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Elisabeth Kjær Jensen,1,* Thomas K Ringsted,1,* Joakim M Bischoff,1 Morten A Petersen,2 Kirsten Møller,3,4 Henrik Kehlet,5 Mads U Werner1,6 1Department of Anaesthesia, Pain and Respiratory Support, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 2Statistical Research Unit, Department of Palliative Care, Bispebjerg Hospital, Copenhagen, Denmark; 3Department of Neuroanaesthesiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 4Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 5Section for Surgical Pathophysiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; 6Department of Clinical Sciences, Lund University, Lund, Sweden*These authors contributed equally to this workCorrespondence: Elisabeth Kjær Jensen, Multidisciplinary Pain Center 7612, Department of Anesthesia, Pain and Respiratory Support, Neuroscience Center, Rigshospitalet, Ole Maaløes Vej 26, Copenhagen N, 2200, Denmark, Tel +45 3545 7612, Email elisabeth.kjaer@live.dkPurpose: After groin hernia repair (globally more than 20 million/year) 2– 4% will develop persistent severe pain (PSPG). Pain management is challenging and may require multimodal interventions, including re-surgery. Quantitative somatosensory testing (QST) is an investigational psychophysiological tool with the potential to uncover the pathophysiological mechanisms behind the pain, ie, revealing neuropathic or inflammatory components. The primary objective was to examine and describe the underlying pathophysiological changes in the groin areas by QST before and after re-surgery with mesh removal and selective neurectomy.Patients and Methods: Sixty patients with PSPG scheduled for re-surgery and with an inflammatory “component” indicated by blunt pressure algometry were examined in median (95% CI) 7.9 (5.8– 11.5) months before and 4.0 (3.5– 4.6) months after re-surgery. The QST-analyses included standardized assessments of cutaneous mechanical/thermal detection and pain thresholds. Suprathreshold heat stimuli were applied. Deep tissue sensitivity was tested by pressure algometry. Testing sites were the groin areas and the lower arm. Before/after QST data were z-transformed.Results: Re-surgery resulted in median changes in rest, average, and maximal pain intensity scores of − 2.0, − 2.5, and − 2.0 NRS (0/10) units, respectively (P = 0.0001), and proportional increases in various standardized functional scores (P = 0.0001). Compared with the control sites, the cutaneous somatosensory detection thresholds of the painful groin were increased before re-surgery and increased further after re-surgery (median difference: 1.28 z-values; P = 0.001), indicating a successive post-surgical loss of nerve fiber function (“deafferentation”). Pressure algometry thresholds increased after re-surgery (median difference: 0.30 z-values; P = 0.001).Conclusion: In this subset of patients with PSPG who underwent re-surgery, the procedure was associated with improved pain and functional outcomes. While the increase in somatosensory detection thresholds mirrors the surgery-induced cutaneous deafferentation, the increase in pressure algometry thresholds mirrors the removal of the deep “pain generator”. The QST-analyses are useful adjuncts in mechanism-based somatosensory research.Keywords: groin, hernia repair, chronic post-surgical pain, reoperation, sensory thresholds

Structural studies using x-ray scattering methods for investigating molecules in solution are shifting focus toward describing the role and effects of the surrounding solvent. However, forward models based on molecular dynamics (MD) simulations to simulate structure factors and x-ray scattering from interatomic distributions such as radial distribution functions (RDFs) face limitations imposed by simulations, particularly at low values of the scattering vector q. In this work, we show how the value of the structure factor at q = 0 calculated from RDFs sampled from finite MD simulations is effectively dependent on the size of the simulation cell. To eliminate this error, we derive a new scheme to renormalize the sampled RDFs based on a model of the excluded volume of the particle-pairs they were sampled from, to emulate sampling from an infinite system. We compare this new correction method to two previous RDF-correction methods, developed for Kirkwood–Buff theory applications. We present a quantitative test to assess the reliability of the simulated low-q scattering signal and show that our RDF-correction successfully recovers the correct q = 0 limit for neat water. We investigate the effect of MD-sampling time on the RDF-corrections, before advancing to a molecular example system, comprised of a transition metal complex solvated in a series of water cells with varying densities. We show that our correction recovers the correct q = 0 behavior for all densities. Furthermore, we employ a simple continuum scattering model to dissect the total scattering signal from the solvent–solvent structural correlations in a solute–solvent model system to find two distinct contributions: a non-local density-contribution from the finite, fixed cell size in NVT simulations, and a local contribution from the solvent shell. We show how the second contribution can be approximated without also including the finite-size contribution. Finally, we provide a "best-practices"-checklist for experimentalists planning to incorporate explicit solvation MD simulations in future work, offering guidance for improving the accuracy and reliability of structural studies using x-ray scattering methods in solution. [ABSTRACT FROM AUTHOR]

Aim: To examine trends in all body mass index (BMI) groups in children from 1936 to 2011. Methods: We included 197 694 girls and 201 276 boys from the Copenhagen School Health Records Register, born between 1930 and 1996, with longitudinal weight and height measurements (6–14 years). Using International Obesity Task Force criteria, BMI was classified as underweight, normal‐weight, overweight and obesity. Sex‐ and age‐specific prevalences were calculated. Results: From the 1930s, the prevalence of underweight was stable until a small increase occurred from 1950 to 1970s, and thereafter it declined into the early 2000s. Using 7‐year‐olds as an example, underweight changed from 10% to 7% in girls and from 9% to 6% in boys during the study period. The prevalence of overweight plateaued from 1950 to 1970s and then steeply increased from 1970s onwards and in 1990–2000s 15% girls and 11% boys at 7 years had overweight. The prevalence of obesity particularly increased from 1980s onwards and in 1990–2000s 5% girls and 4% boys at 7 years had obesity. These trends slightly differed by age. Conclusion: Among Danish schoolchildren, the prevalence of underweight was greater than overweight until the 1980s and greater than obesity throughout the period. Thus, monitoring the prevalence of childhood underweight remains an important public health issue. [ABSTRACT FROM AUTHOR]

Correctly torquing bone screws is important to achieve good patient outcomes. An automated system has been previously proposed that may allow more objective torquing of bone screws. Here the system is tested vs. a static torque limit in pig bone. 5 screws were first inserted until stripping to calibrate the dynamic and static limits. Then 6 were inserted limited to 80% of the mean stripping torque. Then 7 were inserted using 80% of the dynamic model-predicted stripping torque. The pull-out strength of the dynamic and static insertions were compared and no statistically significant difference was found. Future work should consider at using larger screws and different bone samples, with more repetitions to try and obtain a statistically significant result.

Convolutional neural networks (CNNs) have proved their efficiency in performing image classification tasks, as they can automatically extract the image features and make the corresponding prediction. Meanwhile, the CNNs application is highly challenged by their vulnerability to adversarial samples. These samples are slightly different from the legitimate samples, but the CNN gives wrong classification. There are various ways to find the adversarial samples. The most common method is using backpropagation to generate gradients as the directed perturbation. Contrarily to set a constrained limitation, in this paper, we use iterative fast gradient sign method to generate adversarial images with the minimum perturbation. The CNNs were trained to perform surgical tool recognition as a configuration for the modern operation room. The coefficient or the learning rate which influenced the modification per iteration, was set to be adaptive instead of a fixed number. A few functions were utilized to perform the learning rate decay to compare the performance. Especially, we propose a new adaptive learning rate algorithm that consider the loss as a part of influence factor constitute the learning rate for the rest iterations. According to the experiments, our loss adaptive learning rate method was proved to be efficient to get the minimal perturbations for adversarial attack.

