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BACKGROUND: Patients hospitalized with COVID-19 can clinically deteriorate after a period of initial stability, making optimal timing of discharge a clinical and operational challenge. OBJECTIVE: To determine risks for post-discharge readmission and death among patients hospitalized with COVID-19. DESIGN: Multicenter retrospective observational cohort study, 2020-2021, with 30-day follow-up. PARTICIPANTS: Adults admitted for care of COVID-19 respiratory disease between March 2, 2020, and February 11, 2021, to one of 180 US hospitals affiliated with the HCA Healthcare system. MAIN MEASURES: Readmission to or death at an HCA hospital within 30 days of discharge was assessed. The area under the receiver operating characteristic curve (AUC) was calculated using an internal validation set (33% of the HCA cohort), and external validation was performed using similar data from six academic centers associated with a hospital medicine research network (HOMERuN). KEY RESULTS: The final HCA cohort included 62,195 patients (mean age 61.9 years, 51.9% male), of whom 4704 (7.6%) were readmitted or died within 30 days of discharge. Independent risk factors for death or readmission included fever within 72 h of discharge; tachypnea, tachycardia, or lack of improvement in oxygen requirement in the last 24 h; lymphopenia or thrombocytopenia at the time of discharge; being ≤ 7 days since first positive test for SARS-CoV-2; HOSPITAL readmission risk score ≥ 5; and several comorbidities. Inpatient treatment with remdesivir or anticoagulation were associated with lower odds. The models AUC for the internal validation set was 0.73 (95% CI 0.71-0.74) and 0.66 (95% CI 0.64 to 0.67) for the external validation set. CONCLUSIONS: This large retrospective study identified several factors associated with post-discharge readmission or death in models which performed with good discrimination. Patients 7 or fewer days since test positivity and who demonstrate potentially reversible risk factors may benefit from delaying discharge until those risk factors resolve.

Abstract Background Early pregnancy Zika virus (ZIKV) infection is associated with major brain damage in fetuses, leading to microcephaly in 0.6–5.0% of cases, but the underlying mechanisms remain largely unknown. Methods To understand the kinetics of ZIKV infection during fetal development in a nonhuman primate model, four cynomolgus macaque fetuses were exposed in utero through echo-guided intramuscular inoculation with 103 PFU of ZIKV at 70–80 days of gestation, 2 controls were mock inoculated. Clinical, immuno-virological and ultrasound imaging follow-ups of the mother/fetus pairs were performed until autopsy after cesarean section 1 or 2 months after exposure (n = 3 per group). Results ZIKV was transmitted from the fetus to the mother and then replicate in the peripheral blood of the mother from week 1 to 4 postexposure. Infected fetal brains tended to be smaller than those of controls, but not the femur lengths. High level of viral RNA ws found after the first month in brain tissues and placenta. Thereafter, there was partial control of the virus in the fetus, resulting in a decreased number of infected tissue sections and a decreased viral load. Immune cellular and humoral responses were effectively induced. Conclusions ZIKV infection during the second trimester of gestation induces short-term brain injury, and although viral genomes persist in tissues, most of the virus is cleared before delivery.

AbstractIn a retrospective metatranscriptomics study, we identified tick-borne encephalitis virus (TBEV) to be the causative agent for a fatal non-suppurative meningoencephalitis in a three-week-old Dalmatian puppy in Switzerland. Further investigations showed that the two other littermates with similar signs and pathological lesions were also positive for TBEV. By using an unbiased approach of combining high-throughput sequencing (HTS) and bioinformatics we were able to solve the etiology and discover an unusual case of TBEV in three young puppies. Based on our findings, we suggest that a vector-independent transmission of TBEV occurred and that most likely an intrauterine infection led to the severe and fulminant disease of the entire litter. We were able to demonstrate the presence of TBEV RNA by in situ hybridization (ISH) in the brain of all three puppies. Furthermore, we were able to detect TBEV by RT-qPCR in total RNA extracted from formalin-fixed and paraffin embedded (FFPE) blocks containing multiple peripheral organs. Overall, our findings shed light on alternative vector-independent transmission routes of TBEV infections in dogs and encourage veterinary practitioners to consider TBEV as an important differential diagnosis in neurological cases in dogs.

