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Does neoadjuvant chemoradiation downstage locally advanced pancreatic cancer?

Recent studies suggest that neoadjuvant chemoradiation can downstage locally advanced pancreatic tumors. There is limited evaluable data to support this approach. We review our experience with preoperative chemoradiation for surgically staged, locally advanced pancreatic cancer to determine whether patients are downstaged with multimodal therapy allowing for curative resection. A prospectively collected database from Memorial Sloan-Kettering Cancer Center was reviewed. Patients admitted between January 1993 and March 1999 with locally advanced pancreatic adenocarcinoma were identified (N = 163). Chemoradiation was administered to 87 (53.3%) of 163, and regimens varied from standard 5-fluorouracil/gemcitabine-based therapies to experimental protocols. Only three patients (3/87; 3.4%) had a sufficient clinical response on restaging to warrant reexploration. Of these, two thirds were unresectable on subsequent laparoscopy because of extensive vascular involvement or metastatic disease. Only one patient underwent a potentially curative resection, with a survival of 18 months despite negative margins and no nodal involvement. The overall median survival for all patients with locally advanced disease treated with chemoradiation was 11 months (6.5 months without multimodal therapy; P = 0.004). Although chemoradiation is associated with improved overall survival in locally advanced disease, it rarely leads to surgical "downstaging" allowing for potentially curative pancreatic resections. Novel multimodality approaches are required.

Adenocarcinoma↗

Assessment of deposition of inhaled aerosol in the respiratory tract of man using three-dimensional multimodality imaging and mathematical modeling.

Multimodality medical imaging enables measurement of the three-dimensional spatial distribution of a radiolabeled aerosol within the lung. Using a conceptual spatial morphological model these data may be transformed to provide information on deposition per airway generation. This methodology has been used to study the intrapulmonary deposition patterns of two formulations of a metered dose inhaler and two nebulizers in control subjects. The nebulizer study has also been stimulated using a computer model of deposition. The comparison between derived experimental results and those from computer modeling shows areas of agreement, although there are also areas of discrepancy. The new methodology has considerable potential value in the fields of inhalation therapy and deposition modeling, although more detailed validation is still required.

Administration, Inhalation↗

Return to work following whiplash and back injury: a review and evaluation.

The purpose of this study is to review the reported return-to-work rates following whiplash and back-injury. The return-to-work rates for the 71 relevant studies that were reviewed varied from 29% to 100% with a median of 67%. The results suggest considerable residual return-to-work potential for persons with whiplash and back injury. Return-to-work rates were substantially higher for motor vehicle (96%) compared to work-related (71%) studies and also considerably higher for whiplash (95%) compared to back injuries (65%). It is suggested that these indices may form potential benchmarks for personal injury claims outcomes. The purpose of this paper is to analyse the published rates of return to work following whiplash and back injury. This criterion of return to work is not without limitations or controversy and Pfingsten, Hildebrandt Leibing, Franz and Saur (1997) noted: "... a high variability exists in data on return-to-work. Results often range from either no return to a very high return rate, with an approximate average of 68% following multimodal treatment procedures...".

Back Injuries↗

Visualization of multimodal image information in medicine.

Radiological and clinical practice can be enhanced by improved access to multimodal image informations. Analysis, visualization, method characteristic image processing and image synthesis is needed not only for the interpretation of the images but also for performing effective consultations with clinical colleagues and computer supported therapy planning and control strategies. The distributed system RADVIS (radiological visualization) is presented which enables the fast display, three dimensional visualization and the modality oriented analysis of multimodal image informations. Based on a unique image format, modality specific evaluation procedures and two- or three dimensional processing tools of image analysis produce the input data for therapy planning programs. The easy use of this multimedia visualisation tool enables radiologists and clinicians to deal with their image data. The description of methods and procedures of the prototype, as well as typical examples of radiologic practice will demonstrate the efficiency of the presented system.

Humans↗

Assessment of the role and effectiveness of nurse-led multimodal intervention in the rehabilitation of dysphagia in patients with brain tumors.

