Organ support therapy in the intensive care unit and return to work: a nationwide,register-based cohort study

Purpose

The association between severity of illness and ability to return to work is unclear. Therefore, we investigated return to work and associations with measures of illness severity in ICU survivors.

Methods

We conducted this cohort study using Danish registry data for the period 2005–2014 on ICU patients who were discharged alive from hospital, had an ICU length of stay (LOS) of at least 72 h, were not treated with dialysis before hospital admission and were working prior to admission. We assessed (1) the cumulative incidence (chance) of return to work (2005–2017) and receipt of social benefits after discharge from a hospital stay with ICU admission and (2) the association between organ support therapies (renal replacement therapy, cardiovascular support and mechanical ventilation), and during 2011–2014 SAPS II and ICU LOS, and return to work, using multivariable Cox regression.

Results

Among 5762 ICU survivors, 68% returned to work within 2 years after hospital discharge. Disability and sickness benefits constituted 89% of social benefits among patients not returning to work and 59% among patients withdrawing from work following an initial return to work. Mechanical ventilation (HR 0.70, 95% CI [0.65–0.77]), but not RRT (HR 0.85, 95% CI [0.71–1.02]), cardiovascular support (HR 0.93, 95% CI [0.82–1.07]) and increasing SAPS II, was associated with decreased chance of return to work. Increasing ICU LOS was also associated with a decreased chance of return to work.

Conclusions

The majority of a nationwide cohort of ICU survivors returned to work. Sick leave and receipt of disability pension were common following ICU admission. Mechanical ventilation and longer ICU LOS were associated with reduced chances of return to work.

     

Genome-wide nucleosome map and cytosine methylation levels of an ancient human genome

Epigenetic information is available from contemporary organisms, but is difficult to track back in evolutionary time. Here, we show that genome-wide epigenetic information can be gathered directly from next-generation sequence reads of DNA isolated from ancient remains. Using the genome sequence data generated from hair shafts of a 4000-yr-old Paleo-Eskimo belonging to the Saqqaq culture, we generate the first ancient nucleosome map coupled with a genome-wide survey of cytosine methylation levels. The validity of both nucleosome map and methylation levels were confirmed by the recovery of the expected signals at promoter regions, exon/intron boundaries, and CTCF sites. The top-scoring nucleosome calls revealed distinct DNA positioning biases, attesting to nucleotide-level accuracy. The ancient methylation levels exhibited high conservation over time, clustering closely with modern hair tissues. Using ancient methylation information, we estimated the age at death of the Saqqaq individual and illustrate how epigenetic information can be used to infer ancient gene expression. Similar epigenetic signatures were found in other fossil material, such as 110,000- to 130,000-yr-old bones, supporting the contention that ancient epigenomic information can be reconstructed from a deep past. Our findings lay the foundation for extracting epigenomic information from ancient samples, allowing shifts in epialleles to be tracked through evolutionary time, as well as providing an original window into modern epigenomics.Ancient DNA research started in the mid-1980s with the successful cloning and sequencing of a short mitochondrial DNA fragment from the quagga zebra, a species that became extinct in the early 20th century (Higuchi et al. 1984). Soon after, the invention of PCR unlocked access to this fragmented and degraded DNA material (Pääbo 1989), making it possible to amplify short gene markers of interest and compare their sequence to that from extant organisms. This illuminated a range of topics ranging from the reconstruction of the evolutionary origins of several now-extinct iconic mammals (Orlando et al. 2003; Krause et al. 2006), the evaluation of the possible role played by major past climatic changes in driving mega-fauna extinctions (Shapiro et al. 2004; Campos et al. 2010; Lorenzen et al. 2011), to the identification of the pathogens responsible for massive historical outbreaks (Taubenberger et al. 1997).However, before the advent of next-generation sequencing (NGS) platforms, the amount of ancient sequence information one had access to was limited to several tens of thousands of nucleotides at best (Noonan et al. 2005, 2006), and until very recently, sequencing whole ancient mitochondrial genomes was considered a major achievement (Cooper et al. 2001; Krause et al. 2006). Parallel sequencing of millions to billions of short DNA fragments has revolutionized ancient DNA research, and today a series of ancient genomes has been reconstructed from humans (Rasmussen et al. 2010, 2011; Keller et al. 2012; Raghavan et al. 2013), archaic hominins (Green et al. 2010; Reich et al. 2010; Meyer et al. 2012), the woolly mammoth (Miller et al. 2008), and several microbial pathogens (Bos et al. 2011; Martin et al. 2013; Schuenemann et al. 2013; Yoshida et al. 2013). Those mainly date back to recent historical periods or the Late Pleistocene, but most recently, the characterization of a 560,000- to 780,000-yr-old horse draft genome revealed that genomic information could be retrieved over much longer evolutionary time scales, probably up until the last million years (Orlando et al. 2013).Ancient genomes have provided important new insights into human evolution and dispersals (Rasmussen et al. 2010, 2011; Keller et al. 2012; Raghavan et al. 2013), revealing an admixture between contemporary human ancestors and archaic hominins (Green et al. 2010; Reich et al. 2010; Meyer et al. 2012) and multiple early human expansions into both Asia and North America (Rasmussen et al. 2010, 2011). The information gained from these samples has largely been limited to nucleotide polymorphisms. Unlike mutations, epigenetic modifications do not alter the underlying DNA sequence, but can be inherited across cell divisions and from parents to offspring and can control gene expression by reshaping cytosine methylation landscapes, nucleosome organization, and histone modification patterns. The range of biological processes that depend on some level of epigenetic regulation is diverse and includes imprinting (Bird 2002), transposition (Hollister and Gaut 2009), cell differentiation (Meissner et al. 2008), and cancer (Teschendorff et al. 2011). In this study, we use the Saqqaq genome that was retrieved from an ∼4000-yr-old tuft of hair of a Paleo-Eskimo from Greenland and sequenced to an average depth of 20× (Rasmussen et al. 2010). We demonstrate that NGS data can be used in the absence of bisulfite or further experimental treatment to directly infer genome-wide nucleosome organization and regional methylation levels, thereby providing the first survey of an ancient epigenome.     

