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Abstract Introduction Migraine‐related stigma (MiRS) and social burden is increasingly recognized. We assessed perspectives and attitudes toward migraine in people with and without migraine in Japan. Methods OVERCOME (Japan) was a cross‐sectional, population‐based web survey of people with and without migraine (July−September 2020). People with migraine were individuals who met the modified International Classification of Headache Disorders criteria or had self‐reported physician‐diagnosed migraine. People without migraine were selected per quota sampling to represent the Japanese adult population. People with migraine reported their experiences on stigma and social burden and answered how frequently they experienced stigma using the MiRS questionnaire. Associations between MiRS and disability and MiRS and interictal burden were examined using the migraine disability assessment and Migraine Interictal Burden Scale‐4. People without migraine reported their experiences and attitudes toward people with migraine by answering an 11‐item attitudinal migraine questionnaire. Results A total of 17,071 and 2008 people with and without migraine, respectively, completed the survey. Overall, 11,228 (65.8%) respondents with migraine reported that they have never experienced stigma or burden; however, of the 12,383 employed respondents, 5841 (47.2%) reported that their current employers are not “extremely” or “very” understanding about their conditions. Moreover, ∼30%−40% of respondents “sometimes,” “often,” or “very often” hid their migraine from others. The proportion of respondents who experienced stigma often or very often, as assessed by MiRS, was 16.5%; this increased with the increasing number of monthly migraine headache days. The proportion of respondents with moderate‐to‐severe disability and interictal burden increased with increasing stigma. Among respondents without migraine, the proportion holding a stigmatizing attitude toward those with migraine was low (

Abstract Soluble angiotensin‐converting enzyme 2 (ACE2) can act as a decoy molecule that neutralizes severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) by blocking spike (S) proteins on virions from binding ACE2 on host cells. Based on structural insights of ACE2 and S proteins, we designed a “muco‐trapping” ACE2‐Fc conjugate, termed ACE2‐(G4S)6‐Fc, comprised of the extracellular segment of ACE2 (lacking the C‐terminal collectrin domain) that is linked to mucin‐binding IgG1‐Fc via an extended glycine‐serine flexible linker. ACE2‐(G4S)6‐Fc exhibits substantially greater binding affinity and neutralization potency than conventional full length ACE2‐Fc decoys or similar truncated ACE2‐Fc decoys without flexible linkers, possessing picomolar binding affinity and strong neutralization potency against pseudovirus and live virus. ACE2‐(G4S)6‐Fc effectively trapped fluorescent SARS‐CoV‐2 virus like particles in fresh human airway mucus and was stably nebulized using a commercial vibrating mesh nebulizer. Intranasal dosing of ACE2‐(G4S)6‐Fc in hamsters as late as 2 days postinfection provided a 10‐fold reduction in viral load in the nasal turbinate tissues by Day 4. These results strongly support further development of ACE2‐(G4S)6‐Fc as an inhaled immunotherapy for COVID‐19, as well as other emerging viruses that bind ACE2 for cellular entry.

Abstract Conductive polymers (CPs) are widely studied for their ability to influence a myriad of tissue systems. While their mixed ionic/electronic conductivity is commonly considered the primary driver of these benefits, the mechanisms by which CPs influence cell fate remain unclear. In this study, CP‐biomaterial interactions are investigated using collagen, due to its widespread prevalence throughout the body and in tissue engineering constructs. Collagen is functionalized with both electrostatically and covalently bound derivatives of the CP poly(3,4‐ethylenedioxythiophene) (PEDOT) doped via backbone‐tethered sulfonate groups, which enable high solubility and loading to the collagen biomatrix. Intrinsically doped scaffolds are compared to those incorporated with a commercially available PEDOT formulation, which is complexed with polyanionic polystyrene sulfonate (PSS). Low loadings of intrinsically doped PEDOT do not increase substrate conductivity compared to collagen alone, enabling separate investigation into CP loading and conductivity. Interestingly, higher PEDOT loading bolsters human mesenchymal stromal (hMSC) cell gene expression of Oct‐4 and NANOG, which are key transcription factors regulating cell stemness. Conductive collagen composites with commercial PEDOT:PSS do not significantly affect the expression of these transcription factors in hMSCs. Furthermore, it is demonstrated that PEDOT regulates cellular fate independently from physical changes to the material but directly to the loading of the polymer.

Abstract Background Clients want to know the ultimate cause of death in their pet after cancer treatment. The cause of euthanasia and investigation of urinary obstruction in treated dogs with urothelial carcinoma (UC) has not been specifically reported in veterinary literature. Hypothesis/Objectives Our hypothesis was that the majority of treated dogs with UC are euthanized secondary to primary tumor factors, such as urinary obstruction. Animals Fifty‐nine client‐owned dogs diagnosed with UC. Methods Retrospective observational study on clinical signs and disease at euthanasia of dogs with UC treated by radiation therapy or chemotherapy or both. Results The median overall survival time (OST) of all dogs was 339 days (range, 17‐1996; 95% confidence interval [CI], 185‐392; interquartile range [IQR], 112‐505). Of dogs deemed to have been euthanized because of UC (50/59, 85%), the primary cause was considered to be local progression in 31/50 (62%), most often because of perceived complete or partial urinary obstruction (24/31, 77%). No variables were found to be predictive of urinary obstruction. The overall documented metastatic rate was 56%. In dogs euthanized because of UC, metastasis was deemed to be the cause in 19/50 (38%) dogs. Conclusions and Clinical Importance Regardless of the type of treatment, UC in dogs has a poor prognosis and there is a continuing need to improve treatments that focus on local control of the primary tumor, given its high contribution to the decision for euthanasia. Proactive management to avoid the high frequency of urinary obstruction may be worthy of future investigation.