BACKGROUND: Dysphagia is a common complication in patients with brain tumors, which has a profound adverse impact on patients' health status and quality of life. However, there is a relative lack of research on the rehabilitation of dysphagia in brain tumor patients, especially regarding the role and effectiveness of nurse-led multimodal interventions in the rehabilitation of dysphagia in brain tumor patients, which lacks systematic assessment and in-depth discussion. AIM: This study aimed to evaluate the role and effectiveness of a nurse-led multimodal intervention in improving swallowing function and quality of life in brain tumor patients with dysphagia. METHODS: In this study, a randomized controlled trial (RCT) design was used to select 120 dysphagia patients among brain tumor patients admitted to our hospital during the period of January 2024 to May 2024 as the study subjects, and they were stratified and randomly divided into an intervention group (n&#x2009;=&#x2009;60) and a control group (n&#x2009;=&#x2009;60). While the control group received conventional nursing care and treatment protocols, the intervention group received a nurse-led multimodal intervention program, including personalized swallowing training, nutritional support, psychological care, and a family-participatory rehabilitation program, which was developed and dynamically adjusted by nurses, rehabilitation therapists, and dietitians. Differences in data before and after the intervention were analyzed using the paired t-test or Wilcoxon signed-rank test, and between-group comparisons were made using the independent samples t-test or Mann-Whitney U test. RESULTS: Both the intervention and control groups showed improvement in swallowing function among the patients. The Kubota drinking test score, Saito's swallowing function grading, and the quality of life scores for patients in the intervention group showed a significant enhancement compared to those in the control group (P&#x2009;<&#x2009;0.05), indicating that the intervention was more effective than the control. When compared within groups, all scores in both the intervention and control groups improved gradually with the time of intervention (P&#x2009;<&#x2009;0.05). The improvement was significantly higher in the intervention group than in the control group. CONCLUSION: This study demonstrates that a nurse-led multimodal intervention is significantly effective in improving swallowing function and quality of life in patients with brain tumors. The intervention provides comprehensive rehabilitation support for patients through multidisciplinary collaboration and personalized care and has certain clinical promotion value.

Humans↗

Spectral vs. compartmental averaging of VA/Q distributions: confidence limits.

We have investigated the method of statistical averaging as a nonparametric approach to obtain a representative ventilation-perfusion (VA/Q) distribution that exemplifies the family of compatible solutions for multiple inert gas elimination data. The variability of the compatible solutions was examined by determining the standard deviation of the statistical average. For six inert gases, it can be predicted that a distribution with up to seven contiguous nonzero VA/Q compartments can be uniquely recovered, whereas the compatible family becomes more diverse, the broader the distribution. For a given compatible family consisting of multimodal distributions with various phase relationships, the average distribution was found to display an uncharacteristically unimodal shape as a result of modal smoothing. To avoid this possible artifact, an alternative approach was adopted in which statistical averaging was performed in the frequency domain. For both deterministic and empirical data, the energy spectra of all feasible VA/Q distributions displayed a well-defined low-frequency band that was invariant within the compatible family and with a bandwidth that approximated the predicted sampling cutoff frequency. The nonuniqueness of the result was ascribable to a variable high-frequency band that was due to an aliasing effect. For a wide range of clinical data, the representative distributions resulting from compartmental and spectral averaging were indistinguishable from each other and had little variability both in the VA/Q and frequency domains. For these cases, therefore, the resolving power of the recovery algorithm was not critical. Finally, an efficient method of finding the average distribution was proposed.

Biometry↗

Translational neurochemical research in acute human brain injury: the current status and potential future for cerebral microdialysis.

