Imprecision of high-sensitivity cardiac troponin assays at the female 99th-percentile.

BACKGROUND: An analytical benchmark for high-sensitivity cardiac troponin (hs-cTn) assays is to achieve a coefficient of variation (CV) of ≤ 10.0 % at the 99th percentile upper reference limit (URL) used for the diagnosis of myocardial infarction. Few prospective multicenter studies have evaluated assay imprecision and none have determined precision at the female URL which is lower than the male URL for all cardiac troponin assays. METHODS: Human serum and plasma matrix samples were constructed to yield hs-cTn concentrations near the female URLs for the Abbott, Beckman, Roche, and Siemens hs-cTn assays. These materials were sent (on dry ice) to 35 Canadian hospital laboratories (n = 64 instruments evaluated) participating in a larger clinical trial, with instructions for storage, handling, and monthly testing over one year. The mean concentration, standard deviation, and CV for each instrument type and an overall pooled CV for each manufacturer were calculated. RESULTS: The CVs for all individual instruments and overall were ≤ 10.0 % for two manufacturers (Abbott CVpooled = 6.3 % and Beckman CVpooled = 7.0 %). One of four Siemens Atellica instruments yielded a CV > 10.0 % (CVpooled = 7.7 %), whereas 15 of 41 Roche instruments yielded CVs > 10.0 % at the female URL of 9 ng/L used worldwide (6 cobas e411, 1 cobas e601, 4 cobas e602, and 4 cobas e801) (CVpooled = 11.7 %). Four Roche instruments also yielded CVs > 10.0 % near the female URL of 14 ng/L used in the United States (CVpooled = 8.5 %). CONCLUSIONS: The number of instruments achieving a CV ≤ 10.0 % at the female 99th-percentile URL varies by manufacturer and by instrument. Monitoring assay precision at the female URL is necessary for some assays to ensure optimal use of this threshold in clinical practice.

Importance of Adequate qPCR Controls in Infection Control.

Respiratory screening assays lacking Sample Adequacy Controls (SAC) may result in inadequate sample quality and thus false negative results. The non-adequate samples might represent a significant proportion of the total performed tests, thus resulting in sub-optimal infection control measures with implications that may be critical during pandemic times. The quantitative sample adequacy threshold can be established empirically, measuring the change in the frequency of positive results, as a function of the numerical value of "sample adequacy". Establishing a quantitative threshold for SAC requires a big number/volume of tests to be analyzed in order to have a statistically valid result. Herein, we are offering for the first time clear clinical evidence that a subset of results, which did not pass minimal sample adequacy criteria, have a significantly lower frequency of positivity compared with the "adequate" samples. Flagging these results and/or re-sampling them is a mitigation strategy, which can dramatically improve infection control measures.

Sample Adequacy Control (SAC) Lowers False Negatives and Increases the Quality of Screening: Introduction of "Non-Competitive" SAC for qPCR Assays.

Sample Adequacy Control (SAC) has critical analytical, clinical and epidemiological value that increases confidence in a negative test result. The SAC is an integral qPCR assay control, which ensures that all pre-analytical and analytical steps are adequate for accurate testing and reporting. As such, a negative SAC with a negative result on pathogen screen specifies that the result should be reported as inconclusive instead of negative. Despite this, many regulatory approved tests do not incorporate SAC into their assay design. Herein, we emphasize the universal value of SAC and offer for the first time, a simple technical strategy to introduce non-competitive SAC which does not interfere with the limit of detection for the screened pathogen. Integration of SAC can provide key benefits towards identifying, isolating, quarantining and contact tracing infected individuals and in turn can improve worldwide efforts in infection control.

The association between glycaemic control during hospitalization and risk of adverse events: A retrospective cohort study.

