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Kliniker berichten haufig von einer Veranderung des mimisch-affektiven Verhaltens im Laufe der Behandlung posttraumatischer Belastungsstorungen (PTBS). Dabei wird die Zunahme der Mimik in Zusammenhang mit dem Ruckgang der „Numbing“-Symptomatik gebracht. Die Zunahme des mimisch-affektiven Verhaltens (insbesondere des negativen Affekts) im Laufe einer Behandlung in Form des Eye Movement Desensitization and Reprocessing (EMDR) sollte dokumentiert werden. Des Weiteren erfolgte eine explorative Analyse der Zusammenhange der mimischen Veranderungen mit wichtigen Therapie-Outcomes. Das mimisch-affektive Verhalten wahrend der Therapiesitzungen wurde fur 16 Patientinnen, die vor ihrem 18. Lebensjahr traumatisiert wurden, mithilfe des „facial action coding system“ (FACS) im Vorfeld, wahrend und ein Jahr nach einer stationaren EMDR-Behandlung codiert. Zur Quantifizierung der Symptombelastung kamen die Impact of Event Scale Revised (IES-R), die Symptomcheckliste (SCL-90®), das Beck-Depressions-Inventar (BDI-V) sowie der Fragebogen zu Dissoziativen Symptomen (FDS) zum Einsatz. Es zeigt sich uber die 3 Erhebungszeitpunkte hinweg eine bedeutsame Mimikveranderung, die eine Zunahme der Gesamtmimik und den Ausdruck negativen Affekts betraf. Zusammenhange zu den Veranderungen der erhobenen Symptomschwere liesen sich jedoch nicht belegen. Anhand weiterer Untersuchungen wird geklart werden mussen, inwiefern die Zunahme des mimisch-affektiven Verhaltens relevant ist, um insbesondere im Hinblick auf soziale Interaktionen von Behandlungserfolg sprechen zu konnen.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with respect to outcome. Features of the tumor microenvironment (TME) are associated with prognosis when assessed by gene expression profiling. However, it is uncertain whether assessment of the microenvironment can add prognostic information to the most relevant and clinically well-established molecular subgroups when analyzed by immunohistochemistry (IHC).We carried out a histopathologic analysis of biomarkers related to TME in a very large cohort (n = 455) of DLBCL treated in prospective trials and correlated with clinicopathologic and molecular data, including chromosomal rearrangements and gene expression profiles for cell-of-origin and TME.The content of PD1+, FoxP3+ and CD8+, as well as vessel density, was not associated with outcome. However, we found a low content of CD68+ macrophages to be associated with inferior progression-free survival (PFS) and overall survival (OS; P = 0.023 and 0.040, respectively) at both univariable and multivariable analyses, adjusted for the factors of the International Prognostic Index (IPI), MYC break and BCL2/MYC and BCL6/MYC double-hit status. The subgroup of PDL1+ macrophages was not associated with survival. Instead, secreted protein acidic and cysteine rich (SPARC)-positive macrophages were identified as the subtype of macrophages most associated with survival. SPARC-positive macrophages and stromal cells directly correlated with favorable PFS and OS (both, P[log rank]0.001, P[trend]0.001). The association of SPARC with prognosis was independent of the factors of the IPI, MYC double-/triple-hit status, Bcl2/c-myc double expression, cell-of-origin subtype and a recently published gene expression signature [lymphoma-associated macrophage interaction signature (LAMIS)].SPARC expression in the TME detected by a single IHC staining with fair-to-good interobserver reproducibility is a powerful prognostic parameter. Thus SPARC expression is a strong candidate for risk assessment in DLBCL in daily practice.

The cognitive control system matures gradually with age and shows age-related sex differences. To gain knowledge concerning error adaptation in familial high-risk groups, investigating error adaptation among the offspring of parents with severe mental disorders is important and may contribute to the understanding of cognitive functioning in at-risk individuals. We identified an observational cohort through Danish registries and measured error adaptation using an Eriksen flanker paradigm. We tested 497 7-year-old children with a familial high risk of schizophrenia (N = 192) or bipolar disorder (N = 116) for deficits in error adaptation compared with a control group (N = 189). We investigated whether error adaptation differed between high-risk groups compared with controls and sex differences in the adaptation to errors, irrespective of high-risk status. Overall, children exhibited post-error slowing (PES), but the slowing of responses did not translate to significant improvements in accuracy. No differences were detected between either high-risk group compared with the controls. Boys showed less PES and PES after incongruent trials than girls. Our results suggest that familial high risk of severe mental disorders does not influence error adaptation at this early stage of cognitive control development. Error adaptation behavior at age 7 years shows specific sex differences.

Background: Although graft choice may be limited in the revision setting based on previously used grafts, most surgeons believe that graft choice for anterior cruciate ligament (ACL) reconstruction is an important factor related to outcome. Hypothesis: In the ACL revision setting, there would be no difference between autograft and allograft in rerupture rate and patient-reported outcomes (PROs) at 6-year follow-up. Study Design: Cohort study; Level of evidence, 2. Methods: Patients who had revision surgery were identified and prospectively enrolled in this cohort study by 83 surgeons over 52 sites. Data collected included baseline characteristics, surgical technique and pathology, and a series of validated PRO measures. Patients were followed up at 6 years and asked to complete the identical set of PRO instruments. Incidence of additional surgery and reoperation because of graft failure were also recorded. Multivariable regression models were used to determine the predictors (risk factors) of PROs, graft rerupture, and reoperation at 6 years after revision surgery. Results: A total of 1234 patients including 716 (58%) men were enrolled. A total of 325 (26%) underwent revision using a bone-patellar tendon-bone (BTB) autograft; 251 (20%), soft tissue autograft; 289 (23%), BTB allograft; 302 (25%), soft tissue allograft; and 67 (5%), other graft. Questionnaires and telephone follow-up for subsequent surgery information were obtained for 809 (66%) patients, while telephone follow-up was only obtained for an additional 128 patients for the total follow-up on 949 (77%) patients. Graft choice was a significant predictor of 6-year Marx Activity Rating Scale scores ( P = .024). Specifically, patients who received a BTB autograft for revision reconstruction had higher activity levels than did patients who received a BTB allograft (odds ratio [OR], 1.92; 95% CI, 1.25-2.94). Graft rerupture was reported in 5.8% (55/949) of patients by their 6-year follow-up: 3.5% (16/455) of patients with autografts and 8.4% (37/441) of patients with allografts. Use of a BTB autograft for revision resulted in patients being 4.2 times less likely to sustain a subsequent graft rupture than if a BTB allograft were utilized ( P = .011; 95% CI, 1.56-11.27). No significant differences were found in graft rerupture rates between BTB autograft and soft tissue autografts ( P = .87) or between BTB autografts and soft tissue allografts ( P = .36). Use of an autograft was found to be a significant predictor of having fewer reoperations within 6 years compared with using an allograft ( P = .010; OR, 0.56; 95% CI, 0.36-0.87). Conclusion: BTB and soft tissue autografts had a decreased risk in graft rerupture compared with BTB allografts. BTB autografts were associated with higher activity level than were BTB allografts at 6 years after revision reconstruction. Surgeons and patients should consider this information when choosing a graft for revision ACL reconstruction.

Visual Abstract, Highlights • Myocardial matrix hydrogel preserves LV volumes and apical wall thickening in a chronic MI model. • Myocardial matrix hydrogel trends toward reduced fibrosis. • In vivo differential gene expression analysis shows the matrix modulates cardiac muscle contraction, metabolism, fibrosis, and the inflammatory/immune response in a chronic MI model., Summary A first-in-man clinical study on a myocardial-derived decellularized extracellular matrix hydrogel suggested the potential for efficacy in chronic myocardial infarction (MI) patients. However, little is understood about the mechanism of action in chronic MI. In this study, the authors investigated the efficacy and mechanism by which the myocardial matrix hydrogel can mitigate negative left ventricular (LV) remodeling in a rat chronic MI model. Assessment of cardiac function via magnetic resonance imaging demonstrated preservation of LV volumes and apical wall thickening. Differential gene expression analyses showed the matrix is able to prevent further negative LV remodeling in the chronic MI model through modulation of the immune response, down-regulation of pathways involved in heart failure progression and fibrosis, and up-regulation of genes important for cardiac muscle contraction.

