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Societal Impact Statement Free‐air CO2 enrichment (FACE) experiments provide essential data on forest responses to increasing atmospheric CO2 for evaluations of climate change impacts on humanity. Understanding and reducing the uncertainty in the experimental results is critical to ensure scientific and public confidence in the models and policy initiatives that derive therefrom. One source of uncertainty is the estimation of tree biomass using mathematical relationships between biomass and easily obtained and non‐destructive measurements (allometry). We evaluated the robustness of the allometric relationships established at the beginning of a FACE experiment and discuss the challenges and opportunities for the new generation of FACE experiments. Summary Long‐term field experiments to elucidate forest responses to rising atmospheric CO2 concentration require allometric equations to estimate tree biomass from non‐destructive measurements of tree size. We analyzed whether the allometric equations established at the beginning of a free‐air CO2 enrichment (FACE) experiment in a Liquidambar styraciflua plantation were still valid at the end of the 12 year experiment. Aboveground woody biomass was initially predicted by an equation that included bole diameter, taper, and height, assuming that including taper and height as predictors would accommodate changes in tree structure that might occur over time and in response to elevated CO2. At the conclusion of the FACE experiment, we harvested 23 trees, measured dimensions and dry mass of boles and branches, and extracted and measured the woody root mass of 10 trees. Although 10 of the harvested trees were larger than the trees used to establish the allometric relationship, measured aboveground woody biomass was well predicted by the original allometry. The initial linear equation between bole basal area and woody root biomass underestimated final root biomass by 28%, but root biomass was just 21% of total wood mass, and errors in aboveground and belowground estimates were offsetting. The allometry established at the beginning of the experiment provided valid predictions of tree biomass throughout the experiment. New allometric approaches using terrestrial laser scanning should reduce an important source of uncertainty in decade‐long forest experiments and in assessments of centuries‐long forest biomass accretion used in evaluating carbon offsets and climate mitigation.

Abstract Background Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal radiotherapy regimen, particularly in terms of total dose and planned range of irradiation field, remains unclear. This phase III clinical trial aimed to compare the survival benefits between different radiation doses and different target fields. Methods This trial compared two aspects of radiation treatment, total dose and field, using a two‐by‐two factorial design. The high‐dose (HD) group received 59.4 Gy radiation, and the standard‐dose (SD) group received 50.4 Gy. The involved field irradiation (IFI) group and elective nodal irradiation (ENI) group adopted different irradiation ranges. The participants were assigned to one of the four groups (HD+ENI, HD+IFI, SD+ENI and SD+IFI). The primary endpoint was overall survival (OS), and the secondary endpoints included progression‐free survival (PFS). The synergy indexwas used to measure the interaction effect between dose and field. Results The interaction analysis did not reveal significant synergistic effects between the dose and irradiation field. In comparison to the target field, patients in IFI or ENI showed similar OS (hazard ratio [HR] = 0.99, 95% CI: 0.80‐1.23, p = 0.930) and PFS (HR = 1.02, 95% CI: 0.82–1.25). The HD treatment did not show significantly prolonged OS compared with SD (HR = 0.90, 95% CI: 0.72–1.11, p = 0.318), but it suggested improved PFS (25.2 months to 18.0 months). Among the four groups, the HD+IFI group presented the best survival, while the SD+IFI group had the worst prognosis. No significant difference in the occurrence of severe adverse events was found in dose or field comparisons. Conclusions IFI demonstrated similar treatment efficacy to ENI in CCRT of ESCC. The HD demonstrated improved PFS, but did not significantly improve OS. The dose escalation based on IFI (HD+IFI) showed better therapeutic efficacy than the current recommendation (SD+ENI) and is worth further validation.

Abstract Background Chronic lymphocytic leukemia (CLL) is a heterogeneous disease. Whereas some patients have an indolent disease, others experience an aggressive course and early death. Our aim was to investigate if modifiable and non‐modifiable medical history and lifestyle factors prior to diagnosis had an impact on the natural course of the disease. Method In 1154 CLL patients, we assessed if the weight, physical activity, smoking, and alcohol consumption or non‐modifiable characteristics including family history of lymphoid malignancy and medical history were associated with time‐to‐first‐treatment (TTFT) and adjusted all results for the CLL‐International Prognostic Index (CLL‐IPI). Results TTFT was shorter for patients with high/very high‐risk CLL‐IPI than those with low/intermediate risk CLL‐IPI. In the adjusted analysis we did not find additional impact on TTFT besides CLL‐IPI from any environmental characteristics assessed. Conclusions We found limited impact of environmental factors on the natural course of CLL (measured as the TTFT in treatment naïve patients) providing valuable knowledge, and potential relief, to share with patients at the time of diagnosis.

Abstract Clinical bleeding events are reported here from 773 patients with B‐cell malignancies receiving pirtobrutinib monotherapy from the phase 1/2 BRUIN study (ClinicalTrials.gov identifier: NCT03740529), either in the presence or absence of antithrombotic therapy (antithrombotic exposed [AT‐E], n = 216; antithrombotic nonexposed [AT‐NE], n = 557). Among the AT‐E cohort, 51.9% received platelet aggregation inhibitors, 36.6% received direct factor Xa inhibitors, 18.5% received heparins, 5.6% received salicylic acid for indications other than platelet aggregation inhibition, and 2.3% received thrombolytics. Warfarin was not permitted. Any‐grade bleeding/bruising events occurred in 97 patients (44.9%; 95% confidence interval [CI], 38.3–51.5) in the AT‐E cohort and 181 patients (32.5%; 95% CI, 28.6–36.4) in the AT‐NE cohort. Most bleeding/bruising events in both cohorts began within the first 6 months of treatment (AT‐E: 65.4%; AT‐NE: 72.5%). Contusion was the most common bleeding/bruising event in both cohorts (AT‐E: 22.7%; AT‐NE: 18.1%). Grade ≥3 bleeding/bruising events were reported in six patients (2.8%) in the AT‐E cohort and 11 patients (2.0%) in the AT‐NE cohort. Bleeding/bruising events requiring or prolonging hospitalization were reported in 2.3% and 1.6% of patients in the AT‐E and AT‐NE cohorts, respectively. No bleeding/bruising events led to pirtobrutinib dose reduction or permanent discontinuation in the AT‐E cohort, and one patient (0.2%) in the AT‐NE cohort experienced an event requiring dose reduction. These data support the safety of pirtobrutinib in patients requiring antithrombotic therapies.

Abstract Introduction The novel Confirm Rx™ implantable cardiac monitor (ICM) with SharpSense™ technology incorporates a new P‐wave discriminator designed to improve AF detection. This study aimed to evaluate the diagnostic performance of the Confirm Rx™ ICM in detecting AF episodes of varying durations. Methods We conducted a multicenter retrospective analysis of consecutive patients implanted with a Confirm Rx™ ICM (v1.2) across nine UK hospitals, all with documented AF lasting at least 6 min. Electrocardiograms (ECGs) were manually adjudicated by cardiologists. To account for intra‐ and inter‐reviewer variability, a random sample of 10% of ECGs underwent additional review. Disagreements were resolved by a third reviewer. Diagnostic performance was determined by calculating the gross and patient‐averaged positive predictive value (PPV) for AF episodes of different duration. The source of false positive (FP) detection was also categorized. Results Overall, 16,230 individual ECGs from 232 patients were included. The median AF episode duration was 14 min. R‐wave amplitude remained stable during follow‐up (0.52 ± 0.27 mV [initial] vs. 0.54 ± 0.29 mV [end of follow‐up], p = .10). The gross and patient‐averaged PPV were 75.0% and 67.0%, respectively. Diagnostic performance (gross) increased with progressively longer AF episodes: 88.0% for ≥1 h, 97.3% for 6 h, and 100% for 24 h. The main source of FP during tachycardia was T‐wave oversensing (54.2%), while in non‐tachycardic episodes it was predominantly ectopy (71.2%). The AF burden precision was excellent (93.3%). Conclusion The Confirm Rx™ ICM diagnostic performance was modest for all AF episodes (75%), with accuracy increasing for longer AF episodes.

