Chest X-Ray-Based Telemedicine Platform for Pediatric Tuberculosis Diagnosis in Low-Resource Settings: Development and Validation Study.

BACKGROUND: Tuberculosis (TB) remains a major cause of morbidity and death worldwide, with a significant impact on children, especially those under the age of 5 years. The complex diagnosis of pediatric TB, compounded by limited access to more accurate diagnostic tests, underscores the need for improved tools to enhance diagnosis and care in resource-limited settings. OBJECTIVE: This study aims to present a telemedicine web platform, BITScreen PTB (Biomedical Image Technologies Screen for Pediatric Tuberculosis), aimed at improving the evaluation of pulmonary TB in children based on digital chest x-ray (CXR) imaging and clinical information in resource-limited settings. METHODS: The platform was evaluated by 3 independent expert readers through a retrospective assessment of a data set with 218 imaging examinations of children under 3 years of age, selected from a previous study performed in Mozambique. The key aspects assessed were the usability through a standardized questionnaire, the time needed to complete the assessment through the platform, the performance of the readers to identify TB cases based on the CXR, the association between the TB features identified in the CXRs and the initial diagnostic classification, and the interreader agreement of the global assessment and the radiological findings. RESULTS: The platform's usability and user satisfaction were evaluated using a questionnaire, which received an average rating of 4.4 (SD 0.59) out of 5. The average examination completion time ranged from 35 to 110 seconds. In addition, the study on CXR showed low sensitivity (16.3%-28.2%) but high specificity (91.1%-98.2%) in the assessment of the consensus case definition of pediatric TB using the platform. The CXR finding having a stronger association with the initial diagnostic classification was air space opacification (χ21>20.38, P<.001). The study found varying levels of interreader agreement, with moderate/substantial agreement for air space opacification (κ=0.54-0.67) and pleural effusion (κ=0.43-0.72). CONCLUSIONS: Our findings support the promising role of telemedicine platforms such as BITScreen PTB in enhancing pediatric TB diagnosis access, particularly in resource-limited settings. Additionally, these platforms could facilitate the multireader and systematic assessment of CXR in pediatric TB clinical studies.

Optical and Chemical Measurements of Solvated Electrons Produced in Plasma Electrolysis with a Water Cathode.

It is known that glow discharges with a water anode inject and form solvated electrons at the plasma-liquid interface, driving a wide variety of reduction reactions. However, in systems with a water cathode, the production and role of solvated electrons are less clear. Here, we present evidence for the direct detection of solvated electrons produced at the interface of an argon plasma and a water cathode via absorption spectroscopy. We further quantify their yield using the dissociative electron attachment of chloroacetate, measuring a yield of 1.04 ± 0.59 electrons per incident ion, corresponding to approximately 100% faradaic efficiency. Additionally, we estimate a yield of 2.09 ± 0.93 hydroxyl radicals per incident ion. Comparison of this yield with other findings in the literature supports that these hydroxyl radicals are likely formed directly in the liquid phase rather than by diffusion from the vapor phase.

Placebo and nocebo effects of percutaneous needle electrolysis and dry-needling: an intra and inter-treatment sessions analysis of a three-arm randomized double-blinded controlled trial in patients with patellar tendinopathy.