Bioimpedance spectroscopy can be used to investigate the composition and monitor the human body, organs, tissues, or cell cultures by measuring the voltage developed by the injection of small alternating currents at different frequencies. These currents are injected sequentially through a frequency sweep and a with a Howland current source or one of its modifications. However, the frequency sweep is not time efficient and introduces problems with data coherence in the case of bioinstability. On the other hand, the Howland current source requires high precision matching between its components. In this contribution we developed a custom-made device for bioimpedance measurements based on a multisine current waveform and on a negative-feedback topology for the current source. Measurements on passive elements showed that the device had less than 1Ω and 0.05∘ uncertainty in the frequency range between 500 Hz and 200 kHz for impedance between 1 kΩ and 10 kΩ. The measurements were affected by an inductive artifact connected with the limited common-mode rejection at high frequencies. Nevertheless, we could characterize the artifacts through a fitting procedure to recover the expected value of the targeted impedance.

Scientific facts about the relationships between the goals are indispensable for the rational social discourse on solving the various conflicting goals on the way to sustainable crop production. Therefore, the German Society for Agronomy has compiled scientific findings on the topics of biodiversity, climate relevance and climate resilience, nutrient management, crop protection, soil protection and production of renewable raw materials, and identified the existing need for research. After an executive summary that highlights the findings, the subject areas are explained in detail. The purpose of this paper is not to make recommendations for policy-making, but to support the public debate by providing factual information.

Convolutional neural networks (CNNs) have proved to be successful in many applications such as image processing. However, even imperceptible perturbations applied to the images can make the neural network performance unreliable. To guarantee an accurate performance in safety critical fields, it is necessary to assess the robustness of CNN solutions before launching. Adversarial attack is a machine learning approach to generate perturbations on real samples to detect the vulnerability of CNN. In this paper, we will use an adversarial attack technique to evaluate a CNN at different training states. The model was trained to perform surgical tool classification task, which was applied to recognize surgical tool in Cholecystectomy to further analyze surgical process. The experiments demonstrate the relation between training states and robustness, i.e. the robustness improved at higher training states, especially for some particular classes. In future work, additional training with generated adversarial images may improve the robustness of the model.

Correctly torquing bone screws is important for implant fixation longevity and strength. A model-based smart screwdriver has been proposed to regulate torque, however current models ignore axial force and the initial engagement of the screw. This was addressed here by deriving a model based on the concept of a net axial force generated by a difference in contact areas on the inward and outward sides of the screw threads. This force is opposed by the shear strength of the material around the threads. The results of the derivation were able to predict the effects of different axial forces during insertion in relation to the hole material strength. The results may be used to compensate for initial thread breakage in future model-based smart screwdrivers to improve their accuracy.

Many hearing aid manufacturers now offer tools for audiologists to be able to conduct remote fine-tuning of hearing aids. There are obvious benefits for patients to use remote fine-tuning, including, for example, saving time on travel. However, little is known about the outcomes of patients who utilize remote fine-tuning versus traditional, face-to-face fine-tuning. This talk will present the results of two studies investigating similarities and differences in patient outcomes when patients have follow-up visits using remote fine-tuning versus face-to-face follow-up visits. In one study, thirty hearing aid users were fit with hearing aids face-to-face by an audiologist. Half of the participants were assigned to a control group and came in after two weeks for face-to-face fine-tuning. The other half of the participants were assigned to an intervention group and were instructed to make requests for fine-tuning via a smartphone app. At the end of a six-week wear trial, independent samples t-tests showed no signifi- cant differences between the intervention and control groups for speech-in-noise tests, hearing aid benefit, or hearing aid satisfaction. Of note, however, is that 41% of the problems encountered by test participants were issues that required a clinic visit and could not be addressed by remote changes to the hearing instrument programming. In a second study, fourteen hearing aid users were initially seen in a clinic and fit with hearing aids, face-to-face, by an audiologist. After one week, the test participants returned to the clinic for a second visit and were split into two groups. One of the groups met in person with the audiologist for traditional, face-to-face fine-tuning. The other group used a smartphone app to request fine-tuning changes. Each group of test participants then wore the fine-tuned hearing aids for one to two weeks before returning for a third visit. At the third visit, the group that had previously been fine-tuned face-to-face then used the smartphone app to request finetuning, and the group that had previously been fine-tuned remotely met with the audiologist for face-to-face fine-tuning. At the end of the trial, there were no significant differences between the two groups for an outcomes questionnaire nor in terms of relative speech-in-noise test improvements over the trial. Furthermore, real ear measurement results at the end of the study indicated no differences between the two groups. One interesting finding, however, was that, after the first fine tuning, real ear measurements showed that the group who underwent face-to-face fine-tuning had on average 1 dB smaller changes made to their initial fittings than the group who requested fine-tuning remotely. At the end of both studies, participants in each group did not differ significantly from one another on any of the outcome measures. These results suggest that remote fine-tuning tools can be used to offer audiological services without compromising outcomes. The studies, however, emphasize that remote finetuning should be used as a supplementary tool and not a replacement for face-to-face meetings which are still required to solve many patient problems. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to evaluate the effects of flexor tendon tenotomy treatment of the diabetic hammertoe deformity on plantar pressure., Research Design and Methods: The study was a substudy including participants from a randomized study on tenotomy treatment of diabetic hammertoes. This study was conducted between December 20, 2019 and June 22, 2021. Participants were randomized to tenotomy and standard non-surgical treatment or standard non-surgical treatment alone. Barefoot plantar pressure measurement was performed pre-intervention and 3 months post-intervention. Primary outcome was change in peak plantar pressure post tenotomy treatment., Results: Of the 95 participants screened in the original study, 45 (57.8% male) were included andcompleted this substudy. Of the 45 participants, 22 were randomized to intervention. The average age of participants was 65.6 ((SD±) 9.5) years and 30 (66.7%) had type 2 diabetes.The average peak plantar pressure (PPP) in toe regions of the participants in the intervention group was significantly (p<0.0001) reduced from 205.6 kPa ((Q1-Q3) 152.0-289.1) pre-intervention to 61.3 kPa (39.1-100.5) post-intervention. The average reduction in PPP of toe regions for participants in the intervention group (-145.3 kPa (-225.9 to -56.2)) was significantly (p=0.00017) higher than what was observed for participants in the control group (-1.6 kPa (-30.2 to 27.9))., Conclusion: This study found that tenotomies of the diabetic hammertoe reduces plantar pressure affecting the treated toes. This likely explains the positive effects of tenotomy treatment on diabetic foot ulcers., Competing Interests: Competing interests: None of the authors have any competing interests related to this work. Outside of this work: PR has received consultancy and/or speaking fees (to SDCC) from AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Eli Lilly, MSD, Novo Nordisk and Sanofi Aventis, and research grants from Novo Nordisk and AstraZeneca. MF-M has received speaking fees from Boehringer Ingelheim, Novartis, Baxter and Sanofi. KK-M has received consultancy and/or speaking fees from Coloplast, Mölnlycke, SoftOx A/S and Bayer Pharmaceuticals AG. SE is employed in Novo Nordisk A/S., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To investigate patients with disorders of consciousness (DoC) for residual awareness, guidelines recommend quantifying glucose brain metabolism using positron emission tomography. However, this is not feasible in the intensive care unit (ICU). Cerebral blood flow (CBF) assessed by arterial spin labeling magnetic resonance imaging (ASL-MRI) could serve as a proxy for brain metabolism and reflect consciousness levels in acute DoC. We hypothesized that ASL-MRI would show compromised CBF in coma and unresponsive wakefulness states (UWS) but relatively preserved CBF in minimally conscious states (MCS) or better., Methods: We consecutively enrolled ICU patients with acute DoC and categorized them as being clinically unresponsive (i.e., coma or UWS [≤ UWS]) or low responsive (i.e., MCS or better [≥ MCS]). ASL-MRI was then acquired on 1.5 T or 3 T. Healthy controls were investigated with both 1.5 T and 3 T ASL-MRI., Results: We obtained 84 ASL-MRI scans from 59 participants, comprising 36 scans from 35 patients (11 women [31.4%]; median age 56 years, range 18-82 years; 24 ≤ UWS patients, 12 ≥ MCS patients; 32 nontraumatic brain injuries) and 48 scans from 24 healthy controls (12 women [50%]; median age 50 years, range 21-77 years). In linear mixed-effects models of whole-brain cortical CBF, patients had 16.2 mL/100 g/min lower CBF than healthy controls (p = 0.0041). However, ASL-MRI was unable to discriminate between ≤ UWS and ≥ MCS patients (whole-brain cortical CBF: p = 0.33; best hemisphere cortical CBF: p = 0.41). Numerical differences of regional CBF in the thalamus, amygdala, and brainstem in the two patient groups were statistically nonsignificant., Conclusions: CBF measurement in ICU patients using ASL-MRI is feasible but cannot distinguish between the lower and the upper ends of the acute DoC spectrum. We suggest that pilot testing of diagnostic interventions at the extremes of this spectrum is a time-efficient approach in the continued quest to develop DoC neuroimaging markers in the ICU., Competing Interests: Conflict of interest: The authors report no competing interests. Ethical approval/informed consent: This study was approved by the Ethics Committee of the Capital Region of Denmark (H-21015473)., (© 2024. The Author(s).)