Background Altered structural brain development has been identified in fetuses with congenital heart disease (CHD), suggesting that the neurodevelopmental impairment observed later in life might originate in utero. There are many interacting factors that may perturb neurodevelopment during the fetal period and manifest as structural brain alterations, such as altered cerebral substrate delivery and aberrant fetal hemodynamics. Methods and Results We extracted structural covariance networks from the log Jacobian determinants of 435 in utero T2 weighted image magnetic resonance imaging scans, (n=67 controls, 368 with CHD) acquired during the third trimester. We fit general linear models to test whether age, sex, expected cerebral substrate delivery, and CHD diagnosis were significant predictors of structural covariance. We identified significant effects of age, sex, cerebral substrate delivery, and specific CHD diagnosis across a variety of structural covariance networks, including primary motor and sensory cortices, cerebellar regions, frontal cortex, extra‐axial cerebrospinal fluid, thalamus, brainstem, and insula, consistent with widespread coordinated aberrant maturation of specific brain regions over the third trimester. Conclusions Structural covariance networks offer a sensitive, data‐driven approach to explore whole‐brain structural changes without anatomical priors. We used them to stratify a heterogenous patient cohort with CHD, highlighting similarities and differences between diagnoses during fetal neurodevelopment. Although there was a clear effect of abnormal fetal hemodynamics on structural brain maturation, our results suggest that this alone does not explain all the variation in brain development between individuals with CHD.

Abstract Structural fetal body MRI provides true 3D information required for volumetry of fetal organs. However, current clinical and research practice primarily relies on manual slice-wise segmentation of raw T2-weighted stacks, which is time consuming, subject to inter- and intra-observer bias and affected by motion-corruption. Furthermore, there are no existing standard guidelines defining a universal approach to parcellation of fetal organs. This work produces the first parcellation protocol of the fetal body organs for motion-corrected 3D fetal body MRI. It includes 10 organ ROIs relevant to fetal quantitative volumetry studies. We also introduce the first population-averaged T2w MRI atlas of the fetal body. The protocol was used as a basis for training of a neural network for automated organ segmentation. It showed robust performance for different gestational ages. This solution minimises the need for manual editing and significantly reduces time. The general feasibility of the proposed pipeline was also assessed by analysis of organ growth charts created from automated parcellations of 91 normal control 3T MRI datasets that showed expected increase in volumetry during 22–38 weeks gestational age range.

Abstract The stronger people hold self-enhancing (that is, egoistic or hedonic) values, the less they tend agree with pro-environmental efforts. An exploratory (N = 901) and a confirmatory study (N = 404) examined the effectiveness of pro-environmental messages matched to individuals' values. Findings indicate that strong endorsement of self-transcendent (that is, altruistic or biospheric) values is associated with unspecific endorsement of pro-environmental messages, while individuals endorsing self-enhancement values respond positively only to value-matched appeals.

Abstract This study explores the potential of 3D Slice-to-Volume Registration (SVR) motion-corrected fetal MRI for craniofacial assessment, traditionally used only for fetal brain analysis. In addition, we present the first description of an automated pipeline based on 3D Attention UNet trained for 3D fetal MRI craniofacial segmentation, followed by surface refinement. Results of 3D printing of selected models are also presented. Qualitative analysis of multiplanar volumes, based on the SVR output and surface segmentations outputs, were assessed with computer and printed models, using standardised protocols that we developed for evaluating image quality and visibility of diagnostic craniofacial features. A test set of 25, postnatally confirmed, Trisomy 21 fetal cases (24–36 weeks gestational age), revealed that 3D reconstructed T2 SVR images provided 66–100% visibility of relevant craniofacial and head structures in the SVR output, and 20–100% and 60–90% anatomical visibility was seen for the baseline and refined 3D computer surface model outputs respectively. Furthermore, 12 of 25 cases, 48%, of refined surface models demonstrated good or excellent overall quality with a further 9 cases, 36%, demonstrating moderate quality to include facial, scalp and external ears. Additional 3D printing of 12 physical real-size models (20–36 weeks gestational age) revealed good/excellent overall quality in all cases and distinguishable features between healthy control cases and cases with confirmed anomalies, with only minor manual adjustments required before 3D printing. Despite varying image quality and data heterogeneity, 3D T2w SVR reconstructions and models provided sufficient resolution for the subjective characterisation of subtle craniofacial features. We also contributed a publicly accessible online 3D T2w MRI atlas of the fetal head, validated for accurate representation of normal fetal anatomy. Future research will focus on quantitative analysis, optimizing the pipeline, and exploring diagnostic, counselling, and educational applications in fetal craniofacial assessment.

