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A 56-year-old woman was admitted due to new ulceration and acute digital ischaemia on a background of chronic leg ulcers bilaterally. Vasculitis screening returned strongly positive lupus anticoagulant levels and elevated anticardiolipin antibodies; these remained elevated at repeat testing. A diagnosis of antiphospholipid syndrome was made. Transthoracic echocardiogram identified a mitral valve lesion suggestive of vegetation and mild mitral valve regurgitation. Blood cultures taken throughout her inpatient admission were negative. Mechanical mitral valve replacement was performed 3 months later, and subsequent culture of the excised tissue returned as sterile. Histological examination showed no morphological signs of infective endocarditis.

We develop a statistical method to assess CMIP6 simulations of large-scale surface temperature change during the historical period (1850–2014), considering all time scales, allowing for the different unforced variability of each model and the observations, observational uncertainty, and variable ensemble size. The generality of this method, and the fact that it incorporates information about the unforced variability, makes it a useful model assessment tool. We apply this method to the historical simulations of the CMIP6 multimodel ensemble. We use three indices that measure different aspects of large-scale surface air temperature change: global mean, hemispheric gradient, and a recently developed index that captures the sea surface temperature (SST) pattern in the tropics (SST#; see Fueglistaler and Silvers). We use the following observations: HadCRUT5 for the first two indices, and AMIPII and ERSSTv5 for SST#. In each case, we test the hypothesis that the model’s forced response is compatible with the observations, accounting for unforced variability in both models and observations as well as measurement uncertainty. This hypothesis is accepted more often (75% of the models) for the hemispheric gradient than for the global mean, for which half of the models fail the test. The tropical SST pattern is poorly simulated in all models. Given that the tropical SST pattern can strongly modulate the relationship between energy imbalance and global-mean surface temperature anomalies on annual to decadal time scales (short-term feedback parameter), we suggest this should be a focus area for future improvements due to its potential implications for the global-mean temperature evolution in decadal time scales.

BackgroundClinician-led secondary triage, following primary triage by the NHS 111 phone line, is central to England’s urgent care system. However, little is known about how secondary triage influences the urgency attributed to patients’ needs.AimTo describe patterns of secondary triage outcomes and call-related factors (such as call length and time of call) associated with upgrading/downgrading of primary triage outcomes.Design and settingCross-sectional analysis of secondary triage call records from four urgent care providers in England using the same digital triage system to support clinicians’ decision making.MethodStatistical analyses (mixed-effects regression) of approximately 200 000 secondary triage call records were undertaken.ResultsFollowing secondary triage, 12% of calls were upgraded (including 2% becoming classified as emergencies) from the primary triage urgency. The highest odds of upgrade related to chest pain (odds ratio [OR] 2.68, 95% confidence interval [CI] = 2.34 to 3.07) and breathlessness (OR 1.62, 95% CI = 1.42 to 1.85; reference: abdominal pain) presentations. However, 74% of calls were downgraded; notably, 92% (n= 33 394) of calls classified at primary triage as needing clinical attention within 1 h were downgraded. Secondary triage outcomes were associated with operational factors (day/time of call), and most substantially with the clinician conducting triage.ConclusionNon-clinician primary triage has significant limitations, highlighting the importance of secondary triage in the English urgent care system. It may miss key symptoms that are subsequently triaged as requiring immediate care, while also being too risk averse for most calls leading to downgrading of urgency. There is unexplained inconsistency between clinicians, despite all using the same digital triage system. Further research is needed to improve the consistency and safety of urgent care triage.