Key Clinical Message We present a case of Cronkhite–Canada syndrome in a patient with decompensated cirrhosis who had successful induction of remission with nutritional supplementation alone. We propose that early institution of high‐protein, high‐energy enteral supplementation should be offered to all patients, especially those with compelling contraindications to immunosuppression.

Abstract Altering plant carbon allocation from leaves to stems is key to improve biomass for forage, fuel, and renewable chemicals. The sorghum dry stalk (D) locus controls a quantitative trait for sugar accumulation, with enhanced carbon allocation in the stems of juicy green (dd) sorghum but reduced carbon allocation in that of dry white (DD) sorghum. However, it remains unclear whether altering sorghum sugar accumulation in stem affects below‐ground microbiome. Here we investigated sorghum rhizosphere soil microbiome in near isogenic lines with different magnitude of carbon allocations and accumulation in the stems. Results showed that enhanced carbon accumulation in stems of juicy green sorghum results in stronger selection in rhizosphere microbiome assembly. The rhizosphere soil microbial communities selected in juicy green sorghum tended to be fast‐growing microbial taxa which possessed potential functions that would promote higher potential capacity to use chemically labile carbon sources and potentially result in higher potential decomposition rates. We found the rhizosphere microbes selected by juicy green sorghum form weaker interactions than dry white sorghum. This is the first comprehensive study revealing how the different magnitude of carbon allocations to stems regulates microbial community assembly, microbial interaction, and microbial functions. This study indicates that future plant modification for bioenergy crops should also consider the impacts on belowground microbial community without compromising the sustainability.

Abstract Macrotermes termite mounds in the Kruger National Park occupy a significant part of the savanna landscapes, occurring at densities of up to 70 km−2 and often exceeding 10 m in width and 4 m in height. The mounds are usually devoid of trees, but have dense grass cover in wet years. As a result, these mounds form large patches of grassland amongst the wooded savanna. To our knowledge, it is not known why trees are largely excluded from the mounds. We analysed soil surface nutrient concentrations on and off mounds (0–2 cm deep, n = 80) to ascertain whether the availability of nutrients could be influencing competition between grasses and tree seedlings. The results showed that potential deficiencies in P, Ca, Cu, Zn and B in soils off the mounds are likely to be constraining plant growth. Notably, only B, with an average concentration of 0.19 mg kg−1, was likely to be limiting plant growth on the mounds. Notwithstanding likely interactions with herbivory and fire, we hypothesise that because grasses are far less susceptible to deficiencies of B than dicotyledonous trees, it is likely that grass competition with tree seedlings is considerably greater on mounds than off mounds.

Abstract Background Understanding healthcare professionals' (HCPs) experiences of caring for women with false‐positive screening test results in the National Health Service Breast Screening Programme (NHSBSP) is important for reducing the impact of such results. Methods Interviews were undertaken with 12 HCPs from a single NHSBSP unit, including advanced radiographer practitioners, breast radiographers, breast radiologists, clinical nurse specialists (CNSs), and a radiology healthcare assistant. Data were analysed thematically using Template Analysis. Results Two themes were produced: (1) Gauging and navigating women's anxiety during screening assessment was an inevitable and necessary task for all participants. CNSs were perceived as particularly adept at this, while breast radiographers reported a lack of adequate formal training. (2) Controlling the delivery of information to women (including amount, type and timing of information). HCPs reported various communication strategies to facilitate women's information processing and retention during a distressing time. Conclusions Women's anxiety could be reduced through dedicated CNS support, but this should not replace support from other HCPs. Breast radiographers may benefit from more training to emotionally support recalled women. While HCPs emphasised taking a patient‐centred communication approach, the use of other strategies (e.g., standardised scripts) and the constraints of the ‘one‐stop shop’ model pose challenges to such an approach. Patient and Public Contribution During the study design, two Patient and Public Involvement members (women with false‐positive‐breast screening test results) were consulted to gain an understanding of patient perspectives and experiences of being recalled specifically in the NHSBSP. Their feedback informed the formulations of the research aim, objectives and the direction of the interview guide.

Abstract Pyrosomes are colonial tunicates that form gelatinous tubes and occasionally produce bioluminescent swarms. The rapid “bloom‐bust” dynamics of pyrosomes have the potential to outcompete other zooplankton, restructure marine food webs, enhance carbon export, and interfere with human activities. Pyrosomes have been recorded for at least two centuries, yet much remains unknown about their physiology, bloom mechanisms, and ecosystem impacts. Recent bloom reports prompt the question of whether frequencies or densities are increasing, and whether potential population changes are caused by ocean change. This review clarifies current information on pyrosome biology and ecology and explores apparent contradictions in habitat preferences and diel vertical migration (DVM). We posit that the dominant species, Pyrosoma atlanticum, may preferentially inhabit waters below 18°C and alter its DVM activity to maintain overall body temperature near this threshold. Expanding our knowledge of pyrosomes is needed to facilitate their inclusion in ecosystem models and forecasts of future population distributions.