INTRODUCTION: Hyperglycaemia is common during hospitalization; glycaemic targets in non-critical care settings have not been well studied. We assessed associations between inpatient glycaemic control and adverse events. METHODS: We conducted a retrospective cohort study on non-critically ill medical patients hospitalized in a tertiary care hospital between 2015 and 2018. Mean glycaemia during the first four days of hospitalization was categorized as 4.0-7.0 mmol/L, 7.1-10.0 mmol/L and >10.0 mmol/L. The primary outcome was a composite of adverse events including mortality, infections, acute kidney injury, thromboembolic and cardiovascular events. The secondary outcome was hypoglycaemia, defined as any glycaemia <4.0 mmol/L. Logistic regression was used to assess adverse events, and a Cox proportional hazards model was used to estimate hypoglycaemia risk. RESULTS: Our cohort included 1,368 patients, of whom 407 (29.8%) experienced an adverse event. We did not find associations between glycaemia of 4.0-7.0 mmol/L (adjusted odds ratio [OR]: 0.88, 95% confidence interval [CI]: 0.63-1.23) or glycaemia of >10.0 mmol/L (adjusted OR: 0.98, 95% CI: 0.75-1.28) and the occurrence of adverse events, compared to a glycaemia of 7.1-10.0 mmol/L. Glycaemia of >10.0 mmol/L was associated with an increased risk of hypoglycaemia (adjusted hazard ratio [HR]: 1.72, 95% CI: 1.21-2.45). Hypoglycaemia was associated with adverse events (adjusted OR 1.85, 95% CI 1.31-2.60). CONCLUSIONS: Neither glycaemia of 4.0-7.0 mmol/L nor glycaemia of >10.0mmol/L during non-critical care hospitalization was associated with increased adverse events. Glycaemia of >10.0 mmol/L was associated with increased hypoglycaemia, likely due to aggressive glucose lowering. These findings highlight the need for further studies to discern optimal inpatient glycaemic targets.

Muscle Mass and Direct Oral Anticoagulant Activity in Older Adults With Atrial Fibrillation.

BACKGROUND: Direct oral anticoagulants (DOAC) are hydrophilic drugs with plasma levels inversely proportional to lean body mass. Sarcopenic patients with low muscle mass may be at risk for supra-therapeutic DOAC levels and bleeding complications. We therefore sought to examine the influence of lean body mass on DOAC levels in older adults with atrial fibrillation (AF). METHODS: A prospective cohort study was conducted with patients 65 years of age or more receiving rivaroxaban or apixaban for AF. Appendicular lean mass (ALM) was measured using a bioimpedance device and a dual X-ray absorptiometry scanner. DOAC levels were measured using a standardized anti-Xa assay 4 hours after (peak) and 1 hour before (trough) ingestion. RESULTS: The cohort consisted of 62 patients (47% female, 77.0 ± 6.1 years). The prescribed DOACs were apixaban 2.5 mg (21%), apixaban 5 mg (53%), and rivaroxaban 20 mg (26%). Overall, 16% had supra-therapeutic DOAC levels at trough and 25% at peak. In the multivariable logistic regression model, lower ALM was independently associated with supra-therapeutic DOAC levels at trough (odds ratio per ↓ 1-kg 1.23, 95% confidence interval 1.02 to 1.49) and peak (odds ratio per ↓ 1-kg 1.18, 95% confidence interval 1.02 to 1.37). Addition of ALM to a model consisting of age, total body weight, and renal function resulted in improved discrimination for supra-therapeutic DOAC levels. CONCLUSION: Our proof-of-concept study has identified an association between ALM and DOAC levels in older adults with AF. Further research is needed to determine the impact of ALM on bleeding complications and the potential role of ALM-guided dosing for sarcopenic patients.

Characterization and heme oxygenase-1 content of extracellular vesicles in human biofluids.

Heme oxygenase-1 (HO-1), a highly inducible stress protein that degrades heme to biliverdin, carbon monoxide, and free ferrous iron, is increased in blood and other biofluids of subjects with various systemic and neurological disorders. HO-1 does not contain an N-terminal signal peptide and the mechanism responsible for its secretion remains unknown. Extracellular vesicles (EVs) are membrane-bound inclusions that transport microRNAs, messenger RNAs, lipids, and proteins among diverse cellular and extracellular compartments. The objective of the current study was to determine whether EVs in human biofluids contain HO-1, and whether the latter may be transported in EVs from brain to periphery. Total, L1 cell adhesion molecule protein (L1CAM)-enriched (neuron-derived), and glutamate aspartate transporter 1 (GLAST)-enriched (astrocyte-derived) EVs were purified from five different human biofluids (saliva [n = 40], plasma [n = 14], serum [n = 10], urine [n = 10], and cerebrospinal fluid [n = 11]) using polymer precipitation and immuno-affinity-based capture methods. L1CAM-enriched, GLAST-enriched, and L1CAM/GLAST-depleted (LGD) EV, along with EV-depleted (EVD), fractions were validated by nanoparticle tracking analysis, enzyme-linked immunosorbent assay (ELISA), and western blot. HO-1 was assayed in all fractions using ELISA and western blot. The majority of HO-1 protein was localized to LGD, L1CAM-enriched, and GLAST-enriched EVs of all human biofluids surveyed after adjusting for age and sex, with little HO-1 protein detected in EVD fractions. HO-1 protein in human biofluids is predominantly localized to EV compartments. A substantial proportion of EV HO-1 in peripheral human biofluids is derived from the central nervous system and may contribute to the systemic manifestations of various neurological conditions.

