Symptom Duration, Recurrence, and Long-Term Effects of Swimming-Induced Pulmonary Edema: A 30-Month Follow-Up Study.

BACKGROUND: Swimming-induced pulmonary edema (SIPE) has been reported to subside within 24 to 48 h, but comprehensive follow-up studies on symptom duration and long-term effects are missing. RESEARCH QUESTION: What are the symptom duration, recurrence, and long-term effects of SIPE? STUDY DESIGN AND METHODS: A follow-up study was conducted, based on 165 cases of SIPE from Sweden's largest open-water swimming event with 26,125 individuals participating during 2017-2019. Data on patient characteristics, clinical findings, and symptoms were collected at admission. Telephone interviews at 10 days and 30 months were performed to explore symptom duration, recurrence of SIPE symptoms, need for medical evaluation, and long-term effects of self-assessed general health and physical activity level. RESULTS: Follow-up at 10 days was performed for 132 cases and at 30 months for 152 cases. Most of the patients were women, and their mean age was 48 years. At the 10-day follow-up, symptom duration > 2 days after the swimming race was reported by 38%. The most common symptoms were dyspnea and cough. In patients at 30-month follow-up, recurrence of respiratory symptoms during open-water swimming was reported by 28%. In multivariable logistic regression, asthma was independently associated with both symptom duration > 2 days and recurrence of SIPE symptoms (P = .045 and P = .022, respectively). Most participants reported equal or improved general health (93%) and physical activity level (85%) after experiencing SIPE, but 58% had not swum in open water since the event. INTERPRETATION: The present large cohort study challenges the established hallmark of SIPE symptom duration < 48 h, whereas SIPE recurrence was in the previously reported range. At 30 months, most patients reported unchanged self-assessed general health and physical activity level. These findings add to our understanding of the course of SIPE and can provide evidence-based information to swimmers and health care professionals.

Swimming-Induced Pulmonary Edema: Evaluation of Prehospital Treatment With CPAP or Positive Expiratory Pressure Device.

BACKGROUND: Swimming-induced pulmonary edema (SIPE) occasionally occurs during swimming in cold open water. Although optimal treatment for SIPE is unknown, non-invasive positive pressure ventilation (NPPV) is an option for prehospital treatment. RESEARCH QUESTION: Is NPPV a feasible and safe prehospital treatment for SIPE, and which outcome measures reflect recovery after treatment? STUDY DESIGN AND METHODS: A prospective observational study was conducted at Vansbrosimningen, Sweden's largest open water swimming event, from 2017 through 2019. Swimmers with a diagnosis of SIPE and with peripheral oxygen saturation (Spo2) of ≤ 95%, persistent respiratory symptoms, or both were eligible for the study. NPPV was administered on site as CPAP by facial mask or as positive expiratory pressure (PEP) by a PEP device. Discharge criteria were Spo2 of > 95% and clinical recovery. Four outcome measures were evaluated: Spo2, crackles on pulmonary auscultation, pulmonary edema on lung ultrasound (LUS), and patient-reported respiratory symptoms. RESULTS: Of 119 treated individuals, 94 received CPAP, 24 received treatment with a PEP device, and one required tracheal intubation. In total, 108 individuals (91%) were discharged after NPPV for a median of 10 to 20 min and 11 individuals (9%) required hospital transfer. NPPV resulted in increased Spo2 from a median of 91% to 97% (P < .0001) together with improvement of six patient-reported respiratory symptoms (median numerical rating scales, 1-7 to 0-1; P < .0001). No significant decrease in auscultation of crackles (93% vs 87%; P = .508) or pulmonary edema on LUS (100% vs 97%; P = .500) was seen during NPPV treatment. INTERPRETATION: NPPV administered as CPAP or via a PEP device proved feasible and safe as prehospital treatment for SIPE with a vast majority of patients discharged on site. Spo2 and patient-reported respiratory symptoms reflected recovery after treatment, whereas pulmonary auscultation or LUS findings did not.

Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma.

Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.

Incidence of Swimming-Induced Pulmonary Edema: A Cohort Study Based on 47,600 Open-Water Swimming Distances.