Abstract Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in infants, the immunocompromised, and the elderly. RSV infects the airway epithelium via the apical membrane and almost exclusively sheds progeny virions back into the airway mucus (AM), making RSV difficult to target by systemically administered therapies. An inhalable “muco‐trapping” variant of motavizumab (Mota‐MT), a potent neutralizing mAb against RSV F is engineered. Mota‐MT traps RSV in AM via polyvalent Fc‐mucin bonds, reducing the fraction of fast‐moving RSV particles in both fresh pediatric and adult AM by ≈20–30‐fold in a Fc‐glycan dependent manner, and facilitates clearance from the airways of mice within minutes. Intranasal dosing of Mota‐MT eliminated viral load in cotton rats within 2 days. Daily nebulized delivery of Mota‐MT to RSV‐infected neonatal lambs, beginning 3 days after infection when viral load is at its maximum, led to a 10 000‐fold and 100 000‐fold reduction in viral load in bronchoalveolar lavage and lung tissues relative to placebo control, respectively. Mota‐MT‐treated lambs exhibited reduced bronchiolitis, neutrophil infiltration, and airway remodeling than lambs receiving placebo or intramuscular palivizumab. The findings underscore inhaled delivery of muco‐trapping mAbs as a promising strategy for the treatment of RSV and other acute respiratory infections.

Abstract Mivavotinib (TAK‐659/CB‐659), a dual SYK/FLT3 inhibitor, reduced immunosuppressive immune cell populations and suppressed tumor growth in combination with anti‐PD‐1 therapy in cancer models. This dose‐escalation/expansion study investigated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mivavotinib plus nivolumab in patients with advanced solid tumors. Patients received oral mivavotinib 60–100 mg once‐daily plus intravenous nivolumab 3 mg/kg on days 1 and 15 in 28‐day cycles until disease progression or unacceptable toxicity. The dose‐escalation phase evaluated the recommended phase II dose (RP2D; primary endpoint). The expansion phase evaluated overall response rate (primary end point) at the RP2D in patients with triple‐negative breast cancer (TNBC). During dose‐escalation (n = 24), two dose‐limiting toxicities (grade 4 lipase increased and grade 3 pyrexia) occurred in patients who received mivavotinib 80 mg and 100 mg, respectively. The determined RP2D was once‐daily mivavotinib 80 mg plus nivolumab 3 mg/kg. The expansion phase was terminated at ~50% enrollment (n = 17) after failing to meet an ad hoc efficacy futility threshold. Among all 41 patients, common treatment‐emergent adverse events (TEAEs) included dyspnea (48.8%), aspartate aminotransferase increased, and pyrexia (46.3% each). Common grade ≥3 TEAEs were hypophosphatemia and anemia (26.8% each). Mivavotinib plasma exposure was generally dose‐proportional (60–100 mg). One patient had a partial response. Mivavotinib 80 mg plus nivolumab 3 mg/kg was well tolerated with no new safety signals beyond those of single‐agent mivavotinib or nivolumab. Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. Trial registration ID NCT02834247.

Background Bystander cardiopulmonary resuscitation (B‐CPR) and defibrillation for out‐of‐hospital cardiac arrest (OHCA) vary by sex, with women being less likely to receive these interventions in public. It is unknown whether sex differences persist when considering neighborhood racial and ethnic composition. We examined the odds of receiving B‐CPR stratified by location and neighborhood. We hypothesized that women in predominantly Black neighborhoods will have a lower odds of receiving B‐CPR. Methods and Results We conducted a retrospective study using the Cardiac Arrest Registry to Enhance Survival (CARES). Neighborhoods were classified by census tract. We modeled the odds of receipt of B‐CPR (primary outcome), automatic external defibrillation application, and survival to hospital discharge (secondary outcomes) by sex. CARES collected 457 621 arrests (2013–2019); after appropriate exclusion, 309 662 were included. Women who had public OHCA had a 14% lower odds of receiving B‐CPR (odds ratio [OR], 0.86 [95% CI, 0.82–0.89]), but effect modification was not seen by neighborhood (P=not significant). In predominantly Black neighborhoods, women who had public OHCA had a 13% lower odds of receiving B‐CPR (adjusted OR, 0.87 [95% CI, 0.76–0.98]) and 12% lower odds of receiving automatic external defibrillation application (adjusted OR, 0.88 [95% CI, 0.78–0.99]). In predominantly Hispanic neighborhoods, women who had public OHCA were less likely to receive B‐CPR (adjusted OR, 0.83 [95% CI, 0.73–0.96]) and less likely to receive automatic external defibrillation application (adjusted OR, 0.74 [95% CI, 0.64–0.87]). Conclusions Women with public OHCA have a decreased likelihood of receiving B‐CPR and automatic external defibrillation application. Findings did not differ significantly according to neighborhood composition. Despite this, our work has implications for considering strategies to reduce disparities around bystander response.

Abstract Evaluating salmon hatchery supplementation programs requires assessing not only program objectives but identifying potential risks to wild populations as well. Such evaluations can be hampered by difficulty in distinguishing between hatchery‐ and wild‐born returning adults. Here, we conducted 3 years (2011–2013) of experimental hatchery supplementation of sockeye salmon in Auke Lake, Juneau, Alaska where a permanent weir allows sampling and genotyping of every returning adult (2008–2019). We identified both hatchery‐ and wild‐born returning adults with parentage assignment, quantified the productivity (adult offspring/spawner) of hatchery spawners relative to that of wild spawners, and compared run timing, age, and size at age between hatchery‐ and wild‐born adults. Hatchery‐spawning females produced from approximately six to 50 times more returning adults than did naturally spawning females. Supplementation had no discernable effect on run timing and limited consequences for size at age, but we observed a distinct shift to younger age at maturity in the hatchery‐born individuals in all three brood years. The shift appeared to be driven by hatchery‐born fish being more likely to emigrate after one, rather than two, years in the lake but the cause is unknown. In cases when spawning or incubation habitat is limiting sockeye salmon production, hatchery supplementation can be effective for enhancing the number of returning adult fish but not without the risk of phenotypic change in the recipient population, which can be an undesired outcome of hatchery supplementation. This study adds to a growing body of evidence suggesting that phenotypic change within a single generation of captive spawning might be widespread in salmon hatchery programs.