Abstract Cancer‐associated cachexia is a multifactorial wasting disorder characterized by anorexia, unintentional weight loss (skeletal muscle mass with or without loss of fat mass), progressive functional impairment, and poor prognosis. This systematic literature review (SLR) examined the relationship between cachexia and survival in patients with colorectal or pancreatic cancer in recent literature. The SLR was conducted following PRISMA guidelines. Embase® and PubMed were searched to identify articles published in English between 1 January 2016 and 10 October 2021 reporting survival in adults with cancer and cachexia or at risk of cachexia, defined by international consensus (IC) diagnostic criteria or a broader definition of any weight loss. Included publications were studies in ≥100 patients with colorectal or pancreatic cancer. Thirteen publications in patients with colorectal cancer and 13 with pancreatic cancer met eligibility criteria. Included studies were observational and primarily from Europe and the United States. Eleven studies (42%) reported cachexia using IC criteria and 15 (58%) reported any weight loss. An association between survival and cachexia or weight loss was assessed across studies using multivariate (n = 23) or univariate (n = 3) analyses and within each study across multiple weight loss categories. Cachexia/weight loss was associated with a statistically significantly poorer survival in at least one weight loss category in 16 of 23 studies that used multivariate analyses and in 1 of 3 studies (33%) that used univariate analyses. Of the 17 studies demonstrating a significant association, 9 were in patients with colorectal cancer and 8 were in patients with pancreatic cancer. Cachexia or weight loss was associated with significantly poorer survival in patients with colorectal or pancreatic cancer in nearly two‐thirds of the studies. The classification of weight loss varied across and within studies (multiple categories were evaluated) and may have contributed to variability. Nonetheless, awareness of cachexia and routine assessment of weight change in clinical practice in patients with colorectal or pancreatic cancer could help inform prognosis and influence early disease management strategies.

Abstract During pregnancy an increased cardiac output (Q̇) and blood volume (BV) occur to support fetal growth. Increased Q̇ and BV also occur during chronic endurance exercise training and benefit performance. We investigated if sprint interval training (SIT) undertaken early postpartum maintains the elevated Q̇ and BV of pregnancy and benefits performance. The participant, a competitive field hockey player and former cyclist, visited our laboratory at 2 weeks of gestation (baseline) and postpartum pre‐, mid‐ and post‐intervention (PPpre, PPmid and PPpost). Delivery was uncomplicated and she felt ready to start the SIT programme 5 weeks postpartum. Inert gas rebreathing was used to measure peak exercise Q̇ (Q̇peak); V̇O2peak was measured with a metabolic cart; and postpartum haematological values were measured with carbon monoxide rebreathing. The 18 SIT sessions progressed from four to eight sprints at 130% of V̇O2peak peak power output. Q̇peak increased from baseline at all postpartum time points (baseline 16.2 vs. 17.5, 16.8 and 17.2 L/min at PPpre, PPmid and PPpost, respectively). Relative V̇O2peak remained below baseline values at all postpartum measurements (baseline 44.9 vs. 41.0, 42.3 and 42.5 mL/kg/min at PPpre, PPmid and PPpost, respectively) whereas absolute V̇O2peak rapidly reached baseline values postpartum (baseline 3.19 vs. 3.12, 3.23 and 3.18 L/min at PPpre, PPmid and PPpost, respectively). Postpartum BV (5257, 4271 and 5214 mL at PPpre, PPmid and PPpost, respectively) and Hbmass (654, 525 and 641 g at PPpre, PPmid and PPpost, respectively) were similar between PPpre and PPpost but decreased alongside Q̇peak at PPmid. Peak power was returned to pre‐pregnancy values by intervention end (302 vs. 303 W, baseline vs. PPpost). These findings show that SIT undertaken early postpartum defends the elevated Q̇peak of pregnancy and rapidly returns absolute V̇O2peak and peak power to baseline levels.

Abstract Aims Interatrial shunts are under evaluation as a treatment for heart failure (HF); however, their in vivo flow performance has not been quantitatively studied. We aimed to investigate the fluid dynamics properties of the 0.51 cm orifice diameter Ventura shunt and assess its lumen integrity with serial transesophageal echocardiography (TEE). Methods and results Computational fluid dynamics (CFD) and bench flow tests were used to establish the flow‐pressure relationship of the shunt. Open‐label patients from the RELIEVE‐HF trial underwent TEE at shunt implant and at 6 and 12 month follow‐up. Shunt effective diameter (Deff) was derived from the vena contracta, and flow was determined by the continuity equation. CFD and bench studies independently validated that the shunt's discharge coefficient was 0.88 to 0.89. The device was successfully implanted in all 97 enrolled patients; mean age was 70 ± 11 years, 97% were NYHA class III, and 51% had LVEF ≤40%. Patency was confirmed in all instances, except for one stenotic shunt at 6 months. Deff remained unchanged from baseline at 12 months (0.47 ± 0.01 cm, P = 0.376), as did the trans‐shunt mean pressure gradient (5.1 ± 3.9 mmHg, P = 0.316) and flow (1137 ± 463 mL/min, P = 0.384). TEE measured flow versus pressure closely correlated (R2 ≥ 0.98) with a fluid dynamics model. At 12 months, the pulmonary/systemic flow Qp/Qs ratio was 1.22 ± 0.12. Conclusions When implanted in patients with advanced HF, this small interatrial shunt demonstrated predictable and durable patency and performance.

Abstract Objectives Implantation of an artificial urinary sphincter (AUS) to treat post‐prostatectomy incontinence (PPI) has been traditionally offered with an overnight hospital stay. The aim of this prospective, comparative pilot study was to assess the feasibility and outcomes of the AUS procedure in a day‐case setting. Patients and methods We included consecutive patients having primary or redo AUS surgery over an 18‐month period. We excluded patients with previous urethral erosion of AUS, urethroplasty or high anaesthetic risk. All patients were offered day‐case surgery. Patients who declined or could not have day‐case surgery for logistical reasons had standard care with overnight stay and formed the control group for the study. Primary outcome was the proportion of successful same day‐discharges in the day‐case group. We also compared baseline characteristics, complications and continence at 1 year post surgery. Results Twelve patients consented for day‐case procedure, and 13 patients had standard overnight care. Mean age was 69.5 years (range 58–79). Twenty‐one patients (84%) had primary AUS, whereas 4 (16%) had a redo procedure. There were no significant differences between the groups in baseline demographics. Median number of pads/24 h was 5 in the day‐case group and 4 in the overnight group. Eight of 12 patients (66.7%) in the day‐case group were successfully discharged on the same day. Failed discharges were due to anaesthetic recovery (n = 2), high post‐void residuals that resolved spontaneously (n = 1) and intraoperative superficial urethral injury (n = 1). All patients in the day‐case group and all but one in the standard of care group were socially continent (0–1 pads) at 1 year post procedure. Conclusion Day‐case catheter‐free discharge of AUS patients is feasible and safe in selected patients with comparable continence outcomes and complication rates to those with standard overnight stays.

Abstract Human papillomavirus (HPV)‐related cervical and nasopharyngeal cancers differ in molecular mechanisms underlying the oncogenic processes. The disparity may be attributed to differential expression of oncoproteins. The current study investigated the host oncogenes expression pattern in HPV‐associated cervical and nasopharyngeal cancer. Formalin‐fixed paraffin‐embedded tissues originating from the nasopharyngeal and cervical regions were screened using Hematoxylin and Eosin staining. Genomic DNA and total RNA were extracted from confirmed cancer biopsies and non‐cancer tissues (NC). HPV was detected by PCR using MY09/GP5+/6+ primers. Protein expression levels of AKT, IQGAP1, and MMP16 in HPV‐infected cancers and controls were determined by immunohistochemistry. RT‐qPCR was used to profile mRNAs of the oncogenes. AKT and IQGAP1 proteins were highly expressed in the epithelial cancers compared with the non‐cancer tissues (p 0.05). The oncoproteins expression level between the HPV‐positive and HPV‐negative cancer biopsies showed no significant difference (p

Abstract Background HyBryteTM is a photodynamic therapy of topical hypericin that has recently been shown to be safe and efficacious in early stage cutaneous T‐cell lymphoma (CTCL). However, its efficacy, absorption, and effect on heart function parameters in patients who require greater HyBryteTM exposure is unknown. Objectives The primary objectives in this study were to assess hypericin blood levels using a validated detection method with a cut‐off value of 0.05 ng/mL and to determine if topical HyBryteTM induces any electrocardiogram (EKG) changes during 8 weeks of treatment. A secondary endpoint of this study was to assess the effectiveness of HyBryteTM in this patient population as well as assessing a different additional light device than the one used in the Phase 3 HPN‐CTCL‐01/fluorescent light activated synthetic hypericin trial also entitled “A phase 3 multicenter randomised placebo‐controlled study to determine the efficacy of topical hypericin and light irradiation for the treatment of cutaneous T‐cell lymphoma”. Methods A confirmatory, prospective, open‐label, single‐centre, interventional study focused on stage IB and IIA mycosis fungoides with more than 10% of their body surface areas involved was performed. Results Hypericin concentration in K2EDTA whole blood samples collected before and after light activation at Weeks 4, 6 and 8 showed an average blood concentration of 0.13 ng/mL and achieved steady state by Week 4. EKGs were examined for clinical changes at each study visit, including changes in QT intervals and correction of heart rates. No significant clinical changes in EKGs were observed. Conclusions Hypericin does not appear to be significantly absorbed through the skin nor cause significant cardiac changes overall or prolong the QT interval when applied topically. A larger study is necessary to clearly define these results.