BACKGROUND: Despite increasing awareness of swimming-induced pulmonary edema (SIPE), large population-based studies are lacking and the incidence is unknown. RESEARCH QUESTION: What is the incidence of SIPE in a mixed group of competitive and recreational swimmers during a large open-water swimming event? METHODS: In four consecutive years (2016-2019), a prospective cohort study was conducted during Sweden's largest open-water swimming event, Vansbrosimningen. All swimmers seeking medical care with acute respiratory symptoms were eligible for the study. SIPE diagnosis was based on clinical findings in 2016 and 2017 and pulmonary edema assessed by lung ultrasound in 2018 and 2019. Data on patient characteristics, clinical findings, and information about the race were collected. RESULTS: Based on 47,573 consecutive swimming distances, 322 patients with acute respiratory symptoms (0.68%; CI, 0.61%-0.75%) were treated at the mobile medical unit. Of these, 211 patients (0.44%; CI, 0.39%-0.51%) received a diagnosis of SIPE. The annual incidence of SIPE was 0.34%, 0.47%, 0.41%, and 0.57%, respectively, from 2016 through 2019. Most patients diagnosed with SIPE were women (90%), despite about equal percentages of men and women participating (47% men and 53% women). The incidence of SIPE overall was 0.75% in women and 0.09% in men. The incidence increased with age, from 0.08% in the youngest age group (18-30 years) to 1.1% in the oldest age group (≥ 61 years). Based on multiple logistic regression analysis, the adjusted odds for SIPE occurring was 8.59 times higher for women compared with men and 12.74 times higher for the oldest age group compared with the youngest age group. INTERPRETATION: The incidence of SIPE over 4 years during a large open-water swimming event in Sweden was 0.44%. The incidence was higher in women than in men and increased with age.

Swimming-Induced Pulmonary Edema: Diagnostic Criteria Validated by Lung Ultrasound.

BACKGROUND: Despite the increasing popularity of open water swimming worldwide, swimming-induced pulmonary edema (SIPE) is a poorly recognized condition lacking established diagnostic criteria. RESEARCH QUESTION: The aim of this study was to identify diagnostic criteria of SIPE during a large open water swimming event. STUDY DESIGN AND METHODS: In this cross-sectional study, 17,904 individuals swam 1,000, 1,500, or 3,000 m in cold open water during Sweden's largest open water swimming event in 2018 and 2019. Of 166 swimmers seeking medical attention for acute respiratory symptoms, 160 were included in the study. Medical history, symptoms, and clinical findings were collected. On-site lung ultrasound (LUS) was performed to verify pulmonary edema. RESULTS: Pulmonary edema was confirmed by LUS in 102 patients (64%); findings were unilateral in 11 (7%). Peripheral oxygen saturation was identified as a strong independent diagnostic test for pulmonary edema, with ≤ 95% as the suggested cut off based on receiver-operating characteristic curve analysis (area under the curve, 0.893; P < .0001). Crackles on lung auscultation, predominantly over the anterior chest, identified 88% of patients with edema. Peripheral oxygen saturation ≤ 95% or auscultation findings of crackles identified pulmonary edema with a sensitivity of 97% and a specificity of 86%. A specificity of 98% and a positive predictive value of 99% for LUS-verified pulmonary edema were reached if patients presented with both oxygen saturation ≤ 95% and auscultation of crackles. INTERPRETATION: We suggest a clinical algorithm for diagnosis of SIPE for swimmers with acute respiratory symptoms during swimming in cold open water. Novel features of focally distributed edema in the anterior parts of the lungs, sometimes unilateral, add to this unique dataset of an underreported condition.

Patient experience of the informed consent process during acute myocardial infarction: a sub-study of the VALIDATE-SWEDEHEART trial.

OBJECTIVE: We aimed to assess the patient experience of informed consent (IC) during acute myocardial infarction (AMI) in a sub-study of the VALIDATE-SWEDEHEART trial. The original trial compared two anticoagulant agents in patients undergoing coronary intervention. A witnessed oral IC was required prior to randomization in patients with ST-segment elevation myocardial infarction, which was subsequently complemented with a written IC after percutaneous coronary intervention. Written consent was obtained before angiography in patients with non-ST-segment elevation myocardial infarction. BACKGROUND: The IC process in patients with AMI is under debate. Earlier trials in this population have required prospective consent before randomization. A trial published some years ago used deferred consent, but the patient experience of this process is poorly studied. METHODS: A total of 414 patients who participated in the main trial were enrolled and asked the following questions: (1) Do you remember being asked to participate in a study? (2) How was your experience of being asked to participate; do you remember it being positive or negative? (3) Would you have liked more information about the study? (4) Do you think it would have been better if you were included in the study without being informed until a later time? RESULTS: Of these patients, 94% remembered being included; 85% of them experienced this positively, 12% were neutral and 3% negative. Regarding more information, 88% did not want further information, and 68% expressed that they wanted to be consulted before inclusion. Of the patients, 5% thought it would have been better to have study inclusion without consent, and 27% considered it of no importance. CONCLUSION: It is reasonable to ask patients for verbal IC in the acute phase of AMI. Most patients felt positively about being asked to participate and had knowledge of being enrolled in a scientific study. In addition they objected to providing IC after randomization and treatment. TRIAL REGISTRATION: VALIDATE-SWEDEHEART European Union Clinical Trials Register: 2012-005260-10. ClinicalTrials.gov: NCT02311231. Registered on 8 Dec 2014.