Association of Serum 25-Hydroxyvitamin D With Prevalence, Incidence, and Clearance of Vaginal HPV Infection in Young Women.

BACKGROUND: We assessed the association between serum 25-hydroxyvitamin D levels and genital human papillomavirus (HPV) prevalence, incidence, and clearance among female participants in the HPV Infection and Transmission among Couples through Heterosexual activity (HITCH) Cohort Study. METHODS: We genotyped HPV DNA in vaginal samples and quantified baseline serum 25-hydroxyvitamin D levels using Roche's Linear Array and Total vitamin D assay, respectively. We used logistic and Cox proportional hazards models, respectively, to estimate adjusted odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: There was no association between vitamin D levels (every 10-ng/mL increase) at baseline and HPV prevalence (OR, 0.88; 95% CI, .73-1.03) or incidence (HR, 0.88; 95% CI, .73-1.06), but we observed a modest negative association with HPV clearance (HR, 0.76; 95% CI, .60-.96). Vitamin D levels <30 ng/mL, compared with those ≥30 ng/mL, were not associated with HPV prevalence (OR, 0.98; 95% CI, .57-1.69) or incidence (HR, .87; 95% CI, .50-1.43), but they were associated with a marginally significant increased clearance (OR, 2.14; 95% CI, .99-4.64). We observed consistent results with restricted cubic spline modeling of vitamin D levels and clinically defined categories. HPV type-specific analyses accounting for multiple HPV infections per participant showed no association between vitamin D levels and all study outcomes. CONCLUSIONS: This study provided no evidence of an association between low vitamin D levels and increased HPV prevalence, acquisition, or clearance.

An LC-MRM assay for the quantification of metanephrines from dried blood spots for the diagnosis of pheochromocytomas and paragangliomas.

The quantitation of metanephrine (MN), normetanephrine (NMN), and 3-methoxytyramine (3-MT) - referred to as metanephrines -- by LC-MS/MS is the gold-standard for screening for pheochromocytoma and paragangliomas (PPGLs), tumours of the adrenal gland and the peripheral nervous system. An assay for metanephrines from dried blood spots (DBSs) would be of high clinical utility as it simplifies sample collection, enables remote sampling, and could increase compliance with the clinical recommendation for supine sampling. Moreover, DBS sampling facilitates the measurement of blood-derived metanephrines in pediatric patients - where DBSs are well-established - in order to diagnose neuroblastomas. Here, we adapted an established derivatization-based LC-MRM-MS assay for plasma catecholamines, and optimized the sample extraction, LC, and MS parameters to produce a fast, sensitive, and robust method for the measurement of metanephrines from DBSs, including 3-methoxytyramine. The DBS samples were excised, derivatized with phenyl isothiocyanate (PITC) on-spot, extracted, and measured by LC-MRM-MS. To validate assay suitability and performance, we assessed the linearity, precision, accuracy, recovery, and matrix effects of the method, and determined the stability of metanephrines in DBSs under different storage conditions. Assay performance for NMN, MN, and 3-MT was sufficient for quantitation from a single DBS within a linear range from 40 to 2000 pg/mL. MN and NMN were stable in DBSs for 2 weeks, whereas 3-MT was stable for one week regardless of storage temperature. Altogether, this work represents the first quantitative LC-MS/MS method for metanephrines from DBSs and provides a novel opportunity for the diagnosis of PPGLs and neuroblastomas in the future.

Maximizing confidence in a negative result: Quantitative sample adequacy control.

