A Brief Introduction on Latent Variable Based Ordinal Regression Models With an Application to Survey Data.

The analysis of survey data is a frequently arising issue in clinical trials, particularly when capturing quantities which are difficult to measure. Typical examples are questionnaires about patient's well-being, pain, or consent to an intervention. In these, data is captured on a discrete scale containing only a limited number of possible answers, from which the respondent has to pick the answer which fits best his/her personal opinion. This data is generally located on an ordinal scale as answers can usually be arranged in an ascending order, for example, "bad", "neutral", "good" for well-being. Since responses are usually stored numerically for data processing purposes, analysis of survey data using ordinary linear regression models are commonly applied. However, assumptions of these models are often not met as linear regression requires a constant variability of the response variable and can yield predictions out of the range of response categories. By using linear models, one only gains insights about the mean response which may affect representativeness. In contrast, ordinal regression models can provide probability estimates for all response categories and yield information about the full response scale beyond the mean. In this work, we provide a concise overview of the fundamentals of latent variable based ordinal models, applications to a real data set, and outline the use of state-of-the-art-software for this purpose. Moreover, we discuss strengths, limitations and typical pitfalls. This is a companion work to a current vignette-based structured interview study in pediatric anesthesia.

A simplified approach to discriminate between healthy subjects and patients with heart failure using cardiac magnetic resonance myocardial deformation imaging.

Aims: Left ventricular global longitudinal strain (LV-GLS) shows promise as a marker to detect early heart failure (HF). This study sought to (i) establish cardiac magnetic resonance imaging (CMR)-derived LV-GLS cut-offs to differentiate healthy from HF for both acquisition-based and post-processing techniques, (ii) assess agreement, and (iii) provide a method to convert LV-GLS between both techniques. Methods and results: A secondary analysis of a prospective study enrolling healthy subjects (n = 19) and HF patients (n = 56) was conducted. LV-GLS was measured using fast strain-encoded imaging (fSENC) and feature tracking (FT). Receiver operating characteristic (ROC) analyses were performed to derive and evaluate LV-GLS cut-offs discriminating between healthy, HF with mild deformation impairment (DI), and HF with severe DI. Linear regression and Bland-Altman analyses assessed agreement. Cut-offs discriminating between healthy and HF were identified at -19.3% and -15.1% for fSENC and FT, respectively. Cut-offs of -15.8% (fSENC) and -10.8% (FT) further distinguished mild from severe DI. No significant differences in area under ROC curve were identified between fSENC and FT. Bland-Altman analysis revealed a bias of -4.01%, 95% CI -4.42, -3.50 for FT, considering fSENC as reference. Linear regression suggested a factor of 0.76 to rescale fSENC-derived LV-GLS to FT. Using this factor on fSENC-derived cut-offs yielded rescaled FT LV-GLS cut-offs of -14.7% (healthy vs. HF) and -12% (mild vs. severe DI). Conclusion: LV-GLS distinguishes healthy from HF with high accuracy. Each measurement technique requires distinct cut-offs, but rescaling factors facilitate conversion. An FT-based LV-GLS ≥ -15% simplifies HF detection in clinical routine.

Intraoperative zero-heat-flux thermometry overestimates nasopharyngeal temperature by 0.39 °C: an observational study in patients undergoing congenital heart surgery.

During surgery for congenital heart disease (CHD) temperature management is crucial. Vesical (Tves) and nasopharyngeal (TNPH) temperature are usually measured. Whereas Tves slowly responds to temperature changes, TNPH carries the risk of bleeding. The zero-heat-flux (ZHF) temperature monitoring systems SpotOn™ (TSpotOn), and Tcore™ (Tcore) measure temperature non-invasively. We evaluated accuracy and precision of the non-invasive devices, and of Tves compared to TNPH for estimating temperature. In this prospective observational study in pediatric and adult patients accuracy and precision of TSpotOn, Tcore, and Tves were analyzed using the Bland-Altman method. Proportion of differences (PoD) and Lin´s concordance correlation coefficient (LCC) were calculated. Data of 47 patients resulted in sets of matched measurements: 1073 for TSpotOn vs. TNPH, 874 for Tcore vs. TNPH, and 1102 for Tves vs. TNPH. Accuracy was - 0.39 °C for TSpotOn, -0.09 °C for Tcore, and 0.07 °C for Tves. Precisison was between - 1.12 and 0.35 °C for TSpotOn, -0.88 to 0.71 °C for Tcore, and - 1.90 to 2.05 °C for Tves. PoD ≤ 0.5 °C were 71% for TSpotOn, 71% for Tcore, and 60% for Tves. LCC was 0.9455 for TSpotOn, 0.9510 for Tcore, and 0.9322 for Tves. Temperatures below 25.2 °C (TSpotOn) or 27.1 (Tcore) could not be recorded non-invasively, but only with Tves. Trial registration German Clinical Trials Register, DRKS00010720.

