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BACKGROUND: A consistent gap exists between evidence-based guideline recommendations and clinical practice across all medical disciplines, including nephrology. This study aims to explore nephrologists' perspectives on guidelines and elicit their perspectives on the effects of guidelines on clinical decisions. METHODS: Semistructured face-to-face interviews were undertaken with 19 nephrologists from a variety of clinical settings across Australia. Participants were asked about their views of clinical practice guidelines in nephrology, both local (Caring for Australasians With Renal Impairment [CARI]) and international, and their opinions of other factors that shape their decision making. Interviews were recorded, transcribed, and analyzed qualitatively. RESULTS: 4 major themes were identified. First, overall, the nephrologists interviewed trusted the CARI guideline process and output. Second, guidelines served a variety of purposes, providing a good summary of evidence, a foundation for practice, an educational resource, and justification for funding requests to policy makers, as well as promoting patient adherence to treatment. Third, guidelines were only one input into decision making. Other inputs included individual patient quality of life and circumstances, opinion leaders, peers, nephrologists' own experiences, the regulation and subsidy framework for drugs and devices, policies and work practices of the local unit, and other sources of evidence. Fourth, guideline uptake varied. Factors that favored the use of guidelines included having a strong evidence base, being current, including specific targets and an explicit treatment algorithm, being sent frequent reminders, and having local peer support for implementation and the necessary personnel and other resources for effective implementation. CONCLUSIONS: Evidence-based guidelines appear to impact strongly on clinical decision making of Australian nephrologists, but are only one input. Improvements in the evidence that underpins guidelines and improvements in the content and formatting of guidelines are likely to make them more influential on decision making. Trust in the guideline groups' processes is a prerequisite for implementation. [ABSTRACT FROM AUTHOR]

Evidence-based clinical practice guidelines have been a major development in nephrology internationally, but it is uncertain how the nephrology community regards these guidelines. This study aimed to determine the views of nephrologists on the content and effects of their local guidelines (Caring for Australasians with Renal Impairment [CARI]). In 2006, a self-administered survey was distributed to all Australian and New Zealand nephrologists. Seven questions were repeated from a similar survey in 2002. A total of 211 nephrologists (70% of practicing nephrologists) responded. More than 90% agreed that the CARI guidelines were a useful summary of evidence, and nearly 60% reported that the guidelines had significantly influenced their practice. The proportion of nephrologists reporting that the guidelines had improved patient outcomes increased from 14% in 2002 to 38% in 2006. The proportion of nephrologists indicating that the guidelines did not match the best available evidence decreased from 30% in 2002 to 8% in 2006. Older age and male sex showed some associations with a less favorable response for some domains. The CARI approach of rigorous evidence-based guidelines has been shown to be a successful model of guideline production. Almost all nephrologists regarded the CARI guidelines as useful evidence summaries, although only one-third believed that the guidelines affected health outcomes. Attitudes to the guidelines have become more favorable over time; this may reflect changes in the CARI process or attitudinal changes to evidence among nephrologists. Evaluation by the end user is fundamental to ensuring the applicability of guidelines in clinical practice in the future. Copyright © 2009 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Explicit incorporation of patients' values and preferences is important in health care decision making. However, there are few data about this topic for patients with chronic kidney disease (CKD). We conducted 9 focus groups (3 each for CKD stages 1 to 5, CKD stage 5D, and CKD stages 1 to 5T). Five major themes were identified: (1) personal meaning of CKD, (2) managing and monitoring health, (3) lifestyle consequences, (4) family impact, and (5) informal support structures. Patients had to adjust to the disruptive and permanent implications of the illness on their physical health, identity, emotions, family, lifestyle, relationships, and employment. The overwhelming fatigue, complex treatment regimens, side effects, and liquid and diet restrictions constrained patients' lives. Patients appreciated specialist care, but described the health care system as nonintegrated and believed they received insufficient information and psychosocial support. Choice of treatments was based on lifestyle, family impact, and physical comfort, seldom on clinical outcomes. Time was needed to comprehend the diagnosis, cope with uncertainty, integrate their treatment regimen into their daily routine, and reestablish a sense of normality in their lives. Rather than focusing on clinical targets, greater attention may need to be given to providing information and psychosocial and practical support at a patient-level not organ-specific level, to maximize patient quality of life. Copyright © 2009 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare injection site pain of subcutaneous (sc) epoetin beta and darbepoetin alfa in adult patients with chronic kidney disease. RESEARCH DESIGN AND METHODS: This was a multi-centre, randomised, two-arm, single-blind, cross-over study. Patients were randomised to receive weekly sc darbepoetin alfa 30 mug or weekly sc epoetin beta 6000 IU for 2 weeks and were then crossed over to the alternative treatment for 2 weeks. Injection site pain was assessed using a 10 cm ungraduated visual analogue scale (0 = no pain, 10 = worst pain) and a six-point verbal rating scale. Patient preference for treatment was also assessed. TRIAL REGISTRATION: http://clinicaltrials. gov/(NCT00377481). RESULTS: All randomised patients (N = 48) completed the study. The sample comprised 29 chronic kidney disease patients (Stage 3 or Stage 4), 11 peritoneal dialysis patients and 8 renal transplant patients. Patients perceived significantly less pain with epoetin beta than darbepoetin alfa, using the visual analogue scale (relative pain score = 2.75, darbepoetin alfa:epoetin beta, 95% CI: 1.85, 4.07; p < 0.0001) and the verbal rating scale (median: 0.5, 95% CI: 0.5, 1.0 vs. median: 1.5, 95% CI: 1.0, 2.0; p < 0.0001). Epoetin beta was preferred by significantly more patients (65%) than darbepoetin alfa (10%) (p < 0.001); 25% of patients reported no preference. CONCLUSIONS: Limitations included lack of an epoetin alfa comparator and limited blinding (patients were blinded to treatment, however, an unblinded nurse administered treatment). We show that sc injection of epoetin beta is significantly less painful than darbepoetin alfa and patient preference for epoetin beta confirms that the difference is clinically meaningful. [ABSTRACT FROM AUTHOR]