Quantitative PCR (qPCR) is a leading screening tool, permitting rapid detection of pathogens and the maintenance of effective infection control programs. Unfortunately, qPCR assays frequently do not incorporate Sample Adequacy Control (SAC). A SAC controls for the quantity, quality and adequacy of the specimen. Without SAC, the confidence in a negative result remains questionable and the efficacy of screening is compromised. Ultimately, the exclusion of SAC from qPCR may result in false negative results. One should consider SAC to be an integral critical type of laboratory control; addressing diverse analytical problems, such as sample adequacy, sample processing and assay inhibition. Following distribution of cycle threshold values (Cq) of Influenza A positive results and Cq values of SAC, obtained from nasopharyngeal swabs, we showed that the confidence in a negative result cannot be guaranteed in the presence of a weak positive SAC signal (late Cq values). Herein, we explain why widespread inclusion of sample adequacy control in routine screening is blocked. A protocol and methods for SAC threshold establishment are offered.

Hypersensitivity reactions to high osmolality Total Parenteral Nutrition: a case report.

BACKGROUND: The full range of allergic reactions to Total Parenteral Nutrition (TPN) remains unknown. Additionally, beyond individual allergens, there may be other factors contributing to TPN hypersensitivity reactions. CASE PRESENTATION: We present a case of a patient with negative skin testing to common TPN allergens who had recurrent urticarial reactions to TPN. Her skin reactions resolved once TPN was stopped. Following a literature review, we postulated that the reactions could be due to the high osmolality of her TPN. Consequently, lowering her TPN from 2785 to 1928 mOsm/kg and premedicating with cetirizine resulted in resolution of her urticaria. CONCLUSIONS: When looking at patients who have hypersensitivity reactions to TPN, one must consider that their reactions may be due to factors other than allergens. More studies are needed to clarify the relationship between high osmolality TPN infusions and non-IgE mediated hypersensitivity reactions.

Laboratory-developed test for detection of acute Clostridium difficile infections with the capacity for quantitative sample normalization.

We describe a laboratory-developed test intended for the detection of acute Clostridium difficile infections (CDI) with the capacity for quantitative sample normalization. The test is based on the detection of the tcdB gene. However, this biomarker is also present among people without symptoms, implying that individuals with diarrhea, not caused by C. difficile may nonetheless test positive. Therefore, clinical diagnosis based on this format of testing can be challenging. In order to improve diagnostic assays capability, tcdB-based quantification methods were suggested as a potential solution, however they did not increase clinical specificity. We report methodology for a dual biomarker monitoring (total bacterial load and tcdB assay), allowing for the calculation of the relative presence of tcdB in the total bacterial population in the tested samples. We believe that this approach is clinically relevant to current assays and can improve CDI testing algorithms.

Rectal swab screening assays of public health importance in molecular diagnostics: Sample adequacy control.

Rectal swabs are routinely used by public health authorities to screen for multi-drug resistant enteric bacteria including vancomycin-resistant enterococci (VRE) and carbapenem-resistant enterobacteriaceae (CRE). Screening sensitivity can be influenced by the quality of the swabbing, whether performed by the patient (self-swabbing) or a healthcare practitioner. One common exclusion criterion for rectal swabs is absence of "visible soiling" from fecal matter. In our institution, this criterion excludes almost 10% of rectal swabs received in the microbiology laboratory. Furthermore, over 30% of patients in whom rectal swabs are cancelled will not be re-screened within the next 48h, resulting in delays in removing infection prevention measures. We describe two quantitative polymerase chain reaction (qPCR)-based assays, human RNAse P and eubacterial 16S rDNA, which might serve as suitable controls for sampling adequacy. However, lower amounts of amplifiable human DNA make the 16s rDNA assay a better candidate for sample adequacy control.

Effect of Hemodialysis on Levels of High-Sensitivity Cardiac Troponin T.

Cardiac troponin (cTn) is essential for the diagnosis of an acute coronary syndrome (ACS). However, in end-stage renal disease (ESRD) baseline cTn levels are often elevated, and it is unknown whether the hemodialysis (HD) procedure affects cTn levels. This leaves clinicians unsure of how to interpret cTn in HD patients with cardiac ischemia. We therefore sought to determine if plasma levels of high-sensitivity cardiac troponin T (hs-cTnT) vary during or after HD treatment. We prospectively enrolled 10 chronic HD patients who were admitted to our institution. All participants were receiving thrice weekly HD before admission and were medically stable. Those admitted for ACS or to critical care units were excluded. Baseline hs-cTnT was measured immediately before HD. For the subsequent 6 hours, hs-cTnT was measured every 2 hours and every 3 hours thereafter for a total collection period of 24 hours. A significant decline in mean hs-cTnT was noted with HD. During HD (2 hours after HD initiation), hs-cTnT decreased by 10.7% (confidence interval 5% to 17%). Immediately after HD (4 hours after HD initiation), a decline of 12% (confidence interval 5% to 19%) was observed. Thereafter hs-cTnT began to rise. Hs-cTnT levels returned to baseline by 11 hours after HD completion and remained stable for the reminder of the study. In conclusion, HD induces a short-lived negative bias in hs-cTnT. When measured for investigation of ACS, hs-cTnT concentration should be interpreted with respect to time of dialysis and specimen collection.