Introduction and Objective: Muscle invasive bladder cancer with extravesical extension is an aggressive disease entity that requires multimodal therapy. The benefits of adjuvant chemotherapy (AC) in patients with a positive soft-tissue surgical margin (STSM), however, are relatively unknown due to exclusion of this population in randomized controlled trials of AC. We sought to define survival benefits in this patient population through our institutional bladder cancer database. Methods: Retrospective review of all patients undergoing radical cystectomy for urothelial carcinoma of the bladder from 2004–2020 with ≥pT3b disease irrespective of neoadjuvant chemotherapy (NAC) use was conducted. Progression-free survival (PFS) and overall survival (OS) estimates were obtained using the Kaplan-Meier method with log-rank test, and the Cox-proportional hazards model was used to identify predictors of improved PFS and OS. AC was defined by any chemotherapy use within 90 days of cystectomy, regardless of STSM status. Results: 476 patients with pT3b disease or worse were identified. Median follow-up was 12.3 months. An amount of 21% of patients were treated with AC. An amount of 24% of patients had positive STSM. Median OS for patients with positive STSM was 8.4 months [95% CI 7–11.5] and 18.3 months [95% CI 15.6–20.8] (p < 0.001) for patients with negative STSM. In the overall cohort, positive STSM (HR 1.93, 95% CI 1.45–2.57, p < 0.001), AC use (HR 0.68, 95% CI 0.51–0.90, p = 0.007), and pN1–3 disease (HR 1.47, 95% CI 1.16–1.87, p = 0.002) were independent predictors of OS when adjusted for performance status, pT-stage, and neoadjuvant chemotherapy use. In patients with positive STSM, median survival was seven months [95% CI 5.2–8.4] without AC, compared to 16.2 months [95% CI 11.5–52.5] with AC (p = 0.0038). For patients with negative STSM, median survival was 17.4 months [95% CI 14–20.1] without AC compared to 22.3 months [95% CI 17.2–36.9] with AC (p = 0.23). In patients with positive STSM, AC use was the only factor associated with an OS benefit with a HR of 0.41 (95% CI 0.21–0.78, p = 0.007). In patients with negative STSM, pT4 and pN1–3 disease were the only factors associated with worse overall survival with a HR of 1.32 (95% CI 1.00–1.74, p = 0.050) and 1.97 (95% CI 1.49–2.60, p < 0.001), respectively. Conclusions: Administration of adjuvant chemotherapy is of particular benefit in patients with positive STSM following radical cystectomy for gross extravesical disease. Positive STSM may be a representative of “early metastatic” or micrometastatic disease.

This study continues to delineate muscle biology differences between lower and higher responders to resistance training and is unique in that a female population was interrogated. As has been reported in prior studies, increases in satellite cell numbers are related to positive responses to resistance training. Satellite cell responsivity, rather than changes in muscle ribosome content per milligrams of tissue, may be a more important factor in delineating resistance-training responses in women.

Although past studies have examined aspects of extracellular matrix remodeling in relation to mechanical overload or resistance training, this study serves to expand our knowledge on a multitude of extracellular matrix markers and whether these markers adapt to resistance training or are associated with differential hypertrophic responses.

Olga Sergeeva,1 Yifan Zhang,1 Songqi Gao,2 E Ricky Chan,3 Maxim Sergeev,4 Renuka Iyer,5 Sandra Sexton,5 Norbert Avril,4 Zheng-Rong Lu,2 Zhenghong Lee1 1Department of Radiology, Case Western Reserve University, Cleveland, OH, USA; 2Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA; 3Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA; 4Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; 5Medical Oncology and Laboratory Animal Shared Resources, Roswell Park Cancer Institute, Buffalo, NY, USACorrespondence: Zhenghong Lee, Nuclear Medicine, Radiology, Case Western Reserve University, Bolwell S107, 11100 Euclid Avenue, Cleveland, OH, 44106, USA, Tel +1216-844-7920, Email zxl11@case.edu Zheng-Rong Lu, Biomedical Engineering, Case Western Reserve University, Wickenden 427, Mail Stop 7207, 10900 Euclid Ave, Cleveland, OH, 44106, USA, Tel +1 216-368-0187, Email zxl125@case.eduPurpose: We tested a recently developed short peptide radioligand for PET imaging of hepatocellular carcinoma (HCC) by targeting an oncoprotein, extra-domain B fibronectin (EDB-FN) in the tumor microenvironment.Methods: The radioligand consists of a small linear peptide ZD2 with 68Ga-NOTA chelator, and specifically binds to EDB-FN. PET images were acquired dynamically for 1 hour after intravenously (i.v.) injecting 37 MBq (1.0 mCi) of the radioligand into the woodchuck model of naturally occurring HCC. Woodchuck HCC originated from chronic viral hepatitis infection, which recapitulates the corresponding human primary liver cancer. The animals were euthanized post-imaging for tissue collection and validation.Results: For ZD2 avid liver tumors, the radioligand accumulation plateaued a few minutes after injection, while the liver background uptake stabilized 20 min post-injection. The status of EDB-FN in woodchuck HCC was confirmed by histology and validated by PCR and western blocking.Conclusion: We have showed the viability of using the ZD2 short peptide radioligand targeting EDB-FN in liver tumor tissue for PET imaging of HCC, which can potentially impact the clinical care for HCC patients.Keywords: peptide ligand, EDB fibronectin, positron emission tomography, woodchuck model

The Pliocene-Recent is associated with many important climatic and paleoceanographic changes, which have shaped the biotic and abiotic nature of the modern world. The closure of the Central American Seaway and the development and intensification of Northern Hemisphere ice sheets had profound global impacts on the latitudinal and vertical structure of the oceans, triggering the extinction and radiation of many marine groups. In particular, marine calcifying planktonic foraminifera, which are highly sensitive to water column structure, exhibited a series of extinctions as global temperatures fell. By analyzing high-resolution (∼ 5 kyr) sedimentary records from the Eastern Equatorial Pacific Ocean, complemented with global records from the novel Triton dataset, we document the biotic changes in this microfossil group, within which three species displayed isochronous co-extinction, and species with cold-water affinity increased in dominance as meridional temperature gradients steepened. We suggest that these changes were associated with the terminal stages of the closure of the Central American Seaway, where following the sustained warmth of the mid-Pliocene Warm Period, bipolar ice sheet expansion initiated a world in which cold- and deep-dwelling species became increasingly more successful. Such global-scale paleoecological and macroevolutionary variations between the Pliocene and the modern icehouse climate would suggest significant deviations from pre-industrial baselines within modern and future marine plankton communities as anthropogenic climate forcing continues.