Cognitive heterogeneity characterizes individuals with schizophrenia and bipolar disorder; however, little is known of cognitive heterogeneity within young children at familial high-risk of schizophrenia or bipolar disorder. This study aimed to investigate heterogeneity across social cognitive and language functions in children at familial high-risk of schizophrenia or bipolar disorder, i.e. severe mental illness (FHR-SMI). This may help designate subgroups in need of intervention initiatives. A data-driven, hierarchical cluster analysis was applied across a sample of 322 children at FHR-SMI (FHR-SZ, n = 200; FHR-BP, n = 120) on measures of Theory of Mind, facial emotion recognition, social cognitive processing speed, receptive and pragmatic language. We examined differences between subgroups as well as differences between subgroups and a control group. Exploratively, the subgroups were compared in terms of social responsiveness and global functioning. A Typical-High Functioning Subgroup with intact social cognitive and language functioning (34.5%), a Mildly Impaired Subgroup with selective impairments in explicit Theory of Mind and language functioning (58.7%), and a Significantly Impaired Subgroup with social cognitive and language functioning impairments (6.8%) were identified. The subgroups differed significantly from each other and overall compares to the controls. The Significantly and Mildly Impaired Subgroups presented with poorer social responsiveness and global functioning than the Typical-High Functioning Subgroup. In young children with FHR-SMI, three subgroups with relatively homogeneous social cognitive and language functioning profiles were observed. Only a small proportion of children at FHR-SMI displayed large social cognitive and language functioning impairments in middle childhood.

Infection is a rare occurrence after revision anterior cruciate ligament reconstruction (rACLR). Because of the low rates of infection, it has been difficult to identify risk factors for infection in this patient population. The purpose of this study was to report the rate of infection following rACLR and assess whether infection is associated with patient- and surgeon- dependent risk factors. We reviewed two large prospective cohorts to identify patients with postoperative infections following rACLR. Age, sex, body mass index (BMI), smoking status, history of diabetes, and graft choice were recorded for each patient. The association of these factors with postoperative infection following rACLR was assessed. There were 1423 rACLR cases in the combined cohort, with 9 (0.6%) reporting post-operative infections. Allografts had a higher risk of infection than autografts (odds ratio=6.8; 95% CI: 0.9-54.5; p=0.045). Diabetes (odds ratio=28.6; 95% CI: 5.5-149.9; p=0.004) was a risk factor for infection. Patient age, sex, BMI and smoking status were not associated with risk of infection after rACLR. STATEMENT OF CLINICAL SIGNIFICANCE: While there is a low rate of infection following rACLR, use of allograft and comorbidity with diabetes are associated with a higher risk of infection following this surgery.

Context Gait biomechanics are linked to biochemical changes that contribute to the development of posttraumatic knee osteoarthritis in individuals with anterior cruciate ligament reconstruction (ACLR). It remains unknown if modifying peak loading during gait using real-time biofeedback will result in acute biochemical changes related to cartilage metabolism. Objective To determine if acutely manipulating peak vertical ground reaction force (vGRF) during gait influences acute changes in serum cartilage oligomeric matrix protein concentration (sCOMP) among individuals with ACLR. Design Crossover study. Patients or Other Participants Thirty individuals with unilateral ACLR participated (70% female, age = 20.43 ± 2.91 years old, body mass index = 24.42 ± 4.25, months post-ACLR = 47.83 ± 26.97). Additionally, we identified a subgroup of participants who demonstrated an increase in sCOMP after the control or natural loading condition (sCOMPCHANGE > 0 ng/mL, n = 22, 70% female, age = 20.32 ± 3.00 years old, body mass index = 24.73 ± 4.33, months post-ACLR = 47.27 ± 29.32). Main Outcome Measure(s) Serum was collected both prior to and immediately after each condition to determine sCOMPchange. Intervention(s) All participants attended 4 sessions that involved 20 minutes of walking on a force-measuring treadmill consisting of a control condition (natural loading) followed by random ordering of 3 loading conditions with real-time biofeedback: (1) symmetric vGRF between limbs, (2) a 5% increase in vGRF (high loading) and (3) a 5% decrease in vGRF (low loading). A general linear mixed model was used to determine differences in sCOMPCHANGE between altered loading conditions and the control group in the entire cohort and the subgroup. Results The sCOMPCHANGE was not different across loading conditions for the entire cohort (F3,29 = 1.34, P = .282). Within the subgroup, sCOMPCHANGE was less during high loading (1.95 ± 24.22 ng/mL, t21 = −3.53, P = .005) and symmetric loading (9.93 ± 21.45 ng/mL, t21 = −2.86, P = .025) compared with the control condition (25.79 ± 21.40 ng/mL). Conclusions Increasing peak vGRF during gait decreased sCOMP in individuals with ACLR who naturally demonstrated an increase in sCOMP after 20 minutes of walking. Trial Registry ClinicalTrials.gov (NCT03035994)

Background: Meniscal preservation has been demonstrated to contribute to long-term knee health. This has been a successful intervention in patients with isolated tears and tears associated with anterior cruciate ligament (ACL) reconstruction. However, the results of meniscal repair in the setting of revision ACL reconstruction have not been documented. Purpose: To examine the prevalence and 2-year operative success rate of meniscal repairs in the revision ACL setting. Study Design: Case-control study; Level of evidence, 3. Methods: All cases of revision ACL reconstruction with concomitant meniscal repair from a multicenter group between 2006 and 2011 were selected. Two-year follow-up was obtained by phone and email to determine whether any subsequent surgery had occurred to either knee since the initial revision ACL reconstruction. If so, operative reports were obtained, whenever possible, to verify the pathologic condition and subsequent treatment. Results: In total, 218 patients (18%) from 1205 revision ACL reconstructions underwent concurrent meniscal repairs. There were 235 repairs performed: 153 medial, 48 lateral, and 17 medial and lateral. The majority of these repairs (n = 178; 76%) were performed with all-inside techniques. Two-year surgical follow-up was obtained on 90% (197/218) of the cohort. Overall, the meniscal repair failure rate was 8.6% (17/197) at 2 years. Of the 17 failures, 15 were medial (13 all-inside, 2 inside-out) and 2 were lateral (both all-inside). Four medial failures were treated in conjunction with a subsequent repeat revision ACL reconstruction. Conclusion: Meniscal repair in the revision ACL reconstruction setting does not have a high failure rate at 2-year follow-up. Failure rates for medial and lateral repairs were both

Anterior cruciate ligament reconstruction (ACLR) incurs a high risk of posttraumatic knee osteoarthritis (PTOA). Aberrant gait biomechanics contribute to PTOA and are attributable in part to quadriceps dysfunction. Vibration improves quadriceps function following ACLR, but its effects on gait biomechanics are unknown. The purpose of this study was to evaluate the effects of whole-body vibration (WBV) and local muscle vibration (LMV) on gait biomechanics in individuals with ACLR. Seventy-five volunteers (time since ACLR 27 ± 16 months) were randomized to WBV, LMV, or Control interventions. Walking biomechanics were assessed prior to and following a single exposure to the interventions. Outcomes included pre-post change scores in the ACLR limb for the peak vertical ground reaction force (vGRF) and its loading rate, peak internal knee extension (KEM) and abduction moments, and peak knee flexion and varus angles. LMV produced a significant decrease in the vGRF loading rate (-3.6 BW/s) that was greater than the changes in the WBV (-0.3 BW/s) and Control (0.5 BW/s) groups. Additionally, WBV produced an increase in the peak KEM (0.27% BW × Ht) that was greater than the change in the Control group (-0.17% BW × Ht) but not the LMV group (0.01% BW × Ht). Lower KEM and greater loading rates have been linked to declines in joint health following ACLR. WBV acutely increased the peak KEM and LMV decreased loading rates. These data suggest that vibration has the potential to mitigate aberrant gait biomechanics, and may represent an effective approach for reducing PTOA risk following ACLR.

Cognitive impairments are strongly associated with schizophrenia (SZ) and bipolar disorder (BP) with executive functions (EF) impairments as a likely key feature. Studies of everyday behavior rated EF in young children at familial high risk of SZ (FHR-SZ) are scarce and, to our knowledge, non-existent in young children at familial high risk of BP (FHR-BP). We aimed to compare everyday behavior-rated EF of FHR-SZ, FHR-BP, and control children. A nationwide population-based cohort of 522 7-year-old children with parents diagnosed with either SZ (N = 202) or BP (N = 120) and matched controls (N = 200) were recruited using the Danish national registries. The children's EF were assessed with the Behavior Rating Inventory of Executive Functions questionnaire rated by primary caregivers and teachers. According to primary caregiver assessments, FHR-SZ children displayed widespread EF impairments and had an odds ratio of 3.7 (2.0-6.9) of having clinically significant global EF impairments compared to controls. FHR-BP children were most severely impaired regarding EF related to emotional control and had an odds ratio of 2.5 (1.2-5.1) of clinically significant global EF impairments compared to controls. Teacher assessments were overall comparable to primary caregiver assessments but teachers rated more difficulties in the FHR-SZ group than primary caregivers. Already at age 7, children with a parental history of SZ or BP displayed significant impairments of EF in everyday-life situations. FHR-SZ children displayed widespread significant impairments of EF, whereas FHR-BP children were most severely impaired on emotional control. Clinicians should be aware of potential EF impairments in FHR children.