Background: No conventional immunosuppressive agent preferentially inhibits antibody production. Studies in experimental animals and in human cells in vitro suggested mycophenolate mofetil (MMF) might have such an effect. If this was the case in vivo it could have significant implications in terms of both MMF toxicity and the rational design of immunotherapeutic regimens. [ABSTRACT FROM PUBLISHER]

Background: About 30-60% of individuals are non-adherent to their prescribed medications and this risk increases as the number of prescribed medications increases. This paper outlines the development of a consumer-centred Medicine Self-Management Intervention (MESMI), designed to improve blood pressure control and medication adherence in consumers with diabetes and chronic kidney disease recruited from specialist outpatients' clinics. Methods: We developed a multifactorial intervention consisting of Self Blood Pressure Monitoring (SBPM), medication review, a twenty-minute interactive Digital Versatile Disc (DVD), and follow-up support telephone calls to help consumers improve their blood pressure control and take their medications as prescribed. The intervention is novel in that it has been developed from analysis of consumer and health professional views, and includes consumer video exemplars in the DVD. The primary outcome measure was a drop of 3-6 mmHg systolic blood pressure at three months after completion of the intervention. Secondary outcome measures included: assessment of medication adherence, medication self-efficacy and general wellbeing. Consumers' adherence to their prescribed medications was measured by manual pill count, self-report of medication adherence, and surrogate biochemical markers of disease control. Discussion: The management of complex health problems is an increasing component of health care practice, and requires interventions that improve patient outcomes. We describe the preparatory work and baseline data of a single blind, randomized controlled trial involving consumers requiring cross-specialty care with a follow-up period extending to 12 months post-baseline. Trial Registration: The trial was registered with the Australian and New Zealand Clinical Trials Register (ACTRN12607000044426). [ABSTRACT FROM AUTHOR]

OBJECTIVES:: The definition of defibrillation shock 'success' endorsed by the International Liaison Committee on Resuscitation since the publication of Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiac Care has been removal of ventricular fibrillation at 5 secs after shock delivery. Although this success criterion provides a direct assessment of the primary task of a shock, it may not be the only clinically useful measure of shock outcome. We evaluated a different defibrillation success criterion to determine whether it could provide additional insight into the relative performance of different defibrillation shocks. DESIGN:: A randomized study comparing monophasic and biphasic waveform shocks is reported with return of organized rhythm as the primary outcome measure of defibrillation success. PATIENTS:: A total of 120 patients with out-of-hospital ventricular fibrillation as the first recorded rhythm were treated with defibrillation with automated external defibrillators. MEASUREMENTS AND MAIN RESULTS:: Return of organized rhythm (two QRS complexes, <5 secs apart, <60 secs after defibrillation) was achieved in 31 monophasic shock (45%) and 35 biphasic shock (69%) patients (relative risk, 1.53, 95% confidence interval, 1.11-2.10). Logistic regression analysis revealed that shock waveform was the strongest independent predictor of return of organized rhythm (odds ratio, 4.0; 95% confidence interval, 1.67-10.0). Defibrillation success with the conventional International Liaison Committee on Resuscitation criterion was very high (91% and 98%, respectively) and not significantly different between groups. CONCLUSIONS:: Return of organized rhythm proved to be a more sensitive measure of relative defibrillation shock performance than the conventional shock success criterion. Inclusion of return of organized rhythm as an end point in future clinical research could help discern more subtle defibrillation shock effects and contribute to further optimization of defibrillation technology. [ABSTRACT FROM AUTHOR]

