Influenza vaccine format mediates distinct cellular and antibody responses in human immune organoids.

Highly effective vaccines elicit specific, robust, and durable adaptive immune responses. To advance informed vaccine design, it is critical that we understand the cellular dynamics underlying responses to different antigen formats. Here, we sought to understand how antigen-specific B and T cells were activated and participated in adaptive immune responses within the mucosal site. Using a human tonsil organoid model, we tracked the differentiation and kinetics of the adaptive immune response to influenza vaccine and virus modalities. Each antigen format elicited distinct B and T cell responses, including differences in their magnitude, diversity, phenotype, function, and breadth. These differences culminated in substantial changes in the corresponding antibody response. A major source of antigen format-related variability was the ability to recruit naive vs. memory B and T cells to the response. These findings have important implications for vaccine design and the generation of protective immune responses in the upper respiratory tract.

Vaccination against SARS-CoV-2 using extracellular blebs derived from spike protein-expressing dendritic cells.

COVID-19 has caused significant morbidity and mortality worldwide but also accelerated the clinical use of emerging vaccine formulations. To address the current shortcomings in the prevention and treatment of SARS-CoV-2 infection, this study developed a novel vaccine platform that closely mimics dendritic cells (DCs) in antigen presentation and T-cell stimulation in a cell-free and tunable manner. Genetically engineered DCs that express the SARS-CoV-2 spike protein (S) were chemically converted into extracellular blebs (EBs). The resulting EBs elicited potentially protective humoral immunity in vivo, indicated by the production of antibodies that potently neutralized S-pseudotyped virus, presenting EBs as a promising and safe vaccine.

Engineering Protein Nanoparticles Functionalized with an Immunodominant Coxiella burnetii Antigen to Generate a Q Fever Vaccine.

Coxiella burnetii is the causative agent of Q fever, for which there is yet to be an FDA-approved vaccine. This bacterial pathogen has both extra- and intracellular stages in its life cycle, and therefore both a cell-mediated (i.e., T lymphocyte) and humoral (i.e., antibody) immune response are necessary for effective eradication of this pathogen. However, most proposed vaccines elicit strong responses to only one mechanism of adaptive immunity, and some can either cause reactogenicity or lack sufficient immunogenicity. In this work, we aim to apply a nanoparticle-based platform toward producing both antibody and T cell immune responses against C. burnetii. We investigated three approaches for conjugation of the immunodominant outer membrane protein antigen (CBU1910) to the E2 nanoparticle to obtain a consistent antigen orientation: direct genetic fusion, high affinity tris-NTA-Ni conjugation to polyhistidine-tagged CBU1910, and the SpyTag/SpyCatcher (ST/SC) system. Overall, we found that the ST/SC approach yielded nanoparticles loaded with the highest number of antigens while maintaining stability, enabling formulations that could simultaneously co-deliver the protein antigen (CBU1910) and adjuvant (CpG1826) on one nanoparticle (CBU1910-CpG-E2). Using protein microarray analyses, we found that after immunization, antigen-bound nanoparticle formulations elicited significantly higher antigen-specific IgG responses than soluble CBU1910 alone and produced more balanced IgG1/IgG2c ratios. Although T cell recall assays from these protein antigen formulations did not show significant increases in antigen-specific IFN-γ production compared to soluble CBU1910 alone, nanoparticles conjugated with a CD4 peptide epitope from CBU1910 generated elevated T cell responses in mice to both the CBU1910 peptide epitope and whole CBU1910 protein. These investigations highlight the feasibility of conjugating antigens to nanoparticles for tuning and improving both humoral- and cell-mediated adaptive immunity against C. burnetii.

Ablation versus anti-arrhythmic therapy for reducing all hospital episodes from recurrent atrial fibrillation: a prospective, randomized, multi-centre, open label trial.