Objective: This study aimed to investigate the influence of potential placebo and nocebo effects on pain perception of percutaneous needle electrolysis (PNE) in individuals with patellar tendinopathy. Methods: In this secondary analysis of a three-arm randomized double-blinded controlled trial, intra and inter-session pain perception data from 48 sporting participants with patellar tendinopathy between 18 and 45 years were investigated. Participants were divided into 3 parallel groups: "no-sham group" [PNE intervention], "single-sham group" [sham PNE by using dry needling], and "double-sham group" [sham PNE by using sham needles]. Every group received 4 sessions of the needling therapies targeting the patellar tendon over 8 weeks and was instructed to perform a unilateral eccentric exercise program of the quadriceps muscle on the affected side. Clinical and needle-related pain was assessed before, during, and after each treatment session using a visual analog scale. Results: No differences were found between groups intra- or inter-session in terms of pain reduction (P = 0.424) despite clinical pain decreased in all groups since the first treatment session (P < 0.001). Furthermore, although the double-sham group showed a lower percentage of participants reporting needle-related pain during needle intervention (P = 0.005), the needle-related pain intensity after needle intervention was similar between groups (P = 0.682). Moreover, there were no group differences for the duration of pain sensation after any needle intervention (P = 0.184), extending in many cases beyond 24 h. Conclusion: Needling therapies for individuals with patellar tendinopathy are prone to elicit placebo effects regarding clinical pain and nocebo effects regarding needling-related pain. Clinicians and physical therapists treating musculoskeletal pain conditions should consider the added value and potential mechanisms of action before routinely using needle techniques.

The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.

BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. METHODS: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. RESULTS: Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. CONCLUSIONS: Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

SARS-CoV-2 Infection of Salivary Glands Compromises Oral Antifungal Innate Immunity and Predisposes to Oral Candidiasis.

Saliva contains antimicrobial peptides considered integral components of host innate immunity, and crucial for protection against colonizing microbial species. Most notable is histatin-5 which is exclusively produced in salivary glands with uniquely potent antifungal activity against the opportunistic pathogen Candida albicans. Recently, SARS-CoV-2 was shown to replicate in salivary gland acinar cells eliciting local immune cell activation. In this study, we performed mechanistic and clinical studies to investigate the implications of SARS-CoV-2 infection on salivary histatin-5 production and Candida colonization. Bulk RNA-sequencing of parotid salivary glands from COVID-19 autopsies demonstrated statistically significant decreased expression of histatin genes. In situ hybridization, coupled with immunofluorescence for co-localization of SARS-CoV-2 spike and histatin in salivary gland cells, showed that histatin was absent or minimally present in acinar cells with replicating viruses. To investigate the clinical implications of these findings, salivary histatin-5 levels and oral Candida burden in saliva samples from three independent cohorts of mild and severe COVID-19 patients and matched healthy controls were evaluated. Results revealed significantly reduced histatin-5 in SARS-CoV-2 infected subjects, concomitant with enhanced prevalence of C. albicans. Analysis of prospectively recovered samples indicated that the decrease in histatin-5 is likely reversible in mild-moderate disease as concentrations tended to increase during the post-acute phase. Importantly, salivary cytokine profiling demonstrated correlations between activation of the Th17 inflammatory pathway, changes in histatin-5 concentrations, and subsequent clearance of C. albicans in a heavily colonized subject. The importance of salivary histatin-5 in controlling the proliferation of C. albicans was demonstrated using an ex vivo assay where C. albicans was able to proliferate in COVID-19 saliva with low histatin-5, but not with high histatin-5. Taken together, the findings from this study provide direct evidence implicating SARS-CoV-2 infection of salivary glands with compromised oral innate immunity, and potential predisposition to oral candidiasis.

Emergency Physicians' Ethical Issues with Hospital Business Models.

BACKGROUND: The changing hospital business model has raised ethical issues for emergency physicians (EPs) in a healthcare system that often prioritizes profits over patient welfare. For-profit hospitals, driven by profit motives, may prioritize treating patients with lucrative insurance plans and those who can afford expensive treatments. Private equity investors, who now own many for-profit hospitals, focus on short-term financial gains, leading to cost-cutting measures and pressure on EPs to prioritize financial goals over patient welfare. Nonprofit hospitals, mandated to provide charity care to the underserved, may fail to meet their community service obligations, resulting in disparities in healthcare access. OBJECTIVE: This review examines the ethical challenges faced by emergency physicians (EPs) in response to the evolving hospital business model, which increasingly prioritizes profits over patient welfare. DISCUSSION: Emergency physicians face ethical dilemmas in this changing environment, including conflicts between patient care and financial interests. Upholding professional ethics and the principle of beneficence is essential. Another challenge is equitable access to healthcare, with some nonprofit hospitals reducing charity care, thus exacerbating disparities. EPs must uphold the ethical principle of justice, ensuring quality care for all patients, regardless of financial means. Conflicts of interest may arise when EPs work in hospitals owned by private equity firms or with affiliations with pharmaceutical companies or medical device manufacturers, potentially compromising patient care. CONCLUSION: Emergency physicians must navigate these ethical issues while upholding professional ethics and advocating for patients' best interests. Collaboration with hospital administrators, policymakers, and stakeholders is vital to address these concerns and prioritize patient welfare in healthcare delivery.