In recent years, mathematical models of decision making, such as the diffusion model, have been endorsed in individual differences research. These models can disentangle different components of the decision process, like processing speed, speed-accuracy trade-offs, and duration of non-decisional processes. The diffusion model estimates individual parameters of cognitive process components, thus allowing the study of individual differences. These parameters are often assumed to show trait-like properties, that is, within-person stability across tasks and time. However, the assumption of temporal stability has so far been insufficiently investigated. With this work, we explore stability and change in diffusion model parameters by following over 270 participants across a time period of two years. We analysed four different aspects of stability and change: rank-order stability, mean-level change, individual differences in change, and profile stability. Diffusion model parameters showed strong rank-order stability and mean-level changes in processing speed and speed-accuracy trade-offs that could be attributed to practice effects. At the same time, people differed little in these patterns across time. In addition, profiles of individual diffusion model parameters proved to be stable over time. We discuss implications of these findings for the use of the diffusion model in individual differences research.

[This corrects the article DOI: 10.1158/2767-9764.CRC-21-0060.][This corrects the article DOI: 10.1158/2767-9764.CRC-21-0060.].

7SK non-coding RNA (7SK) negatively regulates RNA polymerase II (RNA Pol II) elongation by inhibiting positive transcription elongation factor b (P-TEFb), and its ribonucleoprotein complex (RNP) is hijacked by HIV-1 for viral transcription and replication. Methylphosphate capping enzyme (MePCE) and La-related protein 7 (Larp7) constitutively associate with 7SK to form a core RNP, while P-TEFb and other proteins dynamically assemble to form different complexes. Here, we present the cryo-EM structures of 7SK core RNP formed with two 7SK conformations, circular and linear, and uncover a common RNA-dependent MePCE-Larp7 complex. Together with NMR, biochemical, and cellular data, these structures reveal the mechanism of MePCE catalytic inactivation in the core RNP, unexpected interactions between Larp7 and RNA that facilitate a role as an RNP chaperone, and that MePCE-7SK-Larp7 core RNP serves as a scaffold for switching between different 7SK conformations essential for RNP assembly and regulation of P-TEFb sequestration and release.

The EU and other states have made legislative efforts to clarify data mining in copyrightable works, but the situation remains obscure and confusing, especially in a globalised field where international legislation can contribute to opacity. The present paper aims at asserting a common position of three communities representing biodiversity sciences and data specialists on this issue and to propose common and best practice guidelines so that they become universally accepted rules.As scientific data users, we take the standpoint that scientific data are not copyrightable and, furthermore, they can be accessed, shared and reused freely. Thus, once legal access has been gained to copyrighted publications, the data within those scholarly publications can be considered to be open data that is freely extractable. This set of recommendations has been reached specifically for scientific use and societal benefits.