Objectives. To characterize the association between pulmonary embolism (PE) severity and bleeding risk with treatment approaches, outcomes, and complications. Methods. Secondary analysis of an 11-hospital registry of adult ED patients treated by a PE response team (August 2016–November 2022). Predictors were PE severity and bleeding risk. The primary outcome was treatment approach: anticoagulation monotherapy vs. advanced intervention (categorized as “immediate” or “delayed” based on whether the intervention was received within 12 hours of PE diagnosis or not). Secondary outcomes were death, clinical deterioration, and major bleeding. Results. Of the 1832 patients, 139 (7.6%), 977 (53.3%), and 9 (0.5%) were classified as high-risk, intermediate-high, intermediate-low, and low-risk severity, respectively. There were 94 deaths (5.1%) and 218 patients (11.9%) had one or more clinical deterioration events. Advanced interventions were administered to 86 (61.9%), 195 (27.6%), and 109 (11.2%) patients with high-risk, intermediate-high, and intermediate-low severity, respectively.Major bleeding occurred in 61/1440 (4.2%) on ACm versus 169/392 (7.6%) with advanced interventions (p

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies in the world, for which the mortality is almost as high as the disease incidence and is predicted to be the second‐highest cause of cancer‐related deaths by 2030. These cancerous tumors consist of diversified gene expressions within the different cellular subpopulations that include neoplastic ductal cells, cancer‐associated fibroblasts, and immune cells, all of which collectively facilitate cellular heterogeneity in the PDAC tumor microenvironment (TME). Active intratumoral interaction within the cell populations in TME induces the proliferation of cancerous cells, accounting for tumorigenesis and rapid metastasis. Methods This review will focus on novel findings uncovering PDAC heterogeneity in different cellular subpopulations using single‐cell RNA‐sequencing (scRNA‐seq) and other single‐cell analysis technologies. It will further explore the emerging role of single‐cell technologies in assessing the role of different subpopulations of neoplastic ductal cells, cancer‐associated fibroblasts, and immune cells in PDAC progression. Results and Conclusion The application of scRNA‐seq in PDAC has started to unveil associations between disease progression and heterogeneity in pancreatic TME and could influence future PDAC treatment. Recent advances in scRNA‐seq have uncovered comprehensive analyses of heterogeneous ecosystems present within the TME. These emerging findings underpins further need for a more in‐depth understanding of intratumoral heterogeneity in the PDAC microenvironment.

Abstract Aim Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all major cancers. Chemotherapy is the mainstay systemic therapy for PDAC, and chemoresistance is a major clinical problem leading to therapeutic failure. This study aimed to identify key differences in gene expression profile in tumors from chemoresponsive and chemoresistant patients. Methods Archived formalin‐fixed paraffin‐embedded tumor tissue samples from patients treated with neoadjuvant chemotherapy were obtained during surgical resection. Specimens were macrodissected and gene expression analysis was performed. Multi‐ and univariate statistical analysis was performed to identify differential gene expression profile of tumors from good (0%–30% residual viable tumor [RVT]) and poor (>30% RVT) chemotherapy‐responders. Results Initially, unsupervised multivariate modeling was performed by principal component analysis, which demonstrated a distinct gene expression profile between good‐ and poor‐chemotherapy responders. There were 396 genes that were significantly (p

Abstract Introduction Critical illness associated with intensive care unit (ICU) admission often results in persistent skeletal muscle wasting and may lead to frailty in older and patients with multi‐morbidity. Early recognition of patients at high‐risk of long‐term complications could provide opportunities to minimize the impact of critical illness and improve health and quality of life. MicroRNAs (miRs) are short, non‐coding RNAs that regulate approximately two‐thirds of the human genome and are involved in most biological processes. Multiple studies have demonstrated their role in muscle development and disease and their potential as biomarkers of muscle wasting. Aim and methods This systematic review examined the potential of miRs as biomarkers and therapeutics for muscle wasting during and following critical illness. PubMed and Scopus databases were searched for terms associated with critical illness, ICU, muscle wasting, frailty and microRNAs from inception to June 2022 (PROSPERO number CRD42022339531). Results Out of 537 articles, seven studies met the inclusion criteria and examined skeletal muscle and circulating miRs in the context of muscle wasting and/or frailty related to critical illness. Across the seven studies, 27 different miRs were identified that were reported to be dysregulated in the muscle and four in the blood, plasma or serum of critically ill patients. Four miRs were reported to be altered in both muscle and blood during critical illness and their levels moderately correlated with parameters of muscle function. These included canonical muscle‐enriched miRs (myomiRs), such as miR‐133, miR‐1 and miR‐181, which correlated with muscle strength in critically ill patients. However, most of the miRs reported to be dysregulated in the muscle following critical illness were examined in one article only. Conclusions This systematic review highlights the potential of miRs as biomarkers of skeletal muscle wasting and ICU‐associated weakness following critical illness, suggesting the need for larger validation studies using unbiased techniques. We have described circulating and muscle microRNAs, which correlated with muscle parameters during critical illness. However, the limited number of studies in this area highlights the requirement for further studies before these could be considered in clinical practice.

