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Abstract Atrial fibrillation (AF) is a common arrhythmia encountered in acute and critical illness and is associated with poor short and long-term outcomes. Given the consequences of developing AF, research into prevention, prediction and treatment of this arrhythmia in the critically ill are of great potential benefit, however, study of AF in critically ill patients faces unique challenges, leading to a sparse evidence base to guide management in this population. Major obstacles to the study of AF in acute and critical illness include absence of a common definition, challenges in designing studies that capture complex etiology and assess causality, lack of a clear outcome set, difficulites in recruitment in acute environments with respect to timing, consent, and workflow, and failure to embed studies into clinical care platforms and capitalize on emerging technologies. Collaborative effort by researchers, clinicians, and stakeholders should be undertaken to address these challenges, both through interdisciplinary cooperation for the optimization of research efficiency and advocacy to advance the understanding of this common and complex arrhythmia, resulting in improved patient care and outcomes. The Symposium on Atrial Fibrillation in Acute and Critical Care was convened to address some of these challenges and propose potential solutions.

Abstract Background Chromosome organization plays an important role in biological processes such as replication, regulation, and transcription. One way to study the relationship between chromosome structure and its biological functions is through Hi-C studies, a genome-wide method for capturing chromosome conformation. Such studies generate vast amounts of data. The problem is exacerbated by the fact that chromosome organization is dynamic, requiring snapshots at different points in time, further increasing the amount of data to be stored. We present a novel approach called the High-Efficiency Contact Matrix Compressor (HiCMC) for efficient compression of Hi-C data. Results By modeling the underlying structures found in the contact matrix, such as compartments and domains, HiCMC outperforms the state-of-the-art method CMC by approximately 8% and the other state-of-the-art methods cooler, LZMA, and bzip2 by over 50% across multiple cell lines and contact matrix resolutions. In addition, HiCMC integrates domain-specific information into the compressed bitstreams that it generates, and this information can be used to speed up downstream analyses. Conclusion HiCMC is a novel compression approach that utilizes intrinsic properties of contact matrix, such as compartments and domains. It allows for a better compression in comparison to the state-of-the-art methods. HiCMC is available at https://github.com/sXperfect/hicmc .

Abstract Background Rhabdomyolysis describes a syndrome characterized by muscle necrosis and the subsequent release of creatine kinase and myoglobin into the circulation. Myoglobin elimination with extracorporeal hemoadsorption has been shown to effectively remove myoglobin from the circulation. Our aim was to provide best practice consensus statements developed by the Hemoadsorption in Rhabdomyolysis Task Force (HRTF) regarding the use of hemadsorption for myoglobin elimination. Methods A systematic literature search was performed until 11th of January 2023, after which the Rhabdomyolysis RTF was assembled comprising international experts from 6 European countries. Online conferences were held between 18th April − 4th September 2023, during which 37 consensus questions were formulated and using the Delphi process, HRTF members voted online on an anonymised platform. In cases of 75 to 90% agreement a second round of voting was performed. Results Using the Delphi process on the 37 questions, strong consensus (> 90% agreement) was achieved in 12, consensus (75 to 90% agreement) in 10, majority (50 to 74%) agreement in 13 and no consensus ( 10,000 ng/ml should be considered for extracorporeal myoglobin removal by hemoadsorption; (3) Hemoadsorption should ideally be started within 24 h of admission; (4) If myoglobin cannot be measured then hemoadsorption may be indicated based on clinical picture and creatinine kinase levels; (5) Cartridges should be replaced every 8–12 h until myoglobin levels

Abstract Background Paediatric oncology/haematology patients and their families are confronted with a life-threatening situation for which music therapy can be a cross-linguistic field of action. The creative act of making music together offers the possibility to strengthen competences and make conflicts tangible. Besides its complementing of evidence-based biomedical care, there is little research on the feasibility and efficacy of interactive music therapy including the diagnosed child and their significant others. Methods We conducted an assessor blind, prospective, multicentric feasibility randomized controlled trial (RCT) with subsequent intervention. Including overall 52 child-significant other dyads, INMUT investigates interaction-focused music therapy with cancer-affected children and their significant others (INMUT-KB; n = 21) compared to music therapy only with the child (MUT-K; n = 21) and a wait-list group (WLG; n = 10). The measurement points include the screening for a cancer diagnosis, psychometric baseline (pre-T1), initial assessment (T1/T2), music therapy sessions (T3–T9), final assessment (T10), final psychometric evaluation (post-T10), and 3-month follow-up (cat-T11). Feasibility and acceptability of the (1) research methodology, (2) intervention and (3) estimation of effect sizes will be assessed using qualitative and quantitative data. The proposed primary outcome includes the parent–child interaction (APCI), and the proposed secondary outcomes refer to subjective goal achievement (GAS), quality of life (KINDL), system-related functional level (EXIS), psychosocial stress (BAS), psychosomatic complaints (SCL-9k), and resources (WIRF). We plan to investigate the efficacy of INMUT-KB and MUT-K post-intervention (post-T10) within the RCT design and at 3-month follow-up (cat-T11). Discussion This study will provide insights into the feasibility of INMUT and the final sample needed for a confirmatory RCT. We will reflect on successfully implemented study procedures and, if necessary, provide recommendations for changes considering the design, procedures, measures, and statistical analyses. The discussion will conclude with an evaluation whether a confirmatory RCT is worth the investment of future resources, including the calculated number of child-significant other dyads needed based on the efficacy trends derived from this feasibility study. Trial registration ClinicalTrials.gov: NCT05534282; date of registration: June 23, 2022.

Abstract Background During the COVID-19 pandemic, many intensive care units (ICUs) halted research to focus on COVID-19-specific studies. Objective To describe the conduct of an international randomized trial of stress ulcer prophylaxis (Re-Evaluating the Inhibition of Stress Erosions in the ICU [REVISE]) during the pandemic, addressing enrolment patterns, center engagement, informed consent processes, data collection, a COVID-specific substudy, patient transfers, and data monitoring. Methods REVISE is a randomized trial among mechanically ventilated patients, comparing pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important upper gastrointestinal bleeding and the primary safety outcome of 90-day mortality. We documented protocol implementation status from March 11th 2020-August 30th 2022. Results The Steering Committee did not change the scientific protocol. From the first enrolment on July 9th 2019 to March 10th 2020 (8 months preceding the pandemic), 267 patients were enrolled in 18 centers. From March 11th 2020-August 30th 2022 (30 months thereafter), 41 new centers joined; 59 were participating by August 30th 2022 which enrolled 2961 patients. During a total of 1235 enrolment-months in the pandemic phase, enrolment paused for 106 (8.6%) months in aggregate (median 3 months, interquartile range 2;6). Protocol implementation involved a shift from the a priori consent model pre-pandemic (188, 58.8%) to the consent to continue model (1615, 54.1%, p

Abstract Background The REVISE (Re-Evaluating the Inhibition of Stress Erosions in the ICU) trial will evaluate the impact of the proton pump inhibitor pantoprazole compared to placebo in invasively ventilated critically ill patients. Objective To outline the statistical analysis plan for the REVISE trial. Methods REVISE is a randomized clinical trial ongoing in intensive care units (ICUs) internationally. Patients ≥ 18 years old, receiving invasive mechanical ventilation, and expected to remain ventilated beyond the calendar day after randomization are allocated to either 40 mg pantoprazole intravenously or placebo while mechanically ventilated. Results The primary efficacy outcome is clinically important upper GI bleeding; the primary safety outcome is 90-day mortality. Secondary outcomes are ventilator-associated pneumonia, Clostridioides difficile infection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine concentration, and duration of mechanical ventilation, ICU, and hospital length of stay. Following an interim analysis of results from 2400 patients (50% of 4800 target sample size), the data monitoring committee recommended continuing enrolment. Conclusions This statistical analysis plan outlines the statistical analyses of all outcomes, sensitivity analyses, and subgroup analyses. REVISE will inform clinical practice and guidelines worldwide. Trial registration www.ClinicalTrials.gov NCT03374800. November 21, 2017.

Abstract Background Critically ill patients commonly receive proton pump inhibitors (PPIs) to prevent gastrointestinal (GI) bleeding from stress-induced ulceration. Despite widespread use in the intensive care unit (ICU), observational data suggest that PPIs may be associated with adverse outcomes in patients with COVID-19 infection. This preplanned study is nested within a large randomized trial evaluating pantoprazole versus placebo in invasively ventilated patients. The 3 objectives are as follows: (1) to describe the characteristics of patients with COVID-19 in terms of demographics, biomarkers, venous thromboembolism, tracheostomy incidence and timing, and other clinical outcomes; (2) to evaluate the impact of COVID-19 infection on clinically important GI bleeding, 90-day mortality, and other outcomes compared to a propensity-matched non-infected cohort; and (3) to explore whether pantoprazole has a differential treatment effect on clinically important GI bleeding, 90-day mortality, and other outcomes in patients with and without COVID-19 infection. Methods The ongoing trial Re-EValuating the Inhibition of Stress Erosions (REVISE) compares pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important GI bleeding and the primary safety outcome of 90-day mortality. The protocol described in this report is for a substudy focused on patients with COVID-19 infection that was not in the original pre-pandemic trial protocol. We developed a one-page case report form to characterize these patients including data related to biomarkers, venous thromboembolism, COVID-19 therapies, tracheostomy incidence and timing, duration of mechanical ventilation, and ICU and hospital stay. Our analysis will describe the trajectory of patients with COVID-19 infection, a propensity-matched analysis of infected and non-infected patients, and an extended subgroup analysis comparing the effect of PPI among patients with and without COVID-19 infection. Discussion Prophylactic acid suppression in invasively ventilated critically ill patients with COVID-19 infection has unknown consequences. The results of these investigations will inform practice, guidelines, and future research. Trial registration REVISE Trial [NCT03374800 December 15, 2017], COVID-19 Cohort Study [NCT05715567 February 8, 2023].

