Major advances in understanding the pathogenesis of inherited metabolic disease caused by mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber's hereditary ...optic neuropathy is the most common mitochondrial DNA disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber's hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber's hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the mitochondrial disorder, Leber's hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.
Postoperative delirium (POD) is the most common complication following surgery in elderly patients. During pharmacist-led medication reconciliation (PhMR), a predictive risk score considering ...delirium risk-increasing drugs and other available risk factors could help to identify risk patients.
Orthopaedic and trauma surgery patients aged ≥ 18 years with PhMR were included in a retrospective observational single-centre study 03/2022-10/2022. The study cohort was randomly split into a development and a validation cohort (6:4 ratio). POD was assessed through the 4 A's test (4AT), delirium diagnosis, and chart review. Potential risk factors available at PhMR were tested via univariable analysis. Significant variables were added to a multivariable logistic regression model. Based on the regression coefficients, a risk score for POD including delirium risk-increasing drugs (DRD score) was established.
POD occurred in 42/328 (12.8%) and 30/218 (13.8%) patients in the development and validation cohorts, respectively. Of the seven evaluated risk factors, four were ultimately tested in a multivariable logistic regression model. The final DRD score included age (66-75 years, 2 points; > 75 years, 3 points), renal impairment (eGFR < 60 ml/min/1.73m
, 1 point), anticholinergic burden (ACB-score ≥ 3, 1 point), and delirium risk-increasing drugs (n ≥ 2; 2 points). Patients with ≥ 4 points were classified as having a high risk for POD. The areas under the receiver operating characteristic curve of the risk score model were 0.89 and 0.81 for the development and the validation cohorts, respectively.
The DRD score is a predictive risk score assessable during PhMR and can identify patients at risk for POD. Specific preventive measures concerning drug therapy safety and non-pharmacological actions should be implemented for identified risk patients.
Delirium is a common disorder affecting around 31% of patients in the intensive care unit (ICU). Delirium assessment scores such as the Confusion Assessment Method (CAM) are time-consuming, they ...cannot differentiate between different types of delirium and their etiologies, and they may have low sensitivities in the clinical setting. While today, electroencephalography (EEG) is increasingly being applied to delirious patients in the ICU, a lack of clear cut EEG signs, leads to inconsistent assessments.
We therefore conducted a scoping review on EEG findings in delirium. One thousand two hundred thirty-six articles identified through database search on PubMed and Embase were reviewed. Finally, 33 original articles were included in the synthesis.
EEG seems to offer manifold possibilities in diagnosing delirium. All 33 studies showed a certain degree of qualitative or quantitative EEG alterations in delirium. Thus, normal routine (rEEG) and continuous EEG (cEEG) make presence of delirium very unlikely. All 33 studies used different research protocols to at least some extent. These include differences in time points, duration, conditions, and recording methods of EEG, as well as different patient populations, and diagnostic methods for delirium. Thus, a quantitative synthesis and common recommendations are so far elusive.
Future studies should compare the different methods of EEG recording and evaluation to identify robust parameters for everyday use. Evidence for quantitative bi-electrode delirium detection based on increased relative delta power and decreased beta power is growing and should be further pursued. Additionally, EEG studies on the evolution of a delirium including patient outcomes are needed.
Aneurysmal subarachnoid hemorrhage (aSAH) often necessitates prolonged sedation to manage elevated intracranial pressure (ICP) and to prevent secondary brain injury. Optimal timing and biomarkers for ...predicting adverse events (AEs) during interruption of sedation (IS) after prolonged sedation are not well established. To guide sedation management in aSAH, we aimed to explore the frequency, risk factors, and outcomes of IS in aSAH.
In a retrospective cohort study, a total of 148 patients with aSAH from January 2015 to April 2020 were screened. In total, 30 patients accounting for 42 IS were included in the analysis. Adverse events (AEs) during IS were used as core outcome measures and were categorized into neurological and non-neurological AEs. Baseline characteristics, clinical parameters before IS, AEs, and functional outcomes were collected using health records. Statistical analysis used generalized linear mixed-effects models with regularization to identify candidate predictors with subsequent bootstrapping to test model stability. As an exploratory analysis, multivariate linear and logistic regression was used to analyze the association between IS and intensive care unit length of stay, duration of mechanical ventilation, and functional outcomes.
The mean age was 56.9 (SD 14.8) years, and a majority of the patients presented with poor-grade SAH (16/30, 53.3%). Neurological and non-neurological AEs occurred in 60.0% (18/30) of the patients. Timing, number of IS attempts, ICP burden, craniectomy status, level of consciousness, heart rate, cerebral perfusion pressure, oxygen saturation, fraction of inspired oxygen, and temperature were selected as candidate predictors. Through bootstrapping, elapsed time since disease onset (OR 0.85, 95% confidence interval (95% CI) 0.75-0.97), ICP burden (OR 1.24, 95% CI 1.02-1.52), craniectomy (OR 0.68, 95% CI 0.48-0.69), and oxygen saturation (OR, 0.80 0.72-0.89) were revealed as relevant biomarkers for neurological AEs, while none of the pre-selected predictors was robustly associated with non-neurological AEs.