Microdialysis (MD) was introduced as an intracerebral sampling method for clinical neurosurgery by Hillered et al. and Meyerson et al. in 1990. Since then MD has been embraced as a research tool to measure the neurochemistry of acute human brain injury and epilepsy. In general investigators have focused their attention to relative chemical changes during neurointensive care, operative procedures, and epileptic seizure activity. This initial excitement surrounding this technology has subsided over the years due to concerns about the amount of tissue sampled and the complicated issues related to quantification. The interpretation of mild to moderate MD fluctuations in general remains an issue relating to dynamic changes of the architecture and size of the interstitial space, blood-brain barrier (BBB) function, and analytical imprecision, calling for additional validation studies and new methods to control for in vivo recovery variations. Consequently, the use of this methodology to influence clinical decisions regarding the care of patients has been restricted to a few institutions. Clinical studies have provided ample evidence that intracerebral MD monitoring is useful for the detection of overt adverse neurochemical conditions involving hypoxia/ischemia and seizure activity in subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), thromboembolic stroke, and epilepsy. There is some data strongly suggesting that MD changes precede the onset of secondary neurological deterioration following SAH, hemispheric stroke, and surges of increased ICP in fulminant hepatic failure. These promising investigations have relied on MD-markers for disturbed glucose metabolism (glucose, lactate, and pyruvate) and amino acids. Others have focused on trying to capture other important neurochemical events, such as excitotoxicity, cell membrane degradation, reactive oxygen species (ROS) and nitric oxide (NO) formation, cellular edema, and BBB dysfunction. However, these other applications need additional validation. Although these cerebral events and their corresponding changes in neurochemistry are important, other promising MD applications, as yet less explored, comprise local neurochemical provocations, drug penetration to the human brain, MD as a tool in clinical drug trials, and for studying the proteomics of acute human brain injury. Nevertheless, MD has provided new important insights into the neurochemistry of acute human brain injury. It remains one of very few methods for neurochemical measurements in the interstitial compartment of the human brain and will continue to be a valuable translational research tool for the future. Therefore, this technology has the potential of becoming an established part of multimodality neuro-ICU monitoring, contributing unique information about the acute brain injury process. However, in order to reach this stage, several issues related to quantification and bedside presentation of MD data, implantation strategies, and quality assurance need to be resolved. The future success of MD as a diagnostic tool in clinical neurosurgery depends heavily on the choice of biomarkers, their sensitivity, specificity, and predictive value for secondary neurochemical events, and the availability of practical bedside methods for chemical analysis of the individual markers. The purpose of this review was to summarize the results of clinical studies using cerebral MD in neurosurgical patients and to discuss the current status of MD as a potential method for use in clinical decision-making. The approach was to focus on adverse neurochemical conditions in the injured human brain and the MD biomarkers used to study those events. Methodological issues that appeared critical for the future success of MD as a routine intracerebral sampling method were addressed.

Biomarkers↗

Role of electrostatic and hydrophobic interactions in Ca(2+)-dependent phospholipid binding by the C(2)A-domain from synaptotagmin I.

Most C(2)-domains bind to phospholipid bilayers as a function of Ca(2+). Although phospholipid binding is central for the normal functions of C(2)-domain proteins, the precise mechanism of phospholipid binding is unclear. One of the key questions is whether phospholipid binding by C(2)-domains is primarily governed by electrostatic or hydrophobic interactions. We have now examined this question for the C(2)A-domain of synaptotagmin I, a membrane protein of secretory vesicles with an essential function in Ca(2+)-triggered exocytosis. Our results confirm previous data showing that Ca(2+)-dependent phospholipid binding by the synaptotagmin C(2)A-domain is exquisitely sensitive to ionic strength, suggesting an essential role for electrostatic interactions. However, we find that hydrophobic interactions mediated by exposed residues in the Ca(2+)-binding loops of the C(2)A-domain, in particular methionine 173, are also essential for tight phospholipid binding. Furthermore, we demonstrate that the apparent Ca(2+) affinity of the C(2)A-domain is determined not only by electrostatic interactions as shown previously, but also by hydrophobic interactions. Together these data indicate that phospholipid binding by the C(2)A-domain, although triggered by an electrostatic Ca(2+)-dependent switch, is stabilized by a hydrophobic mechanism. As a result, Ca(2+)-dependent phospholipid binding proceeds by a multimodal mechanism that mirrors the amphipathic nature of the phospholipid bilayer. The complex phospholipid binding mode of synaptotagmins may be important for its role in regulated exocytosis of secretory granules and synaptic vesicles.

Amino Acid Sequence↗

[Structure quality of independent physicians for pain management--is there a standard?].