Monoclonal antibodies (mAbs) have been shown to be effective and generally safe across a continually expanding list of therapeutic areas. We describe the advantages and limitations of mAbs as a therapeutic option compared with small molecules. Specifically, we discuss a novel mAb in the treatment of hereditary angioedema (HAE), a rare and potentially life-threatening condition characterized by recurrent unpredictable swelling attacks. HAE is mediated by dysregulation of plasma kallikrein activity leading to overproduction of bradykinin. Current prophylactic treatment for HAE includes androgens or replacement of the endogenous plasma kallikrein inhibitor, C1 inhibitor. However, there remains an unmet need for an effective, less burdensome treatment option. Lanadelumab is a fully human mAb targeting plasma kallikrein. Results from clinical trials, including a pivotal Phase 3 study and its ensuing open-label extension study, demonstrated that lanadelumab is associated with few treatment-related adverse events and reduced the rate of HAE attacks. This novel treatment option has the potential to significantly improve the lives of patients with HAE.

Dogs have a special place in human history as the first domesticated species and play important roles in many cultures around the world. However, their role in scientific studies has been relatively recent. With a few notable exceptions (e.g., Darwin, Pavlov, Scott, and Fuller), domestic dogs were not commonly the subject of rigorous scientific investigation of behavior until the late 1990s. While the number of canine science studies has increased dramatically over the last 20 years, most research groups are limited in the inferences they can draw due to the relatively small sample sizes used, along with the exceptional diversity observed in dogs (e.g., breed, geographic location, experience). To this end, we introduce the ManyDogs Project, an international consortium of researchers interested in taking a big team science approach to understanding canine behavioral science. We begin by discussing why studying dogs provides valuable insights into behavior and cognition, evolutionary processes, human health, and applications for animal welfare. We then highlight other big team science projects that have previously been conducted in canine science and emphasize the benefits of our approach. Finally, we introduce the ManyDogs Project and our mission: (1) replicating important findings, (2) investigating moderators that need a large sample size such as breed differences, (3) reaching methodological consensus, (4) investigating cross-cultural differences, and finally (5) setting a standard for replication studies in general. In doing so, we hope to address previous limitations in individual lab studies and previous big team science frameworks to deepen our understanding of canine behavior and cognition.

Data on response and safety of repeated vaccinations and hybrid immunity in patients with immune-mediated inflammatory diseases on immunosuppressive therapy is needed to further develop vaccination strategies in this vulnerable population. This study aimed to evaluate hybrid immunity and humoral immune response and safety of four SARS-CoV-2 vaccine doses in patients with immune-mediated inflammatory diseases on immunosuppressive therapy.This prospective observational Norwegian study of vaccine response to COVID-19 (Nor-vaC) included adult patients aged 18 years and older with immune-mediated inflammatory diseases (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, Crohn's disease, or ulcerative colitis) on immunosuppressive therapy, who had received four SARS-CoV-2 vaccine doses (vaccine group) or three vaccine doses followed by COVID-19 (hybrid group), and healthy controls receiving three vaccine doses (control group). Patients were recruited from the Division of Rheumatology at Diakonhjemmet Hospital, Oslo, and the Department of Gastroenterology at Akershus University Hospital, Lørenskog. Patients who had COVID-19 before the third vaccine dose, and patients with allergies or intolerances to elements of the vaccine were excluded. Antibodies to the receptor-binding domain of SARS-CoV-2 spike protein (anti-RBD antibodies) were assessed 2-4 weeks following vaccination or COVID-19. This study is registered at Clinialtrials.gov, NCT04798625.Between Nov 12, 2021, and April 19, 2022, 1458 participants with immune-mediated inflammatory diseases provided post-vaccination samples at 2-4 weeks following a third vaccine dose. After 544 participants were excluded, 715 (78%) of the remaining 914 participants received the fourth dose of the vaccine, and of these, 536 (75%) provided post-vaccination samples 2-4 weeks after their fourth vaccination (vaccine group). 199 (22%) of the 914 had COVID-19 after their third dose of the vaccine and of these, 167 (84%) provided samples (hybrid group). 256 of the eligible 703 patients had rheumatoid arthritis, 107 had spondyloarthritis, 115 had psoriatic arthritis, 130 had Crohn's disease, and 95 had ulcerative colitis). Median age was 56 years [IQR 45-65], 398 (57%) were women, and 305 (43%) were men. Patients in the vaccine group had higher anti-RBD antibody concentrations following the fourth vaccine dose (median 6192 BAU/ml [IQR 2878-11 243]) than after the third dose (median 5087 BAU/ml [1250-9081]; p0·0001), but lower antibody concentrations than the control group following the third dose (median 7595 BAU/ml [5916-12 001]; p0·0001). Antibody concentrations were higher in the patients in the hybrid group (23 548 BAU/ml [IQR 11 440-35 935]) than in the vaccine group (p0·0001). No difference was found in antibody concentrations between the fourth dose of BNT162b2 (full-dose) and mRNA-1273 (half-dose). Patients and controls had a comparable safety profile after both three and four vaccine doses.Vaccine boosters improve humoral immune responses and are safe in patients with immune-mediated inflammatory diseases on immunosuppressive therapy, and administration should be considered regularly in this patient group. Hybrid immunity with omicron induces a strong humoral response suggesting longer intervals between booster doses in this patient group.The South-Eastern Norway Regional Health Authority, The Coalition for Epidemic Preparedness Innovations, Akershus University Hospital.