The development of clinical practice guidelines for the treatment of anemia in chronic kidney disease has been instrumental in identifying and reducing variations in the use of erythropoiesis-stimulating agents and iron replacement. Challenges to the effectiveness and safety of recommendations made in these guidelines were magnified when recent clinical trials showed no benefit or harm with respect to cardiovascular outcomes in subjects randomized to higher target hemoglobin levels. To address these concerns, Kidney Disease: Improving Global Outcomes (KDIGO) convened an international conference to examine the problems and shortcomings of existing anemia guidelines, which are a prime example of duplication of efforts to derive recommendations from a limited evidence base. The meeting was attended by representatives of the major guideline developing organizations, who agreed to avoid future duplicative efforts and to save resources in generating a common evidence report, whose recommendations could then be prioritized and implemented locally. This is a report to the international nephrology community of the recommendations for and timeline of the next anemia guidelines. It has been reviewed by the conference participants and approved as a position statement by the KDIGO Board of Directors.Kidney International (2008) 74, 1237-1240; doi:10.1038/ki.2008.299; published online 2 July 2008. [ABSTRACT FROM AUTHOR]

Background: Time in ventricular fibrillation (VF) is associated with survival after out-of-hospital cardiac arrest (OHCA). The impact of vector change defibrillation (VC) and double sequential external defibrillation (DSED) on VF duration has not been explored., Objective: To compare the effects of VC and DSED on VF duration and defibrillation outcomes., Methods: We conducted a secondary analysis of patients enrolled in the Double Sequential External Defibrillation for Refractory VF RCT. We assessed the ECG after each shock, calculating VF time (median, IQR) and shock outcomes. The Kruskal-Wallis test was used to compare VF duration across groups, with post-hoc pairwise comparisons using Dunn's test and Bonferroni correction. Chi-square tests compared shock outcomes., Results: Among 342 patients, 1842 shocks were analyzed (834 after three failed standard shocks: 429 standard, 218 VC, 187 DSED). Median VF time was significantly shorter for DSED (83 [0, 120] s) and VC (98 [0, 120] s) compared to standard shocks (108 [38, 120] s) (P=0.003). The proportion of shocks leading to return of spontaneous circulation (ROSC) and survival to hospital discharge respectively was higher for DSED (17.6%, 10.2% p<.001 ROSC, p=.002 survival) and VC (14.2%, 7.3% p<.002 ROSC, p=.049 survival) than for standard shocks (5.3%,3.5%) The proportion of shocks in which VF was not terminated was significantly lower for DSED shocks (29.9%) then standard shocks (40.6%) (P=0.013)., Conclusions: DSED and VC reduced VF duration and increased the likelihood of ROSC and survival compared to standard shocks. These findings may contribute to the improved survival., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Chest compressions generating good perfusion during cardiopulmonary resuscitation (CPR) in cardiac arrest patients are critical for positive patient outcomes. Conventional wisdom advises minimizing compression pauses because several compressions are required to recover arterial blood pressure (ABP) back to pre-pause values. Our study examines how compression pauses influence ABP recovery post-pause in out-of-hospital cardiac arrest., Methods: We analyzed data from a subset of a prospective, randomized LUCAS 2 Active Decompression trial. Patients were treated by an anesthesiologist-staffed rapid response car program in Oslo, Norway (2015-2017) with mechanical chest compressions using the LUCAS device at 102 compressions/min. Patients with an ABP signal during CPR and at least one compression pause >2 sec were included. Arterial cannulation, compression pauses, and ECG during the pause were verified by physician review of patient records and physiological signals. Pauses were excluded if return of spontaneous circulation occurred during the pause (pressure pulses associated with ECG complexes). Compression, mean, and decompression ABP for 10 compressions before/after each pause and the mean ABP during the pause were measured with custom MATLAB code. The relationship between pause duration and ABP recovery was investigated using linear regression., Results: We included 56 patients with a total of 271 pauses (pause duration: median = 11 sec, Q1 = 7 sec, Q3 = 18 sec). Mean ABP dropped from 53 ± 10 mmHg for the last pre-pause compression to 33 ± 7 mmHg during the pause. Compression and mean ABP recovered