Cell-cell communication is an essential process in life, with endosomes acting as key organelles for regulating uptake and secretion of signaling molecules. Endocytosed material is accepted by the sorting endosome where it either is sorted for recycling or remains in the endosome as it matures to be degraded in the lysosome. Investigation of the endosome maturation process has been hampered by the small size and rapid movement of endosomes in most cellular systems. Here, we report an easy versatile live-cell imaging assay to monitor endosome maturation kinetics, which can be applied to a variety of mammalian cell types. Acute ionophore treatment led to enlarged early endosomal compartments that matured into late endosomes and fused with lysosomes to form endolysosomes. Rab5-to-Rab7 conversion and PI(3)P formation and turn over were recapitulated with this assay and could be observed with a standard widefield microscope. We used this approach to show that Snx1 and Rab11-positive recycling endosome recruitment occurred throughout endosome maturation and was uncoupled from Rab conversion. In contrast, efficient endosomal acidification was dependent on Rab conversion. The assay provides a powerful tool to further unravel various aspects of endosome maturation.

8 pages, 2 figures, 1 table, 2 boxes, supplementary information https://doi.org/10.1038/s41564-020-0733-x.-- Author Correction: Roadmap for naming uncultivated Archaea and Bacteria: n the version of this Consensus Statement originally published, Pablo Yarza was mistakenly not included in the author list. Also, in Supplementary Table 1, Alexander Jaffe was missing from the list of endorsees. These errors have now been corrected and the updated Supplementary Table 1 is available online, The assembly of single-amplified genomes (SAGs) and metagenome-assembled genomes (MAGs) has led to a surge in genome-based discoveries of members affiliated with Archaea and Bacteria, bringing with it a need to develop guidelines for nomenclature of uncultivated microorganisms. The International Code of Nomenclature of Prokaryotes (ICNP) only recognizes cultures as ‘type material’, thereby preventing the naming of uncultivated organisms. In this Consensus Statement, we propose two potential paths to solve this nomenclatural conundrum. One option is the adoption of previously proposed modifications to the ICNP to recognize DNA sequences as acceptable type material; the other option creates a nomenclatural code for uncultivated Archaea and Bacteria that could eventually be merged with the ICNP in the future. Regardless of the path taken, we believe that action is needed now within the scientific community to develop consistent rules for nomenclature of uncultivated taxa in order to provide clarity and stability, and to effectively communicate microbial diversity, Support for this effort was provided by the National Science Foundation (grant no. DEB-1841658). We extend deep appreciation to all who attended the Microbial Taxonomy 2018 seminars, the Microbial Systematics for the Next Decade workshop held in Hood River, Oregon, USA, in October 2018, and those that participated in subsequent, With the funding support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S), of the Spanish Research Agency (AEI)

Nonrandom mating in parents with schizophrenia or bipolar disorder increases the population-level genetic variance among the offspring generation and creates familial (risk) environments likely to be shaped by specific conditions. The objective of this study was to investigate the occurrence of mental disorder and levels of cognitive and social functioning in individuals who have children by partners with schizophrenia or bipolar disorder compared to controls. The Danish High Risk and Resilience Study VIA 7 is a population-based cohort study conducted in Denmark between 2013 and 2016. This study focus on parents diagnosed with schizophrenia (n = 150) or bipolar disorder (n = 100) and control parents (n = 182), as well as their partners without schizophrenia or bipolar disorder (n = 440). We used linear mixed-effect models, and main outcomes were mental disorders, intelligence, processing speed, verbal working memory, and social functioning. We found that parents having children by a partner with schizophrenia or bipolar disorder more often fulfilled the criteria for a mental disorder and had poorer social functioning compared to parents having children by a partner without schizophrenia or bipolar disorder. Furthermore, parents having children by a partner with schizophrenia performed poorer on processing speed compared to parents in the control group. The presence of nonrandom mating found in this study has implications for our understanding of familial transmission of these disorders and our findings should be considered in future investigations of potential risk factors for children with a parent with schizophrenia or bipolar disorder.

Endosomal transport is essential for cellular organization and compartmentalization and cell-cell communication. Sorting endosomes provide a crossroads for various trafficking pathways and determine recycling, secretion or degradation of proteins. The organization of these processes requires membrane-tethering factors to coordinate Rab GTPase function with membrane fusion. Here, we report a conserved tethering platform that acts in the Rab11 recycling pathways at sorting endosomes, which we name factors for endosome recycling and Rab interactions (FERARI). The Rab-binding module of FERARI consists of Rab11FIP5 and rabenosyn-5/RABS-5, while the SNARE-interacting module comprises VPS45 and VIPAS39. Unexpectedly, the membrane fission protein EHD1 is also a FERARI component. Thus, FERARI appears to combine fusion activity through the SM protein VPS45 with pinching activity through EHD1 on SNX-1-positive endosomal membranes. We propose that coordination of fusion and pinching through a kiss-and-run mechanism drives cargo at endosomes into recycling pathways.

Establishing gene regulatory networks during differentiation or reprogramming requires master or pioneer transcription factors (TFs) such as PU.1, a prototype master TF of hematopoietic lineage differentiation. To systematically determine molecular features that control its activity, here we analyze DNA-binding in vitro and genome-wide in vivo across different cell types with native or ectopic PU.1 expression. Although PU.1, in contrast to classical pioneer factors, is unable to access nucleosomal target sites in vitro, ectopic induction of PU.1 leads to the extensive remodeling of chromatin and redistribution of partner TFs. De novo chromatin access, stable binding, and redistribution of partner TFs both require PU.1’s N-terminal acidic activation domain and its ability to recruit SWI/SNF remodeling complexes, suggesting that the latter may collect and distribute co-associated TFs in conjunction with the non-classical pioneer TF PU.1., PU.1 is a master TF of hematopoietic lineage differentiation. Here the authors analyse properties of PU.1 DNA-binding in vitro and genome-wide in vivo across different cell types with native or ectopic PU.1 expression, and uncover the mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1.

Purpose To compare gait biomechanics throughout stance phase 6 and 12 months after unilateral anterior cruciate ligament reconstruction (ACLR) between ACLR and contralateral limbs and compared with controls. Methods Vertical ground reaction force (vGRF), knee flexion angle (KFA), and internal knee extension moment (KEM) were collected bilaterally 6 and 12 months post-ACLR in 30 individuals (50% female, 22 ± 3 yr, body mass index = 23.8 ± 2.2 kg·m) and at a single time point in 30 matched uninjured controls (50% female, 22 ± 4 yr, body mass index = 23.6 ± 2.1 kg·m). Functional analyses of variance were used to evaluate the effects of limb (ACLR, contralateral, and control) and time (6 and 12 months) on biomechanical outcomes throughout stance. Results Compared with the uninjured controls, the ACLR group demonstrated bilaterally lesser vGRF (ACLR, 9% body weight [BW]; contralateral, 4%BW) during early stance and greater vGRF during midstance (ACLR, 5%BW; contralateral, 4%BW) 6 months post-ACLR. Compared to the uninjured controls, the ACLR group demonstrated bilaterally lesser vGRF (ACLR, 10%BW; contralateral, 8%BW) during early stance and greater vGRF during midstance (ACLR, 5%BW; contralateral, 5%BW) 12 months post-ACLR. Compared with controls, the ACLR limb demonstrated lesser KFA during early stance at 6 (2.3°) and 12 months post-ACLR (2.0°), and the contralateral limb demonstrated lesser KFA during early stance at 12 months post-ACLR (2.8°). Compared with controls, the ACLR limb demonstrated lesser KEM during early stance at both 6 months (0.011BW × height) and 12 months (0.007BW × height) post-ACLR, and the contralateral limb demonstrated lesser KEM during early stance only at 12 months (0.006BW × height). Conclusions Walking biomechanics are altered bilaterally after ACLR. During the first 12 months post-ACLR, both the ACLR and contralateral limbs demonstrate biomechanical differences compared with control limbs. Differences between the contralateral and control limbs increase from 6 to 12 months post-ACLR.

