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Abstract Objective To characterize the experience of people with epilepsy and aligned healthcare workers (HCWs) during the first 18 months of the COVID‐19 pandemic and compare experiences in high‐income countries (HICs) with non‐HICs. Methods Separate surveys for people with epilepsy and HCWs were distributed online in April 2020. Responses were collected to September 2021. Data were collected for COVID‐19 infections, the effect of COVID‐related restrictions, access to specialist help for epilepsy (people with epilepsy), and the impact of the pandemic on work productivity (HCWs). The frequency of responses for non‐HICs and HICs were compared using non‐parametric Chi‐square tests. Results Two thousand one hundred and five individuals with epilepsy from 53 countries and 392 HCWs from 26 countries provided data. The same proportion of people with epilepsy in non‐HICs and HICs reported COVID‐19 infection (7%). Those in HICs were more likely to report that COVID‐19 measures had affected their health (32% vs. 23%; p

ABSTRACT Background and Aim Pseudomyxoma peritonei (PMP) is an unusual condition with unique behaviour caused by a mucinous neoplasm, usually arising from the appendix. The aim of this study was to evaluate the prevalence of genomic alterations in clinical specimens of PMP using a targeted assay and correlate the findings with clinical, pathological and outcome data. Sequencing data from 223 patients were analysed. Results The median follow‐up interval was 48 months. The primary neoplasm was appendiceal in 216 patients, ovarian in 4, urachal in 2 and renal in one. We confirmed common mutations in GNAS and KRAS (42% each) with significant co‐occurrence of variants in these genes. TP53 mutations were found in 8%. Other mutations were rare but included novel mutations in BAP1 and ERBB4. Of 17 patients with acellular peritoneal mucin, 6 (35%) were positive for DNA mutations. The non‐appendiceal cases generally showed a similar mutational landscape to the appendiceal lesions with GNAS and KRAS commonly mutated, although one urachal lesion showed multi‐hit TP53 mutation without variants in either GNAS or KRAS. Survival was significantly associated with the grade of the primary neoplasm, the grade of the peritoneal disease, the completeness of cytoreduction score and with mutation in either GNAS, KRAS or both. The hazard ratio (HR) associated with mutation in GNAS and/or KRAS was 1.87 (p = 0.004). Conclusions Survival outcome was more closely associated with the grade of the peritoneal disease than with the grade of the primary neoplasm. Our findings support the developing concept that mutational analysis may provide prognostic information in patients with PMP.

ABSTRACT Introduction Evidence examines how persons experiencing Long COVID (LC) struggle to secure healthcare for symptoms. However, few studies examine healthcare workers experiencing LC, nor the complex and multiple difficulties faced when seeking and receiving healthcare. Methods This study is based on two phases of longitudinally conducted qualitative interviews, 6 months apart, with National Health Service (NHS) workers experiencing LC, from different occupational roles at NHS locales in Scotland (first interviews, n = 50; second interviews, n = 44). Results Multiple factors restricted healthcare access, including worries about pressuring the NHS and concerns over LC being legitimised. When healthcare was sought, workers struggled to secure support, referrals and treatment. The following reasons were included: (1) context: the restrictive pandemic healthcare context; (2) illness climate: low GP knowledge surrounding LC and how this could be treated, trends for ascribing symptoms to other causes and reluctance to diagnose LC; (3) sense‐making of LC: healthcare availability linked to occupational role identity. To visualise and examine healthcare barriers, candidacy theory is applied, drawing inferences between healthcare context, illness climate, sense‐making and identities. Conclusion NHS workers' complex journeys represent Disrupted Candidacy, intersecting challenges across candidacy domains, restricting the seeking and receiving of LC healthcare. Findings provide insights into why NHS workers resisted and withdrew from healthcare‐seeking, and the barriers they faced when attempting to secure LC support. This study presents a pathway for future LC illness research to use a modified candidacy theory framework. Patient and Public Contribution This research focuses on amplifying and learning from lived experiences, and the voices of NHS workers in Scotland experiencing LC. Interviews represent primary data for this study; thus, participants and their healthcare journeys are centred in this research and all aspects of production, reporting and output. Explicit discussions of stakeholder group involvement are highlighted in the methods section.

Abstract The aim was to examine the acute effects of sprint exercise (SIT) on global gene expression in subcutaneous adipose tissue (AT) in healthy subjects, to enhance understanding of how SIT influences body weight regulation. The hypothesis was that SIT upregulates genes involved in mitochondrial function and fat metabolism. A total of 15 subjects performed three 30‐s all‐out sprints (SIT). Samples were collected from AT, skeletal muscle (SM) and blood (brachial artery and a subcutaneous AT vein) up to 15 min after the last sprint. Results showed that markers of oxidative stress, such as the purines hypoxanthine, xanthine and uric acid, increased markedly by SIT in both the artery and the AT vein. Purines also increased in AT and SM tissue. Differential gene expression analysis indicated a decrease in signaling for mitochondrial‐related pathways, including oxidative phosphorylation, electron transport, ATP synthesis, and heat production by uncoupling proteins, as well as mitochondrial fatty acid beta oxidation. This downregulation of genes related to oxidative metabolism suggests an early‐stage inhibition of the mitochondria, potentially as a protective mechanism against SIT‐induced oxidative stress.

ABSTRACT Background Congenital disorders of glycosylation (CDG) are a group of neurometabolic diseases that result from genetic defects in the glycosylation of proteins and/or lipids. Multiple pathogenic genes contribute to the varying reported phenotypes of individuals with CDG‐1 syndromes, most of which are inherited as autosomal recessive traits, although X‐linked inheritance has also been reported. Pathogenic variants in the asparagine‐linked glycosylation 13 homolog (ALG13) gene have been implicated in the aetiology of developmental and epileptic encephalopathy (DEE) 36 (OMIM:*300776, DEE36). The NM_001099922.3:c.320A>G; p.(Asn107Ser) variant is the most frequently described pathogenic variant in ALG13, with 59 females and 2 males with this variant reported to date. Methods We report on a male with a de novo, hemizygous variant in ALG13: c.320A>G; p.(Asn107Ser), whose phenotype resembles that of two previously reported males with the same variant. Results All three males have a de novo mutation, infantile spasms, DEE, drug‐resistant epilepsy, intellectual disability, dysmorphic findings, recurrent infections, skeletal anomalies, brain abnormalities and a movement disorder: a phenotype not consistently reported in males with other pathogenic variants in ALG13. Conclusion The similarity of phenotype in the three males with the c.320A>G variant in ALG13, suggests a possible genotype–phenotype correlation.

Abstract Background With the burden of colorectal cancer in Canada, there is a need to address the psycho‐oncologic challenges, including mental health. This study aims to explore the lived mental health experiences in patients with CRC across the phases of the CRC care continuum. Methods We employed a patient‐oriented constructivist grounded theory design and recruited English speaking participants ≥18 years, diagnosed with CRC within the last 10 years, residing in Canada. We collected data through semi‐structured individual interviews using a guide co‐constructed with patient research partners. Data collection and analysis were iterative, employed theoretical sampling, and culminated in a theoretical model. Results Twenty‐eight participants diagnosed with CRC (18 females, 10 males), aged 18–63 years at time of diagnosis were interviewed, with representation across all CRC stages. There were 10 participants (36%) in treatment, 12 participants (43%) in follow‐up, and 6 participants (21%) in the beyond phase. We constructed a patient‐oriented theory illustrating the dynamic nature between one's self‐identity and their mental health experiences across the CRC care continuum. Mental health experiences encompass emotional and cognitive‐behavioral responses, expressed differently across phases. Mental health care experiences are also shaped by barriers, facilitators, and individual contextual factors, all of which influence their access to care. Conclusion Our theory provides insight into the mental health experiences of patients with CRC across phases of the CRC care continuum. Understanding patients' emotional and cognitive‐behavioral responses and care experiences can help identify opportunities to integrate mental health into CRC care.