Abstract Gut motility undergoes a switch from myogenic to neurogenic control in late embryonic development. Here, we report on the electrical events that underlie this transition in the enteric nervous system, using the GCaMP6f reporter in neural crest cell derivatives. We found that spontaneous calcium activity is tetrodotoxin (TTX) resistant at stage E11.5, but not at E18.5. Motility at E18.5 was characterized by periodic, alternating high‐ and low‐frequency contractions of the circular smooth muscle; this frequency modulation was inhibited by TTX. Calcium imaging at the neurogenic‐motility stages E18.5–P3 showed that CaV1.2‐positive neurons exhibited spontaneous calcium activity, which was inhibited by nicardipine and 2‐aminoethoxydiphenyl borate (2‐APB). Our protocol locally prevented muscle tone relaxation, arguing for a direct effect of nicardipine on enteric neurons, rather than indirectly by its relaxing effect on muscle. We demonstrated that the ENS was mechanosensitive from early stages on (E14.5) and that this behaviour was TTX and 2‐APB resistant. We extended our results on L‐type channel‐dependent spontaneous activity and TTX‐resistant mechanosensitivity to the adult colon. Our results shed light on the critical transition from myogenic to neurogenic motility in the developing gut, as well as on the intriguing pathways mediating electro‐mechanical sensitivity in the enteric nervous system. Highlights What is the central question of this study? What are the first neural electric events underlying the transition from myogenic to neurogenic motility in the developing gut, what channels do they depend on, and does the enteric nervous system already exhibit mechanosensitivity? What is the main finding and its importance? ENS calcium activity is sensitive to tetrodotoxin at stage E18.5 but not E11.5. Spontaneous electric activity at fetal and adult stages is crucially dependent on L‐type calcium channels and IP3R receptors, and the enteric nervous system exhibits a tetrodotoxin‐resistant mechanosensitive response. Abstract figure legend Tetrodotoxin‐resistant Ca2+ rise induced by mechanical stimulation in the E18.5 mouse duodenum.

Abstract Pharmacogenomic (PGx) biomarkers integrated using machine learning can be embedded within the electronic health record (EHR) to provide clinicians with individualized predictions of drug treatment outcomes. Currently, however, drug alerts in the EHR are largely generic (not patient‐specific) and contribute to increased clinician stress and burnout. Improving the usability of PGx alerts is an urgent need. Therefore, this work aimed to identify principles for optimal PGx alert design through a health‐system‐wide, mixed‐methods study. Clinicians representing multiple practices and care settings (N = 1062) in urban, rural, and underserved regions were invited to complete an electronic survey comparing the usability of three drug alerts for citalopram, as a case study. Alert 1 contained a generic warning of pharmacogenomic effects on citalopram metabolism. Alerts 2 and 3 provided patient‐specific predictions of citalopram efficacy with varying depth of information. Primary outcomes included the System's Usability Scale score (0–100 points) of each alert, the perceived impact of each alert on stress and decision‐making, and clinicians' suggestions for alert improvement. Secondary outcomes included the assessment of alert preference by clinician age, practice type, and geographic setting. Qualitative information was captured to provide context to quantitative information. The final cohort comprised 305 geographically and clinically diverse clinicians. A simplified, individualized alert (Alert 2) was perceived as beneficial for decision‐making and stress compared with a more detailed version (Alert 3) and the generic alert (Alert 1) regardless of age, practice type, or geographic setting. Findings emphasize the need for clinician‐guided design of PGx alerts in the era of digital medicine.

Abstract Introduction and aims Retroperitoneal fibrosis (RPF) is a fibroinflammatory disease in which patients may suffer obstructive uropathy (OU). The optimum treatment strategy for RPF with secondary OU is currently unclear, and the aim of this literature review is to assess the methods used to treat this patient cohort. Methods Medline, Embase, Cinahl, the Cochrane Library and PubMed were systematically searched to find studies assessing treatment outcomes in this patient cohort. After reviewing the studies' titles, abstracts and full texts, 12 were found that matched our search aims. Data from these publications were analysed and reported. Results The demographic and symptomatic features of patients across the 12 studies were representative of the general RPF population. No randomised control trials (RCTs) were found, and just one study formally compared outcomes between patients who underwent different treatment strategies. Many of the studies concluded that using medical and surgical methods in combination led to positive outcomes; whereas, others found positive outcomes following a variety of regimens. Many studies also highlighted, however, that significant minorities required further treatment after initial therapy. Conclusions regarding optimum treatment methods were limited as most publications did not formally compare outcomes following different strategies and had an observational study design. Conclusion Although positive outcomes were commonly seen following medical, surgical and a combination of treatments, the literature currently lacks research formally comparing outcomes after assigning specific treatment protocols to groups of RPF patients. More research is therefore required to determine how to best manage RPF leading to secondary OU.

Abstract Andexanet alfa is a recombinant, modified factor Xa (FXa) molecule that is used for the reversal of the anticoagulant effect of oral anti‐FXa anticoagulants in patients with major haemorrhage. Here, we present a case of an 85‐year‐old man taking rivaroxaban for atrial fibrillation, who presented with an acute, upper gastrointestinal bleed. He was stabilised with red cell transfusion and then received a 400 mg bolus of andexanet alfa. Within minutes of this, he developed chest tightness, shortness of breath, ischaemic electrocardiographic changes and then cardiac arrest from which he could not be resuscitated. The onset of symptoms was clearly temporally related to andexanet alfa administration and the differential diagnosis includes anaphylaxis with Kounis syndrome, or myocardial infarction. Although infusion site reactions have been reported and are relatively common, this is to date the first case of a fatal drug reaction andexanet alfa. This knowledge can be factored into physicians’ risk–benefit decisions when treating patients with oral anti‐FXa anticoagulant‐associated major haemorrhage.