Osteoarthritis is common following anterior cruciate ligament reconstruction (ALCR), and aberrant gait biomechanics are considered a primary contributor. Somatosensory dysfunction potentially alters gait biomechanics, but this association is unclear. Therefore, the purposes of this investigation were to compare somatosensory function between limbs and evaluate associations between somatosensory function and gait biomechanics linked to osteoarthritis development in individuals with ALCR. Seventy-three volunteers with ALCR participated. Gait biomechanics (peak vertical ground reaction force magnitude and loading rate, peak internal knee extension and valgus moments, peak knee flexion and varus angles, and quadriceps/hamstrings co-activation) were assessed as subjects walked at their preferred speed. The somatosensory function was assessed via joint position sense error (knee flexion) and vibratory perception threshold (femoral epicondyles, malleoli, and first metatarsal). Though somatosensory function did not differ between the ACLR and contralateral limbs, poorer joint position sense in the ACLR limb was associated with lower loading rates and internal knee extension moments, and greater co-activation. Poorer vibratory perception at the medial and lateral malleoli and first metatarsal head in the ACLR limb was associated with lower loading rates, greater internal knee valgus moments and varus angles, and greater co-activation. Poorer vibratory perception at the medial malleolus and first metatarsal head in the contralateral limb was associated with greater peak knee varus angles and internal knee valgus moments. These results suggest that future research evaluating rehabilitation approaches for improving somatosensory function is warranted as a potential approach for restoring normal gait biomechanics and reducing osteoarthritis risk. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:620-628, 2020.

Language is one of the cognitive domains often impaired across many neurodevelopmental disorders. While for some disorders the linguistic deficit is the primary impairment (e.g., specific language impairment, SLI), for others it may accompany broader behavioral problems (e.g., autism). The precise nature of this phenotypic overlap has been the subject of debate. Moreover, several studies have found genetic overlaps across neurodevelopmental disorders. This raises the question of whether these genetic overlaps may correlate with phenotypic overlaps and, if so, in what manner. Here, we apply a genome‐wide approach to the study of the linguistic deficit in SLI, autism spectrum disorder (ASD), and attention deficit/hyperactivity disorder (ADHD). Using a discovery genome‐wide association study of SLI, we generate polygenic risk scores (PRS) in an independent sample which includes children with language impairment, SLI, ASD or ADHD and age‐matched controls and perform regression analyses across groups. The SLI‐trained PRS significantly predicted risk in the SLI case–control group (adjusted R 2 = 6.24%; P = 0.024) but not in the ASD or ADHD case‐control groups (adjusted R 2 = 0.0004%, 0.01%; P = 0.984, 0.889, respectively) nor for height, used as a negative control (R 2 = 0.2%; P = 0.452). Additionally, there was a significant difference in the normalized PRS between children with SLI and children with ASD (common language effect size = 0.66; P = 0.044). Our study suggests no additive common‐variant genetic overlap between SLI and ASD and ADHD. This is discussed in the context of phenotypic studies of SLI and related disorders. Autism Res 2020, 13: 369–381. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. Lay Summary Language deficits are characteristic of specific language impairment (SLI), but may also be found in other neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Many studies examined the overlaps and differences across the language deficits in these disorders, but few studies have examined the genetic aspect thereof. In this study, we use a genome‐wide approach to evaluate whether common genetic variants increasing risk of SLI may also be associated with ASD and ADHD in the same manner. Our results suggest that this is not the case, and we discuss this finding in the context of theories concerning the etiologies of these disorders.

Diffuse large B-cell lymphoma (DLBCL) is a disease with heterogeneous outcome. Stromal signatures have been correlated to survival in DLBCL. Their use, however, is hampered by the lack of assays for formalin-fixed paraffin-embedded material (FFPE). We constructed a lymphoma-associated macrophage interaction signature (LAMIS) interrogating features of the microenvironment using a NanoString assay applicable to FFPE. The clinical impact of the signature could be validated in a cohort of 466 patients enrolled in prospective clinical trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Patients with high expression of the signature (LAMIShigh) had shorter EFS, PFS, and OS. Multivariate analyses revealed independence from IPI factors in EFS (HR 1.7, 95% CI 1.2–2.4, p-value = 0.001), PFS (HR 1.8, 95% CI 1.2–2.5, p-value = 0.001) and OS (HR 1.8, 95% CI 1.3–2.7, p-value = 0.001). Multivariate analyses adjusted for the IPI factors showed the signature to be independent from COO, MYC rearrangements and double expresser status (DE). LAMIShigh and simultaneous DE status characterized a patient subgroup with dismal prognosis and early relapse. Our data underline the importance of the microenvironment in prognosis. Combined analysis of stromal features, the IPI and DE may provide a new rationale for targeted therapy.

It is well established that children with familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) have a higher risk of developing mental disorders, however, little is known of to what degree the genetic and environmental vulnerabilities affect the quality of life and self-esteem of these children. We aimed to compare the quality of life and self-esteem between children with FHR-SZ or FHR-BP and controls. We used Danish nationwide registers to retrieve a cohort of 522 7-year-old children with FHR-SZ or FHR-BP and controls. Quality of life was assessed with the 'Health-related Quality of Life Screening Instrument', KIDSCREEN-27, and the scale 'Social Acceptance (Bullying)' from the KIDSCREEN-52. Self-esteem was assessed with the self-report scale 'I think I am'. Assessors were blind to familial risk status of the children. Children with FHR-SZ displayed lower levels of the general quality of life, as well as lower scores on the 'Psychological Well-being' scale and the 'School Environment' scale of the KIDSCREEN-27 compared with controls. Both children with FHR-SZ and FHR-BP reported more bullying victimization compared with controls. Children with FHR-SZ reported lower self-esteem on the total scale of 'I think I am', as well as on the 'Skills and talents', the 'Psychological well-being', and the 'Relationships with others' subscales compared with controls. The findings of lower quality of life and self-esteem in children with FHR-SZ together with more bullying victimization in both familial high-risk groups call for studies on low risk, early intervention strategies towards this group of vulnerable children.

Brefeldin A resistance factor 1 (Bfr1p) is a nonessential RNA-binding protein and multicopy suppressor of brefeldin A sensitivity in Saccharomyces cerevisiae. Deletion of BFR1 leads to multiple defects, including altered cell shape and size, change in ploidy, induction of P-bodies and chromosomal missegregation. Bfr1p has been shown to associate with polysomes, binds to several hundred mRNAs, and can target some of them to P-bodies. Although this implies a role of Bfr1p in translational control of mRNAs, its molecular function remains elusive. In the present study, we show that mutations in RNA-binding residues of Bfr1p impede its RNA-dependent colocalization with ER, yet do not mimic the known cellular defects seen upon BFR1 deletion. However, a Bfr1 RNA-binding mutant is impaired in binding to ERG4 mRNA, which encodes an enzyme required for the final step of ergosterol biosynthesis. Consistently, bfr1Δ strains show a strong reduction in Erg4p protein levels, most likely because of degradation of misfolded Erg4p. Polysome profiling of bfr1Δ or bfr1 mutant strains reveals a strong shift of ERG4 mRNA to polysomes, consistent with a function of Bfr1p in elongation or increased ribosome loading. Collectively, our data reveal that Bfr1 has at least two separable functions: one in RNA binding and cotranslational protein translocation into the ER and one in ploidy control or chromosome segregation.

After a stroke involving the left occipitotemporal cortex our patient shows a word-length effect and has problems to identify letters or numbers in strings of symbols. But he is normal in identifying isolated letters and in non-verbally categorizing even complex images such as faces or natural scenes. His cortical lesion is stretching from the visual word form area (VWFA) anteriorly causing additional problems to name visual stimuli and to match acoustic stimuli with images. We conclude that our patient suffers from pure alexia without deficits to identify even complex visual stimuli. Our results directly contradict several explanations for letter-by-letter reading.