Abstract Background The Cohen-Mansfield Agitation Inventory-Short Form (CMAI-SF) is a 14-item scale for assessing agitation and aggression, derived from the original 29-item CMAI, and completed by a proxy. Because the CMAI-SF has not yet been validated in German language, the aim of this study is to explore its construct validity. Methods Baseline data from a cluster-randomized trial to evaluate a non-pharmacological complex intervention for people living with dementia (PlwD) and mild cognitive impairment (MCI) were analyzed. The study sample consisted of 97 shared-housing arrangements (SHAs) in Germany, comprising N = 341 residents with mild to severe dementia and MCI. Trained nursing staff collected data by proxy-rating the CMAI-SF, Neuropsychiatric Inventory-Nursing Home Version (NPI-NH), and QUALIDEM. They also conducted the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Results In an exploratory factor analysis, three factors emerged: “aggressive behavior”, “verbally agitated behavior”, and “physically non-aggressive behavior”. The CMAI-SF total score showed good internal consistency (α = .85), and the factors themselves showed adequate internal consistency (α = .75/.76/.73). The CMAI-SF showed convergent validity with the NPI-NH agitation item (r = .66) and the NPI-NH “agitation & restless behavior” factor (r = .82). Discriminant validity was confirmed by a low (r = .28) correlation with the NPI-NH apathy item. Quality of life decreased significantly with agitation, as the CMAI-SF showed a moderate negative correlation with the QUALIDEM total score (r = -.35). Conclusions The 14-item CMAI-SF is a time-efficient, reliable, and valid assessment instrument. Three factors emerged that were similar to those already found in nursing home samples for the original CMAI and the CMAI-SF and in day care samples for the CMAI-SF. The findings provide preliminary evidence that the CMAI-SF can be used instead of the CMAI to reduce time, costs, and burden in future trials. Trial registration The DemWG study from which data were used to draft this manuscript was prospectively registered on 16 July 2019 at ISRCTN registry (ISRCTN89825211).

Abstract Background The identification of dyadic subgroups of individuals living with dementia and their informal caregivers can help to design effective tailored support. In a previous German study, we identified six dementia dyad subgroups by applying Latent Class Analysis (LCA). Results showed sociodemographic heterogeneity as well as differences in health care outcomes (i.e., quality of life, health status, caregiver burden) between subgroups. The objective of this study is to determine if the dyad subgroups from the previous analysis can be replicated in a similar but distinct Dutch sample. Methods A LCA 3-step procedure was applied to baseline data from the COMPAS study, a prospective cohort study. LCA is a statistical approach used to identify heterogeneous subgroups within populations based on their pattern of answers on a set of categorical variables. Data comprises 509 community-living individuals with predominantly mild to moderate dementia and their informal caregivers. A narrative analysis was used to compare latent class structures of the original versus the replication study. Results Six distinct dementia dyad subgroups were identified: A subgroup of “adult–child-parent relation with younger informal caregiver” (31.8%), a “couple with female informal caregiver of older age” group (23.1%), an “adult–child-parent relation with middle-aged informal caregiver” group (14.2%), a “couple with middle-aged female informal caregiver” group (12.4%), a “couple with older male informal caregiver” group (11.2%) and a “couple with middle-aged male informal caregiver” group (7.4%). Quality of life of individuals with dementia was rated better in couples than in adult–child-relationships. Worst health for caregivers was reported by subgroups with female informal caregivers living together with male individuals with dementia in couple relationships. A subgroup with older female informal caregivers in couple relationships report the most severe burden on physical and mental health. In both studies, a model with six subgroups fitted the data best. Although substantive similarities between the subgroups of both studies appeared, considerable differences are also evident. Conclusion This replication study confirmed the existence of informal dementia dyad subgroups. The observed differences between the subgroups provide useful contributions for a more tailored health care services for informal caregivers and individuals living with dementia. Furthermore, it underlines the relevance of dyadic perspectives. To facilitate replication studies and increase the validity of evidence, a standardization of collected data across studies would be beneficial.

Abstract Critical illness is a continuum, but patient care is often fragmented. Value-based critical care focuses on the overall health of the patient, not on an episode of care. The “ICU without borders” model incorporates a concept where members of the critical care team are involved in the management of patients from the onset of critical illness until recovery and beyond. In this paper, we summarise the potential benefits and challenges to patients, families, staff and the wider healthcare system and list some essential requirements, including a tight governance framework, advanced technologies, investment and trust. We also argue that “ICU without borders” should be viewed as a bi-directional model, allowing extended visiting hours, giving patients and families direct access to experienced critical care staff and offering mutual aid when needed.

Abstract Background High dose vasopressors portend poor outcome in vasodilatory shock. We aimed to evaluate the impact of baseline vasopressor dose on outcomes in patients treated with angiotensin II (AT II). Methods Exploratory post-hoc analysis of the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial data. The ATHOS-3 trial randomized 321 patients with vasodilatory shock, who remained hypotensive (mean arterial pressure of 55–70 mmHg) despite receiving standard of care vasopressor support at a norepinephrine-equivalent dose (NED) > 0.2 µg/kg/min, to receive AT II or placebo, both in addition to standard of care vasopressors. Patients were grouped into low (≤ 0.25 µg/kg/min; n = 104) or high (> 0.25 µg/kg/min; n = 217) NED at the time of study drug initiation. The primary outcome was the difference in 28-day survival between the AT II and placebo subgroups in those with a baseline NED ≤ 0.25 µg/kg/min at the time of study drug initiation. Results Of 321 patients, the median baseline NED in the low-NED subgroup was similar in the AT II (n = 56) and placebo (n = 48) groups (median of each arm 0.21 µg/kg/min, p = 0.45). In the high-NED subgroup, the median baseline NEDs were also similar (0.47 µg/kg/min AT II group, n = 107 vs. 0.45 µg/kg/min placebo group, n = 110, p = 0.75). After adjusting for severity of illness, those randomized to AT II in the low-NED subgroup were half as likely to die at 28-days compared to placebo (HR 0.509; 95% CI 0.274–0.945, p = 0.03). No differences in 28-day survival between AT II and placebo groups were found in the high-NED subgroup (HR 0.933; 95% CI 0.644–1.350, p = 0.71). Serious adverse events were less frequent in the low-NED AT II subgroup compared to the placebo low-NED subgroup, though differences were not statistically significant, and were comparable in the high-NED subgroups. Conclusions This exploratory post-hoc analysis of phase 3 clinical trial data suggests a potential benefit of AT II introduction at lower doses of other vasopressor agents. These data may inform design of a prospective trial. Trial registration: The ATHOS-3 trial was registered in the clinicaltrials.gov repository (no. NCT02338843). Registered 14 January 2015.

Abstract Background In recent years, advances in high-throughput sequencing technologies have enabled the use of genomic information in many fields, such as precision medicine, oncology, and food quality control. The amount of genomic data being generated is growing rapidly and is expected to soon surpass the amount of video data. The majority of sequencing experiments, such as genome-wide association studies, have the goal of identifying variations in the gene sequence to better understand phenotypic variations. We present a novel approach for compressing gene sequence variations with random access capability: the Genomic Variant Codec (GVC). We use techniques such as binarization, joint row- and column-wise sorting of blocks of variations, as well as the image compression standard JBIG for efficient entropy coding. Results Our results show that GVC provides the best trade-off between compression and random access compared to the state of the art: it reduces the genotype information size from 758 GiB down to 890 MiB on the publicly available 1000 Genomes Project (phase 3) data, which is 21% less than the state of the art in random-access capable methods. Conclusions By providing the best results in terms of combined random access and compression, GVC facilitates the efficient storage of large collections of gene sequence variations. In particular, the random access capability of GVC enables seamless remote data access and application integration. The software is open source and available at https://github.com/sXperfect/gvc/ .

Abstract Background Non-pharmacologic treatments such as physical therapy (PT) are advocated for musculoskeletal pain. Early access to PT through self-referral has been shown to decrease costs and improve outcomes. Although self-referral is permitted in most U.S. states and supported by some health insurance plans, patients’ utilization of self-referral remains low. Objective To identify factors, beyond legislative policies and health insurance, associated with patients’ decisions to access physical therapy through self-referral or provider-referral. Methods We recruited 26 females and 6 males whose employer-sponsored insurance benefits included financial incentives for self-referral to physical therapy. Between August 2017 and March 2018, participants completed semi-structured interviews about their beliefs about physical therapy and reasons for choosing self-referral (15 participants) or provider referral (17 participants) for accessing physical therapy. Grounded theory approach was employed to identify themes in the data. Results Patients selecting self-referral reported major thematic differences compared to the provider-referral patients including knowledge of the direct access program, attitudes and beliefs about physical therapy and pharmacologic treatment, and prior experiences with physical therapy. Self-referral patients were aware that their plan benefits included reduced cost for self-referral and felt confident in selecting that pathway. They also had negative beliefs about the effectiveness of pharmacological treatments and surgery, and previously had positive direct or indirect experiences with physical therapy. Conclusion Knowledge of the ability to self-refer, attitudes and beliefs about treatment, and prior experience with physical therapy were associated with self-referral to physical therapy. Interventions aimed at improving knowledge and changing attitudes toward self-referral to physical therapy to increase utilization appear warranted.

