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

Abstract

• 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.

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

Abstract

• 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.

• Conclusions: 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.

Morphine and Hydromorphone Effects, Side Effects and Variability—a Crossover Study in Human Volunteers

Abstract

• 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. We tested the hypothesis that intravenous morphine and hydromorphone differ in onset, magnitude, duration and variability of analgesic and ventilatory effects.

• Methods: We conducted a randomized crossover study in healthy volunteers. Forty-two subjects received a 2-hour intravenous infusion of hydromorphone (0.05 mg/kg) or morphine (0.2 mg/kg) 1-2 weeks apart. We measured arterial opioid concentrations, analgesia in response to heat pain (maximally tolerated temperature, and verbal analog pain scores at discreet preset temperatures to determine half-maximum temperature effect), dark-adapted pupil diameter and miosis, end-expired CO2, and respiratory rate for 12 h after dosing.

• Results: For morphine and hydromorphone, respectively: maximum miosis was less (3.9 [3.4,4.2] vs 4.6 mm [4.0,5.0], P<0.001; median and 25%-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 [45,50] and 48 mmHg [46,51] (P=0.007), and occurred later (5.5 ± 2.8 vs 3.0 ± 1.5 h after infusion start, P<0.001); respiratory nadir was 9 ± 1 and 11 ± 2 breaths/min (P<0.001) and occurred at similar times. Area under the temperature tolerance-time curve was less for morphine (1.8 [0.0,4.4]) than hydromorphone (5.4°C-h [1.6,12.1] P<0.001). Inter-individual 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

Abstract

• 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.

• Conclusions: 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.

Ventilatory Ratio, Dead Space, and Venous Admixture in Acute Respiratory Distress Syndrome

Abstract

• 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 Harrise-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 V_D/V_Tphys, VCO₂, PaO₂/FiO₂ (OR_adj=1.2; 95% CI, 0.7-2.1). These three variables remained independent predictors of ICU mortality (V_D/V_Tphys [OR_adj=17.9; 95% CI, 1.8-185; P<0.05]; VCO₂ [OR_adj=0.99; 95% CI, 0.99-1.00; P<0.001]; and PaO₂/FiO₂ (OR_adj=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.

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

Abstract

• 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 length 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: 200 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 one hour, 0.64°C after two hours and reached a peak of 0.66°C at 147 minutes. Overall, 33 children were hyperthermic 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 ten minutes 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 one 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.

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

Abstract

• 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.

• 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.

• 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).

• Conclusions: The results are promising and warrant further evaluation in studies with an extended microbial panel and indications concerning its transferability to human samples.

Characteristic and necessary minutiae in fingerprints

Abstract

Fingerprints feature a ridge pattern with moderately varying ridge frequency (RF), following an orientation field (OF), which usually features some singularities. Additionally, at some points, called minutiae, ridge lines end or fork and this point pattern is usually used for fingerprint identification and authentication. Whenever the OF features divergent ridge lines (e.g. near singularities), a nearly constant RF necessitates the generation of more ridge lines, originating at minutiae. We call these the necessary minutiae. It turns out that fingerprints feature additional minutiae which occur at rather arbitrary locations. We call these the random minutiae or, since they may convey fingerprint individuality beyond the OF, the characteristic minutiae. In consequence, the minutiae point pattern is assumed to be a realization of the superposition of two stochastic point processes: a Strauss point process (whose activity function is given by the divergence field) with an additional hard core, and a homogeneous Poisson point process, modelling the necessary and the characteristic minutiae, respectively. We perform Bayesian inference using an MCMC-based minutiae separating algorithm (MiSeal). In simulations, it provides good mixing and good estimation of underlying parameters. In application to fingerprints, we can separate the two minutiae patterns and verify by example of two different prints with similar OF that characteristic minutiae convey fingerprint individuality.

An algorithm for computing Fréchet means on the sphere

Abstract

For most optimisation methods an essential assumption is the vector space structure of the feasible set. This condition is not fulfilled if we consider optimisation problems over the sphere. We present an algorithm for solving a special global problem over the sphere, namely the determination of Fréchet means, which are points minimising the mean distance to a given set of points. The Branch and Bound method derived needs no further assumptions on the input data, but is able to cope with this objective function which is neither convex nor differentiable. The algorithm’s performance is tested on simulated and real data.

Non-Asymptotic Confidence Sets for Circular Means

Abstract

The mean of data on the unit circle is defined as the minimizer of the average squared Euclidean distance to the data. Based on Hoeffding’s mass concentration inequalities, non-asymptotic confidence sets for circular means are constructed which are universal in the sense that they require no distributional assumptions. These are then compared with asymptotic confidence sets in simulations and for a real data set.

Universal, non-asymptotic confidence sets for circular means

Abstract

Based on Hoeffding’s mass concentration inequalities, non-asymptotic confidence sets for circular means are constructed which are universal in the sense that they require no distributional assumptions. These are then compared with asymptotic confidence sets in simulations and for a real data set.