The barriers to and facilitators of implementing early mobilisation for patients with delirium on intensive care units: A systematic review.

Background: Early mobilisation of critically ill patients remains variable across practice. This study set out to determine barriers to and facilitators of early mobilisation for patients diagnosed with delirium in the intensive care unit (ICU). Methods: A mixed-methods descriptive systematic review. Electronic databases (AMED, BNI, CINAHL Plus, Cochrane Library, Medline and EMBASE) were searched for publications up to 22nd December 2021. Independent reviewers screened studies and extracted data using Covidence Systematic Review Management software. Data were summarised according to frequency (n/%) of barriers and facilitators. Thematic analysis of qualitative studies was carried out in order to address the secondary aim. Quantitative studies were assessed using the GRADE quality assessment tool. Qualitative studies were analysed according to the GRADE-CERQual quality assessment tool. This study was prospectively registered on PROSPERO (CRD 42021227655). Results: Ten studies met the inclusion criteria. Quantitative findings demonstrated the presence of delirium was the most common reported barrier to early mobilisation. The most common facilitator was ICU staff experience of positive outcomes as a result of early mobilisation interventions. Thematic analysis identified six main themes that may describe potential meanings behind these findings: (1) knowledge, (2) personal preferences, (3) perceived burden of delirium, (4) perceived complexity, (5) decision-making and (6) culture. Conclusion: These findings highlight the reported need to further understand the impact and value of early mobilisation as a non-pharmacological intervention for patients diagnosed with delirium in ICU. Evaluation of early mobilisation interventions involving key stakeholders may address these concerns and provide effective implementation strategies.

Evaluating the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care: Protocol for the UK-ROX trial.

Background: In the United Kingdom, around 184,000 adults are admitted to an intensive care unit (ICU) each year with over 30% receiving mechanical ventilation. Oxygen is the commonest therapeutic intervention provided to these patients but it is unclear how much oxygen should be administered for the best clinical outcomes. Methods: The UK-ROX trial will evaluate the clinical and cost-effectiveness of conservative oxygen therapy (the minimum oxygen concentration required to maintain an oxygen saturation of 90% ± 2%) versus usual oxygen therapy in critically ill adults receiving supplemental oxygen when invasively mechanically ventilated in ICUs in England, Wales and Northern Ireland. The trial will recruit 16,500 patients from approximately 100 UK adult ICUs. Using a deferred consent model, enrolled participants will be randomly allocated (1:1) to conservative or usual oxygen therapy until ICU discharge or 90 days after randomisation. Objectives: The primary clinical outcome is all cause mortality at 90 days following randomisation. Discussion: The UK-ROX trial has received ethical approval from the South Central - Oxford C Research Ethics Committee (Reference: 20/SC/0423) and the Confidentiality Advisory Group (Reference: 22/CAG/0154). The trial commenced in May 2021 and, at the time of publication, 95 sites had opened to recruitment.

Health-Related Quality of Life and Injuries in Physical Education Students: A Multi-Group Model According to the Degree of Adherence to the Mediterranean Diet.