Novel Chemical Series of 5-Lipoxygenase-Activating Protein Inhibitors for Treatment of Coronary Artery Disease.

5-Lipoxygenase (5-LO)-activating protein (FLAP) inhibitors have proven to attenuate 5-LO pathway activity and leukotriene production in human clinical trials. However, previous clinical candidates have been discontinued and the link between FLAP inhibition and outcome in inflammatory diseases remains to be established. We here describe a novel series of FLAP inhibitors identified from a screen of 10k compounds and the medicinal chemistry strategies undertaken to progress this series. Compound 4i showed good overall properties and a pIC50 hWBfree of 8.1 and an lipophilic ligand efficiency of 5.2. Target engagement for 4i was established in dogs using ex vivo measurement of leukotriene B4 (LTB4) levels in blood with good correlation to in vitro potency. A predicted human dose of 280 mg b.i.d. suggests a wide margin to any identified in vitro off-target effects and sufficient exposure to achieve an 80% reduction of LTB4 levels in humans. Compound 4i is progressed to preclinical in vivo safety studies.

Discovery and Early Clinical Development of an Inhibitor of 5-Lipoxygenase Activating Protein (AZD5718) for Treatment of Coronary Artery Disease.

5-Lipoxygenase activating protein (FLAP) inhibitors attenuate 5-lipoxygenase pathway activity and reduce the production of proinflammatory and vasoactive leukotrienes. As such, they are hypothesized to have therapeutic benefit for the treatment of diseases that involve chronic inflammation including coronary artery disease. Herein, we disclose the medicinal chemistry discovery and the early clinical development of the FLAP inhibitor AZD5718 (12). Multiparameter optimization included securing adequate potency in human whole blood, navigation away from Ames mutagenic amine fragments while balancing metabolic stability and PK properties allowing for clinically relevant exposures after oral dosing. The superior safety profile of AZD5718 compared to earlier frontrunner compounds allowed us to perform a phase 1 clinical study in which AZD5718 demonstrated a dose dependent and greater than 90% suppression of leukotriene production over 24 h. Currently, AZD5718 is evaluated in a phase 2a study for treatment of coronary artery disease.

Evolution of PI3Kγ and δ Inhibitors for Inflammatory and Autoimmune Diseases.

Phosphoinositol 3-kinases (PI3Ks) γ and δ are key enzymes in hematopoietic cells and have been seen as high-value targets for the treatment of diseases with inflammatory and immunomodulatory components since their discovery and the identification of their roles. In this Perspective we review progress in the application of inhibitors of PI3Kγ and δ to inflammatory and immunological conditions over the past 6 years. We consider progress in the understanding of the roles of PI3Kγ and PI3Kδ in immunology and inflammation, the experience from clinical trials where inhibitors have been tested, and what has been learned about the safety of their use. The extensive medicinal chemistry efforts to discover both isoform selective and dual PI3Kγδ inhibitors are analyzed and detailed. Developments in understanding the structural chemistry of the PI3K enzymes and the factors that govern isoform selectivity are discussed. The effects observed with the known inhibitor compounds in animal models are described.

A fine-needle aspiration-based protein signature discriminates benign from malignant breast lesions.