AIMS: There is rising healthcare utilization related to the increasing incidence and prevalence of atrial fibrillation (AF) worldwide. Simplifying therapy and reducing hospital episodes would be a valuable development. The efficacy of a streamlined AF ablation approach was compared to drug therapy and a conventional catheter ablation technique for symptom control in paroxysmal AF. METHODS AND RESULTS: We recruited 321 patients with symptomatic paroxysmal AF to a prospective randomized, multi-centre, open label trial at 13 UK hospitals. Patients were randomized 1:1:1 to cryo-balloon ablation without electrical mapping with patients discharged same day [Ablation Versus Anti-arrhythmic Therapy for Reducing All Hospital Episodes from Recurrent (AVATAR) protocol]; optimization of drug therapy; or cryo-balloon ablation with confirmation of pulmonary vein isolation and overnight hospitalization. The primary endpoint was time to any hospital episode related to treatment for atrial arrhythmia. Secondary endpoints included complications of treatment and quality-of-life measures. The hazard ratio (HR) for a primary endpoint event occurring when comparing AVATAR protocol arm to drug therapy was 0.156 (95% CI, 0.097-0.250; P < 0.0001 by Cox regression). Twenty-three patients (21%) recorded an endpoint event in the AVATAR arm compared to 76 patients (74%) within the drug therapy arm. Comparing AVATAR and conventional ablation arms resulted in a non-significant HR of 1.173 (95% CI, 0.639-2.154; P = 0.61 by Cox regression) with 23 patients (21%) and 19 patients (18%), respectively, recording primary endpoint events (P = 0.61 by log-rank test). CONCLUSION: The AVATAR protocol was superior to drug therapy for avoiding hospital episodes related to AF treatment, but conventional cryoablation was not superior to the AVATAR protocol. This could have wide-ranging implications on how demand for AF symptom control is met. TRIAL REGISTRATION: Clinical Trials Registration: NCT02459574.

The concurrent emergence and causes of double volcanic hotspot tracks on the Pacific plate.

Mantle plumes are buoyant upwellings of hot rock that transport heat from Earth's core to its surface, generating anomalous regions of volcanism that are not directly associated with plate tectonic processes. The best-studied example is the Hawaiian-Emperor chain, but the emergence of two sub-parallel volcanic tracks along this chain, Loa and Kea, and the systematic geochemical differences between them have remained unexplained. Here we argue that the emergence of these tracks coincides with the appearance of other double volcanic tracks on the Pacific plate and a recent azimuthal change in the motion of the plate. We propose a three-part model that explains the evolution of Hawaiian double-track volcanism: first, mantle flow beneath the rapidly moving Pacific plate strongly tilts the Hawaiian plume and leads to lateral separation between high- and low-pressure melt source regions; second, the recent azimuthal change in Pacific plate motion exposes high- and low-pressure melt products as geographically distinct volcanoes, explaining the simultaneous emergence of double-track volcanism across the Pacific; and finally, secondary pyroxenite, which is formed as eclogite melt reacts with peridotite, dominates the low-pressure melt region beneath Loa-track volcanism, yielding the systematic geochemical differences observed between Loa- and Kea-type lavas. Our results imply that the formation of double-track volcanism is transitory and can be used to identify and place temporal bounds on plate-motion changes.

Sural communicating nerve for application as a vascularized nerve graft: A microneurovascular anatomic study in cadavers.

INTRODUCTION: Sural nerve harvest causes paraesthesia to the lateral heel of the foot, which can debilitate those with already compromised proprioception. To circumvent this, we investigated an alternative donor nerve, branch of the lateral sural nerve complex called the sural communicating nerve (SCoNe), for its harvest and use as a vascularized nerve graft, in cadaver. METHODS: The SCoNe was visualized by dissection in 15 legs from 8 human cadavers and the relationship of the SCoNe to the overall sural nerve complex was documented. The surface markings, dimensions, and the micro-neurovascular anatomy in the super-microsurgery range (up to 0.30 mm) of the SCoNe was recorded and analyzed. RESULTS: SCoNe graft surface marking was confined within a triangle drawn between the fibular head laterally, the popliteal vertical midline medially and the tip of the lateral malleolus inferiorly. The proximal end of the SCoNe was situated at a mean intersection distance of 5 cm from both the fibular head and popliteal midline respectively. The mean length of the SCoNe was 226 ± 43 mm with a mean proximal diameter of 0.82 mm and mean distal diameter of 0.93 mm. In 53% of the cadavers, an arterial input was present in the proximal third of the SCoNe and veins were predominantly (87%) present in the distal third. In 46% and 20% of the 15 legs respectively, there was a nutrient artery and vein perfusing the SCoNe in its central segment. The external mean diameter of this artery was 0.60 ± 0.30 mm, while the vein was slightly larger with a mean diameter of 0.90 ± 0.50 mm. DISCUSSION: SCoNe graft may preserve lateral heel sensation, compared to sural nerve harvest, pending clinical studies. It may have wide applications as a vascularized nerve graft, including being ideal as a vascularized cross-facial nerve graft because its nerve diameter is similar to the distal facial nerve branches. The accompanying artery is a good anastomotic match to the superior labial artery.