Factors Influencing Willingness to Participate in Clinical Studies in Pediatric Anesthesia (FILIPPA): A vignette-based, structured interview study.

BACKGROUND: Informed consent is a relevant backdrop for conducting clinical trials, particularly those involving children. While several factors are known to influence the willingness to consent to pediatric anesthesia studies, the influence of study design on consenting behavior is unknown. AIMS: To quantify the impact of study complexity on willingness to consent to pediatric anesthesia studies. METHODS: We conducted a vignette-based interview study by presenting three hypothetical studies to 106 parents or legal guardians whose children were scheduled to undergo anesthesia. These studies differed in level of complexity and included an example of a prospective observational study, a randomized controlled trial, and a phase-II-pharmacological study. Primary outcome was the willingness to consent, using a 5-point Likert scale ranging from "absolutely consent" to "absolutely decline". Secondary outcomes were the effects of child-related (such as sex, age, previous anesthesia, research exposure) and proxy-related factors. RESULTS: Response probabilities for "absolute consent" were 90.9% [95% CI 85.3-96.5] for the observational study, 48.6% [95% CI 38.3-58.9] for the randomized controlled trial, and 32.7% [95% CI 23.9-41.6] for the phase-II-pharmacological study. Response probabilities for "absolutely decline" were 1.6% [95% CI 0.3-2.8], 14.4% [95% CI 8.3-20.5], and 24.7% [95% CI 16.6-32.7], respectively. Significant effects were found for previous research exposure (OR = 0.486 [95% CI 0.256-0.923], p = .027), older age (OR = 0.963 [95% CI 0.927-0.999], p = .045) and the gender of the parent or legal guardian, as mothers were less willing to consent (OR = 0.234 [95% CI 0.107-0.512], p < .001). CONCLUSIONS: Willingness to consent decreased with increasing level of study complexity. When conducting more complex studies, greater efforts need to be made to increase the enrollment of pediatric patients.

Internet-delivered cognitive behavioural therapy programme to reduce depressive symptoms in patients with multiple sclerosis: a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Depression is three to four times more prevalent in patients with neurological and inflammatory disorders than in the general population. For example, in patients with multiple sclerosis, the 12-month prevalence of major depressive disorder is around 25% and it is associated with a lower quality of life, faster disease progression, and higher morbidity and mortality. Despite its clinical relevance, there are few treatment options for depression associated with multiple sclerosis and confirmatory trials are scarce. We aimed to evaluate the safety and efficacy of a multiple sclerosis-specific, internet-based cognitive behavioural therapy (iCBT) programme for the treatment of depressive symptoms associated with the disease. METHODS: This parallel-group, randomised, controlled, phase 3 trial of an iCBT programme to reduce depressive symptoms in patients with multiple sclerosis was carried out at five academic centres with large outpatient care units in Germany and the USA. Patients with a neurologist-confirmed diagnosis of multiple sclerosis and depressive symptoms were randomly assigned (1:1:1; automated assignment, concealed allocation, no stratification, no blocking) to receive treatment as usual plus one of two versions of the iCBT programme Amiria (stand-alone or therapist-guided) or to a control condition, in which participants received treatment as usual and were offered access to the iCBT programme after 6 months. Masking of participants to group assignment between active treatment and control was not possible, although raters were masked to group assignment. The predefined primary endpoint, which was analysed in the intention-to-treat population, was severity of depressive symptoms as measured by the Beck Depression Inventory-II (BDI-II) at week 12 after randomisation. This trial is registered at ClinicalTrials.gov, NCT02740361, and is complete. FINDINGS: Between May 3, 2017, and Nov 4, 2020, we screened 485 patients for eligibility. 279 participants were enrolled, of whom 101 were allocated to receive stand-alone iCBT, 85 to receive guided iCBT, and 93 to the control condition. The dropout rate at week 12 was 18% (50 participants). Both versions of the iCBT programme significantly reduced depressive symptoms compared with the control group (BDI-II between-group mean differences: control vs stand-alone iCBT 6·32 points [95% CI 3·37-9·27], p<0·0001, effect size d=0·97 [95% CI 0·64-1·30]; control vs guided iCBT 5·80 points [2·71-8·88], p<0·0001, effect size d=0·96 [0·62-1·30]). Clinically relevant worsening of depressive symptoms was observed in three participants in the control group, one in the stand-alone iCBT group, and none in the guided iCBT group. No occurrences of suicidality were observed during the trial and there were no deaths. INTERPRETATION: This trial provides evidence for the safety and efficacy of a multiple sclerosis-specific iCBT tool to reduce depressive symptoms in patients with the disease. This remote-access, scalable intervention increases the therapeutic options in this patient group and could help to overcome treatment barriers. FUNDING: National Multiple Sclerosis Society (USA).

