Seize the day and seize seizures after cardiac arrest

Non peer reviewe

From Stem Cells to Populations—Using hiPSC, Next-Generation Sequencing, and GWAS to Explore the Genetic and Molecular Mechanisms of Congenital Heart Defects

Congenital heart defects (CHD) are developmental malformations affecting the heart and the great vessels. Early heart development requires temporally regulated crosstalk between multiple cell types, signaling pathways, and mechanical forces of early blood flow. While both genetic and environmental factors have been recognized to be involved, identifying causal genes in non-syndromic CHD has been difficult. While variants following Mendelian inheritance have been identified by linkage analysis in a few families with multiple affected members, the inheritance pattern in most familial cases is complex, with reduced penetrance and variable expressivity. Furthermore, most non-syndromic CHD are sporadic. Improved sequencing technologies and large biobank collections have enabled genome-wide association studies (GWAS) in non-syndromic CHD. The ability to generate human to create human induced pluripotent stem cells (hiPSC) and further differentiate them to organotypic cells enables further exploration of genotype–phenotype correlations in patient-derived cells. Here we review how these technologies can be used in unraveling the genetics and molecular mechanisms of heart development

Toipuminen tehohoitoa vaatineesta koronavirusinfektiosta

Vertaisarvioitu.• Vaikeaan COVID-19-tautiin liittyy toimintakykyyn ja elämänlaatuun vaikuttavia jälkioireita, joista erityisesti uupumus ja hengitysoireet ovat yleisiä. Tehohoidon jälkeen esiintyy myös mielenterveysongelmia. • Hengityslaitehoidossa olleille potilaille voi jäädä restriktiivinen hengitystoiminnan vajaus ja diffuusiokapasiteetin heikentymä. Myös lihasheikkous on tavallista ja vaikuttaa suorituskykyyn. • Jälkioireissa tapahtuu korjaantumista. • Tehohoidon aikana hoitoon liittyviä haittoja pyritään minimoimaan. Hoidon jälkeen on tärkeää tunnistaa kuntoutusta ja tukea tarvitsevat potilaat.Peer reviewe