On the importance of integrating comparative anatomy and One Health perspectives in anatomy education.

As a result of many factors, including climate change, unrestricted population growth, widespread deforestation and intensive agriculture, a new pattern of diseases in humans is emerging. With increasing encroachment by human societies into wild domains, the interfaces between human and animal ecosystems are gradually eroding. Such changes have led to zoonoses, vector-borne diseases, infectious diseases and, most importantly, the emergence of antimicrobial-resistant microbial strains as challenges for human health. Now would seem to be an opportune time to revisit old concepts of health and redefine some of these in the light of emerging challenges. The One Health concept addresses some of the demands of modern medical education by providing a holistic approach to explaining diseases that result from a complex set of interactions between humans, environment and animals, rather than just an amalgamation of isolated signs and symptoms. An added advantage is that the scope of One Health concepts has now expanded to include genetic diseases due to advancements in omics technology. Inspired by such ideas, a symposium was organised as part of the 19th International Federation of Associations of Anatomists (IFAA) Congress (August 2019) to investigate the scope of One Health concepts and comparative anatomy in contemporary medical education. Speakers with expertise in both human and veterinary anatomy participated in the symposium and provided examples where these two disciplines, which have so far evolved largely independent of each other, can collaborate for mutual benefit. Finally, the speakers identified some key concepts of One Health that should be prioritised and discussed the diverse opportunities available to integrate these priorities into a broader perspective that would attempt to explain and manage diseases within the scopes of human and veterinary medicine.

Tuning Subunit Vaccines with Novel TLR Triagonist Adjuvants to Generate Protective Immune Responses against Coxiella burnetii.

Coxiella burnetii is an obligate intracellular bacterium and the causative agent of Q fever. C. burnetii is considered a potential bioterrorism agent because of its low infectious dose; resistance to heat, drying, and common disinfectants; and lack of prophylactic therapies. Q-Vax, a formalin-inactivated whole-bacteria vaccine, is currently the only prophylactic measure that is protective against C. burnetii infections but is not U.S. Food and Drug Administration approved. To overcome the safety concerns associated with the whole-bacteria vaccine, we sought to generate and evaluate recombinant protein subunit vaccines against C. burnetii To accomplish this, we formulated C. burnetii Ags with a novel TLR triagonist adjuvant platform, which used combinatorial chemistry to link three different TLR agonists together to form one adjuvanting complex. We evaluated the immunomodulatory activity of a panel of TLR triagonist adjuvants and found that they elicited unique Ag-specific immune responses both in vitro and in vivo. We evaluated our top candidates in a live C. burnetii aerosol challenge model in C56BL/6 mice and found that several of our novel vaccine formulations conferred varying levels of protection to the challenged animals compared with sham immunized mice, although none of our candidates were as protective as the commercial vaccine across all protection criteria that were analyzed. Our findings characterize a novel adjuvant platform and offer an alternative approach to generating protective and effective vaccines against C. burnetii.

Assessment of factual recall and higher-order cognitive domains in an open-book medical school examination.

Open-book examinations (OBEs) will likely become increasingly important assessment tools. We investigated how access to open-book resources affected questions testing factual recall, which might be easy to look-up, versus questions testing higher-order cognitive domains. Few studies have investigated OBEs using modern Internet resources or as summative assessments. We compared performance on an examination conducted as a traditional closed-book exam (CBE) in 2019 (N = 320) and a remote OBE with free access to Internet resources in 2020 (N = 337) due to COVID-19. This summative, end-of-year assessment focused on basic science for second-year medical students. We categorized questions by Bloom's taxonomy ('Remember', versus 'Understand/Apply'). We predicted higher performance on the OBE, driven by higher performance on 'Remember' questions. We used an item-centric analysis by using performance per item over all examinees as the outcome variable in logistic regression, with terms 'Open-Book, 'Bloom Category' and their interaction. Performance was higher on OBE questions than CBE questions (OR 2.2, 95% CI: 2.14-2.39), and higher on 'Remember' than 'Understand/Apply' questions (OR 1.13, 95% CI: 1.09-1.19). The difference in performance between 'Remember' and 'Understand/Apply' questions was greater in the OBE than the CBE ('Open-Book' * 'Bloom Category' interaction: OR 1.2, 95% CI: 1.19-1.37). Access to open-book resources had a greater effect on performance on factual recall questions than higher-order questions, though performance was higher in the OBE overall. OBE design must consider how searching for information affects performance, particularly on questions measuring different domains of knowledge.