Abstract Changes in myonuclear architecture and positioning are associated with exercise adaptations and ageing. However, data on the positioning and number of myonuclei following exercise are inconsistent. Additionally, whether myonuclear domains (MNDs; i.e., the theoretical volume of cytoplasm within which a myonucleus is responsible for transcribing DNA) and myonuclear positioning are altered with age remains unclear. The aim of this investigation was to investigate relationships between age and activity status and myonuclear domains and positioning. Vastus lateralis muscle biopsies from younger endurance‐trained (YT) and older endurance‐trained (OT) individuals were compared with age‐matched untrained counterparts (YU and OU; OU samples were acquired during surgical operation). Serial, optical z‐slices were acquired throughout isolated muscle fibres and analysed to give three‐dimensional coordinates for myonuclei and muscle fibre dimensions. The mean cross‐sectional area (CSA) of muscle fibres from OU individuals was 33%–53% smaller compared with the other groups. The number of nuclei relative to fibre CSA was 90% greater in OU compared with YU muscle fibres. Additionally, scaling of MND volume with fibre size was altered in older untrained individuals. The myonuclear arrangement, in contrast, was similar across groups. Fibre CSA and most myonuclear parameters were significantly associated with age in untrained individuals, but not in trained individuals. These data indicate that regular endurance exercise throughout the lifespan might better preserve the size of muscle fibres in older age and maintain the relationship between fibre size and MND volumes. Inactivity, however, might result in reduced muscle fibre size and altered myonuclear parameters.

Abstract Solute carriers (SLCs) regulate transfer of a wide range of molecules across cell membranes using facilitative or secondary active transport. In pregnancy, these transporters, expressed at the placental barrier, are important for delivery of nutrients to the fetus, whilst also limiting entry of potentially harmful substances, such as drugs. In the present study, RNA‐sequencing analysis was used to investigate expression of SLCs in the fetal (embryonic day 19) rat brain, choroid plexus and placenta in untreated control animals and following maternal paracetamol treatment. In the treated group, paracetamol (15 mg/kg) was administered to dams twice daily for 5 days (from embryonic day 15 to 19). In untreated animals, overall expression of SLCs was highest in the placenta. In the paracetamol treatment group, expression of several SLCs was significantly different compared with control animals, with ion, amino acid, neurotransmitter and sugar transporters most affected. The number of SLC transcripts that changed significantly following treatment was the highest in the choroid plexus and lowest in the brain. All SLC transcripts that changed in the placenta following paracetamol treatment were downregulated. These results suggest that administration of paracetamol during pregnancy could potentially disrupt fetal nutrient homeostasis and affect brain development, resulting in major consequences for the neonate and extending into childhood.

Abstract Keratoderma climactericum is characterized by palmoplantar hyperkeratosis developing after the onset of menopause. Although rare, keratoderma climactericum can profoundly impact quality of life and may be refractory to prescription‐strength topical steroids and keratolytics. We report a 52‐year‐old female with a 1‐year history of palmoplantar keratoderma. She had a medical history of generalized anxiety disorder and had reached menopause 2 years before presentation. Previously failed treatments included clotrimazole 1% cream twice daily, triamcinolone 0.1% cream twice daily, and betamethasone 0.05% cream mixed with tazarotene 0.1% cream twice daily. She was diagnosed with keratoderma climactericum, and conjugated oestrogen 0.625 mg/g cream twice daily was initiated. After 4 weeks, she had dramatically reduced erythema and hyperkeratosis of her bilateral palms and soles. No adverse effects to treatment were reported. Although the utility of topical oestrogen for keratoderma climactericum has been debated, our case provides further evidence for its efficacy and safety.

Abstract Background and Aims Chronic wounds present a growing challenge in the aging population, resulting in an extended course of treatment and an increased influx of patients with recalcitrant wounds seeking admission to hospitals. Furthermore, the general trend in patient care is toward simple and inexpensive treatment methods, feasible in an outpatient setting with little material costs. This retrospective case study aims to elucidate the operative procedure and outcomes associated with hair follicle unit transplantation utilizing punch grafts from the scalp for the management of hard‐to‐heal wounds. Methods A cohort of 28 patients, comprising 20 males and eight females, with a mean age of 72.61 years (range: 48−89) and an average wound area of 82.49 cm2, underwent dissection of punch grafts containing hair follicles (2−3 mm in diameter) from the scalp. Subsequently, these grafts were transplanted into the wound bed. The retrospective evaluation of ulcer healing encompassed photo documentation and clinical records, while patient satisfaction was assessed through structured questionnaires. Results In 78.6% (22) of the cases, a favorable impact on wound healing was observed, characterized by epithelization, and in 57.1% (16) of the patients, complete wound closure was achieved. With the exception of one donor site, all other sites healed without complications. The patient survey indicated that the majority of individuals subjected to the procedure did not perceive it as painful or time‐consuming. Notably, 81% (17) of individuals expressed a willingness to undergo the treatment again. Even in challenging wound conditions, such as pyoderma gangrenosum, our method demonstrated a positive effect on wound healing. Conclusion Within our cohort, the utilization of hair follicle units in the management of hard‐to‐heal wounds resulted in either complete or partial wound closure for the majority of patients, accompanied by minimal morbidity, reduced operation time, and a low incidence of complications and associated costs.

Abstract Carbon‐based nanomaterials have catalyzed breakthroughs across various scientific and engineering disciplines. The key to unlocking a new generation of tailor‐made nanomaterials based on single‐walled carbon nanotubes (SWCNTs) lies in the precise sorting of raw material into individual chiralities, each possessing unique properties. This can be achieved using conjugated polymer extraction (CPE), but to a very limited extent since the process generates only a few chirality‐enriched suspensions. Therefore, it is imperative to comprehend the mechanism of the wrapping of SWCNTs by polymers to unleash CPE's full potential. However, the lack of a diverse palette of chirality‐selective polymers with varying macromolecular parameters has hindered a comprehensive understanding of how the nature of the polymer affects the performance and selectivity of SWCNT isolation. To address this gap, multiple batches of such polymers are synthesized to elucidate the impact of molecular weight and dispersity on the purity and concentrations of the generated SWCNT suspensions. The obtained results explain the inconsistent outcomes reported in the literature, greatly improving the application potential of this promising SWCNT sorting approach. Concomitantly, the discovered significant influence of the macromolecular characteristics of conjugated polymers on the SWCNT isolation efficacy sheds considerable insight into the unresolved mechanism of this sorting technique.

Abstract Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse reaction characterised by fever, lymphadenopathy, morbilliform rash, haematologic abnormalities, and multiorgan involvement. Herein, we describe a 32‐year‐old female presenting with a 9‐day history of facial oedema, cervical and inguinal lymphadenopathy, and a pruritic rash comprised of vesicles and pustules on her face, trunk, and extremities. Her only medications were valproate, which she had been taking for several years, and levetiracetam, which was initiated 41 days prior to rash onset. On the 16th day of her rash, she was diagnosed with DRESS induced by levetiracetam (Registry of Severe Cutaneous Adverse Reactions: 5). At this point, her absolute eosinophil count was 0.9 × 109 cells/L and aspartate and alanine transaminase levels were 357 and 339 U/L, respectively. Pustules with a morbilliform rash may occur in up to 30% of DRESS cases. In rarer instances, as in our patient, DRESS can present with isolated pustules and vesicles. Similarly, although rare, DRESS can be induced by levetiracetam.

