Activation of the Calcium Receptor by Calcimimetic Agents Is Preserved Despite Modest Attenuating Effects of Hyperphosphatemia.

BACKGROUND: Phosphorus levels in the range seen clinically among patients undergoing dialysis have been reported to attenuate calcium receptor activation and modify parathyroid hormone (PTH) release from isolated parathyroid glands in vitro. Some clinicians and providers of dialysis thus have suggested that calcimimetic agents are ineffective and should not be used to manage secondary hyperparathyroidism among those undergoing dialysis when serum phosphorus concentrations exceed certain threshold levels. METHODS: To determine whether hyperphosphatemia diminishes the therapeutic response to calcimimetic agents, we used data from large clinical trials to analyze the effects of etelcalcetide and cinacalcet to lower plasma PTH levels in individuals on hemodialysis who had secondary hyperparathyroidism and varying degrees of hyperphosphatemia. RESULTS: Plasma PTH levels declined progressively during 26 weeks of treatment with either etelcalcetide or cinacalcet without regard to the degree of hyperphosphatemia at baseline. However, with each calcimimetic agent, the decreases in PTH from baseline were less at each interval of follow-up during the trials among participants with serum phosphorus levels above one of three prespecified threshold values compared with those with serum phosphorus levels below these thresholds. CONCLUSIONS: These in vivo findings are the first in humans to support the idea that hyperphosphatemia attenuates calcium receptor activation by calcium ions and by calcimimetic agents. The effect of hyperphosphatemia on the responsiveness to calcimimetic agents appears relatively modest, however, and unlikely to be significant therapeutically. The efficacy of treatment with calcimimetic agents for lowering plasma PTH levels among those with secondary hyperparathyroidism remains robust despite substantial elevations in serum phosphorus.

Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II: A Phase II Randomized Trial.

OBJECTIVES: A relationship between reduced brain tissue oxygenation and poor outcome following severe traumatic brain injury has been reported in observational studies. We designed a Phase II trial to assess whether a neurocritical care management protocol could improve brain tissue oxygenation levels in patients with severe traumatic brain injury and the feasibility of a Phase III efficacy study. DESIGN: Randomized prospective clinical trial. SETTING: Ten ICUs in the United States. PATIENTS: One hundred nineteen severe traumatic brain injury patients. INTERVENTIONS: Patients were randomized to treatment protocol based on intracranial pressure plus brain tissue oxygenation monitoring versus intracranial pressure monitoring alone. Brain tissue oxygenation data were recorded in the intracranial pressure -only group in blinded fashion. Tiered interventions in each arm were specified and impact on intracranial pressure and brain tissue oxygenation measured. Monitors were removed if values were normal for 48 hours consecutively, or after 5 days. Outcome was measured at 6 months using the Glasgow Outcome Scale-Extended. MEASUREMENTS AND MAIN RESULTS: A management protocol based on brain tissue oxygenation and intracranial pressure monitoring reduced the proportion of time with brain tissue hypoxia after severe traumatic brain injury (0.45 in intracranial pressure-only group and 0.16 in intracranial pressure plus brain tissue oxygenation group; p < 0.0001). Intracranial pressure control was similar in both groups. Safety and feasibility of the tiered treatment protocol were confirmed. There were no procedure-related complications. Treatment of secondary injury after severe traumatic brain injury based on brain tissue oxygenation and intracranial pressure values was consistent with reduced mortality and increased proportions of patients with good recovery compared with intracranial pressure-only management; however, the study was not powered for clinical efficacy. CONCLUSIONS: Management of severe traumatic brain injury informed by multimodal intracranial pressure and brain tissue oxygenation monitoring reduced brain tissue hypoxia with a trend toward lower mortality and more favorable outcomes than intracranial pressure-only treatment. A Phase III randomized trial to assess impact on neurologic outcome of intracranial pressure plus brain tissue oxygenation-directed treatment of severe traumatic brain injury is warranted.

Reliability of the NINDS common data elements cranial tomography (CT) rating variables for traumatic brain injury (TBI).