A checklist of larval Digenea (Platyhelminthes: Trematoda) in molluscs from inland waters of Argentina: one hundred years of research.

A checklist of larval digeneans parasitising molluscs from inland waters of Argentina is presented here. Based on the bibliographical survey of 113 scientific articles and nine theses published between 1930 and 2021, 213 digeneans were found, which were distributed within 13 superfamilies and 35 families. The parasites were identified in 102 locations, encompassing eight of the sixteen biogeographical provinces in Argentina. Digeneans were found in 34 mollusc species (31 gastropods and three bivalves) belonging to 17 genera. The available data are presented for each digenean species, and included host information, localities, prevalence values, type of habitat, life cycle information (natural or experimental host), and information on material and genetic sequences deposited in repositories. Only 21.1% of individuals were identified to species level, and 8.5% to genus level. In addition, the genetic sequences of only 10 species (4.7%) were available at GenBank. This survey constitutes the first checklist of parasitic helminths in molluscs from inland waters of Argentina.

Human Antibody Responses Following Vaccinia Immunization Using Protein Microarrays and Correlation With Cell-Mediated Immunity and Antibody-Dependent Cellular Cytotoxicity Responses.

BACKGROUND: There are limited data regarding immunological correlates of protection for the modified vaccinia Ankara (MVA) smallpox vaccine. METHODS: A total of 523 vaccinia-naive subjects were randomized to receive 2 vaccine doses, as lyophilized MVA given subcutaneously, liquid MVA given subcutaneously (liquid-SC group), or liquid MVA given intradermally (liquid-ID group) 28 days apart. For a subset of subjects, antibody-dependent cellular cytotoxicity (ADCC), interferon-γ release enzyme-linked immunospot (ELISPOT), and protein microarray antibody-binding assays were conducted. Protein microarray responses were assessed for correlations with plaque reduction neutralization titer (PRNT), enzyme-linked immunosorbent assay, ADCC, and ELISPOT results. RESULTS: MVA elicited significant microarray antibody responses to 15 of 224 antigens, mostly virion membrane proteins, at day 28 or 42, particularly WR113/D8L and WR101H3L. In the liquid-SC group, responses to 9 antigens, including WR113/D8L and WR101/H3L, correlated with PRNT results. Three were correlated in the liquid-ID group. No significant correlations were observed with ELISPOT responses. In the liquid-ID group, WR052/F13L, a membrane glycoprotein, correlated with ADCC responses. CONCLUSIONS: MVA elicited antibodies to 15 vaccinia strain antigens representing virion membrane. Antibody responses to 2 proteins strongly increased and significantly correlated with increases in PRNT. Responses to these proteins are potential correlates of protection and may serve as immunogens for future vaccine development. CLINICAL TRIALS REGISTRATION: NCT00914732.

Multifunctional Dendronized Polypeptides for Controlled Adjuvanticity.

Vaccination has been playing an important role in treating both infectious and cancerous diseases. Nevertheless, many diseases still lack proper vaccines due to the difficulty to generate sufficient amounts of antigen-specific antibodies or T cells. Adjuvants provide an important route to improve and direct immune responses. However, there are few adjuvants approved clinically and many of them lack the clear structure/adjuvanticity relationship. Here, we synthesized and evaluated a series of dendronized polypeptides (denpols) functionalized with varying tryptophan/histidine (W/H) molar ratios of 0/100, 25/75, 50/50, 75/25, and 100/0 as tunable synthetic adjuvants. The denpols showed structure-dependent inflammasome activation in THP1 monocytic cells and structure-related activation and antigen cross-presentation in vitro in bone marrow-derived dendritic cells. We used the denpols with bacterial pathogen Coxiella burnetii antigens in vivo, which showed both high and tunable adjuvating activities, as demonstrated by the antigen-specific antibody and T cell responses. The denpols are easy to make and scalable, biodegradable, and have highly adjustable chemical structures. Taken together, denpols show great potential as a new and versatile adjuvant platform that allows us to adjust adjuvanticity based on structure-activity correlation with the aim to fine-tune the immune response, thus advancing vaccine development.