Key Clinical Message This case report explores the clinical journey of a patient initially diagnosed with botryomycosis, only to later reveal the underlying and rare condition of actinomycosis. The report highlights the challenges in getting to an accurate diagnosis, emphasizing the importance of considering uncommon pathologies, the utility of multi‐disciplinary teams and clinico‐pathologic correlation in clinical practice.

Abstract Beyond SARS‐CoV2 vaccines, mRNA drugs are being explored to overcome today's greatest healthcare burdens, including cancer and cardiovascular disease. Synthetic mRNA triggers immune responses in transfected cells, which can be reduced by chemically modified nucleotides. However, the side effects of mRNA‐triggered immune activation on cell function and how different nucleotides, such as the N1‐methylpseudouridine (m1Ψ) used in SARS‐CoV2 vaccines, can modulate cellular responses is not fully understood. Here, cellular responses toward a library of uridine‐modified mRNAs are investigated in primary human cells. Targeted proteomics analyses reveal that unmodified mRNA induces a pro‐inflammatory paracrine pattern marked by the secretion of chemokines, which recruit T and B lymphocytes toward transfected cells. Importantly, the magnitude of mRNA‐induced changes in cell function varies quantitatively between unmodified, Ψ‐, m1Ψ‐, and 5moU‐modified mRNA and can be gradually tailored, with implications for deliberately exploiting this effect in mRNA drug design. Indeed, both the immunosuppressive effect of stromal cells on T‐cell proliferation, and the anti‐inflammatory effect of IL‐10 mRNA are enhanced by appropriate uridine modification. The results provide new insights into the effects of mRNA drugs on cell function and cell‐cell communication and open new possibilities to tailor mRNA‐triggered immune activation to the desired pro‐ or anti‐inflammatory application.

Abstract Objective To evaluate the longitudinal correlations between sulfatide/lysosulfatide levels and central and peripheral nervous system function in children with metachromatic leukodystrophy (MLD) and to explore the impact of intravenous recombinant human arylsulfatase A (rhASA) treatment on myelin turnover. Methods A Phase 1/2 study of intravenous rhASA investigated cerebrospinal fluid (CSF) and sural nerve sulfatide levels, 88‐item Gross Motor Function Measure (GMFM‐88) total score, sensory and motor nerve conduction, brain N‐acetylaspartate (NAA) levels, and sural nerve histology in 13 children with MLD. Myelinated and unmyelinated nerves from an untreated MLD mouse model were also analyzed. Results CSF sulfatide levels correlated with neither Z‐scores for GMFM‐88 nor brain NAA levels; however, CSF sulfatide levels correlated negatively with Z‐scores of nerve conduction parameters, number of large (≥7 μm) myelinated fibers, and myelin/fiber diameter slope, and positively with nerve g‐ratios and cortical latencies of somatosensory‐evoked potentials. Quantity of endoneural litter positively correlated with sural nerve sulfatide/lysosulfatide levels. CSF sulfatide levels decreased with continuous high‐dose treatment; this change correlated with improved nerve conduction. At 26 weeks after treatment, nerve g‐ratio decreased by 2%, and inclusion bodies per Schwann cell unit increased by 55%. In mice, abnormal sulfatide storage was observed in non‐myelinating Schwann cells in Remak bundles of sciatic nerves but not in unmyelinated urethral nerves. Interpretation Lower sulfatide levels in the CSF and peripheral nerves correlate with better peripheral nerve function in children with MLD; intravenous rhASA treatment may reduce CSF sulfatide levels and enhance sulfatide/lysosulfatide processing and remyelination in peripheral nerves.

Abstract Biallelic CNTNAP2 variants have been associated with Pitt‐Hopkins‐like syndrome. We describe six novel and one previously reported patients from six independent families and review the literature including 64 patients carrying biallelic CNTNAP2 variants. Initial reports highlighted intractable focal seizures and the failure of epilepsy surgery in children, but subsequent reports did not expand on this aspect. In all our patients (n = 7), brain MRI showed bilateral temporal gray/white matter blurring with white matter high signal intensity, more obvious on the T2‐FLAIR sequences, consistent with bilateral temporal lobe dysplasia. All patients had focal seizures with temporal lobe onset and semiology, which were recorded on EEG in five, showing bilateral independent temporal onset in four. Epilepsy was responsive to anti‐seizure medications in two patients (2/7, 28.5%), and pharmaco‐resistant in five (5/7, 71.5%). Splice‐site variants identified in five patients (5/7, 71.5%) were the most common mutational finding. Our observation expands the phenotypic and genetic spectrum of biallelic CNTNAP2 alterations focusing on the neuroimaging features and provides evidence for an elective bilateral anatomoelectroclinical involvement of the temporal lobes in the associated epilepsy, with relevant implications on clinical management.

Abstract Biological resistance to pesticides, vaccines, antibiotics, and chemotherapies creates huge costs to society, including extensive morbidity and mortality. We simultaneously face costly resistance to social changes, such as those required to resolve human–wildlife conflicts and conserve biodiversity and the biosphere. Viewing resistance as a force that impedes change from one state to another, we suggest that an analysis of biological resistance can provide unique and potentially testable insights into understanding resistance to social changes. We review key insights from managing biological resistance and develop a framework that identifies seven strategies to overcome resistance. We apply this framework to consider how it might be used to understand social resistance and generate potentially novel hypotheses that may be useful to both enhance the development of strategies to manage resistance and modulate change in socio‐ecological systems.

Abstract Aims Heart failure with reduced ejection fraction (HFrEF) is associated with excessive sympathetic and impaired parasympathetic activity. The Barostim Neo™ device is used for electronical baroreflex activation therapy (BAT) to counteract autonomic nervous system dysbalance. Randomized trials have shown that BAT improves walking distance and reduces N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP) levels at least in patients with only moderate elevation at baseline. Its impact on the risk of heart failure hospitalization (HFH) and death is not yet established, and experience in clinical routine is limited. Methods and results We report on patient characteristics and clinical outcome in a retrospective, non‐randomized single‐centre registry of BAT in HFrEF. Patients in the New York Heart Association (NYHA) Classes III and IV with a left ventricular ejection fraction (LVEF) 1600 pg/mL, or estimated glomerular filtration rate (eGFR)

Abstract Current global warming results in an uptake of heat by the Earth system, which is distributed among the different components of the climate system. However, current‐generation climate models deliver heat inventory and partitioning estimates of Earth system components that differ from recent observations. Here we investigate the global heat distribution under warming by using fully‐coupled CMIP6 Earth system model experiments, including a version of the MPI‐ESM with a deep land model component, accommodating the required space for more realistic terrestrial heat storage. The results show that sufficiently deep land models exert increased subsurface land heat uptake, leading to a heat uptake partitioning among the Earth system components that is closer to observational estimates. The results are relevant for the understanding of Earth's heat partitioning and highlight the importance of the land heat sink in the Earth heat inventory.