BACKGROUND: Non-contrast head computer tomography (CT) is widely used to evaluate eligibility of patients after acute traumatic brain injury (TBI) for clinical trials. The NINDS Common Data Elements (CDEs) TBI were developed to standardize collection of CT variables. The objectives of this study were to train research assistants (RAs) to rate CDEs and then to evaluate their performance. The aim was to assess inter-rater reliability (IRR) of CDEs between trained RAs and a neurologist and to evaluate applicability of CDEs in acute and sub-acute TBI to test the feasibility of using CDE CT ratings in future trials and ultimately in clinical practice. The second aim was to confirm that the ratings of CDEs reflect pathophysiological events after TBI. METHODS AND RESULTS: First, a manual was developed for application of the CDEs, which was used to rate brain CTs (n = 100). An excellent agreement was found in combined kappas between RAs on admission and on 24-hour follow-up CTs (Iota = 0.803 and 0.787, respectively). Good IRR (kappa > 0.61) was shown for six CDEs on admissions and for seven CDEs on follow-up CTs. Low IRR (kappa < 0.4) was determined for five CDEs on admission and for four CDEs on follow-up CT. Combined IRR of each assistant with the neurologist were good on admission (Iota = 0.613 and 0.787) and excellent on follow-up CT (Iota = 0.906 and 0.977). Second, Principal Component Analysis (PCA) was applied to cluster the rated CDEs (n = 255) and five major components were found that explain 53% of the variance. CONCLUSIONS: CT CDEs are useful in clinical studies of TBI. Trained RAs can reliably collect variables. PCA identifies CDE clusters with clinical and biologic plausibility. ABBREVIATIONS: RA, research assistant; CT, Cranial Tomography; TBI, Traumatic Brain Injury; CDE, Common Data Elements; IRR, inter-rater reliability; PCA, Principal Component Analysis; GCS, Glasgow Coma Scale; R, rater; CI, confidence interval; CCC, Concordance correlation coefficient; IVH, Intraventricular haemorrhage; DCA, Discriminant Component analysis; SAH, Subarachnoid Haemorrhage.

Cytotoxic and vasogenic cerebral oedema in traumatic brain injury: assessment with FLAIR and DWI imaging.

PRIMARY OBJECTIVE: Cerebral oedema is a common complication of traumatic brain injury (TBI). The use of Fluid-Attenuated Inversion Recovery (FLAIR) imaging in combination with Diffusion Weighted Imaging (DWI) has the potential to distinguish between cytotoxic and vasogenic oedema. This study hypothesized a significant relationship between cytotoxic lesion volume and outcome. RESEARCH DESIGN: This observational study reports on a convenience sample where MRI was obtained for clinical purposes. METHODS AND PROCEDURES: Clinical post-TBI FLAIR and DWI images were analysed. For this study, lesions were defined as primarily cytotoxic oedema if the ratio of FLAIR to DWI lesion volume was comparable, defined as a ratio <2. If the ratio of FLAIR to DWI lesion volume was ≥2, oedema was considered predominantly of vasogenic origin. MAIN OUTCOMES AND RESULTS: The sample consisted primarily of males with TBIs whose injury severity ranged from complicated mild to severe. Analysis revealed that both oedema types are common after TBI and both are associated with functional deficits 6 months after injury. CONCLUSIONS: Acute MRI may be useful to assess pathology at the tissue after traumatic brain injury. Clinical trials targeting cytotoxic and vasogenic mechanisms of oedema formation may benefit from using DWI and FLAIR MRI as a means to differentiate the predominant oedema type after TBI.

Safety and efficacy of statins in patients with end-stage renal disease.

OBJECTIVE: To review statins in the prevention of cardiovascular disease (CVD) events and their associated safety in patients with end-stage renal disease (ESRD). DATA SOURCES: Peer-reviewed clinical trials, review articles, and treatment guidelines were identified from MEDLINE (1966-July 2013) using the following search terms: end stage renal disease, statin, HMG-CoA (hydroxymethylglutaryl-coenzyme A) reductase inhibitor, chronic kidney disease, cardiovascular outcomes, and cardiovascular disease. Results were limited to human trials published in English. Citations from articles were reviewed for additional references. STUDY SELECTION AND DATA EXTRACTION: Only clinical trials evaluating cardiovascular end points of statins used in patients with ESRD were included. DATA SYNTHESIS: In patients with ESRD, CVD is the leading cause of death. Statin therapy has been evaluated in 3 clinical trials in patients with ESRD. The 4D and AURORA trials failed to show a benefit with statin therapy, and the SHARP trial, although positive, also included patients with earlier stages of chronic kidney disease. Despite the lack of efficacy, statin therapy was well tolerated. The cause of cardiovascular death in this patient population may not be a result of atherosclerotic events and possibly dependent on the type of renal replacement therapy. For patients on hemodialysis, lipid profiles may not be amenable to statin therapy. CONCLUSIONS: Statin therapy has failed to significantly alter the course of CVD events in patients with ESRD. Evidence supports avoiding the routine use of statins in this patient population and instead reserving them for patients with elevated cholesterol levels or those with recent CVD events.