Abstract Although guidelines provide excellent expert guidance for managing patients with septic shock, they leave room for personalization according to patients’ condition. Hemodynamic monitoring depends on the evolution phase: salvage, optimization, stabilization, and de-escalation. Initially during the salvage phase, monitoring to identify shock etiology and severity should include arterial pressure and lactate measurements together with clinical examination, particularly skin mottling and capillary refill time. Low diastolic blood pressure may trigger vasopressor initiation. At this stage, echocardiography may be useful to identify significant cardiac dysfunction. During the optimization phase, echocardiographic monitoring should be pursued and completed by the assessment of tissue perfusion through central or mixed-venous oxygen saturation, lactate, and carbon dioxide veno-arterial gradient. Transpulmonary thermodilution and the pulmonary artery catheter should be considered in the most severe patients. Fluid therapy also depends on shock phases. While administered liberally during the resuscitation phase, fluid responsiveness should be assessed during the optimization phase. During stabilization, fluid infusion should be minimized. In the de-escalation phase, safe fluid withdrawal could be achieved by ensuring tissue perfusion is preserved. Norepinephrine is recommended as first-line vasopressor therapy, while vasopressin may be preferred in some patients. Essential questions remain regarding optimal vasopressor selection, combination therapy, and the most effective and safest escalation. Serum renin and the angiotensin I/II ratio may identify patients who benefit most from angiotensin II. The optimal therapeutic strategy for shock requiring high-dose vasopressors is scant. In all cases, vasopressor therapy should be individualized, based on clinical evaluation and blood flow measurements to avoid excessive vasoconstriction. Inotropes should be considered in patients with decreased cardiac contractility associated with impaired tissue perfusion. Based on pharmacologic properties, we suggest as the first test a limited dose of dobutamine, to add enoximone or milrinone in the second line and substitute or add levosimendan if inefficient. Regarding adjunctive therapies, while hydrocortisone is nowadays advised in patients receiving high doses of vasopressors, patients responding to corticosteroids may be identified in the future by the analysis of selected cytokines or specific transcriptomic endotypes. To conclude, although some general rules apply for shock management, a personalized approach should be considered for hemodynamic monitoring and support.

Abstract Background As circulating DNA (cirDNA) is mainly detected as mononucleosome-associated circulating DNA (mono-N cirDNA) in blood, apoptosis has until now been considered as the main source of cirDNA. The mechanism of cirDNA release into the circulation, however, is still not fully understood. This work addresses that knowledge gap, working from the postulate that neutrophil extracellular traps (NET) may be a source of cirDNA, and by investigating whether NET may directly produce mono-N cirDNA. Methods We studied (1) the in vitro kinetics of cell derived genomic high molecular weight (gHMW) DNA degradation in serum; (2) the production of extracellular DNA and NET markers such as neutrophil elastase (NE) and myeloperoxidase (MPO) by ex vivo activated neutrophils; and (3) the in vitro NET degradation in serum; for this, we exploited the synergistic analytical information provided by specifically quantifying DNA by qPCR, and used shallow WGS and capillary electrophoresis to perform fragment size analysis. We also performed an in vivo study in knockout mice, and an in vitro study of gHMW DNA degradation, to elucidate the role of NE and MPO in effecting DNA degradation and fragmentation. We then compared the NET-associated markers and fragmentation size profiles of cirDNA in plasma obtained from patients with inflammatory diseases found to be associated with NET formation and high levels of cirDNA (COVID-19, N = 28; systemic lupus erythematosus, N = 10; metastatic colorectal cancer, N = 10; and from healthy individuals, N = 114). Results Our studies reveal that gHMW DNA degradation in serum results in the accumulation of mono-N DNA (81.3% of the remaining DNA following 24 h incubation in serum corresponded to mono-N DNA); “ex vivo” NET formation, as demonstrated by a concurrent 5-, 5-, and 35-fold increase of NE, MPO, and cell-free DNA (cfDNA) concentration in PMA-activated neutrophil culture supernatant, leads to the release of high molecular weight DNA that degrades down to mono-N in serum; NET mainly in the form of gHMW DNA generate mono-N cirDNA (2 and 41% of the remaining DNA after 2 h in serum corresponded to 1–10 kbp fragments and mono-N, respectively) independent of any cellular process when degraded in serum; NE and MPO may contribute synergistically to NET autocatabolism, resulting in a 25-fold decrease in total DNA concentration and a DNA fragment size profile similar to that observed from cirDNA following 8 h incubation with both NE and MPO; the cirDNA size profile of NE KO mice significantly differed from that of the WT, suggesting NE involvement in DNA degradation; and a significant increase in the levels of NE, MPO, and cirDNA was detected in plasma samples from lupus, COVID-19, and mCRC, showing a high correlation with these inflammatory diseases, while no correlation of NE and MPO with cirDNA was found in HI. Conclusions Our work describes the mechanisms by which NET and cirDNA are linked. In doing so, we demonstrate that NET are a major source of mono-N cirDNA independent of apoptosis and establish a new paradigm of the mechanisms of cirDNA release in normal and pathological conditions. We also demonstrate a link between immune response and cirDNA.

Abstract Background Among critically ill patients with acute kidney injury (AKI), earlier initiation of renal replacement therapy (RRT) may mitigate fluid accumulation and confer better outcomes among individuals with greater fluid overload at randomization. Methods We conducted a pre-planned post hoc analysis of the STandard versus Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial. We evaluated the effect of accelerated RRT initiation on cumulative fluid balance over the course of 14 days following randomization using mixed models after censoring for death and ICU discharge. We assessed the modifying effect of baseline fluid balance on the impact of RRT initiation strategy on key clinical outcomes. Patients were categorized in quartiles of baseline fluid balance, and the effect of accelerated versus standard RRT initiation on clinical outcomes was assessed in each quartile using risk ratios (95% CI) for categorical variables and mean differences (95% CI) for continuous variables. Results Among 2927 patients in the modified intention-to-treat analysis, 2738 had available data on baseline fluid balance and 2716 (92.8%) had at least one day of fluid balance data following randomization. Over the subsequent 14 days, participants allocated to the accelerated strategy had a lower cumulative fluid balance compared to those in the standard strategy (4509 (− 728 to 11,698) versus 5646 (0 to 13,151) mL, p = 0.03). Accelerated RRT initiation did not confer greater 90-day survival in any of the baseline fluid balance quartiles (quartile 1: RR 1.11 (95% CI 0.92 to 1.34), quartile 2: RR 1.03 (0.87 to 1.21); quartile 3: RR 1.08 (95% CI 0.91 to 1.27) and quartile 4: RR 0.87 (95% CI 0.73 to 1.03), p value for trend 0.08). Conclusions Earlier RRT initiation in critically ill patients with AKI conferred a modest attenuation of cumulative fluid balance. Nonetheless, among patients with greater fluid accumulation at randomization, accelerated RRT initiation did not have an impact on all-cause mortality. Trial registration: ClinicalTrials.gov number, https://clinicaltrials.gov/ct2/show/NCT02568722 , registered October 6, 2015.

Abstract Background Timing of initiation of kidney-replacement therapy (KRT) in critically ill patients remains controversial. The Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial compared two strategies of KRT initiation (accelerated versus standard) in critically ill patients with acute kidney injury and found neutral results for 90-day all-cause mortality. Probabilistic exploration of the trial endpoints may enable greater understanding of the trial findings. We aimed to perform a reanalysis using a Bayesian framework. Methods We performed a secondary analysis of all 2927 patients randomized in multi-national STARRT-AKI trial, performed at 168 centers in 15 countries. The primary endpoint, 90-day all-cause mortality, was evaluated using hierarchical Bayesian logistic regression. A spectrum of priors includes optimistic, neutral, and pessimistic priors, along with priors informed from earlier clinical trials. Secondary endpoints (KRT-free days and hospital-free days) were assessed using zero–one inflated beta regression. Results The posterior probability of benefit comparing an accelerated versus a standard KRT initiation strategy for the primary endpoint suggested no important difference, regardless of the prior used (absolute difference of 0.13% [95% credible interval [CrI] − 3.30%; 3.40%], − 0.39% [95% CrI − 3.46%; 3.00%], and 0.64% [95% CrI − 2.53%; 3.88%] for neutral, optimistic, and pessimistic priors, respectively). There was a very low probability that the effect size was equal or larger than a consensus-defined minimal clinically important difference. Patients allocated to the accelerated strategy had a lower number of KRT-free days (median absolute difference of − 3.55 days [95% CrI − 6.38; − 0.48]), with a probability that the accelerated strategy was associated with more KRT-free days of 0.008. Hospital-free days were similar between strategies, with the accelerated strategy having a median absolute difference of 0.48 more hospital-free days (95% CrI − 1.87; 2.72) compared with the standard strategy and the probability that the accelerated strategy had more hospital-free days was 0.66. Conclusions In a Bayesian reanalysis of the STARRT-AKI trial, we found very low probability that an accelerated strategy has clinically important benefits compared with the standard strategy. Patients receiving the accelerated strategy probably have fewer days alive and KRT-free. These findings do not support the adoption of an accelerated strategy of KRT initiation.