Objective Positive antineutrophil cytoplasmic antibodies (ANCAs) may occur in the setting of interstitial lung disease (ILD), with or without ANCA‐associated vasculitis (AAV). We aim to compare the characteristics and clinical course of patients with ILD and positive ANCA (ANCA‐ILD) to those with negative ANCA. Methods We performed a single‐center retrospective cohort study from 2018 to 2021. All patients with ILD and ANCA testing were included. Patient characteristics (symptoms, dyspnea scale, and systemic AAV), test results (pulmonary high‐resolution computed tomography and pulmonary function tests), and adverse events were collected from electronic medical records. Descriptive statistics and the Fisher exact test were used to compare the outcomes of patients with ANCA‐ILD to those with ILD and negative ANCA. Results A total of 265 patients with ILD were included. The mean follow‐up duration was 69.3 months, 26 patients (9.8%) were ANCA positive, and 69.2% of those with ANCA‐ILD had another autoantibody. AAV occurred in 17 patients (65.4%) with ANCA‐ILD. In 29.4% of patients, AAV developed following ILD diagnosis. Usual interstitial pneumonia was the most common radiologic pattern in patients with ANCA‐ILD. There was no association between ANCA status and the evolution of dyspnea, diffusing capacity of the lungs for carbon monoxide, and lung imaging. Forced vital capacity improved over time in 42% of patients with ANCA‐ILD and in 17% of patients with negative ANCA (P = 0.006). Hospitalization occurred in 46.2% of patients with ANCA‐ILD and in 21.8% of patients with negative ANCA (P = 0.006). Both groups had similar mortality rates. Conclusion Routine ANCA testing should be considered in patients with ILD. Patients with ANCA‐ILD are at risk for AAV. More research is required to better understand and manage patients with ANCA‐ILD.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a limited number of known driver mutations but considerable cancer cell heterogeneity. Phosphoproteomics provides a direct read‐out of aberrant signaling and the resultant clinically relevant phenotype. Mass spectrometry (MS)‐based proteomics and phosphoproteomics were applied to 42 PDAC tumors. Data encompassed over 19 936 phosphoserine or phosphothreonine (pS/T; in 5412 phosphoproteins) and 1208 phosphotyrosine (pY; in 501 phosphoproteins) sites and a total of 3756 proteins. Proteome data identified three distinct subtypes with tumor intrinsic and stromal features. Subsequently, three phospho‐subtypes were apparent: two tumor intrinsic (Phos1/2) and one stromal (Phos3), resembling known PDAC molecular subtypes. Kinase activity was analyzed by the Integrative iNferred Kinase Activity (INKA) scoring. Phospho‐subtypes displayed differential phosphorylation signals and kinase activity, such as FGR and GSK3 activation in Phos1, SRC kinase family and EPHA2 in Phos2, and EGFR, INSR, MET, ABL1, HIPK1, JAK, and PRKCD in Phos3. Kinase activity analysis of an external PDAC cohort supported our findings and underscored the importance of PI3K/AKT and ERK pathways, among others. Interestingly, unfavorable patient prognosis correlated with higher RTK, PAK2, STK10, and CDK7 activity and high proliferation, whereas long survival was associated with MYLK and PTK6 activity, which was previously unknown. Subtype‐associated activity profiles can guide therapeutic combination approaches in tumor and stroma‐enriched tissues, and emphasize the critical role of parallel signaling pathways. In addition, kinase activity profiling identifies potential disease markers with prognostic significance.

Abstract Objective This study investigates the prevalent issues of healthcare access and the impact of antiseizure treatments among people with epilepsy (PWE) in rural Limpopo and Mpumalanga, South Africa, where healthcare facilities and affordable treatments are often inadequate. Methods Using a cross‐sectional survey, 162 PWE were selected using multistage sampling across the provinces. Data were collected via a structured questionnaire and analyzed descriptively using SPSS v27. Results Most of the participants experienced seizures intermittently, with 70.6% in Limpopo and 53.3% in Mpumalanga reporting occasional episodes, whereas a significant minority in both regions—20.6% and 40%, respectively—suffered from frequent seizures. A notable portion of PWE also reported recurring side effects from antiseizure drugs, which led to consequential life disruptions, including educational dropout and unemployment. Significance The findings underscore an urgent need for enhanced educational programs and increased awareness to improve the understanding and management of epilepsy in these underserved areas. Optimizing care for PWE requires a multifaceted approach, including evaluating healthcare accessibility, affordability, and societal beliefs influencing treatment adherence. The study advocates for government and policy interventions to mitigate the quality of life deterioration caused by epilepsy and its treatment in rural communities. Plain Language Summary In Limpopo and Mpumalanga, many individuals with epilepsy experience seizures occasionally, while a significant minority have them frequently. Numerous people also suffer recurring side effects from antiseizure medications, impacting their lives severely by causing school dropouts and job losses. This underscores the urgent need for improved education and awareness programs to manage epilepsy in these provinces effectively. The study urges government action and policy reforms to enhance care and support for people with epilepsy in rural areas, aiming to improve their quality of life.

Abstract Cachexia, with weight loss (WL) as a major component, is highly prevalent in patients with cancer and indicates a poor prognosis. The primary objective of this study was to conduct a meta‐analysis to estimate the risk of mortality associated with cachexia (using established WL criteria prior to treatment initiation) in patients with non‐small‐cell lung cancer (NSCLC) in studies identified through a systematic literature review. The review was conducted according to PRISMA guidelines. Embase® and PubMed were searched to identify articles on survival outcomes in adult patients with NSCLC (any stage) and cachexia published in English between 1 January 2016 and 10 October 2021. Two independent reviewers screened titles, abstracts and full texts of identified records against predefined inclusion/exclusion criteria. Following a feasibility assessment, a meta‐analysis evaluating the impact of cachexia, defined per the international consensus criteria (ICC), or of pre‐treatment WL ≥ 5% without a specified time interval, on overall survival in patients with NSCLC was conducted using a random‐effects model that included the identified studies as the base case. The impact of heterogeneity was evaluated through sensitivity and subgroup analyses. The standard measures of statistical heterogeneity were calculated. Of the 40 NSCLC publications identified in the review, 20 studies that used the ICC for cachexia or reported WL ≥ 5% and that performed multivariate analyses with hazard ratios (HRs) or Kaplan–Meier curves were included in the feasibility assessment. Of these, 16 studies (80%; n = 6225 patients; published 2016–2021) met the criteria for inclusion in the meta‐analysis: 11 studies (69%) used the ICC and 5 studies (31%) used WL ≥ 5%. Combined criteria (ICC plus WL ≥ 5%) were associated with an 82% higher mortality risk versus no cachexia or WL

Abstract Aims Patients with a reduced left ventricular ejection fraction (LVEF) following an acute myocardial infarction (MI) are at risk of progressive adverse cardiac remodelling that can lead to the development of heart failure and death. The early addition of a sodium‐glucose cotransporter 2 (SGLT2) inhibitor to standard treatment may delay or prevent progressive adverse remodelling in these patients. Methods and results EMpagliflozin to PREvent worSening of left ventricular volumes and Systolic function after Myocardial Infarction (EMPRESS‐MI) is a randomized, double‐blind, placebo‐controlled, multi‐centre trial designed to assess the effect of empagliflozin on cardiac remodelling evaluated using cardiovascular magnetic resonance (CMR) in 100 patients with left ventricular systolic dysfunction following MI. Eligible patients were those ≥12 h and ≤14 days following acute MI, with an LVEF

Abstract To enable real‐time monitoring and control strategies for floating offshore wind turbines, accurate information about the state of the system is needed. This paper details the application of a Kalman filter to the UMaine VolturnUS‐S floating wind platform to provide accurate state estimates in real time using minimal system measurements. The midfidelity nonlinear simulation tool OpenFAST was used to generate the underlying linear state‐space model for the Kalman filter. This linear model and its limitations are demonstrated through comparison with experimental data collected on a 1:70 froude‐scaled model of the floating platform and tower. Using a selection of five measurements from the real system, a Kalman filter was developed to provide estimates for the remaining system states and measurements. These estimates were then validated against the experimental values collected from testing of the scale model. Validation of the Kalman filter produced accurate estimates of surge, heave, and tower base bending moment, measurements of which were not available to the Kalman filter. Performance of the Kalman filter was tested and validated over a range of sea conditions from rated wind speed to storm events and demonstrated robustness in the Kalman filter to maintain accuracy across all operating conditions despite significant error in the underlying linear model for extreme conditions.

Abstract Background Universal skin cancer screening for the Latino population is impractical. Objectives We focused on melanoma education by conducting an online education campaign and collected baseline, postintervention, and 3‐month follow‐up surveys to assess sun‐protective behaviors. Methods Participants were recruited through (1) social media ads and (2) emails sent to Mayo Clinic Latino patients. Results Total social media impressions were 508,442 and 413,007 in Spanish and English, respectively. There were 18,790 and 11,731 clicks for the Spanish and English ads, respectively, resulting in 175 baseline survey responses. From email distribution, 4151 emails translated to 219 baseline participants. Of the 394 patients who participated in the baseline survey, 89 completed the postintervention survey, and 57 completed the 3‐month follow‐up survey (28 from social media and 29 Mayo Clinic patients). Social media provides a unique opportunity for the medical community to promote melanoma education, distribute content quickly, and provide medical education in disparate healthcare areas. Our Spanish ad click‐through rate was 3.70% compared to 2.84% for English. The click‐to‐action rate was 0.57%, and the baseline‐to‐completion rate was 16.00%. Conclusions Our study suggests social media could be a unique tool for distributing melanoma educational materials to Latino populations. The click‐through rates for this study were several‐fold higher than other studies' reported click‐through rates (0.4%–0.93%). It is important to develop melanoma educational materials that are culturally relevant and focused on Latino populations that can provide persistent improvements in mitigating melanoma risk behaviors such as sunscreen application and self‐skin examinations.

