Life after extracorporeal membrane oxygenation : long-term survival and quality of life

Background: The use of Extracorporeal membrane oxygenation (ECMO) has steadily increased in the last decades and has evolved in several ways. From originally being a means to support the neonatal patient with respiratory or circulatory failure for days to weeks, ECMO is now mainly used in paediatric and adult patients. Survival after ECMO varies depending on the underlying condition, and survival to discharge and 6-12 months has been readily reported in the literature. Likewise, quality-of-life and health status are well-investigated in the 3-24-month period after discharge. However, there is a paucity of data concerning long-term outcomes several years after ECMO treatment. Aim: To identify long-term survival and causes of death in ECMO treated patients (study I and II), and to investigate the long-term health and mental status after treatment, including cognitive functions and brain radiographic findings (study III), pulmonary function, pulmonary morphology, mood disorders and quality of life (study IV). Overview of methods: Using the Swedish national causes of death registry, study I and II attained survival status and causes of death in all commonly treated patient groups at the ECMO Centre of the Karolinska University Hospital. Survival was depicted using the Kaplan-Meier technique. For study III and IV, a retrospective cohort was created by contacting consecutive long-term adult survivors, starting with the first adult survivor treated at the centre. Thirty-eight patients treated with ECMO for respiratory failure were investigated. This included magnetic resonance imaging of the brain and extensive neurocognitive tests (study III), followed by computed tomography of the lungs, spirometry, a six-minute walk test and self-reported forms of quality of life and mood symptoms (study IV, including Short form 36, St George’s respiratory questionnaire, Hospital anxiety and depression scale and Trauma screening questionnaire). Summary of research results: Survival status in 255 adults was investigated in median 4.4 years after treatment (study I). The mortality was high in the first three months after treatment (17% of the ECMO survivors died in the first 90 days). This time point served as a cut-off to define late survival. In patients who were alive at 90 days, 87% were alive five years later. Long-term survival differed between groups and was highest in patients treated for a known or suspected infectious disease. In study II, 400 children were investigated in median 7.2 years after treatment. Similar to the results in adults, there was high 90-day mortality, and 93% of neonates and 89% of paediatric patients were alive 10 years later in the group who survived to this time point. Patients who died generally had severe comorbidities or an underlying disease which caused deterioration later in life. Brain lesions were seen in 37% of the long-term survivors (14/38, study III). In the group treated with venoarterial ECMO, 64% had signs of brain lesions. General intelligence depicted as the full-scale intelligence quotient (normal mean 100, SD 15) was 97 in median (IQR 86-104). In patients with brain lesions, the median full-scale intelligence quotient was 88, compared to 102 in patients with normal brain imaging (p=0.28). Memory functions and executive functions, also reported as indices with a normal mean of 100 and a SD of 15, were significantly reduced in patients with brain lesions (p=0.03 and 0.02, respectively). Patients with hypoxaemia during ECMO treatment, defined as <93% pulse oximetry haemoglobin saturation in median during ECMO treatment (or the first 10 days if treated for a long time) had similar intelligence as patients with normoxaemia. Quality of life was reduced in the present cohort, but the results were similar to previously published data on patients with acute respiratory distress syndrome not treated with ECMO. A reduction in diffusion capacity was seen in 47% of the patients, and lung function varied greatly between patients. Lung parenchymal damage was common, in mean 7% of the parenchyma was damaged (range 0-44%). In 50% of the patients, this damage was predominantly localised anteriorly, possibly indicating ventilator-induced lung injury. Parenchymal damage correlated with time on ECMO and time with mechanical ventilation, and with reductions in quality of life and diffusion capacity

Global visibility for global health: Is it time for a new descriptor in Medical Subject Heading (MeSH) of MEDLINE/PubMed?