The Mediterranean diet is considered a healthy eating pattern. It has been shown to improve people's quality of life. When a person suffers injuries, their quality of life suffers. This research aims to accomplish the following: (a) to study the differences in the effect of the health-related quality of life on injuries according to the degree of adherence to the Mediterranean diet, (b) to analyse the existing differences in the variables that make up the health-related quality of life according to the degree of adherence to the Mediterranean diet, and (c) to analyse the degree of adherence to the Mediterranean diet according to whether the participants have suffered any injury. The study was descriptive, cross-sectional, and exploratory in a sample of 556 physical education students. The PREDIMED questionnaire, the SF-36 questionnaire, and a self-administered questionnaire were used. The results showed that high adherence to the Mediterranean diet was associated with higher quality of life and lower injury rates. It was also observed that high adherence to the Mediterranean diet improved the effect of the quality of life on injuries. In conclusion, the Mediterranean diet is beneficial for the quality of life of young university students.

Transcriptomic Signature and Pro-Osteoclastic Secreted Factors of Abnormal Bone-Marrow Stromal Cells in Fibrous Dysplasia.

Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants of GNAS encoding for Gαs and leading to excessive cyclic adenosine monophosphate signaling in bone-marrow stromal cells (BMSCs). The effect of Gαs activation in the BMSC transcriptome and how it influences FD lesion microenvironment are unclear. We analyzed changes induced by Gαs activation in the BMSC transcriptome and secretome. RNAseq analysis of differential gene expression of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, was performed, and the transcriptomic profiles of both models were combined to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. To assess the modulation of several key secreted factors in FD pathogenesis, cytokines and other factors were measured in culture media. Cytokines were also screened in a collection of plasma samples from patients with FD, and positive correlations of several cytokines to their disease burden score, as well as to one another and bone turnover markers, were found. These data support the pro-inflammatory, pro-osteoclastic behavior of FD BMSCs and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.

Inhibition of JAK-STAT pathway corrects salivary gland inflammation and interferon driven immune activation in Sjögren's disease.

OBJECTIVES: Inflammatory cytokines that signal through the Janus kinases-signal transducer and activator of transcription (JAK-STAT) pathway, especially interferons (IFNs), are implicated in Sjögren's disease (SjD). Although inhibition of JAKs is effective in other autoimmune diseases, a systematic investigation of IFN-JAK-STAT signalling and the effect of JAK inhibitor (JAKi) therapy in SjD-affected human tissues has not been fully investigated. METHODS: Human minor salivary glands (MSGs) and peripheral blood mononuclear cells (PBMCs) were investigated using bulk or single-cell (sc) RNA sequencing (RNAseq), immunofluorescence (IF) microscopy and flow cytometry. Ex vivo culture assays on PBMCs and primary salivary gland epithelial cell (pSGEC) lines were performed to model changes in target tissues before and after JAKi. RESULTS: RNAseq and IF showed activated JAK-STAT pathway in SjD MSGs. Elevated IFN-stimulated gene (ISGs) expression associated with clinical variables (eg, focus scores, anti-SSA positivity). scRNAseq of MSGs exhibited cell type-specific upregulation of JAK-STAT and ISGs; PBMCs showed similar trends, including markedly upregulated ISGs in monocytes. Ex vivo studies showed elevated basal pSTAT levels in SjD MSGs and PBMCs that were corrected with JAKi. SjD-derived pSGECs exhibited higher basal ISG expressions and exaggerated responses to IFN-ß, which were normalised by JAKi without cytotoxicity. CONCLUSIONS: SjD patients' tissues exhibit increased expression of ISGs and activation of the JAK-STAT pathway in a cell type-dependent manner. JAKi normalises this aberrant signalling at the tissue level and in PBMCs, suggesting a putative viable therapy for SjD, targeting both glandular and extraglandular symptoms. Predicated on these data, a phase Ib/IIa randomised controlled trial to treat SjD with tofacitinib was initiated.

Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Syndrome: A Case Report and Review of Literature.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant genetic disorder of the small arteries that causes ischemic vascular events, subcortical dementia, behavioral changes, and migraine-like headaches. It is caused by a mutation in the NOTCH3 gene; this disease was first described in 1955 by van Bogaert. We present a 29-year-old woman who presented to the neurology department. She has no history of chronic degenerative diseases. She has been complaining of migraine-like headaches for the past six months. She has cognitive impairment with arithmetic and executive function deficits on neurological examination. Blood biometry and blood chemistry are within normal parameters in her laboratory studies. A viral panel and immunological profile were also performed and were not reactive. A lumbar puncture was performed, and the composition of the cerebrospinal fluid was within normal limits. An MRI was performed, which showed bilateral and symmetric white matter hyperintensities consistent with CADASIL syndrome. There is no specific treatment. Management of these patients is based on symptom control. Neurological sequelae have an important impact on the quality of life and mortality of these patients. For this reason, pharmacological preventive therapies have been sought with controversial evidence.

Perioperative oxygenation-what's the stress?

Oxygen is the most used drug in anaesthesia. Despite such widespread use, optimal perioperative oxygen administration remains highly controversial because of concerns about the competing harms of both hyperoxia and hypoxia. Notwithstanding a Cochrane review concluding that routinely administering a fractional inspired oxygen concentration (FiO2) >0.6 intraoperatively might increase postoperative morbidity and mortality, the World Health Organization (WHO) currently recommends all anaesthetised patients receive 0.8 FiO2 during and immediately after surgery to reduce surgical site infections. Results from the largest trial available at the time of these two reviews (suggesting long-term survival may be worse with high FiO2, particularly in patients with malignant disease) were considered 'biologically implausible' by the WHO's Guideline Development Group. In addition, the integrity of some perioperative oxygen studies has been challenged. Resolving these controversies is of fundamental importance to all perioperative clinicians. This narrative review is based on the inaugural BJA William Mapleson lecture delivered by the senior author (AC) at the 2023 annual meeting of the Royal College of Anaesthetists in Birmingham. We present the current evidence for perioperative oxygen administration and contrast this with how oxygen therapy is targeted in other specialties (e.g. intensive care medicine). We will explore whether anaesthetists follow the WHO recommendations and consider how oxygen administration affects the stress response to surgery. We reason that novel clinical trial designs in combination with targeted experimental medicine studies will be required to improve our understanding of how best to optimise individualised perioperative oxygenation-a cornerstone of anaesthesia.

Transcriptomic signature and pro-osteoclastic secreted factors of abnormal bone marrow stromal cells in fibrous dysplasia.

Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants in GNAS, encoding for Gαs, which leads to excessive cAMP signaling in bone marrow stromal cells (BMSCs). Despite advancements in our understanding of FD pathophysiology, the effect of Gαs activation in the BMSC transcriptome remains unclear, as well as how this translates into their local influence in the lesional microenvironment. In this study, we analyzed changes induced by Gαs activation in BMSC transcriptome and performed a comprehensive analysis of their production of cytokines and other secreted factors. We performed RNAseq of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, and combined their transcriptomic profiles to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. In addition, a comprehensive profile of their secreted cytokines and other factors was performed to identify modulation of several key factors we hypothesized to be involved in FD pathogenesis. We also screened circulating cytokines in a collection of plasma samples from patients with FD, finding positive correlations of several cytokines to their disease burden score, as well as to one another and bone turnover markers. Overall, these data support a pro-inflammatory, pro-osteoclastic behavior of BMSCs bearing hyperactive Gαs variants, and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.

Drug Approval for the Treatment of Geographic Atrophy: How We Got Here and Where We Need to Go.