Abstract Background Little is known about knee mechanics and muscle control after augmented ACL repair. Our aim was to compare knee biomechanics and leg muscle activity during walking between the legs of patients 2 years after InternalBraceTM-augmented anterior cruciate ligament repair (ACL-IB) and between patients after ACL-IB and ACL reconstruction (ACL-R), and controls. Methods Twenty-nine ACL-IB, 27 sex- and age-matched ACL-R (hamstring tendon autograft) and 29 matched controls completed an instrumented gait analysis. Knee joint angles, moments, power, and leg muscle activity were compared between the involved and uninvolved leg in ACL-IB (paired t-tests), and between the involved legs in ACL patients and the non-dominant leg in controls (analysis of variance and posthoc Bonferroni tests) using statistical parametric mapping (SPM, P uninvolved) and maximum knee flexion moment during stance (-0.07Nm/kg, CI [-0.13;-0.00]; involved ACL-R). Compared to controls, ACL-IB (SPM: 0–3%GC, P = 0.015; 98–100%, P = 0.016; DP: -6.3 mm, CI [-11.7;-0.8]) and ACL-R (DP: -6.0 mm, CI [-11.4;-0.2]) had lower (maximum) anterior tibia position around heel strike. ACL-R also had lower maximum knee extension moment (DP: -0.13Nm/kg, CI [-0.23;-0.02]) and internal knee rotation moment (SPM: 34–41%GC, P

Abstract Background While clinical and patient-reported outcomes have been investigated in patients after InternalBrace™-augmented anterior cruciate ligament repair (ACL-IB), less is known regarding restoration of functional performance. We aimed to determine differences in functional performance within and between patients 2 years after ACL-IB, patients 2 years after ACL reconstruction (ACL-R), and healthy controls. Materials and Methods A total of 29 ACL-IB, 27 ACL-R (hamstring autograft), and 29 controls performed single-leg hop (maximum forward distance hop, SLH; side hop > 40 cm in 30 s, SH), proprioception (knee joint position sense at 30° and 60° flexion), and dynamic postural balance (Y Balance) tests. Differences were calculated within groups (side-to-side difference) and between the involved leg of patients and the non-dominant leg of controls, and were evaluated to predefined statistical (P

Oral leukoplakia is common and may, in some cases, progress to carcinoma. Proliferative leukoplakia is a progressive, often multifocal subtype with a high rate of malignant transformation compared with the more common localized leukoplakia. We hypothesized that the immune microenvironment and gene expression patterns would be distinct for proliferative leukoplakia compared with localized leukoplakia. We summarize key clinicopathologic features among proliferative leukoplakia and localized leukoplakia and compare cancer-free survival (CFS) between subgroups. We analyze immunologic gene expression profiling in proliferative leukoplakia and localized leukoplakia tissue samples (NanoString PanCancer Immune Oncology Profiling). We integrate immune cell activation and spatial distribution patterns in tissue samples using multiplexed immunofluorescence and digital image capture to further define proliferative leukoplakia and localized leukoplakia. Among N = 58 patients (proliferative leukoplakia, n = 29; localized leukoplakia, n = 29), only the clinical diagnosis of proliferative leukoplakia was associated with significantly decreased CFS (HR, 11.25; P < 0.01; 5-year CFS 46.8% and 83.6% among patients with proliferative leukoplakia and localized leukoplakia, respectively). CD8+ T cells and T regulatory (Treg) were more abundant among proliferative leukoplakia samples (P < 0.01) regardless of degree of epithelial dysplasia, and often colocalized to the dysplasia-stromal interface. Gene set analysis identified granzyme M as the most differentially expressed gene favoring the proliferative leukoplakia subgroup (log2 fold change, 1.93; P adj < 0.001). Programmed death ligand 1 (PD-L1) was comparatively overexpressed among proliferative leukoplakia samples, with higher (>5) PD-L1 scores predicting worse CFS (P adj < 0.01). Proliferative leukoplakia predicts a high rate of malignant transformation within 5 years of diagnosis. A prominent CD8+ T-cell and Treg signature along with relative PD-L1 overexpression compared with localized leukoplakia provides strong rationale for PD-1/PD-L1 axis blockade using preventative immunotherapy.SignificanceThis is the first in-depth profiling effort to immunologically characterize high-risk proliferative leukoplakia as compared with the more common localized leukoplakia. We observed a notable cytotoxic T-cell and Treg signature with relative overexpression of PD-L1 in high-risk proliferative leukoplakia providing a strong preclinical rationale for investigating PD-1/PD-L1 axis blockade in this disease as preventative immunotherapy.

