Focused abdominal ultrasound.

A focused point-of-care abdominal ultrasound is an examination performed at the patient's location and interpreted within the clinical context. This review gives an overview of this examination modality. The objective is to rapidly address predefined dichotomised questions about the presence of an abdominal aortic aneurysm, gallstones, cholecystitis, hydronephrosis, urinary retention, free intraperitoneal fluid, and small bowel obstruction. FAUS is a valuable tool for emergency physicians to promptly confirm various conditions upon the patients' arrival, thus reducing the time to diagnosis and in some cases eliminating the need for other imaging.

Point-of-Care Lung Ultrasound in Emergency Medicine: A Scoping Review With an Interactive Database.

BACKGROUND: This scoping review was conducted to provide an overview of the evidence of point-of-care lung ultrasound (LUS) in emergency medicine. By emphasizing clinical topics, time trends, study designs, and the scope of the primary outcomes, a map is provided for physicians and researchers to guide their future initiatives. RESEARCH QUESTION: Which study designs and primary outcomes are reported in published studies of LUS in emergency medicine? STUDY DESIGN AND METHODS: We performed a systematic search in the PubMed/MEDLINE, Embase, Web of Science, Scopus, and Cochrane Library databases for LUS studies published prior to May 13, 2023. Study characteristics were synthesized quantitatively. The primary outcomes in all papers were categorized into the hierarchical Fryback and Thornbury levels. RESULTS: A total of 4,076 papers were screened and, following selection and handsearching, 406 papers were included. The number of publications doubled from January 2020 to May 2023 (204 to 406 papers). The study designs were primarily observational (n = 375 [92%]), followed by randomized (n = 18 [4%]) and case series (n = 13 [3%]). The primary outcome measure concerned diagnostic accuracy in 319 papers (79%), diagnostic thinking in 32 (8%), therapeutic changes in 4 (1%), and patient outcomes in 14 (3%). No increase in the proportions of randomized controlled trials or the scope of primary outcome measures was observed with time. A freely available interactive database was created to enable readers to search for any given interest (https://public.tableau.com/app/profile/blinded/viz/LUSinEM_240216/INFO). INTERPRETATION: Observational diagnostic studies have been produced in abundance, leaving a paucity of research exploring clinical utility. Notably, research exploring whether LUS causes changes to clinical decisions is imperative prior to any further research being made into patient benefits.

Impact of serial cardiopulmonary point-of-care ultrasound exams in patients with acute dyspnoea: a randomised, controlled trial.

BACKGROUND: Serial point-of-care ultrasound (PoCUS) can potentially improve acute patient care through treatment adjusted to the dynamic ultrasound findings. The objective was to investigate if treatment guided by monitoring patients with acute dyspnoea with serial cardiopulmonary PoCUS and usual care could reduce the severity of dyspnoea compared with usual care alone. METHODS: This was a randomised, controlled, blinded-outcome trial conducted in three EDs in Denmark between 9 October 2019 and 26 May 2021. Patients aged ≥18 years admitted with a primary complaint of dyspnoea were allocated 1:1 with block randomisation to usual care, which included a single cardiopulmonary PoCUS within 1 hour of arrival (control group) or usual care (including a PoCUS within 1 hour of arrival) plus two additional PoCUS performed at 2 hours interval from the initial PoCUS (serial ultrasound group). The primary outcome was a reduction of dyspnoea measured on a verbal dyspnoea scale (VDS) from 0 to 10 recorded at inclusion and after 2, 4 and 5 hours. RESULTS: There were 206 patients recruited, 102 in the serial ultrasound group and 104 in the control group, all of whom had complete follow-up. The mean difference in VDS between patients in the serial ultrasound and the control group was -1.09 (95% CI -1.51 to -0.66) and -1.66 (95% CI -2.09 to -1.23) after 4 and 5 hours, respectively. The effect was more pronounced in patients with a presumptive diagnosis of acute heart failure (AHF). A larger proportion of patients received diuretics in the serial ultrasound group. CONCLUSION: Therapy guided by serial cardiopulmonary PoCUS may, together with usual care, facilitate greater improvement in the severity of dyspnoea, especially in patients with AHF compared with usual care with a single PoCUS in the ED. Serial PoCUS should therefore be considered for routine use to aid the physician in stabilising the patient faster. TRIAL REGISTRATION NUMBER: NCT04091334.