BACKGROUND: Evidence based standards for structure quality in out-patient management of chronic pain states do not exist. Therefore we tried to evaluate if german standards for outpatient management of chronic pain states which are based on opinions of experts for pain management influence the outcome quality of independent physicians for treatment of chronic low back pain. METHODS: 35 independent physicians, selected on a voluntary basis from 2100 physicians of a bavarian greater district with 1,6 Mio. inhabitants, and one outpatient treatment facility for pain patients of the university of Erlangen-Nuremberg have been evaluated by questionnaires. Questions examined certain structural conditions of the treatment facility as compared to german guidelines for outpatient treatment of pain patients ("Schmerztherapievereinbarung"). 157 patients suffering from chronic low back pain documented before and after a treatment interval of 6 months their pain intensity during the last 24 hours (numeric rating scale), the interference of pain with daily living (german version of the Brief Pain Inventory) and their quality of life (SF-36). Pre-post changes have been used as parameters for outcome quality. RESULTS: Neither baseline data nor pre-post differences of outcome parameter did correlate significantly with the scores of structure quality (17-71% of maximum) of the treatment facilities. However, multimodal therapy programs have not been used for pain management. CONCLUSIONS: Structural indicators of german guidelines for outpatient treatment of pain patients ("Schmerztherapievereinbarung") are not sufficient to improve outcome quality of patients with chronic back pain. Multimodal therapy programs have been shown to be effective in chronic back pain and should be implemented in the guidelines.

English Abstract↗

Tuning of an electrospray ionization source for maximum peptide-ion transmission into a mass spectrometer.

We describe assembly and optimization of a continuous flow nanoelectrospray source for high-performance analysis on a routine basis. It is derived from an inJection adaptable Fine Ionization Source ("JaFIS"), previously shown to be durable and easy to use (Geromanos, S.; et al. Rapid Commun. Mass Spectrom. 1998, 12, 551-556) and now modified for maximum sensitivity. Proper design, manufacturing, and quality control of spray needles with specific orifice diameters, in combination with precisely controlled helium backpressure and applied voltage, enable stable flows at 1-2 nL/min. Needle positioning and ion spray potential are hereby exceedingly important, as shifts by 0.5 mm or 25 V, respectively, cause significant reduction in signal strength. In addition to prolonged analysis times, ultralow flows also yield higher sensitivity, the result of an improved "overall ion transfer efficiency" measured to be approximately 5% at 1.6 nL/min. Used in combination with a "microtip" (Erdjument-Bromage, H.; et al. J. Chromatogr. A 1998, 826, 167-181), the optimized JaFIS implements infusion-style ESI-MS at sensitivities approaching capillary LC-MS. Spraying times in excess of 20 h allow for any number of tandem mass spectrometric analysis routines to be performed, and to average thousands of scans in every experiment, thereby further improving sensitivity. This was fully illustrated by extensive analysis of a 2-fmol peptide mixture, in a 2-microL volume, using a multimode MS approach.

Amino Acid Sequence↗

A multicompartment vascular model for inferring baseline and functional changes in cerebral oxygen metabolism and arterial dilation.

Functional hemodynamic responses are the composite results of underlying variations in cerebral oxygen consumption and the dilation of arterial vessels after neuronal activity. The development of biophysically based models of the cerebral vasculature allows the separation of the neuro-metabolic and neuro-vascular influences on measurable hemodynamic signals such as functional magnetic resonance imaging or optical imaging. We describe a multicompartment model of the vascular and oxygen transport dynamics associated with stimulus-driven neuronal activation. Our model offers several unique features compared with previous formulations such as the ability to estimate baseline blood flow, volume, and oxygen consumption from functional data. In addition, we introduce a capillary compliance model, arterial and venous oxygen permeability, and model the dynamics of extravascular tissue oxygenation. We apply this model to multimodal optical spectroscopic and laser speckle imaging of the rat somato-sensory cortex during nine conditions of whisker stimulation. By fitting the model using a psuedo-Bayesian framework to incorporate multimodal observations, we estimate baseline blood flow to be 94 (+/-15) mL/100 g min and baseline oxygen consumption to be 6.7 (+/-1.3) mL O(2)/100 g min. We calculate parametric, linear increases in arterial dilation (R(2)=0.96) and CMRO(2) (R(2)=0.87) responses over the nine conditions. Other parameters estimated by the model include vascular transit time and volume reserve, oxygen content, saturation, diffusivity rate constants, and partial pressure of oxygen in the vascular compartments and in the extravascular tissue. Finally, we compare this model to earlier work and find that the multicompartment model more accurately describes the observed oxygenation changes when compared with a single compartment version.

Arteries↗

Anaplastic thyroid carcinoma: behavior, biology, and therapeutic approaches.