Abstract Objectives International guidelines recommend resection of suspected localised renal cell carcinoma (RCC), with surgical series showing benign pathology in 30%. Non‐invasive diagnostic tests to differentiate benign from malignant tumours are an unmet need. Our objective was to determine diagnostic accuracy of imaging modalities for detecting cancer in T1 renal tumours. Methods A systematic review was performed for reports of diagnostic accuracy of any imaging test compared to a reference standard of histopathology for T1 renal masses, from inception until January 2023. Twenty‐seven publications (including 2277 tumours in 2044 participants) were included in the systematic review, and nine in the meta‐analysis. Results Forest plots of sensitivity and specificity were produced for CT (seven records, 1118 participants), contrast‐enhanced ultrasound (seven records, 197 participants), [99mTc]Tc‐sestamibi SPECT/CT (five records, 263 participants), MRI (three records, 220 participants), [18F]FDG PET (four records, 43 participants), [68Ga]Ga‐PSMA‐11 PET (one record, 27 participants) and [111In]In‐girentuximab SPECT/CT (one record, eight participants). Meta‐analysis returned summary estimates of sensitivity and specificity for [99mTc]Tc‐sestamibi SPECT/CT of 88.6% (95% CI 82.7%–92.6%) and 77.0% (95% CI 63.0%–86.9%) and for [18F]FDG PET 53.5% (95% CI 1.6%–98.8%) and 62.5% (95% CI 14.0%–94.5%), respectively. A comparison hierarchical summary receiver operating characteristic (HSROC) model did not converge. Meta‐analysis was not performed for other imaging due to different thresholds for test positivity. Conclusion The optimal imaging strategy for T1 renal masses is not clear. [99mTc]Tc‐sestamibi SPECT/CT is an emerging tool, but further studies are required to inform its role in clinical practice. The field would benefit from standardisation of diagnostic thresholds for CT, MRI and contrast‐enhanced ultrasound to facilitate future meta‐analyses.

Abstract Objective Neurofilament heavy‐chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. Methods Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta‐analyses of published case–control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole‐genome sequencing data. Results Fixed‐effects meta‐analysis found that rare (MAF

Abstract The recent SarsCov2 pandemic has disrupted healthcare system notably impacting intensive care units (ICU). In severe cases, the immune system is dysregulated, associating signs of hyperinflammation and immunosuppression. In the present work, we investigated, using a joint modeling approach, whether the trajectories of cellular immunological parameters were associated with survival of COVID‐19 ICU patients. This study is based on the REA‐IMMUNO‐COVID cohort including 538 COVID‐19 patients admitted to ICU between March 2020 and May 2022. Measurements of monocyte HLA‐DR expression (mHLA‐DR), counts of neutrophils, of total lymphocytes, and of CD4+ and CD8+ subsets were performed five times during the first month after ICU admission. Univariate joint models combining survival at day 28 (D28), hospital discharge and longitudinal analysis of those biomarkers’ kinetics with mixed‐effects models were performed prior to the building of a multivariate joint model. We showed that a higher mHLA‐DR value was associated with a lower risk of death. Predicted mHLA‐DR nadir cutoff value that maximized the Youden index was 5414 Ab/C and led to an AUC = 0.70 confidence interval (95%CI) = [0.65; 0.75] regarding association with D28 mortality while dynamic predictions using mHLA‐DR kinetics until D7, D12 and D20 showed AUCs of 0.82 [0.77; 0.87], 0.81 [0.75; 0.87] and 0.84 [0.75; 0.93]. Therefore, the final joint model provided adequate discrimination performances at D28 after collection of biomarker samples until D7, which improved as more samples were collected. After severe COVID‐19, decreased mHLA‐DR expression is associated with a greater risk of death at D28 independently of usual clinical confounders.

Abstract The construction of sub‐daily pressure series is described for the cities of London (GB) and Paris (FR). The series extend back 1692 and 1748, respectively, and as such they represent two of the longest sub‐daily series of barometric pressure available. These series are updated from the previously documented London and Paris daily series and offer more homogeneous series, and in the case of the London series a more temporally complete sequence of data. A pairwise homogenization procedure has been applied to the two series alongside the long series of pressure that exists for De Bilt (NL). The De Bilt series has been available for some time in the International Surface Pressure Dataset (ISPD), but further quality control and homogeneity‐checking procedures have been applied to the data in this paper and therefore the three series are released together in this dataset. The series are of immediate interest for understanding changes to storm activity across the English Channel and North Atlantic region over an extended timeframe but may also be assimilated into reanalysis datasets such as the 20th‐century reanalysis.

Objective Self‐monitored point‐of‐care urate‐measuring devices are an underexplored strategy to improve adherence to urate‐lowering therapy and clinical outcomes in gout. This study observed patient‐led urate self‐monitoring practice and assessed its influence on allopurinol adherence, urate control, and health‐related quality of life. Methods People with gout (n = 31) and prescribed allopurinol self‐monitored their urate concentrations (HumaSens2.0plus) at baseline and thereafter monthly for 12 months (3 months per quarter). Adherence to allopurinol was measured using medication event monitoring technology (Medication Event Monitoring System cap). Time spent below the target urate concentration (

Abstract Background Sudden unexpected death in epilepsy (SUDEP) is the most common cause of epilepsy‐related mortality. Although most witnessed SUDEPs follow seizures, mechanisms are uncertain. Investigations into the pathophysiology of SUDEP have relied on models and rare recordings of brain function at the time of the event. The brain‐responsive neurostimulation (RNS) device from Neuropace offers a therapeutic option for drug‐refractory epilepsy (DRE), enabling the recording of brain activity and the preemptive termination of seizures. Therefore, patients who experience SUDEP while being treated with an RNS device can provide insights into neural activity at the moment of this event. Objective We report the history and electrocorticographic (ECoG) recordings of a patient with DRE who experienced SUDEP years after RNS placement. Patient History A girl with Phelan–McDermid syndrome and Lennox–Gastaut syndrome had an RNS device implanted at the age of 14 to treat DRE. Initially, electrodes were positioned in the right orbitofrontal (OF) and right premotor frontal regions, with the OF lead later changed to the centromedian thalamic nucleus. At age 19, the patient was found unconscious and in cardiac arrest by her parents. Although spontaneous circulation returned en route to the hospital, the patient did not regain consciousness and died. Subsequent analysis of ECoGs from RNS recordings at the time of death indicated seizure onset in the right premotor frontal cortex, which persisted despite seizure termination attempts by the RNS. Conclusions We present a patient with SUDEP associated with the onset of RNS‐refractory seizures. The significance of this report is highlighted by the rarity of literature on neuronal function at the time of SUDEP. Moreover, it underscores the potential for devices capable of monitoring ECoG activity to shed light on the mechanisms underlying SUDEP and to inform interventions.

Abstract Background The ability to finish livestock on pasture over the summer–autumn period could improve the profitability of red meat enterprises in drought‐prone temperate regions. In south‐eastern Australia, traditional perennial options are limited by poor warm‐season performance (phalaris, Phalaris aquatica L.) and widespread environmental constraints (lucerne, Medicago sativa L.). We aimed to identify perennial species suitable for summer–autumn finishing. Methods We tested pure swards of summer‐active perennial grasses and herbs (20 cultivars across 14 species) in replicated small‐plot experiments at two sites on the Southern Tablelands of New South Wales, Australia. We assessed early persistence, productivity and warm‐season nutritive characteristics over 2–3 years. Results Lucerne and chicory (Cichorium intybus L.) persisted well through drought and produced herbage of high quantity and quality through summer–autumn. Digit grass (Digitaria eriantha Steud.) was highly persistent and productive but nutritive values were generally poor. Cocksfoot (Dactylis glomerata L.), tall fescue (Festuca arundinacea Schreb.), perennial ryegrass (Lolium perenne L.), prairie grass (Bromus willdenowii Kunth.) and plantain (Plantago lanceolata L.) were productive but less persistent through drought, while nutritive values were sometimes inadequate. Conclusions Chicory is a good alternative to lucerne, given its excellent summer–autumn performance, ability to survive droughts and superior acid soil tolerance. If appropriate management resolves issues with persistence and nutritive value, several of the other species could also be used to close the warm‐season feed gap in drought‐prone temperate environments.