Chronic wounds and chronic ulcers are an increasing problem associated with high health care burden and patient burden. The arrested healing of chronic wounds has, in part, been attributed to the presence of biofilms. Substantial research has documented the presence of biofilms in chronic wounds, and many mechanisms of host-pathogen interactions have been uncovered to explain the arrested healing. However, the paradigm of whether biofilms are only observed in chronic infections was recently challenged when biofilms were also observed in acute infections. Here, we characterize the distribution of bacteria in lower leg wounds with particular emphasis on Pseudomonas aeruginosa and Staphylococcus aureus by confocal laser scanning microscopy combined with PNA-FISH staining and routine culture of bacteria. We show that 40% of wounds contained either P. aeruginosa or S. aureus biofilms and demonstrate the presence of scattered single cells in tissues stained with a universal bacterial PNA-FISH probe. Thus, we demonstrate that chronic wounds do not only harbor bacteria organized in biofilms, but also carry populations of scattered single cells and small cell clusters of only a few bacteria. Our findings may influence diagnostic tools being developed to only target biofilms, where single-cell subpopulations thus may be overlooked and possibly lead to false-negative results., (© 2023 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

Importance: Blood transfusions are commonly administered to patients with acute brain injury. The optimal hemoglobin transfusion threshold is uncertain in this patient population., Objective: To assess the impact on neurological outcome of 2 different hemoglobin thresholds to guide red blood cell transfusions in patients with acute brain injury., Design, Setting, and Participants: Multicenter, phase 3, parallel-group, investigator-initiated, pragmatic, open-label randomized clinical trial conducted in 72 intensive care units across 22 countries. Eligible patients had traumatic brain injury, aneurysmal subarachnoid hemorrhage, or intracerebral hemorrhage; hemoglobin values below 9 g/dL within the first 10 days after injury; and an expected intensive care unit stay of at least 72 hours. Enrollment occurred between September 1, 2017, and December 31, 2022. The last day of follow-up was June 30, 2023., Interventions: Eight hundred fifty patients were randomly assigned to undergo a liberal (transfusion triggered by hemoglobin <9 g/dL; n = 408) or a restrictive (transfusion triggered by hemoglobin <7 g/dL; n = 442) transfusion strategy over a 28-day period., Main Outcomes and Measures: The primary outcome was occurrence of an unfavorable neurological outcome, defined as a Glasgow Outcome Scale Extended score between 1 and 5, at 180 days following randomization. There were 14 prespecified serious adverse events, including occurrence of cerebral ischemia after randomization., Results: Among 820 patients who completed the trial (mean age, 51 years; 376 [45.9%] women), 806 had available data on the primary outcome, 393 in the liberal strategy group and 413 in the restrictive strategy group. The liberal strategy group received a median of 2 (IQR, 1-3) units of blood, and the restrictive strategy group received a median of 0 (IQR, 0-1) units of blood, with an absolute mean difference of 1.0 unit (95% CI, 0.87-1.12 units). At 180 days after randomization, 246 patients (62.6%) in the liberal strategy group had an unfavorable neurological outcome compared with 300 patients (72.6%) in the restrictive strategy group (absolute difference, -10.0% [95% CI, -16.5% to -3.6%]; adjusted relative risk, 0.86 [95% CI, 0.79-0.94]; P = .002). The effect of the transfusion thresholds on neurological outcome at 180 days was consistent across prespecified subgroups. In the liberal strategy group, 35 (8.8%) of 397 patients had at least 1 cerebral ischemic event compared with 57 (13.5%) of 423 in the restrictive strategy group (relative risk, 0.65 [95% CI, 0.44-0.97])., Conclusions and Relevance: Patients with acute brain injury and anemia randomized to a liberal transfusion strategy were less likely to have an unfavorable neurological outcome than those randomized to a restrictive strategy., Trial Registration: ClinicalTrials.gov Identifier: NCT02968654.

Objective: Biofilm infections in chronic wounds are common and pose a significant clinical challenge. This challenge was addressed by developing the SoftOx Biofilm Eradicator (SBE) composed of hypochlorous acid (HOCl) and acetic acid with strong broad-spectrum antimicrobial activity. Approach: First-in-human study investigating the safety and tolerability as primary endpoints and wound size effect and antimicrobial efficacy as secondary endpoints of SBE treatment in chronic leg wound patients. The study was divided into two as follows: a randomized, double-blinded, Single Ascending Dose (SAD) phase ( n = 16 SBE; n = 4 placebo), where patients were treated with SBE or saline (placebo) only once, followed by an open-label, Multiple Ascending Dose (MAD) phase ( n = 8), where patients were treated with SBE once daily or twice daily over five days. Reporting is according to CONSORT guidelines. Results: SBE was safe and well-tolerated in chronic leg wound patients. There were no significant differences in pain during and after treatment with SBE or the placebo. The SBE treatment reduced bioburden in wounds compared to baseline, with 98% and 49% median reduction after SBE or placebo treatment, respectively. A dose-dependent trend in absolute wound size reduction was observed in the MAD groups with a median (min, max) change of -2.99 (-14.25, -1.5) cm 2 in the once-daily and -10.48 (-17.95, -0.38) cm 2 in the twice-daily group, respectively. Innovation and Conclusion: This study demonstrated the safe use of HOCl-based SBE in chronic leg wounds with promising trends of immediate antimicrobial action and beneficial effect on wound healing.