Anaplastic thyroid carcinoma (ATC), although exceedingly rare, is the most aggressive solid tumor known. Early studies on the effects of different therapies may be biased by the inclusion of responsive "small cell" ATC patients, which are now known to be mostly lymphoma patients. Local control of disease with surgery and/or external beam radiotherapy (XRT) is of fundamental importance to enhance survival. Ultimately, nearly all ATC patients die from their disease, which is widely metastatic. Development of effective systemic chemotherapy agents would provide the best chance for long-term survival of patients. Early preliminary data suggest that paclitaxel may be helpful, although no agent has yet been identified to result in dramatic improvements in survival. Select patients may benefit from aggressive multimodal therapy, although it is important to provide appropriate palliative care when desired.

Antineoplastic Agents, Phytogenic↗

Sinonasal undifferentiated carcinoma: an update.

PURPOSE OF REVIEW: Sinonasal undifferentiated carcinoma is a rare and extremely malignant tumor of the paranasal sinuses. Historically, treatment outcomes have been poor. This review presents recent data on the management of sinonasal undifferentiated carcinoma and examines treatment trends that may result in improved locoregional control and survival. RECENT FINDINGS: Patients who receive aggressive multimodality treatments have improved outcomes. In particular, a chemoradiotherapy regimen including concurrent platinum-based chemotherapy given preoperatively or postoperatively to patients with resectable disease seems to result in better disease-free survival. Neoadjuvant chemotherapy, although strongly advocated by some, is currently not offered by many. Although surgery seems to be an important part of the treatment for sinonasal undifferentiated carcinoma, its ideal timing, either upfront or after radiotherapy, remains uncertain. SUMMARY: Overall, outcomes for sinonasal undifferentiated carcinoma are poor. An aggressive approach using surgery, platinum-based chemotherapy, and radiation seems to offer the greatest chance for significant locoregional control and survival.

Carcinoma↗

Hepatocellular carcinoma: interventional bridging to liver transplantation.

Hepatocellular carcinoma (HCC) is one of the most common solid cancers worldwide with surgery being considered the treatment of choice. However, it is limited in view of the hepatic dysfunction and high recurrence rates associated with the disease. Liver transplantation offers the advantage of both, eradicating the tumor and treating the underlying liver disease and is the only chance for cure in patients suffering from HCC. Survival is known to reach 70% after 5 years and recurrent tumor can be found in less than 20% provided transplantation is restricted to patients with single tumors < or =5 cm or three nodules <3 cm (Milan criteria). However, donor organs are limited and the time on the transplant waiting list is up to 6 or 12 months in Europe and the United States with up to 30-40% dropouts per year. It has been demonstrated that patients with untreated HCC while on the waiting list longer than 6-10 months do not have any benefit in survival after liver transplantation. Interventional treatment options such as transarterial chemoembolization and percutaneous ablation techniques documented promising results concerning the reduction of dropouts from the waiting list and the potential risk for recurrent tumor. Mortality and morbidity were considerably low when radiological interventions had been considered as bridging therapies for liver transplantation. Percutaneous therapies come along with tumoral seeding of 0.1% to 0.6%. Adjuvant treatment with TACE, PEI, and/ or RFA in T1- and T2-staged HCC resulted in tumor-free survival after transplantation of 95.2% after 4 years and intention-to-treat survival of 94%, 85%, and 79% at 1, 2, and 3 years, respectively. Aggressive ablation therapy with a short transplant waiting time has the potential to optimize the use of liver transplantation for curative intent in selected cirrhotic HCC patients. Especially combined treatments seemed to play a key role in achieving complete tumor necrosis associated with improved disease-free survival after liver transplantation. In conclusion, no evidence based data exist in the literature supporting the efficacy of adjuvant interventional treatment modalities for HCC in patients awaiting liver transplantation. However, it has been shown that adjuvant (multimodal) interventional treatments seem a promising option for safe and effective bridging.

Carcinoma, Hepatocellular↗

8th international conference: primary therapy of early breast cancer, St Gallen, Switzerland, March 12-15 2003.

The International St Gallen Breast Cancer Conference concentrates almost exclusively on adjuvant, multimodal primary therapy for early breast cancer. Begun 25 years ago, this meeting was initially held every 4 years, but therapeutic progress, new strategies and provocative trials data have accelerated to the extent that conferences are now held biennially. The meeting this year was attended by almost 3000 delegates. Major topics included new prognostic and predictive markers in early breast cancer, the best use of adjuvant chemotherapy and endocrine therapy, and innovations in local surgery and radiation therapy.