Abstract Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high‐grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi‐institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36–3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11–2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

Abstract Early life adversity predicts shorter adult lifespan in several animal taxa. Yet, work on long‐lived primate populations suggests the evolution of mechanisms that contribute to resiliency and long lives despite early life insults. Here, we tested associations between individual and cumulative early life adversity and lifespan on rhesus macaques at the Cayo Santiago Biological Field Station using 50 years of demographic data. We performed sex‐specific survival analyses at different life stages to contrast short‐term effects of adversity (i.e., infant survival) with long‐term effects (i.e., adult survival). Female infants showed vulnerability to multiple adversities at birth, but affected females who survived to adulthood experienced a reduced risk later in life. In contrast, male infants showed vulnerability to a lower number of adversities at birth, but those who survived to adulthood were negatively affected by both early life individual and cumulative adversity. Our study shows profound immediate effects of insults on female infant cohorts and suggests that affected female adults are more robust. In contrast, adult males who experienced harsh conditions early in life showed an increased mortality risk at older ages as expected from hypotheses within the life course perspective. Our analysis suggests sex‐specific selection pressures on life histories and highlights the need for studies addressing the effects of early life adversity across multiple life stages.

Abstract Background and Aims Given the growing utilization of critical care services by an aging population, development of population‐level risk models which predict intensive care unit (ICU) survivorship and mortality may offer advantages for researchers and health systems. Our objective was to develop a risk model for ICU survivorship and mortality among community dwelling older adults. Methods This was a population‐based cohort study of 48,127 patients who were 50 years and older with at least one primary care visit between January 1, 2017, and December 31, 2017. We used electronic health record (EHR) data to identify variables predictive of ICU survivorship. Results ICU admission and mortality within 2 years after index primary care visit date were used to divide patients into three groups of “alive without ICU admission”, “ICU survivors,” and “death.” Multinomial logistic regression was used to identify EHR predictive variables for the three patient outcomes. Cross‐validation by randomly splitting the data into derivation and validation data sets (60:40 split) was used to identify predictor variables and validate model performance using area under the receiver operating characteristics (AUC) curve. In our overall sample, 92.2% of patients were alive without ICU admission, 6.2% were admitted to the ICU at least once and survived, and 1.6% died. Greater deciles of age over 50 years, diagnoses of chronic obstructive pulmonary disorder or chronic heart failure, and laboratory abnormalities in alkaline phosphatase, hematocrit, and albumin contributed highest risk score weights for mortality. Risk scores derived from the model discriminated between patients that died versus remained alive without ICU admission (AUC = 0.858), and between ICU survivors versus alive without ICU admission (AUC = 0.765). Conclusion Our risk scores provide a feasible and scalable tool for researchers and health systems to identify patient cohorts at increased risk for ICU admission and survivorship. Further studies are needed to prospectively validate the risk scores in other patient populations.

Background There is growing consideration of sleep disturbances and disorders in early cardiovascular risk, including atrial fibrillation (AF). Obstructive sleep apnea confers risk for AF but is highly comorbid with insomnia, another common sleep disorder. We sought to first determine the association of insomnia and early incident AF risk, and second, to determine if AF onset is earlier among those with insomnia. Methods and Results This retrospective analysis used electronic health records from a cohort study of US veterans who were discharged from military service since October 1, 2001 (ie, post‐9/11) and received Veterans Health Administration care, 2001 to 2017. Time‐varying, multivariate Cox proportional hazard models were used to examine the independent contribution of insomnia diagnosis to AF incidence while serially adjusting for demographics, lifestyle factors, clinical comorbidities including obstructive sleep apnea and psychiatric disorders, and health care utilization. Overall, 1 063 723 post‐9/11 veterans (Mean age=28.2 years, 14% women) were followed for 10 years on average. There were 4168 cases of AF (0.42/1000 person‐years). Insomnia was associated with a 32% greater adjusted risk of AF (95% CI, 1.21–1.43), and veterans with insomnia showed AF onset up to 2 years earlier. Insomnia‐AF associations were similar after accounting for health care utilization (adjusted hazard ratio [aHR], 1.27 [95% CI, 1.17–1.39]), excluding veterans with obstructive sleep apnea (aHR, 1.38 [95% CI, 1.24–1.53]), and among those with a sleep study (aHR, 1.26 [95% CI, 1.07–1.50]). Conclusions In younger adults, insomnia was independently associated with incident AF. Additional studies should determine if this association differs by sex and if behavioral or pharmacological treatment for insomnia attenuates AF risk.

Background Wearable devices may be useful for identification, quantification and characterization, and management of atrial fibrillation (AF). To date, consumer wrist‐worn devices for AF detection using photoplethysmography‐based algorithms perform only periodic checks when the user is stationary and are US Food and Drug Administration cleared for prediagnostic uses without intended use for clinical decision‐making. There is an unmet need for medical‐grade diagnostic wrist‐worn devices that provide long‐term, continuous AF monitoring. Methods and Results We evaluated the performance of a wrist‐worn device with lead‐I ECG and continuous photoplethysmography (Verily Study Watch) and photoplethysmography‐based convolutional neural network for AF detection and burden estimation in a prospective multicenter study that enrolled 117 patients with paroxysmal AF. A 14‐day continuous ECG monitor (Zio XT) served as the reference device to evaluate algorithm sensitivity and specificity for detection of AF in 15‐minute intervals. A total of 91 857 intervals were contributed by 111 subjects with evaluable reference and test data (18.3 h/d median watch wear time). The watch was 96.1% sensitive (95% CI, 92.7%–98.0%) and 98.1% specific (95% CI, 97.2%–99.1%) for interval‐level AF detection. Photoplethysmography‐derived AF burden estimation was highly correlated with the reference device burden (R2=0.986) with a mean difference of 0.8% (95% limits of agreement, −6.6% to 8.2%). Conclusions Continuous monitoring using a photoplethysmography‐based convolutional neural network incorporated in a wrist‐worn device has clinical‐grade performance for AF detection and burden estimation. These findings suggest that monitoring can be performed with wrist‐worn wearables for diagnosis and clinical management of AF. Registration Information URL: https://www.clinicaltrials.gov; Unique identifier: NCT04546763.