Matrix metalloproteinases in critically ill patients

The systemic levels of matrix metalloproteinases (MMPs) -7, -8 and -9 and the tissue inhibitor of metalloproteinases-1 (TIMP-1) were investigated in 877 critically ill patients. In Study I, 15 intensive care unit-(ICU) treated adult patients with secondary peritonitis were prospectively included. Peritoneal fluid, blood and urine samples were collected at the ICU after surgery. The serum and urine levels of MMP-8 were compared with those obtained from ten healthy volunteers, and were found to be significantly higher in patients. In peritoneal fluid, MMP-8 levels were significantly higher than in serum and urine. This study was the first to identify MMP-8 in the peritoneal fluid of peritonitis patients. Study II was a sub-study of the FINNSEPSIS study where patients with severe sepsis or septic shock were prospectively included in 24 Finnish ICUs. Serum samples of 248 patients were analysed for MMP-8, MMP-9 and TIMP-1 levels, that were found to be higher than those of healthy controls. MMP-8, -9 and TIMP-1 levels were compared between ICU survivors and non-survivors. Median MMP-8 (p<0.01) and TIMP-1 (p<0.001) were higher and median MMP-9 levels lower (p=0.047) in ICU non-survivors than in ICU survivors. Study III investigated MMP-7, MMP-8, MMP-9, and TIMP-1 levels on 51 patients resuscitated from cardiac arrest (CA). The patients were a subgroup of the Hypothermia After Cardiac Arrest study. Thirty patients had received mild therapeutic hypothermia treatment (MTH) and 21 non-hypothermia treatment (non-MTH). Serum samples taken at 24 and 48 hours from restoration of spontaneous circulation were analysed and compared between patients and healthy volunteers. Serum MMP and TIMP-1 levels of MTH-treated patients were compared during and after MTH with the levels of non-MTH-treated patients. MMP-8 and MMP-9 were higher in CA patients than controls. Patients receiving MTH treatment had lower median MMP-9 levels during MTH than non-MTH-treated patients (p<0.001). This is one novel potential mechanism of how MTH treatment improves outcome of CA patients. Study IV was a 563-patient sub-study of the FINNALI study that included acute respiratory failure patients at 25 Finnish ICUs. MMP-8 and TIMP-1 were analysed from blood samples taken on study admission and 48 hours thereafter. Association of MMP-8 and TIMP-1 with 90-day mortality was examined. Serum MMP-8 predicted 90-day mortality of acute respiratory failure patients poorly. Admission TIMP-1 levels were higher in non-survivors than in survivors (p<0.001).TIMP-1 was an independent predictor of 90-day mortality, with a moderate discriminative power (AUC 0.633, 95% CI 0.580- 0.686). TIMP-1 was also associated with the severity of oxygenation disturbance. Thus, TIMP-1 is a potentially useful biomarker for predicting outcome in acute respiratory failure patients.Valtaosaan tehohoitoon johtavista sairaustiloista liittyy yleistynyt tulehdusreaktio, joka voi johtaa eri elinjärjestelmien toimintahäiriöihin. Matrix metalloproteinaasit (MMP) 8 ja 9 vapautuvat neutrofiilisista valkosoluista nopeasti tulehduksen alkuvaiheessa. Niiden toimintaa kudostasolla säätelee mm metalloproteinaasien kudosinhibiittori TIMP-1. Myös MMP-7 säätelee tulehdusreaktioita ja lisäksi MMP-8:aa ja MMP-9:ää. Väitöskirjatyössä selvitettiin MMP-7:n, -8:n, -9:n ja TIMP-1:n roolia kriittisesti sairailla potilailla. Aineisto koostui neljästä eri potilasryhmästä, yhteensä potilaita kerättiin 877. Osatöissä I ja III potilaat kerättiin yhdestä keskuksesta ja osatöissä II ja IV osana kansallisia monikeskustutkimuksia (FINNSEPSIS ja FINNALI). Osatyössä I määritettiin 15 akuutin vatsakalvontulehduksen takia leikatun potilaan vatsaonteloeritteestä, seerumista ja virtsasta MMP-8-pitoisuuksia. MMP-8-tasot olivat potilaiden seerumissa ja virtsassa korkeammat kuin terveillä verrokeilla. Korkeimmat pitoisuudet todettiin vatsaonteloeritteessä. Osatyössä II tutkittiin 248 vaikean sepsiksen tai septisen sokin vuoksi tehohoitoon päätyneen potilaan verinäytteitä. Tulovaiheen seeruminäytteistä määritettiin MMP-8, MMP-9 ja TIMP-1-pitoisuuksia. Niiden tasot olivat korkeammat kuin terveillä verrokeilla. Potilailla, jotka menehtyivät tehohoidon aikana, oli tulovaiheessa korkeammat MMP-8- ja TIMP-1-pitoisuudet kuin niillä, jotka selviytyivät. MMP-9-tasot olivat selviytyneillä matalammat. Osatyössä III tutkittiin MMP-7,-8 ja -9 sekä TIMP-1 pitoisuuksia 51 kammiovärinästä elvytetyllä potilaalla. Potilaat kuuluivat HACA-tutkimukseen, jossa heidät satunnaistettiin saamaan silloista standardihoitoa normaalissa lämpötilassa tai viilennyshoitoa, jossa keho viilennettiin 33 asteen lämpötilaan 24 tunnin ajaksi. MMP-8- ja -9 seerumitasot olivat elvytetyillä korkeammat kuin terveillä verrokeilla, MMP-7 ei ollut merkitsevästi koholla. TIMP-1 oli elvytetyillä verrokkeja matalampi. Viilennyshoidon aikana MMP-8- ja MMP-9-tasot olivat merkittävästi alhaisemmat kuin normaalilämpöti-lassa hoidetuilla potilailla. Tämä ero hävisi hoidon jälkeen. Tulos tuo uutta tietoa mekanismeista, jotka liittyvät viilennyshoidon vaikutuksiin tässä potilasryhmässä. Osatyössä IV selvitettiin, voidaanko akuuttia hengitysvajausta sairastavien potilaiden selviytymistä ennustaa alkuvaiheen MMP-8- ja TIMP-1-tasojen avulla. Tässä 563 potilaan aineistossa seerumin TIMP-1, muttei MMP-8, ennusti itsenäisesti 90 vuorokauden kuolleisuutta ja oli yhteydessä hengitysvajauksen vaikeusasteeseen. Väitöskirjatutkimus tuo lisätietoa yleisen tulehdusreaktion mekanismeista

From Stem Cells to Populations—Using hiPSC, Next-Generation Sequencing, and GWAS to Explore the Genetic and Molecular Mechanisms of Congenital Heart Defects

Congenital heart defects (CHD) are developmental malformations affecting the heart and the great vessels. Early heart development requires temporally regulated crosstalk between multiple cell types, signaling pathways, and mechanical forces of early blood flow. While both genetic and environmental factors have been recognized to be involved, identifying causal genes in non-syndromic CHD has been difficult. While variants following Mendelian inheritance have been identified by linkage analysis in a few families with multiple affected members, the inheritance pattern in most familial cases is complex, with reduced penetrance and variable expressivity. Furthermore, most non-syndromic CHD are sporadic. Improved sequencing technologies and large biobank collections have enabled genome-wide association studies (GWAS) in non-syndromic CHD. The ability to generate human to create human induced pluripotent stem cells (hiPSC) and further differentiate them to organotypic cells enables further exploration of genotype–phenotype correlations in patient-derived cells. Here we review how these technologies can be used in unraveling the genetics and molecular mechanisms of heart development.Peer reviewe

Premorbid functional status as an outcome predictor in intensive care patients aged over 85 years