G protein–coupled receptors (GPCRs) are the largest family of cell surface receptors. Class B1 GPCRs constitute a subfamily of 15 receptors that characteristically contain large extracellular domains (ECDs) and respond to long polypeptide hormones. Class B1 GPCRs are critical regulators of homeostasis, and, as such, many are important drug targets. While most transmembrane proteins, including GPCRs, are recalcitrant to crystallization, recent advances in cryo-electron microscopy (cryo-EM) have facilitated a rapid expansion of the structural understanding of membrane proteins. As a testament to this success, structures for all the class B1 receptors bound to G proteins have been determined by cryo-EM in the past 5 years. Further advances in cryo-EM have uncovered dynamics of these receptors, ligands, and signaling partners. Here, we examine the recent structural underpinnings of the class B1 GPCRs with an emphasis on structure–function relationships.

This article examines the concept of co-created and person-centred recordkeeping and the needs for this in out-of-home child-care contexts, drawing out a recordkeeping framework. The article uses the research of the UK MIRRA (Memory – Identity – Rights in Records – Access) project as its critical evidence base. MIRRA is a participatory research project, hosted at the Department of Information Studies at University College London (UCL) since 2017, which places Care Leavers as co-researchers at the heart of the work. The study has gathered evidence from care-experienced people, social workers, archivists, records managers, and researchers. The case context of care-experienced people provides a powerful focus for shifting views of records creation and ownership. Care-experienced people across the globe are situated within organizational systems that act as surrogate parents, but where the children or young people are often powerless to co-create and store their own memories, which would enable them to forge positive identities and revisit these through time. Positive and holistic life story narratives are rarely found. In addition, children’s care records are often accessible to care-experienced people only through legislative processes and without critical support. This research reframes the recordkeeping model, placing the care-experienced person at the heart of the process in order to ensure the co-creation of records and the maintenance of identity through time. The research acknowledges the complex and sometimes conflicting needs of diverse actors in children’s recordkeeping, including social workers, archivists, records managers, and researchers. It rethinks the actors’ relationships and responsibilities around the records and systems, drawing out a framework that makes explicit the value of active person-centred recordkeeping., Cet article, en élaborant un cadre d’archivage, examine le concept de co-création et de préservation d’archives basée sur les personnes. Il souligne la nécessité de ce concept dans le contexte de la garde d’enfants hors domicile. L’article utilise la recherche du projet UK MIRRA (Mémoire – Identité – Droits aux documents – Accès) comme fondement critique d’analyse. MIRRA est un projet de recherche participatif chapeauté depuis 2017 par le Department of Information Studies at University College London (UCL). Ce projet positionne ceux et celles ayant quitté les institutions de « soins » comme étant des co-chercheurs.euses se trouvant au coeur de la recherche. L’étude a recueilli des preuves provenant de personnes qui ont été présentes dans ces institutions, de travailleurs.euses sociaux.ales, d’archivistes, de gestionnaires de documents et de chercheurs.euses. Le contexte de l’étude de cas de personnes évoluant dans les milieux de soins offre une démonstration éloquente des changements de perspectives face à la création et la possession des documents. Les personnes ayant vécu dans les milieux de soins à travers la planète sont positionnées à l’intérieur de systèmes organisationnels qui agissent comme parents de substitution. Toutefois, les enfants et les jeunes se trouvent souvent impuissants pour façonner leurs propres récits et mémoires. Cette dimension leur permettrait de se construire des identités et de les revisiter à travers le temps. Des histoires de vie positives et holistiques sont largement absentes. De plus, les dossiers des enfants se trouvant dans les institutions de soins sont souvent accessibles à celles et ceux-ci seulement qu’à travers des procédés légaux et sans soutien critique. Cette recherche recadre le modèle de gestion des archives en positionnant la personne présente dans les milieux de soins au coeur des procédés afin d’assurer la co-création des documents et le maintien de leur identité à travers le temps. La recherche reconnaît les besoins complexes et parfois conflictuels des divers acteurs.trices impliqué.e.s dans la gestion des documents des enfants, entre autres les travailleurs.euses sociaux.ales, les archivistes, les gestionnaires de documents et les chercheurs.euses. Elle repense alors les relations et les responsabilités des différents acteurs.trices concernant les documents et les systèmes, en développant un cadre qui rend explicite la valeur active des personnes impliquées dans la portée des archives.