Introduction: Chronic wounds affect 1%-2% of the global population, with rising incidence due to ageing and lifestyle-related diseases. Bacterial biofilms, found in 80% of chronic wounds, and scattered single-cell bacteria may hinder healing. Microbes are believed to negatively impact healing by exacerbating inflammation and host immune response., Methods and Analysis: The primary objective of the chronic wound characterisation (CWC) study is to investigate chronic wounds through a prospective observational cohort study exploring bacterial community composition, inflammatory responses and the influence of bacteria on wound-healing trajectories. The CWC study will be investigated through two cohorts: the predictive and in-depth .The predictive cohort includes patients with a chronic wound scheduled for mechanical debridement. The debrided material will be collected for dual RNA sequencing and 16s ribosomal RNA gene sequencing, as well as samples for microbial culturing and a photo to assess the wound. Clinical data is recorded, and healing and/or other clinical endpoints are established through medical records.The in-depth cohort includes and follows patients undergoing split-thickness skin grafting. Extensive sampling (ESwabs, biopsies, tape strips, debrided material and a sample of the skin graft) will be performed on surgery and patients will be seen at two follow-up visits. Samples will be analysed through culturing and next-generation sequencing methods. A biobank will be established comprising longitudinal clinical samples and clinical data., Ethics and Dissemination: The study has been approved by the board of health ethics, Capital Region of Denmark, under protocol number H-20032214. The study findings will be disseminated through peer-reviewed publications and showcased at both national and international conferences and meetings within the domains of microbiology, wound healing and infection., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with acute brain injury are vulnerable to secondary deterioration, which may go undetected by traditional monitoring. However, multimodal neuromonitoring of brain tissue oxygen tension (PbtO 2 ) and energy metabolism may be able to detect such episodes. We report a retrospective, observational study of 94 patients with aneurysmal subarachnoid haemorrhage (SAH) or traumatic brain injury (TBI) who underwent multimodal neuromonitoring during admission. We examined the co-occurrence of pathological neuromonitoring values: elevated intracranial pressure (ICP, > 20 mmHg), inadequate cerebral perfusion pressure (CPP, < 60 mmHg), brain hypoxia (PbtO 2  < 20 mmHg), and metabolic crisis (lactate/pyruvate ratio > 40 and a glucose level < 0.2 mmol/L in cerebral microdialysate). Mixed effects linear regression demonstrated significant associations between abnormal ICP/CPP, cerebral hypoxia and metabolic crisis. However, brain hypoxia occurred in 40% and 31% of observations in patients with SAH and TBI, respectively, despite normal concurrent values of ICP. Similarly, metabolic crisis was observed in 8% and 16% of measurements for SAH and TBI, respectively, despite a normal ICP. The pattern was identical for CPP. In conclusion, although all neuromonitoring variables are interrelated, brain hypoxia and metabolic crisis are common despite an absence of abnormalities in conventional monitoring. Multimodal neuromonitoring may help identify such episodes and guide individualised treatment., (© 2024. The Author(s).)

Hyperlactatemia is common during tumor craniotomy, but the underlying pathophysiology is unclear. This study measured simultaneous arterial and jugular-bulb lactate concentrations in patients undergoing brain tumor craniotomy to investigate the hypothesis that hyperlactatemia was associated with a net cerebrovascular lactate input. In 20 patients, arterial and jugular-bulb blood was collected hourly from the start of surgery to 6 h postoperatively for measurement of lactate, glucose, and oxygen concentration. For each marker, data were analyzed using a linear mixed-effects model with jugular-bulb concentration as dependent variable, arterial concentration as fixed effect, and patient as random effect. Furthermore, we generated regression lines between arterial and jugular-bulb concentrations. The slope of the regression line between arterial and jugular-bulb lactate was 0.95 (95% CI 0.93-0.97, R 2  = 0.98), indicating that increasing arterial lactate levels were associated with an increasingly positive net cerebrovascular balance (net input). The line crossed the identity line at 2.86 (95% CI 0.57-5.16) mmol/L, indicating that lower levels of lactate were associated with a negative net cerebrovascular balance (net output). This suggests a switch from net lactate output during normolactatemia towards net input during hyperlactatemia. Hyperlactatemia in tumor-craniotomy patients probably does not originate from the brain., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: In intensive care patients with disorders of consciousness, the pupillary light reflex is a measure of pupillary parasympathetic function. By contrast, the pupillary light-off reflex leads to pupil dilation in response to an abrupt change from light to darkness ("light-off") and reflects combined parasympathetic and sympathetic pupillary function. To our knowledge, this reflex has not been systematically investigated in patients with disorders of consciousness. We hypothesized that the pupillary light-off reflex correlates with consciousness levels after acute brain injury., Methods: From November 2022 to March 2023, we enrolled 100 study participants: 25 clinically unresponsive (coma or unresponsive wakefulness syndrome) and 25 clinically low-responsive (minimally conscious state or better) patients from the intensive care units of a tertiary referral center, and 50 age-matched and sex-matched healthy controls. Exclusion criteria were active or chronic eye disease. We used automated pupillometry to assess the pupillary light-off reflex and the pupillary light reflex of both eyes under scotopic conditions in all study participants., Results: The pupillary light-off reflex was strongly correlated with consciousness levels (r = 0.62, p < 0.001), the increase in pupillary diameters being smallest in unresponsive patients (mean ± standard deviation 20% ± 21%), followed by low-responsive patients (mean ± standard deviation 47% ± 26%) and healthy controls (mean ± standard deviation 67% ± 17%; p < 0.001). Similar yet less pronounced patterns were observed for the pupillary light reflex. Twenty-one of 25 (84%) unresponsive patients had preserved pupillary light reflexes, but only seven (28%) had fully preserved pupillary light-off reflexes (p < 0.0001). Of these 7 patients, five (71%) regained awareness., Conclusions: The pupillary light-off reflex may be more sensitive to consciousness levels than the pupillary light reflex. The clinical implications of this finding seem worthy of further investigation, particularly regarding possible benefits for neuromonitoring and prognostication after brain injury., (© 2024. The Author(s).)

Personalizing psychotherapy can be challenging within standardized group Cognitive Behavioral Therapy (CBT), in which sessions are structured according to a protocol and must accommodate the needs and preferences of multiple patients. In the current study, we aimed to examine patients' and therapists' experiences of standardized group CBT and identify their perceptions of different patient needs. Furthermore, we explored how these needs can inform possible content of add-on interventions for patients who are not improving as expected during group CBT.We conducted 21 individual in-depth interviews with patients with depression and their therapists about their experiences during group CBT with Routine Outcome Monitoring (ROM) and feedback. Interviews were analyzed by using a hermeneutic-phenomenological thematic analysis. Five themes, representing different patient needs, were identified: (1) Individual attention, (2) Psychological exploration, (3) A focus on the patient's life outside of therapy, (4) Extended assessment, and (5) Agreement on therapeutic tasks.The study supports that "one size does not fit all" when it comes to psychotherapy. Patients have varying needs when they are not making progress in therapy, and these needs, when unmet, can negatively impact the overall experience of group CBT. By acknowledging the unique needs of each patient and providing additional individual sessions as necessary, we can move towards a more personalized approach that maximizes the benefits of group psychotherapy., (© 2023. The Author(s).)

Background: Identifying covert consciousness in intensive care unit (ICU) patients with coma and other disorders of consciousness (DoC) is crucial for treatment decisions, but sensitive low-cost bedside markers are missing. We investigated whether automated pupillometry combined with passive and active cognitive paradigms can detect residual consciousness in ICU patients with DoC., Methods: We prospectively enrolled clinically low-response or unresponsive patients with traumatic or nontraumatic DoC from ICUs of a tertiary referral center. Age-matched and sex-matched healthy volunteers served as controls. Patients were categorized into clinically unresponsive (coma or unresponsive wakefulness syndrome) or clinically low-responsive (minimally conscious state or better). Using automated pupillometry, we recorded pupillary dilation to passive (visual and auditory stimuli) and active (mental arithmetic) cognitive paradigms, with task-specific success criteria (e.g., ≥ 3 of 5 pupillary dilations on five consecutive mental arithmetic tasks)., Results: We obtained 699 pupillometry recordings at 178 time points from 91 ICU patients with brain injury (mean age 60 ± 13.8 years, 31% women, and 49.5% nontraumatic brain injuries). Recordings were also obtained from 26 matched controls (59 ± 14.8 years, 38% women). Passive paradigms yielded limited distinctions between patients and controls. However, active paradigms enabled discrimination between different states of consciousness. With mental arithmetic of moderate complexity, ≥ 3 pupillary dilations were seen in 17.8% of clinically unresponsive patients and 50.0% of clinically low-responsive patients (odds ratio 4.56, 95% confidence interval 2.09-10.10; p < 0.001). In comparison, 76.9% healthy controls responded with ≥ 3 pupillary dilations (p = 0.028). Results remained consistent across sensitivity analyses using different thresholds for success. Spearman's rank analysis underscored the robust association between pupillary dilations during mental arithmetic and consciousness levels (rho = 1, p = 0.017). Notably, one behaviorally unresponsive patient demonstrated persistent command-following behavior 2 weeks before overt signs of awareness, suggesting prolonged cognitive motor dissociation., Conclusions: Automated pupillometry combined with mental arithmetic can identify cognitive efforts, and hence covert consciousness, in ICU patients with acute DoC., (© 2024. The Author(s).)