Teachers' beliefs about teaching have been found to affect students' learning growth. The aim of this study was to investigate effects of teachers' constructivist and direct-transmissive beliefs on learners' reading progress and whether these effects are influenced by students' ability. We measured constructivist and direct-transmissive beliefs of 29 teachers and the progress in reading fluency and reading comprehension of their students (N = 568) at eight points of measurement over one school year. Results of three-level latent growth curve modeling revealed that only teachers' global, but not reading specific constructivist beliefs, were generally positively related to learners' progress in reading fluency. Beliefs about teaching had no general effect on growth in reading comprehension, but the relation between constructivist beliefs and students' progress in reading comprehension was affected by students' prior skills. Teachers with stronger constructivist beliefs effected higher learning growth for high ability compared to low ability learners within their classrooms. No effects were found for direct-transmissive beliefs. This study adds a more differentiated view to findings concerning the effects of teacher beliefs by showing that effects vary depending on the skill under study (fluency vs. comprehension), and that effects of teacher beliefs may depend on students' ability.

Background This study aimed to quantify the mechanoresponse of 10 blood marker candidates for joint metabolism to a walking stress test in patients with knee osteoarthritis and to determine the association among marker kinetics and with accumulated load and patient reported outcomes. Methods 24 patients with knee osteoarthritis completed questionnaires, and a 30-minute walking stress test with six blood serum samples and gait analysis. Concentrations of cartilage oligomeric matrix protein (COMP), matrix metalloproteinases (MMP)-1, -3, and -9, epitope resulting from cleavage of type II collagen by collagenases (C2C), type II procollagen (CPII), interleukin (IL)-6, proteoglycan (PRG)-4, A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and resistin were determined by enzyme-linked immunosorbent assays, Joint load (moments and compartmental forces) was estimated using musculoskeletal modeling using gait analysis data. Results COMP and MMP-3 showed an immediate increase after the walking stress followed by a decrease. MMP-9 and resistin showed a delayed decrease below pre-stress levels. ∆COMP correlated with ∆MMP-3 for most time points. ∆MMP-9 correlated with ∆resistin for most time points. The load-induced increase in blood marker levels correlated among blood markers and time points. C2C and resistin correlated positively and C2C/CPII and MMP2 correlated negatively with load during gait. Immediate relative ∆CPII and ∆MMP1 and delayed relative ∆COMP, ∆IL6, ∆C2C, ∆CPII, ∆MMP1 and ∆MMP3 correlated with the load accumulated during the walking stress. Baseline C2C levels correlated with Knee Osteoarthritis Outcome Score (KOOS) subscales and load-induced changes in MMP-3 with KOOS and Short Form 36 quality of life subscores (P

IntroductionUltra-high field MR imaging offers marked gains in signal-to-noise ratio, spatial resolution, and contrast which translate to improved pathological and anatomical sensitivity. These benefits are particularly relevant for the neonatal brain which is rapidly developing and sensitive to injury. However, experience of imaging neonates at 7T has been limited due to regulatory, safety, and practical considerations. We aimed to establish a program for safely acquiring high resolution and contrast brain images from neonates on a 7T system.MethodsImages were acquired from 35 neonates on 44 occasions (median age 39 + 6 postmenstrual weeks, range 33 + 4 to 52 + 6; median body weight 2.93 kg, range 1.57 to 5.3 kg) over a median time of 49 mins 30 s. Peripheral body temperature and physiological measures were recorded throughout scanning. Acquired sequences included T2 weighted (TSE), Actual Flip angle Imaging (AFI), functional MRI (BOLD EPI), susceptibility weighted imaging (SWI), and MR spectroscopy (STEAM).ResultsThere was no significant difference between temperature before and after scanning (p = 0.76) and image quality assessment compared favorably to state-of-the-art 3T acquisitions. Anatomical imaging demonstrated excellent sensitivity to structures which are typically hard to visualize at lower field strengths including the hippocampus, cerebellum, and vasculature. Images were also acquired with contrast mechanisms which are enhanced at ultra-high field including susceptibility weighted imaging, functional MRI, and MR spectroscopy.DiscussionWe demonstrate safety and feasibility of imaging vulnerable neonates at ultra-high field and highlight the untapped potential for providing important new insights into brain development and pathological processes during this critical phase of early life.

PurposePembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)-unrelated HNSCC.Patients and methodsNeoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation. Postoperative (chemo)radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) received adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (

Abstract Background Trait anxiety refers to a stable tendency to experience fears and worries across many situations. High trait anxiety is a vulnerability factor for the development of psychopathologies. Self-reported trait anxiety appears to be associated with an automatic processing advantage for threat-related information. Self-report measures assess aspects of the explicit self-concept of anxiety. Indirect measures can tap into the implicit self-concept of anxiety. Methods We examined automatic brain responsiveness to non-conscious threat as a function of trait anxiety using functional magnetic resonance imaging. Besides a self-report instrument, we administered the Implicit Association Test (IAT) to assess anxiety. We used a gender-decision paradigm presenting brief (17 ms) and backward-masked facial expressions depicting disgust and fear. Results Explicit trait anxiety was not associated with brain responsiveness to non-conscious threat. However, a relation of the implicit self-concept of anxiety with masked fear processing in the thalamus, precentral gyrus, and lateral prefrontal cortex was observed. Conclusions We provide evidence that a measure of the implicit self-concept of anxiety is a valuable predictor of automatic neural responses to threat in cortical and subcortical areas. Hence, implicit anxiety measures could be a useful addition to explicit instruments. Our data support the notion that the thalamus may constitute an important neural substrate in biased non-conscious processing in anxiety.

Abstract Background Image-domain motion correction of black-blood contrast T2-weighted fetal cardiovascular magnetic resonance imaging (CMR) using slice-to-volume registration (SVR) provides high-resolution three-dimensional (3D) images of the fetal heart providing excellent 3D visualisation of vascular anomalies [1]. However, 3D segmentation of these datasets, important for both clinical reporting and the application of advanced analysis techniques is currently a time-consuming process requiring manual input with potential for inter-user variability. Methods In this work, we present novel 3D fetal CMR population-averaged atlases of normal and abnormal fetal cardiovascular anatomy. The atlases are created using motion-corrected 3D reconstructed volumes of 86 third trimester fetuses (gestational age range 29-34 weeks) including: 28 healthy controls, 20 cases with postnatally confirmed neonatal coarctation of the aorta (CoA) and 38 vascular rings (21 right aortic arch (RAA), 17 double aortic arch (DAA)). We used only high image quality datasets with isolated anomalies and without any other deviations in the cardiovascular anatomy.In addition, we implemented and evaluated atlas-guided registration and deep learning (UNETR) methods for automated 3D multi-label segmentation of fetal cardiac vessels. We used images from CoA, RAA and DAA cohorts including: 42 cases for training (14 from each cohort), 3 for validation and 6 for testing. In addition, the potential limitations of the network were investigated on unseen datasets including 3 early gestational age (22 weeks) and 3 low SNR cases. Results We created four atlases representing the average anatomy of the normal fetal heart, postnatally confirmed neonatal CoA, RAA and DAA. Visual inspection was undertaken to verify expected anatomy per subgroup. The results of the multi-label cardiac vessel UNETR segmentation showed 100 $$\%$$ % per-vessel detection rate for both normal and abnormal aortic arch anatomy. Conclusions This work introduces the first set of 3D black-blood T2-weighted CMR atlases of normal and abnormal fetal cardiovascular anatomy including detailed segmentation of the major cardiovascular structures. Additionally, we demonstrated the general feasibility of using deep learning for multi-label vessel segmentation of 3D fetal CMR images.