Focused cardiac ultrasound in emergency medicine.

Focused cardiac ultrasound (FoCUS) is a point-of-care cardiac examination performed and interpreted by the emergency physician in the clinical context. This review summarises the current knowledge of FoCUS. The objective is to answer four predefined clinical questions: Are there any signs of pericardial effusion? Are there any signs of right ventricular dilatation? Are there any signs of reduced or hyperdynamic left ventricular function? Are there any signs of abnormal inferior vena cava? FoCUS is not a replacement for echocardiography but a useful tool in detecting cardiopulmonary pathology and haemodynamic abnormalities in the emergency setting.

Increased liver markers in rhabdomyolysis in a young recruit from the field trip.

We present a case report of rhabdomyolysis after intense physical activity. Tests showed increased creatine kinase compatible with rhabdomyolysis. Liver damage was suspected due to a significant elevation of aspartate transaminase (AST) and alanine transaminase (ALT). This case report discusses how an increase in AST and ALT reflects skeletal muscle damage in rhabdomyolysis instead of liver damage, especially when assessing more specific liver markers such as international normalised ratio and ϒ-glutamyl transferase, which both were within normal range in this case. This knowledge can prevent unnecessary test.

High-throughput analysis of the transcriptional patterns of sexual genes in malaria.

BACKGROUND: Plasmodium falciparum (Pf) is the leading protozoan causing malaria, the most devastating parasitic disease. To ensure transmission, a small subset of Pf parasites differentiate into the sexual forms (gametocytes). Since the abundance of these essential parasitic forms is extremely low within the human host, little is currently known about the molecular regulation of their sexual differentiation, highlighting the need to develop tools to investigate Pf gene expression during this fundamental mechanism. METHODS: We developed a high-throughput quantitative Reverse-Transcription PCR (RT-qPCR) platform to robustly monitor Pf transcriptional patterns, in particular, systematically profiling the transcriptional pattern of a large panel of gametocyte-related genes (GRG). Initially, we evaluated the technical performance of the systematic RT-qPCR platform to ensure it complies with the accepted quality standards for: (i) RNA extraction, (ii) cDNA synthesis and (iii) evaluation of gene expression through RT-qPCR. We then used this approach to monitor alterations in gene expression of a panel of GRG upon treatment with gametocytogenesis regulators. RESULTS: We thoroughly elucidated GRG expression profiles under treatment with the antimalarial drug dihydroartemisinin (DHA) or the metabolite choline over the course of a Pf blood cycle (48 h). We demonstrate that both significantly alter the expression pattern of PfAP2-G, the gametocytogenesis master regulator. However, they also markedly modify the developmental rate of the parasites and thus might bias the mRNA expression. Additionally, we screened the effect of the metabolites lactate and kynurenic acid, abundant in severe malaria, as potential regulators of gametocytogenesis. CONCLUSIONS: Our data demonstrate that the high-throughput RT-qPCR method enables studying the immediate transcriptional response initiating gametocytogenesis of the parasites from a very low volume of malaria-infected RBC samples. The obtained data expand the current knowledge of the initial alterations in mRNA profiles of GRG upon treatment with reported regulators. In addition, using this method emphasizes that asexual parasite stage composition is a crucial element that must be considered when interpreting changes in GRG expression by RT-qPCR, specifically when screening for novel compounds that could regulate Pf sexual differentiation.

miR-4734 conditionally suppresses ER stress-associated proinflammatory responses.

Prolonged metabolic stress can lead to severe pathologies. In metabolically challenged primary fibroblasts, we assigned a novel role for the poorly characterized miR-4734 in restricting ATF4 and IRE1-mediated upregulation of a set of proinflammatory cytokines and endoplasmic reticulum stress-associated genes. Conversely, inhibition of this miRNA augmented the expression of those genes. Mechanistically, miR-4734 was found to restrict the expression of the transcriptional activator NF-kappa-B inhibitor zeta (NFKBIZ), which is required for optimal expression of the proinflammatory genes and whose mRNA is targeted directly by miR-4734. Concordantly, overexpression of NFKBIZ compromised the effects of miR-4734, underscoring the importance of this direct targeting. As the effects of miR-4734 were evident under stress but not under basal conditions, it may possess therapeutic utility towards alleviating stress-induced pathologies.