Neonatal outcome in a Danish national cohort of 3438 IVF/ICSI and 10,362 non-IVF/ICSI twins born between 1995 and 2000

BACKGROUND: In Denmark, one-third of twin pregnancies are the result of IVF/ICSI treatment. Limited data on neonatal outcome in IVF/ICSI twins are available in the literature. METHODS: A register study was conducted on neonatal morbidity and mortality in a complete national twin cohort including all 3438 (3393 live-born) IVF/ICSI and 10,362 (10,239 live-born) non-IVF/ICSI twins born between 1995 and 2000. Twins were identified in the National Medical Birth Registry and dichotomized into IVF/ICSI and non-IVF/ICSI by cross-reference with the Danish IVF Registry. Data on neonatal morbidity and mortality were retrieved from the Danish Patient Registry and the Danish Registry of Causes of Deaths. In order to exclude monozygotic twins, sub-analyses on unlike-sex twins were conducted. RESULTS: A birth weight discordance of >20% was observed in 20.6% of IVF/ICSI versus 15.7% of control twin pairs (P < 0.001). The risk of discordant birth weight >20% was OR 1.29 (95% CI 1.04-1.58) in unlike-sex IVF/ICSI twins versus control twins. The risk of delivery at <37 completed weeks and birth weight <2500 g was similar in the two cohorts; however, in unlike-sex IVF/ICSI versus control twins the risk of delivery at <37 weeks and birth weight <2500 g was OR 1.22 (95% CI 1.09-1.38) and OR 1.25 (1.11-1.40) respectively. After stratification for maternal age and parity, these risks disappeared. IVF/ICSI twins carried a higher risk of admittance to a neonatal intensive care unit (NICU) than control twins (OR 1.18, 95% CI 1.09-1.27), and this was even more pronounced in unlike-sex twins [OR 1.34 (95% CI 1.19-1.51)]. No differences were observed in malformation or mortality rates between the two cohorts. CONCLUSIONS: Despite higher birth weight discordance and more NICU admissions among IVF/ICSI twins, neonatal outcome in IVF/ICSI twins seems to be comparable with that of non-IVF/ICSI twins, when only dizygotic twins were considered in the comparisons.     