Abstract Objective The aim of this study was to investigate whether pre‐operative comorbidity status measured by the Charlson comorbidity index (CCI) or cardiopulmonary exercise testing (CPET) is associated with postoperative complications and length of stay (LOS) in patients undergoing robot‐assisted radical cystectomy and intracorporeal urinary diversion (RARC‐ICUD). Patients and methods We conducted a retrospective study of a prospectively maintained database of 428 consecutive patients who underwent RARC‐ICUD at a tertiary referral centre between 2011 and 2019. CCI was correlated with peri‐operative outcomes including postoperative LOS, Clavien–Dindo (CD) complications and survival. A planned subgroup analysis was performed to evaluate the relationship between pre‐operative CPET, and the same outcomes utilising the threshold of anaerobic threshold (AT) ≥ 11/

Abstract Background Machine learning methods are used in the classification of various cardiovascular diseases through ECG data analysis. The concept of varying subcutaneous implantable cardiac defibrillator (S‐ICD) eligibility, owing to the dynamicity of ECG signals, has been introduced before. There are practical limitations to acquiring longer durations of ECG signals for S‐ICD screening. This study explored the potential use of deep learning methods in S‐ICD screening. Methods This was a retrospective study. A deep learning tool was used to provide descriptive analysis of the T:R ratios over 24 h recordings of S‐ICD vectors. Spearman's rank correlation test was used to compare the results statistically to those of a “gold standard” S‐ICD simulator. Results A total of 14 patients (mean age: 63.7 ± 5.2 years, 71.4% male) were recruited and 28 vectors were analyzed. Mean T:R, standard deviation of T:R, and favorable ratio time (FVR)—a new concept introduced in this study—for all vectors combined were 0.21 ± 0.11, 0.08 ± 0.04, and 79 ± 30%, respectively. There were statistically significant strong correlations between the outcomes of our novel tool and the S‐ICD simulator (p

Abstract Background American adults have gained weight during the COVID‐19 pandemic. Little is known about how patients who are medically managed for overweight and obesity, including patients who are prescribed antiobesity pharmacotherapy, have fared. Objective To assess the COVID‐19 pandemic's effect on weight, food choices, and health behaviors in patients receiving medical treatment for overweight or obesity. Methods Adult patients treated at an urban academic weight management center between 1 May 2019 and 1 May 2020 were electronically surveyed between 23 February and 23 March 2021. The survey assessed changes in weight, eating, behaviors, and the use of antiobesity medications (AOMs) following issuance of social distancing/stay‐at‐home policies in March 2020. Results In 970 respondents, median percent weight change for those taking AOMs was −0.459% [interquartile range −5.46%–(+3.73%)] compared to +2.33% [IQR −1.92%–(+6.52%)] for those not taking AOMs (p

Objective Despite a wealth of studies evaluating rheumatoid arthritis (RA) therapies, it remains difficult to compare efficacies across trials due to heterogeneous study populations. We sought to identify patient/trial characteristics associated with clinical response to enable fairer comparisons. Methods We reviewed 565 disease‐modifying antirheumatic drug studies compiled for American College of Rheumatology (ACR) management guidelines. Seventy‐two articles on randomized controlled phase II/III trials from 1995 to 2018 reporting the proportion of patients achieving 20%, 50% or 70% improvement in the ACR's RA disease score (ACR20/50/70) or Disease Activity Score‐28 with erythrocyte sedimentation rate or C‐reactive protein (DAS28‐ESR or DAS28‐CRP) with follow‐up more than 3 months were included. We explored associations between 34 patient/trial characteristics and ACR responses. We constructed multivariable models using these factors to compute expected response rates and to compare observed with expected response rates across therapies. Results Among eligible clinical trials, later publication year, baseline DAS28‐CRP score, methotrexate/biologic naivety, baseline ESR, follow‐up of 52 weeks or more, number of subjects enrolled, and anticitrullinated peptide antibody seropositivity were associated with greater ACR response. Greater age, longer disease duration, higher baseline Sharp score, and steroid use were associated with lower response rates. Predictive models incorporating these factors explained 29%, 37%, and 53% of variance in ACR20, ACR50, and ACR70, respectively. Overall, comparing observed versus expected rates of response across trials more closely approximated results of head‐to‐head trials. For example, although observed responses numerically favored adalimumab to tofacitinib, comparison of observed versus expected results across trials more closely approximated the results from a head‐to‐head trial (“Oral Rheumatoid Arthritis triaL [ORAL] Strategy”). Conclusion We identified factors associated with ACR response in RA trials. Adjusting for expected outcomes yielded therapy comparisons somewhat more similar to head‐to‐head trials. These findings could inform other across‐trial comparisons, particularly when head‐to‐head trials are lacking.