What is the best way to keep the patient warm during technical rescue? Results from two prospective randomised controlled studies with healthy volunteers.

BACKGROUND: Accidental hypothermia is a manifest problem during the rescue of entrapped victims and results in different subsequent problems as coagulopathy and wound infection. Different warming methods are available for the preclinicial use. However, their effectiveness has hardly been evaluated. METHODS: In a first step a survey among German fire brigades was performed with questions about the most used warming methods. In a second step two crossover studies were conducted. In each study two different warming method were compared with forced air warming - which is the most frequently used and highly effective warming method in operation rooms (Study A: halogen floodlight vs. forced air warming; Study B: forced air warming vs. fleece blanket). In both studies healthy volunteers (Study A: 30 volunteers, Study B: 32 volunteers) were sitting 60 min in a cold store. In the first 21 min there was no subject warming. Afterwards the different warming methods were initiated. Every 3 min parameters like skin temperature, core body temperature and cold perception on a 10-point numeric rating scale were recorded. Linear mixed models were fitted for each parameter to check for differences in temperature trajectories and cold perception with regard to the different warming methods. RESULTS: One hundred fifty-one German fire brigades responded to the survey. The most frequently used warming methods were different rescue blankets (gold/silver, wool) and work light (halogen floodlights). Both studies (A and B) showed significantly (p < 0.05) higher values in mean skin temperature, mean body temperature and total body heat for the forced air warming methods compared to halogen floodlight respectively fleece blanket shortly after warming initiation. In contrast, values for the cold perception were significantly lower (less unpleasant cold perception) during the phase the forced air warming methods were used, compared to the fleece blanket or the halogen floodlight was used. CONCLUSION: Forced air warming methods used under the standardised experimental setting are an effective method to keep patients warm during technical rescue. Halogen floodlight has an insufficient effect on the patient's heat preservation. In healthy subjects, fleece blankets will stop heat loss but will not correct heat that has already been lost. TRIAL REGISTRATION: The studies were registered retrospectively on 14/02/2022 on the German Clinical Trials registry (DRKS) with the number DRKS00028079.

Morphine and Hydromorphone Effects, Side Effects, and Variability: A Crossover Study in Human Volunteers.

BACKGROUND: Balancing between opioid analgesia and respiratory depression continues to challenge clinicians in perioperative, emergency department, and other acute care settings. Morphine and hydromorphone are postoperative analgesic standards. Nevertheless, their comparative effects and side effects, timing, and respective variabilities remain poorly understood. This study tested the hypothesis that IV morphine and hydromorphone differ in onset, magnitude, duration, and variability of analgesic and ventilatory effects. METHODS: The authors conducted a randomized crossover study in healthy volunteers. Forty-two subjects received a 2-h IV infusion of hydromorphone (0.05 mg/kg) or morphine (0.2 mg/kg) 1 to 2 weeks apart. The authors measured arterial opioid concentrations, analgesia in response to heat pain (maximally tolerated temperature, and verbal analog pain scores at discrete preset temperatures to determine half-maximum temperature effect), dark-adapted pupil diameter and miosis, end-expired carbon dioxide, and respiratory rate for 12 h after dosing. RESULTS: For morphine and hydromorphone, respectively, maximum miosis was less (3.9 [3.4 to 4.2] vs. 4.6 mm [4.0 to 5.0], P < 0.001; median and 25 to 75% quantiles) and occurred later (3.1 ± 0.9 vs. 2.3 ± 0.7 h after infusion start, P < 0.001; mean ± SD); maximum tolerated temperature was less (49 ± 2 vs. 50 ± 2°C, P < 0.001); verbal pain scores at end-infusion at the most informative stimulus (48.2°C) were 82 ± 4 and 59 ± 3 (P < 0.001); maximum end-expired CO2 was 47 (45 to 50) and 48 mmHg (46 to 51; P = 0.007) and occurred later (5.5 ± 2.8 vs. 3.0 ± 1.5 h after infusion start, P < 0.001); and respiratory nadir was 9 ± 1 and 11 ± 2 breaths/min (P < 0.001), and occurred at similar times. The area under the temperature tolerance-time curve was less for morphine (1.8 [0.0 to 4.4]) than hydromorphone (5.4°C-h [1.6 to 12.1] P < 0.001). Interindividual variability in clinical effects did not differ between opioids. CONCLUSIONS: For morphine compared to hydromorphone, analgesia and analgesia relative to respiratory depression were less, onset of miosis and respiratory depression was later, and duration of respiratory depression was longer. For each opioid, timing of the various clinical effects was not coincident. Results may enable more rational opioid selection, and suggest hydromorphone may have a better clinical profile.