There are increasing demands for informative cancer biomarkers, accessible via minimally invasive procedures, both for initial diagnostics and to follow-up personalized cancer therapy. Fine-needle aspiration (FNA) biopsy provides ready access to relevant tissues; however, the minute sample amounts require sensitive multiplex molecular analysis to achieve clinical utility. We have applied proximity extension assays (PEA) and NanoString (NS) technology for analyses of proteins and of RNA, respectively, in FNA samples. Using samples from patients with breast cancer (BC, n = 25) or benign lesions (n = 33), we demonstrate that these FNA-based molecular analyses (a) can offer high sensitivity and reproducibility, (b) may provide correct diagnosis in shorter time and at a lower cost than current practice, (c) correlate with results from routine analysis (i.e., benchmarking against immunohistochemistry tests for ER, PR, HER2, and Ki67), and (d) may also help identify new markers related to immunotherapy. A specific 11-protein signature, including FGF binding protein 1, decorin, and furin, distinguished all cancer patient samples from all benign lesions in our main cohort and in smaller replication cohort. Due to the minimally traumatic sampling and rich molecular information, this combined proteomics and transcriptomic methodology is promising for diagnostics and evaluation of treatment efficacy in BC.

Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-γ Inhibitors.

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally.

Cell-based computational model of early ovarian development in mice.

Despite its importance to reproduction, certain mechanisms of early ovarian development remain a mystery. To improve our understanding, we constructed the first cell-based computational model of ovarian development in mice that is divided into two phases: Phase I spans embryonic day 5.5 (E5.5) to E12.5; and Phase II spans E12.5 to postnatal day 2. We used the model to investigate four mechanisms: in Phase I, (i) whether primordial germ cells (PGCs) undergo mitosis during migration; and (ii) if the mechanism for secretion of KIT ligand from the hindgut resembles inductive cell-cell signaling or is secreted in a static manner; and in Phase II, (iii) that changes in cellular adhesion produce germ cell nest breakdown; and (iv) whether localization of primordial follicles in the cortex of the ovary is due to proliferation of granulosa cells. We found that the combination of the first three hypotheses produced results that aligned with experimental images and PGC abundance data. Results from the fourth hypothesis did not match experimental images, which suggests that more detailed processes are involved in follicle localization. Phase I and Phase II of the model reproduce experimentally observed cell counts and morphology well. A sensitivity analysis identified contact energies, mitotic rates, KIT chemotaxis strength, and diffusion rate in Phase I and oocyte death rate in Phase II as parameters with the greatest impact on model predictions. The results demonstrate that the computational model can be used to understand unknown mechanisms, generate new hypotheses, and serve as an educational tool.

[Swimming-induced pulmonary edema in Swedish conditions has been insufficiently studied]. / Simningsorsakat lungödem vid svenska förhållanden otillräckligt studerat - Erfarenheter från Vansbrosimningen 2016.

Swimming-induced pulmonary edema (SIPE) has been described in sports and military medicine during strenuous swimming in open water. Symptoms include dyspnea, cough, frothy mucus and hemoptysis. Hypertension, a tight wetsuit, overhydration and previous episodes of SIPE are suggested risk factors. Immediate interruption of swimming prevents more serious symptoms. In the open water race at Vansbro 2016, 69 swimmers (of 13,878 in total) were treated for symptoms suspected for SIPE. Continuous positive airway pressure (CPAP) was successfully used to treat suspected SIPE in 46 patients in the on-site emergency care center. Open water swimming races are increasingly popular and also attract many unexperienced swimmers. There is a need of validated guidelines for organizers of open water races, swimmers and health professionals.

Regional diffusion of botulinum toxin in facial muscles: a randomised double-blind study and a consideration for clinical studies with split-face design.

Despite the extensive use of botulinum toxin A (BoNTA) in medical and cosmetic treatments, the potential spreading of BoNTA to surrounding tissues remains unknown. A patient with hemifacial paralysis upon blepharospasm treatment with low dose of BoNTA, prompted us to investigate the spreading effect. A randomised, double-blind study was conducted in which 5 healthy women (33-52 years) were treated with different doses of onabotulinum toxin unilaterally in the corrugator muscle. Parameters of efficacy and diffusion (CMAP; EMG and jitter analysis) in both glabellar and frontalis muscles were assessed at baseline, 2 and 4 weeks following BoNTA injection. CMAP of the treated glabellar muscles was reduced to approximately 40% in all dose groups. Additionally, contralateral CMAP reduction was observed in 3 of 5 subjects. These data confirm regional diffusion of BoNTA in facial muscle application, which raises question on the reliability of split-face models in BoNTA studies.

The effect of music intervention in relation to gender during coronary angiographic procedures: a randomized clinical trial.

