Intracranial pulse pressure waveform analysis using the higher harmonics centroid.

Funder: National Health Research Institutes; doi: http://dx.doi.org/10.13039/501100004737BACKGROUND: The pulse waveform of intracranial pressure (ICP) is its distinctive feature almost always present in the clinical recordings. In most cases, it changes proportionally to rising ICP, and observation of these changes may be clinically useful. We introduce the higher harmonics centroid (HHC) which can be defined as the center of mass of harmonics of the ICP pulse waveform from the 2nd to 10th, where mass corresponds to amplitudes of these harmonics. We investigate the changes in HHC during ICP monitoring, including isolated episodes of ICP plateau waves. MATERIAL AND METHODS: Recordings from 325 patients treated between 2002 and 2010 were reviewed. Twenty-six patients with ICP plateau waves were identified. In the first step, the correlation between HHC and ICP was examined for the entire monitoring period. In the second step, the above relation was calculated separately for periods of elevated ICP during plateau wave and the baseline. RESULTS: For the values averaged over the whole monitoring period, ICP (22.3 ± 6.9 mm Hg) correlates significantly (R = 0.45, p = 0.022) with HHC (3.64 ± 0.46). During the ICP plateau waves (ICP increased from 20.9 ± 6.0 to 53.7 ± 9.7 mm Hg, p < 10-16), we found a significant decrease in HHC (from 3.65 ± 0.48 to 3.21 ± 0.33, p = 10-5). CONCLUSIONS: The good correlation between HHC and ICP supports the clinical application of pressure waveform analysis in addition to the recording of ICP number only. Mean ICP may be distorted by a zero drift, but HHC remains immune to this error. Further research is required to test whether a decline in HHC with elevated ICP can be an early warning sign of intracranial hypertension, whether individual breakpoints of correlation between ICP and its centroid are of clinical importance

Ectopic T Cell Receptor-α Locus Control Region Activity in B Cells Is Suppressed by Direct Linkage to Two Flanking Genes at Once

The molecular mechanisms regulating the activity of the TCRα gene are required for the production of the circulating T cell repertoire. Elements of the mouse TCRα locus control region (LCR) play a role in these processes. We previously reported that TCRα LCR DNA supports a gene expression pattern that mimics proper thymus-stage, TCRα gene-like developmental regulation. It also produces transcription of linked reporter genes in peripheral T cells. However, TCRα LCR-driven transgenes display ectopic transcription in B cells in multiple reporter gene systems. The reasons for this important deviation from the normal TCRα gene regulation pattern are unclear. In its natural locus, two genes flank the TCRα LCR, TCRα (upstream) and Dad1 (downstream). We investigated the significance of this gene arrangement to TCRα LCR activity by examining transgenic mice bearing a construct where the LCR was flanked by two separate reporter genes. Surprisingly, the presence of a second, distinct, reporter gene downstream of the LCR virtually eliminated the ectopic B cell expression of the upstream reporter observed in earlier studies. Downstream reporter gene activity was unaffected by the presence of a second gene upstream of the LCR. Our findings indicate that a gene arrangement in which the TCRα LCR is flanked by two distinct transcription units helps to restrict its activity, selectively, on its 5′-flanking gene, the natural TCRα gene position with respect to the LCR. Consistent with these findings, a TCRα/Dad1 locus bacterial artificial chromosome dual-reporter construct did not display the ectopic upstream (TCRα) reporter expression in B cells previously reported for single TCRα transgenes

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Analysis of intracranial pressure pulse waveform in traumatic brain injury patients: a CENTER-TBI study