Non-invasive detection of exercise-induced cardiac conduction abnormalities in sudden cardiac death survivors in the inherited cardiac conditions.

AIMS: Rate adaptation of the action potential ensures spatial heterogeneities in conduction across the myocardium are minimized at different heart rates providing a protective mechanism against ventricular fibrillation (VF) and sudden cardiac death (SCD), which can be quantified by the ventricular conduction stability (V-CoS) test previously described. We tested the hypothesis that patients with a history of aborted SCD due to an underlying channelopathy or cardiomyopathy have a reduced capacity to maintain uniform activation following exercise. METHODS AND RESULTS: Sixty individuals, with (n = 28) and without (n = 32) previous aborted-SCD event underwent electro-cardiographic imaging recordings following exercise treadmill test. These included 25 Brugada syndrome, 13 hypertrophic cardiomyopathy, 12 idiopathic VF, and 10 healthy controls. Data were inputted into the V-CoS programme to calculate a V-CoS score that indicate the percentage of ventricle that showed no significant change in ventricular activation, with a lower score indicating the development of greater conduction heterogeneity. The SCD group, compared to those without, had a lower median (interquartile range) V-CoS score at peak exertion [92.8% (89.8-96.3%) vs. 97.3% (94.9-99.1%); P < 0.01] and 2 min into recovery [95.2% (91.1-97.2%) vs. 98.9% (96.9-99.5%); P < 0.01]. No significant difference was observable later into recovery at 5 or 10 min. Using the lowest median V-CoS scores obtained during the entire recovery period post-exertion, SCD survivors had a significantly lower score than those without for each of the different underlying aetiologies. CONCLUSION: Data from this pilot study demonstrate the potential use of this technique in risk stratification for the inherited cardiac conditions.

Lithospheric controls on magma composition along Earth's longest continental hotspot track.

Hotspots are anomalous regions of volcanism at Earth's surface that show no obvious association with tectonic plate boundaries. Classic examples include the Hawaiian-Emperor chain and the Yellowstone-Snake River Plain province. The majority are believed to form as Earth's tectonic plates move over long-lived mantle plumes: buoyant upwellings that bring hot material from Earth's deep mantle to its surface. It has long been recognized that lithospheric thickness limits the rise height of plumes and, thereby, their minimum melting pressure. It should, therefore, have a controlling influence on the geochemistry of plume-related magmas, although unambiguous evidence of this has, so far, been lacking. Here we integrate observational constraints from surface geology, geochronology, plate-motion reconstructions, geochemistry and seismology to ascertain plume melting depths beneath Earth's longest continental hotspot track, a 2,000-kilometre-long track in eastern Australia that displays a record of volcanic activity between 33 and 9 million years ago, which we call the Cosgrove track. Our analyses highlight a strong correlation between lithospheric thickness and magma composition along this track, with: (1) standard basaltic compositions in regions where lithospheric thickness is less than 110 kilometres; (2) volcanic gaps in regions where lithospheric thickness exceeds 150 kilometres; and (3) low-volume, leucitite-bearing volcanism in regions of intermediate lithospheric thickness. Trace-element concentrations from samples along this track support the notion that these compositional variations result from different degrees of partial melting, which is controlled by the thickness of overlying lithosphere. Our results place the first observational constraints on the sub-continental melting depth of mantle plumes and provide direct evidence that lithospheric thickness has a dominant influence on the volume and chemical composition of plume-derived magmas.

Determining the therapist's contribution in therapist multicultural competence process and outcome.

Efforts to help therapists improve their multicultural competence (MCC) rely on measures that can distinguish between different levels of competence. MCC is often assessed by asking clients to rate their experiences with their therapists. However, differences in client ratings of therapist MCC do not necessarily provide information about the relative performance of therapists and can be influenced by other factors including the client's own characteristics. In this study, we used a repeated measures design of 8,497 observations from 1,458 clients across 35 therapists to clarify the proportion of variability in MCC ratings attributed to the therapist versus the client and better understand the extent that an MCC measure detects therapist differences. Overall, we found that a small amount of variability in MCC ratings was attributed to the therapist (2%) and substantial amount attributed to the client (70%). These findings suggest that our measure of MCC primarily detected differences at the client level versus therapist level, indicating that therapist MCC scores were largely dependent on the client. Clinical implications and recommendations for future MCC research and measurement are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Engineering of chimeric natural killer cell receptors to develop precision adoptive immunotherapies for cancer.