Chief Complaints, Underlying Diagnoses, and Mortality in Adult, Non-trauma Emergency Department Visits: A Population-based, Multicenter Cohort Study.

INTRODUCTION: Knowledge about the relationship between symptoms, diagnoses, and mortality in emergency department (ED) patients is essential for the emergency physician to optimize treatment, monitoring, and flow. In this study, we investigated the association between symptoms and discharge diagnoses; symptoms and mortality; and we then analyzed whether the association between symptoms and mortality was influenced by other risk factors. METHODS: This was a population-based, multicenter cohort study of all non-trauma ED patients ≥18 years who presented at a hospital in the Region of Southern Denmark between January 1, 2016-March 20, 2018. We used multivariable logistic regression to examine the association between symptoms and mortality adjusted for other risk factors. RESULTS: We included 223,612 ED visits with a median patient age of 63 and even distribution of females and males. The frequency of the chief complaints at presentation were as follows: non-specific symptoms (19%); abdominal pain (16%); dyspnea (12%); fever (8%); chest pain (8%); and neurologic complaints (7%). Discharge diagnoses were symptom-based (24%), observational (hospital visit for observation or examination, 17%), circulatory (12%), or respiratory (12%). The overall 30-day mortality was 3.5%, with 1.7% dead within 0-7 days and 1.8% within 8-30 days. The presenting symptom was associated with mortality at 0-7 days but not with mortality at 8-30 days. Patients whose charts were missing documentation of symptoms (adjusted odds ratio [aOR] 3.5) and dyspneic patients (aOR 2.4) had the highest mortality at 0-7 days across patients with different primary symptoms. Patients ≥80 years and patients with a higher degree of comorbidity had increased mortality from 0-7 days to 8-30 days (aOR from 24.0 to 42.7 and 1.9 to 2.8, respectively). CONCLUSION: Short-term mortality was more strongly associated with patient-related factors than with the primary presenting symptom at arrival to the hospital.

Clinical assessment as a part of an early warning score-a Danish cluster-randomised, multicentre study of an individual early warning score.

BACKGROUND: The clinical benefit of Early Warning Scores (EWSs) is undocumented. Nursing staff's clinical assessment might improve the prediction of outcome and allow more efficient use of resources. We aimed to investigate whether the combination of clinical assessment and EWS would reduce the number of routine measurements without increasing mortality. METHODS: We did a cluster-randomised, crossover, non-inferiority study at eight hospitals in Denmark. Patients aged 18 years or older, admitted for more than 24 h were included. Admissions to paediatric or obstetric wards were excluded. The participating hospitals were randomly assigned 1:1 to start as either intervention or control with subsequent crossover. Primary outcomes were 30-day all-cause mortality (non-inferiority margin=0·5%) and average number of EWS per day per patient. The intervention was implementation of the Individual EWS (I-EWS), in which nursing staff can adjust the calculated score on the basis of their clinical assessment of the patient. I-EWS was compared with the National Early Warning Score (NEWS). The study is registered at ClinicalTrials.gov, NCT03690128 and is complete. FINDINGS: Unique admissions longer than 24 h were included from Oct 15, 2018 to Sept 30, 2019. Of 90 964 patients assessed, n=46 470 were assigned to the I-EWS group and n=44 494 to the NEWS group. Mortality within 30 days was 4·6% for the I-EWS group, and 4·3% for the NEWS group (adjusted odds ratio 1·05 [95% CI 0·99-1·12], p=0·12). In subgroup analyses I-EWS showed increased 30-day mortality for hospitals that did I-EWS in fall-winter, which was probably due to seasonality, and within patients admitted in a surgical specialty. Overall risk difference was 0·22% (95% CI -0·04 to 0·48) meaning that the non-inferiority criteria were met. The average number of scorings per patient per day was reduced from 3·14 to 3·10 (ie, a relative reduction of 0·64% [95% CI -0·16 to -1·11], p=0·0084) in the I-EWS group. INTERPRETATION: Including clinical assessment in I-EWS was feasible and overall non-inferior to the widely implemented NEWS in terms of all-cause mortality at 30 days, and the number of routine measurements was minimally reduced. However I-EWS should be used with caution in surgical patients. FUNDING: Capital Region Research Foundation, Gangsted Foundation, Candys Foundation, Herlev-Gentofte Hospital Research Foundation, Laerdal Foundation, and The Foundation of Director Boennelycke and wife.