Despite a large body of research in global health (almost 9000 articles published in PubMed until 2012), the term “global health” is not included in the Medical Subject Headings (MeSH) of the NLM – its controlled vocabulary thesaurus which NLM uses to index articles in MEDL INE. There are only 6 journals currently covered by PubMed which specialize in global health, including Journal of Global Health

Graft-versus-host disease and treatment with mesenchymal stromal cells

Graft-versus-host disease of both the acute (aGvHD) and chronic (cGvHD) variety remains a major cause of mortality and morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). During the last 15 years, mesenchymal stromal cells (MSC) have been explored as a promising new treatment for aGvHD, but there are many questions to be answered in this young field. The aim of this thesis is to expand our understanding of MSC treatment and GvHD with a specific focus on safety, factors affecting the outcome of MSC therapy and the possibility of treating also cGvHD with MSC. In paper I we performed a long-term follow up study of the first patients treated with MSC, and reported on their outcome. We demonstrated a high frequency of infections and recommend the use of prophylactic drugs and close surveillance of patients during and following MSC treatment. Regarding factors affecting the outcome, we reported an association between low passage MSC and better clinical outcome, indicating that MSC lose some of their potency with extensive culturing. In paper II, we analysed autopsy reports and tissue samples from patients treated with MSC and could demonstrate that MSC do not appear to engraft in the patients. The risk of malignant transformation of donated MSC should therefore be very low. In paper III we demonstrated a correlation between vitamin D deficiency prior to HSCT and an increased incidence of cGvHD, indicating vitamin D deficiency as a possible risk factor for cGvHD. Paper IV reports on a clinical trial of MSC therapy in refractory cGvHD. Eleven patients were included; of whom nine received up to six repeated infusions of MSC and could be evaluated for response. Of these nine, six patients responded to MSC therapy with durable improvement in cGvHD symptoms and could significantly reduce systemic immunosuppression. To summarize, this thesis provides new data regarding the safety of MSC therapy and suggests that the use of MSC is relatively safe, provided that necessary precautions are taken regarding infectious complications. With this information at hand, we could move forward to expanding the use of MSC in conditions with less dire expectations than refractory aGvHD, such as cGvHD. The clinical study of MSC therapy in cGvHD is one of the largest reported worldwide and suggests that repeated infusions of MSC could be a valuable treatment option for these patients

Moment conditions in strong laws of large numbers for multiple sums and random measures

The validity of the strong law of large numbers for multiple sums $S_n$ of independent identically distributed random variables $Z_k$, $k\leq n$, with $r$-dimensional indices is equivalent to the integrability of $|Z|(\log^+|Z|)^{r-1}$, where $Z$ is the typical summand. We consider the strong law of large numbers for more general normalisations, without assuming that the summands $Z_k$ are identically distributed, and prove a multiple sum generalisation of the Brunk--Prohorov strong law of large numbers. In the case of identical finite moments of irder $2q$ with integer $q\geq1$, we show that the strong law of large numbers holds with the normalisation $\|n_1\cdots n_r\|^{1/2}(\log n_1\cdots\log n_r)^{1/(2q)+\varepsilon}$ for any $\varepsilon>0$. The obtained results are also formulated in the setting of ergodic theorems for random measures, in particular those generated by marked point processes.Comment: 15 page

Adaptive Covariance Estimation with model selection

We provide in this paper a fully adaptive penalized procedure to select a covariance among a collection of models observing i.i.d replications of the process at fixed observation points. For this we generalize previous results of Bigot and al. and propose to use a data driven penalty to obtain an oracle inequality for the estimator. We prove that this method is an extension to the matricial regression model of the work by Baraud

Plasma signaling factors in patients with langerhans cell histiocytosis (LCH) correlate with relative frequencies of LCH cells and t cells within lesions