Background Infants with congenital heart disease (CHD) are at risk of neurodevelopmental impairments, which may be associated with impaired brain growth. We characterized how perioperative brain growth in infants with CHD deviates from typical trajectories and assessed the relationship between individualized perioperative brain growth and clinical risk factors. Methods and Results A total of 36 infants with CHD underwent preoperative and postoperative brain magnetic resonance imaging. Regional brain volumes were extracted. Normative volumetric development curves were generated using data from 219 healthy infants. Z‐scores, representing the degree of positive or negative deviation from the normative mean for age and sex, were calculated for regional brain volumes from each infant with CHD before and after surgery. The degree of Z‐score change was correlated with clinical risk factors. Perioperative growth was impaired across the brain, and it was associated with longer postoperative intensive care stay (false discovery rate P

Abstract Background The redislocation rate of conservatively treated patella instability is high. One of the leading surgical strategies is medial patellofemoral ligament reconstruction. Over-tensioning is one of the most challenging complications in static medial patellofemoral ligament reconstruction as the graft used for reconstruction is isometric and the anatomical MPFL is a mostly dynamic structure. As an alternative to established static reconstruction techniques, dynamic graft techniques have been introduced for stabilizing the patella with the aim of providing a more physiological reconstruction of the medial patellofemoral ligament. To date, data on clinical outcomes are scarce and on biomechanical outcomes of the dynamic MPFL reconstruction are lacking. Here, we present the protocol of a randomized clinical trial for comparing clinical and biomechanical outcomes of dynamic versus static medial patellofemoral ligament reconstruction. Methods This study is a prospective, single blinded, randomized, multicenter, multimodal (clinical and biomechanical) clinical trial. Patients with recurrent patella dislocation requiring isolated MPFL reconstruction will be recruited and randomized to the dynamic or static reconstruction technique. Participants will be followed up for 2 years with a total of five follow-ups. Preoperative magnetic resonance imaging, upright radiographs, surgical reports and patient records will be evaluated, and clinical and functional outcomes will be measured. Patient-reported knee function and anterior knee pain as assessed with the Kujala score will serve as primary outcome. For biomechanical outcome, pre- and postoperative evaluations will be performed to assess isokinetic muscle strength, gait asymmetry, joint kinematics and kinetics, and timing of muscle activity. Discussion The results of the study will clarify whether the reported surgery success for patella stabilization via dynamic MPFL reconstruction is due to muscle contraction or to the passive tenodesis effect combined with clinical outcome measures. With this study, we will provide much needed information on knee biomechanics after dynamic versus static MPFL reconstruction to provide evidence to support orthopedic surgeons in evidence-based decision-making in their quest for surgical techniques most favorable for their patients. Trial registration The study protocol was registered at clinicaltrials.gov (NCT04849130). Registered 19 April 2021, https://clinicaltrials.gov/ct2/show/NCT04849130 .

Background High-risk human papillomavirus (HPV) is a primary cause of an increasing number of oropharyngeal squamous cell carcinomas (OPSCCs). The viral etiology of these cancers provides the opportunity for antigen-directed therapies that are restricted in scope compared with cancers without viral components. However, specific virally-encoded epitopes and their corresponding immune responses are not fully defined.Methods To understand the OPSCC immune landscape, we conducted a comprehensive single-cell analysis of HPV16+ and HPV33+ primary tumors and metastatic lymph nodes. We used single-cell analysis with encoded peptide-human leukocyte antigen (HLA) tetramers to analyze HPV16+ and HPV33+ OPSCC tumors, characterizing the ex vivo cellular responses to HPV-derived antigens presented in major Class I and Class II HLA alleles.Results We identified robust cytotoxic T-cell responses to HPV16 proteins E1 and E2 that were shared across multiple patients, particularly in HLA-A*01:01 and HLA-B*08:01. Responses to E2 were associated with loss of E2 expression in at least one tumor, indicating the functional capacity of these E2-recognizing T cells and many of these interactions validated in a functional assay. Conversely, cellular responses to E6 and E7 were limited in quantity and cytotoxic capacity, and tumor E6 and E7 expression persisted.Conclusions These data highlight antigenicity beyond HPV16 E6 and E7 and nominate candidates for antigen-directed therapies.