Abstract Over 60% of relapsed/refractory (R/R) large B‐cell lymphoma (LBCL) patients who receive chimeric antigen receptor (CAR) T cells will experience disease progression. There is no standard next line of therapy and information in this setting is scarce and heterogeneous. We analyzed 387 R/R LBCL patients who progressed after CAR T cells from July 2018 until March 2022 in Spain and the United Kingdom. Median overall survival (OS) was 5.3 months, with significant differences according to the interval between infusion and progression (6 months [not reached]). After progression, 237 (61%) patients received treatment. Focusing on the first subsequent therapy, overall (complete) response rates were 67% (38%) for polatuzumab–bendamustine–rituximab (POLA), 51% (36%) for bispecific antibodies (BsAb), 45% (35%) for radiotherapy (RT), 33% (26%) for immune checkpoint inhibitors (ICIs), 25% (0%) for lenalidomide (LENA), and 25% (14%) for chemotherapy (CT). In terms of survival, 12‐month progression‐free survival and OS was 36.2% and 51.0% for POLA, 32.0% and 50.1% for BsAb, 30.8% and 37.5% for RT, 29.9% and 27.8% for ICI, 7.3% and 20.8% for LENA, and 6.1% and 18.3% for CT. Thirty‐two (14%) patients received an allogeneic hematopoietic cell transplant with median OS not reached after a median follow‐up of 15.1 months. In conclusion, patients with R/R LBCL who progress within the first 2 months after CAR T‐cell therapy have dismal outcomes. Novel targeted agents, such as polatuzumab and BsAbs, can achieve prolonged survival after CAR T‐cell therapy failure.

Key Clinical Message This case suggests using dual orexin receptor antagonists to treat alcohol use disorder and comorbid sleep disorders may be effective, commencing treatment in withdrawal and continuing it to prevent relapse. Abstract Effective medications for the treatment of alcohol use disorder are limited. This is partially due to the heterogenous nature of the symptomatology associated with alcohol use disorder and the abundance of presenting comorbidities. One common, and often overlooked, symptom that occurs during withdrawal of alcohol use is sleep disruption. Here, we report a case study of a participant with comorbid alcohol use disorder and insomnia. This participant was treated with a dual orexin receptor antagonist, suvorexant (Belsomra®), currently approved to treat insomnia. We demonstrate improvements in alcohol cravings, physical and psychological health, and sleep outcomes with treatment. These data support abundant preclinical and emerging clinical data in this space. The findings from this case report highlight the potential for suvorexant to treat comorbid alcohol use disorder and insomnia with fully powered, randomized controlled trials moving forward.

Abstract Amongst a cohort of 88 alkaptonuria (AKU) patients attending the United Kingdom National Alkaptonuria Centre (NAC), four unrelated patients had co‐existing Parkinson's disease (PD). Two of the NAC patients developed PD before receiving nitisinone (NIT) while the other two developed overt PD during NIT therapy. NIT lowers redox‐active homogentisic acid (HGA) and profoundly increases tyrosine (TYR). A further unpublished case of a Dutch patient with AKU and PD on deep brain stimulation is included in this report. A Pubmed search revealed a further five AKU patients with PD, all without NIT usage. The prevalence of PD in AKU in the NAC appears to be nearly 20‐times higher than in the non‐AKU population (p

Abstract The current move towards digital pathology enables pathologists to use artificial intelligence (AI)‐based computer programmes for the advanced analysis of whole slide images. However, currently, the best‐performing AI algorithms for image analysis are deemed black boxes since it remains – even to their developers – often unclear why the algorithm delivered a particular result. Especially in medicine, a better understanding of algorithmic decisions is essential to avoid mistakes and adverse effects on patients. This review article aims to provide medical experts with insights on the issue of explainability in digital pathology. A short introduction to the relevant underlying core concepts of machine learning shall nurture the reader's understanding of why explainability is a specific issue in this field. Addressing this issue of explainability, the rapidly evolving research field of explainable AI (XAI) has developed many techniques and methods to make black‐box machine‐learning systems more transparent. These XAI methods are a first step towards making black‐box AI systems understandable by humans. However, we argue that an explanation interface must complement these explainable models to make their results useful to human stakeholders and achieve a high level of causability, i.e. a high level of causal understanding by the user. This is especially relevant in the medical field since explainability and causability play a crucial role also for compliance with regulatory requirements. We conclude by promoting the need for novel user interfaces for AI applications in pathology, which enable contextual understanding and allow the medical expert to ask interactive ‘what‐if’‐questions. In pathology, such user interfaces will not only be important to achieve a high level of causability. They will also be crucial for keeping the human‐in‐the‐loop and bringing medical experts' experience and conceptual knowledge to AI processes.

Abstract Objectives We will demonstrate that FIRDA (frontal intermittent rhythmic delta activity)—otherwise related to systemic disorders and encephalopathy—has a role as an epileptic biomarker of deep‐seated midline SOZ. Its abolishment following SEEG‐guided radiofrequency of such SOZ correlates with clinical improvement suggesting its role as a noninvasive biomarker of otherwise inaccessible SOZs. Methods We report the case of AK who was admitted with “psychiatric and gastrointestinal complaints.” AK's complaints were further associated with FIRDA during VEEG. His previous refractoriness to AEDs, the clinico‐electroencephalographic correlation, MRI showing bilateral hippocampal atrophy (more to the left) and severe memory deficits, prompted us to suggest a left temporo‐mesial SOZ, for which SEEG was done. Dual SEEG and scalp electrodes were used primarily for diagnostic purposes but taking into account an option for a therapeutic action by RF ablation. Results The dual array demonstrated a clear association between left hippocampal high voltage spikes and HFOs on SEEG recordings with FIRDA on concomitant scalp EEG parallel to behavioral changes, as suspected in our preliminary hypothesis. A further RF ablation eliminated the epileptiform activity (Spikes, HFOs, and FIRDA) followed by clinical improvement. Significance This is the first report showing the clinical significance of FIRDA associated with behavioral changes as a marker for latent refractory mesial epilepsy. SEEG exploration has the potential to uncover deep sources, which are manifested as FIRDA on scalp EEG. These abnormalities and clinical symptoms can be eliminated by RF ablation.

Key Clinical Message D. dimer could be useful as an indicator in diagnosis of mesenteric ischemia in COVID patients. A two staged damage control emergency laparotomy is of good benefits in such patients. Abstract Bowel ischemia in COVID 19 patients is extremely rare condition results from migrating thrombus formed by a hypercoagulable inflammatory state that is frequently associated COVID 19 infection. A two staged damage control emergency laparotomy is of good benefits in general especially in those with active COVID 19 infection.

Abstract Introduction Telepractice service delivery of allied health interventions to people with disability can potentially reduce access barriers and improve service equity. However, questions remain regarding telepractice functionality for people with disability. This study addressed questions related to how allied health clinicians and managers perceive telepractice as functioning in the provision of therapy services to people with disability. Methods Thirteen interviews of allied health clinicians and managers from across Australia were conducted between 21 November and 22 February via MS teams. Qualitative methodology and critical realist theoretical paradigm underpin the study. Data analysis was completed using a reflective thematic analysis method and five themes were generated and described utilising an analytic metaphor. Results The study themes were described in relation to a shopping for shoes analytic metaphor and the five themes included (1) a shoe for every foot, (2) planned purchases, (3) shoe on the other foot, (4) you need both shoes and (5) help choosing their shoes. In summary, the function of telepractice fits differently for each individual, similar to pairs of shoes. Conclusions Telepractice has its own strengths and weaknesses and isn't a direct substitute for in‐person sessions, much like left and right shoes are similar but not the same. The results support participant perceptions that telepractice functions best as an adjunct to in‐person sessions through a flexible hybrid delivery model in the provision of therapy services to people with a disability. A strategy for improving perceived usefulness may involve positioning telepractice as unique with strengths and weaknesses, not replacing in‐person care. Patient or Public Contribution The paper forms part of a larger codesign process which included customer and carer participants throughout the design and planning of the project, inclusion of a peer researcher, and the selection of the analytic metaphor including in the findings of this article production.