Abstract Objectives Existing pulmonary embolism (PE) risk scores were developed to predict death within weeks, but not more proximate adverse events. We determined the ability of 3 PE risk stratification tools (simplified pulmonary embolism severity index [sPESI], 2019 European Society of Cardiology guidelines [ESC], and PE short‐term clinical outcomes risk estimation [PE‐SCORE]) to predict 5‐day clinical deterioration after emergency department (ED) diagnosis of PE. Methods We analyzed data from six EDs on ED patients with confirmed PE. Clinical deterioration was defined as death, respiratory failure, cardiac arrest, new dysrhythmia, sustained hypotension requiring vasopressors or volume resuscitation, or escalated intervention within 5 days of PE diagnosis. We determined sensitivity and specificity of sPESI, ESC, and PE‐SCORE for predicting clinical deterioration. Results Of 1569 patients, 24.5% had clinical deterioration within 5 days. sPESI, ESC, and PE‐SCORE classifications were low‐risk in 558 (35.6%), 167 (10.6%), and 309 (19.6%), respectively. Sensitivities of sPESI, ESC, and PE‐SCORE for clinical deterioration were 81.8 (78, 85.7), 98.7 (97.6, 99.8), and 96.1 (94.2, 98), respectively. Specificities of sPESI, ESC, and PE‐SCORE for clinical deterioration were 41.2 (38.4, 44), 13.7 (11.7, 15.6), and 24.8 (22.4, 27.3). Areas under the curve were 61.5 (59.1, 63.9), 56.2 (55.1, 57.3), and 60.5 (58.9, 62.0). Negative predictive values were 87.5 (84.7, 90.2), 97 (94.4, 99.6), and 95.1 (92.7, 97.5). Conclusions ESC and PE‐SCORE were better than sPESI for detecting clinical deterioration within 5 days after PE diagnosis.

Abstract Populations are locally adapted when they exhibit higher fitness than foreign populations in their native habitat. Maize landrace adaptations to highland and lowland conditions are of interest to researchers and breeders. To determine the prevalence and strength of local adaptation in maize landraces, we performed a reciprocal transplant experiment across an elevational gradient in Mexico. We grew 120 landraces, grouped into four populations (Mexican Highland, Mexican Lowland, South American Highland, South American Lowland), in Mexican highland and lowland common gardens and collected phenotypes relevant to fitness and known highland‐adaptive traits such as anthocyanin pigmentation and macrohair density. 67k DArTseq markers were generated from field specimens to allow comparisons between phenotypic patterns and population genetic structure. We found phenotypic patterns consistent with local adaptation, though these patterns differ between the Mexican and South American populations. Quantitative trait differentiation (QST) was greater than neutral allele frequency differentiation (FST) for many traits, signaling directional selection between pairs of populations. All populations exhibited higher fitness metric values when grown at their native elevation, and Mexican landraces had higher fitness than South American landraces when grown in these Mexican sites. As environmental distance between landraces’ native collection sites and common garden sites increased, fitness values dropped, suggesting landraces are adapted to environmental conditions at their natal sites. Correlations between fitness and anthocyanin pigmentation and macrohair traits were stronger in the highland site than the lowland site, supporting their status as highland‐adaptive. These results give substance to the long‐held presumption of local adaptation of New World maize landraces to elevation and other environmental variables across North and South America.

Abstract Monitoring water quality at high frequency is challenging and costly. Compressed sensing (CS) offers an approach to reconstruct high‐frequency water quality data from limited measurements, given that water quality signals are commonly “sparse” in the frequency domain. In this study, we investigated the sparsity of stream flow and concentration time‐series and tested reconstruction with CS. All stream signals were sparse using 15‐min discrete time‐series transformed to the Fourier domain. Stream temperature, conductance, dissolved oxygen, and nitrate plus nitrite (NOx‐N) concentration were sparser than discharge, turbidity, and total phosphorus (TP) concentration. CS effectively reconstructed these signals with only 5%–10% of measurements needed. Stream NOx‐N and TP loads were well estimated with errors of −6.6% ± 3.8% and −9.0% ± 2.9% with effective sampling frequencies of 10 and 0.4 days, respectively. For broader applications in environmental geosciences and engineering domains, CS can be integrated with dimensionality reduction and optimization techniques for more efficient sampling schemes.

Abstract Objectives Thymus implantation is a recently FDA‐approved therapy for congenital athymia. Patients receiving thymus implantation develop a functional but incomplete T cell compartment. Our objective was to develop a mouse model to study clinical thymus implantation in congenital athymia and to optimise implantation procedures to maximise T cell education and expansion of naïve T cells. Methods Using Foxn1nu athymic mice as recipients, we tested MHC‐matched and ‐mismatched donor thymi that were implanted as fresh tissue or cultured to remove donor T cells. We first implanted thymus under the kidney capsule and then optimised intramuscular implantation. Using competitive adoptive transfer assays, we investigated whether the failure of newly developed T cells to expand into a complete T cell compartment was because of intrinsic deficits or whether there were deficits in engaging MHC molecules in the periphery. Finally, we tested whether recombinant IL‐7 would promote the expansion of host naïve T cells educated by the implanted thymus. Results We determined that thymus implants in Foxn1nu athymic mice mimic many aspects of clinical thymus implants in patients with congenital athymia. When we implanted cultured, MHC‐mismatched donor thymus into Foxn1nu athymic mice, mice developed a limited T cell compartment with notably underdeveloped naïve populations and overrepresented memory‐like T cells. Newly generated T cells were predominantly educated by MHC molecules expressed by the donor thymus, thus potentially undergoing another round of selection once in the peripheral circulation. Using competitive adoptive transfer assays, we compared expansion rates of T cells educated on donor thymus versus T cells educated during typical thymopoiesis in MHC‐matched and ‐mismatched environments. Once in the circulation, regardless of the MHC haplotypes, T cells educated on a donor thymus underwent abnormal expansion with initially more robust proliferation coupled with greater cell death, resembling IL‐7 independent spontaneous expansion. Treating implanted mice with recombinant interleukin (IL‐7) promoted homeostatic expansion that improved T cell development, expanded the T cell receptor repertoire, and normalised the naïve T cell compartment. Conclusion We conclude that implanting cultured thymus into the muscle of Foxn1nu athymic mice is an appropriate system to study thymus implantation for congenital athymia and immunodeficiencies. T cells are educated by the donor thymus, yet naïve T cells have deficits in expansion. IL‐7 greatly improves T cell development after thymus implantation and may offer a novel strategy to improve outcomes of clinical thymus implantation.