to >90% of pre-pause pressure within 2 compressions, or 1.7 sec. Pause duration did not affect the recovery of ABP post-pause (R 2 : 0.05, 0.03, 0.01 for compression, mean, and decompression ABP, respectively)., Conclusions: ABP generated by mechanical CPR recovered quickly after pauses. Recovery of ABP after a pause was independent of pause duration., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: “Lars Wik reports financial support was provided by Stryker. Per Olav Berve reports financial support was provided by Norwegian Association of Heart and Lung Patients. Elisabete Aramendi reports financial support was provided by Spain Ministry of Science and Innovation, State Research Agency. Andoni Elola reports financial support was provided by Spain Ministry of Science and Innovation, State Research Agency. Rose Yin, Tyson Taylor, Rob Walker, and Fred Chapman report a relationship with Stryker that includes: employment. Lars Wik reports a relationship with Stryker that includes: consulting or advisory, funding grants, and travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.”., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Little is known about the impact of tidal volumes delivered by emergency medical services (EMS) to adult patients with out-of-hospital cardiac arrest (OHCA). A large urban EMS system changed from standard adult ventilation bags to small adult bags. We hypothesized that the incidence of return of spontaneous circulation (ROSC) at the end of EMS care would increase after this change., Methods: We performed a retrospective analysis evaluating adults treated with advanced airway placement for nontraumatic OHCA between January 1, 2015 and December 31, 2021. We compared rates of ROSC, ventilation rate, and mean end tidal carbon dioxide (ETCO 2 ) by minute before and after the smaller ventilation bag implementation using linear and logistic regression., Results: Of the 1,994 patients included, 1,331 (67%) were treated with a small adult bag. ROSC at the end of EMS care was lower in the small bag cohort than the large bag cohort, 33% vs 40% (p = 0.003). After adjustment, small bag use was associated with lower odds of ROSC at the end of EMS care [OR 0.74, 95% CI 0.61 - 0.91]. Ventilation rates did not differ between cohorts. ETCO 2 values were lower in the large bag cohort (33.2 ± 17.2 mmHg vs. 36.9 ± 19.2 mmHg, p < 0.01)., Conclusion: Use of a small adult bag during OHCA was associated with lower odds of ROSC at the end of EMS care. The effects on acid base status, hemodynamics, and delivered minute ventilation remain unclear and warrant additional study., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This research did not receive any external funding. Robert Walker is a biomedical engineer employed by Stryker Emergency Care. Nicholas Johnson receives research funding from National Institutes of Health, Centers for Disease Control and Prevention, and University of Washington Royalty Research Fund for unrelated work and serves on a Scientific Advisory Board for Neuroptics, Inc. Thomas Rea has received support from Philips. Michael Sayre has received consulting fees from Stryker Emergency Care. The remaining authors have no conflicts of interest to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Since the exogenous administration of GDF11, a TGF-ß superfamily member, was reported to have beneficial effects in some models of human disease, there have been many research studies in GDF11 biology. However, many studies have now confirmed that exogenous administration of GDF11 can improve physiology in disease models, including cardiac fibrosis, experimental stroke, and disordered metabolism. GDF11 is similar to GDF8 (also called Myostatin), differing only by 11 amino acids in their mature signaling domains. These two proteins are now known to be biochemically different both in vitro and in vivo . GDF11 is much more potent than GDF8 and induces more strongly SMAD2 phosphorylation in the myocardium compared to GDF8. GDF8 and GDF11 prodomain are only 52% identical and are cleaved by different Tolloid proteases to liberate the mature signaling domain from inhibition of the prodomain. Here, we review the state of GDF11 biology, highlighting both resolved and remaining controversies., Competing Interests: Conflicts of interest Lee RT, Rubin LL, and Wagers AJ are cofounders and members of the scientific advisory board for and hold private equity in Elevian, Inc., a company that aims to develop medicines to restore regenerative capacity. Elevian also provided sponsored research support to the Lee RT, Rubin LL, and Wagers AJ labs. Lee RT, Rubin LL, Wagers AJ, and Thompson TB have filed patents related to GDF11 and GDF8 through their institutions.

