to further evaluate whether linear or non-linear heart rate metrics are suitable for the assessment of workload. RESULTS: Mean HR and several linear and non-linear HRV metrics including subjective workload ratings differed significantly between stages of anaesthesia. Permutation Entropy (PeEn, AUC=0.828) and mean HR (AUC=0.826) discriminated best between the anaesthesia stages induction and maintenance. In the multiparametric approach using logistic regression models, the model based on non-linear heart rate metrics provided a higher AUC compared with the models based on linear metrics. CONCLUSIONS: In this exploratory study based on short ECG segment analysis, PeEn and HR seem to be promising to separate workload levels between different stages of anaesthesia. The multiparametric analysis of the regression models favours non-linear heart rate metrics over linear metrics.