Background: Anterior cruciate ligament (ACL) revision cohorts continually report lower outcome scores on validated knee questionnaires than primary ACL cohorts at similar time points after surgery. It is unclear how these outcomes are associated with physical activity after physician clearance for return to recreational or competitive sports after ACL revision surgery. Hypotheses: Participants who return to either multiple sports or a singular sport after revision ACL surgery will report decreased knee symptoms, increased activity level, and improved knee function as measured by validated patient-reported outcome measures (PROMs) and compared with no sports participation. Multisport participation as compared with singular sport participation will result in similar increased PROMs and activity level. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 1205 patients who underwent revision ACL reconstruction were enrolled by 83 surgeons at 52 clinical sites. At the time of revision, baseline data collected included the following: demographics, surgical characteristics, previous knee treatment and PROMs, the International Knee Documentation Committee (IKDC) questionnaire, Marx activity score, Knee injury and Osteoarthritis Outcome Score (KOOS), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). A series of multivariate regression models were used to evaluate the association of IKDC, KOOS, WOMAC, and Marx Activity Rating Scale scores at 2 years after revision surgery by sports participation category, controlling for known significant covariates. Results: Two-year follow-up was obtained on 82% (986 of 1205) of the original cohort. Patients who reported not participating in sports after revision surgery had lower median PROMs both at baseline and at 2 years as compared with patients who participated in either a single sport or multiple sports. Significant differences were found in the change of scores among groups on the IKDC ( P < .0001), KOOS-Symptoms ( P = .01), KOOS–Sports and Recreation ( P = .04), and KOOS–Quality of Life ( P < .0001). Patients with no sports participation were 2.0 to 5.7 times more likely than multiple-sport participants to report significantly lower PROMs, depending on the specific outcome measure assessed, and 1.8 to 3.8 times more likely than single-sport participants (except for WOMAC-Stiffness, P = .18), after controlling for known covariates. Conclusion: Participation in either a single sport or multiple sports in the 2 years after ACL revision surgery was found to be significantly associated with higher PROMs across multiple validated self-reported assessment tools. During follow-up appointments, surgeons should continue to expect that patients who report returning to physical activity after surgery will self-report better functional outcomes, regardless of baseline activity levels.

Context: Orthotic devices such as medial unloader knee braces and lateral heel wedges may limit cartilage loading following trauma or surgical repair. However, little is known regarding their effects on gait biomechanics in young, healthy individuals who are at risk of cartilage injury during physical activity due to greater athletic exposure compared with older adults. Objective: Determine the effect of medial unloader braces and lateral heel wedges on lower-extremity kinematics and kinetics in healthy, young adults. Design: Cross-sectional crossover design. Setting: Laboratory setting. Patients: Healthy, young adults who were recreationally active (30 min/d for 3 d/wk) between 18 and 35 years of age, who were free from orthopedic injury for at least 6 months, and with no history of lower-extremity orthopedic surgery. Interventions: All subjects completed normal over ground walking with a medial unloader brace at 2 different tension settings and a lateral heel wedge for a total of 4 separate walking conditions. Main Outcome Measures: Frontal plane knee angle at heel strike, peak varus angle, peak internal knee valgus moment, and frontal plane angular impulse were compared across conditions. Results: The medial unloader brace at 50% (−2.04° [3.53°]) and 100% (−1.80° [3.63°]) maximum load placed the knee in a significantly more valgus orientation at heel strike compared with the lateral heel wedge condition (−0.05° [2.85°]). However, this difference has minimal clinical relevance. Neither of the orthotic devices altered knee kinematics or kinetics relative to the control condition. Conclusions: Although effective in older adults and individuals with varus knee alignment, medial unloader braces and lateral heel wedges do not influence gait biomechanics in young, healthy individuals.

Despite multiple publications, molecular signatures predicting the course of hepatocellular carcinoma (HCC) have not yet been integrated into clinical routine decision-making. Given the diversity of published signatures, optimal number, best combinations, and benefit of functional associations of genes in prognostic signatures remain to be defined. We investigated a vast number of randomly chosen gene sets (varying between 1 and 10,000 genes) to encompass the full range of prognostic gene sets on 242 transcriptomic profiles of patients with HCC. Depending on the selected size, 4.7 to 23.5% of all random gene sets exhibit prognostic potential by separating patient subgroups with significantly diverse survival. This was further substantiated by investigating gene sets and signaling pathways also resulting in a comparable high number of significantly prognostic gene sets. However, combining multiple random gene sets using "swarm intelligence" resulted in a significantly improved predictability for approximately 63% of all patients. In these patients, approx. 70% of all random 50-gene containing gene sets resulted in equal and stable prediction of survival. For all other patients, a reliable prediction seems highly unlikely for any selected gene set. Using a machine learning and independent validation approach, we demonstrated a high reliability of random gene sets and swarm intelligence in HCC prognosis. Ultimately, these findings were validated in two independent patient cohorts and independent technical platforms (microarray, RNASeq). In conclusion, we demonstrate that using "swarm intelligence" of multiple gene sets for prognosis prediction may not only be superior but also more robust for predictive purposes. KEY MESSAGES: Molecular signatures predicting HCC have not yet been integrated into clinical routine Depending on the selected size, 4.7 to 23.5% of all random gene sets exhibit prognostic potential; independent of the technical platform (microarray, RNASeq) Using "swarm intelligence" resulted in a significantly improved predictability In these patients, approx. 70% of all random 50-gene containing gene sets resulted in equal and stable prediction of survival Overall, "swarm intelligence" is superior and more robust for predictive purposes in HCC.

Classical Hodgkin lymphoma is dominated by the non-neoplastic microenvironment, while the neoplastic Hodgkin-Reed-Sternberg cells compose only a minority of cells in the lymphoma tissue. Both the Hodgkin-Reed-Sternberg cells due to their expression of CD30 and PD-L1 and the microenvironment with abundant T cells and expression of PD1 are specifically targeted by new treatment concepts. We aimed to understand the dynamics of therapeutic targets in patients treated with conventional chemotherapy. We analyzed sequential biopsy specimens obtained at diagnosis and at relapse from the same patient for morphology, immunophenotype, and microenvironmental components. The morphological subtype changed between primary and relapse biopsy in 20% of cases. The immunophenotype was stable with respect to CD30, CD3, and LMP1 but variable with respect to CD15 and CD20 expression. Gene expression revealed 8 upregulated and 20 downregulated genes at relapse (p

Identification of chronic kidney disease patients at risk of progressing to end-stage renal disease (ESRD) is essential for treatment decision-making and clinical trial design. Here, we explored whether proton nuclear magnetic resonance (NMR) spectroscopy of blood plasma improves the currently best performing kidney failure risk equation, the so-called Tangri score. Our study cohort comprised 4640 participants from the German Chronic Kidney Disease (GCKD) study, of whom 185 (3.99%) progressed over a mean observation time of 3.70 ± 0.88 years to ESRD requiring either dialysis or transplantation. The original four-variable Tangri risk equation yielded a C statistic of 0.863 (95% CI, 0.831-0.900). Upon inclusion of NMR features by state-of-the-art machine learning methods, the C statistic improved to 0.875 (95% CI, 0.850-0.911), thereby outperforming the Tangri score in 94 out of 100 subsampling rounds. Of the 24 NMR features included in the model, creatinine, high-density lipoprotein, valine, acetyl groups of glycoproteins, and Ca2+-EDTA carried the highest weights. In conclusion, proton NMR-based plasma fingerprinting improved markedly the detection of patients at risk of developing ESRD, thus enabling enhanced patient treatment.

Cholesterol is an essential component of cellular membranes regulating the structural integrity and fluidity of biological bilayers and cellular processes such as signal transduction and membrane trafficking. However, tools to investigate the role and dynamics of cholesterol in live cells are still scarce and often show limited applicability. To address this, we previously developed a class of imidazolium-based cholesterol analogs, CHIMs. Here we confirm that CHIM membrane integration characteristics largely mimic those of cholesterol. Computational studies in simulated phospholipid bilayers and biophysical analyses of model membranes reveal that in biologically relevant systems CHIMs behave similarly to natural cholesterol. Importantly, the analogs can functionally replace cholesterol in membranes, can be readily labeled by click chemistry and follow trafficking pathways of cholesterol in live cells. Thus, CHIMs represent chemically versatile cholesterol analogs that can serve as a flexible toolbox to study cholesterol behavior and function in live cells and organisms., Matos et al characterise previously developed cholesterol analogues, named CHIMs, which can be fluorescently labelled by click-chemistry. They find that CHIMs segregate similarly to cholesterol in lipid bilayers, allow the visualisation of cholesterol dynamics in cells, and can functionally replace cholesterol in C.elegans.