Background: Patients with severe acute brain injury have a high risk of a poor clinical outcome due to primary and secondary brain injury. Ketamine reportedly inhibits cortical spreading depolarization, an electrophysiological phenomenon that has been associated with secondary brain injury, making ketamine potentially attractive for patients with severe acute brain injury. The aim of this systematic review is to explore the current literature regarding ketamine for patients with severe acute brain injury., Methods: We systematically searched international databases for randomized clinical trials comparing ketamine by any regimen versus placebo, no intervention, or any control drug for patients with severe acute brain injury. Two authors independently reviewed and selected trials for inclusion, extracted data, assessed risk of bias, and performed analysis using Review Manager and Trial Sequential Analysis. Evidence certainty was assessed using Grading of Recommendations Assessment, Development and Evaluation. The primary outcomes were the proportion of participants with an unfavorable functional outcome, the proportion of participants with one or more serious adverse events, and quality of life., Results: We identified five randomized trials comparing ketamine versus sufentanil, fentanyl, other sedatives, or saline (total N = 149 participants). All outcomes were at overall high risk of bias. The proportions of participants with one or more serious adverse events did not differ between ketamine and sufentanil or fentanyl (relative risk 1.45, 95% confidence interval 0.81-2.58; very low certainty). Trial sequential analysis showed that further trials are needed., Conclusions: The level of evidence regarding the effects of ketamine on functional outcome and serious adverse events in patients with severe acute brain injury is very low. Ketamine may markedly, modestly, or not at all affect these outcomes. Large randomized clinical trials at low risk of bias are needed., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Insertion of an external ventricular drain (EVD) is a first-line treatment of acute hydrocephalus caused by aneurysmal subarachnoid haemorrhage (aSAH). Once the patient is clinically stable, the EVD is either removed or replaced by a permanent internal shunt. The optimal strategy for cessation of the EVD is unknown. Prompt closure carries a risk of acute hydrocephalus or redundant shunt implantations, whereas gradual weaning may increase the risk of EVD-related infections., Methods: DRAIN (Danish RAndomised Trial of External Ventricular Drainage Cessation IN Aneurysmal Subarachnoid Haemorrhage) is an international multicentre randomised clinical trial comparing prompt closure versus gradual weaning of the EVD after aSAH. The primary outcome is a composite of VP-shunt implantation, all-cause mortality, or EVD-related infection. Secondary outcomes are serious adverse events excluding mortality and health-related quality of life (EQ-5D-5L). Exploratory outcomes are modified Rankin Scale, Fatigue Severity Scale, Glasgow Outcome Scale Extended, and length of stay in the neurointensive care unit and hospital. Outcome assessment will be performed 6 months after ictus. Based on the sample size calculation (event proportion 80% in the gradual weaning group, relative risk reduction 20%, alpha 5%, power 80%), 122 participants are required in each intervention group. Outcome assessment for the primary outcome, statistical analyses, and conclusion drawing will be blinded. Two independent statistical analyses and reports will be tracked using a version control system, and both will be published. Based on the final statistical report, the blinded steering group will formulate two abstracts., Conclusion: We present a pre-defined statistical analysis plan for the randomised DRAIN trial, which limits bias, p-hacking, and data-driven interpretations. This statistical analysis plan is accompanied by tables with simulated data, which increases transparency and reproducibility., Trial Registration: ClinicalTrials.gov identifier: NCT03948256. Registered on May 13, 2019., (© 2024. The Author(s).)

Background: Bacterial meningitis can cause a life-threatening increase in intracranial pressure (ICP). ICP-targeted treatment including an ICP monitoring device and external ventricular drainage (EVD) may improve outcomes but is also associated with the risk of complications. The frequency of use and complications related to ICP monitoring devices and EVDs among patients with bacterial meningitis remain unknown. We aimed to investigate the use of ICP monitoring devices and EVDs in patients with bacterial meningitis including frequency of increased ICP, drainage of cerebrospinal fluid (CSF), and complications associated with the insertion of ICP monitoring and external ventricular drain (EVD) in patients with bacterial meningitis., Method: In a single-center prospective cohort study (2017-2021), we examined the frequency of use and complications of ICP-monitoring devices and EVDs in adult patients with bacterial meningitis., Results: We identified 108 patients with bacterial meningitis admitted during the study period. Of these, 60 were admitted to the intensive care unit (ICU), and 47 received an intracranial device (only ICP monitoring device N = 16; EVD N = 31). An ICP > 20 mmHg was observed in 8 patients at insertion, and in 21 patients (44%) at any time in the ICU. Cerebrospinal fluid (CSF) was drained in 24 cases (51%). Severe complications (intracranial hemorrhage) related to the device occurred in two patients, but one had a relative contraindication to receiving a device., Conclusions: Approximately half of the patients with bacterial meningitis needed intensive care and 47 had an intracranial device inserted. While some had conservatively correctable ICP, the majority needed CSF drainage. However, two patients experienced serious adverse events related to the device, potentially contributing to death. Our study highlights that the incremental value of ICP measurement and EVD in managing of bacterial meningitis requires further research., (© 2024. The Author(s).)

