The reliability of a portable steam sauna pod for the whole-body passive heating of humans.

INTRODUCTION: Passive heating is receiving increasing attention within human performance and health contexts. A low-cost, portable steam sauna pod may offer an additional tool for those seeking to manipulate physiological (cardiovascular, thermoregulatory and sudomotor) and perceptual responses for improving sporting or health profiles. This study aimed to 1) report the different levels of heat stress and determine the pods' inter-unit reliability, and 2) quantify the reliability of physiological and perceptual responses to passive heating. METHOD: In part 1, five pods were assessed for temperature and relative humidity (RH) every 5 min across 70 min of heating for each of the 9 settings. In part 2, twelve males (age: 24 ± 4 years) completed two 60 min trials of passive heating (3 × 20 min at 44 °C/99% RH, separated by 1 week). Heart rate (HR), rectal (Trectal) and tympanic temperature (Ttympanic) were recorded every 5 min, thermal comfort (Tcomfort) and sensation (Tsensation) every 10 min, mean arterial pressure (MAP) at each break period and sweat rate (SR) after exiting the pod. RESULTS: In part 1, setting 9 provided the highest temperature (44.3 ± 0.2 °C) and longest time RH remained stable at 99% (51±7 min). Inter-unit reliability data demonstrated agreement between pods for settings 5-9 (intra-class correlation [ICC] >0.9), but not for settings 1-4 (ICC <0.9). In part 2, between-visits, high correlations, and low typical error of measurement (TEM) and coefficient of variation (CV) were found for Trectal, HR, MAP, SR, and Tcomfort, but not for Ttympanic or Tsensation. A peak Trectal of 38.09 ± 0.30 °C, HR of 124 ± 15 b min-1 and a sweat loss of 0.73 ± 0.33 L were reported. No between-visit differences (p > 0.05) were observed for Trectal, Ttympanic, Tsensation or Tcomfort, however HR (+3 b.min-1) and MAP (+4 mmHg) were greater in visit 1 vs. 2 (p < 0.05). CONCLUSION: Portable steam sauna pods generate reliable heat stress between-units. The highest setting (44 °C/99% RH) also provides reliable but modest adjustments in physiological and perceptual responses.

The Michigan Genetic Hereditary Testing (MiGHT) study's innovative approaches to promote uptake of clinical genetic testing among cancer patients: a study protocol for a 3-arm randomized controlled trial.

BACKGROUND: Although most cancers are sporadic, germline genetic variants are implicated in 5-10% of cancer cases. Clinical genetic testing identifies pathogenic germline genetic variants for hereditary cancers. The Michigan Genetic Hereditary Testing (MiGHT) study is a three-arm randomized clinical trial that aims to test the efficacy of two patient-level behavioral interventions on uptake of cancer genetic testing. METHODS: The two interventions being tested are (1) a virtual genetics navigator and (2) motivational interviewing by genetic health coaches. Eligible participants are adults with a diagnosis of breast, prostate, endometrial, ovarian, colorectal, or pancreatic cancer who meet the National Comprehensive Cancer Network (NCCN) criteria for genetic testing. Participants are recruited through community oncology practices affiliated with the Michigan Oncology Quality Consortium (MOQC) and have used the Family Health History Tool (FHHT) to determine testing eligibility. The recruitment goal is 759 participants, who will be randomized to usual care or to either the virtual genetics navigator or the motivational interviewing intervention arms. The primary outcome will be the proportion of individuals who complete germline genetic testing within 6 months. DISCUSSION: This study addresses patient-level factors which are associated with the uptake of genetic testing. The study will test two different intervention approaches, both of which can help address the shortage of genetic counselors and improve access to care. TRIAL REGISTRATION: This study has been approved by the Institutional Review Board of the University of Michigan Medical School (HUM00192898) and registered in ClinicalTrials.gov (NCT05162846).

Pharmacodynamics of ceftriaxone for the treatment of methicillin-susceptible Staphylococcus aureus: is it a viable treatment option?