Several studies have evaluated music interventions prior and after coronary angiography and percutaneous coronary intervention (PCI), but there is no clear evidence showing that music has an effect on patients during these procedures. The purpose was to investigate the effects of music on anxiety, angina, pain, relaxation, and comfort in patients during angiographic procedures and to evaluate gender differences. The study was a four-armed, prospective randomized controlled trial included 240 patients undergoing coronary angiography and/or PCI. Patients were allocated to receive relaxing music, MusiCure or standard care during the procedure. Outcome measures were; puncture pain and the discomfort related to it, angina and the discomfort related to it, anxiety, experience of the sound environment, discomfort of lying still, and the doses of anxiolytics and analgesics during the procedure. No differences were found between the music and control groups regarding any of the trial endpoints or gender-related differences. The overall rating of the sound environment and feeling of relaxation was high. In conclusion, music intervention in patients undergoing angiographic procedures was highly feasible, but not effective in this study though the delivery of music went smoothly and did not disturb the examination and patients and staff alike looked favorably on it.

Effect of broad-spectrum matrix metalloproteinase inhibition on atherosclerotic plaque stability.

OBJECTIVE: Matrix metalloproteinases (MMPs) form a large family of enzymes that collectively can degrade all components of the extracellular matrix, and there is widespread interest in developing MMP inhibitors for the prevention of atherosclerotic plaque rupture. We have therefore investigated the effects of a broad-spectrum MMP inhibitor, RS-130830, on plaque development and stability. This compound inhibits a wide range of MMPs at concentrations below 20 nmol/L. METHODS: Apolipoprotein E knockout mice were fed a Western diet. Dietary administration of RS-130830 commenced at the same time as fat-feeding and continued for 8, 12, 26 or 36 weeks. To investigate the effect of RS-130830 on established plaques, mice were fed high-fat diet for 16 weeks before initiation of drug treatment and were terminated 20 weeks after this. RESULTS: Broad-spectrum MMP inhibition was associated with a significant increase in plaque area, but there was no change in the incidence of plaque rupture. There were unfavourable changes in phenotypic characteristics associated with plaque instability, such as an increased lipid content and decreased collagen content. CONCLUSIONS: These data suggest that broad-spectrum MMP inhibition RS-130830 does not have a beneficial effect on atherosclerosis in the apolipoprotein E knockout mouse model, and indicate that more selective compounds would be preferable.

Mouse embryonic stem cells form follicle-like ovarian structures but do not progress through meiosis.

Several recent studies have suggested that mouse embryonic stem cells (ESCs) can differentiate into female and male germ cells in vitro. The meiotic process in germ cell-like cells derived from ESCs has not been studied in detail, but it has been reported that synaptonemal complex protein-3 (SYCP3) is expressed in these cells. Here, we have carefully evaluated the meiotic process in germ cell-like cells derived from ESCs, using a panel of meiosis-specific markers that identify distinct meiotic signatures unique to meiotic prophase I development in vivo. We find that whereas SYCP3 is expressed in germ cell-like cells, other meiotic proteins, such as SYCP1, SYCP2, STAG3 (stromal antigen 3), REC8 (meiotic protein similar to the rad21 cohesins), and SMC1 (structural maintenance of chromosomes-1)-beta, are not expressed. The nuclear distribution of SYCP3 in the germ cell-like cells is highly abnormal and not associated with the chromosomes of these cells. Fluorescence in situ hybridization analysis shows that the SYCP3-positive germ cell-like cells do not contain synapsed homologous chromosomes but instead display a chromosomal organization normally found in somatic cells. The absence of expression of essential meiotic proteins and a normal meiotic chromosomal organization strongly suggests that the germ cell-like cells formed from ESCs fail to progress through meiosis.

Dirubidium aquapentachlorochromate(III) and dicaesium aquapentachlorochromate(III).

The structures of the two novel title compounds, Rb(2)[CrCl(5)(H(2)O)], (I), and Cs(2)[CrCl(5)(H(2)O)], (II), have been determined by single-crystal X-ray diffraction. Compounds (I) and (II) crystallize with Pnma and Cmcm symmetry, respectively. In (I), the Cr, three Cl and water O atom lie on a mirror plane; in (II), the Cs, Cr, O and one of the Cl atoms are at sites with m2m symmetry. The chromate anions are in a pseudo-cubic environment of eight Rb(+) cations in (I) and in a pseudo-octahedral environment of six Cs(+) cations in (II). The structural arrangement correlates with the r(anion)/r(cation) radius ratio.