Background: Children with inflammatory bowel disease (IBD) experience extraintestinal side effects including altered body composition, impaired muscle strength, and aerobic capacity. Exercise training may remedy these issues., Purpose: To assess the feasibility, safety, participant satisfaction, and efficacy of a training program for youth with IBD., Methods: Children with IBD completed 16 weeks of training (2 supervised + 1 home sessions per week). Feasibility was assessed by tracking recruitment, adherence, and compliance rates. Safety was assessed by tracking symptoms and adverse events. Posttraining interviews gauged satisfaction. Circulating inflammatory markers, body composition, muscle strength, aerobic fitness, and habitual physical activity were measured at baseline, midtraining (8 wk), and posttraining., Results: Eleven youth were recruited and 10 completed the study. Participants adhered to 28 (1) of 32 prescribed supervised sessions and 8 (4) of 16 prescribed home sessions. There were no adverse events, and overall feedback on training was positive. Posttraining, we observed an increase in lean mass (+2.4 [1.1] kg), bone density (+0.0124 [0.015] g·cm-2), aerobic fitness (+2.8 [5.7] mL·kg LM-1· min-1), and vigorous physical activity levels (+13.09 [8.95] min·h-1) but no change in inflammation or muscle strength., Conclusion: Supervised exercise training is feasible, safe, and effective for youth with IBD and should be encouraged.

Aim: The aim of this study was to evaluate chest compression rates (CCR) with and without the use of a metronome during treatment of out-of-hospital cardiac arrest (OHCA)., Methods: We performed a retrospective cohort investigation of non-traumatic OHCA cases treated by Seattle Fire Department from January 1, 2013, to December 31, 2019. The exposure was a metronome running during CPR at a rate of 110 beats per minute. The primary outcome was the median CCR for all periods of CPR with a metronome compared to periods without a metronome., Results: We included 2,132 OHCA cases with 32,776 minutes of CPR data; 15,667 (48%) minutes had no metronome use, and 17,109 (52%) minutes had a metronome used. Without a metronome, the median CCR was 112.8 per minute with an interquartile range of 108.4 - 119.1, and 27% of minutes were above 120 or less than 100. With a metronome, the median CCR was 110.5 per minute with an interquartile range of 110.0-112.0, and less than 4% of minutes were above 120 or less than 100. The compression rate was 109, 110, or 111 in 62% of minutes with a metronome compared to 18% of minutes with no metronome., Conclusion: The use of a metronome during CPR resulted in increased compliance to a predetermined compression rate. Metronomes are a simple tool that improves achievement of a target compression rate with little variance from that target., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Growth differentiation factor 11 (GDF11) and GDF8 (MSTN) are closely related TGF-β family proteins that interact with nearly identical signaling receptors and antagonists. However, GDF11 appears to activate SMAD2/3 more potently than GDF8 in vitro and in vivo. The ligands possess divergent structural properties, whereby substituting unique GDF11 amino acids into GDF8 enhanced the activity of the resulting chimeric GDF8. We investigated potentially distinct endogenous activities of GDF11 and GDF8 in vivo by genetically modifying their mature signaling domains. Full recoding of GDF8 to that of GDF11 yielded mice lacking GDF8, with GDF11 levels ∼50-fold higher than normal, and exhibiting modestly decreased muscle mass, with no apparent negative impacts on health or survival. Substitution of two specific amino acids in the fingertip region of GDF11 with the corresponding GDF8 residues resulted in prenatal axial skeletal transformations, consistent with Gdf11 -deficient mice, without apparent perturbation of skeletal or cardiac muscle development or homeostasis. These experiments uncover distinctive features between the GDF11 and GDF8 mature domains in vivo and identify a specific requirement for GDF11 in early-stage skeletal development., (© 2023 Lian et al.)