Abstract A combined multiscale approach using ground, drone and satellite surveys can provide accurate landscape scale spatial mapping and monitoring. We used field observations with drone collected imagery covering 70 ha annually for a 5‐year period to estimate changes in living and dead vegetation of four widespread and abundant arid zone woody shrub species. Random forest classifiers delivered high accuracy (> 95%) using object‐based detection methods, with fast repeatable and transferrable processing using Google Earth Engine. Our classifiers performed well in both dominant arid zone landscape types: dune and swale, and at extremes of dry and wet years with minimal alterations. This highlighted the flexibility of the approach, potentially delivering insights into changes in highly variable environments. We also linked this classified drone vegetation to available temporally and spatially explicit Landsat satellite imagery, training a new, more accurate fractional vegetation cover model, allowing for accurate tracking of vegetation responses at large scales in the arid zone. Our method promises considerable opportunity to track vegetation dynamics including responses to management interventions, at large geographic scales, extending inference well beyond ground surveys.

Abstract Background Patients who have recurrent atrial fibrillation (AF) following redo catheter ablation may eventually be managed with a pace‐and‐ablate approach, involving pacemaker implant followed by atrioventricular nodal ablation (AVNA). We sought to determine which factors would predict subsequent AVNA in patients undergoing redo AF ablation. Methods We analyzed patients undergoing redo AF ablations between 2013 and 2019 at our institution. Follow‐up was censored on December 31, 2021. Patients with no available follow‐up data were excluded. Time‐to‐event analysis with Cox proportional hazard regression was used to compare those who underwent AVNA to those who did not. Results A total of 467 patients were included, of whom 39 (8.4%) underwent AVNA. After multivariable adjustment, female sex (aHR 4.68 [95% CI 2.30–9.50]; p

Abstract Multiple myeloma remains an incurable cancer mostly affecting older adults and is characterized by a series of remission inductions and relapses. This study aims to evaluate the outcomes in newly diagnosed transplant‐ineligible patients using bortezomib/lenalidomide‐based regimens in the Canadian real world as well as their outcomes in the second line. The Canadian Myeloma Research Group Database (CMRG‐DB) is a national database with input from multiple Canadian Centres with now up to 8000 patients entered. A total of 1980 transplant ineligible patients were identified in the CMRG‐DB between the years of 2007–2021. The four most commonly used induction regimens are bortezomib/melphalan/prednisone (VMP) (23%), cyclophosphamide/bortezomib/dexamethasone (CyBorD) (47%), lenalidomide/dexamethasone (Rd) (24%), and bortezomib/lenalidomide/dexamethasone (VRd) (6%). After a median follow‐up of 30.46 months (0.89–168.42), the median progression‐free survival (mPFS) and median overall survival (mOS) of each cohort are 23.5, 22.9, 34.0 months, and not reached (NR) and 64.1, 51.1, 61.5 months, and NR respectively. At the time of data cut‐off, 1128 patients had gone on to second‐line therapy. The mPFS2 based on first‐line therapy, VMP, CyBorD, Rd, and VRd is 53.3, 48.4, 62.7 months, and NR respectively. The most common second‐line regimens are Rd (47.4%), DRd (12.9%), CyBorD (10.3%), and RVd (8.9%) with a mPFS and a mOS of 17.0, 31.1, 15.4, and 14.0 months and 34.7, NR, 47.6, 33.4 months, respectively. This study represents the real‐world outcomes in newly diagnosed transplant‐ineligible myeloma patients in Canada. The spectra of therapy presented here reflect the regimens still widely used around the world. While this is sure to change with anti‐CD38 monoclonal antibodies now reflecting a new standard of care in frontline therapy, this cohort is reflective of the type of multiple myeloma patient currently experiencing relapse in the real‐world setting.

Abstract Understanding the impact of induction and maintenance therapy on patients’ quality of life (QoL) is important for treatment selection. This study aims to compare patient‐reported QoL between patients treated with KTd or KRd induction therapy and K maintenance therapy or observation. QoL was assessed using the EORTC QOL‐C 30 and QOL‐MY20 questionnaires in the AGMT‐02 study, in which 123 patients with newly diagnosed transplant ineligible multiple myeloma were randomized to nine cycles of either KTd or KRd induction therapy, followed by 12 cycles of K maintenance therapy, or observation. Longitudinal assessments showed statistically significant improvements in global health‐related QoL, various disease symptoms and pain for both treatment regimens. KTd improved insomnia and fatigue, and KRd improved physical functioning. Cross‐sectional comparisons indicated a “slight” superiority of KTd over KRd in several scales, with the exception of higher neuropathy scores with KTd. During maintenance, longitudinal comparisons showed no statistically significant changes. Cross‐sectional comparisons revealed a “slight” improvement in cognitive functioning during carfilzomib therapy, but a worsening in most other QoL scales. Induction therapy led to improvements in most QoL items, while maintenance therapy with K maintenance was associated with “slight” or “moderate” impairments in several QoL scales compared with the observation group.

Abstract Myeloproliferative neoplasms (MPNs) are associated with immune dysregulation and increased susceptibility to infection, emphasizing the importance of vaccination for patients. This pilot study evaluated immune responses to influenza vaccination in MPN patients compared with healthy donors using mass cytometry and serology. We observed diminished CXCR5+ B‐cell, CXCR3+ T‐cell, activated CD127+ memory T‐cell subsets, and a trend toward lower hemagglutinin inhibition titer in MPN patients. These results indicate that patients with MPN exhibit distinct responses to influenza vaccination suggestive of impaired migration to lymphoid organs and T‐cell maturation which may impact the development of protective immunity.

Abstract Primary large B‐cell lymphomas of immune‐privileged sites (IP‐LBCLs) comprise LBCLs arising within “immune sanctuaries,” including the central nervous system (CNS), vitreoretina, and testes. Although patients present with localized disease, the prognosis remains poor with high relapse rates, either at the originating site or within another immune‐privileged site. Generally, in the presence of an antecedent IP‐LBCL, subsequent LBCLs are expected to be clonally related. However, we present a primary CNS LBCL and later primary testicular LBCL in a middle‐aged man, diagnosed over a decade apart, which proved to be clonally unrelated by targeted ultra‐deep next‐generation sequencing of the IgH locus.

Abstract Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in adults. The cardiovascular safety of zavegepant nasal spray was assessed in both single‐ascending dose (SAD) and multiple‐ascending dose (MAD) studies in healthy participants. The SAD study included 72 participants (54 active/18 placebo) who received 0.1–40 mg zavegepant or placebo. The MAD study included 72 participants (56 active/16 placebo) who received 5–40 mg zavegepant or placebo for 1–14 days. Plasma zavegepant pharmacokinetics and electrocardiographic (ECG) parameters (Fridericia‐corrected QT interval [QTcF], heart rate, PR interval, ventricular depolarization [QRS], T‐wave morphology, and U‐wave presence) were analyzed pre‐ and post‐zavegepant administration. Using pooled data from the SAD and MAD studies, the relationship between time‐matched plasma zavegepant concentrations and QTc interval was assessed using a linear mixed‐effects model to evaluate the potential for QTc interval prolongation. Results showed that single and multiple doses of zavegepant had no significant impact on ECG parameters versus placebo, and there was no concentration‐dependent effect on QTcF interval. The estimated slope of the plasma zavegepant concentration‐QTcF model was −0.053 ms per ng/mL with a 90% confidence interval of −0.0955 to −0.0110 (p = 0.0415), which is not considered clinically meaningful. At doses up to four times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.