Background Poor premorbid functional status (PFS) is associated with mortality after intensive care unit (ICU) admission in patients aged 80 years or older. In the subgroup of very old ICU patients, the ability to recover from critical illness varies irrespective of age. To assess the predictive ability of PFS also among the patients aged 85 or older we set out the current study. Methods In this nationwide observational registry study based on the Finnish Intensive Care Consortium database, we analysed data of patients aged 85 years or over treated in ICUs between May 2012 and December 2015. We defined PFS as good for patients who had been independent in activities of daily living (ADL) and able to climb stairs and as poor for those who were dependent on help or unable to climb stairs. To assess patients' functional outcome one year after ICU admission, we created a functional status score (FSS) based on how many out of five physical activities (getting out of bed, moving indoors, dressing, climbing stairs, and walking 400 m) the patient could manage. We also assessed the patients' ability to return to their previous type of accommodation. Results Overall, 2037 (3.3% of all adult ICU patients) patients were 85 years old or older. The average age of the study population was 87 years. Data on PFS were available for 1446 (71.0%) patients (good for 48.8% and poor for 51.2%). The one-year mortalities of patients with good and those with poor PFS were 29.2% and 50.1%, respectively, p < 0.001. Poor PFS increased the probability of death within 12 months, adjusted odds ratio (OR), 2.15; 95% confidence interval (CI) 1.68-2.76, p < 0.001. For 69.5% of survivors, the FSS one year after ICU admission was unchanged or higher than their premorbid FSS and 84.2% of patients living at home before ICU admission still lived at home. Conclusions Poor PFS doubled the odds of death within one year. For most survivors, functional status was comparable to the premorbid status.Peer reviewe

Prevalence of risk-drinking in critically ill patients, screened with carbohydrate-deficient transferrin and AUDIT-C score : A retrospective study

Background Studies demonstrate that up to one-third of intensive care unit (ICU) admissions are directly or indirectly related to alcohol. Screening for alcohol use is not routine. This study examined the prevalence of elevated %CDT (carbohydrate-deficient transferrin) and above risk-level AUDIT-C (Alcohol Use Disorders Identification Test, Consumption) in patients admitted to ICU. Methods We conducted a retrospective analysis of clinical and laboratory data from a single ICU where %CDT and AUDIT-C were included in routine assessment. After excluding readmissions, 2532 adult patients from a 21-month period were included. Admission values of %CDT were available for 2049 patients, and AUDIT-C was available for 1617 patients. The association of %CDT and AUDIT-C with short- and long-term outcome was studied by using univariate and multivariate logistic regression analysis. Results %CDT was above the reference value in 23.7% (486/2048) of patients with available %CDT. Of patients with available AUDIT-C, 33% (544/1617) had a risk-level AUDIT-C score. Patients with a risk-level AUDIT-C score were significantly younger than those with a lower score (51 vs 64 years, P <.0001). Increased %CDT was associated with higher severity of illness. AUDIT-C was associated independently with increased risk of long-term mortality in multivariate analysis (P = .007). Conclusion One in three of ICU patients are risk-level alcohol users as measured with AUDIT-C score, and one in four are analysed with %CDT. The prevalence varies according to the method used and any method alone may be insufficient to detect risk-level consumption reliably. Editorial Comment Alcohol overconsumption is associated with need for ICU admission and with less favorable outcomes. Diagnosis of alcohol overconsumption though is problematic due to low sensitivity in screening. In a pilot study, a biomarker and a screening tool are compared. The finding is that multiple tools are needed to achieve an adequate sensitivity for detection.Peer reviewe

Overlooking the Obvious during the COVID-19 Pandemic : Dyspnoea with Asymmetric Breath Sounds in a Toddler

Background. Paediatric healthcare specialists are concerned about the secondary effects of the COVID-19 pandemic on children. We report a case of acute respiratory distress in a healthy toddler whose healthcare providers were sidetracked from the correct diagnosis by suspicion of COVID-19. Case Presentation. The patient was a 20-month-old healthy boy. In the morning, he had coughed while drinking milk. He was asymptomatic for the day but presented with acute respiratory distress when lying down in the evening. An ambulance was called, and he was taken to a tertiary hospital's paediatric emergency department, where his condition and oxygen saturation fluctuated. He had mildly elevated temperature and petechiae on his trunk, showed asymmetrical radiographic and auscultatory pulmonary findings, and did not tolerate any exertion. Pneumonia was suspected, SARS-CoV-2 was considered as potential causative agent, and the child was admitted to a Paediatric Intensive Care Unit. As the patient did not show clear signs of infection or bronchial obstruction, the events were thoroughly rediscussed with the caregiver next morning. It was then found out that the child had also been eating cashew nuts. Multiple pieces of cashew nuts were removed from the left bronchial tree in a bronchoscopy. After the procedure, all symptoms promptly resolved. Foreign body aspiration-an obvious cause of acute respiratory distress in our patient's age group-was overlooked by experienced emergency medical care providers and paediatric critical care physicians due to the slightly unusual presentation, incomplete anamnestic information, and a bias to consider COVID-19 in the current exceptional circumstances. Conclusions. Emergency care providers are instructed to consider all patients with respiratory distress as potential COVID-19 patients. However, the clinical course of COVID-19 infection is usually mild in children. Therefore, alternative causes for serious breathing difficulty are more likely, and all differential diagnoses should be considered in the usual unbiased manner.Peer reviewe

NSE concentrations and haemolysis after cardiac arrest

Non peer reviewe