(1) Background: Reconditioning of the paraspinal lumbar extensor muscles by isolated lumbar extension resistance exercises (ILEX) has shown good clinical results for patients with chronic unspecific low back pain. However, the clinical value and safety for patients with specific spine pathologies is unclear. In this study, clinical outcome and influencing factors were retrospectively analyzed for patients with lumbar disk herniation (LDH) and radiculopathy. (2) Methods: 189 consecutive patients (123 men and 66 women, mean age, 36 years) with clinically diagnosed LDH and relative indications for surgery started a 9-week rehabilitation program (2x/week) including ILEX in limited range of motion (ROM) adjusted to patients’ symptoms. Patients diagnosed with advanced levels of spine degeneration were excluded. Pain/radiculopathy (PR), influence on mental health (IOMH), satisfaction rates were measured via Numeric Rating Scales (NRS, 0–10), and overall clinical outcome was stated in % (100% = full recovery). Isometric extension strength was tested before and after the program. (3) Results: 168 patients (88.9%) completed the program. For 162 out of 168 patients (96.4%) there was a significant reduction of clinical symptoms, whereas 6 patients reported no changes in symptoms. Scores (mean) for symptom intensity decreased from 4.2 (±1.5) to 1.9 (±1.5) (p &lt, 0.001), the impact on mental health decreased from 5.9 (±2.3) to 2.4 (±2.0) (p &lt, 0.001). There was a (weak) correlation between lower scores for PR and IOMH before the study and better clinical outcomes, PR also weakly correlated with satisfaction. Other factors such as age, strength increase, level/location and number of LDH did not have a significant impact on the clinical results. (4) Conclusion: The results indicate that ILEX in limited ROM can be an effective treatment for the majority of patients with LDH. For patients with high pain levels, the results are less consistent, and surgery may be considered.

Summary Objective To compare gait biomechanics 6 months following anterior cruciate ligament (ACL) reconstruction (ACLR) between patients with the highest and lowest concentrations of synovial fluid (SF) interleukin-6 (IL-6) and matrix metalloproteinase-3 (MMP-3), as well as compared to uninjured controls. Design SF concentrations of IL-6 and MMP-3 were collected 7 ± 4 days post injury in 38 ACL injured patients (55% female, 21±4yrs, 25.3 ± 5.2BMI). ACL injured individuals were stratified into the lowest and highest quartiles based on IL-6 (IL-6Lowest and IL-6Highest) and MMP-3 (MMP-3Lowest and MMP-3Highest) concentrations. Gait biomechanics were collected on the injured limb 6 months post-ACLR and in 38 uninjured controls (50% female, 21±3yrs, 23.8 ± 2.8BMI). Functional analyses of variance were used to compare vertical ground reaction force (vGRF), knee flexion angle (KFA), and internal knee extension moment (KEM) waveforms throughout stance phase of gait to determine the proportions of stance differing between limbs and groups. Results Compared to uninjured controls, IL-6High and MMP-3High ACL subgroups demonstrated lesser vGRF (largest differences: IL-6, 7.88%BW; MMP-3, 11.05%BW) during early-stance and greater vGRF (largest differences: IL-6, 6.21%BW; MMP-3, 5.85%BW) in mid-stance, lesser KFA (largest differences: IL-6, 3.11°; MMP-3, 3.72°) and lesser KEM (largest differences: IL-6, 0.96%BW•m; MMP-3, 1.07%BW•m) in early-stance, as well as greater KFA in mid-stance (largest differences: IL-6, 1.5°; MMP-3, 2.95°). Conclusions High SF concentrations of a proinflammatory cytokine and a degradative enzyme early post-ACL injury are associated with aberrant gait biomechanics in the injured limb at 6 months post-ACLR (i.e., lesser vGRF, KFA and KEM) linked to posttraumatic osteoarthritis development.

Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells). Pre-therapy CD4+ TEM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4+ TEM expansion. Pre-therapy CD4+ TEM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4+ TEM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4+ TEM expansion given prophylactic valganciclovir and αPD-1/αCTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations., Checkpoint blocking therapies are used to treat metastatic melanoma, but can have adverse immune-mediated effects, including liver pathology. Here the authors identify an expanded pool of CD4+ effector memory T cells resulting from prior CMV exposure as a risk factor for this adverse effect in these patients.

There is a need for the development of effective treatments for focal articular cartilage injuries. We previously developed a multiphasic 3D-bioplotted osteochondral scaffold design that can drive site-specific tissue formation when seeded with adipose-derived stem cells (ASC). The objective of this study was to evaluate this scaffold in a large animal model. Osteochondral defects were generated in the trochlear groove of Yucatan minipigs and repaired with scaffolds that either contained or lacked an electrospun tidemark and were either unseeded or seeded with ASC. Implants were monitored via computed tomography (CT) over the course of 4 months of in vivo implantation and compared to both open lesions and autologous explants. ICRS II evaluation indicated that defects with ASC-seeded scaffolds had healing that most closely resembled the aulogous explant. Scaffold-facilitated subchondral bone repair mimicked the structure of native bone tissue, but cartilage matrix staining was not apparent within the scaffold. The open lesions had the highest volumetric infill detected using CT analysis (p < 0.05), but the repair tissue was largely disorganized. The acellular scaffold without a tidemark had significantly more volumetric filling than either the acellular or ASC seeded groups containing a tidemark (p < 0.05), suggesting that the tidemark limited cell infiltration into the cartilage portion of the scaffold. Overall, scaffold groups repaired the defect more successfully than an open lesion but achieved limited repair in the cartilage region. With further optimization, this approach holds potential to treat focal cartilage lesions in a highly personalized manner using a human patient's own ASC cells.

The purpose of this multi-campus research was to investigate the relationships of food type and personal factors with food choice, consumption, and waste behaviors of college students at all-you-care-to-eat dining facilities. The amount of food taken and wasted was indirectly measured in units relative to the plate size using before and after photos taken by the diners themselves. Animal protein and mixed dishes (e.g., stir fry, sandwich) took up more of diners’ plate space and these items were correlated to both greater hedonic appeal as well as a higher likelihood of the item being pre-plated. Greater confidence in liking an item before choosing it was correlated to a larger portion being taken. Finally, increased satisfaction with the meal and frequency of visiting the dining commons was correlated to less food waste. Understanding these potential food choice drivers can help dining facilities better target healthier meals to diners while reducing food waste.

Advancing technology and higher availability of Virtual Reality (VR) devices sparked its application in various research fields. For instance, health-related research showed that simulated nature environments in VR could reduce arousal and increase valence levels. This study investigates how the amount of possible interactivity influences the presence in nature environments and consequences on arousal and valence. After inducing fear (high arousal and low valence) through a VR-horror game, it was tested how participants recovered if they played a VR-nature game with either no, limited, or extensive interaction. The horror game proved to be a valid stimulus for inducing high arousal and low valence with a successful manipulation check. Igroup presence questionnaire (IPQ) scores showed that more interaction with the virtual environment increases spatial presence. A beneficial effect of experiencing nature can also be concluded. Results from the Self-Assessment Manikin questionnaire (SAM) scores for valence indicate a significant increase in the conditions with extensive and limited interaction compared to the control group. The VR Nature experience did significantly decrease arousal and increase valence compared to the post-horror game ratings. The physiological responses support this finding. These results can increase the effectiveness of health-related VR-applications to elevate mood levels by either implementing plenty of interactions and consequently increasing spatial presence or doing the opposite and leaving out any interactions at all.

BACKGROUND: Slower and suboptimal decision making has been identified in adults with schizophrenia and bipolar disorder. Owing to the limited evidence on decision making in first-degree relatives, we aimed to investigate, whether alterations in decision making are present in young children at familial high risk of bipolar disorder or schizophrenia.METHODS: In this population-based cohort study we assessed decision making in 197 children at familial high risk of schizophrenia (FHR-SZ), 115 children at familial high risk of bipolar disorder (FHR-BP), and 190 controls aged seven using the Cambridge Gambling Task. Potential associations to neurocognition, psychopathology, and the home environment were investigated.RESULTS: Children at FHR-SZ or FHR-BP displayed intact decision making. Quality of decision making showed significant but weak cross-sectional associations to neurocognition and adequacy of the home environment. Associations to aspects of executive functions and the home environment differed across groups.LIMITATIONS: Due to the cross-sectional nature of this study, the predictive value of efficient and inefficient decision making remains to be investigated in planned follow-up studies of this cohort.CONCLUSIONS: Young children at FHR-SZ or FHR-BP do not differ from controls in decision making efficacy, which does not appear to be an early risk marker of bipolar disorder or schizophrenia. Decision making is weakly associated to neurocognition and the home environment, but not to general intelligence or psychopathology.