Ceftriaxone is a broad-spectrum cephalosporin that may be one option to treat methicillin-susceptible Staphylococcus aureus (MSSA). Although MSSA may be susceptible to ceftriaxone, the minimum inhibitory concentration (MIC) is generally two- to four-fold higher than other susceptible bacterial pathogens. This study aimed to explore the pharmacodynamics of ceftriaxone against MSSA and to determine the likely optimal dose. A hollow-fibre infection model was used with one clinical MSSA isolate (MIC = 4 mg/L) at an initial inoculum of 1 × 106 CFU/mL. Ceftriaxone dosing regimens of 1 g once and twice daily and 2 g once and twice daily were simulated. Ceftriaxone 1 g dosing regimens did not substantially impact bacterial killing within the first 12 h. Conversely, when administered as a 2 g dose either once or twice daily, an approximate 1-log10 bacterial reduction was observed where it plateaued for up to 96 h. No resistance was identified. Only a high ceftriaxone dose of 2 g twice daily achieves bacterial killing and sustained inhibition of bacterial growth. Ceftriaxone at routinely used doses is unsuitable for the treatment of MSSA infections and alternative agents should be preferentially used.

Zinc hydroxychloride supplementation improves tibia bone development and intestinal health of broiler chickens.

This study was conducted to investigate the effects of zinc (Zn), as a combination of oxide (ZnO) and sulfate (ZnSO4), compared with incremental levels of zinc hydroxychloride (ZH) on tibia traits, intestinal integrity, expression of selected jejunal genes, cecal short chain fatty acids and microbial composition in broilers. Day-old male Ross 308 chicks (n = 784) were randomly allocated to seven dietary treatments, each replicated seven times with 16 chicks per replication. The dietary treatments included a negative control diet (NC) with no supplemental Zn, a positive control (PC) with 100 mg/kg supplemental Zn from an ionic bound source combination (50 mg/kg ZnO + 50 mg/kg ZnSO4), and the NC diet supplemented with one of 20, 40, 60, 80, or 100 mg/kg Zn as ZH. The diets were fed over starter (1-14 d) and grower (14-35 d) phases, with tissue and digesta samples collected from 3 birds per replicate on days 14 and 35. The results showed that dietary Zn level had a significant effect on tibia breaking strength on d 35 (P < 0.05), and tibia Zn concentration both on d 14 and d 35 (P < 0.01). Dietary Zn levels linearly (P < 0.01) increased cecal lactic acid production, increased Lactobacillus, and decreased Bacillus and total bacteria counts (P < 0.05). Inclusion of 80 and 100 mg/kg Zn as ZH tended to upregulate the expression of claudin-1 (P = 0.088) and tight junction protein-1 (P = 0.086). The results obtained in this study suggest that a non-Zn supplemented diet can negatively influence tibia development and gut microbiota composition in broiler chickens. Higher supplemental Zn in the diet alters cecal microbiota population in favor of Lactobacillus and can decrease the total bacterial load. Supplemental Zn level in the feed have the potential to manipulate the jejunal gut integrity at a molecular level.

Copper hydroxychloride is more efficacious than copper sulfate in improving broiler chicken's growth performance, both at nutritional and growth-promoting levels.

This study was designed to compare the effects of nutritional and growth-promoting levels of copper hydroxychloride (CH) with copper sulfate (CuSO4) on growth, carcass characteristics, tibia traits and mineral concentration in broilers fed a conventional wheat-soybean meal-based diet. Day-old Ross 308 male chicks (n = 864) were randomly assigned into 8 dietary treatments with 6 replicates of 18 chicks per treatment. The dietary treatments included a basal diet containing no supplemental copper (Cu) serving as the negative control (NC); basal diet supplemented with 15 or 200 mg/kg Cu as CuSO4; basal diet supplemented with either 15, 50, 100, 150, or 200 mg/kg Cu from CH. Diets were fed over the starter (day 1-14) and grower (day 14-35) phases. Birds in the NC group gained the same body weight and had similar feed conversion ratio (FCR) to birds receiving 15 mg/kg Cu as CuSO4, but birds receiving 15 mg/kg Cu as CH had a lower FCR than the NC birds (day 0-35; P < 0.05). Birds fed 200 mg/kg Cu as CH gained more weight (77 g/bird) and had a lower FCR (3.2 point) compared with those fed 200 mg/kg Cu as CuSO4 (P < 0.01). Based on broken-line regression models, the optimum inclusion level of Cu as CH in the diet for optimal body weight gain and FCR were estimated to be 109.5 and 72.3 mg/kg, respectively (P < 0.001). Carcass characteristics were not affected by dietary Cu sources or levels (P > 0.05). The highest and lowest tibia ash content were observed in birds fed diet with 150 mg/kg Cu as CH and 200 mg/kg Cu as CuSO4, respectively (P < 0.05). Supplementation with 200 mg/kg Cu as CH resulted in higher duodenal mucosa Cu content compared with the diet containing 200 mg/kg Cu as CuSO4 (P < 0.001). In conclusion, supplementation of Cu from CH was more efficacious than CuSO4 in promoting growth performance, both at nutritional and pharmacological levels.