Screening versus multidimensional assessment of symptoms and psychosocial distress in cancer patients from the time of incurability.

Objective: Previous symptom prevalence studies show a diverse spectrum of symptoms and a large diversity in symptom intensities in patients being just diagnosed as having incurable cancer. It is unclear, how physical symptoms and psychosocial burden should be recorded in order to determine the variable need for palliative care and further support. Therefore, we compared two different strategies for detecting physical symptoms and psychosocial burden of patients with newly diagnosed incurable cancer and their effects on the further course of the disease. Methods: SCREBEL is a controlled, randomized, non-blinded, longitudinal study of the research network of the Palliative Medicine Working Group (APM) of the German Cancer Society (DKG). We compared: a less complex repeated brief screening for symptoms and burden in patients using the NCCN Distress Thermometer and IPOS questionnaire versus a multidimensional comprehensive assessment using the FACT-G and their entity-specific questionnaires, the PHQ4 scales, SCNS-34-SF, IPOS and NCCN Distress Thermometer. The primary study endpoint was quality of life (QoL), measured using FACT-G, after six months. Secondary study endpoints were QoL by using evaluation of secondary scores (NCCN DT, IPOS, PHQ4, SCNS-SF-34G) at time 6 months, the number of hospital days, the utilization of palliative care, emergency services, and psychosocial care structures. To assess effects and differences, multiple linear regression models were fitted and survival analyses were conducted. Results: 504 patients were included in the study. 262 patients were lost to follow-up, including 155 fatalities. There were no significant differences between the low-threshold screening approach and a comprehensive assessment with respect to symptoms and other aspects of QoL. Using the IPOS, we were able to measure an improvement in the quality of life in the low-threshold screening arm by a decrease of 0.67 points (95%-CI: 0.34 to 0.99) every 30 days. (p<0.001). Data on the involvement of emergency facilities and on supportive services were insufficient for analysis. Conclusion: A comprehensive, multidimensional assessment did not significantly differ from brief screening in preserving several dimensions of quality of life. These findings may positively influence the implementation of structured low-threshold screening programs for supportive and palliative needs in DKG certified cancer centers.DRKS -No. DRKS00017774 https://drks.de/search/de/trial/DRKS00017774.

Modeling iatrogenic intraoperative hyperthermia from external warming in children: A pooled analysis from two prospective observational studies.

BACKGROUND: Maintenance of normothermia is an important quality metric in pediatric anesthesia. While inadvertent hypothermia is effectively prevented by forced-air warming, this therapeutic approach can lead to iatrogenic hyperthermia in young children. AIMS: To estimate the influence of external warming by forced air on the development of intraoperative hyperthermia in anesthetized children aged 6 years or younger. METHODS: We pooled data from two previous clinical studies. Primary outcome was the course of core temperature over time analyzed by a quadratic regression model. Secondary outcomes were the incidence of hyperthermia (body core temperature >38°C), the probability of hyperthermia over the duration of warming in relation to age and surface-area-to-weight ratio, respectively, analyzed by multiple logistic regression models. The influence of baseline temperature on hyperthermia was estimated using a Cox proportional hazards model. RESULTS: Two hundred children (55 female) with a median age of 2.1 [1st -3rd quartile 1-4.2] years were analyzed. Mean temperature increased by 0.43°C after 1 h, 0.64°C after 2 h, and reached a peak of 0.66°C at 147 min. Overall, 33 children were hyperthermic at at least one measurement point. The odds ratios of hyperthermia were 1.14 (95%-CI: 1.07-1.22) or 1.13 (95%-CI: 1.06-1.21) for every 10 min of warming therapy in a model with age or surface-area-to weight ratio (ceteris paribus), respectively. Odds ratio was 1.33 (95%-CI: 1.07-1.71) for a decrease of 1 year in age and 1.63 (95%-CI: 0.93-2.83) for an increase of 0.01 in the surface-to-weight-area ratio (ceteris paribus). An increase of 0.1°C in baseline temperature increased the hazard of becoming hyperthermic by a factor of 1.33 (95%-CI: 1.23-1.43). CONCLUSIONS: In children, external warming by forced-air needs to be closely monitored and adjusted in a timely manner to avoid iatrogenic hyperthermia especially during long procedures, in young age, higher surface-area-to-weight ratio, and higher baseline temperature.