Phosphodiesterase-5 (PDE-5) Inhibitors as Therapy for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury.

Multiple phase III randomized controlled trials (RCTs) for pharmacologic interventions in traumatic brain injury (TBI) have failed despite promising results in experimental models. The heterogeneity of TBI, in terms of pathomechanisms and impacted brain structures, likely contributes to these failures. Biomarkers have been recommended to identify patients with relevant pathology (predictive biomarkers) and confirm target engagement and monitor therapy response (pharmacodynamic biomarkers). Our group focuses on traumatic cerebrovascular injury as an understudied endophenotype of TBI and is validating a predictive and pharmacodynamic imaging biomarker (cerebrovascular reactivity; CVR) in moderate-severe TBI. We aim to extend these studies to milder forms of TBI to determine the optimal dose of sildenafil for maximal improvement in CVR. We will conduct a phase II dose-finding study involving 160 chronic TBI patients (mostly mild) using three doses of sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor. The study measures baseline CVR and evaluates the effect of escalating sildenafil doses on CVR improvement. A 4-week trial of thrice daily sildenafil will assess safety, tolerability, and clinical efficacy. This dual-site 4-year study, funded by the Department of Defense and registered in ClinicalTrials.gov (NCT05782244), plans to launch in June 2023. Biomarker-informed RCTs are essential for developing effective TBI interventions, relying on an understanding of underlying pathomechanisms. Traumatic microvascular injury (TMVI) is an attractive mechanism which can be targeted by vaso-active drugs such as PDE-5 inhibitors. CVR is a potential predictive and pharmacodynamic biomarker for targeted interventions aimed at TMVI. (Trial registration: NCT05782244, ClinicalTrials.gov ).

Daptomycin versus vancomycin for bloodstream infections due to methicillin-resistant Staphylococcus aureus with a high vancomycin minimum inhibitory concentration: a case-control study.

BACKGROUND: Reports have found a link between vancomycin treatment failure in methicillin-resistant Staphyloccocus aureus (MRSA) bloodstream infections (BSIs) and higher vancomycin minimum inhibitory concentrations (MICs), despite MICs being below the susceptibility breakpoint of 2 µg/mL. Consensus guidelines recommend considering use of alternative agents for infections involving a higher vancomycin MIC, despite few data to support this approach. METHODS: This retrospective case-control study evaluated the effectiveness and safety of vancomycin, compared with that of daptomycin, in the treatment of MRSA BSIs with a high vancomycin MIC (ie, >1 µg/mL). RESULTS: A total of 118 vancomycin-treated subjects were compared with 59 daptomycin-treated subjects. Clinical failure, defined compositely as mortality, microbiologic failure, and/or recurrence of infection, was numerically lower in daptomycin-treated subjects (31% vs 17%; P = .084) and was mainly driven by a lower incidence of mortality in the daptomycin group (20% vs 9%; P = .046). Factors independently associated with clinical failure included acute renal failure (odds ratio [OR], 3.91 [95% confidence interval {CI}, 1.05-14.56]) and vancomycin treatment group (OR, 3.13 [95%, CI, 1.00-9.76]). Right-sided endocarditis was independently associated with clinical success (OR, 0.07 [95% CI, .01-.83]). A comparison of 60-day mortality between vancomycin- and daptomycin-treated subjects found a higher probability of survival in the daptomycin-treated group (P = .022). CONCLUSIONS: The results demonstrated that daptomycin was associated with a better outcome compared with vancomycin for the treatment of BSIs due to MRSA with higher vancomycin MICs. These findings support the recommendations of recent guidelines, which suggest consideration of the switch to alternative agents when the isolate has a high vancomycin MIC or when patients are not improving during receipt of therapy.