Frailty and chronic kidney disease (CKD) both increase with age and are prevalent in older adults. However, studies in older adults examining the relationship between frailty and milder impairments of kidney function are relatively sparse. We examined the cross-sectional association of baseline estimated glomerular filtration rate (eGFR), albuminuria and CKD ([eGFR <60 ml/min/1.73 m 2 ] and/or albuminuria [>3.0 mg/mmol]) with prefrailty and frailty in the ASPirin in Reducing Events in the Elderly (ASPREE) trial cohort of healthy older participants. Univariate logistic regression models measured the unadjusted odds ratios (OR) and 95% confidence intervals (CI) for prevalent combined prefrailty and frailty (respectively defined as presence of 1-2 or 3+ of 5 modified fried criteria) for the association between CKD, eGFR, albuminuria and other potential risk factors. Multivariable models calculated OR for prefrailty-frailty adjusted for potential confounders and either CKD, (i) eGFR and albuminuria measured as either continuous variables; (ii) or categorical variables; (iii). Of 17 759 eligible participants, 6934 were classified as prefrail, 389 were frail. CKD, eGFR and albuminuria were all associated with combined prefrailty-frailty on univariate analysis. In the multivariable modelling, neither CKD (reduced eGFR and/or albuminuria), nor eGFR (either continuous or categorical variables) were associated with prefrailty-frailty. However, albuminuria, either as a continuous variable (OR [95% CI] 1.07 [1.04-1.10]; p < .001), or categorical variable (OR 1.21 [1.08-1.36]; p = .001) was consistently associated with prefrailty-frailty. The complex relationship between albuminuria (which may be a biomarker for vascular inflammation), ageing, progressive CKD and frailty requires further investigation., (© 2022 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

Introduction: Guidelines recommend monitoring end-tidal carbon dioxide (E T CO 2 ) during out-of-hospital cardiac arrest (OHCA), though its prognostic value is poorly understood. This study investigated the relationship between E T CO 2 and return of spontaneous circulation (ROSC) after defibrillation in intubated non-traumatic OHCA patients., Methods: This retrospective, observational cohort analysis included adult OHCA patients who received a defibrillation shock during treatment by an urban EMS agency from 2015 to 2021. Peak E T CO 2 values were determined for the 90-second periods before and after the first defibrillation in an intubated patient (shock of interest [SOI]). Values were analyzed for association between the change in E T CO 2 from pre- to post-shock and the presence of ROSC on the subsequent pulse check., Results: Of 518 eligible patients, mean age was 61, 72% were male, 50% had a bystander-witnessed arrest, and 62% had at least one episode of ROSC. The most common arrest etiology was medical (92%). Among all patients, peak E T CO 2 during resuscitation prior to SOI was 36.8 mmHg (18.6). E T CO 2 increased in patients who achieved ROSC immediately after SOI (from 38.3 to 47.6 mmHg; +9.3 CI: 6.5, 12.1); patients with sustained ROSC experienced the greatest increase in E T CO 2 after SOI (from 37.8 to 48.2 mmHg; +10.4 CI: 7.2, 13.6), while E T CO 2 in patients who did not achieve ROSC after SOI rose (from 36.4 to 37.8 mmHg; +1.4 CI: -0.1, 2.8)., Conclusions: E T CO 2 rises after defibrillation in most patients during cardiac arrest. Patients with sustained ROSC experience larger rises, though the majority experience rises of less than 10 mmHg., (Copyright © 2022. Published by Elsevier B.V.)

Airway management is a critical component of resuscitation but also carries the potential to disrupt perfusion, oxygenation, and ventilation as a consequence of airway insertion efforts, the use of medications, and the conversion to positive-pressure ventilation. NAEMSP recommends:Airway management should be approached as an organized system of care, incorporating principles of teamwork and operational awareness.EMS clinicians should prevent or correct hypoxemia and hypotension prior to advanced airway insertion attempts.Continuous physiological monitoring must be used during airway management to guide the timing of, limit the duration of, and inform decision making during advanced airway insertion attempts.Initial and ongoing confirmation of advanced airway placement must be performed using waveform capnography. Airway devices must be secured using a reliable method.Perfusion, oxygenation, and ventilation should be optimized before, during, and after advanced airway insertion.To mitigate aspiration after advanced airway insertion, EMS clinicians should consider placing a patient in a semi-upright position.When appropriate, patients undergoing advanced airway placement should receive suitable pharmacologic anxiolysis, amnesia, and analgesia. In select cases, the use of neuromuscular blocking agents may be appropriate.

A 3 month old boy, with no known health conditions, suffered a sudden collapse at home. On first EMS arrival, ventricular fibrillation (VF) cardiac arrest was identified and resuscitation following UK national guidelines was initiated. He remained in cardiac arrest for over 25 min, during which he received 10 defibrillation shocks, each effective, but with VF reoccurring within a few seconds of each of the first 9. A return of spontaneous circulation (ROSC) was achieved after the 10th shock. The resuscitation was conducted fully in his home, with the early involvement of Advanced Paramedic Practitioners specialising in critical care (APP- CC). Throughout his resuscitation, there remained a strong focus on delivering quality resuscitation in situ, rather than a 'load and go' approach that would have resulted in very early conveyance to hospital with on-going CPR.The patient was subsequently discharged home and is making an excellent recovery. The arrest was later determined to have been caused by a primary arrhythmia as a result of a previously unidentified non-obstructive variant hypertrophic cardiomyopathy.We present data downloaded from the defibrillator used during the resuscitation that illustrates clearly the recurrent nature of his fibrillation.