Transfer function analysis (TFA) is a widely used method for assessing dynamic cerebral autoregulation in humans. In the present study, we assessed the test-retest reliability of established TFA metrics derived from spontaneous blood pressure oscillations and based on 5 min recordings. The TFA-based gain, phase and coherence in the low-frequency range (0.07-0.20 Hz) from 19 healthy volunteers, 37 patients with subarachnoid haemorrhage and 19 patients with sepsis were included. Reliability assessments included the smallest real difference (SRD) and the coefficient of variance for comparing consecutive 5 min recordings, temporally separated 5 min recordings and consecutive recordings with a minimal length of 10 min. In healthy volunteers, temporally separating the 5 min recordings led to a 0.38 (0.01-0.79) cm s -1  mmHg -1 higher SRD for gain (P = 0.032), and extending the duration of recordings did not affect the reliability. In subarachnoid haemorrhage, temporal separation led to a 0.85 (-0.13 to 1.93) cm s -1  mmHg -1 higher SRD (P = 0.047) and a 20 (-2 to 41)% higher coefficient of variance (P = 0.038) for gain, but neither metric was affected by extending the recording duration. In sepsis, temporal separation increased the SRD for phase by 94 (23-160)° (P = 0.006) but was unaffected by extending the recording. A recording duration of 8 min was required to achieve stable gain and normalized gain measures in healthy individuals, and even longer recordings were required in patients. In conclusion, a recording duration of 5 min appears insufficient for obtaining stable and reliable TFA metrics when based on spontaneous blood pressure oscillations, particularly in critically ill patients with subarachnoid haemorrhage and sepsis., (© 2024 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: Carbapenems are widely used for empiric treatment of healthcare-associated central nervous system (CNS) infections. We investigated the feasibility of a carbapenem-sparing strategy, utilising a third-generation cephalosporin (ceftriaxone or cefotaxime) (combined with vancomycin) for the empirical treatment of healthcare-associated CNS infections in Eastern Denmark., Methods: The departments of neurosurgery and neuro-intensive care at Copenhagen University Hospital Rigshospitalet. First, we analysed local microbiological data (1st January 2020-31st August 2022) to identify microorganisms non-susceptible to third-generation cephalosporin. Subsequently, we assessed all carbapenem prescriptions over a three-month period for their indication and justification., Results: In total, 25,247 bacterial cultures were identified, of which 2,563 CNS-related, were included in the analysis. The positivity rate was 10.5% ( n  = 257/2439) for cerebrospinal-fluid samples and 75.8% ( n  = 95/124) for brain parenchyma. CNS samples from five individual patients revealed bacteria non-susceptible to third generation cephalosporins ( Enterobacter spp . ( n  = 3), Pseudomonas spp. (n = 2), Klebsiella spp. (n = 2), Citrobacter freundii (n = 1)). All five patients had been hospitalised for ≥10days at the time-point of antibiotic therapy. Out of 11,626 sets of blood cultures, a total of 10 individual patients had Gram-negative blood-stream infections with resistance to ceftriaxone and piperacillin/tazobactam. 140 days-of-therapy (32%) with carbapenem in 18 patients (36%) were definitively or possibly indicated according to guidelines, none were indicated for healthcare-associated CNS-infections., Conclusion: An empiric treatment strategy relying on a third-generation cephalosporin appears suitable for healthcare-associated CNS infections at our tertiary hospital, serving a population of 2.6 million. However, in patients with prolonged hospitalization (≥10 days), immunosuppression, prior broad-spectrum antibiotic use, or history of resistant Gram-negative bacteria, empirical prescription of carbapenem may be needed.

The objective of this study was to develop a population pharmacokinetic-pharmacodynamic model of subcutaneously administered bupivacaine in a novel extended-release microparticle formulation for postoperative pain management. Bupivacaine was administered subcutaneously in the lower leg to 28 healthy male subjects in doses from 150 to 600 mg in a phase 1 randomized, placebo-controlled, double-blind, dose-ascending study with two different microparticle formulations, LIQ865A and LIQ865B. Warmth detection threshold was used as a surrogate pharmacodynamic endpoint. Population pharmacokinetic-pharmacodynamic models were fitted to plasma concentration-effect-time data using non-linear mixed-effects modelling. The pharmacokinetics were best described by a two-compartment model with biphasic absorption as two parallel absorption processes: a fast, zero-order process and a slower, first-order process with two transit compartments. The slow absorption process was found to be dose-dependent and rate-limiting for elimination at higher doses. Apparent bupivacaine clearance and the transit rate constant describing the slow absorption process both appeared to decrease with increasing doses following a power function with a shared covariate effect. The pharmacokinetic-pharmacodynamic relationship between plasma concentrations and effect was best described by a linear function. This model gives new insight into the pharmacokinetics and pharmacodynamics of microparticle formulations of bupivacaine and the biphasic absorption seen for several local anaesthetics., (© 2024 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

A novel microparticle-based extended-release local anaesthetic containing a bupivacaine/poly-lactic-co-glycolic acid (PLGA; LIQ865A) or plain bupivacaine (LIQ865B) was examined in a first-in-human trial. The objectives were to examine the dose safety/tolerability and pharmacodynamics. Randomized subcutaneous injections of LIQ865A (n = 16) or LIQ865B (n = 12) and diluent, contralaterally, were administered in a dose-ascending manner (150- to 600-mg bupivacaine). Subjects were admitted 24 h post-injection and followed for 30 days post-injection. The risk ratios (RRs; 95% CI) of erythematous reactions for LIQ865A versus diluent was 9.00 (1.81-52.23; P = 0.006) and for LIQ865B versus diluent 2.50 (0.69-9.94; P = 0.37). The RR for the development of hematomas (LIQ865A versus diluent) were 3.25 (1.52-8.16; P = 0.004) and 4.00 (0.72-24.89; P = 0.32) (LIQ865B versus diluent). Subcutaneous indurations persisting for 4-13 weeks were seen in 6/16 subjects receiving LIQ865A. One subject receiving LIQ865A (600-mg bupivacaine) developed intermittent central nervous system (CNS) symptoms of local anaesthetic systemic toxicity (85 min to 51 h post-injection) coinciding with plasma peak bupivacaine concentrations (490-533 ng/ml). Both LIQ865 formulations demonstrated dose-dependent hypoesthesia and hypoalgesia. The duration of analgesia ranged between 37 and 86 h. The overall number of local adverse events, however, prohibits clinical application without further pharmacological modifications., (© 2024 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

This review summarises the present knowledge of acute foot attacks in patients with diabetes. Diagnosis and treatment of acute foot attacks in patients with diabetes are often delayed, which increases the risk of amputations. To prevent this, urgent action is necessary, as it is for acute myocardial infarction and stroke, to ensure that patients are seen by competent specialists in a multidisciplinary team within hours. By following evidence-based guidelines, such as the National Treatment Guideline for diabetic foot disease from the Danish Endocrine Society, and seeking immediate medical attention, the risk of amputation and complications can be significantly reduced., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Background: In intensive care unit (ICU) patients with coma and other disorders of consciousness (DoC), outcome prediction is key to decision-making regarding prognostication, neurorehabilitation, and management of family expectations. Current prediction algorithms are largely based on chronic DoC, whereas multimodal data from acute DoC are scarce. Therefore, the Consciousness in Neurocritical Care Cohort Study Using Electroencephalography and Functional Magnetic Resonance Imaging (i.e. CONNECT-ME; ClinicalTrials.gov identifier: NCT02644265) investigates ICU patients with acute DoC due to traumatic and nontraumatic brain injuries, using electroencephalography (EEG) (resting-state and passive paradigms), functional magnetic resonance imaging (fMRI) (resting-state) and systematic clinical examinations., Methods: We previously presented results for a subset of patients (n = 87) concerning prediction of consciousness levels in the ICU. Now we report 3- and 12-month outcomes in an extended cohort (n = 123). Favorable outcome was defined as a modified Rankin Scale score ≤ 3, a cerebral performance category score ≤ 2, and a Glasgow Outcome Scale Extended score ≥ 4. EEG features included visual grading, automated spectral categorization, and support vector machine consciousness classifier. fMRI features included functional connectivity measures from six resting-state networks. Random forest and support vector machine were applied to EEG and fMRI features to predict outcomes. Here, random forest results are presented as areas under the curve (AUC) of receiver operating characteristic curves or accuracy. Cox proportional regression with in-hospital death as a competing risk was used to assess independent clinical predictors of time to favorable outcome., Results: Between April 2016 and July 2021, we enrolled 123 patients (mean age 51 years, 42% women). Of 82 (66%) ICU survivors, 3- and 12-month outcomes were available for 79 (96%) and 77 (94%), respectively. EEG features predicted both 3-month (AUC 0.79 [95% confidence interval (CI) 0.77-0.82]) and 12-month (AUC 0.74 [95% CI 0.71-0.77]) outcomes. fMRI features appeared to predict 3-month outcome (accuracy 0.69-0.78) both alone and when combined with some EEG features (accuracies 0.73-0.84) but not 12-month outcome (larger sample sizes needed). Independent clinical predictors of time to favorable outcome were younger age (hazard ratio [HR] 1.04 [95% CI 1.02-1.06]), traumatic brain injury (HR 1.94 [95% CI 1.04-3.61]), command-following abilities at admission (HR 2.70 [95% CI 1.40-5.23]), initial brain imaging without severe pathological findings (HR 2.42 [95% CI 1.12-5.22]), improving consciousness in the ICU (HR 5.76 [95% CI 2.41-15.51]), and favorable visual-graded EEG (HR 2.47 [95% CI 1.46-4.19])., Conclusions: Our results indicate that EEG and fMRI features and readily available clinical data predict short-term outcome of patients with acute DoC and that EEG also predicts 12-month outcome after ICU discharge., (© 2023. The Author(s).)