Abstract Background Dementia is a multi-factorial condition rather than a natural and inevitable consequence of ageing. Some factors related to dementia have been studied much more extensively than others. To gain an overview of known or suspected influential factors is a prerequisite to design studies that aim to identify causal relationships and interactions between factors. This article aims to develop a visual model that a) identifies factors related to cognitive decline that signal the onset of dementia, b) structures them by different domains and c) reflects on and visualizes the possible causal links and interactions between these factors based on expert input using a causal loop diagram. Method We used a mixed-method, step-wise approach: 1. A systematic literature review on factors related to cognitive decline; 2. A group model building (GMB) workshop with experts from different disciplines; 3. Structured discussions within the group of researchers. The results were continuously synthesized and graphically transformed into a causal loop diagram. Results The causal loop diagram comprises 73 factors that were structured into six domains: physical (medical) factors (23), social health factors (21), psychological factors (14), environmental factors (5), demographic factors (5) and lifestyle factors (3). 57 factors were identified in the systematic literature review, additionally 16 factors, mostly of the social health cluster, were identified during the GMB session and the feedback rounds. Conclusion The causal loop diagram offers a comprehensive visualisation of factors related to cognitive decline and their interactions. It supports the generation of hypotheses on causal relationships and interactions of factors within and between domains.

Abstract Introduction The identification of typologies of health care users and their specific characteristics can be performed using cluster analysis. This statistical approach aggregates similar users based on their common health-related behavior. This study aims to examine health care utilization patterns using cluster analysis; and the associations of health care user types with sociodemographic, health-related and health-system related factors. Methods Cross-sectional data from the 2012 National Health Interview Survey were used. Health care utilization was measured by consultations with a variety of medical, allied and complementary health practitioners or the use of several interventions (exercise, diet, supplementation etc.) within the past 12 months (used vs. not used). A model-based clustering approach based on finite normal mixture modelling, and several indices of cluster fit were determined. Health care utilization within the cluster was analyzed descriptively, and independent predictors of belonging to the respective clusters were analyzed using logistic regression models including sociodemographic, health- and health insurance-related factors. Results Nine distinct health care user types were identified, ranging from nearly non-use of health care modalities to over-utilization of medical, allied and complementary health care. Several sociodemographic and health-related characteristics were predictive of belonging to the respective health care user types, including age, gender, health status, education, income, ethnicity, and health care coverage. Conclusions Cluster analysis can be used to identify typical health care utilization patterns based on empirical data; and those typologies are related to a variety of sociodemographic and health-related characteristics. These findings on individual differences regarding health care access and utilization can inform future health care research and policy regarding how to improve accessibility of different medical approaches.

Abstract Background Nursing home residents have high medical care needs. Their medical care utilization is, however, lower compared to community-dwelling elderly and varies widely among nursing homes. This study quantified the utilization of general practitioners (GPs), dentists, and medical specialists among nursing homes and residents, and investigated whether dentist utilization is associated with individual and nursing home characteristics. Methods Forty-four nursing homes invited 2124 residents to participate in a cross-sectional study. For 10 medical specialties, data on contacts in nursing homes, practices, and by telephone in the last 12 months were assessed at individual and nursing home level. The proportion of nursing homes and residents with any form of contact, and the median number and interquartile range (IQR) of contacts among individuals with contact were determined. Using multilevel logistic regression, associations between the probability of individual dental care utilization and sex, age, LTC grade, years of residence, sponsorship, number of nursing home beds, and transport and medical escort services for consultations at a practice were investigated. Results The proportion of nursing homes with any form of contact with physicians ranged from 100% for GPs, dentists, and urologists to 76.7% for gynecologists and orthopedists. Among the nursing homes, 442 residents participated (20.8% response). The proportion of residents with any contact varied from 97.8% for GPs, 38.5% for neurologists/psychiatrists, and 32.3% for dentists to 3.0% for gynecologists. Only for GPs, neurologists/psychiatrists, dentists, otorhinolaryngologists, urologists, and dermatologists, the proportion was higher for nursing home contacts than for practice and telephone contacts. Among residents with any contact, the median number of contacts was highest for GPs (11.0 [IQR 7.0-16.0]), urologists (4.0 [IQR 2.0-7.0]), and neurologists/psychiatrists (3.0 [IQR 2.0-5.0]). Dentist utilization varied widely among nursing homes (median odds ratio 2.5) and was associated with higher age. Conclusions Almost all residents had regular contact to GPs, but only one third had contact with dentists. Lower proportions with contact were found for medical specialists, except for neurologists/psychiatrists. Reasons for the large variations in dental care utilization among nursing homes should be identified. Trial registration DRKS00012383 [2017/12/06].

Abstract Background Multimorbidity poses a challenge for high quality primary care provision for nursing care-dependent people with (PWD) and without (PWOD) dementia. Evidence on the association of primary care quality of multimorbid PWD and PWOD with the event of a nursing home admission (NHA) is missing. This study aimed to investigate the contribution of individual quality of primary care for chronic diseases in multimorbid care-dependent PWD and PWOD on the duration of ongoing residence at home before the occurrence of NHA. Methods We conducted a retrospective cohort study among elderly care-dependent PWD and PWOD in Germany for six combinations of chronic diseases using statutory health insurance claims data (2007–2016). Primary care quality was measured by 21 process and outcome indicators for hypertension, diabetes, depression, chronic obstructive pulmonary disease and heart failure. The primary outcome was time to NHA after initial onset of care-dependency. Multivariable Cox proportional hazard models were used to compare the time-to-event between PWD and PWOD. Results Among 5876 PWD and 12,837 PWOD 5130 NHA occurred. With the highest proportion of NHA for PWD with hypertension and depression and for PWOD with hypertension, diabetes and depression. Average duration until NHA ranged from 6.5 to 8.9 quarters for PWD and from 9.6 to 13.5 quarters for PWOD. Adjusted analyses show consistent associations of the quality of diabetes care with the duration of remaining in one’s own home regardless of the presence of dementia. Process indicators assessing guideline-fidelity are associated with remaining in one’s home longer, while indicators assessing complications, such as emergency inpatient treatment (HR = 2.67, 95% CI 1.99–3.60 PWD; HR = 2.81, 95% CI 2.28–3.47 PWOD) or lower-limb amputation (HR = 3.10, 95% CI 1.78–5.55 PWD; HR = 2.81, 95% CI 1.94–4.08 PWOD) in PWD and PWOD with hypertension and diabetes, increase the risk of NHA. Conclusions The quality of primary care provided to care-dependent multimorbid PWD and POWD, influences the time individuals spend living in their own homes after onset of care-dependency before a NHA. Health care professionals should consider possibilities and barriers of guideline-based, coordinated care for multimorbid care-dependent people. Further research on quality indicator sets that acknowledge the complexity of care for multimorbid elderly populations is needed.

Abstract Purpose Antibiotics are one possible treatment for patients with recurrent acute throat infections (ATI), but effectiveness can be modest. In view of worries over antibiotic resistance, treatment pathways that reduce recurrence of ATI are essential from a public health perspective. Integrative treatment strategies can be an option but there is still a high demand to provide evidence of their cost effectiveness. Methods We constructed a 4-state Markov model to compare the cost-effectiveness of SilAtro-5-90 as adjuvant homeopathic therapy to care as usual with care as usual alone in reducing the recurrence of ATI for children and adults with suspected moderate recurrent tonsillitis. The analysis was performed from a societal perspective in Germany over a 2-year period. Results are reported separately for children < 12 and for individuals aged 12 and over. The model draws on evidence from a multi-centre randomised clinical trial that found this strategy effective in reducing recurrence of ATI. Costs in 2019 € and outcomes after 1 year are discounted at a rate of 3% per annum. Results For adults and adolescents aged 12 years and over, incremental cost per ATI averted in the adjuvant therapy group was €156.64. If individuals enter the model on average with a history of 3.33 previous ATIs, adjuvant therapy has both lower costs and better outcomes than care as usual. For children (< 12 years) adjuvant therapy had both lower costs and ATI than care as usual. The economic case is stronger if adjuvant treatment reduces surgical referral. At a hypothetical cost per ATI averted threshold of €1000 probabilistic sensitivity analysis suggests Silatro-5-90 has a 65% (adults) and 71% (children) chance of being cost-effective. Conclusion Our results indicate the importance of considering homeopathy as adjuvant therapy in the treatment of ATIs in individuals with recurrent tonsillitis from a socio-economic perspective. Further evaluation should assess how differences in uptake and sustained use of homeopathic adjuvant therapy, as well as changing patterns of antibiotic prescribing, impact on cost effectiveness.

Abstract This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2021. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2021 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901 .