Non-polymyxin-based combinations as potential alternatives in treatment against carbapenem-resistant Acinetobacter baumannii infections.

Due to limited therapeutic options, combination therapy has been used empirically to treat carbapenem-resistant Acinetobacter baumannii (CRAB). Polymyxin-based combinations have been widely studied and used in the clinical setting. However, the use of polymyxins is often limited due to nephrotoxicity and neurotoxicity. This study aimed to evaluate the activity of non-polymyxin-based combinations relative to polymyxin-based combinations and to identify potential synergistic and bactericidal two-drug non-polymyxin-based combinations against CRAB. In vitro activity of 14 two-drug combinations against 50 A. baumannii isolates was evaluated using the checkerboard method. Subsequently, the two best-performing non-polymyxin-based combinations from the checkerboard assay were explored in static time-kill experiments. Concentrations of antibiotics corresponding to the fractional inhibitory concentrations (FIC) and the highest serum concentration achievable clinically were tested. The most synergistic combinations were fosfomycin/sulbactam (synergistic against 37/50 isolates; 74%), followed by meropenem/sulbactam (synergistic against 28/50 isolates; 56%). No antagonism was observed for any combination. Both fosfomycin/sulbactam and meropenem/sulbactam combinations exhibited bactericidal and synergistic activity against both isolates at the highest clinically achievable concentrations in the time-kill experiments. The meropenem/sulbactam combination displayed synergistic and bactericidal activity against one of two strains at concentrations equal to the FIC. Non-polymyxin-based combinations such as fosfomycin/sulbactam and meropenem/sulbactam may have a role in the treatment of CRAB. Further in vivo and clinical studies are required to scrutinise these activities further.

Soaking up the oil: Biological impacts of dispersants and crude oil on the sponge Halichondria panicea.

Used during an oil spill to minimise the formation of an oil slick, dispersants have negative biological effects on marine model organisms. However, no study has investigated the impacts of dispersants on adult sponge individuals. Here, we examine the effects of water accommodated oil fraction (WAF - oil in seawater), chemically enhanced WAF (CEWAF - oil and dispersant in seawater) and Benzo[A]Pyrene on sponge Halichondria panicea at physiological and molecular levels. Sponge clearance rate decreased sharply when exposed to WAF and CEWAF but the oil loading at which the clearance rate was reduced by 50% (ED50) was 39-fold lower in CEWAF than in WAF. Transcriptomic analysis revealed a homogenous molecular response with the greatest number of differentially expressed genes identified in CEWAF samples (1,461 genes). Specifically, genes involved in stress responses were up-regulated. This study presents evidence that the use of dispersants should be considered carefully in areas where sponges are present.

Individualising Therapy to Minimize Bacterial Multidrug Resistance.

The scourge of antibiotic resistance threatens modern healthcare delivery. A contributing factor to this significant issue may be antibiotic dosing, whereby standard antibiotic regimens are unable to suppress the emergence of antibiotic resistance. This article aims to review the role of pharmacokinetic and pharmacodynamic (PK/PD) measures for optimising antibiotic therapy to minimise resistance emergence. It also seeks to describe the utility of combination antibiotic therapy for suppression of resistance and summarise the role of biomarkers in individualising antibiotic therapy. Scientific journals indexed in PubMed and Web of Science were searched to identify relevant articles and summarise existing evidence. Studies suggest that optimising antibiotic dosing to attain defined PK/PD ratios may limit the emergence of resistance. A maximum aminoglycoside concentration to minimum inhibitory concentration (MIC) ratio of > 20, a fluoroquinolone area under the concentration-time curve to MIC ratio of > 285 and a ß-lactam trough concentration of > 6 × MIC are likely required for resistance suppression. In vitro studies demonstrate a clear advantage for some antibiotic combinations. However, clinical evidence is limited, suggesting that the use of combination regimens should be assessed on an individual patient basis. Biomarkers, such as procalcitonin, may help to individualise and reduce the duration of antibiotic treatment, which may minimise antibiotic resistance emergence during therapy. Future studies should translate laboratory-based studies into clinical trials and validate the appropriate clinical PK/PD predictors required for resistance suppression in vivo. Other adjunct strategies, such as biomarker-guided therapy or the use of antibiotic combinations require further investigation.

Pasture, multi-enzymes, benzoic acid and essential oils positively influence performance, intestinal organ weight and egg quality in free-range laying hens.