Does neuromuscular blockade affect the assessment of pelvic organ prolapse?

INTRODUCTION AND HYPOTHESIS: The purpose of this study was to determine if anesthesia with neuromuscular blockade alters the Pelvic Organ Prolapse Quantification (POP-Q) examination. METHODS: A prospective, multi-center trial was conducted of women undergoing pelvic surgery. A POP-Q examination performed pre-operatively was compared with an examination performed intra-operatively under neuromuscular blockade. For the latter examination, an Allis clamp was used to apply gentle traction until the point being examined did not undergo further descent. International Continence Society (ICS) stages and individual POP-Q points were compared using a paired sample t test. A sample size of 32 provided 80% power to detect a clinically significant difference between office and operating room measurements (Sample Power, SPSS, 1997). RESULTS: Of 153 women, 76% received general endotracheal anesthesia and 21% laryngeal mask airway. With an increase of 3 cm, the apical compartment was significantly more prolapsed in the operating room (OR; p < 0.05); however, a comparison of the mean values demonstrated a larger change in means for all points except total vaginal length. When separated into anterior, apical, and posterior compartments, the ICS stages were systematically different in the OR than in the office for all stages (p < 0.0005). CONCLUSIONS: Neuromuscular blockade leads to significantly greater increases in POP-Q examination measurements compared with the office measurements, and this increase is most pronounced apically.

Cerebrovascular Reactivity Measurement with Functional Near Infrared Spectroscopy.

Cerebrovascular reactivity (CVR) is the capacity of blood vessels in the brain to alter cerebral blood flow (either with dilation or constriction) in response to chemical or physical stimuli. The amount of reactivity in the cerebral microvasculature depends on the integrity of the capacitance vasculature and is the primary function of endothelial cells. CVR is, therefore, an indicator of the microvasculature's physiology and overall health. Imaging methods that can measure CVR are available but can be costly, and require magnetic resonance imaging centers and technical expertise. In this study, we used fNIRS technology to monitor changes of oxyhemoglobin (HbO) and deoxyhemoglobin (HbR) in the cerebral microvasculature to assess the CVR of 15 healthy controls (HC) in response to a vasoactive stimulus (inhaled 5% carbon dioxide or CO2). Our results suggest that this is a promising imaging technology that offers a non-invasive, accurate, portable, and cost-effective method of mapping cortical CVR and associated microvasculature function, resulting from a traumatic brain injury or other conditions associated with cerebral microvasculopathy.

Targeted dietary interventions to reduce pain in persistent post-traumatic headache among service members: Protocol for a randomized, controlled parallel-group trial.

INTRODUCTION: Post-traumatic headache (PTH) is common after traumatic brain injury (TBI), especially among active-duty service members (SMs), affecting up to 35% of patients with chronic TBI. Persistent PTH is disabling and frequently unresponsive to treatment and is often migrainous. Here, we describe a trial assessing whether dietary modifications to increase n-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and reduce n-6 linoleic acid (LA), will alter nociceptive lipid mediators and result in clinical improvements in persistent PTH. METHODS: This prospective, randomized, controlled trial tests the efficacy, safety, and biochemical effects of targeted, controlled alterations in dietary n-3 and n-6 fatty acids in 122 adult SMs and military healthcare beneficiaries with diagnosed TBI associated with actively managed persistent frequent (>8 /month) PTH with migraine. Following a 4-week baseline, participants are randomized to one of two equally intensive dietary regimens for 12 additional weeks: 1) increased n-3 EPA + DHA with low n-6 LA (H3L6); 2) usual US dietary content of n-3 and n-6 fatty acids (Control). During the intervention, participants receive diet arm-specific study oils and foods sufficient for 75% of caloric needs and comprehensive dietary counseling. Participants complete daily headache diaries throughout the intervention. Clinical outcomes, including the Headache Impact Test (HIT-6), headache hours per day, circulating blood fatty acid levels, and bioactive metabolites, are measured pre-randomization and at 6 and 12 weeks. Planned primary analyses include pre-post comparisons of treatment groups on clinical measures using ANCOVA and mixed-effects models. Similar approaches to explore biochemical and exploratory clinical outcomes are planned. CLINICALTRIALS: gov registration: NCT03272399.