Abstract Background Studies revealed the importance to assess dementia care dyads, composed of persons with dementia and their primary informal caregivers, in a differentiated way and to tailor support services to particular living and care circumstances. Therefore, this study aims first to identify classes of dementia care dyads that differ according to sociodemographic, care-related and dementia-specific characteristics and second, to compare these classes with regard to healthcare-related outcomes. Methods We used data from the cross-sectional German DemNet-D study (n = 551) and conducted a latent class analysis to investigate different classes of dementia care dyads. In addition, we compared these classes with regard to the use of health care services, caregiver burden (BIZA-D), general health of the informal caregiver (EQ-VAS) as well as quality of life (QoL-AD) and social participation (SACA) of the person with dementia. Furthermore, we compared the stability of the home-based care arrangements. Results Six different classes of dementia care dyads were identified, based on best Bayesian Information Criterion (BIC), significant likelihood ratio test (p

Abstract Background Cancer registries usually assess data of conventional treatments and/or patient survival. Beyond that, little is known about the influence of other predictors of treatment response related to the use of complementary therapies (CM) and lifestyle factors affecting patients’ quality and quantity of life. Methods INTREST is a prospective cohort study collecting register data at multiple German certified cancer centers, which provide individualized, integrative, in- and outpatient breast cancer care. Patient-reported outcomes and clinical cancer data of anticipated N = 715 women with pTNM stage I-III breast cancer are collected using standardized case report forms at the time of diagnosis, after completing neo−/adjuvant chemotherapy, after completing adjuvant therapy (with the exception of endocrine therapy) as well as 1, 2, 5, and 10 years after baseline. Endpoints for multivariable prediction models are quality of life, fatigue, treatment adherence, and progression-based outcomes/survival. Predictors include the study center, sociodemographic characteristics, histologic cancer and comorbidity data, performance status, stress perception, depression, anxiety, sleep quality, spirituality, social support, physical activity, diet behavior, type of conventional treatments, use of and belief in CM treatments, and participation in a clinical trial. Safety is recorded following the Common Terminology Criteria for Adverse Events. Discussion This trial is currently recruiting participants. Future analyses will allow to identify predictors of short- and long-term response to integrative breast cancer treatment in women, which, in turn, may improve cancer care as well as quality and quantity of life with cancer. Trial registration German Clinical Trial Register DRKS00014852 . Retrospectively registered at July 4th, 2018.

Abstract Background Postoperative acute kidney injury (PO-AKI) is a leading cause of short- and long-term morbidity and mortality, as well as progression to chronic kidney disease (CKD). The aim of this study was to explore the physicians’ attitude toward the use of perioperative serum creatinine (sCr) for the identification of patients at risk for PO-AKI and long-term CKD. We also evaluated the incidence and risk factors associated with PO-AKI and renal function deterioration in patients undergoing major surgery for malignant disease. Methods Adult oncological patients who underwent major abdominal surgery from November 2016 to February 2017 were considered for this single-centre, observational retrospective study. Routinely available sCr values were used to define AKI in the first three postoperative days. Long-term kidney dysfunction (LT-KDys) was defined as a reduction in the estimated glomerular filtration rate by more than 10 ml/min/m2 at 12 months postoperatively. A questionnaire was administered to 125 physicians caring for the enrolled patients to collect information on local attitudes regarding the use of sCr perioperatively and its relationship with PO-AKI. Results A total of 423 patients were observed. sCr was not available in 59 patients (13.9%); the remaining 364 (86.1%) had at least one sCr value measured to allow for detection of postoperative kidney impairment. Among these, PO-AKI was diagnosed in 8.2% of cases. Of the 334 patients who had a sCr result available at 12-month follow-up, 56 (16.8%) developed LT-KDys. Data on long-term kidney function were not available for 21% of patients. Interestingly, 33 of 423 patients (7.8%) did not have a sCr result available in the immediate postoperative period or long term. All the physicians who participated in the survey (83 out of 125) recognised that postoperative assessment of sCr is required after major oncological abdominal surgery, particularly in those patients at high risk for PO-AKI and LT-KDys. Conclusion PO-AKI after major surgery for malignant disease is common, but clinical practice of measuring sCr is variable. As a result, the exact incidence of PO-AKI and long-term renal prognosis are unclear, including in high-risk patients. Trial registration ClinicalTrials.gov , NCT04341974 .

Abstract Background People prefer to age in place and not move into a nursing home as long as possible. The prevention of cognitive and functional impairments is feasible to support this goal. Health services play a key role in providing support for underlying medical conditions. We examined differentials in nursing home admissions between patient sharing networks in Germany and whether potential variations can be attributed to indicators of health care provision. Methods We conducted an ecological study using data of patients of 65 years and above from all 11 AOK statutory health insurance companies in Germany. Nursing home admissions were observed in a cohort of persons becoming initially care-dependent in 2006 (n = 118,213) with a follow-up of up to 10 years. A patient sharing network was constructed and indicators for quality of health care were calculated based on data of up to 6.6 million patients per year. Community detection was applied to gain distinct patient populations. Analyses were conducted descriptively and through regression analyses to identify the variation explained by included quality indicators. Results The difference in the proportion of nursing home admissions between identified clusters shows an interquartile range (IQR) of 12.6% and the average time between onset of care-dependency and admission to a nursing home an IQR of 10,4 quarters. Included quality indicators attributed for 40% of these variations for the proportion of nursing home admissions and 49% for the time until nursing home admission, respectively. Indicators of process quality showed the single highest contribution. Effects of single indicators were inconclusive. Conclusions Health services can support persons in their preference to age in place. Research and discussion on adequate health care for care-dependent persons and on conditions, where nursing home admission may be beneficial, is necessary.

Abstract Background The impact of dementia for communication skills can result in difficulties in social interactions between people with dementia and their conversation partner, as initiating and maintaining conversations becomes increasingly challenging. The role of technology in enhancing social health and participation for people with dementia is increasing, but the use of technological devices to support social interactions and aid communication quality is still in its infancy. The objective of this literature review is to provide a comprehensive description of technology-driven interventions for people with dementia and their conversation partners to prompt communication and facilitate positive social interactions. Methods A systematic search was conducted using PubMed, CINAHL and PsycINFO, with titles and abstracts independently screened by two researchers. Quality appraisal of the included studies was assessed using the Mixed Methods Appraisal Tool. Results Of the 18 papers included, the technology most commonly used to facilitate communication and interactions was tablet-computers (n = 7), social robots (n = 5) and computers systems (n = 4). By analyzing the impact of the device(s) for social interaction and communication, four major themes emerged: i) breaking the ice; ii) increased interaction; iii) better understanding of the person with dementia; and iv) reduced pressure for the conversation partner. Conclusion While the majority of the included studies are small-scale, they indicate promising findings for the potential of technology to promote interaction in a way that relieves strain on the caregiver, enhances relationships and engages people with dementia in social activities. Rigorous investigation using standard, comparable measurements is needed to demonstrate the effects of technological solutions, as well as to explore and address barriers and potential adverse outcomes.

Abstract Background Informal caregivers of persons living with dementia have an increased risk of adverse mental health effects. It is therefore important to systematically summarize published literature in order to find out which mental health interventions generate effective support for informal caregivers of persons living with dementia. The objective of this study is to conduct a systematic review of intervention content, effectiveness and subgroup differentiation of mental health interventions for informal caregivers of persons with dementia living at home. Method We searched four electronic databases (PubMed, PsychINFO, Scopus and CINAHL) and included only methodically high-quality randomized controlled trials (RCTs), published in English or German language between 2009 and 2018. The intervention programmes focused on mental health of family caregivers. A narrative synthesis of the included studies is given. Results Forty-eight publications relating to 46 intervention programmes met the inclusion criteria. Burden, depression and quality of life (QoL) are the predominant parameters that were investigated. Twenty-five of forty-six interventions (54.3%) show positive effects on at least one of the outcomes examined. Most often, positive effects are reported for the outcome subjective burden (46.2%). Only six studies explicitly target on a certain subgroup of informal dementia caregivers (13%), whereas all other interventions (87%) target the group as a whole without differentiation. Conclusion The most beneficial results were found for cognitive behavioural approaches, especially concerning the reduction of depressive symptoms. Besides this, leisure and physical activity interventions show some good results in reducing subjective caregiver burden. In order to improve effectiveness, research and practice may focus on developing more targeted interventions for special dementia informal caregiver subgroups.