Abstract Introduction Telepractice has the potential to align with the directive to reduce inequalities by United Nations Sustainable Development Goal 10. Telepractice additionally addresses a national digital health strategic plan for accessible digitally enabled models of care. To plan improvements, it is essential to understand the experience of telepractice for people with disability, which may be achieved through an approach such as journey mapping. The current article provides both a disability‐specific case study and a methodological guide for the inclusion of customers and clinicians in the meaningful redevelopment of services. The Perth, Australia‐based case study aimed to gain insights into the experience of telepractice for people with disability. The methodological aim describes using co‐design to produce a journey map in collaboration with customers and clinicians, for potential replication in a wide range of health and social care contexts. Method Interview transcripts gathered from a cohort of customer participants (n = 17) were used to inform the journey map. A group of customers (n = 5) and clinicians plus one manager (n = 5) distributed the findings onto a customer experience journey map during a co‐design workshop. The journey map describes the emotional experience and actions taken, along five phases of a timeline through telepractice service interactions: (1) before, (2) selecting telepractice, (3) telepractice preparation, (4) during telepractice sessions and (5) after. Results A journey map visualisation of customer experiences was produced that identified strengths of telepractice service delivery (flexibility) while noting challenges (with technology) as opportunities for improvement. The consensus of participants was the desire to have access to telepractice currently and in the future, in addition to in‐person delivery. Conclusion These findings are valuable in the context of advocating for the incorporation of customers and clinicians through co‐design workshops in the content analysis and creation of a journey map that is representative of the lived experience of accessing telepractice services. Patient or Public Contribution The paper forms part of a larger co‐design process that included customer participants throughout the design and planning of the project, inclusion of a peer researcher and the co‐designers in the workshops, journey map and this article production.

Abstract Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year‐on‐year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non‐vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its ‘Minimal Information for Studies of Extracellular Vesicles’, which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.

Background This study evaluated the effects of canagliflozin in patients with type 2 diabetes with and without prevalent cardiovascular disease (secondary and primary prevention). Methods and Results This was a pooled participant‐level analysis of the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program and CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. The CANVAS Program included participants with type 2 diabetes at elevated cardiovascular risk, whereas the CREDENCE trial included participants with type 2 diabetes and albuminuric chronic kidney disease. Hazard ratios (HRs) with interaction terms were obtained from Cox regression models to estimate relative risk reduction with canagliflozin versus placebo across the primary and secondary prevention groups. We analyzed 5616 (38.9%) and 8804 (61.1%) individuals in the primary and secondary prevention subgroups, respectively. Primary versus secondary prevention participants were on average younger (62.2 versus 63.8 years of age) and more often women (42% versus 31%). Canagliflozin reduced the risk of major adverse cardiovascular events (HR, 0.84 [95% CI, 0.76–0.94]) consistently across primary and secondary prevention subgroups (Pinteraction=0.86). Similarly, no treatment effect heterogeneity was observed with canagliflozin for hospitalization for heart failure, cardiovascular death, end‐stage kidney disease, or all‐cause mortality (all Pinteraction>0.5). Conclusions Canagliflozin reduced cardiovascular and kidney outcomes with no statistical evidence of heterogeneity for the treatment effect across the primary and secondary prevention subgroups in the CANVAS Program and CREDENCE trial. Although studies on the optimal implementation of canagliflozin within these populations are warranted, these results reinforce canagliflozin's role in cardiorenal prevention and treatment in individuals with type 2 diabetes. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01032629, NCT01989754, NCT02065791.

A formulated photocurable poly(ethylene glycol) diacrylate (PEGDA) and 2-hydroxylethyl methacrylate (HEMA) polymer matrix (PEGDA:HEMA) was developed for constructing an adsorptive 3D cubic monolith using masked stereolithography (MSLA) 3D-printing technique. A pure PEGDA formulation served as a control in comparative studies. Additionally, two structural designs (solid cube and cubic lattice) were also quantitatively compared to determine the adsorption performance for Rhodamine B (RhB) dye removal. Results indicated that the cubic lattice formulated with hydrophilic PEGDA:HEMA (θ~47.20°) was more effective at removing RhB dye. Additionally, the preliminary study identified pH 9 as the optimal level for RhB dye removal using 3D cubic monolith for both formulations. A Taguchi orthogonal array of L9 (33) was used to concurrently vary three parameters: adsorbent dosage (0.65±0.02 g per cubic lattice), operating temperature (30°C, 40°C, and 50°C), and initial RhB concentration (20, 60, and 100 ppm). The highest mean of the signal-to-noise (S/N) ratio was chosen to obtain the highest adsorption performance. The removal efficiency (R%) of RhB dye ranged from 44.48% to 94.86%, and the adsorption capacity (K) ranged from 0.59 to 3.73 (mg/g) after 5 h. Seven adsorption isotherms and five adsorption kinetics modelling were performed. Adsorption isotherm data fitted well with the Redlich–Peterson model for both linear (R2=0.998) and nonlinear (R2=1). Besides that, the pseudo-second-order model (PSO) accurately described adsorption kinetics (R2=0.995). The separation factor (RL) confirmed favourable adsorption (0

Background Arterial stiffening and increased intima‐media thickness can be seen as early as childhood and are associated with increased risk of cardiovascular events in adult life. The authors hypothesized that exposure to prenatal smokeless tobacco (Swedish snus) without additional nicotine exposure after the breastfeeding period would be associated with increased arterial stiffness and intima‐media thickening in preschool children. Methods and Results This was a longitudinal follow‐up cohort study of children aged 5 to 6 years exposed to high doses of nicotine in utero. Women exclusively using snus and unexposed controls were enrolled in early pregnancy (gestational age range, 6–12 weeks). Exposure data were collected during and after pregnancy with questionnaires from both groups. For this study, only children of women using >48 mg nicotine per day during their entire pregnancy were included in the exposure group. Outcomes were determined in 40 healthy children (21 exposed to snus in utero). Ultrasonography of the common carotid artery was used to determine carotid intima‐media thickness and calculate arterial stiffness index from the relationship between pulsatile changes in arterial diameter and arterial pressure. Children exposed to snus in fetal life had higher carotid stiffness (median 4.1 [interquartile range (IQR), 2.4–5] versus 2.9 [IQR, 2.1–3.5]; P=0.014) than tobacco‐free controls. Carotid strain (relative diameter change) was lower in children exposed to snus (mean 16% [SD, 5.7%] versus 21% [SD, 6.6%]) than in controls (P=0.015). Carotid intima‐media thickness did not differ significantly between children exposed to snus and controls. Conclusions Exposure to snus during fetal life was associated with a stiffer carotid artery in preschool children.