Monitoring patients with acute dyspnea with serial point-of-care ultrasound of the inferior vena cava (IVC) and the lungs (LUS): a systematic review.

PURPOSE: The primary aim was to investigate if treatment guided by serial ultrasound of the inferior vena cava-collapsibility index (IVC-CI) and B-lines on lung ultrasound (LUS) could reduce mortality, readmissions, and length of stay (LOS) in acutely dyspneic patients admitted to a hospital, compared to standard monitoring. The secondary aim was to determine how the changes of B-lines and IVC-CI are correlated to vitals and symptoms. METHODS: A systematic search was conducted on PubMed, Embase, Cochrane, Google Scholar, Web of Science, Scopus, OpenGrey, ProQuest, and databases for ongoing trials. The risk of bias was assessed according to study design. RESULTS: Of the 8258 studies identified, 50 were selected for full-text screening, and 24 studies were chosen for data extraction (19 pre-post-, two non-randomized controlled-, two randomized controlled-, and one retrospective cohort study), covering 2040 patients. Most studies were single-center and had small study populations with only heart failure patients. The risk of bias was high. No studies evaluated how the difference between two ultrasound measurements correlated with the primary outcomes. Seven studies reported that a decline in either B-lines or IVC size, or an increased IVC-CI reduced mortality, readmissions, and LOS when correlated to a single ultrasound measurement. All studies showed changes in the IVC-CI and B-lines, but these were not related to vitals or symptoms. CONCLUSION: B-lines and IVC-CI are dynamic variables that change over time and with treatment. A single ultrasound measurement can influence prognostic outcomes, but it remains uncertain if repeated scans can have the same impact.

[Point-of-care ultrasound in emergency departments in Denmark].

Point-of-are ultrasound (PoCUS) has become an integrated part of initial diagnostics and procedural guidance after establishing emergency departments and a speciality in emergency medicine in Denmark. Focused PoCUS is a fast examination, which is done and interpreted bedside to answer clinical, predefined dichotomous questions. Emergency physicians have an obligate course in PoCUS as part of their training and must be certified to get speciality recognition. In this review we argue, that the future of PoCUS is continuing the development of the education and training in PoCUS and in further research.

Adjusting Early Warning Score by clinical assessment: a study protocol for a Danish cluster-randomised, multicentre study of an Individual Early Warning Score (I-EWS).

INTRODUCTION: Track and trigger systems (TTSs) based on vital signs are implemented in hospitals worldwide to identify patients with clinical deterioration. TTSs may provide prognostic information but do not actively include clinical assessment, and their impact on severe adverse events remain uncertain. The demand for prospective, multicentre studies to demonstrate the effectiveness of TTSs has grown the last decade. Individual Early Warning Score (I-EWS) is a newly developed TTS with an aggregated score based on vital signs that can be adjusted according to the clinical assessment of the patient. The objective is to compare I-EWS with the existing National Early Warning Score (NEWS) algorithm regarding clinical outcomes and use of resources. METHOD AND ANALYSIS: In a prospective, multicentre, cluster-randomised, crossover, non-inferiority study. Eight hospitals are randomised to use either NEWS in combination with the Capital Region of Denmark NEWS Override System (CROS) or implement I-EWS for 6.5 months, followed by a crossover. Based on their clinical assessment, the nursing staff can adjust the aggregated score with a maximum of -4 or +6 points. We expect to include 150 000 unique patients. The primary endpoint is all-cause mortality at 30 days. Coprimary endpoint is the average number of times per day a patient is NEWS/I-EWS-scored, and secondary outcomes are all-cause mortality at 48 hours and at 7 days as well as length of stay. ETHICS AND DISSEMINATION: The study was presented for the Regional Ethics committee who decided that no formal approval was needed according to Danish law (J.no. 1701733). The I-EWS study is a large prospective, randomised multicentre study that investigates the effect of integrating a clinical assessment performed by the nursing staff in a TTS, in a head-to-head comparison with the internationally used NEWS with the opportunity to use CROS. TRIAL REGISTRATION NUMBER: NCT03690128.