Abstract Objective The aim of this study was to assess the relative efficacy of medications used following severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection on self‐reported alterations in taste and/or smell function. Methods Seven hundred and fourteen persons with self‐reported postcoronavirus disease 2019 (post‐COVID‐19) chemosensory disorders were personally interviewed regarding specific medications they were administered following the acute phase of the disease. The dependent measure—self‐reported total recovery of chemosensory symptoms—was subjected to stepwise logistic regression. Independent predictors included demographic and clinical variables, in addition to specific medications used to mitigate disease symptoms (i.e., systemic corticosteroids, oseltamivir, vitamin C, ibuprofen, hydroxychloroquine, azithromycin, ivermectin, nitazoxanide, anticoagulants, and zinc). Results The median time between COVID‐19 symptom onset and the interviews was 81 days (interquartile range: 60–104). Of the 714 subjects, 249 (34.9%) reported total recovery of their chemosensory function; 437 (61.2%) had at least one treatment since the beginning of the disease. Women and those with more comorbidities had undergone more treatments. The recovery rates of the treated and nontreated groups did not differ significantly. Nonetheless, respondents who had used nitazoxanide tended to have a higher rate of self‐reported taste or smell recovery. Those who took oral zinc were less likely to improve. Conclusions No medication employed during the first months after SARS‐CoV‐2 infection had a clear positive effect on returning self‐reported smell or taste function to normal, although nitrazoxide trended in a positive direction. Oral zinc had a negative effect on the reported recovery of these senses.

Abstract Objective The aim of this study was to review findings from a large prospective national database of chemosensory disturbances associated with coronavirus disease 2019 (COVID‐19) infection. Data Sources The Virginia Commonwealth University Smell and Taste Center national database of COVID‐19 chemosensory disturbances. Methods A series of online surveys, first opened on April 10, 2020, was made accessible nationwide to any adult with sudden chemosensory dysfunction since January 2020. Participants received subsequent follow‐up surveys 14 days, 1 month, 3 months, and 6 months after enrollment. An additional survey was sent to all participants on May 28, 2022 to assess long‐term outcomes. Information pertaining to demographics, symptoms, comorbidities, treatments, and life impact was collected. Results Of 363 participants who reported complete smell recovery, 51.2% recovered within 1 month, 70% within 3 months, and 79% within 6 months, while 8.8% took over 1 year to completely recover. Among all participants, 7.5% had no smell recovery. Positive predictors of recovery included age

Abstract Biophobia refers to a fear of living things, which leads to alienation from nature. The literature examining the underlying mechanisms and treatment of biophobia is sparse. This review aims to increase the readers' understanding of biophobia by examining the more extensive literature on specific phobias, namely animal phobia, as it most closely resembles biophobia. Fear, anxiety and disgust play an important role in specific phobias. Their triggers and functions are reviewed in the context of animal phobia. Theoretical models for specific phobias suggest that phobias develop because genetically linked behavioural patterns interact with normal development fears and environmental factors. Phobias are then maintained by cognitive and behavioural mechanisms. Exposure therapy, the gold standard treatment for specific phobia, functions to override the maladaptive stimulus–stimulus and stimulus‐response associations responsible for animal and other specific phobias. Its delivery and efficacy are reviewed. We recommend that readers interested in biophobia use the existing knowledge on animal phobia and specific phobia in general to treat biophobia and generate research hypotheses for future study. Read the free Plain Language Summary for this article on the Journal blog.

Abstract The use of patient‐reported outcomes (PROMs) of quality of life (QOL) is common in cachexia trials. Patients' self‐report on health, functioning, wellbeing, and perceptions of care, represent important measures of efficacy. This review describes the frequency, variety, and reporting of QOL endpoints used in cancer cachexia clinical trials. Electronic literature searches were performed in Medline, Embase, and Cochrane (1990–2023). Seven thousand four hundred thirty‐five papers were retained for evaluation. Eligibility criteria included QOL as a study endpoint using validated measures, controlled design, adults (>18 years), ≥40 participants randomized, and intervention exceeding 2 weeks. The Covidence software was used for review procedures and data extractions. Four independent authors screened all records for consensus. Papers were screened by titles and abstracts, prior to full‐text reading. PRISMA guidance for systematic reviews was followed. The protocol was prospectively registered via PROSPERO (CRD42022276710). Fifty papers focused on QOL. Twenty‐four (48%) were double‐blind randomized controlled trials. Sample sizes varied considerably (n = 42 to 469). Thirty‐nine trials (78%) included multiple cancer types. Twenty‐seven trials (54%) featured multimodal interventions with various drugs and dietary supplements, 11 (22%) used nutritional interventions alone and 12 (24%) used a single pharmacological intervention only. The median duration of the interventions was 12 weeks (4–96). The most frequent QOL measure was the EORTC QLQ‐C30 (60%), followed by different FACIT questionnaires (34%). QOL was a primary, secondary, or exploratory endpoint in 15, 31 and 4 trials respectively, being the single primary in six. Statistically significant results on one or more QOL items favouring the intervention group were found in 18 trials. Eleven of these used a complete multidimensional measure. Adjustments for multiple testing when using multicomponent QOL measures were not reported. Nine trials (18%) defined a statistically or clinically significant difference for QOL, five with QOL as a primary outcome, and four with QOL as a secondary outcome. Correlation statistics with other study outcomes were rarely performed. PROMs including QOL are important endpoints in cachexia trials. We recommend using well‐validated QOL measures, including cachexia‐specific items such as weight history, appetite loss, and nutritional intake. Appropriate statistical methods with definitions of clinical significance, adjustment for multiple testing and few co‐primary endpoints are encouraged, as is an understanding of how interventions may relate to changes in QOL endpoints. A strategic and scientific‐based approach to PROM research in cachexia trials is warranted, to improve the research base in this field and avoid the use of QOL as supplementary measures.

Abstract Background Skeletal muscle dysfunction is a common extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD). Alterations in skeletal muscle myosin heavy chain expression, with reduced type I and increased type II myosin heavy chain expression, are associated with COPD severity when studied in largely male cohorts. The objectives of this study were (1) to define an abnormal myofibre proportion phenotype in both males and females with COPD and (2) to identify transcripts and transcriptional networks associated with abnormal myofibre proportion in COPD. Methods Forty‐six participants with COPD were assessed for body composition, strength, endurance and pulmonary function. Skeletal muscle biopsies from the vastus lateralis were assayed for fibre‐type distribution and cross‐sectional area via immunofluorescence microscopy and RNA‐sequenced to generate transcriptome‐wide gene expression data. Sex‐stratified k‐means clustering of type I and IIx/IIax fibre proportions was used to define abnormal myofibre proportion in participants with COPD and contrasted with previously defined criteria. Single transcripts and weighted co‐expression network analysis modules were tested for correlation with the abnormal myofibre proportion phenotype. Results Abnormal myofibre proportion was defined in males with COPD (n = 29) as 22% type IIx/IIax fibres and in females with COPD (n = 17) as 12% type IIx/IIax fibres. Half of the participants with COPD were classified as having an abnormal myofibre proportion. Participants with COPD and an abnormal myofibre proportion had lower median handgrip strength (26.1 vs. 34.0 kg, P = 0.022), 6‐min walk distance (300 vs. 353 m, P = 0.039) and forced expiratory volume in 1 s‐to‐forced vital capacity ratio (0.42 vs. 0.48, P = 0.041) compared with participants with COPD and normal myofibre proportions. Twenty‐nine transcripts were associated with abnormal myofibre proportions in participants with COPD, with the upregulated NEB, TPM1 and TPM2 genes having the largest fold differences. Co‐expression network analysis revealed that two transcript modules were significantly positively associated with the presence of abnormal myofibre proportions. One of these co‐expression modules contained genes classically associated with muscle atrophy, as well as transcripts associated with both type I and type II myofibres, and was enriched for genetic loci associated with bone mineral density. Conclusions Our findings indicate that there are significant transcriptional alterations associated with abnormal myofibre proportions in participants with COPD. Transcripts canonically associated with both type I and type IIa fibres were enriched in a co‐expression network associated with abnormal myofibre proportion, suggesting altered transcriptional regulation across multiple fibre types.