Prediction of failure in vancomycin-treated methicillin-resistant Staphylococcus aureus bloodstream infection: a clinically useful risk stratification tool.

Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of bloodstream infection (BSI) and is often associated with invasive infections and high rates of mortality. Vancomycin has remained the mainstay of therapy for serious Gram-positive infections, particularly MRSA BSI; however, therapeutic failures with vancomycin have been increasingly reported. We conducted a comprehensive evaluation of the factors (patient, strain, infection, and treatment) involved in the etiology and management of MRSA BSI to create a risk stratification tool for clinicians. This study included consecutive patients with MRSA BSI treated with vancomycin over 2 years in an inner-city hospital in Detroit, MI. Classification and regression tree analysis (CART) was used to develop a risk prediction model that characterized vancomycin-treated patients at high risk of clinical failure. Of all factors, the Acute Physiology and Chronic Health Evaluation II (APACHE-II) score, with a cutoff point of 14, was found to be the strongest predictor of failure and was used to split the population into two groups. Forty-seven percent of the population had an APACHE-II score < 14, a value that was associated with low rates of clinical failure (11%) and mortality (4%). Fifty-four percent of the population had an APACHE-II score ≥ 14, which was associated with high rates of clinical failure (35%) and mortality (23%). The risk stratification model identified the interplay of three other predictors of failure, including the vancomycin MIC as determined by Vitek 2 analysis, the risk level of the source of BSI, and the USA300 strain type. This model can be a useful tool for clinicians to predict the likelihood of success or failure in vancomycin-treated patients with MRSA bloodstream infection.

Diffusion tensor imaging biomarkers for traumatic axonal injury: analysis of three analytic methods.

Traumatic axonal injury (TAI) is a common mechanism of traumatic brain injury not readily identified using conventional neuroimaging modalities. Novel imaging modalities such as diffusion tensor imaging (DTI) can detect microstructural compromise in white matter (WM) in various clinical populations including TAI. DTI-derived data can be analyzed using global methods (i.e., WM histogram or voxel-based approaches) or a regional approach (i.e., tractography). While each of these methods produce qualitatively comparable results, it is not clear which is most useful in clinical research and ultimately in clinical practice. This study compared three methods of analyzing DTI-derived data with regard to detection of WM injury and their association with clinical outcomes. Thirty patients with TAI and 19 demographically similar normal controls were scanned using a 3 Tesla magnet. Patients were scanned approximately eight months postinjury, and underwent an outcomes assessment at that time. Histogram analysis of fractional anisotropy (FA) and mean diffusivity showed global WM integrity differences between patients and controls. Voxel-based and tractography analyses showed significant decreases in FA within centroaxial structures involved in TAI. All three techniques were associated with functional and cognitive outcomes. DTI measures of microstructural integrity appear robust, as the three analysis techniques studied showed adequate utility for detecting WM injury.

Brain morphometry changes and depressive symptoms after traumatic brain injury.

Traumatic brain injury (TBI) is associated with an increased risk of depressive symptoms. Recent imaging studies on spontaneous depression have implicated several brain structures; however, few studies have done the same for post-TBI depression. We report on a pilot observational study correlating atrophy of brain regions of interest in subjects after TBI with depressive symptoms measured by the Beck Depression Inventory-II. Regional brain volumes were calculated on both acute and 6-month MRI using an automated segmentation algorithm (FreeSurfer). Percent volume changes in brain regions were correlated with BDI-II scores using Spearman's rank order correlation coefficient. Correction for multiple comparisons was performed using the false discovery rate (FDR). Three regions of interest (left rostral anterior cingulate and bilateral orbitofrontal cortex) were found to be significantly correlated with depressive symptoms (FDR 0.05). With FDR 0.1, six regions were significantly correlated. The use of volumetric analysis of brain regions of interest to study post-TBI depression is worthy of further study. Regions associated with depressive symptoms in this pilot study were similar to those implicated in study of spontaneous depression.

Imaging biomarkers of vascular and axonal injury are spatially distinct in chronic traumatic brain injury.