Langerhans cell histiocytosis (LCH) lesions contain an inflammatory infiltrate of immune cells including myeloid-derived LCH cells. Cell-signaling proteins within the lesion environment suggest that LCH cells and T cells contribute majorly to the inflammation. Foxp3+ regulatory T cells (Tregs) are enriched in lesions and blood from patients with LCH and are likely involved in LCH pathogenesis. In contrast, mucosal associated invariant T (MAIT) cells are reduced in blood from these patients and the consequence of this is unknown. Serum/plasma levels of cytokines have been associated with LCH disease extent and may play a role in the recruitment of cells to lesions. We investigated whether plasma signaling factors differed between patients with active and non-active LCH. Cell-signaling factors (38 analytes total) were measured in patient plasma and cell populations from matched lesions and/or peripheral blood were enumerated. This study aimed at understanding whether plasma factors corresponded with LCH cells and/or LCH-associated T cell subsets in patients with LCH. We identified several associations between plasma factors and lesional/circulating immune cell populations, thus highlighting new factors as potentially important in LCH pathogenesis. This study highlights plasma cell-signaling factors that are associated with LCH cells, MAIT cells or Tregs in patients, thus they are potentially important in LCH pathogenesis. Further study into these associations is needed to determine whether these factors may become suitable prognostic indicators or therapeutic targets to benefit patients. Copyright © 2022 Mitchell, Kvedaraite, von Bahr Greenwood, Lourda, Henter, Berzins and Kannourakis

Screening for neurodegeneration in Langerhans cell histiocytosis with neurofilament light in plasma

Patients with Langerhans cell histiocytosis (LCH) may develop progressive neurodegeneration in the central nervous system (ND-CNS-LCH). Neurofilament light protein (NFL) in cerebrospinal fluid (CSF) is a promising biomarker to detect and monitor ND-CNS-LCH. We compared paired samples of NFL in plasma (p-NFL) and CSF in 10 patients (19 samples). Nine samples had abnormal CSF-NFL (defined as ≥380 ng/l) with corresponding p-NFL ≥ 2 ng/l. Ten samples had CSF-NFL < 380 ng/l; eight (80%) with p-NFL < 2 ng/l (p < 0.001; Fisher's exact test). Thus, our results suggest that p-NFL may be used to screen for ND-CNS-LCH. Further studies are encouraged, including the role of p-NFL for monitoring of ND-CNS-LCH

Abrupt changes of temperature and water chemistry in the late Pleistocene and early Holocene Black Sea

Author Posting. © American Geophysical Union, 2008. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 9 (2008): Q01004, doi:10.1029/2007GC001683.New Mg/Ca, Sr/Ca, and published stable oxygen isotope and 87Sr/86Sr data obtained on ostracods from gravity cores located on the northwestern Black Sea slope were used to infer changes in the Black Sea hydrology and water chemistry for the period between 30 to 8 ka B.P. (calibrated radiocarbon years). The period prior to 16.5 ka B.P. was characterized by stable conditions in all records until a distinct drop in δ 18O values combined with a sharp increase in 87Sr/86Sr occurred between 16.5 and 14.8 ka B.P. This event is attributed to an increased runoff from the northern drainage area of the Black Sea between Heinrich Event 1 and the onset of the Bølling warm period. While the Mg/Ca and Sr/Ca records remained rather unaffected by this inflow; they show an abrupt rise with the onset of the Bølling/Allerød warm period. This rise was caused by calcite precipitation in the surface water, which led to a sudden increase of the Sr/Ca and Mg/Ca ratios of the Black Sea water. The stable oxygen isotopes also start to increase around 15 ka B.P., although in a more gradual manner, due to isotopically enriched meteoric precipitation. While Sr/Ca remains constant during the following interval of the Younger Dryas cold period, a decrease in the Mg/Ca ratio implies that the intermediate water masses of the Black Sea temporarily cooled by 1–2°C during the Younger Dryas. The 87Sr/86Sr values drop after the cessation of the water inflow at 15 ka B.P. to a lower level until the Younger Dryas, where they reach values similar to those observed during the Last Glacial Maximum. This might point to a potential outflow to the Mediterranean Sea via the Sea of Marmara during this period. The inflow of Mediterranean water started around 9.3 ka B.P., which is clearly detectable in the abruptly increasing Mg/Ca, Sr/Ca, and 87Sr/86Sr values. The accompanying increase in the δ 18O record is less pronounced and would fit to an inflow lasting ∼100 a.This research was funded by the DFG grants LA 1273/2-1, LA 1273/2, and WE 992/47-3. RCOM 0517