Heparin and heparan sulfate (HS) are highly sulfated polysaccharides covalently bound to cell surface proteins, which directly interact with many extracellular proteins, including the transforming growth factor-β (TGFβ) family ligand antagonist, follistatin 288 (FS288). Follistatin neutralizes the TGFβ ligands, myostatin and activin A, by forming a nearly irreversible non-signaling complex by surrounding the ligand and preventing interaction with TGFβ receptors. The FS288-ligand complex has higher affinity than unbound FS288 for heparin/HS, which accelerates ligand internalization and lysosomal degradation; however, limited information is available for how FS288 interactions with heparin affect ligand binding. Using surface plasmon resonance (SPR) we show that preincubation of FS288 with heparin/HS significantly decreased the association kinetics for both myostatin and activin A with seemingly no effect on the dissociation rate. This observation is dependent on the heparin/HS chain length where small chain lengths less than degree of polymerization 10 (dp10) did not alter association rates but chain lengths >dp10 decreased association rates. In an attempt to understand the mechanism for this observation, we uncovered that heparin induced dimerization of follistatin. Consistent with our SPR results, we found that dimerization only occurs with heparin molecules >dp10. Small-angle X-ray scattering of the FS288 heparin complex supports that FS288 adopts a dimeric configuration that is similar to the FS288 dimer in the ligand-bound state. These results indicate that heparin mediates dimerization of FS288 in a chain-length-dependent manner that reduces the ligand association rate, but not the dissociation rate or antagonistic activity of FS288.

We have previously reported the discovery of a series of rhodanine-based inhibitors of the PIM family of serine/threonine kinases. Here we described the optimisation of those compounds to improve their physicochemical and ADME properties as well as reducing their off-targets activities against other kinases. Through molecular modeling and systematic structure activity relationship (SAR) studies, advanced molecules with high inhibitory potency, reduced off-target activity and minimal efflux were identified as new pan-PIM inhibitors. One example of an early lead, OX01401, was found to inhibit PIMs with nanomolar potency (15 nM for PIM1), inhibit proliferation of two PIM-expressing leukaemic cancer cell lines, MV4-11 and K562, and to reduce intracellular phosphorylation of a PIM substrate in a concentration dependent manner., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Insulin resistance is associated with aging in mice and humans. We have previously shown that administration of recombinant GDF11 (rGDF11) to aged mice alters aging phenotypes in the brain, skeletal muscle, and heart. While the closely related protein GDF8 has a role in metabolism, limited data are available on the potential metabolic effects of GDF11 or GDF8 in aging. To determine the metabolic effects of these two ligands, we administered rGDF11 or rGDF8 protein to young or aged mice fed a standard chow diet, short-term high-fat diet (HFD), or long-term HFD. Under nearly all of these diet conditions, administration of exogenous rGDF11 reduced body weight by 3-17% and significantly improved glucose tolerance in aged mice fed a chow (~30% vs. saline) or HF (~50% vs. saline) diet and young mice fed a HFD (~30%). On the other hand, exogenous rGDF8 showed signifcantly lesser effect or no effect at all on glucose tolerance compared to rGDF11, consistent with data demonstrating that GFD11 is a more potent signaling ligand than GDF8. Collectively, our results show that administration of exogenous rGDF11, but not rGDF8, can reduce diet-induced weight gain and improve metabolic homeostasis.

Organ transplant guidelines in many settings recommend that people with potential hepatitis C virus (HCV) exposure or infection are deemed ineligible to donate. The recent availability of highly-effective treatments for HCV means that this may no longer be necessary. We used a mathematical model to estimate the expected difference in healthcare costs, difference in disability-adjusted life years (DALYs) and cost-effectiveness of removing HCV restrictions for lung and kidney donations in Australia. Our model suggests that allowing organ donations from people who inject drugs, people with a history of incarceration and people who are HCV antibody-positive could lead to an estimated 10% increase in organ supply, population-level improvements in health (reduction in DALYs), and on average save AU$2,399 (95%CI AU$1,155-3,352) and AU$2,611 (95%CI AU$1,835-3,869) per person requiring a lung and kidney transplant respectively. These findings are likely to hold for international settings, since this policy change remained cost saving with positive health gains regardless of HCV prevalence, HCV treatment cost and waiting list survival probabilities. This study suggests that guidelines on organ donation should be revisited in light of recent changes to clinical outcomes for people with HCV.