The mean flow index-usually referred to as Mx-has been used for assessing dynamic cerebral autoregulation (dCA) for almost 30 years. However, concerns have arisen regarding methodological consistency, construct and criterion validity, and test-retest reliability. Methodological nuances, such as choice of input (cerebral perfusion pressure, invasive or non-invasive arterial pressure), pre-processing approach and artefact handling, significantly influence mean flow index values, and previous studies correlating mean flow index with other established dCA metrics are confounded by inherent methodological flaws like heteroscedasticity, while the mean flow index also fails to discriminate individuals with presumed intact versus impaired dCA (discriminatory validity), and its prognostic performance (predictive validity) across various conditions remains inconsistent. The test-retest reliability, both within and between days, is generally poor. At present, no single approach for data collection or pre-processing has proven superior for obtaining the mean flow index, and caution is advised in the further use of mean flow index-based measures for assessing dCA, as current evidence does not support their clinical application., (© 2024 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: Ventriculostomy-associated infection (VAI) is common after external ventricular drains (EVD) insertion but is difficult to diagnose in patients with acute brain injury. Previously, we proposed a set of criteria for ruling out VAI in traumatic brain injury. This study aimed to validate these criteria. For exploratory purposes, we sought to develop and validate a score for VAI risk assessment in patients with different types of severe acute brain injury., Methods: This retrospective cohort study included adults with acute brain injury who received an EVD and in whom CSF samples were taken over a period of 57 months. As standard non-coated bolt-connected EVDs were used. The predictive performance of biomarkers was analyzed as defined previously. A multivariable regression model was performed with five variables., Results: A total of 683 patients with acute brain injury underwent EVD placement and had 1272 CSF samples; 92 (13.5%) patients were categorized as culture-positive VAI, 130 (19%) as culture-negative VAI, and 461 (67.5%) as no VAI. A low CSF WBC/RBC ratio (< 0.037), high CSF/plasma glucose ratio (> 0.6), and low CSF protein (< 0.5g/L) showed a positive predictive value of 0.09 (95%CI, 0.05-0.13). In the multivariable logistic regression model, days to sample (OR 1.09; 95%CI, 1.03-1.16) and CSF WBC/RBC ratio (OR 34.86; 95%CI, 3.94-683.15) were found to predict VAI., Conclusion: In patients with acute brain injury and an EVD, our proposed combined cut-off for ruling out VAI performed satisfactorily. Days to sample and CSF WBC/RBC ratio were found independent predictors for VAI in the multivariable logistic regression model., (© 2024. The Author(s).)

This study aimed to develop and validate "the Imprint method,", a technique for sampling microbes from chronic wounds while preserving their two-dimensional spatial organization. We used nylon filters to sample bacteria and compared with sampling using Eswabs in 12 patients. The Imprint method identified a mean of 0.93 unique species more than Eswab (4.3 ± 2.2 and 3.4 ± 1.4 unique species, respectively; mean ± SD; n = 30). Accuracy between the Eswab and the Imprint method was 93.2% and in cases of disagreement between methods, Imprint had a higher sensitivity in 6/8 of the most prevalent species. In vitro validation confirmed that the Imprint method could transfer bacterial colonies while replicating their two-dimensional organization and the area covered by bacteria on the plate sampled. Clinical testing demonstrated that the imprint method is a rapid and feasible technique that identified more unique bacterial species than Eswab with a good agreement between methods but that Imprint was better at detecting important pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. The Imprint method is a novel technique that cultures and records the two-dimensional organization of microbes, providing an alternative or supplement to conventional surface culture using Eswab., (© 2024 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

The study aimed to investigate the prevalence and characteristics of pain in different ulcer types and to identify factors associated with pain experience in patients with lower-extremity ulcers. A cross-sectional single-centre study was performed, including 130 newly referred outpatients with lower-extremity ulcers. Pain intensity was measured with a visual analog scale (VAS) and pain characteristics with the short form mcgill pain questionnaire-2 (SF-MPQ-2). The mean pain intensity was 29.5 (SD 31.8) at rest and 35.5 (SD 34.1) during movement (0-100 VAS). 61.5% of the patients experienced pain (VAS > 0) at rest and 70.8% during movement. Moderate to severe pain at rest was seen in 39.2% and in 43.8% of patients during movement. The mean total score on SF-MPQ-2 (range 0-220) was 35.9 (SD 32.6). Most of the patients described pain as intermittent (mean 11.8 SD 13.9). Analgesics were prescribed for 78% of the patients. Ulcer type (i.e., arterial, immunological, pressure and venous) and age were associated with pain severity, and women had a significantly lower well-being score than men. Prevalence of pain in patients with lower-extremity ulcers was high across different ulcer aetiologies. Pain intensity and quality must be assessed to obtain adequate pain management., (© 2024 The Authors. Wound Repair and Regeneration published by Wiley Periodicals LLC on behalf of The Wound Healing Society.)

Purpose: Intensive care for patients with traumatic brain injury (TBI) aims, among other tasks, at avoiding high intracranial pressure (ICP), which is perceived to worsen motor and cognitive deficits and increase mortality. International recommendations for threshold values for ICP were increased from 20 to 22 mmHg in 2016 following the findings in a study by Sorrentino et al., which were based on an observational study of patients with TBI of averaged ICP values. We aimed to reproduce their approach and validate the findings in a separate cohort., Methods: Three hundred thirty-one patients with TBI were included and categorised according to survival/death and favourable/unfavourable outcome at 6 months (based on Glasgow Outcome Score-Extended of 6-8 and 1-5, respectively). Repeated chi-square tests of survival and death (or favourable and unfavourable outcome) vs. high and low ICP were conducted with discrimination between high and low ICP sets at increasing values (integers) between 10 and 35 mmHg, using the average ICP for the entire monitoring period. The ICP limit returning the highest chi-square score was assumed to be the threshold with best discriminative ability. This approach was repeated after stratification by sex, age, and initial Glasgow Coma Score (GCS)., Results: An ICP limit of 18 mmHg was found for both mortality and unfavourable outcome for the entire cohort. The female and the low GCS subgroups both had threshold values of 18 mmHg; for all other subgroups, the threshold varied between 16 and 30 mmHg. According to a multiple logistic regression analysis, age, initial GCS, and average ICP are independently associated with mortality and outcome., Conclusions: Using identical methods and closely comparable cohorts, the critical thresholds for ICP found in the study by Sorrentino et al. could not be reproduced., (© 2024. The Author(s).)