Successful protocol for eliminating excessive urine microscopies: Quality improvement and cost savings with physician support.

BACKGROUND: Clinical laboratories are under growing pressure to provide faster turn-around-time and maintain high quality while decreasing costs. In a setting of rising test volumes, implementation of evidence-based protocols with physician cooperation and feedback may provide frameworks and support for laboratory utilization optimization. The purpose of this study was to eliminate wasteful urine microscopy by targeting physician ordering behavior, and to ensure quality of care with physician satisfaction surveys. METHODS: We evaluated how physicians use the laboratory for routine urine testing. Urinalysis requisition was redesigned with emphasis on clinical indications for testing. In collaboration with requesting physicians, restriction in reflex microscopy testing was applied with exceptions. Cost saving analysis was conducted based on test volume. After policy change, 2 physician satisfaction surveys were conducted 5year apart to address potential complaints. RESULTS: Over 47,000 urine microscopies have been eliminated annually, while the number of urine dipsticks and cultures remained stable. This translated into a 95% reduction in manual microscopy performed, and an estimated annual saving of $200,000. In both satisfaction surveys, 9 out of 10 physicians considered the change to have "no" or "a beneficial effect" on their clinical practice. Our laboratory did not receive any formal complaints in regards to the protocol change. CONCLUSION: By implementing changes to the way physicians order urinalysis, the number of tests can be substantially reduced. Satisfaction survey proved to be an effective tool for obtaining physician feedback, and support. The results of surveys indicated that new policy achieved significant savings without compromising on patient care. This experience has provided us with strategies on taking initiatives to further optimize utilization of laboratory tests.

Appropriate vitamin D loading regimen for patients with advanced lung cancer.

BACKGROUND: Most patients attending cancer clinics have hypovitaminosis D. Correcting or preventing this abnormal condition could mitigate the emotional and physical complications of their disease, but clinical trials of vitamin D therapy in this setting are hindered by the unavailability of safe, effective and practical loading dose regimens. METHODS: In this single arm open-label pharmacokinetic trial, outpatients with advanced lung cancer consumed 20,000 IU vitamin D daily with the largest meal of the day for 14 days followed by 10,000 IU per day for a further 7 days. Plasma concentrations of 25-hydroxyvitamin D [25(OH)D], parathyroid hormone, calcium, vitamin C and C-reactive protein were measured on protocol days 0, 14 and 21, and serum vitamin D binding protein (VDBP) concentrations on days 0 and 21. As a secondary objective, preliminary information was obtained regarding clinical effects of rapid vitamin D loading on mood and symptoms by administering appropriate questionnaires two times at baseline and after 14 and 21 days of vitamin D therapy. RESULTS: Of the 91 patients enrolled in the study, 85 % had hypovitaminosis D and 41 % had hypovitaminosis C. Plasma VDBP concentrations were in the normal range. The vitamin D load increased the average plasma 25(OH)D concentration to 116 ± 34 nmol/L (mean ± SD); the median concentration was 122 nmol/L (interquartile range 103-134); VDBP concentrations did not change. Final plasma 25(OH)D concentrations were subnormal (<75 nmol/L) for 13 % of the patients and sub-target (<120 nmol/L) for 44 % of them. In most cases, subnormal and sub-target 25(OH)D concentrations were attributable to obesity and/or a low baseline 25(OH)D concentration. Mood and symptom scores did not change significantly throughout the 3-week protocol. CONCLUSION: Hypovitaminosis D and C are very common in outpatients with advanced lung cancer. A vitamin D load of 20,000 IU per day for 14 days failed to achieve the target concentration in 44 % of the participants in this trial. These results suggest that a loading dose of 30,000 IU per day for 14 days would be safe and effective for patients who are obese or at risk of severe hypovitaminosis D. The preliminary nature of the study design, and the failure to achieve target 25(OH)D concentrations for a large proportion of the patients, do not allow any firm conclusion about the clinical effects of correcting hypovitaminosis D in this patient population. Nevertheless, no evidence was obtained that partial correction of hypovitaminosis D greatly improved mood, reduced distress or relieved cancer-related symptoms. This trial was registered at clinicaltrials.gov as NCT01631526.