Classical Hodgkin Lymphoma (cHL) is a B cell-derived lymphoid malignancy, affecting 2.5–3/100,000 people per year. To date, in patients diagnosed with advanced cHL no reliable tool is able to—a priori—distinguish the subset of patients at high risk for relapse or refractory disease. Clinical risk indices for cHL, such as the International Prognostic Score (IPS), have not been successfully applied as a treatment decision tool in advanced stage cHL [1]. In this study we show, that a previously published gene expression-based predictor in advanced stage cHL patients treated with ABVD [2] does not prove prognostic in 401 BEACOPP-treated advanced stage cHL patients. Using transcriptome profiling, we identified however that three individual genes, PDGFRA, TNFRSF8 (encoding CD30) and CCL17 (encoding TARC), were significantly associated with progression-free survival (PFS) after multiple test correction in the BEACOPP-treated cohort, highlighting the potential of a modified gene expression profiling approach for pre-treatment risk assessment., Letter

Correction to: Nature Microbiology https://doi.org/10.1038/s41564-020-0733-x , published online 8 June 2020. In the version of this Consensus Statement originally published, Pablo Yarza was mistakenly not included in the author list. Also, in Supplementary Table 1, Alexander Jaffe was missing from the list of endorsees. These errors have now been corrected and the updated Supplementary Table 1 is available online.

In order to differentiate prognostic subgroups of patients with aggressive B-cell lymphoma, we analyzed the expression of 800 miRNAs with the NanoString nCounter human miRNA assay on a cohort of 228 FFPE samples of patients enrolled in the RICOVER-60 and MegaCHOEP trials. We identified significant miRNA signatures for overall survival (OS) and progression-free survival (PFS) by LASSO-penalized linear Cox-regression. High expression levels of miR-130a-3p and miR-423-5p indicate a better prognosis, whereas high levels of miR-374b-5p, miR-590-5p, miR-186-5p, and miR-106b-5p increase patients' risk levels for OS. Regarding PFS high expression of miR-365a-5p in addition to the other two miRNAs improves the prognosis and high levels of miR374a-5p, miR-106b-5p, and miR-590-5p, connects with increased risk and poor prognosis. We identified miRNA signatures to subdivide patients into two different risk groups. These prognostic models may be used in risk stratification in future clinical trials and help making personalized therapy decisions.

Background: Excessively high joint loading during dynamic movements may negatively influence articular cartilage health and contribute to the development of posttraumatic osteoarthritis after anterior cruciate ligament reconstruction (ACLR). Little is known regarding the link between aberrant jump-landing biomechanics and articular cartilage health after ACLR. Purpose/Hypothesis: The purpose of this study was to determine the associations between jump-landing biomechanics and tibiofemoral articular cartilage composition measured using T1ρ magnetic resonance imaging (MRI) relaxation times 12 months postoperatively. We hypothesized that individuals who demonstrate alterations in jump-landing biomechanics, commonly observed after ACLR, would have longer T1ρ MRI relaxation times (longer T1ρ relaxation times associated with less proteoglycan density). Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 27 individuals with unilateral ACLR participated in this cross-sectional study. Jump-landing biomechanics (peak vertical ground-reaction force [vGRF], peak internal knee extension moment [KEM], peak internal knee adduction moment [KAM]) and T1ρ MRI were collected 12 months postoperatively. Mean T1ρ relaxation times for the entire weightbearing medial femoral condyle, lateral femoral condyle (global LFC), medial tibial condyle, and lateral tibial condyle (global LTC) were calculated bilaterally. Global regions of interest were further subsectioned into posterior, central, and anterior regions of interest. All T1ρ relaxation times in the ACLR limb were normalized to the uninjured contralateral limb. Linear regressions were used to determine associations between T1ρ relaxation times and biomechanics after accounting for meniscal/chondral injury. Results: Lower ACLR limb KEM was associated with longer T1ρ relaxation times for the global LTC (Δ R 2 = 0.24; P = .02), posterior LTC (Δ R 2 = 0.21; P = .03), and anterior LTC (Δ R 2 = 0.18; P = .04). Greater ACLR limb peak vGRF was associated with longer T1ρ relaxation times for the global LFC (Δ R 2 = 0.20; P = .02) and central LFC (Δ R 2 = 0.15; P = .05). Peak KAM was not associated with T1ρ outcomes. Conclusion: At 12 months postoperatively, lower peak KEM and greater peak vGRF during jump landing were related to longer T1ρ relaxation times, suggesting worse articular cartilage composition.

Interest in animal cell-based meat (ACBM) or laboratory-grown meat has been increasing, however, the economic viability of these potential products has not been thoroughly vetted. Recent studies suggest monoclonal antibody production technology can be adapted for the industrialization of ACBM production. This study provides a scenario-based assessment of the projected cost per kilogram of ACBM produced in the United States based on cellular metabolic requirements and process/chemical engineering conventions. A sensitivity analysis of the model identified the nine most influential cost factors for ACBM production out of 67 initial parameters. The results indicate that technological performance will need to approach technical limits for ACBM to achieve profitably as a commodity. However, the model also suggests that low-volume high-value specialty products could be viable based on current technology.

Significance Much of Earth’s volcanism occurs in the deep sea, yet little is known about the microbial communities inhabiting such extreme and dynamic systems. Using a multidisciplinary approach to study distinct hydrothermal systems at Brothers submarine arc volcano, we provide insights into how microbial community composition and function reflect subtly different fluid chemistries resulting from subsurface fluid interactions with distinct alteration mineral assemblages. These variations can be traced to the subsurface hydrogeologic history beneath Brothers volcano. Further, we show that these systems represent oases of phylogenetically diverse Archaea and Bacteria. Our findings highlight the importance of geologic legacy in understanding drivers of microbial diversity, assembly, and evolution and may have insights into processes that drove early diversification of life on Earth., Hydrothermally active submarine volcanoes are mineral-rich biological oases contributing significantly to chemical fluxes in the deep sea, yet little is known about the microbial communities inhabiting these systems. Here we investigate the diversity of microbial life in hydrothermal deposits and their metagenomics-inferred physiology in light of the geological history and resulting hydrothermal fluid paths in the subsurface of Brothers submarine volcano north of New Zealand on the southern Kermadec arc. From metagenome-assembled genomes we identified over 90 putative bacterial and archaeal genomic families and nearly 300 previously unknown genera, many potentially endemic to this submarine volcanic environment. While magmatically influenced hydrothermal systems on the volcanic resurgent cones of Brothers volcano harbor communities of thermoacidophiles and diverse members of the superphylum “DPANN,” two distinct communities are associated with the caldera wall, likely shaped by two different types of hydrothermal circulation. The communities whose phylogenetic diversity primarily aligns with that of the cone sites and magmatically influenced hydrothermal systems elsewhere are characterized predominately by anaerobic metabolisms. These populations are probably maintained by fluids with greater magmatic inputs that have interacted with different (deeper) previously altered mineral assemblages. However, proximal (a few meters distant) communities with gene-inferred aerobic, microaerophilic, and anaerobic metabolisms are likely supported by shallower seawater-dominated circulation. Furthermore, mixing of fluids from these two distinct hydrothermal circulation systems may have an underlying imprint on the high microbial phylogenomic diversity. Collectively our results highlight the importance of considering geologic evolution and history of subsurface processes in studying microbial colonization and community dynamics in volcanic environments.

Background Explosive outbursts occur in 25%-70% of children with Tourette syndrome (TS) and may cause more distress than the tics themselves. Previous studies have indicated that a comorbid diagnosis of attention-deficit/hyperactivity disorder (ADHD) is associated with emotional dysregulation in TS; however, this relationship has almost exclusively been studied using parent-reported questionnaires. Methods We examined emotion regulation (ER) with an observational measure in 150 medication-naive children aged 7-12 allocated to four groups: Forty-nine children with TS, 23 children with ADHD, 16 children with TS + ADHD, and 62 typically developing controls. We assessed participants' ER ability, as well as parent-child interactions in the context of a complex puzzle task, and coded the observed behavior with the Tangram Emotion Coding Manual (TEC-M). We examined group differences in ER, as well as associations between ER and severity of symptoms pertaining to TS and ADHD. Results Children with TS did not differ from controls in their ER ability. However, children with ADHD and TS + ADHD had more problems with ER than those with TS only and controls. Finally, parents of children with ADHD displayed more tension during the experimental task. ER ability was not associated with tic severity nor premonitory urges; however, better ER ability was associated with less severe symptoms of ADHD. Conclusions This study is the first to evaluate ER with an observational, clinician-rated measure in a controlled social setting in children with TS. Our findings support earlier questionnaire-based studies by showing impaired ER in children with TS + ADHD, but not in children with TS without comorbidity. These findings inform our understanding of the phenomenology of emotional dysregulation in TS and the role of comorbid disorders.