Hypocapnia during hypoxic exercise and its impact on cerebral oxygenation,ventilation and maximal whole body O2 uptake

With hypoxic exposure ventilation is elevated through the hypoxic ventilatory response. We tested the hypothesis that the resulting hypocapnia reduces maximal exercise capacity by decreasing (i) cerebral blood flow and oxygenation and (ii) the ventilatory drive.     

Standardized simulated palpation training – Development of a Palpation Trainer and assessment of palpatory skills in experienced and inexperienced clinicians

Specific palpation skills are required to identify and treat myofascial pain. The aim of this study was to develop a device that reflects absolute pressure values during simulated palpation, and to test the hypothesis that training through standardized manual palpation results in improved skills for experienced and inexperienced examiners. Experienced (n = 30) and inexperienced (n = 30) examiners were randomly divided into either training or control. A device (Palpation Trainer) was constructed to measure pressure intensity (P_peak) and rate of pressure development (RPD). Training consisted of 8–10 min standardized simulated palpation, during which examiners followed a standardized pressure–time curve (visualized in real-time on a pc-monitor). Controls received no training. Tests were performed at baseline, immediately post training and again after 48 h and analyzed for P_peak and RPD. After simulated palpation training, experienced examiners improved palpatory skills related to P_peak and RPD (i.e. performed closer to predetermined guidelines and with reduced inter-examiner variation), while inexperienced examiners only improved RPD (p < 0.05). Thus, standardized training resulted in acute and temporary (48 h) changes in selected analysis variables during simulated palpation in experienced and to some extent also in inexperienced clinicians. Whether this can be transferred to clinical in vivo setting requires further study.     

Psychiatric caseness is a marker of major depressive episode in general practice

Objective

Screening for a major depressive episode (MDE) in high-risk groups of patients within the primary care setting has been suggested by several Central Health Organizations. The objective of this study was to investigate whether patients rated as “psychiatric cases” by their general practitioner (GP) were likely to suffer from MDE and therefore qualified for systematic diagnostic screening.

Design

Cross-sectional survey of primary care patients assessed through depression screening questionnaires and GP consultations.

Setting

A total of 676 general practices in Denmark, Finland, Norway, and Sweden.

Subjects

A total of 8879 unselected primary care patients.

Main outcome measures

Sensitivity, specificity, and Youden Index of the GPs'' diagnoses of depression and psychiatric caseness versus patients'' MDE status.

Results

The proportion of primary care patients receiving a false-positive diagnosis of depression by their GP ranged from 12.4% to 25.2% depending on country. The corresponding numbers for the false-negative diagnoses were 0.5–2.5%. Among patients with MDE, GPs recognize the disease in 56–75% of cases. However, GPs recognize as many as 79–92% of patients with MDE as “psychiatric cases”.

Conclusions

This report confirms that misclassifications of MDE are common in the primary care setting. In addition, it shows that psychiatric caseness is a valid marker for the presence of MDE in primary care patients. This relationship should be considered in future screening recommendations.Key Words: Depression, diagnosis, family practice, mass screening, questionnairesPatients with a major depressive episode (MDE) are often overlooked in the primary care setting. Central Health Organizations suggest screening for MDE in high-risk categories of primary care patients. This study investigated whether patients rated as “psychiatric cases” by their GPs were likely to suffer from MDE and therefore qualified for systematic diagnostic screening.

• Misclassifications of MDE were common in the present sample of primary care patients.
• Among primary care patients with MDE, general practitioners (GPs) recognized the disease in 56–75% of the cases.
• Up to 92% of patients with MDE were identified as psychiatric cases by their GP. This relationship should be considered in future screening recommendations.

Major depressive episode (MDE) is the most common mental disorder in primary care [1]. General practitioners (GPs) play a crucial role in detecting and treating mental disorders, including MDE [2]. Diagnosis and treatment of MDE in primary care remains a difficult challenge for GPs and misclassifications are common. There are two types of misclassifications of MDE, namely false negative (patients meeting MDE criteria, but who are not recognized as depressed by their GPs) and false positive (perceived to suffer from MDE by the GPs without fulfilling the MDE criteria) [3–7]. These misclassifications have obvious adverse effects for the patients and procedures to minimize their likelihood of occurrence are required. The purpose of this study was to examine the GPs'' diagnostic capability in relation to MDE and to evaluate whether patients rated as “psychiatric cases” by their GP were likely to suffer from MDE.