Natural killer (NK) cells are innate immune effectors which play a crucial role in recognizing and eliminating virally infected and cancerous cells. They effectively distinguish between healthy and distressed self through the integration of signals delivered by germline-encoded activating and inhibitory cell surface receptors. The frequent up-regulation of stress markers on genetically unstable cancer cells has prompted the development of novel immunotherapies that exploit such innate receptors. One prominent example entails the development of chimeric antigen receptors (CAR) that detect cell surface ligands bound by NK receptors, coupling this engagement to the delivery of tailored immune activating signals. Here, we review strategies to engineer CARs in which specificity is conferred by natural killer group 2D (NKG2D) or other NK receptor types. Multiple preclinical studies have demonstrated the remarkable ability of chimeric NK receptor-targeted T cells and NK cells to effectively and specifically eliminate cancer cells and to reject established tumour burdens. Importantly, such systems act not only acutely but, in some cases, they also incite immunological memory. Moreover, CARs targeted with the NKG2D ligand binding domain have also been shown to disrupt the tumour microenvironment, through the targeting of suppressive T regulatory cells, myeloid-derived suppressor cells and tumour vasculature. Collectively, these findings have led to the initiation of early-phase clinical trials evaluating both autologous and allogeneic NKG2D-targeted CAR T cells in the haematological and solid tumour settings.

An investigation of the anatomy of the infrapatellar fat pad and its possible involvement in anterior pain syndrome: a cadaveric study.

The infrapatellar fat pad (IFP) is an extrasynovial, intracapsular, adipose body occupying the space in the knee joint between the inferior border of the patella, the femoral condyles, tibial plateau and patellar tendon. Little is known about the anatomy and normal function of the IFP, but it has been suggested to play a role in the aetiology of Anterior knee pain syndrome, including that associated with osteoarthritis. Forty-three knees from 11 male and 15 female embalmed cadavers (mean age 84 years; range 55-97 years) were investigated. The cadavers were donated and the study performed in compliance with the provisions of the UK Human Tissue Act (2004). The quadriceps tendon and the medial and lateral patellar retinacula were dissected from the patella, which was then reflected antero-distally. The IFP was carefully excised and details of its morphology and attachments to components of the knee joint were recorded, together with the presence of articular surface pathology on the patella and femoral condyles. The principal novel findings of the current study were that 81% of IFPs were attached to the superior border of the patella by supero-medial extensions and 65% were attached by supero-lateral extensions; the supero-medial extensions were larger than the supero-lateral extensions. The superior extensions of the IFP were always attached anteriorly to the patellar retinacula and in four individuals the extensions formed a full loop around the superior border of the patella. The volume of IFPs with attachments to the superior border of the patella was significantly greater (p = .007) than those without, and the IFP was attached to the medial meniscus in significantly (p = .009) more knees with IFP attachment to the superior border of the patella than those without. All IFPs were attached to the medial anterior horn of the meniscus and the medial Kaplan's ligament. Ninety-seven per cent were attached to the lateral anterior horn of the meniscus and 97% to the lateral Kaplan's ligament. The length of IFP attachment to the lateral meniscus was significantly longer (p = .004) than that to the medial meniscus. Ninety-seven per cent of IFPs were attached to the superior portion of the patellar tendon with the mean tendon attachment being 60%. Ninety-one per cent of IFPs were attached to the inferior border of the patella. Significantly fewer knees with patellar (p = .001) and femoral (p = .002) articular surface osteophytes exhibited superior IFP extensions and these extensions were significantly shorter in knees with patellar (p = .000) and femoral (p = .006) osteophytes, compared with those without. The IFP was attached to the medial meniscus in significantly fewer knees with femoral (p = .050) and patellar (p = .023) osteophytes than those without. All IFPs not attached to the anterior horn of the lateral menisci, medial Kaplan's ligament, superior patella or inferior border of the patella, were in knees with articular surface osteophytes. This relationship between IFP morphology and knee joint pathology suggests a functional role for the IFP that requires further investigation.

COVID-19 and anatomy: Stimulus and initial response.