Recent advances in CRISPR/Cas gene editing technology have significantly expanded the possibilities and accelerated the pace of creating genetically engineered animal models. However, CRISPR/Cas-based strategies designed to precisely edit the genome can often yield unintended outcomes. Here, we report the use of zygotic CRISPR/Cas9 injections to generate a knock-in GFP reporter mouse at the Gdf11 locus. Phenotypic and genomic characterization of founder animals from these injections revealed a subset that contained the correct targeting event and exhibited GFP expression that, within the hematopoietic system, was restricted predominantly to lymphoid cells. Yet, in another subset of founder mice, we detected aberrant integration events at the target site that dramatically and inaccurately shifted hematopoietic GFP expression from the lymphoid to the myeloid lineage. Additionally, we recovered multiple Gdf11 deletion alleles that modified the C-terminus of the GDF11 protein. When bred to homozygosity, most of these alleles recapitulated skeletal phenotypes reported previously for Gdf11 knockout mice, suggesting that these represent null alleles. However, we also recovered one Gdf11 deletion allele that encodes a novel GDF11 variant protein ("GDF11-WE") predicted to contain two additional amino acids (tryptophan (W) and glutamic acid (E)) at the C-terminus of the mature ligand. Unlike the other Gdf11 deletion alleles recovered in this study, homozygosity for the Gdf11 WE allele did not phenocopy Gdf11 knockout skeletal phenotypes. Further investigation using in vivo and in vitro approaches demonstrated that GDF11-WE retains substantial physiological function, indicating that GDF11 can tolerate at least some modifications of its C-terminus and providing unexpected insights into its biochemical activities. Altogether, our study confirms that one-step zygotic injections of CRISPR/Cas gene editing complexes provide a quick and powerful tool to generate gene-modified mouse models. Moreover, our findings underscore the critical importance of thorough characterization and validation of any modified alleles generated by CRISPR, as unintended on-target effects that fail to be detected by simple PCR screening can produce substantially altered phenotypic readouts.

Administration of active growth differentiation factor 11 (GDF11) to aged mice can reduce cardiac hypertrophy, and low serum levels of GDF11 measured together with the related protein, myostatin (also known as GDF8), predict future morbidity and mortality in coronary heart patients. Using mice with a loxP-flanked ("floxed") allele of Gdf11 and Myh6 -driven expression of Cre recombinase to delete Gdf11 in cardiomyocytes, we tested the hypothesis that cardiac-specific Gdf11 deficiency might lead to cardiac hypertrophy in young adulthood. We observed that targeted deletion of Gdf11 in cardiomyocytes does not cause cardiac hypertrophy but rather leads to left ventricular dilation when compared with control mice carrying only the Myh6-cre or Gdf11 -floxed alleles, suggesting a possible etiology for dilated cardiomyopathy. However, the mechanism underlying this finding remains unclear because of multiple confounding effects associated with the selected model. First, whole heart Gdf11 expression did not decrease in Myh6-cre; Gdf11 -floxed mice, possibly because of upregulation of Gdf11 in noncardiomyocytes in the heart. Second, we observed Cre-associated toxicity, with lower body weights and increased global fibrosis, in Cre-only control male mice compared with flox-only controls, making it challenging to infer which changes in Myh6-cre;Gdf11- floxed mice were the result of Cre toxicity versus deletion of Gdf11 . Third, we observed differential expression of cre mRNA in Cre-only controls compared with the cardiomyocyte-specific knockout mice, also making comparison between these two groups difficult. Thus, targeted Gdf11 deletion in cardiomyocytes may lead to left ventricular dilation without hypertrophy, but alternative animal models are necessary to understand the mechanism for these findings. NEW & NOTEWORTHY We observed that targeted deletion of growth differentiation factor 11 in cardiomyocytes does not cause cardiac hypertrophy but rather leads to left ventricular dilation compared with control mice carrying only the Myh6-cre or growth differentiation factor 11-floxed alleles. However, the mechanism underlying this finding remains unclear because of multiple confounding effects associated with the selected mouse model.