Policies exist to regulate the use of restraint and seclusion so that they are only implemented when necessary and following appropriate standards and procedures. These policies often focus on students with disability. This qualitative study explored school leaders’ understanding, use and perspectives of the Restraint and Seclusion Policy mandated for Victorian government schools, in relation to primary school-aged children with disability. Reflexive thematic analysis was undertaken on interviews conducted with eight leaders from six Victorian government schools. Five themes were developed: (i) Perceptions about behaviours of concern; (ii) Complex policy complicates implementation; (iii) Many factors determine policy implementation; (iv) Reporting is required but stressful; and (v) Support is important and includes, but is not limited to, professional development. Results indicate the Policy was valued but complex. School ethos, educator ideologies and understanding of behaviour, and the physical environment impacted policy implementation. Leaders felt the most effective approach to reducing restraint and seclusion use was preventing challenging behaviour through proactive and holistic approaches. Reporting was necessary but the process often felt arduous and judgmental for educators. The Restraint and Seclusion Policy was valued but needs to be user friendly and supported with professional development about understanding the policy, behaviour and disability.

Managing the physical sequelae of facial trauma is routine for the maxillofacial surgeon. However, managing the psychological consequences is more challenging. The often violent mechanism of injury, changes in appearance, altered self-perception, and self-confidence can significantly impact daily life. This review summarises the literature regarding post-traumatic stress disorder (PTSD) and facial trauma, highlighting evidence to guide clinical practice. PubMed and MEDLINE were searched for relevant keywords and MeSH headings. Articles between 2000-2022 were independently reviewed by two authors. Articles were excluded if the full text was not available in English, did not relate to facial trauma, or was not related to PTSD/psychological sequelae. A total of 211 articles were retrieved. The most common reasons for exclusion were papers not reporting psychological outcomes (n = 68) or not relating to facial trauma (n = 35). Articles were sub-categorised to enable evaluation of key themes. Categories included children and adolescents, cross sectional, longitudinal studies, and interventional studies. Whilst there were potential confounders such as socioeconomic factors, overall, patients who had experienced facial trauma (regardless of the mechanism of injury) had an increased risk of PTSD and anxiety/depression. PTSD following facial injury is increasingly recognised as an important issue. A robust evidence base is desirable to inform clinical practice and provide holistic care to often vulnerable patients. Identifying those at increased risk of negative psychological sequelae is essential. We have appraised the literature relevant to OMFS trauma clinicians.

Deinococcus radiodurans is an atypical diderm bacterium with a remarkable ability to tolerate various environmental stresses, due in part to its complex cell envelope encapsulated within a hyperstable surface layer (S-layer). Despite decades of research on this cell envelope, atomic structural details of the S-layer have remained obscure. In this study, we report the electron cryomicroscopy structure of the D. radiodurans S-layer, showing how it is formed by the Hexagonally Packed Intermediate-layer (HPI) protein arranged in a planar hexagonal lattice. The HPI protein forms an array of immunoglobulin-like folds within the S-layer, with each monomer extending into the adjacent hexamer, resulting in a highly interconnected, stable, sheet-like arrangement. Using electron cryotomography and subtomogram averaging from focused ion beam-milled D. radiodurans cells, we have obtained a structure of the cellular S-layer, showing how this HPI S-layer coats native membranes on the surface of cells. Our S-layer structure from the diderm bacterium D. radiodurans shows similarities to immunoglobulin-like domain-containing S-layers from monoderm bacteria and archaea, highlighting common features in cell surface organization across different domains of life, with connotations on the evolution of immunoglobulin-based molecular recognition systems in eukaryotes.