Halobacteria (henceforth: Haloarchaea) are predominantly aerobic halophiles that are thought to have evolved from anaerobic methanogens. This remarkable transformation most likely involved an extensive influx of bacterial genes. Whether it entailed a single massive transfer event or a gradual stream of transfers remains a matter of debate. To address this, genomes that descend from methanogen-to-halophile intermediates are necessary. Here, we present five such near-complete genomes of Marine Group IV archaea (Hikarchaeia), the closest known relatives of Haloarchaea. Their inclusion in gene tree-aware ancestral reconstructions reveals an intermediate stage that had already lost a large number of genes, including nearly all of those involved in methanogenesis and the Wood-Ljungdahl pathway. In contrast, the last Haloarchaea common ancestor gained a large number of genes and expanded its aerobic respiration and salt/UV resistance gene repertoire. Our results suggest that complex and gradual patterns of gain and loss shaped the methanogen-to-halophile transition., A study of the first genomes of the marine Hikarchaeia, the closest known relatives of Haloarchaea, is presented. Their inclusion in ancestral reconstructions unveils an intermediate stage in the evolutionary transition from ancestral anaerobic methanogens to modern day aerobic halophiles.

Identifying the structures of the lateral knee is critical during knee posterolateral corner reconstruction. Several methods exist that can help estimate the femoral insertions of these structures on lateral radiographs. However, it is important to recognize the limitations of these methods and that anatomic visualization is often more practical and more accurate. Until percutaneous or more minimally invasive techniques become standardized, intraoperative fluoroscopy is seldom needed or used for posterolateral corner reconstruction, whereas radiographic analysis of lateral knee structures could be of benefit in cases of failed reconstruction to assess tunnel placement.

Burkitt lymphoma is a mature aggressive B-cell lymphoma derived from germinal center B cells(1). Its cytogenetic hallmark is the Burkitt translocation t(8;14)(q24;q32) and its variants, which juxtapose the MYC oncogene with one of the three immunoglobulin loci(2). Consequently, MYC is deregulated, resulting in massive perturbation of gene expression(3). Nevertheless, MYC deregulation alone seems not to be sufficient to drive Burkitt lymphomagenesis. By whole-genome, whole-exome and transcriptome sequencing of four prototypical Burkitt lymphomas with immunoglobulin gene (IG)-MYC translocation, we identified seven recurrently mutated genes. One of these genes, ID3, mapped to a region of focal homozygous loss in Burkitt lymphoma(4). In an extended cohort, 36 of 53 molecularly defined Burkitt lymphomas (68%) carried potentially damaging mutations of ID3. These were strongly enriched at somatic hypermutation motifs. Only 6 of 47 other B-cell lymphomas with the IG-MYC translocation (13%) carried ID3 mutations. These findings suggest that cooperation between ID3 inactivation and IG-MYC translocation is a hallmark of Burkitt lymphomagenesis.

The recently discovered DPANN archaea are a potentially deep-branching, monophyletic radiation of organisms with small cells and genomes. However, the monophyly and early emergence of the various DPANN clades and their role in life’s evolution are debated. Here, we reconstructed and analysed genomes of an uncharacterized archaeal phylum (Candidatus Undinarchaeota), revealing that its members have small genomes and, while potentially being able to conserve energy through fermentation, likely depend on partner organisms for the acquisition of certain metabolites. Our phylogenomic analyses robustly place Undinarchaeota as an independent lineage between two highly supported ‘DPANN’ clans. Further, our analyses suggest that DPANN have exchanged core genes with their hosts, adding to the difficulty of placing DPANN in the tree of life. This pattern can be sufficiently dominant to allow identifying known symbiont-host clades based on routes of gene transfer. Together, our work provides insights into the origins and evolution of DPANN and their hosts., The evolutionary relationships within Archaea remain unresolved. Here, the authors used genomic approaches to study the Undinarchaeota, a previously uncharacterized clade of DPANN, shed light on their position in an updated archaeal phylogeny and illuminate the history of archaeal genome evolution.

Reconstructing ancestral bacteria The origin of the eubacteria and phylogenetic relationships between subgroups have been difficult to resolve. Applying a phylogenetic analysis and recent computational methods to the expanded diversity of bacterial sequences from metagenomic analyses, Coleman et al. infer the root of the eubacterial tree (see the Perspective by Katz). The root was determined without using the Archaea as an outgroup, to avoid the possibility of a false result due to long branch attraction. This method places the eubacterial root in the neighborhood of Fusobacteriota. Using this information, the authors reconstructed the eubacterial ancestor, identifying that this organism likely had a double-membrane cell envelope, flagellum-mediated motility, antiphage defense mechanisms, and diverse metabolic pathways. Science , this issue p. eabe0511 ; see also p. 574

Background: There is a lack of evidence regarding the optimum extensor-sided fixation method for medial patellofemoral ligament (MPFL) reconstruction. There is increased interest in avoiding patellar drilling via soft tissue–only fixation to the distal quadriceps, thus reconstructing the medial quadriceps tendon–femoral ligament (MQTFL). The biomechanical implications of differing extensor-sided fixation constructs remain unknown. Hypothesis: The null hypothesis was there would be no differences between traditional MPFL reconstruction and MQTFL reconstruction with respect to resistance to lateral translation, patellar position, or patellofemoral contact pressures. Study Design: Controlled laboratory study. Methods: Nine adult knee specimens were mounted on a jig that applied static, physiologic loads to the quadriceps tendons. Patellar position and orientation, knee flexion angle, and patellofemoral pressure were recorded at 8 different flexion angles between 0° and 110°. Additionally, a lateral patellar excursion test was conducted wherein a load was applied directly to the patella in the lateral direction with the knee at 30° of flexion and subjected to 2-N quadriceps loads. Testing was conducted under 4 conditions: intact, transected MPFL, MQTFL reconstruction, and MPFL reconstruction. For MQTFL reconstruction, the surgical technique established by Fulkerson was employed. For MPFL reconstruction, a traditional technique was utilized. Results: The patellar excursion test showed no significant difference between the MQTFL and intact states with respect to lateral translation. MPFL reconstruction led to significantly less lateral translation ( P < .05) than all other states. There were no significant differences between MPFL and MQTFL reconstructions with respect to peak patellofemoral contact pressure. MPFL and MQTFL reconstructions both resulted in increased internal rotation of the patella with the knee in full extension. Conclusion: Soft tissue-only extensor-sided fixation to the distal quadriceps (MQTFL) during patella stabilization appears to re-create native stability in this time 0 cadaver model. Fixation to the patella (MPFL) was associated with increased resistance to lateral translation. Clinical Relevance: Evolving anatomic knowledge and concern for patellar fracture has led to increased interest in MQTFL reconstruction. Both MQTFL and MPFL reconstructions restored patellofemoral stability to lateral translation without increasing contact pressures under appropriate graft tensioning, with MQTFL more closely restoring native resistance to lateral translation at the time of surgery.

Purpose Manufacturing processes for polypeptide/protein drugs are designed to ensure robust quality, efficacy and safety. Process differences introduced by follow-on manufacturers may result in changes in quality and clinical outcomes. This study investigated the impact of production methods on the stability and impurities of liraglutide and semaglutide drug substances/products, and the potential impact on drug quality, efficacy and safety. Methods State-of-the-art analytical methods were used to compare physical and chemical stability, and impurity profiles of drug substances/products from different suppliers. Identified polypeptide-related impurities were evaluated for immunogenicity potential by in silico T cell epitope prediction. Semaglutide immunogenicity in clinical trials (SUSTAIN) was evaluated using a tiered antibody analysis. Results Manufacturing scale and process strongly impacted the physical stability of the products. Trace metals increased high-molecular-weight protein formation for liraglutide and semaglutide. Synthetic and recombinant liraglutide produced by five suppliers had distinct impurity profiles compared with the originator. In silico evaluation suggested that new impurities could be immunogenic. Immunogenicity of semaglutide in clinical trials was lower than for liraglutide. Conclusions Differences in manufacturing processes affect chemical/physical stability and impurity profile, and may impact immunogenicity. Follow-on versions of liraglutide and semaglutide, and possibly other polypeptides, should be clinically evaluated for efficacy and safety.