In aSAH, complications during the definite withdrawal of sedation are frequent but can potentially be predicted using clinical parameters available at the bedside. Prospective multicenter studies are essential to validate these results and further investigate the impact of IS complications.
Introduction: Akinetic mutism is a severe state of impaired volition that can result from a stroke. Its therapeutic evidence relies on single case reports that used atomoxetine or levodopa with ...variable latency and efficacy. Case presentation: We present the case of a 54-year-old woman who developed akinetic mutism after infarction in the territory of the right anterior cerebral artery, successfully treated with methylphenidate and levodopa/benserazide. Clinical examination showed a patient lacking any spontaneous speech and movement while opening her eyes and fixating. Suspecting akinetic mutism after a comprehensive diagnostic work-up, we started an individual therapy attempt with methylphenidate 10 mg and levodopa/benserazide 100/25 mg twice daily. Both drugs affect the dopaminergic and noradrenergic transmission in the frontal-subcortical circuit, compromised in akinetic mutism. We saw rapid and sustained improvement in her volitional actions, devoid of side effects. Finally, the patient was actively communicating and moving her limbs. Conclusion: We discuss the patient's favorable clinical course in response to the synergistic combination of methylphenidate and levodopa/benserazide, emerging as a promising treatment strategy, and provide a brief literature review of treatment options in akinetic mutism following stroke.
This study aims at evaluating the effect of simulating porcelain firing on the microstructure, corrosion behavior and mechanical properties of a Co–Cr–Mo alloy fabricated by Metal Soft Milling (MSM). ...Two groups of Co-28Cr-5Mo specimens (25 × 20 × 3 mm) were prepared by MSM: The as-sintered (AS) specimens and the post-fired (PF) specimens that were subjected to 5 simulating porcelain firing cycles without applying the ceramic mass onto their surface. Phase identification by X-ray Diffraction (XRD), microstructure examination by optical microscopy and Scanning Electron Microscopy combined with Energy-Dispersive X-ray Spectroscopy (SEM/EDX), corrosion testing by cyclic polarization and chronoamperometry in simulated body fluid (SBF), the latter test accompanied by Cr
3+
and Cr
6+
detection in the electrolyte through the 1.5-diphenylcarbazide (DPC) method and UV/visible spectrophotometry, and mechanical testing by micro-/nano-indentation were conducted to evaluate the effect of the post-firing cycles on the properties of Co–Cr–Mo. The results were statistically analyzed by the t test (p < 0.05: statistically significant). All specimens had a mixed γ-fcc and ε-hcp cobalt-based microstructure with a dispersion of pores filled with SiO
2
and a fine M
23
C
6
intergranular presence. PF led to an increase in the ε-Co content and slight grain coarsening. Both AS and PF alloys showed high resistance to general and localized corrosion, whereas neither Cr
6+
nor Cr
3+
were detected during the passivity-breakdown stage. PF improved the mechanical properties of the AS-alloy, especially the indentation modulus and true hardness (statistically significant differences: p = 0.0009 and 0.006, respectively). MSM and MSM/simulating-porcelain firing have been proven trustworthy fabrication methods of Co–Cr–Mo substrates for metal-ceramic prostheses. Moreover, the post-firing cycles improve the mechanical behavior of Co–Cr–Mo, which is vital under the dynamically changing loads in the oral cavity, whereas they do not degrade the corrosion performance.
The aim of the present study was to record the metal-ceramic bond strength of a feldspathic dental porcelain and a Co-Cr alloy, using the Direct Metal Laser Sintering technique (DMLS) for the ...fabrication of metal substrates.
Ten metal substrates were fabricated with powder of a dental Co-Cr alloy using DMLS technique (test group) in dimensions according to ISO 9693. Another ten substrates were fabricated with a casing dental Co-Cr alloy using classic casting technique (control group) for comparison. Another three substrates were fabricated using each technique to record the Modulus of Elasticity (
) of the used alloys. All substrates were examined to record external and internal porosity. Feldspathic porcelain was applied on the substrates. Specimens were tested using the three-point bending test. The failure mode was determined using optical and scanning electron microscopy. The statistical analysis was performed using t-test.
Substrates prepared using DMLS technique did not show internal porosity as compared to those produced using the casting technique. The E of control and test group was 222 ± 5.13 GPa and 227 ± 3 GPa, respectively. The bond strength was 51.87 ± 7.50 MPa for test group and 54.60 ± 6.20 MPa for control group. No statistically significant differences between the two groups were recorded. The mode of failure was mainly cohesive for all specimens.
Specimens produced by the DMLS technique cover the lowest acceptable metal-ceramic bond strength of 25 MPa specified in ISO 9693 and present satisfactory bond strength for clinical use.
Microstructural and physico-mechanical characterization of highly translucent zirconia, prepared by milling technology (CAD-CAM) and repeated firing cycles, was the main aim of this
study.