Rhodococcus equi is a Gram-positive facultative intracellular pathogen associated with life-threatening bronchopneumonial disease in foals. Key to R. equi’s intracellular survival in host macrophages is the production of virulence associated proteins (Vaps). Numerous vap genes are found on virulence plasmids isolated from different species, and the Vaps share a high degree of sequence identity. VapA has been extensively studied, and although vapK and vapN genes from other R. equi virulence plasmids have been shown to be essential for R. equi intracellular survival, their mode of action is less characterised. We, therefore, examined whether VapK and VapN worked mechanistically in the same way as VapA. Indeed, like VapA, VapK and VapN neutralised lysosomal pH and reduced lysosomal hydrolase activity. A loss of VapA and R. equi virulence could be regained by the presence of either VapK or VapN. The acid-neutralisation activity was also observed to a lesser extent with VapB. There was a differential activity across these virulence-promoting Vaps with the most “acid-neutralising” activity found with VapN, then VapA and K, and finally VapB. These data suggest that VapA production, which is often found in equine infections, can be substituted by VapK and B (produced by plasmids often found in porcine species) or VapN (produced by plasmids often isolated in bovine and human samples). These data imply that the molecular mechanism(s) that VapA uses to neutralise lysosomal acidity should also be seen in VapN and K which will help guide researchers in identifying their precise mode of action and aid the future development of targeted therapeutics.

Introduction. Cystic Fibrosis Foundation guidelines recommend people with CF perform daily airway clearance. This can be difficult for patients, as some find it time consuming or uncomfortable. Data comparing airway clearance methods are limited. We surveyed patients and their families to understand which methods are preferred and identify obstacles to performing airway clearance. Methods. We designed a REDCap survey and enrolled participants in 2021. Respondents reported information on airway clearance usage, time commitment, and medication use. They rated airway clearance methods for effectiveness, comfort, time commitment, importance, and compatibility with other treatments. The analysis included descriptive statistics and clustering. Results. 60 respondents started and 52 completed the survey. The median patient age was 20 years. Respondents experienced a median of four airway clearance methods in their lifetime, including chest wall oscillation (vest, 92%), manual chest physical therapy (CPT, 88%), forced expiration technique (huff or cough, 77%), and exercise (75%). Past 30-day use was highest for exercise (62%) and vest (57%). The time commitment was generally less than 2 hours daily. Of those eligible for CFTR modulators, 53% reported decreased time commitment to airway clearance after starting treatment. On a scale of 0–100, respondents rated CFTR modulators as their most important treatment (median 99.5), followed by exercise (88). Discussion. Patients and caregivers are familiar with several methods of airway clearance for CF. They report distinct strengths and limitations of each method. Exercise and vest are the most common methods of airway clearance. The use of CFTR modulators may reduce patient-reported time commitment to airway clearance.

Abstract The respiratory tract represents the key target for antiviral delivery in early interventions to prevent severe COVID‐19. While neutralizing monoclonal antibodies (mAb) possess considerable efficacy, their current reliance on parenteral dosing necessitates very large doses and places a substantial burden on the healthcare system. In contrast, direct inhaled delivery of mAb therapeutics offers the convenience of self‐dosing at home, as well as much more efficient mAb delivery to the respiratory tract. Here, building on our previous discovery of Fc‐mucin interactions crosslinking viruses to mucins, we showed that regdanvimab, a potent neutralizing mAb already approved for COVID‐19 in several countries, can effectively trap SARS‐CoV‐2 virus‐like particles in fresh human airway mucus. IN‐006, a reformulation of regdanvimab, was stably nebulized across a wide range of concentrations, with no loss of activity and no formation of aggregates. Finally, nebulized delivery of IN‐006 resulted in 100‐fold greater mAb levels in the lungs of rats compared to serum, in marked contrast to intravenously dosed mAbs. These results not only support our current efforts to evaluate the safety and efficacy of IN‐006 in clinical trials, but more broadly substantiate nebulized delivery of human antiviral mAbs as a new paradigm in treating SARS‐CoV‐2 and other respiratory pathologies.

Abstract Introduction S‐ICD eligibility is assessed at pre‐implant screening where surface ECG traces are used as surrogates for S‐ICD vectors. In heart failure (HF) patients undergoing diuresis, electrolytes and fluid shifts can cause changes in R and T waves. Subsequently, T:R ratio, a major predictor of S‐ICD eligibility, can be dynamic. Methods This is a prospective study of patients with structurally normal hearts and HF patients undergoing diuresis. All patients were fitted with Holters® to record their S‐ICD vectors. Our deep learning model was used to analyze the T:R ratios across the recordings. Welch two sample t‐test and Mann–Whitney U were used to compare the data between the two groups. Results Twenty‐one patients (age 58.43 ± 18.92, 62% male, 14 HF, 7 normal hearts) were enrolled. There was a significant difference in the T:R ratios between both groups. Mean T: R was higher in the HF group (0.18 ± 0.08 vs 0.10 ± 0.05, p