We compare two state-of-the-art numerical codes to study the overall accuracy in modeling the intergalactic medium and reproducing Lyman-$\alpha$ forest observables for DESI and high-resolution data sets. The codes employ different approaches to solving both gravity and modeling the gas hydrodynamics. The first code, Nyx, solves the Poisson equation using the Particle-Mesh (PM) method and the Euler equations using a finite volume method. The second code, \CRKHACC, uses a Tree-PM method to solve for gravity, and an improved Lagrangian smoothed particle hydrodynamics (SPH) technique, where fluid elements are modeled with particles, to treat the intergalactic gas. We compare the convergence behavior of the codes in flux statistics as well as the degree to which the codes agree in the converged limit. We find good agreement overall with differences being less than observational uncertainties, and a particularly notable $\lesssim$1\% agreement in the 1D flux power spectrum. This agreement was achieved by applying a tessellation methodology for reconstructing the density in \CRKHACC instead of using an SPH kernel as is standard practice. We show that use of the SPH kernel can lead to significant and unnecessary biases in flux statistics; this is especially prominent at high redshifts, $z \sim 5$, as the Lyman-$\alpha$ forest mostly comes from lower-density regions which are intrinsically poorly sampled by SPH particles., Comment: submitted to MNRAS

ObjectiveTo compare the effectiveness of tumor necrosis factor inhibitors (TNFi) ± comedication and methotrexate (MTX) monotherapy between patients with adult juvenile idiopathic arthritis (JIA) and patients with rheumatoid arthritis (RA).MethodsAdult patients with JIA and RA were identified from the Norwegian Antirheumatic Drug Register (NOR-DMARD) register. Disease activity measurements at baseline, 3, 6, and 12 months were compared between patients with JIA and RA starting (1) TNFi and (2) MTX monotherapy, using age- and gender-weighted analyses. We calculated differences between JIA and RA in mean changes in Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI), among other disease activity measures. DAS28, CDAI, SDAI, and American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) remission rates at 3, 6, and 12 months, as well as 6- and 12-month Lund Efficacy Index (LUNDEX)-corrected rates, were calculated.ResultsWe identified 478 patients with JIA (TNFi/MTX monotherapy, n = 358/120) and 4637 patients with RA (TNFi/MTX monotherapy, n = 2292/2345). Patients with JIA had lower baseline disease activity compared to patients with RA across treatment groups. After baseline disease activity adjustment, there were no significant differences in disease activity change from baseline to 3, 6, and 12-months of follow-up between patients with JIA and RA for either treatment group. Twelve-month remission rates were similar between groups based on DAS28 (TNFi: JIA 55.2%, RA 49.5%; MTX monotherapy: JIA 45.3%, RA 41.2%) and ACR/EULAR remission criteria (TNFi: JIA 20.4%, RA 20%; MTX monotherapy: JIA 17%, RA 12.7%). Median drug survival (yrs) was similar for JIA and RA in both treatment groups (TNFi: JIA 1.2, RA 1.4; MTX monotherapy: JIA 1.3, RA 1.6).ConclusionTNFi and MTX monotherapy are effective in adult JIA, with similar effectiveness to that shown in RA.

To assess the safety profile of antegrade mitomycin gel instillation through a percutaneous nephrostomy tube (PCNT) for upper tract urothelial carcinoma (UTUC) with the aim of decreasing morbidity associated with therapy.Patients undergoing antegrade administration of mitomycin gel via PCNT were retrospectively included for analysis from four tertiary referral centres between 2020 and 2022. The primary outcome was safety profile, as graded by Common Terminology Criteria for Adverse Events (v5.0). Post-therapy disease burden was assessed by primary disease evaluation (PDE) via ureteroscopy.Thirty-two patients received at least one dose of mitomycin gel via PCNT for UTUC, 29 of whom completed induction and underwent PDE. Thirteen patients (41%) had residual tumour present prior to induction therapy. At a median of 15.0 months following first dose of induction therapy, ureteric stenosis occurred in three patients (9%), all of whom were treated without later recurrence or chronic stenosis. Other adverse events included fatigue (27%), flank pain (19%), urinary tract infection (12%), sepsis (8%) and haematuria (8%). No patients had impaired renal function during follow-up and there were no treatment-related deaths. Seventeen patients (59%) had no evidence of disease at PDE and have not experienced recurrence at a median follow-up of 13.0 months post induction.Administration of mitomycin gel via a PCNT offers a low rate of ureteric stenosis, demonstrates a favourable safety profile, and is administered without general anaesthesia.