The outbreak of COVID-19, resulting from widespread transmission of the SARS-CoV-2 virus, represents one of the foremost current challenges to societies across the globe, with few areas of life remaining untouched. Here, we detail the immediate impact that COVID-19 has had on the teaching and practice of anatomy, providing specific examples of the varied responses from several UK, Irish and German universities and medical schools. Alongside significant issues for, and suspension of, body donation programmes, the widespread closure of university campuses has led to challenges in delivering anatomy education via online methods, a particular problem for a practical, experience-based subject such as anatomy. We discuss the short-term consequences of COVID-19 for body donation programmes and anatomical education, and highlight issues and challenges that will need to be addressed in the medium to long term in order to restore anatomy education and practice throughout the world.

Optical pupillometry in traumatic brain injury: neurological pupil index and its relationship with intracranial pressure through significant event analysis.

Primary Objective: Treatment paradigms for traumatic brain injury (TBI) rely on invasive monitoring of intracranial pressure (ICP) for planning intervention. Optical pupillometry is a non-invasive, objective monitoring method, measuring parameters of pupillary response and displaying a scalar value - a neurological pupil index (NPi). An impaired response on NPi has been tentatively correlated with ICP, through analysis of mean/peak NPi and ICP readings. We sought to evaluate this relationship more closely. Research Design: Prospective observational. Methods and Procedures: We obtained hourly pupillometry readings, alongside ICP values, from 40 patients with TBI requiring invasive ICP monitoring. Significant events were identified for analysis based on the significant aberration of ICP or NPi. Main Outcomes and Results: On average, individuals experienced a few significant events. There was a weak relationship between ICP events and a preceding NPi event. The results show that there is a weak but statistically insignificant relationship between NPi and ICP, where reduced pupil reactivity may indicate a raised ICP. The strength of this trend appears to diminish post-decompressive surgery. Conclusions: Whilst pupillometry may not be a reliable surrogate marker for ICP, NPi may still prove to be a useful tool in a multimodal prognostic assessment of the patient with acute brain injury.

Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial.

Importance: Catheter ablation is effective in restoring sinus rhythm in atrial fibrillation (AF), but its effects on long-term mortality and stroke risk are uncertain. Objective: To determine whether catheter ablation is more effective than conventional medical therapy for improving outcomes in AF. Design, Setting, and Participants: The Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation trial is an investigator-initiated, open-label, multicenter, randomized trial involving 126 centers in 10 countries. A total of 2204 symptomatic patients with AF aged 65 years and older or younger than 65 years with 1 or more risk factors for stroke were enrolled from November 2009 to April 2016, with follow-up through December 31, 2017. Interventions: The catheter ablation group (n = 1108) underwent pulmonary vein isolation, with additional ablative procedures at the discretion of site investigators. The drug therapy group (n = 1096) received standard rhythm and/or rate control drugs guided by contemporaneous guidelines. Main Outcomes and Measures: The primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Among 13 prespecified secondary end points, 3 are included in this report: all-cause mortality; total mortality or cardiovascular hospitalization; and AF recurrence. Results: Of the 2204 patients randomized (median age, 68 years; 37.2% female; 42.9% had paroxysmal AF and 57.1% had persistent AF), 89.3% completed the trial. Of the patients assigned to catheter ablation, 1006 (90.8%) underwent the procedure. Of the patients assigned to drug therapy, 301 (27.5%) ultimately received catheter ablation. In the intention-to-treat analysis, over a median follow-up of 48.5 months, the primary end point occurred in 8.0% (n = 89) of patients in the ablation group vs 9.2% (n = 101) of patients in the drug therapy group (hazard ratio [HR], 0.86 [95% CI, 0.65-1.15]; P = .30). Among the secondary end points, outcomes in the ablation group vs the drug therapy group, respectively, were 5.2% vs 6.1% for all-cause mortality (HR, 0.85 [95% CI, 0.60-1.21]; P = .38), 51.7% vs 58.1% for death or cardiovascular hospitalization (HR, 0.83 [95% CI, 0.74-0.93]; P = .001), and 49.9% vs 69.5% for AF recurrence (HR, 0.52 [95% CI, 0.45-0.60]; P < .001). Conclusions and Relevance: Among patients with AF, the strategy of catheter ablation, compared with medical therapy, did not significantly reduce the primary composite end point of death, disabling stroke, serious bleeding, or cardiac arrest. However, the estimated treatment effect of catheter ablation was affected by lower-than-expected event rates and treatment crossovers, which should be considered in interpreting the results of the trial. Trial Registration: ClinicalTrials.gov Identifier: NCT00911508.