OBJECTIVE Intracranial pressure (ICP) pulse waveform analysis may provide valuable information about cerebrospinal pressure-volume compensation in patients with traumatic brain injury (TBI). The authors applied spectral methods to analyze ICP waveforms in terms of the pulse amplitude of ICP (AMP), high frequency centroid (HFC), and higher harmonics centroid (HHC) and also used a morphological classification approach to assess changes in the shape of ICP pulse waveforms using the pulse shape index (PSI). METHODS The authors included 184 patients from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) High-Resolution Sub-Study in the analysis. HFC was calculated as the average power-weighted frequency within the 4- to 15-Hz frequency range of the ICP power density spectrum. HHC was defined as the center of mass of the ICP pulse waveform harmonics from the 2nd to the 10th. PSI was defined as the weighted sum of artificial intelligence–based ICP pulse class numbers from 1 (normal pulse waveform) to 4 (pathological waveform). RESULTS AMP and PSI increased linearly with mean ICP. HFC increased proportionally to ICP until the upper breakpoint (average ICP of 31 mm Hg), whereas HHC slightly increased with ICP and then decreased significantly when ICP exceeded 25 mm Hg. AMP (p < 0.001), HFC (p = 0.003), and PSI (p < 0.001) were significantly greater in patients who died than in patients who survived. Among those patients with low ICP (< 15 mm Hg), AMP, PSI, and HFC were greater in those with poor outcome than in those with good outcome (all p < 0.001). CONCLUSIONS Whereas HFC, AMP, and PSI could be used as predictors of mortality, HHC may potentially serve as an early warning sign of intracranial hypertension. Elevated HFC, AMP, and PSI were associated with poor outcome in TBI patients with low ICP

Relationship between the shape of intracranial pressure pulse waveform and computed tomography characteristics in patients after traumatic brain injury.

BACKGROUND: Midline shift and mass lesions may occur with traumatic brain injury (TBI) and are associated with higher mortality and morbidity. The shape of intracranial pressure (ICP) pulse waveform reflects the state of cerebrospinal pressure-volume compensation which may be disturbed by brain injury. We aimed to investigate the link between ICP pulse shape and pathological computed tomography (CT) features. METHODS: ICP recordings and CT scans from 130 TBI patients from the CENTER-TBI high-resolution sub-study were analyzed retrospectively. Midline shift, lesion volume, Marshall and Rotterdam scores were assessed in the first CT scan after admission and compared with indices derived from the first 24 h of ICP recording: mean ICP, pulse amplitude of ICP (AmpICP) and pulse shape index (PSI). A neural network model was applied to automatically group ICP pulses into four classes ranging from 1 (normal) to 4 (pathological), with PSI calculated as the weighted sum of class numbers. The relationship between each metric and CT measures was assessed using Mann-Whitney U test (groups with midline shift > 5 mm or lesions > 25 cm3 present/absent) and the Spearman correlation coefficient. Performance of ICP-derived metrics in identifying patients with pathological CT findings was assessed using the area under the receiver operating characteristic curve (AUC). RESULTS: PSI was significantly higher in patients with mass lesions (with lesions: 2.4 [1.9-3.1] vs. 1.8 [1.1-2.3] in those without; p  0.7 in classification of patients as presenting pathological CT features compared to AUCs ≤ 0.6 for mean ICP and AmpICP. CONCLUSIONS: ICP pulse shape reflects the reduction in cerebrospinal compensatory reserve related to space-occupying lesions despite comparable mean ICP and AmpICP levels. Future validation of PSI is necessary to explore its association with volume imbalance in the intracranial space and a potential complementary role to the existing monitoring strategies

Liver Transplantation for Hilar Cholangiocarcinoma: A German Survey

Background. The present study reports a German survey addressing outcomes in nonselected historical series of liver transplantation (OLT) for hilar cholangiocarcinoma (HL). Patients and Methods. We sent to all 25 German transplant centers performing OLT a survey that addressed (1) the number of OLTs for HL and the period during which they were performed; (2) the incidence of HL diagnosed prior to OLT/rate of incidental HL (for example, in primary sclerosing cholangitis); (3) tumor stages according to Union Internationale Centre le Cancer; (4) patient survival; and (5) tumor recurrence rate. Results. Eighty percent of centers responded, reporting 47 patients who were transplanted for HL. Tumors were classified as pT2 (25%), pT3 (73%), or pT4 (2%). HL was diagnosed incidentally in 1.0% of cases. A primary diagnosis of PSC was observed in 1.6% of patients. Overall median survival was 35.5 months. When in-hospital mortality (n = 12) was excluded, the median survival was 45.4 months, corresponding to 3- and 5-year survival rates of 42% and 31%, versus 31% and 22% when in-hospital mortality was included. HL recurred in 34% of cases. Three- and 5-year survivals for the 1.5 patients transplanted since 1998 was 57% and 48%, respectively. Median survival ranged from 20 to 42 months based on the time period (P = .014). Conclusions. The acceptable overall survival, the improved results after careful patient selection since 1998, and the encouraging outcomes from recent studies all suggest that OLT may be a potential treatment for selected cases of HL. Prospective multicenter randomized studies with strict selection criteria and multimodal treatments seem necessary