Objectives: Increasing numbers of women living with HIV (WLHIV) worldwide receive combination antiretroviral therapy (cART) during pregnancy. We aimed to assess the risk of adverse perinatal outcomes in pregnant WLHIV receiving cART compared with pregnant WLHIV receiving zidovudine monotherapy. Design: Systematic review and meta-analysis. Methods: We searched four electronic literature databases (PubMed, CINAHL, Global Health, EMBASE) for studies published between 1 January 1980 and 20 April 2020 using a comprehensive search strategy. Studies reporting data on WLHIV receiving cART compared with WLHIV receiving monotherapy for 11 adverse perinatal outcomes were sought: preterm birth (PTB), very PTB, spontaneous PTB, low birthweight (LBW), very LBW, preterm and term LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Random-effects meta-analyses were conducted to calculate relative risk (RR) and 95% confidence intervals (95% CI). Results: We included 30 studies reporting on 317 101 pregnant women in 27 countries. WLHIV receiving cART were at increased risk of PTB (RR 1.32, 95% CI 1.18–1.46), LBW (1.35, 1.19–1.53), SGA (1.32, 1.13–1.53), VSGA (1.64, 1.34–2.02), and stillbirth (2.41, 1.83–3.17) compared to WLHIV receiving monotherapy. The significance of these results was maintained in subgroup analyses for studies conducted in low and middle-income countries and average quality studies. Additionally, WLHIV receiving nonnucleoside reverse transcriptase inhibitor-based cART were associated with increased risk of PTB, LBW, and stillbirth, while WLHIV receiving protease inhibitor-based cART were associated with increased risk of PTB, compared with WLHIV receiving monotherapy. Conclusion: Pregnant WLHIV receiving cART are associated with increased risk of adverse perinatal outcomes, compared with WLHIV receiving monotherapy.

Sophisticated multicomponent treatments for adults with generalized anxiety disorder (GAD) have been developed over the past three decades. Although these comprehensive treatments have produced encouraging results, they appear to be less efficacious than treatments for other anxiety disorders. The goal of this randomized controlled trial is to test a newly developed, highly focused treatment for adults with GAD: Behavioral Experiments for Intolerance of Uncertainty. Sixty (60) participants (51 women, 9 men), with a mean age of 34.60 years (range: 19 to 67 years), were randomized to either treatment (n = 30) or wait-list control (n = 30). Treatment consisted of 12 weekly 1-hour sessions in which participants learned to use behavioral experiments to test their catastrophic beliefs about uncertainty. Assessments were conducted at pre-, mid- and postcondition, and at 6- and 12-month follow-up. The primary outcome was the severity of GAD, and secondary outcomes were worry, depression, somatic anxiety, and intolerance of uncertainty. Using growth curve modeling, we found that (1) the treatment group was superior to the wait-list group in terms of change from pre- to posttest on all outcomes; (2) the combined sample (once wait-listed participants received treatment) evidenced large and significant decreases on all outcomes; and (3) treatment gains were either maintained or increased over the 12-month follow-up period of the study. The new treatment is a promising treatment option for adults with GAD considering that it may be as efficacious as more comprehensive evidence-based psychological treatments for GAD.

Patients boarding in a 14-bed postanesthesia care unit (PACU) impacted throughput in a large university hospital in West Virginia. The PACU and operating room (OR) boarder rate in 2019 was 12% (n = 1241) and 5% (n = 503), respectively. The purpose of this initiative was to improve PACU throughput by developing an efficient and evidence-based handoff communication process between the PACU and the medical-surgical floors.The design of the project was evidence-based quality improvement.An interprofessional team created a nursing patient dashboard in the electronic medical record to be used during handoff communication between the PACU and medical-surgical floor nurses. The dashboard displayed real-time vital signs, patient history, medications, and laboratory results. When the patient met Aldrete score requirements for transfer, PACU nurses notified the floor that the patient was ready for transfer. After allowing 20 minutes for the floor nurse to view the dashboard, the PACU nurse and floor nurse spoke on the phone to discuss any outstanding questions. PACU and OR boarder rates were obtained from the electronic medical record 12 months before and after implementing the nursing patient dashboard. User feedback was gathered via plan-do-study-act cycles, posters, and interviews.The electronic dashboard was a successful strategy to improve handoff communication between the PACU and receiving units. The dashboard was accepted by the staff with 70% (n = 24) of the comments being positive. A significant decrease in the number of PACU (χ2(1, n = 20,608) =122.63, Plt; .00001) and OR boarding (χ2 (1, n = 20,283) =14.55, P = .000136) of patients was found in the C-year compared to 2019. For patients who were boarded in the PACU, no significant difference in PACU delay duration was found (t(11) =1.49, P = .149) with the mean in 2019 of 166.96 (SD = 68.38) and the C-Year mean 132.84 (SD = 39.74). For patients who boarded in the OR, there was a significant difference (t(11) =15.590162, Plt;.00001) between groups for average duration of boarding with the mean in 2019 of 19.06 minutes (SD = 3.72) compared to 1.62 (SD = 1.1) in C-year. However, in July 2020 the PACU intermittently opened 2 flexible beds when the PACU was full, suggesting that OR boarding was not a reliable measure, but PACU boarding remained an accurate measure.The findings of this evidence-based quality improvement project demonstrated the usefulness of an electronic dashboard tool combined with verbal report to improve patient throughput by decreasing the number of patients boarding in the PACU.