Ventilatory ratio, dead space, and venous admixture in patients with acute respiratory distress syndrome.

BACKGROUND: Ventilatory ratio (VR) has been proposed as an alternative approach to estimate physiological dead space. However, the absolute value of VR, at constant dead space, might be affected by venous admixture and CO2 volume expired per minute (VCO2). METHODS: This was a retrospective, observational study of mechanically ventilated patients with acute respiratory distress syndrome (ARDS) in the UK and Italy. Venous admixture was either directly measured or estimated using the surrogate measure PaO2/FiO2 ratio. VCO2 was estimated through the resting energy expenditure derived from the Harris-Benedict formula. RESULTS: A total of 641 mechanically ventilated patients with mild (n=65), moderate (n=363), or severe (n=213) ARDS were studied. Venous admixture was measured (n=153 patients) or estimated using the PaO2/FiO2 ratio (n=448). The VR increased exponentially as a function of the dead space, and the absolute values of this relationship were a function of VCO2. At a physiological dead space of 0.6, VR was 1.1, 1.4, and 1.7 in patients with VCO2 equal to 200, 250, and 300, respectively. VR was independently associated with mortality (odds ratio [OR]=2.5; 95% confidence interval [CI], 1.8-3.5), but was not associated when adjusted for VD/VTphys, VCO2, PaO2/FiO2 (ORadj=1.2; 95% CI, 0.7-2.1). These three variables remained independent predictors of ICU mortality (VD/VTphys [ORadj=17.9; 95% CI, 1.8-185; P<0.05]; VCO2 [ORadj=0.99; 95% CI, 0.99-1.00; P<0.001]; and PaO2/FiO2 (ORadj=0.99; 95% CI, 0.99-1.00; P<0.001]). CONCLUSIONS: VR is a useful aggregate variable associated with outcome, but variables not associated with ventilation (VCO2 and venous admixture) strongly contribute to the high values of VR seen in patients with severe illness.

Blood Culture Headspace Gas Analysis Enables Early Detection of Escherichia coli Bacteremia in an Animal Model of Sepsis.

(1) Background: Automated blood culture headspace analysis for the detection of volatile organic compounds of microbial origin (mVOC) could be a non-invasive method for bedside rapid pathogen identification. We investigated whether analyzing the gaseous headspace of blood culture (BC) bottles through gas chromatography-ion mobility spectrometry (GC-IMS) enables differentiation of infected and non-infected; (2) Methods: BC were gained out of a rabbit model, with sepsis induced by intravenous administration of E. coli (EC group; n = 6) and control group (n = 6) receiving sterile LB medium intravenously. After 10 h, a pair of blood cultures was obtained and incubated for 36 h. The headspace from aerobic and anaerobic BC was sampled every two hours using an autosampler and analyzed using a GC-IMS device. MALDI-TOF MS was performed to confirm or exclude microbial growth in BCs; (3) Results: Signal intensities (SI) of 113 mVOC peak regions were statistically analyzed. In 24 regions, the SI trends differed between the groups and were considered to be useful for differentiation. The principal component analysis showed differentiation between EC and control group after 6 h, with 62.2% of the data variance described by the principal components 1 and 2. Single peak regions, for example peak region P_15, show significant SI differences after 6 h in the anaerobic environment (p < 0.001) and after 8 h in the aerobic environment (p < 0.001); (4) Conclusions: The results are promising and warrant further evaluation in studies with an extended microbial panel and indications concerning its transferability to human samples.