Abstract Background The EMiC2 membrane is a medium cut-off haemofilter (45 kiloDalton). Little is known regarding its efficacy in eliminating medium-sized cytokines in sepsis. This study aimed to explore the effects of continuous veno-venous haemodialysis (CVVHD) using the EMiC2 filter on cytokine clearance. Methods This was a prospective observational study conducted in critically ill patients with sepsis and acute kidney injury requiring kidney replacement therapy. We measured concentrations of 12 cytokines [Interleukin (IL) IL-1β, IL-1α, IL-2, IL-4, IL-6, IL-8, IL-10, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, vascular endothelial growth factor, monocyte chemoattractant protein (MCP)-1, epidermal growth factor (EGF)] in plasma at baseline (T0) and pre- and post-dialyzer at 1, 6, 24, and 48 h after CVVHD initiation and in the effluent fluid at corresponding time points. Outcomes were the effluent and adsorptive clearance rates, mass balances, and changes in serial serum concentrations. Results Twelve patients were included in the final analysis. All cytokines except EGF concentrations declined over 48 h (p

Abstract Background Despite the established relevance of ultrasonography and assessment of pressure pain thresholds in patients with plantar fasciopathy, patient and probe positioning has been mostly ignored and are not necessarily reported in research. The primary aim of this study was to compare plantar fascia thickness in stretched and relaxed positions in patients with plantar fasciopathy. The secondary aim was to compare plantar heel pressure pain thresholds in these positions. Methods In this cross-sectional study, we measured the plantar fascia thickness with ultrasonography, and localised pressure pain thresholds using pressure algometry of 20 patients with plantar fasciopathy. These were assessed bilaterally, with the plantar fascia in both a stretched and relaxed position. In the stretched position, toes were maximally dorsiflexed, while in the relaxed position participants’ feet were hanging freely over the end of the table. Results The plantar fascia of the most symptomatic foot was significantly thicker when stretched compared with the relaxed position (sagittal: mean difference 0.2 mm, 95%CI: 0.1–0.4, P = 0.013; frontal: mean difference − 0.27, 95%CI: − 0.49 to − 0.06, P = 0.014). The plantar fascia was significantly thinner in the frontal plane compared with the sagittal plane in both positions (stretched: mean difference − 0.2 mm, 95%CI: − 0.42 to − 0.03, P = 0.025; relaxed: mean difference − 0.3 mm, 95%CI:-0.49 to − 0.08, P = 0.008). There was no difference between pressure pain thresholds in stretched or relaxed positions in either foot (P > 0.4). Conclusions The plantar fascia was significantly thicker in a stretched compared with a relaxed position and in the sagittal compared with the frontal plane, but differences were smaller than the standard deviation. Pressure pain thresholds were not different between the positions. These results highlight the importance of how ultrasonography is performed and reported in research to allow for replication. Trial registration The study was pre-registered September 25th, 2017 on ClinicalTrials.gov ( NCT03291665 ).

Abstract Background Fluid overload is common in patients in the intensive care unit (ICU) and ultrafiltration (UF) is frequently required. There is lack of guidance on optimal UF practice. We aimed to explore patterns of UF practice, barriers to achieving UF targets, and concerns related to UF practice among practitioners working in Europe. Methods This was a sub-study of an international open survey with focus on adult intensivists and nephrologists, advanced practice providers, and ICU and dialysis nurses working in Europe. Results Four hundred eighty-five practitioners (75% intensivists) from 31 countries completed the survey. The most common criteria for UF initiation was persistent oliguria/anuria (45.6%), followed by pulmonary edema (16.7%). Continuous renal replacement therapy was the preferred initial modality (90.0%). The median initial and maximal rate of net ultrafiltration (UFNET) prescription in hemodynamically stable patients were 149 mL/hr. (IQR 100–200) and 300 mL/hr. (IQR 201–352), respectively, compared to a median UFNET rate of 98 mL/hr. (IQR 51–108) in hemodynamically unstable patients and varied significantly between countries. Two-thirds of nurses and 15.5% of physicians reported assessing fluid balance hourly. When hemodynamic instability occurred, 70.1% of practitioners reported decreasing the rate of fluid removal, followed by starting or increasing the dose of a vasopressor (51.3%). Most respondents (90.7%) believed in early fluid removal and expressed willingness to participate in a study comparing protocol-based fluid removal versus usual care. Conclusions There was a significant variation in UF practice and perception among practitioners in Europe. Future research should focus on identifying the best strategies of prescribing and managing ultrafiltration in critically ill patients.

Abstract Background Vaccine hesitancy has been recognized as an important barrier to timely vaccinations around the world, including in sub-Saharan Africa. In Tanzania, 1 in 4 children is not fully vaccinated. The objective of this mixed methods study was to describe and contextualize parental concerns towards vaccines in Tanzania. Methods Between 2016 and 2017, we conducted a cross-sectional survey (n = 134) and four focus group discussions (FGDs, n = 38) with mothers of children under 2 years of age residing in Mtwara region in Southern Tanzania. The survey and FGDs assessed vaccination knowledge and concerns and barriers to timely vaccinations. Vaccination information was obtained from government-issued vaccination cards. Results In the cross-sectional survey, 72% of mothers reported missed or delayed receipt of vaccines for their child. Although vaccine coverage was high, timeliness of vaccinations was lower and varied by vaccine. Rural mothers reported more vaccine-related concerns compared to urban mothers; literacy and access to information were identified as key drivers of the difference. Mothers participating in FGDs indicated high perceived risk of vaccine-preventable illnesses, but expressed concerns related to poor geographic accessibility, unreliability of services, and missed opportunities for vaccinations resulting from provider efforts to minimize vaccine wastage. Conclusions Findings from our cross-sectional survey indicate the presence of vaccination delays and maternal concerns related to childhood vaccines in Tanzania. In FGDs, mothers raised issues related to convenience more often than issues related to vaccine confidence or complacency. Further research is necessary to understand how these issues may contribute to the emergence and persistence of vaccine hesitancy and to identify effective mitigation strategies.

Abstract Background Integrative Medicine (IM) combines conventional and complementary therapies. It aims to address biological, psychological, social, spiritual and environmental aspects of patients’ health. During the past 20 years, the use and request of IM in children and adults has grown. Anthroposophic Medicine (AM) is an IM approach frequently used in children in Germany. From both public health and health economic perspectives, it is relevant to investigate whether there are differences in the resource utilization between integrative pediatric departments (IPD) and the entirety of all pediatric departments. Methods Standard ward documentation data from all German integrative anthroposophic pediatric departments (2005–2016; N = 29,956) is investigated and systematically compared to data of the entirety of all pediatric departments in Germany derived from the Institute for the Hospital Reimbursement System (2005–2016, N = 8,645,173). The analyses focus on: length of stay, Diagnosis Related Groups (DRG), Major Diagnosis Categories (MDC), and effective Case Mix Index (CMI). Results The length of stay in the IPD (M = 5.38 ± 7.31) was significantly shorter than the DRG defined length of stay (M = 5.8 ± 4.71; p

Abstract Background Most older people, and especially those in need of long-term care, suffer from one or more chronic diseases. Consequently, older people have an increased need of medical care, including specialist care. There is little evidence as yet whether older people with greater medical care needs obtain adequate medical care because existing studies do not sufficiently control for differences in morbidity. In this study we investigate whether differences in medical specialist utilization exist between older people with and without assessed long-term care need in line with Book XI of the German Social Code, while at the same time controlling for individual differences in morbidity. Methods We used data from the 11 German AOK Statutory Health and Long-term Care Insurance funds of 100,000 members aged 60 years or over. Zero-inflated Poisson regression analyses were applied to investigate whether the need for long-term care and the long-term care setting are associated with the probability and number of specialist visits. We controlled for age, gender, morbidity and mortality, residential density, and general practitioner (GP) utilization. Results Older people in need of long-term care are more likely to have no specialist visit than people without the need for long-term care. This applies to nearly all medical specialties and for both care settings. Yet, despite these differences in utilization probability the number of specialist medical care visits between older people with and without the need for long-term care is similar. Conclusion Older people in need of long-term care might face access barriers to specialist care. Once a contact is established, however, utilization does not differ considerably between those who need long-term care and those who don’t; this indicates the importance of securing an initial contact.

Abstract Background Delirium is an acute confusional state, common in critical illness and associated with cognitive decline. There is no effective pharmacotherapy to prevent or treat delirium, although it is scientifically plausible that thiamine could be effective. Thiamine studies in dementia patients are inconclusive. Aside from small numbers, all used oral administration: bioavailability of thiamine is poor; parenteral thiamine bypasses this. In the UK, parenteral thiamine is administered as a compound vitamin B and C solution (Pabrinex®). The aim of this review is to evaluate the effectiveness of parenteral thiamine (alone or in a compound solution) in preventing or treating delirium in critical illness. Methods We will search for studies in electronic databases (MEDLINE (Pro-Quest), EMBASE, CINAHL, LILACS, CNKI, AMED, and Cochrane CENTRAL), clinical trials registries (WHO International Clinical Trials Registry, ClinicalTrials.gov , and Controlled-trials.com ), and grey literature (Google Scholar, conference proceedings, and Index to Theses). We will perform complementary searches of reference lists of included studies, relevant reviews, clinical practice guidelines, or other pertinent documents (e.g. official documents and government reports). We will consider quasi-randomised or randomised controlled trials in critically ill adults. We will include studies that evaluate parenteral thiamine versus standard of care, placebo, or any other non-pharmacological or pharmacological interventions. The primary outcomes will be the delirium core outcome set, including incidence and severity of delirium and cognition. Secondary outcomes are adapted from the ventilation core outcome set: duration of mechanical ventilation, length of stay, and adverse events incidence. Screening, data extraction, and risk of bias assessment will be undertaken independently by two reviewers. If data permits, we will conduct meta-analyses using a random effects model and, where appropriate, sensitivity and subgroup analyses to explore sources of heterogeneity. Discussion This review will provide evidence for the effectiveness of parental thiamine in the prevention or treatment of delirium in critical care. Findings will contribute to establishing the need for a multicentre study of parenteral thiamine in the prevention and treatment of critical care delirium. Systematic review registration PROSPERO CRD42019118808