Abstract Aim The aim of this national study was to examine the experience of nurses 9–12 months after the onset of the pandemic. Design This article reports the reflective thematic analysis of the qualitative portion of a mixed methods study of the experiences of 1319 Canadian nurses between February to May 2021. Methods Data gathering occurred through open‐text box questions in an online survey. Results Three overarching themes were found: (1) the hamster wheel, (2) the shifting sense of control, and (3) the inability to leave the pandemic at work. Conclusion This research presents a national perspective of nurses which contributes to the wider global narrative. The experience of redeployment, nurses as decision‐makers, communication and leadership challenges were all factors impacting mental health and intraprofessional collaboration. Implications for the Profession The findings revealed the immense pressure, mental health concerns, and professional implications for nurses in all domains. Public or Patient Contributions No public or patient contributions.

The introduction of immune checkpoint inhibitors has transformed the treatment landscape of metastatic non‐small cell lung cancer. However, challenges remain to increase the fraction of patients achieving durable clinical responses to these drugs and to help monitor the treatment effect. In this phase II trial, we investigated the toxicity, systemic responses and circulating tumour DNA responses in patients (n = 21) with advanced non‐small‐cell lung cancer treated with atezolizumab and stereotactic body radiotherapy in the second or later line. We found the combined treatment to be safe with grade 3 toxicity reported in three patients. As the best overall response, four patients had a partial response, eight had stable disease and five had progressive disease. Median overall survival time was still not reached after a median follow‐up of 26.5 months and 10/15 patients with programmed death‐ligand 1 negative tumours were alive >18 months after the start of the study treatment. ctDNA was detectable at baseline in 11 patients. A rapid decline in ctDNA to

Abstract Introduction To protect against infection, individuals have evolved context‐dependent pathogen‐avoidant strategies, including selective social behaviors aimed at avoiding foreign individuals who may possess greater risk of infection. Parasympathetic nervous system (PNS) activity is associated with social engagement and regulation of the classical immune system but has not been widely investigated in relation to changes in intergroup perception and the behavioral immune system. Method The current research investigated the relationship between parasympathetic activity and perceived foreignness of in and outgroup speakers during exposure to a pathogen‐relevant odor (butyric acid). High‐frequency heart rate variability was measured at rest and while participants rated foreignness of speakers with and without the odor present. Results Findings show that exposure to the odor was associated with higher foreignness perceptions of outgroup speakers and lower foreignness perceptions of ingroup speakers. This effect was especially evident among individuals with higher resting parasympathetic activity. Conclusion These results suggest that the PNS may play a role in changes in social perceptions during a behavioral immune response.

Introduction Posterior circulation strokes account for 20% of ischemic strokes (1). Optimal management for posterior circulation strokes has been studied less than for anterior circulation strokes (2). Endovascular parent vessel sacrifice is an established technique used to treat vascular pathologies. There is limited evidence for parent artery sacrifice for recurrent strokes and there is no current guideline for standard of care. Methods '‐ Results 51‐year‐old gentleman with history of tobacco use presented with left homonymous hemianopsia, onset 1.5 hours prior to arrival. CT brain showed no bleed and patient received IV tissue‐plasminogen activator (tPA). CT angiography (CTA) demonstrated occlusion of the right posterior cerebral artery (PCA) and dissection of the left vertebral artery (V2 segment) with distal reconstitution. He underwent emergent thrombectomy for right P2 thrombus with complete reperfusion TICI 3 (Thrombolysis in Cerebral Infarction Score). Less than 24 hours later, he developed a right homonymous hemianopsia, and was found to have a new occlusion of the left P1 segment of the left PCA. Emergent thrombectomy was performed with complete reperfusion (TICI3). MRI brain demonstrated bilateral PCA territory infarcts. Within 12 hours of the second thrombectomy, his neurological exam deteriorated, and interval imaging revealed a basilar trunk thrombus, for which he underwent a successful endovascular thrombectomy complete reperfusion (TICI3). His antiplatelet regimen was optimized with Aspirin. Heparin was considered as treatment but was not provided because of the hemorrhagic conversion of his ischemic strokes. Given the persistent recurrence of thromboemboli in the posterior circulation despite being on optimal medical management, and evidence of hemorrhagic conversion, a decision was made to perform endovascular coil embolization of the left vertebral artery V2 segment at the site of dissection. Angiographic imaging demonstrated antegrade blood flow through the dissection as the source of recurrent embolic strokes. Six Stryker Target coils were deployed spanning the region of dissection within the left V2 segment via a right radial access with the guide catheter in the right vertebral artery. Post coil embolization angiographic runs demonstrated complete occlusion of the left vertebral V2 segment at the region of dissection which was confirmed via a left vertebral injection from a left femoral arterial access. There was preservation of ascending cervical collaterals beyond the dissection with patency of the contralateral vertebral artery supplying the intracranial circulation. Following embolization, repeat imaging showed no new infarcts and no new or worsening hemorrhage. He was continued on Aspirin monotherapy. It is notable that though his neurological exam deteriorated during each recurrent thromboembolic event, his neurologic exam at the time of discharge significantly improved with NIHSS of 3. He is currently being followed at our neuroscience institute. Conclusion Cervical arterial dissections pose increased risk for ischemic strokes (3). Vertebral artery dissection accounts for approximately 2%, of which, 10‐25% occur in middle‐aged and younger patients (4). This is a case of a young patient that exemplifies a successful role for vertebral artery sacrifice with coil embolization to prevent recurrent thromboembolic posterior circulation strokes. However controlled studies are needed for safety and efficacy of these interventions.

Introduction Intravenous thrombolytics (IVT) and mechanical thrombectomy (MT) have become the standards of care for treating patients with large vessel occlusion (LVO) acute ischemic strokes (AIS) [1‐4}. Intracerebral hemorrhage (ICH) is a main complication of IVT, with prevalence reported around 3.2% in a large multicentered meta‐analysis [2,6]. However, limited data remains about the safety and efficacy for patients to undergo MT with IVT associated pre‐interventional ICH as no randomized control trials or standard of care guidelines are available [2,4,5,7]. Methods NA Results 56‐yo male with history of alcohol abuse presented via EMS as a stroke alert with acute onset right hemiplegia, global aphasia, right facial droop, and leftward gaze preference two hours prior to arrival. RACE 10+ with NIHSS 24. No known history antiplatelet or anticoagulation use. Computerized Tomography (CT) Brain scan showed left middle cerebral artery (MCA) hyperdense sign with left insular cortical ribboning. CT angiography (CTA) showed near occlusive stenosis of the left carotid bulb with an acute thrombus within Supraclinoid Internal Carotid Artery (ICA) extending into the Left MCA and origin of Left Anterior Cerebral Artery (ACA). Patient was emergently administered IV‐tissue Plasminogen Activator (IV‐tPA) and taken for endovascular thrombectomy. During initial angiogram, after crossing the stenotic cervical bulb, the left Supraclinoid ICA and MCA occlusions were visualized. There was longitudinal partially occlusive thrombus extending from the M1 into the M2 divisions. No opacification of the inferior M2 branch was visualized, with perfusion deficit over the temporal, parietal and frontal regions. Additionally, extravasation of contrast was seen within the left basal ganglia region, concerning for hemorrhagic transformation from IV‐tPA. Reversal of IV‐tPA was initiated, and patient was given cryoprecipitate, platelets, and tranexamic acid. Decision to undergo MT was made secondary to severity of debilitating neurologic symptoms, age, and large perfusion deficit observed. He underwent single pass complete recanalization, TICI 2C using Stent retriever and aspiration. Left ICA stenting was not completed secondary to hemorrhagic transformation. Repeat CT Brain confirmed moderate left frontal lobe hemorrhage with vasogenic edema and 3mm left‐to‐right midline shift. No neurosurgical intervention required. Magnetic resonance imaging (MRI) Brain showed left cerebral hematoma with mass effect, acute infarct within left caudate nucleus, and minimal posterior cortical restricted diffusion without hemorrhagic conversion. Patient was monitored for 1 week with serial brain imaging. Patient was discharged on Aspirin 81 mg daily to inpatient rehabilitation with NIHSS 21, mRS 4 (0 prestroke). Today, in rehab he ambulates with walker with moderate expressive aphasia and right upper extremity weakness. Plan to follow‐up 2‐month post‐hospitalization for left ICA stenting. Conclusion While pre‐interventional IVT‐associated ICH in AIS with LVO are rare, few cases have been shown to have positive neurological outcomes [2,5,7]. We demonstrate a unique case of early identification of reperfusion hemorrhage on fluoroscopy with prompt reversal initiated. The decision to continue with MT based on downstream occlusion of basal ganglia hemorrhage not at further risk of expansion from reperfusion. The patient did well on follow‐up imaging despite the hemorrhage. Further randomized control clinical trials are required to establish best care guidelines, safety, and efficacy.