1. The objective of this study was to investigate the effect of range type, multi-enzyme applications, and a combination of benzoic acid (BA) and essential oils (EO) on the productive performance, organ weight and egg quality of free-range laying hens. 2. Three hundred laying hens were evaluated for the short-term (6 weeks) and long-term (12 weeks) effects of range type (G = no pasture, P = pasture) and feed additives (T1 = control; T2 = betaglucanase/pectinase/protease; T3 = BA/EO). Body weight, feed intake (FI), feed conversion ratio (FCR), egg production (EP), digestive organ weight, and egg quality (EQ) were evaluated. Data were analysed using SPSS 2.2 in a 2×2×3 factorial arrangement. 3. Hens that ranged on pasture were significantly heavier (2043 g vs. 1996 g; p < 0.001), laid heavier eggs (61.9 g vs. 60.3 g; p < 0.001) and produced darker yolk colour (4.3 vs. 7.0; p < 0.001) compared to hens ranged on gravel. Hens fed T2 were significantly heavier (2050 g) compared to hens fed T1 (2005 g) or T3 (2008 g). Organ weights (gizzard, liver and pancreas) were significantly heavier in hens ranged on pasture (16.8 g/kg BW, 22.3 g/kg BW and 1.89 g/kg BW, respectively) compared to hens ranged on gravel (14.2 g/kg BW, 21.7 g/kg BW and 1.83 g/kg BW, respectively). Over time, body weight (1970-2070 g; p < 0.001) and egg weight (59.5-62.8 g; p < 0.001) increased, FI (123-120 g; p = 0.024) was reduced and FCR (2.36-2.10; p = 0.002) improved 4. In conclusion, hens housed on pasture and fed multi-enzyme supplemented diets had significantly heavier body weight and produced heavier eggs with darker yolk colour. Pasture intake and enzyme supplementation increased digestive organ weight significantly.

Effects of pulmonary exposure to chemically-distinct welding fumes on neuroendocrine markers of toxicity.

Exposure to welding fumes may result in disorders of the pulmonary, cardiovascular, and reproductive systems. Welders are also at a greater risk of developing symptoms similar to those seen in individuals with idiopathic Parkinson's disease. In welders, there are studies that suggest that alterations in circulating prolactin concentrations may be indicative of injury to the dopamine (DA) neurons in the substantia nigra. The goal of these studies was to use an established model of welding particulate exposure to mimic the effects of welding fume inhalation on reproductive functions. Since previous investigators suggested that changes in circulating prolactin may be an early marker of DA neuron injury, movement disorders, and reproductive dysfunction, prolactin, hypothalamic tyrosine hydroxylase (TH) levels (a marker of DA synthesis), and other measures of hypothalamic-pituitary-gonadal (HPG) function were measured after repetitive instillation of welding fume particulates generated by flux core arc-hard surfacing (FCA-HS), manual metal arc-hard surfacing (MMA-HS) or gas metal arc-mild steel (GMA-MS) welding, or manganese chloride (MnCl2). Exposure to welding fume particulate resulted in the accumulation of various metals in the pituitary and testes of rats, along with changes in hypothalamic TH and serum prolactin levels. Exposure to particulates with high concentrations of soluble manganese (Mn) appeared to exert the greatest influence on TH activity levels and serum prolactin concentrations. Thus, circulating prolactin levels may serve as a biomarker for welding fume/Mn-induced neurotoxicity. Other reproductive measures were collected, and these data were consistent with epidemiological findings that prolactin and testosterone may serve as biomarkers of welding particulate induced DA neuron and reproductive dysfunction.

Historic scale and persistence of drill cuttings impacts on North Sea benthos.

Despite its long history of hydrocarbon exploitation, the United Kingdom lacks scientific protocols to monitor ecological impacts of drill cuttings (mixtures between rocky material excavated from wells and drilling mud). The present study used the UK Benthos industry database to apply standardised variance partitioning and measure the scale and persistence of these effects at 19 sites across the UK sector of the North Sea. Generally, effects were limited to within 1 km from the platform, but two platforms historically drilled with oil-based mud were impacted up to 1.2 km away. Impacts persisted for at least 6-8 years in the northern and central North Sea, but were undetectable in the south where cuttings piles do not accumulate. This study underpins new recommendations to implement regional, phase-based approaches to drill cuttings monitoring, and to apply a precautionary approach in considering decommissioning options that will minimise disturbance to cuttings piles.