PURPOSE: To discuss the clinical trial results leading to the US Food and Drug Administration (FDA) approval of anti-complement therapies for geographic atrophy (GA), perspectives on functional data from the GA clinical trials, and how lessons from the FDA approval may guide future directions for basic and clinical research in AMD. DESIGN: Selected literature review with analysis and perspective METHODS: We performed a targeted review of publicly available data from the clinical trials of pegcetacoplan and avacincaptad for the treatment of GA, as well as scientific literature on the natural history of GA and the genetics and basic science of complement in AMD. RESULTS: The approval of pegcetacoplan and avacincaptad was based on an anatomic endpoint of a reduction in the rate of GA expansion over time. However, functional data from 2 phase 3 clinical trials for each drug demonstrated no visual benefit to patients in the treatment groups. Review of the genetics of AMD and the basic science of the role for complement in AMD provides only modest support for targeting complement as treatment for GA expansion, and alternative molecular targets for GA treatment are therefore discussed. Reasons for the disconnect between anatomic and functional outcomes in the clinical trials of anti-complement therapies are discussed, providing insight to guide the configuration of future clinical studies for GA. CONCLUSION: Although avacincaptad and pegcetacoplan are our first FDA-approved treatments for GA, results from the clinical trials failed to show any functional improvement after 1 and 2 years, respectively, calling into question whether the drugs represent a "clinically relevant outcome." To improve the chances of more impactful therapies in the future, we provide basic-science rationale for pursuing non-complement targets; emphasize the importance of ongoing clinical research that more closely pins anatomic features of GA to functional outcomes; and provide suggestions for clinical endpoints for future clinical trials on GA.

Trial-by-trial variability in cortical responses exhibits scaling of spatial correlations predicted from critical dynamics.

In the mammalian cortex, even simple sensory inputs or movements activate many neurons, with each neuron responding variably to repeated stimuli-a phenomenon known as trial-by-trial variability. Understanding the spatial patterns and dynamics of this variability is challenging. Using cellular 2-photon imaging, we study visual and auditory responses in the primary cortices of awake mice. We focus on how individual neurons' responses differed from the overall population. We find consistent spatial correlations in these differences that are unique to each trial and linearly scale with the cortical area observed, a characteristic of critical dynamics as confirmed in our neuronal simulations. Using chronic multi-electrode recordings, we observe similar scaling in the prefrontal and premotor cortex of non-human primates during self-initiated and visually cued motor tasks. These results suggest that trial-by-trial variability, rather than being random noise, reflects a critical, fluctuation-dominated state in the cortex, supporting the brain's efficiency in processing information.

Risk Factors for Meeting Criteria for Switching from Bevacizumab to Aflibercept When Treating Eyes with Diabetic Macular Edema and Visual Acuity of < 20/40.

PURPOSE: To identify factors for meeting prespecified criteria for switching from bevacizumab to aflibercept in eyes with center-involved diabetic macular edema (CI-DME) and moderate vision loss initially treated with bevacizumab in DRCR Retina Network protocol AC. DESIGN: Post hoc analysis of data from a randomized clinical trial. PARTICIPANTS: Two hundred seventy participants with one or both eyes harboring CI-DME with visual acuity (VA) letter score of 69 to 24 (Snellen equivalent, 20/50-20/320). METHODS: Eligible eyes were assigned to receive intravitreal aflibercept monotherapy (n = 158) or bevacizumab followed by aflibercept if prespecified criteria for switching were met between 12 weeks and 2 years (n = 154). MAIN OUTCOME MEASURES: Meeting switching criteria: (1) at any time, (2) at 12 weeks, and (3) after 12 weeks. Associations between meeting the criteria for switching and factors measured at baseline and 12 weeks were evaluated in univariable analyses. Stepwise procedures were used to select variables for multivariable models. RESULTS: In the group receiving bevacizumab first, older participants showed a higher risk of meeting the switching criteria at any time, with a hazard ratio (HR) for a 10-year increase in age of 1.32 (95% confidence interval [CI], 1.11-1.58). Male participants or eyes with worse baseline VA were more likely to switch at 12 weeks (for male vs. female: odds ratio [OR], 4.84 [95% CI, 1.32-17.81]; 5-letter lower baseline VA: OR, 1.30 [95% CI, 1.03-1.63]). Worse 12-week central subfield thickness (CST; 10-µm greater: HR, 1.06 [95% CI, 1.04-1.07]) was associated with increased risk of switching after 12 weeks. The mean ± standard deviation improvement in visual acuity after completing the switch to aflibercept was 3.7 ± 4.9 letters compared with the day of switching. CONCLUSIONS: The identified factors can be used to refine expectations regarding the likelihood that an eye will meet protocol criteria to switch to aflibercept when treatment is initiated with bevacizumab. Older patients are more likely to be switched. At 12 weeks, thicker CST was predictive of eyes most likely to be switched in the future. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia.