Introduction Carotid artery dissection (CAD) is an uncommon and potentially life‐threatening condition that can have a delayed presentation. More commonly associated with blunt cervical trauma, CAD due to repetitive stress to the neck goes under‐recognized, making it challenging to diagnose. Herein, we aim to shed light on a unique instance of CAD after continuous microtrauma, as well as highlight diagnostic challenges associated with CAD. Methods We present a case of a 57‐year‐old man who presented with a one‐week course of unequal pupils, left‐sided headaches, left sided ptosis, and intermittent blurry vision. Exam revealed a callous where he held a violin against his left neck, having endorsed playing for several years with repeated contortion of his head to the left (Figure 1A). Magnetic resonance angiogram (MRA) of the head and neck revealed an acute dissection of the left internal carotid artery (ICA) (Figure 1B). A diagnosis of Horner’s syndrome secondary to acute dissection of the left cervical ICA was made. Consent to share this information was obtained from the patient and witnessed by another physician. Results MRA head and neck showed a 2.5 cm irregularity of the distal left ICA with high signal on fat saturated T1‐weighted images consistent with an acute dissection (Figure 1B). The patient underwent an apraclonidine test and was positive for left sided Horner’s syndrome with reversal of anisocoria after application of drops (Figure 1C). Given no evidence of stroke or thrombus on imaging, he was placed on dual antiplatelet therapy (DAPT) for three months. He was advised not to play violin for a month and to restart cautiously with a pad between his neck and the instrument. Follow‐up imaging showed eventual resolution of the CAD, while physical exam revealed improvement in ptosis and miosis. Conclusion While playing the violin involves repetitive stress on the neck, there is limited research on this specific activity as a cause of carotid artery dissection, making it a rare occurrence. Common clinical manifestations of CAD include neck pain, headache, Horner’s syndrome, tinnitus, stroke, and lower cranial nerve palsies, occurring suddenly or over time. Diagnosing CAD typically involves a combination of thorough history, physical examination, and diagnostic imaging. Ongoing research in the optimal management of CAD focuses on minimizing the risk of stroke, after factoring in variables such as location of dissection and whether it is symptomatic or not.

Abstract Despite the high prevalence of psychiatric illness in hospitalised dermatology patients, characterisation of psychiatric comorbidities on an inpatient dermatology consultation service in the United States has yet to be performed. To fill this gap in knowledge, we investigated the prevalence of and factors associated with psychiatric illness on the inpatient dermatology consultation service at the University of Southern California. Of the 429 patients seen by the dermatology consultation service between June 2021 to July 2022, 147 (34%) had psychiatric illness (defined as having at least 1 psychiatric diagnosis). Increasing age was associated with a decreased likelihood of psychiatric illness, while housing instability, chronic dermatologic disease, drug reaction, and pruritus without rash were associated with an increased likelihood of psychiatric illness. The high prevalence of psychiatric illness observed in hospitalised dermatology patients emphasises the importance of collaboration between consultant dermatologists and mental health specialists, particularly when specific sociodemographic or disease factors are present.

Background Over the next few years, atrial fibrillation (AF)–related morbidity and costs will increase significantly. Thus, it is prudent to examine the impact of AF treatment on health care resource use. This study examined the impact of AF ablation on hospitalization, length of stay, and resource use for patients undergoing AF ablation in a multihospital system. Methods and Results In an observational analysis, outcomes of total, cardiovascular, and AF hospitalizations, emergency department visits, and length of stay were compared for 3417 patients between 12 months before and 24 months following AF ablation. Use of electrical cardioversions and antiarrhythmic use were also compared 1 year before to 2 years after AF ablation. There were fewer total (0.7±1.3 versus 0.3±0.7; P

Abstract Objective Symptom counts as the basis for Post‐Traumatic Stress Disorder (PTSD) diagnoses in the DSM presume each symptom is equally reflective of underlying disorder severity. However, the “equal weight” assumption fails to fit PTSD symptom data when tested. The present study developed an enhanced PTSD diagnosis based on (a) a conventional PTSD diagnosis from a clinical interview and (b) an empirical classification of full PTSD that reflected the relative clinical weights of each symptom. Method Baseline structured interview data from Project Harmony (N = 2658) was used. An enhanced diagnosis for full PTSD was estimated using an empirical threshold from moderated nonlinear factor analysis (MNLFA) latent PTSD scale scores, in combination with a full conventional PTSD diagnosis based on interview data. Results One in 4 patients in the sample had a PTSD diagnosis that was inconsistent with their empirical PTSD grouping, such that the enhanced diagnostic standard reduced the diagnostic discrepancy rate by 20%. Veterans, and in particular female Veterans, were at greatest odds for discrepancy between their underlying PTSD severity and DSM diagnosis. Conclusion Psychometric methodologies that differentially weight symptoms can complement DSM criteria and may serve as a platform for symptom prioritization for diagnoses in future editions of DSM.

Background The safety and efficacy of endovascular thrombectomy (EVT) in patients with acute ischemic stroke due to large vessel occlusion presenting beyond 24 hours from last known well (LKW) remains undetermined. Methods In this single center study, we identified patients with large vessel occlusion who were eligible for EVT based on noncontrast computed tomography (CT)/CT angiography (without CT perfusion or magnetic resonance imaging) using an Alberta Stroke Program Early CT Score of ≥5, National Institutes of Health Stroke Scale of ≥6, and presenting beyond 24 hours from LKW, between January 2018 and March 2022. During the study period, EVT service limitations meant patients eligible for EVT presenting outside service hours, routinely received best medical management (BMM). Functional and safety outcomes were compared between patients receiving EVT or BMM following multivariable adjustment for age, baseline stroke severity, Alberta Stroke Program Early CT Score, time from LKW, IV thrombolysis, and clot location. Results Among 35 patients presenting beyond 24 hours from LKW and eligible for EVT, 19 (54%) were treated with EVT and 16 (46%) with BMM. Alberta Stroke Program Early CT Score were similar across both groups (EVT: 7 [6.75–8] versus BMM: 7 [6–8]), but not the baseline National Institutes of Health Stroke Scale (EVT: 17 [11–19.5] versus BMM: 20 [9.75–26]). No significant difference was observed between the EVT and BMM groups in the symptomatic intracranial hemorrhage (5.3% versus 0%; P=0.28) or mortality (26.3% versus 37.5%; P=0.42) rates, respectively. The modified Rankin scale at 90 days (adjusted common odds ratio [OR], 1.94; [95% CI 0.42–8.87]; P=0.39) and functional independence rate, although numerically higher in the EVT group compared with the BMM group (modified Rankin scale≤2; 36.9% versus 18.8%; adjusted OR, 4.34; [95% CI 0.34–54.83]; P=0.25), were not significantly different. 94.7% of patients treated with EVT achieved successful reperfusion (modified thrombolysis in cerebral infarction 2b–3). Conclusion In routine clinical practice, EVT beyond 24 hours from LKW appears safe and feasible, when performed in patients with acute ischemic stroke who were deemed eligible for EVT by noncontrast CT /CT angiography alone. A large collaborative randomized trial assessing the efficacy of EVT beyond 24 hours is warranted. Our findings provide a basis for the sample size estimate for an adequately powered trial.