Abstract Regulatory agencies require evidence that endpoints correlate with clinical benefit before they can be used to approve drugs. Biomarkers are often considered surrogate endpoints. In cancer cachexia trials, the measurement of biomarkers features frequently. The aim of this systematic review was to assess the frequency and diversity of biomarker endpoints in cancer cachexia trials. A comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990–2023) was completed. Eligible trials met the following criteria: adults (≥18 years), prospective design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a biomarker(s) as an endpoint. Biomarkers were defined as any objective measure that was assayed from a body fluid, including scoring systems based on these assays. Routine haematology and biochemistry to monitor intervention toxicity were not considered. Data extraction was performed using Covidence, and reporting followed PRISMA guidance (PROSPERO: CRD42022276710). A total of 5975 studies were assessed, of which 52 trials (total participants = 6522) included biomarkers as endpoints. Most studies (n = 29, 55.7%) included a variety of cancer types. Pharmacological interventions (n = 27, 51.9%) were most evaluated, followed by nutritional interventions (n = 20, 38.4%). Ninety‐nine different biomarkers were used across the trials, and of these, 96 were assayed from blood. Albumin (n = 29, 55.8%) was assessed most often, followed by C‐reactive protein (n = 22, 42.3%), interleukin‐6 (n = 16, 30.8%) and tumour necrosis factor‐α (n = 14, 26.9%), the latter being the only biomarker that was used to guide sample size calculations. Biomarkers were explicitly listed as a primary outcome in six trials. In total, 12 biomarkers (12.1% of 99) were used in six trials or more. Insulin‐like growth factor binding protein 3 (IGFBP‐3) and insulin‐like growth factor 1 (IGF‐1) levels both increased significantly in all three trials in which they were both used. This corresponded with a primary outcome, lean body mass, and was related to the pharmacological mechanism. Biomarkers were predominately used as exploratory rather than primary endpoints. The most commonly used biomarker, albumin, was limited by its lack of responsiveness to nutritional intervention. For a biomarker to be responsive to change, it must be related to the mechanism of action of the intervention and/or the underlying cachexia process that is modified by the intervention, as seen with IGFBP‐3, IGF‐1 and anamorelin. To reach regulatory approval as an endpoint, the relationship between the biomarker and clinical benefit must be clarified.

Abstract Significant variation exists in the outcomes used in cancer cachexia trials, including measures of body composition, which are often selected as primary or secondary endpoints. To date, there has been no review of the most commonly selected measures or their potential sensitivity to detect changes resulting from the interventions being examined. The aim of this systematic review is to assess the frequency and diversity of body composition measures that have been used in cancer cachexia trials. MEDLINE, Embase and Cochrane Library databases were systematically searched between January 1990 and June 2021. Eligible trials examined adults (≥18 years) who had received an intervention aiming to treat or attenuate the effects of cancer cachexia for >14 days. Trials were also of a prospective controlled design and included body weight or at least one anthropometric, bioelectrical or radiological endpoint pertaining to body composition, irrespective of the modality of intervention (e.g., pharmacological, nutritional, physical exercise and behavioural) or comparator. Trials with a sample size of

Abstract Background There is no population‐based evidence on the prevalence and impact of skin diseases in Greece. Objectives To describe the prevalence of 12 main skin diseases and their impact on quality of life (QoL) and feelings of stigmatization in the Greek population. Methods A population‐based survey in an adult Greek representative sample was carried out as part of the multinational ‘EADV burden of skin diseases study’. Quality of life (QOL) was measured using the Dermatology Life Quality Index (DLQI) and the Visual Analogue Scale (VAS) from the EuroQol‐5D (EQ. 5D) questionnaires. Results In 1010 participants, 47.8% (n = 483) declared at least one skin disease or condition or skin‐related unpleasant sensation in the last 12 months. Fungal skin infection was reported with the higher prevalence (7.5%), followed by alopecia (5.7%), atopic dermatitis (5%), acne (3.6%), sexually transmitted diseases (2.7%), psoriasis (2.2%) chronic urticaria (1.5%), rosacea (1.3%), nonmelanoma skin cancer (1.5%), vitiligo (0.6%), cutaneous melanoma (0.6%) and hidradenitis suppurativa (0.3%). Mean VAS‐EQ. 5D and DLQI scores were 77.8 and 2.2, respectively. Among those reporting at least one skin problem, 68.1% reported an impact of the skin condition on their personal life and 51% reported an impact on time to take care of themselves. Regarding the impact on work‐life decisions, 22.2% reoriented their professional activity, 13% were refused a professional offer, 22.2% did not get the job they hoped to and 16.7% chose their work with their skin problem in mind. Regarding feelings of stigmatization, 12% felt left out/rejected by others, 6.6% were refused access to leisure facilities and 9.8% reported the impression to be looked at with disgust. Conclusions Our population‐based study provides new information on the prevalence of skin diseases in the Southern European country of Greece and highlights the impact of prevalent skin disease on life‐altering decisions and stigmatization.

Abstract Background Autofluorescence (AF)‐Raman spectroscopy is a technology that can detect tumour tissue in surgically excised skin specimens. The technique does not require tissue fixation, staining, labelling or sectioning, and provides quantitative diagnosis maps within 30 min. Objectives To explore the clinical application of AF‐Raman microscopy to detect residual basal cell carcinoma (BCC) positive margins in ex vivo skin specimens excised during real‐time Mohs surgery. To investigate the ability to analyse skin specimens from different parts of the head‐and‐neck areas and detect nodular, infiltrative and superficial BCC. Methods Fifty Mohs tissue layers (50 patients) were investigated: 27 split samples (two halves) and 23 full‐face samples. The AF‐Raman results were compared to frozen section histology, carried out intraoperatively by the Mohs surgeon and postoperatively by dermatopathologists. The latter was used as the standard of reference. Results The AF‐Raman analysis was completed within the target time of 30 min and was able to detect all subtypes of BCC. For the split specimens, the AF‐Raman analysis covered 97% of the specimen surface area and detected eight out of nine BCC positive layers (similar to Mohs surgeons). For the full‐face specimens, poorer contact between tissue and cassette coverslip led to lower coverage of the specimen surface area (92%), decreasing the detection rate (four out of six positives for BCC). Conclusions These preliminary results, in particular for the split specimens, demonstrate the feasibility of AF‐Raman microscopy for rapid assessment of Mohs layers for BCC presence. However, for full‐face specimens, further work is required to improve the contact between the tissue and the coverslip to increase sensitivity.

Abstract Aims Inherited cardiomyopathies are relatively rare but carry a high risk of cardiac maternal morbidity and mortality during pregnancy and postpartum. However, data for risk stratification are scarce. The new CARPREG II score improves prediction of prognosis in pregnancies associated with heart disease, though its role in inherited cardiomyopathies is unclear. We aim to describe characteristics and cardiac maternal outcomes in patients with inherited cardiomyopathy during pregnancy, and to evaluate the interest of the CARPREG II risk score in this population. Methods and results In this retrospective single‐centre study, 90 consecutive pregnancies in 74 patients were included (mean age 32 ± 5 years), including 28 cases of dilated cardiomyopathy (DCM), 46 of hypertrophic cardiomyopathy, 11 of arrhythmogenic right ventricular cardiomyopathy and 5 of left ventricular noncompaction, excluding peripartum cardiomyopathy. The discriminatory power of several risk scores was assessed by the area under the receiver‐operating characteristic curve (AUC). Median CARPREG II score was 2 [0;3] and was higher in the DCM subgroup. A severe cardiac maternal complication was observed in 18 (20%) pregnancies, mainly driven by arrhythmia and heart failure (each event in 10 pregnancies), with 3 cardiovascular deaths. Forty‐three pregnancies (48%) presented foetal/neonatal complications (18 premature delivery, 3 foetal/neonatal death). CARPREG II was significantly associated with cardiac maternal complications (P

Abstract Aims The use of large medical or healthcare claims databases is very useful for population‐based studies on the burden of heart failure (HF). Clinical characteristics and management of HF patients differ according to categories of left ventricular ejection fraction (LVEF), but this information is often missing in such databases. We aimed to develop and validate algorithms to identify LVEF in healthcare databases where the information is lacking. Methods and results Algorithms were built by machine learning with a random forest approach. Algorithms were trained and reinforced using the French national claims database [Système National des Données de Santé (SNDS)] and a French HF registry. Variables were age, gender, and comorbidities, which could be identified by medico‐administrative code‐based proxies, Anatomical Therapeutic Chemical codes for drug delivery, International Classification of Diseases (Tenth Revision) coding for hospitalizations, and administrative codes for any other type of reimbursed care. The algorithms were validated by cross‐validation and against a subset of the SNDS that includes LVEF information. The areas under the receiver operating characteristic curve were 0.84 for the algorithm identifying LVEF ≤ 40% and 0.79 for the algorithms identifying LVEF