Traumatic Brain Injury (TBI) is associated with both diffuse axonal injury (DAI) and diffuse vascular injury (DVI), which result from inertial shearing forces. These terms are often used interchangeably, but the spatial relationships between DAI and DVI have not been carefully studied. Multimodal magnetic resonance imaging (MRI) can help distinguish these injury mechanisms: diffusion tensor imaging (DTI) provides information about axonal integrity, while arterial spin labeling (ASL) can be used to measure cerebral blood flow (CBF), and the reactivity of the Blood Oxygen Level Dependent (BOLD) signal to a hypercapnia challenge reflects cerebrovascular reactivity (CVR). Subjects with chronic TBI (n = 27) and healthy controls (n = 14) were studied with multimodal MRI. Mean values of mean diffusivity (MD), fractional anisotropy (FA), CBF, and CVR were extracted for pre-determined regions of interest (ROIs). Normalized z-score maps were generated from the pool of healthy controls. Abnormal ROIs in one modality were not predictive of abnormalities in another. Approximately 9-10% of abnormal voxels for CVR and CBF also showed an abnormal voxel value for MD, while only 1% of abnormal CVR and CBF voxels show a concomitant abnormal FA value. These data indicate that DAI and DVI represent two distinct TBI endophenotypes that are spatially independent.

Cerebrovascular Reactivity Measures Are Associated With Post-traumatic Headache Severity in Chronic TBI; A Retrospective Analysis.

OBJECTIVE: To characterize the relationship between persistent post-traumatic headache (pPTH) and traumatic cerebrovascular injury (TCVI) in chronic traumatic brain injury (TBI). Cerebrovascular reactivity (CVR), a measure of the cerebral microvasculature and endothelial cell function, is altered both in individuals with chronic TBI and migraine headache disorder (Amyot et al., 2017; Lee et al., 2019b). The pathophysiologies of pPTH and migraine are believed to be associated with chronic microvascular dysfunction. We therefore hypothesize that TCVI may contribute to the underlying migraine-like mechanism(s) of pPTH. MATERIALS AND METHODS: 22 moderate/severe TBI participants in the chronic stage (>6 months) underwent anatomic and functional magnetic resonance imaging (fMRI) scanning with hypercapnia gas challenge to measure CVR as well as the change in CVR (ΔCVR) after single-dose treatment of a specific phosphodiesterase-5 (PDE-5) inhibitor, sildenafil, which potentiates vasodilation in response to hypercapnia in impaired endothelium, as part of a Phase2a RCT of sildenafil in chronic TBI (NCT01762475). CVR and ΔCVR measures of each participant were compared with the individual's pPTH severity measured by the headache impact test-6 (HIT-6) survey. RESULTS: There was a moderate correlation between HIT-6 and both CVR and ΔCVR scores [Spearman's correlation = -0.50 (p = 0.018) and = 0.46 (p = 0.03), respectively], indicating that a higher headache burden is associated with decreased endothelial function in our chronic TBI population. CONCLUSION: There is a correlation between PTH and CVR in chronic moderate-severe TBI. This relationship suggests that chronic TCVI may underlie the pathobiology of pPTH. Further, our results suggest that novel treatment strategies that target endothelial function and vascular health may be beneficial in refractory pPTH.

Evaluation of risk factors for coinfection or cocolonization with vancomycin-resistant enterococcus and methicillin-resistant Staphylococcus aureus.

We retrospectively evaluated 410 patients with coinfection or cocolonization due to vancomycin-resistant (VR) enterococcus (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). The prevalence rate was 19.8%. Risk factors included isolation of VR Enterococcus faecalis and use of linezolid or clindamycin. Inc18-like vanA plasmids were found in 7% of VR E. faecalis isolates and none of the VR E. faecium isolates.

Decreased C-reactive protein levels in Alzheimer disease.