Effectiveness of serial focused ultrasound of the lungs and inferior vena cava for monitoring patients with acute dyspnea: a systematic review protocol.

OBJECTIVE: The objective of this review is to evaluate the effectiveness of serial focused ultrasound of the lungs (FLUS) and/or inferior vena cava (IVC) compared to standard care for monitoring patients with acute dyspnea. INTRODUCTION: Acute dyspnea is one of the most common complaints reported by patients in hospital emergency departments, and has high in-hospital mortality rates. The current methods of monitoring patients with acute dyspnea lack both sensitivity and specificity. Point-of-care FLUS and IVC is a promising monitoring tool, but an overview of the existing evidence is absent. INCLUSION CRITERIA: This review will include studies of adult patients admitted to hospital with acute dyspnea that is examined via FLUS, IVC or both a minimum of twice during hospitalization compared to standard care. METHODS: The following electronic databases will be searched: PubMed, Cochrane, Embase, Scopus, Web of Science and Google Scholar. Gray literature will be sought in OpenGrey and ProQuest. The search is limited to articles written in English, Danish, Swedish, Norwegian and German. Articles published before 2003 will be excluded from the search and duplicates will be removed. Two independent reviewers will screen and critically appraise the included studies and perform the data extraction. If possible, data will be synthesized with statistical meta-analysis; otherwise, data will be presented in narrative form. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42018116608.

Blood Management Strategies in Total Knee Arthroplasty

A perioperative blood management program is one of a number of important elements for successful patient care in total knee arthroplasty (TKA) and surgeons should be proactive in its application. The aims of blood conservation are to reduce the risk of blood transfusion whilst at the same time maximizing hemoglobin (Hb) in the postoperative period, leading to a positive effect on outcome and cost. An individualized strategy based on patient specific risk factors, anticipated blood loss and comorbidities are useful in achieving this aim. Multiple blood conservation strategies are available in the preoperative, intraoperative and postoperative periods and can be employed in various combinations. Recent literature has highlighted the importance of preoperative Hb optimization, minimizing blood loss and evidence-based transfusion guidelines. Given TKA is an elective procedure, a zero allogenic blood transfusion rate should be the aim and an achievable goal.

Mdm2 regulates p53 mRNA translation through inhibitory interactions with ribosomal protein L26.

Mdm2 regulates the p53 tumor suppressor by promoting its proteasome-mediated degradation. Mdm2 and p53 engage in an autoregulatory feedback loop that maintains low p53 activity in nonstressed cells. We now report that Mdm2 regulates p53 levels also by targeting ribosomal protein L26. L26 binds p53 mRNA and augments its translation. Mdm2 binds L26 and drives its polyubiquitylation and proteasomal degradation. In addition, the binding of Mdm2 to L26 attenuates the association of L26 with p53 mRNA and represses L26-mediated augmentation of p53 protein synthesis. Under nonstressed conditions, both mechanisms help maintain low cellular p53 levels by constitutively tuning down p53 translation. In response to genotoxic stress, the inhibitory effect of Mdm2 on L26 is attenuated, enabling a rapid increase in p53 synthesis. The Mdm2-L26 interaction thus represents an additional important component of the autoregulatory feedback loop that dictates cellular p53 levels and activity.

A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization.