Biomarkers, Tumor↗

Minimally invasive transforaminal lumbar interbody fusion with unilateral pedicle screw fixation.

OBJECT: Posterior lumbar interbody fusion (PLIF) has been shown to be effective in the treatment of axial low-back pain. Minimally invasive spine surgery for arthrodesis has several advantages, including quicker patient recovery, less postoperative pain, and less destruction of adjacent tissue. The purpose of this paper is to evaluate the clinical outcomes after PLIF procedures in which unilateral pedicle screw fixation was used. METHODS: Prospective data were collected in 34 patients undergoing a one-level minimally invasive transforaminal lumbar interbody fusion (TLIF) in 2003. Conservative therapy, including physical therapy and aggressive multimodality pain management, had failed in all patients. Selection was based on magnetic resonance imaging studies demonstrating degenerative disc disease. All patients underwent a unilateral TLIF procedure in conjunction with posterior unilateral pedicle screw fixation. Twenty patients in whom the follow-up duration was longer than 6 months were included in this study. The follow-up duration in all patients ranged from 6 to 12 months. Seventeen (85%) of 20 patients had a good result, which was defined as a greater than 20-point reduction in the Oswestry Disability Index (ODI) score. The other three patients had no improvement. The mean preoperative ODI score of 57 improved to 25 after surgery (p < 0.005). In the 17 patients who demonstrated improvement, the mean ODI score improved from 57 to 18. The patients' visual analog scale pain scores improved from 8.3 to 1.4 (p < 0.005) after surgery. In patients who received Workers' Compensation, three (75%) of four improved. Follow-up computerized tomography scans were obtained in all 20 patients at 6 months. At that time, 13 of the patients demonstrated some degree of fusion, and no symptomatic pseudarthrosis was noted. CONCLUSIONS: Minimally invasive TLIF in conjunction with unilateral pedicle screw instrumentation is an effective treatment for axial low-back pain in appropriately selected patients.

Adult↗

A lack of evidence in 4-month-old human infants for paternal voice preference.

Several studies have found that human infants recognize the sight, sound, smell, and touch of their mothers. Maternal recognition occurs early in development, often being influenced by prenatal experiences. In contrast, the development of infants' recognition of their fathers is not understood. We investigated whether 4-month-old human infants preferred their fathers' voices, in two different speaking contexts. In both Experiments 1 and 2, infants were tested with fathers' adult-directed (AD) or infant-directed (ID) speech. In all experiments, infants were allowed to listen to recordings of either father's or other's voice contingent on their visual attention. Results from the first two experiments showed that infants did not prefer their fathers' voices over unfamiliar male voices. However, in Experiment 3, 4-month-olds showed that they could discriminate the male voices heard in the previous studies. These data were interpreted as supporting the hypothesis that the experiences necessary for the development of maternal preferences are different from those supporting paternal preferences, and that perhaps multimodal cues are necessary for father recognition in infancy.

Choice Behavior↗

[Multimodal evoked potentials and heart rate variability in comatose patients--1: Method of measuring and normal values].

Multimodal EPs and heart rate variability-measurements in comatose patients have been performed for few years at the university hospitals of Graz and Erlangen. The following data and parameters are analysed and discussed: brainstem auditory evoked potentials, mechanical evoked long-latency SEP, VEP recorded over the central and occipital region and heart rate variability (HRV). The method of data acquisition and processing is described and normative data are introduced. For the long-latency EP-components a signal-to-noise-ratio (SNR) is calculated. SNR is defined as ratio of the largest EP peak-to-peak amplitude and the mean amplitude (standard deviation) of a period prior to the stimulation. An unmeasurable or questionable EP is defined when SNR less than 2.6. For the vertex-SEP the following mean +/- standard deviation was obtained: SNR = 10.6 +/- 4.6; the vertex VEP was calculated with SNR = 7.0 +/- 3.0. The SNR of the bipolar recorded occipitally VEP was 3.9 +/- 2.0. Heart rate variability measurements in normal persons revealed the following mean +/- standard deviation at a heart rate of 67.8/min +/- 10.8/min: HRV = 7.8% +/- 2.5%.

Brain Death↗