Abstract Diffuse large B‐cell lymphoma (DLBCL) arising in the spleen, also known as primary splenic DLBCL (PS‐DLBCL), is a rare form of malignant lymphoma. It is defined as a lymphoma confined to the spleen or involving splenic hilar lymph nodes. Here we report a case of PS‐DLBCL with CD30. The patient was a 62‐year‐old who presented with 2 weeks of left flank pain, chills, and abdominal distension. Computed tomography identified an 8‐cm splenic mass with central necrosis interpreted as an abscess. A drain was placed, yielding purulent necrotic material; cytologically, only neutrophils were identified. However, purulent drainage continued for 28 days without resolution, prompting splenectomy. Pathological dissection revealed a multinodular mass with central necrosis. Microscopic examination revealed extensive karyorrhexis, abundant ghosts of large cells, and scattered large cells with pleomorphic, multilobated, and vesicular nuclei with moderately abundant cytoplasm. Immunohistochemical staining revealed large, atypical cells positive for CD20, CD30, CD45, PAX5, MYC (>40%), MUM1 (>30%), and p53 (focally). The large cells were negative for CD3 (polyclonal), CD4, CD5, CD8, CD10, CD15, CD34, BCL2, BCL6, AE1/AE3, S100, HHV8, and ALK. The Ki‐67 proliferation rate was approximately 80% in large cells. Notably, this PS‐DLBCL was positive for CD30, an unusual finding among non‐Hodgkin B‐cell lymphomas, which, coupled with the Reed‐Sternberg‐like morphology, raised the possibility of classic Hodgkin lymphoma. Therefore, we reviewed the literature to confirm the unique features of this large B‐cell lymphoma, its abscess‐like appearance, and its expression of CD30.

Abstract Background It remains unknown why adiponectin levels are associated with poor physical functioning, skeletal muscle mass and increased mortality in older populations. Methods In 190 healthy adults (59–86 years, BMI 17–37 kg/m2, 56.8% female), whole body skeletal muscle mass (normalized by height, SMI, kg/m2), muscle and liver fat were determined by magnetic resonance imaging. Bone mineral content (BMC) and density (BMD) were assessed by dual X‐ray absorptiometry (n = 135). Levels of insulin‐like growth factor 1 (IGF‐1), insulin, inflammation markers, leptin and fibroblast growth factor 21 were measured as potential determinants of the relationship between adiponectin and body composition. Results Higher adiponectin levels were associated with a lower SMI (r = −0.23, P

Abstract Background Frailty development is partly dependent on multiple factors like low levels of nutrients and high levels of oxidative stress (OS) and inflammation potentially leading to a muscle‐catabolic state. Measures of specific biomarker patterns including nutrients, OS and inflammatory biomarkers as well as muscle related biomarkers like 3‐methylhistidine (3MH) may improve evaluation of mechanisms and the complex networks leading to frailty. Methods In 220 multi‐morbid patients (≥ 60 years), classified as non‐frail (n = 104) and frail (n = 116) according to Fried's frailty criteria, we measured serum concentrations of fat‐soluble micronutrients, amino acids (AA), OS, interleukins (IL) 6 and 10, 3MH (biomarker for muscle protein turnover) and serum spectra of fatty acids (FA). We evaluated biomarker patterns by principal component analysis (PCA) and their cross‐sectional associations with frailty by multivariate logistic regression analysis. Results Two biomarker patterns [principal components (PC)] were identified by PCA. PC1 was characterized by high positive factor loadings (FL) of carotenoids, anti‐inflammatory FA and vitamin D3 together with high negative FL of pro‐inflammatory FA, IL6 and IL6/IL10, reflecting an inflammation‐related pattern. PC2 was characterized by high positive FL of AA together with high negative FL of 3MH‐based biomarkers, reflecting a muscle‐related pattern. Frail patients had significantly lower factor scores than non‐frail patients for both PC1 [median: −0.27 (interquartile range: 1.15) vs. 0.27 (1.23); P = 0.001] and PC2 [median: −0.15 (interquartile range: 1.13) vs. 0.21 (1.38); P = 0.002]. Patients with higher PC1 or PC2 factor scores were less likely to be frail [odds ratio (OR): 0.62, 95% CI: 0.46–0.83, P = 0.001 for PC1; OR: 0.64, 95% CI: 0.48–0.86, P = 0.003 for PC2] compared with patients with lower PC1 or PC2 factor scores. This indicates that increasing levels of anti‐inflammatory biomarkers and increasing levels of muscle‐anabolic biomarkers are associated with a reduced likelihood (38% and 36%, respectively) for frailty. Significant associations remained after adjusting the regression models for potential confounders. Conclusions We conclude that two specific patterns reflecting either inflammation‐related or muscle‐related biomarkers are both significantly associated with frailty among multi‐morbid patients and that these specific biomarker patterns are more informative than single biomarker analyses considering frailty identification.

Abstract The salinization of freshwaters is a global threat to aquatic biodiversity. We quantified variation in chloride (Cl−) tolerance of 19 freshwater zooplankton species in four countries to answer three questions: (1) How much variation in Cl− tolerance is present among populations? (2) What factors predict intraspecific variation in Cl− tolerance? (3) Must we account for intraspecific variation to accurately predict community Cl− tolerance? We conducted field mesocosm experiments at 16 sites and compiled acute LC50s from published laboratory studies. We found high variation in LC50s for Cl− tolerance in multiple species, which, in the experiment, was only explained by zooplankton community composition. Variation in species‐LC50 was high enough that at 45% of lakes, community response was not predictable based on species tolerances measured at other sites. This suggests that water quality guidelines should be based on multiple populations and communities to account for large intraspecific variation in Cl− tolerance.

Abstract Human‐induced salinization increasingly threatens inland waters; yet we know little about the multifaceted response of lake communities to salt contamination. By conducting a coordinated mesocosm experiment of lake salinization across 16 sites in North America and Europe, we quantified the response of zooplankton abundance and (taxonomic and functional) community structure to a broad gradient of environmentally relevant chloride concentrations, ranging from 4 to ca. 1400 mg Cl− L−1. We found that crustaceans were distinctly more sensitive to elevated chloride than rotifers; yet, rotifers did not show compensatory abundance increases in response to crustacean declines. For crustaceans, our among‐site comparisons indicate: (1) highly consistent decreases in abundance and taxon richness with salinity; (2) widespread chloride sensitivity across major taxonomic groups (Cladocera, Cyclopoida, and Calanoida); and (3) weaker loss of functional than taxonomic diversity. Overall, our study demonstrates that aggregate properties of zooplankton communities can be adversely affected at chloride concentrations relevant to anthropogenic salinization in lakes.