Two groups ...of samples of two commercial highly-translucent yttria-stabilized dental zirconia, VITA YZ-HT
(Group A) and Zolid HT + White (Group B), with dimensions according to the ISO 6872 "Dentistry - Ceramic materials", were prepared. The specimens of each group were divided into two subgroups. The specimens of the first subgroups (Group A
and Group B
) were merely the sintered specimens. The specimens of the second subgroups (Group A
and Group B
) were subjected to 4 heat treatment cycles. The microstructural features (microstructure, density, grain size, crystalline phases, and crystallite size) and four mechanical properties (flexural strength, modulus of elasticity, Vickers hardness, and fracture toughness) of the subgroups (i.e. before and after heat treatment) were compared. The statistical significance between the subgroups (A
/A
, and B
/B
) was evaluated by the t-test. In all tests,
values smaller than 5% were considered statistically significant.
A homogenous microstructure, with no residual porosity and grains sized between 500 and 450 nm for group A and B, respectively, was observed. Crystalline yttria-stabilized tetragonal zirconia was exclusively registered in the X-ray diffractograms. The mechanical properties decreased after the heat treatment procedure, but the differences were not statistically significant.
The produced zirconia ceramic materials can be safely (i.e., according to the ISO 6872) used in extensive fixed prosthetic restorations, such as substructure ceramics for three-unit prostheses involving the molar restoration and substructure ceramics for prostheses involving four or more units. Consequently, milling technology is an effective manufacturing technology for producing zirconia substructures for dental fixed all-ceramic prosthetic restorations.
Temporalis muscle (TM) atrophy has emerged as a potential biomarker for muscle wasting. However, its diagnostic utility as a monitoring tool in intensive care remains uncertain. Hence, the objective ...of this study was to evaluate the diagnostic value of sequential ultrasound- and computed tomography (CT)-based measurements of TM thickness (TMT). With a prospective observational design, we included 40 patients without preexisting sarcopenia admitted to a neurointensive care unit. TMT measurements, performed upon admission and serially every 3−4 days, were correlated with rectus femoris muscle thickness (RFT) ultrasound measurements. Interrater reliability was assessed by Bland Altmann plots and intraclass correlation coefficient (ICC). Analysis of variance was performed in subgroups to evaluate differences in the standard error of measurement (SEM). RFT decline was paralleled by ultrasound- as well as CT-based TMT measurements (TMT to RFT: r = 0.746, p < 0.001; CT-based TMT to ultrasound-based RFT: r = 0.609, p < 0.001). ICC was 0.80 95% CI 0.74, 0.84 for ultrasound-based assessment and 0.90 95% CI 0.88, 0.92 for CT-based TMT measurements. Analysis of variance for BMI, Heckmatt score, fluid balance, and agitation showed no evidence of measurement errors in these subgroups. This study demonstrates the clinical feasibility and utility of ultrasound- and CT-based TMT measurements for the assessment of muscle wasting.
Abstract
Background
Neurologic manifestations are increasingly reported in patients with coronavirus disease 2019 (COVID-19). Yet, data on prevalence, predictors and relevance for outcome of ...neurological manifestations in patients requiring intensive care are scarce. We aimed to characterize prevalence, risk factors and impact on outcome of neurologic manifestations in critically ill COVID-19 patients.
Methods
In the prospective, multicenter, observational registry study PANDEMIC (Pooled Analysis of Neurologic DisordErs Manifesting in Intensive care of COVID-19), we enrolled COVID-19 patients with neurologic manifestations admitted to 19 German intensive care units (ICU) between April 2020 and September 2021. We performed descriptive and explorative statistical analyses. Multivariable models were used to investigate factors associated with disorder categories and their underlying diagnoses as well as to identify predictors of outcome.
Results
Of the 392 patients included in the analysis, 70.7% (277/392) were male and the mean age was 65.3 (SD ± 3.1) years. During the study period, a total of 2681 patients with COVID-19 were treated at the ICUs of 15 participating centers. New neurologic disorders were identified in 350 patients, reported by these centers, suggesting a prevalence of COVID-19-associated neurologic disorders of 12.7% among COVID-19 ICU patients. Encephalopathy (46.2%; 181/392), cerebrovascular (41.0%; 161/392) and neuromuscular disorders (20.4%; 80/392) were the most frequent categories identified. Out of 35 cerebrospinal fluid analyses with reverse transcriptase PCR for SARS-COV-2, only 3 were positive. In-hospital mortality was 36.0% (140/389), and functional outcome (mRS 3 to 5) of surviving patients was poor at hospital discharge in 70.9% (161/227). Intracerebral hemorrhage (OR 6.2, 95% CI 2.5–14.9,
p
< 0.001) and acute ischemic stroke (OR 3.9, 95% CI 1.9–8.2,
p
< 0.001) were the strongest predictors of poor outcome among the included patients.
Conclusions
Based on this well-characterized COVID-19 ICU cohort, that comprised 12.7% of all severe ill COVID-19 patients, neurologic manifestations increase mortality and morbidity. Since no reliable evidence of direct viral affection of the nervous system by COVID-19 could be found, these neurologic manifestations may for a great part be indirect para- or postinfectious sequelae of the infection or severe critical illness. Neurologic ICU complications should be actively searched for and treated.
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