Damage to the mitotic spindle and centrosome dysfunction can lead to cancer. To prevent this, cells trigger a succession of checkpoint responses, where an initial mitotic delay is followed by slippage without cytokinesis, spawning tetraploid G1 cells that undergo a p53-dependent G1/S arrest. We describe the importance of Lats2 (Large Tumor Suppressor 2) in this checkpoint response. Lats2 binds Mdm2, inhibits its E3 ligase activity, and activates p53. Nocodazole, a microtubule poison that provokes centrosome/mitotic apparatus dysfunction, induces Lats2 translocation from centrosomes to the nucleus and p53 accumulation. In turn, p53 rapidly and selectively up-regulates Lats2 expression in G2/M cells, thereby defining a positive feedback loop. Abrogation of Lats2 promotes accumulation of polyploid cells upon exposure to nocodazole, which can be prevented by direct activation of p53. The Lats2-Mdm2-p53 axis thus constitutes a novel checkpoint pathway critical for the maintenance of proper chromosome number.

The p53-Mdm2 module and the ubiquitin system.

The p53 tumor suppressor protein is a short-lived protein, which is stabilized in response to cellular stress. The ubiquitination and degradation of p53 are largely controlled by Mdm2, an oncogenic E3 ligase. Stress signals lead to p53 stabilization either by induction of covalent modifications in Mdm2 and p53, or through altered protein-protein interactions. Mdm2 also harbors a post-ubiquitination function, probably enabling efficient targeting of ubiquitinated p53 to the proteasome. p53 ubiquitination is associated with its export from the nucleus into the cytoplasm. However, the exact site of degradation of p53 is presently under debate. p53 may be targeted by other E3 ligases besides Mdm2, as well as by non-proteasomal mechanisms. Despite extensive information about p53 degradation, many important aspects remain unresolved.

Regulation of p53: intricate loops and delicate balances.

The p53 tumor suppressor protein provides a major anti-cancer defense mechanism, as underscored by the fact that the p53 gene is the most frequent target for genetic alterations in human cancer. Recent work has led to the realization that p53 lies at the hub of a very complex network of signaling pathways that integrate a variety of intracellular and extracellular inputs. Part of this network consists of an array of autoregulatory feedback loops, where p53 exhibits very intricate interactions with other proteins known to play important roles in the determination of cell fate. We discuss two such loops, one involving the beta-catenin protein and the other centering on the Akt/PKB protein kinase. In both cases, the central module is the interplay between p53 and the Mdm2 protein, which inactivates p53 and targets it for rapid proteolysis. Whereas deregulated beta-catenin can lead to Mdm2 inactivation and p53 accumulation, active p53 can promote the degradation and down-regulation of beta-catenin. Similarly, Akt can block p53 activation by potentiating Mdm2, whereas activated p53 can tune down Akt in several different ways. In each case, the actual output of the loop is determined by the delicate balance between the opposing effects of its different components. Often, this balance is dictated by additional signaling processes that occur simultaneously within the same cell. Genetic alterations characteristic of cancer are capable of severely distorting this balance, thereby overriding the tumor suppressor effects of p53 in a manner that facilitates neoplastic conversion.

Regulation of p53: intricate loops and delicate balances.

The p53 tumor suppressor protein provides a major anti-cancer defense mechanism, as underscored by the fact that the p53 gene is the most frequent target for genetic alterations in human cancer. Recent work has led to the realization that p53 lies at the hub of a very complex network of signaling pathways, which integrate a variety of intracellular and extracellular inputs. Part of this network consists of an array of autoregulatory feedback loops, where p53 exhibits very intricate interactions with other proteins known to play important roles in the determination of cell fate. We discuss two such loops, one involving the beta catenin protein and the other centering on the Akt/protein kinase B. In both cases, the central module is the interplay between p53 and the murine double minute 2 (Mdm2) protein, which inactivates p53 and targets it for rapid proteolysis. Whereas deregulated beta catenin can lead to Mdm2 inactivation and p53 accumulation, active p53 can promote the degradation and downregulation of beta catenin. Similarly, Akt can block p53 activation by potentiating Mdm2, whereas activated p53 can tune down Akt in several different ways. In each case, the actual output of the loop is determined by the delicate balance between the opposing effects of its different components. Often, this balance is dictated by additional signaling processes that occur simultaneously within the same cell. Genetic alterations characteristic of cancer are capable of severely distorting this balance, thereby overriding the tumor suppressor effects of p53 in a manner that facilitates neoplastic conversion.