Fibrous dysplasia (FD) is a rare, disabling skeletal disease for which there are no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre- and post-treatment in a phase 2 clinical trial of denosumab (NCT03571191) and in murine in vivo and ex vivo preclinical models. Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation, reduced cellularity, and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL inhibition. RNA sequencing of human and mouse tissue supported these findings. The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model, which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts. The results from this study demonstrated that, in addition to its expected antiosteoclastic effect, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions. These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.TRIAL REGISTRATION: ClinicalTrials.gov NCT03571191.

Preoperative aerobic fitness and perioperative outcomes in patients undergoing cystectomy before and after implementation of a national lockdown.

Background: Lower fitness is a predictor of adverse outcomes after radical cystectomy. Lockdown measures during the COVID-19 pandemic affected daily physical activity. We hypothesised that lockdown during the pandemic was associated with a reduction in preoperative aerobic fitness and an increase in postoperative complications in patients undergoing radical cystectomy. Methods: We reviewed routine preoperative cardiopulmonary exercise testing (CPET) data collected prior to the pandemic (September 2018 to March 2020) and after lockdown (March 2020 to July 2021) in patients undergoing radical cystectomy. Differences in CPET variables, Postoperative Morbidity Survey (POMS) data, and length of hospital stay were compared. Results: We identified 267 patients (85 pre-lockdown and 83 during lockdown) who underwent CPET and radical cystectomy. Patients undergoing radical cystectomy throughout lockdown had lower ventilatory anaerobic threshold (9.0 [7.9-10.9] vs 10.3 [9.1-12.3] ml kg-1 min-1; P=0.0002), peak oxygen uptake (15.5 [12.9-19.1] vs 17.5 [14.4-21.0] ml kg-1 min-1; P=0.015), and higher ventilatory equivalents for carbon dioxide (34.7 [31.4-38.5] vs 33.4 [30.5-36.5]; P=0.030) compared with pre-lockdown. Changes were more pronounced in males and those aged >65 yr. Patients undergoing radical cystectomy throughout lockdown had a higher proportion of day 5 POMS-defined morbidity (89% vs 75%, odds ratio [OR] 2.698, 95% confidence interval [CI] 1.143-6.653; P=0.019), specifically related to pulmonary complications (30% vs 13%, OR 2.900, 95% CI 1.368-6.194; P=0.007) and pain (27% vs 9%, OR 3.471, 95% CI 1.427-7.960; P=0.004), compared with pre-lockdown on univariate analysis. Conclusions: Lockdown measures in response to the COVID-19 pandemic were associated with a reduction in fitness and an increase in postoperative morbidity among patients undergoing radical cystectomy.

Pluvicto-Induced 18 F-PSMA PET Bone Flare.

ABSTRACT: A 79-year-old man with a history of metastatic prostate cancer was initially treated with Eligard and switched to relugolix in 2021. The 2022 bone scan presented superscan and extensive osseous metastatic lesions; some had intense PSMA uptake on the initial PSMA PET scan without nodal or visceral metastatic lesions. We treated him with Pluvicto and relugolix. The intermediate PSMA scan demonstrated prominent bone marrow PSMA uptake. However, PSA decreased 58.5%. We hypothesized that the patient might have a bone flare. The final PSMA scan confirmed our hypothesis. Based on our knowledge, this is the first case of Pluvicto-induced bone flare.