Background: The reliability of near-infrared spectroscopy (NIRS) for measuring cerebral oxygenation (ScO 2 ) is controversial due to the possible contamination from extracranial tissues. We compared ScO 2 measured with the NIRS optode on the forehead, the skull and the dura mater in anaesthetised patients undergoing craniotomy. We hypothesised that ScO 2 measured directly on the skull and the dura mater would differ from ScO 2 measured on the skin., Methods: This prospective observational study included 17 adult patients scheduled for elective craniotomy. After induction of general anaesthesia, ScO 2 was measured on the forehead skin, as well as on the skull and on the dura mater in the surgical field. The primary comparison was the difference in ScO 2 measured on the dura mater and on ScO 2 measured on the skin; secondary comparisons were the differences in ScO 2 on the skull and ScO 2 on the skin and the dura mater, respectively. Data were described with median (5%-95% range) and analysed with the Wilcoxon signed-rank test., Results: ScO 2 values on the dura mater were obtained in 11 patients, and median ScO 2 (48%, 29%-95%) did not differ significantly from ScO 2 on the skin (73%, 49%-92%; p = .052), median difference -25% (-35.6% to -1.2%). ScO 2 on the skull (N = 16) was lower than that on the skin (63% [43%-79%] vs. 75% [61%-94%]; p = .0002), median difference -10% (-20.8 to -3.0)., Conclusion: In adults undergoing craniotomy, NIRS-based ScO 2 measured on the dura mater did not reach statistically significantly lower values than ScO 2 measured on the skin, whereas values on the skull were lower than on the skin, indicating a contribution from scalp tissue to the signal., (© 2023 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Background: No standard has been established regarding timing and choice of strategy for discontinuation of external ventricular drainage (EVD) in patients with aneurysmal subarachnoid haemorrhage (aSAH), and little is known about the importance of clinical variables. A proportion of the patients who initially pass their discontinuation attempt return with delayed hydrocephalus and the need of a permanent shunt. Early differentiation between patients who need a shunt and those who do not would facilitate care. We conducted a retrospective analysis on patients with aSAH and an EVD to search significant differences in treatment and clinical variables between patients who received a permanent shunt during initial hospitalization or after readmission, and those who never received a shunt., Methods: We included 183 patients with aSAH who received an EVD over a 4-year period between 2015 and 2018 and divided them into three groups: those who received a shunt during primary admission, those who were readmitted for delayed hydrocephalus and received a shunt, and those who never needed a shunt. Between these groups, we compared selected clinical variables as well as outcome at discharge and after 6 months. Additionally, we assessed the ability of a shunt dependency score (SDASH) to predict the need for permanent drainage in the patients., Results: Of 183 included patients, 108 (59%) ultimately received a ventriculoperitoneal (VP) shunt. Of these, 89 (82%) failed discontinuation during the primary admission and received a permanent shunt before discharge from the neurosurgical department. The remaining 19 (18%) were discharged after successful discontinuation, but subsequently developed delayed hydrocephalus and were admitted for shunt placement a median of 39 (range: 18-235) days after ictus. Ninety-four patients were discharged after successful discontinuation of the EVD, consisting of those who never developed the need for a permanent shunt and the 19 who were readmitted with delayed hydrocephalus, corresponding to a 20% (19/94) readmittance rate. Clinical variables such as drainage volume or discontinuation strategy did not differ across the three groups of patients. The SDASH score failed to provide any clinically useful information regarding prediction of shunt placement., Conclusion: In this study, clinical variables including use of the predictive score SDASH predicted neither the overall need for nor the timing of shunt placement after aSAH. The homogeneous distribution of data between the three different groups renders strong independent clinical predictive factors unlikely. Thus, attempts to predict a permanent shunt requirement from these variables may be futile in these patients., (© 2024. The Author(s).)

Introduction: Acute brain injury can lead to states of decreased consciousness, that is, disorder of consciousness (DoC). Detecting signs of consciousness early is vital for DoC management in the intensive care unit (ICU), neurorehabilitation and long-term prognosis. Our primary objective is to investigate the potential of pharmacological stimulant therapies in eliciting signs of consciousness among unresponsive or low-responsive acute DoC patients., Methods: In a placebo-controlled, randomised, cross-over setting, we evaluate the effect of methylphenidate and apomorphine in 50 DoC patients with acute traumatic or non-traumatic brain injury admitted to the ICU. Patients are examined before and after administration of the trial drugs using (1) neurobehavioural scales to determine the clinical level of consciousness, (2) automated pupillometry to record pupillary responses as a signature for awareness and (3) near-infrared spectroscopy combined with electroencephalography to record neurovascular coupling as a measure for cortical activity. Primary outcomes include pupillary dilations and increase in cortical activity during passive and active paradigms., Ethics: The study has been approved by the ethics committee (Journal-nr: H-21022096) and follows the principles of the Declaration of Helsinki. It is deemed to pose minimal risks and to hold a significant potential to improve treatment options for DoC patients. If the stimulants are shown to enhance cortical modulation of pupillary function and neurovascular coupling, this would warrant a large multicentre trial to evaluate their clinical impact., Dissemination: Results will be available on EudraCT, clinicaltrialsregister.eu and published in an international peer-reviewed journal., Trial Registration Number: EudraCT Number: 2021-001453-31., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We report a surge of patients, especially children and adolescents, with respiratory disease caused by Mycoplasma pneumoniae in Denmark since October 2023. While the surge has reached an epidemic level, no impact on hospital capacity has been observed; only 14% (446/3,195) of cases, primarily adults, required hospitalisation. Macrolide resistance was detected in less than 2% of samples tested. Timely monitoring of hospitalisations linked to M. pneumoniae infections has been established to inform the healthcare system, decisionmakers and the public.

Acute bacterial meningitis (ABM) is associated with increased intracranial pressure (ICP) caused by bacterial invasion and the host response to infection. Antibiotic therapy is a sine qua non, and adjunct dexamethasone decreases mortality. The ICP increase may have a rapid course and death due to herniation is most often seen within the first week. Evidence regarding treatment of increased ICP in ABM is limited; this review summarises observational studies which point towards reduced mortality by applying a structured approach towards normalization of ICP in ABM., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

An expressed and constant wish of the first author's oldest daughter to enhance interaction with her favourite toy animal led to a (re)animation/resuscitation attempt of a 1½-year-old stuffed plush bunny. Initial physical examination found no vital signs. Based on the lack of identifiable airways, we hypothesised that tissue oxygenation might be caused by passive diffusion throughout the body. Hence, animation was attempted by mechanical chest compressions without including airway management or positive-pressure ventilation. Multimodal monitoring of arterial blood pressure (by proxy), intra-'cranial' pressure and oxygen tension, near-infrared spectroscopy of the head and laser-Doppler blood flow was successfully initiated, whereas an attempt at intracranial microdialysis was unsuccessful. Despite achieving measurable arterial blood pressure (by proxy) (12/3 mmHg) and an increase of cerebral perfusion by 30 points, spontaneous circulation or diffusion was not achieved apparently, and ultimately, animation attempts were ceased. Clinical experience, as well as common sense, forces us to conclude that our measurements were contaminated by the intervention, and that we must rethink the method for the animation of stuffed plush bunnies., (Copyright © 2023 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Tick-borne encephalitis (TBE) is a viral tick-borne infection occurring in many parts of Europe and Asia as described in this review. Increasing TBE case numbers have been reported over recent decades. In Denmark the infection is rare (1-14 annual cases). The rise in TBE in Denmark is mainly driven by microfoci outside of Bornholm, primarily North Zealand. Clinical illness has a bi-phasic presentation: "summer-flu" which may be followed by a neuroinfection. No specific treatment exists, and mortality is less-than 1%. A considerable percentage of patients may experience neurological sequelae. TBE is preventable through vaccination., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

With a synchronised data capture and analysis platform, comprehensive data can be collected from the operating room (OR), like in most high-risk industries. This review summarises the various benefits from capturing data from every procedure in the OR. From every surgery there are millions of data which, when synchronised and analysed, can help us to identify, understand and mitigate safety threats. Data can be used to increase efficiency, to identify and predict adverse events, and to increase the quality of teaching in the OR. The rapid advances in modern technology and the introduction of high-reliability culture in healthcare will result in more data-driven, precise, and safer surgical care., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)