Effects of vitamin C and vitamin D administration on mood and distress in acutely hospitalized patients.

BACKGROUND: Hypovitaminosis C and D are highly prevalent in acute-care hospitals. Malnutrition with regard to these vitamins has been linked to mood disturbance and cognitive dysfunction. OBJECTIVE: The objective was to determine whether vitamin C or D supplementation improves mood state or reduces psychological distress in acutely hospitalized patients with a high prevalence of hypovitaminosis C and D. DESIGN: A randomized, double-blind, active-control clinical trial compared the effects of vitamin C (500 mg twice daily) with those of high-dose vitamin D (5000 IU/d) on mood (Profile of Mood States) and psychological distress (Distress Thermometer). RESULTS: Vitamin C provided for a mean of 8.2 d increased plasma vitamin C concentrations to normal (P < 0.0001) and was associated with a 71% reduction in mood disturbance (P = 0.0002) and a 51% reduction in psychological distress (P = 0.0002). High-dose vitamin D provided for a mean of 8.1 d increased plasma 25-hydroxyvitamin D [25(OH)D] concentrations (P < 0.0001), but not into the normal range, and had insignificant effects on mood (P = 0.067) and distress (P = 0.45). The changes in mood and distress in the vitamin C group were greater than those in the vitamin D group (P = 0.045 for mood; P = 0.009 for distress). CONCLUSIONS: Short-term therapy with vitamin C improves mood and reduces psychological distress in acutely hospitalized patients with a high prevalence of hypovitaminosis C and D. No conclusion is possible regarding the effects of vitamin D because the dose and duration of therapy were insufficient to raise 25(OH)D concentrations into the normal range. This trial was registered at clinicaltrials.gov as NCT01630720.

Vitamin C provision improves mood in acutely hospitalized patients.

OBJECTIVE: Hypovitaminosis C and D are highly prevalent in acutely hospitalized patients, but the clinical significance of these biochemical abnormalities is not known. Because deficiencies of vitamin C and D have been linked to psychologic abnormalities, vitamin C or D provision could improve the mood state of acutely hospitalized patients. METHODS: Double-blind clinical trial of the effect of vitamin C (500 mg twice daily) or vitamin D (1000 IU twice daily) on mood, as assessed with a validated instrument, the Profile of Mood States. RESULTS: Vitamin C therapy increased plasma (P < 0.0001) and mononuclear leukocyte (P = 0.014) vitamin C concentrations and was associated with a 34% reduction in mood disturbance (P = 0.013). Vitamin D therapy increased plasma 25-hydroxyvitamin D concentrations (P = 0.0004), but had no significant effect on mood. CONCLUSIONS: Treatment of hypovitaminosis C improves the mood state of acutely hospitalized patients.

Metabolic origin of hypovitaminosis C in acutely hospitalized patients.

OBJECTIVE: Recent studies have indicated a high prevalence of hypovitaminosis C in acutely hospitalized patients. It is unclear whether hypovitaminosis C in this setting represents deficiency or tissue redistribution of the vitamin as part of the acute-phase response. METHODS: We administered vitamin C for 1 wk to acutely hospitalized, but not critically ill patients with hypovitaminosis C, on the assumption that a large increase in plasma and mononuclear leukocyte vitamin C concentrations, a decrease in metabolic markers of oxidative stress, or an improvement in psychologic mood state would implicate the initial condition as nutritional deficiency rather than tissue redistribution. RESULTS: Vitamin C administration increased plasma and mononuclear leukocyte vitamin C concentrations from subnormal (16.3 ± 12.4 µmol/L and 6.5 ± 5.5 mmol/L, respectively) to normal (71.0 ± 30.9 µmol/L, P < 0.0001, and 8.2 ± 6.8 mmol/L, P < 0.015); the mood disturbance score improved by 33% (P < 0.008). There was no increase in plasma glutathione concentrations or a reduction in plasma or mononuclear leukocyte malondialdehyde concentrations. An inverse relation was observed between plasma C-reactive protein and plasma vitamin C concentrations (P = 0.006). CONCLUSION: Although associated with systemic inflammation, the metabolic features of hypovitaminosis C in acutely hospitalized, non-critically ill patients are more consistent with deficiency than with tissue redistribution.