Abstract Background Fluid overload is associated with morbidity and mortality in patients receiving renal replacement therapy (RRT). We aimed to explore whether fluid overload at initiation of RRT was independently associated with mortality and whether changes in cumulative fluid balance during RRT were associated with outcome. Methods We retrospectively analysed the data of patients who were admitted to the multidisciplinary adult intensive care unit (ICU) in a tertiary care centre in the UK between 2012 and 2015 and received continuous RRT (CRRT) for acute kidney injury for at least 24 h. We collected baseline demographics, body mass index (BMI), comorbidities, severity of illness, laboratory parameters at CRRT initiation, daily cumulative fluid balance (FB), daily prescribed FB target, fluid bolus and diuretic administration and outcomes. The day of the lowest cumulative FB during CRRT was identified as nadir FB. Results Eight hundred twenty patients were analysed (median age 65 years; 49% female). At CRRT initiation, the median cumulative FB was + 1772 ml; 89 patients (10.9%) had a cumulative FB > 10% body weight (BW). Hospital survivors had a significantly lower cumulative FB at CRRT initiation compared to patients who died (1495 versus 2184 ml; p

Abstract Background Digital nursing technologies (DNT) comprise an expanding, highly diverse field of research, explored using a wide variety of methods and tools. Study results are therefore difficult to compare, which raises the question how effectiveness of DNT can be adequately measured. Methods currently used might not be sufficient for certain specific nursing contexts. A comprehensive outcome framework that shows the multitude of possible outcome areas could be useful to generate more comparable results. The aim of the present study is to develop an outcome framework for DNT and to indicate which outcome areas have been most frequently evaluated in previous studies and how this has been done. Methods We combined an inductive and deductive approach to develop the framework. The numerical analysis is based on a scoping review focussing on the effectiveness of DNT for persons in need of care, formal or informal caregivers or care institutions. Nine databases were included in the screening: Medline, Scopus, CINAHL, Cochrane Library, ACM Digital Library, IEEE Xplore, the Collection of Computer Science Bibliographies, GeroLit and CareLit. Additional literature searches and expert interviews were included. Results The developed framework comprises four outcome target groups and 47 outcome areas. There are considerable differences in the researched outcome areas for the individual outcome target groups. Persons in need of care were by far the most frequently surveyed, particularly with respect to their psychological health. There are much fewer studies on formal and informal caregivers, and it is particularly noticeable that the quality of life of both groups has rarely been investigated. Care process quality was most frequently researched for organisations. Conclusion We were able to provide a comprehensive DNT outcome framework, thereby identifying the outcome tools used and the less researched outcome areas. We recommend a detailed investigation of all areas and tools in future research projects with a view to initiating a discussion on the differing importance of existing outcome areas and on a standardisation of outcome tools. We also recommend the development of outcome areas for the macro level of effectiveness assessment.

Abstract Background In patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe vasodilation, provide novel insights into its biology, and predict clinical outcomes. The objective of these protocol prespecified and subsequent post hoc analyses was to assess the epidemiology and outcome associations of plasma ANG I and ANG II levels and their ratio in patients with catecholamine-resistant vasodilatory shock (CRVS) enrolled in the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study. Methods We measured ANG I and ANG II levels at baseline, calculated their ratio, and compared these results to values from healthy volunteers (controls). We dichotomized patients according to the median ANG I/II ratio (1.63) and compared demographics, clinical characteristics, and clinical outcomes. We constructed a Cox proportional hazards model to test the independent association of ANG I, ANG II, and their ratio with clinical outcomes. Results Median baseline ANG I level (253 pg/mL [interquartile range (IQR) 72.30–676.00 pg/mL] vs 42 pg/mL [IQR 30.46–87.34 pg/mL] in controls; P

Abstract Background Elderly in need of long-term care tend to have worse health and have higher need of medical care than elderly without need for long-term care. Yet, characteristics associated with long-term care need can impede health care access: Higher levels of long-term care need come with physical and cognitive decline such as frailty and memory loss. Yet, it has not been investigated whether level of long-term care need is related to medical care utilization. Methods We investigated the association between the level of long-term care and medical specialist utilization among nursing home residents and home care recipients. We applied zero-inflated Poisson regression with robust standard errors based on a sample of statutory health insurance members. The sample consisted of 100.000 elderly over age 60. We controlled for age, gender, morbidity and mortality, residential density, and general practitioner utilization. Results We found a strong gradient effect of the level of long-term care for 9 out of 12 medical specialties: A higher level of long-term care need was associated with a lower probability of having a medical specialist visit. Yet, we did not find clear effects of the level of long-term care need on the intensity of medical specialist care. These findings were similar for both the nursing home and home care setting. Conclusion The findings indicate that inequalities in medical specialist utilization exist between elderly with differing levels of long-term care need because differences in morbidity were controlled for. Elderly with higher need of long-term care might face more access barriers to specialist medical care.

Abstract Background Integrative medicine (IM) is a patient-centered, evidence-based, therapeutic paradigm which combines conventional and complementary approaches. The use of IM in pediatrics has increased in the past two decades and parents’ demand for it is growing. An IM whole systems approach is anthroposophic medicine. Considering the growing demand for integrative approaches in children, it is relevant from a public health perspective to find out which kind of children use IM in Germany and whether they differ from the entirety of pediatric inpatients in Germany. Moreover, it would be interesting to known, whether these patients are willing to travel a longer distance to gain integrative treatment. Methods The present study investigates the standard ward documentation datasets of 29,956 patients of all German integrative anthroposophic pediatric inpatient wards from 2005 to 2016 and compares them systematically to collect data of the entirety of all pediatric inpatient wards in Germany. Apart from patients’ age and gender, and the ICD-10 admission diagnoses, the geographical catchment area of the hospitals were analyzed. Results Sociodemographic characteristics of pediatric inpatients in the integrative anthroposophic departments (IAH) did not differ from the entirety of all pediatric inpatients. Regarding clinical characteristics, higher frequencies were found for endocrine, nutritional and metabolic diseases (IAH: 7.24% vs. 2.98%); mental, behavioral, and neurodevelopmental disorders (IAH: 9.83% vs. 3.78%) and nervous diseases (IAH: 8.82% vs. 5.16%) and lower frequencies for general pediatric diseases such as respiratory diseases (IAH: 17.06% vs. 19.83%), digestive diseases (IAH: 3.90% vs. 6.25%), and infectious and parasitic diseases (IAH: 12.88% vs. 14.82%) in comparison to the entirety of all pediatric inpatients in Germany. The IAH showed a broad catchment area, with most patients being from former, Western federal republic of Germany. Large catchment areas (> 100 km) for the IAH are merely covered by severe and chronic diseases. Conclusion Pediatric inpatients of IAH do not differ from the entirety of pediatric inpatients in Germany regarding sociodemographic characteristics but show differences regarding clinical characteristics. Parents are willing to travel further distance to get specialized integrative anthroposophic medical care for children with severe and chronic diseases.

Abstract Background Acute kidney injury (AKI) is common in patients in the intensive care unit (ICU) and may be present on admission or develop during ICU stay. Our objectives were (a) to identify factors independently associated with the development of new AKI during early stay in the ICU and (b) to determine the risk factors for non-recovery of AKI. Methods We retrospectively analysed prospectively collected data of patients admitted to a multi-disciplinary ICU in a single tertiary care centre in the UK between January 2014 and December 2016. We identified all patients without AKI or end-stage renal failure on admission to the ICU and compared the outcome and characteristics of patients who developed AKI according to KDIGO criteria after 24 h in the ICU with those who did not develop AKI in the first 7 days in the ICU. Multivariable logistic regression was applied to identify factors associated with the development of new AKI during the 24–72-h period after admission. Among the patients with new AKI, we identified those with full, partial or no renal recovery and assessed factors associated with non-recovery. Results Among 2525 patients without AKI on admission, the incidence of early ICU-acquired AKI was 33.2% (AKI I 41.2%, AKI II 35%, AKI III 23.4%). Body mass index, Sequential Organ Failure Assessment score on admission, chronic kidney disease (CKD) and cumulative fluid balance (FB) were independently associated with the new development of AKI. By day 7, 69% had fully recovered renal function, 8% had partial recovery and 23% had no renal recovery. Hospital mortality was significantly higher in those without renal recovery. Mechanical ventilation, diuretic use, AKI stage III, CKD, net FB on first day of AKI and cumulative FB 48 h later were independently associated with non-recovery with cumulative fluid balance having a U-shape association. Conclusions Early development of AKI in the ICU is common and mortality is highest in patients who do not recover renal function. Extreme negative and positive FB were strong risk factors for AKI non-recovery.