C-reactive protein (CRP) is an acute-phase reactant that has been found to be associated with Alzheimer disease (AD) in histopathological and longitudinal studies; however, little data exist regarding serum CRP levels in patients with established AD. The current study evaluated CRP levels in 192 patients diagnosed with probable AD (mean age = 75.8 +/- 8.2 years; 50% female) as compared to 174 nondemented controls (mean age = 70.6 +/- 8.2 years; 63% female). Mean CRP levels were found to be significantly decreased in AD (2.9 microg/mL) versus controls (4.9 microg/mL; P = .003). In adjusted models, elevated CRP significantly predicted poorer (elevated) Clinical Dementia Rating Scale sum of boxes (CDR SB) scores in patients with AD. In controls, CRP was negatively associated with Mini-Mental State Examination (MMSE) scores and positively associated with CDR SB scores. These findings, together with previously published results, are consistent with the hypothesis that midlife elevations in CRP are associated with increased risk of AD development though elevated CRP levels are not useful for prediction in the immediate prodrome years before AD becomes clinically manifest. However, for a subgroup of patients with AD, elevated CRP continues to predict increased dementia severity suggestive of a possible proinflammatory endophenotype in AD.

Comfort care packs: a little bit of hospice in hospital?

The Comfort Care Pack initiative is an innovation designed to enhance the inpatient experience of end-of-life patients and their carers. The carer is given a pleasantly decorated box containing a variety of items for use by the patient or the carer themselves: snacks, toiletries and items to promote comfort. This project set out to evaluate the impact of these packs by reviewing the returns of the feedback questionnaires included with the packs. From the first 220 packs, 58 questionnaires were returned, giving quantitative and qualitative data. The response to the packs was overwhelmingly positive and they were much valued by the carers. This was the case despite the fact that relatively few of the items were actually used by the recipients. It is suggested that the value of the packs to recipients lies in the gesture of being thought about during what is a difficult time for them. The implications of this are discussed.

Cost effectiveness analysis of anesthesia providers.

Anesthesiologists and certified registered nurse anesthetists provide high-quality, efficacious anesthesia care to the U.S. population. This research and analyses indicate that CRNAs are less costly to train than anesthesiologists and have the potential for providing anesthesia care efficiently. Anesthesiologists and CRNAs can perform the same set of anesthesia services, including relatively rare and difficult procedures such as open heart surgeries and organ transplantations, pediatric procedures, and others. CRNAs are generally salaried, their compensation lags behind anesthesiologists, and they generally receive no overtime pay. As the demand for health care continues to grow, increasing the number of CRNAs, and permitting them to practice in the most efficient delivery models, will be a key to containing costs while maintaining quality care.

Regioselective degradation of [beta] 1,3 glucan by ferrous ion and hydrogen peroxide (Fenton oxidation).

Many species use Fe+2 and H2O2 to oxidize a wide variety of compounds to simpler molecules. Both pathogen killing by leukocytes (neutrophils and lymphocytes) and degradation of cellulose by brown rot fungi rely on excretion of Fe+2 ions and H2O2, the Fenton reagent. To elucidate the mechanism of Fenton oxidation of carbohydrates, ß1,3 glucan (laminaran), a major fungal wall polysaccharide, was oxidized using a molar ratio of monomer/Fe+2/H2O2 of 10:1:1 (primarily). We labeled the reaction products and profiled them as fluorescent-labeled molecules in polyacrylamide gels and as hydrophobic-tagged molecules using reverse phase liquid chromatography/mass spectrometry (HPLC/MS). Sub-stoichiometric concentrations of Fe+2 and H2O2 fragmented laminaran into smaller molecules containing carbonyl and carboxylic acid groups visible on fluorescent-labeled carbohydrate polyacrylamide gel electrophoresis. HPLC/MS analysis of glucan fragments showed masses consistent with six classes of molecules: aldoses, dialdoses, uronic acids, hexosuloses, aldonic acids, and hexulosonic acids. The results were consistent with published mechanisms where hydrogen radical (H•) abstraction from a C-H or O-H bond begins a cascade of reactions leading to 1) C-C bond cleavage to produce aldose/dialdose pairs; 2) oxo-group (O = ) addition to produce uronic and aldonic acids; 3) hydroxyl group (HO-) addition to produce gluconolactone and hexosuloses; and 4) hexulosonic acids. Most products resulted from regioselective H• abstractions characteristic of oxidations by ferryl-oxo ion [(FeO)+2] or perferryl-oxo ion [(FeO)+3] in close contact with specific positions in the glycan. Therefore, oxidations initiated by regioselectively-bound Fe ions were the predominant initiators of polysaccharide degradations.