Cancer testis antigens have been of interest as possible targets for cancer immunotherapies. To better understand the opportunities for the use of such immunotherapy targets, we used a chemical complementarity scoring algorithm and an original web tool to establish aspects of electrostatic complementarity of the CTAs, MAGEA3 and MAGEA6, with melanoma specimen resident, T-cell receptor (TCR) complementarity determining region 3 (CDR3) amino acid sequences. Greater electrostatic complementarity between T-cell receptor CDR3 and tumor CTAs MAGEA3/6 was associated with a greater probability of overall survival, for both the cancer genome atlas and Moffitt Cancer Center samples; and was associated with high levels of T-cell cytotoxicity-related gene expression. Most importantly, this approach allowed for the highly efficient screening of specific segments of the MAGEA3/6 antigens which indicated that certain MAGE segments would have either more or less risk of auto-reactivity. In sum, the chemical complementarity algorithm, and its efficient application via the web tool, adaptivematch.com, offers a convenient opportunity to identify likely parameters important for immunotherapy considerations and melanoma patient risk stratifications.

Introduction: Cannabigerol (CBG), and its precursor before decarboxylation, cannabigerolic acid is sometimes labeled the "mother of all cannabinoids." The purpose of the present study was to investigate reasons for use and self-reported therapeutic effects in CBG-predominant cannabis users. Usage patterns and adverse effects, including withdrawal symptoms were also explored. Methods: Cannabidiol-predominant cannabis users were recruited online to complete an online survey assessing CBG use patterns, conditions treated with CBG-predominant cannabis (containing >50% CBG), perceived efficacy, associated adverse events, and withdrawal symptoms. One hundred twenty-seven eligible participants (U.S. residents ages 21+ who reported using CBG-predominant cannabis in the past 6 months) completed the survey. Results: Most of the samples (n=65; 51.2%) reported use of CBG-predominant products solely for medical purposes (n=46; 36.2% reported use for medical and recreational purposes; n=8; 6.3% reported recreational use only, and n=8 were missing). The most common conditions the complete sample reported using CBG to treat were anxiety (51.2%), chronic pain (40.9%), depression (33.1%), and insomnia/disturbed sleep (30.7%). Efficacy was highly rated, with the majority reporting their conditions were "very much improved" or "much improved" by CBG. Furthermore, 73.9% claimed superiority of CBG-predominant cannabis over conventional medicines for chronic pain, 80% for depression, 73% for insomnia, and 78.3% for anxiety. Forty-four percent of CBG-predominant cannabis users reported no adverse events, with 16.5% noting dry mouth, 15% sleepiness, 11.8% increased appetite, and 8.7% dry eyes. Around 84.3% reported no withdrawal symptoms, with sleep difficulties representing the most frequently endorsed withdrawal symptom (endorsed by two respondents). Conclusions: This is the first patient survey of CBG-predominant cannabis use to date, and the first to document self-reported efficacy of CBG-predominant products, particularly for anxiety, chronic pain, depression, and insomnia. Most respondents reported greater efficacy of CBG-predominant cannabis over conventional pharmacotherapy, with a benign adverse event profile and negligible withdrawal symptoms. This study establishes that humans are employing CBG and suggests that CBG-predominant cannabis-based medicines should be studied in randomized controlled trials.

What is the central question of this study? Do changes in myofibre cross-sectional area, pennation angle and fascicle length predict vastus lateralis whole-muscle cross-sectional area changes following resistance training? What is the main finding and its importance? Changes in vastus lateralis mean myofibre cross-sectional area, fascicle length and pennation angle following a period of resistance training did not collectively predict changes in whole-muscle cross-sectional area. Despite the limited sample size in this study, these data reiterate that it remains difficult to generalize the morphological adaptations that predominantly drive tissue-level vastus lateralis muscle hypertrophy.Myofibre hypertrophy during resistance training (RT) poorly associates with tissue-level surrogates of hypertrophy. However, it is underappreciated that, in pennate muscle, changes in myofibre cross-sectional area (fCSA), fascicle length (L

Solitary fibrous tumours (SFTs) are rare neoplasms derived from mesenchymal cell lines. They are often asymptomatic, follow an indolent growth pattern and are more often benign than malignant. Here, we present a case of a very large, asymptomatic mediastinal SFT in an otherwise healthy man. A 67-year-old Irish man was referred for workup of an asymptomatic murmur. Auscultation of the lung fields revealed diminished breath sounds on the right side. Chest X-ray identified a 20 cm mass localised within the thorax. CT of the thorax confirmed a pleural based, solid lesion with no local invasion. CT-guided core biopsies were reported as consistent with SFT. Primary excision of the lesion was undertaken via median sternotomy. Histological examination confirmed a diagnosis of SFT. The patient remains well at this time. Primary excisive surgery is a safe and effective treatment modality for SFTs.