Abstract Background This study aims to evaluate the feasibility and efficacy of a complex health intervention, based on the combination of conventional Western medicine and traditional Chinese medicine (TCM), in an outpatient department of a university hospital for patients with frequent episodic or chronic tension-type headaches. Methods/design This is a prospective randomized controlled pilot study with four balanced treatment arms (usual care, acupuncture, training, and training plus acupuncture). Each arm will have 24 patients. After the initial screening examination and randomization, a 6-week treatment period follows, with treatment frequencies decreasing at 2-week intervals. After completion of the intervention, two follow-up evaluations will be performed 3 and 6 months after the start of treatment. At predefined times, the various outcomes (pain intensity, health-related quality of life, pain duration, autonomic regulation, and heart rate variability) as well as the participants’ acceptance of the complex treatment will be evaluated with valid assessment instruments (Migraine Disability Assessment, PHQ-D, GAD-7, and SF-12) and a headache diary. The acupuncture treatment will be based on the rules of TCM, comprising a standardized combination of acupuncture points and additional points selected according to individual pain localization. The training therapy comprises a combination of strength training, endurance training, and training to improve flexibility and coordination. Besides descriptive analyses of the samples, their comparability will be assessed using an analysis of variance (ANOVA) or chi-squared tests. Analyses will be performed on an intention-to-treat basis. Potential interaction effects will be calculated using a repeated-measures ANOVA to test the primary and secondary hypotheses. In supplementary analyses, the proportion of treatment responders (those with a 50% reduction in the frequency of pain episodes) will be determined for each treatment arm. Discussion This trial may provide evidence for the additive effects of acupuncture and medical training therapy as a combination treatment and may scientifically support the implementation of this complex health intervention. Trial registration Registered on 11 Feburary 2019. German Clinical Trials Register, DRKS00016723.

Abstract Background Vaccination is a cost-effective strategy for reducing morbidity and mortality among children under 5 years old. To be fully protected from diseases such as tuberculosis, diphtheria, pertussis, and polio, children must receive all recommended vaccinations in a timely manner. In many countries, including Tanzania, high overall vaccination rates mask substantial regional variation in vaccination coverage and low rates of vaccination timeliness. This study evaluates the efficacy of mobile phone-based (mHealth) reminders and incentives for improving vaccination timeliness in the first year of life. Methods The study, conducted in Mtwara Region in Tanzania, includes 400 late-stage pregnant women enrolled from rural and urban health facilities and surrounding communities. The primary outcome is timeliness of vaccinations among their children at 6, 10, and 14 weeks after birth. Timeliness is defined as vaccination receipt within 28 days after the vaccination due date. The quasi-randomized controlled trial includes three arms: (1) standard of care (no reminders or incentives), (2) mobile phone-based reminders, and (3) mobile phone-based reminders and incentives in the form of conditional financial transfers. Assignment into study arms is based on scheduled vaccination dates. Reminder messages are sent to arms 2 and 3 participants via mobile phones 1 week and 1 day prior to each scheduled vaccination. For arm 3 participants, reminder messages offer an incentive that is provided in the form of a mobile phone airtime recharge voucher code for each timely vaccination. Vaccination dates are recorded via participant contact with an mHealth system, phone calls with mothers, and a review of government-issued vaccination cards during an end-line survey. Random effects logistic regression models will be used to estimate the effects of reminders and incentives on the timeliness of vaccinations. Discussion The results will inform implementation science research on the effectiveness of reminders and incentives as a means of improving vaccination timeliness. Trial registration ClinicalTrials.gov, NCT03252288. Registered on 17 August 2017 (retrospectively registered).

Abstract Background The existence, usage and benefits of digital technologies in nursing care are relevant topics in the light of the current discussion on technologies as possible solutions to problems such as the shortage of skilled workers and the increasing demand for long-term care. A lack of good empirical overviews of existing technologies in the present literature prompted us to conduct this review. Its purpose was to map the field of digital technologies for informal and formal care that have already been explored in terms of acceptance, effectiveness and efficiency (AEE), and to show the scope of the used methods, target settings, target groups and fields of support. Methods A systematic literature search was conducted using Medline, Scopus, CINAHL, Cochrane Library, ACM Digital Library, IEEE Xplore, the Collection of Computer Science Bibliographies, GeroLit and CareLit. In addition, project websites were manually screened for relevant publications. Results Seven hundred fifteen papers were included in the review. Effectiveness studies have been most frequently performed for ICT, robots and sensors. Acceptance studies often focussed on ICT, robots and EHR/EMR. Efficiency studies were generally rare. Many studies were found to have a low level of evidence. Experimental designs with small numbers and without control groups were the most common methods used to evaluate acceptance and effectiveness. Study designs with high evidence levels were most commonly found for ICT, robots and e-learning. Technologies evaluated for informal caregivers and children or indicated for formal care at home or in cross-sectoral care were rare. Conclusion We recommend producing high-quality evaluations on existing digital technologies for AEE in real-life settings rather than systematic reviews with low-quality studies. More focus should be placed on research into efficiency. Future research should be devoted to a closer examination of the applied AEE evaluation methods. Policymakers should provide funding to enable large-scale, long-term evaluations of technologies in the practice of care, filling the research gaps for technologies, target settings and target groups identified in this review.

Abstract Background To elucidate the incidence of acute kidney injury (AKI) after out-of-hospital cardiac arrest (OHCA) and to examine the impact of target temperature management (TTM) and early coronary angiography on renal function. Methods Post hoc analysis of the TTM trial, a multinational randomised controlled trial comparing target temperature of 33 °C versus 36 °C in patients with return of spontaneous circulation after OHCA. The impact of TTM and early angiography (within 6 h of OHCA) versus late or no angiography on the development of AKI during the 7-day period after OHCA was analysed. AKI was defined according to modified KDIGO criteria in patients surviving beyond day 2 after OHCA. Results Following exclusions, 853 of 939 patients enrolled in the main trial were analysed. Unadjusted analysis showed that significantly more patients in the 33 °C group had AKI compared to the 36 °C group [211/431 (49%) versus 170/422 (40%) p = 0.01], with a worse severity (p = 0.018). After multivariable adjustment, the difference was not significant (odds ratio 0.75, 95% confidence interval 0.54–1.06, p = 0.10]. Five hundred seventeen patients underwent early coronary angiography. Although the unadjusted analysis showed less AKI and less severe AKI in patients who underwent early angiography compared to patients with late or no angiography, in adjusted analyses, early angiography was not an independent risk factor for AKI (odds ratio 0.73, 95% confidence interval 0.50–1.05, p = 0.09). Conclusions In OHCA survivors, TTM at 33 °C compared to management at 36 °C did not show different rates of AKI and early angiography was not associated with an increased risk of AKI. Trial registration NCT01020916. Registered on www.ClinicalTrials.gov 26 November 2009 (main trial).

Abstract Background Shared-housing arrangements (SHAs) in Germany are an alternative care arrangement for people with dementia. They are disconnected from traditional nursing homes and are often situated in ordinary apartment buildings. Community health care providers serve persons with dementia in SHAs, and there is no official regulation regarding the staff-resident ratio. The association between the staff-resident ratio and the quality of life (QoL) of persons with dementia has not yet been investigated in SHAs. Method A cross-sectional study was performed in SHAs in Berlin, Germany, using ANCOVA models to analyse whether residents’ QoL (QUALIDEM), as assessed by staff in SHAs, can be explained by the staff-resident ratio, adjusted for residents’ sex, age, length of stay, challenging behaviour (CMAI), cognitive impairment (GDS) and level of care dependency according to the German statutory health care insurance. Results In this study, 58 SHAs with 396 residents (mean age 78.4 years, 69.4% female) participated. The staff-resident ratio was 0.2 and 0.6 for registered nurses and certified nursing assistants, respectively. Associations with QoL were found predominantly for challenging behaviour and cognitive impairment. The analysis showed that there was no significant effect of the total staff-resident ratio (p > 0.05) in explaining the variation in residents’ QoL (total and subdomains). In general, the proportion of explained variance was weak (R2

Abstract Background The study objective was to assess the influence of neutropenia on outcome of critically ill cancer patients by meta-analysis of individual data. Secondary objectives were to assess the influence of neutropenia on outcome of critically ill patients in prespecified subgroups (according to underlying tumor, period of admission, need for mechanical ventilation and use of granulocyte colony stimulating factor (G-CSF)). Methods Data sources were PubMed and the Cochrane database. Study selection included articles focusing on critically ill cancer patients published in English and studies in humans from May 2005 to May 2015. For study selection, the study eligibility was assessed by two investigators. Individual data from selected studies were obtained from corresponding authors. Results Overall, 114 studies were identified and authors of 30 studies (26.3% of selected studies) agreed to participate in this study. Of the 7515 included patients, three were excluded due to a missing major variable (neutropenia or mortality) leading to analysis of 7512 patients, including 1702 neutropenic patients (22.6%). After adjustment for confounders, and taking study effect into account, neutropenia was independently associated with mortality (OR 1.41; 95% CI 1.23–1.62; P = 0.03). When analyzed separately, neither admission period, underlying malignancy nor need for mechanical ventilation modified the prognostic influence of neutropenia on outcome. However, among patients for whom data on G-CSF administration were available (n = 1949; 25.9%), neutropenia was no longer associated with outcome in patients receiving G-CSF (OR 1.03; 95% CI 0.70–1.51; P = 0.90). Conclusion Among 7512 critically ill cancer patients included in this systematic review, neutropenia was independently associated with poor outcome despite a meaningful survival. Neutropenia was no longer significantly associated with outcome in patients treated by G-CSF, which may suggest a beneficial effect of G-CSF in neutropenic critically ill cancer patients. Systematic review registration PROSPERO CRD42015026347. Date of registration: Sept 18 2015