The cost of warfarin treatment for stroke prevention in patients with non-valvular atrial fibrillation in Russia from a collective perspective.

AIMS: Vitamin K antagonists (VKAs) are used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF), but necessitate regular monitoring of prothrombin time via international normalized ratio (INR) testing. This study explores the economic burden of VKA therapy for Russian patients with NVAF. METHOD: Cardiologists provided clinical characteristics and healthcare resource use data relating to the patient's first year of treatment. Data were used to quantify direct medical costs (INR testing, consultations, drug costs). The same patients completed a questionnaire providing data on direct non-medical costs (travel/expenses for attendance at VKA appointments) and indirect costs (opportunity cost and reduced work productivity). Mean costs per patient per year are described (US dollars). RESULTS: Cardiologists (n = 50) provided data on 400 patients (mean age = 63, 47% female), and 351 patients (88%) completed the patient questionnaire. Patients had a mean of nine INR tests. Estimated direct medical costs totaled $151.06, and 18.5% of direct medical costs were attributable to drug costs. Estimated annual direct non-medical costs were $22.89 per patient, and indirect costs were $275.59 per patient. LIMITATIONS: Included patients had been treated for 12-24 months, so are not fully representative of the broader treatment population. CONCLUSION: Although VKA drugs costs are relatively low, regular INR testing and consultations drive the economic burden for Russian NVAF patients treated with VKA.

Personal Genomic Testing for Cancer Risk: Results From the Impact of Personal Genomics Study.

Purpose Significant concerns exist regarding the potential for unwarranted behavior changes and the overuse of health care resources in response to direct-to-consumer personal genomic testing (PGT). However, little is known about customers' behaviors after PGT. Methods Longitudinal surveys were given to new customers of 23andMe (Mountain View, CA) and Pathway Genomics (San Diego, CA). Survey data were linked to individual-level PGT results through a secure data transfer process. Results Of the 1,042 customers who completed baseline and 6-month surveys (response rate, 71.2%), 762 had complete cancer-related data and were analyzed. Most customers reported that learning about their genetic risk of cancers was a motivation for testing (colorectal, 88%; prostate, 95%; breast, 94%). No customers tested positive for pathogenic mutations in highly penetrant cancer susceptibility genes. A minority of individuals received elevated single nucleotide polymorphism-based PGT cancer risk estimates (colorectal, 24%; prostate, 24%; breast, 12%). At 6 months, customers who received elevated PGT cancer risk estimates were not significantly more likely to change their diet, exercise, or advanced planning behaviors or engage in cancer screening, compared with individuals at average or reduced risk. Men who received elevated PGT prostate cancer risk estimates changed their vitamin and supplement use more than those at average or reduced risk (22% v 7.6%, respectively; adjusted odds ratio, 3.41; 95% CI, 1.44 to 8.18). Predictors of 6-month behavior include baseline behavior (exercise, vitamin or supplement use, and screening), worse health status (diet and vitamin or supplement use), and older age (advanced planning, screening). Conclusion Most adults receiving elevated direct-to-consumer PGT single nucleotide polymorphism-based cancer risk estimates did not significantly change their diet, exercise, advanced care planning, or cancer screening behaviors.

Satisfaction with current psoriasis treatment: misalignment between physician and patient perceptions.

Psoriasis patients often report dissatisfaction with treatment. However, the extent to which patients and their treating dermatologists are aligned regarding satisfaction with psoriasis therapy is largely unknown. This was explored using data derived from the Adelphi 2011/2013 Psoriasis Disease Specific Programmes, two real world surveys of US dermatologists and their patients. Physicians and patients independently reported their satisfaction with psoriasis control (satisfied, dissatisfied). Two levels of satisfaction alignment between physician and patient responses were constructed: aligned (same responses) and misaligned (different responses). In addition, dermatologists provided patient treatment history and disease/symptom severity whereas patients reported data on health-related quality of life (HRQoL), using the EuroQOL 5-Dimension Health Questionnaire (EQ-5D) and Dermatology Life Quality Index (DLQI), and work productivity using the Work Productivity Activity index (WPAI). Multivariate regressions were employed to examine the relationship between satisfaction alignment, overall disease and symptom severity, HRQoL, and work productivity controlling for differences in patient demographics and comorbidities.From 627 paired dermatologist and psoriasis patient records, 512 (81.7%) and 115 (18.3%) cases fell into the 'aligned' and 'misaligned' groups, respectively. Compared with patients in the aligned group, those in the misaligned group had more moderate to severe psoriasis (82.3% vs. 43.7%), moderate to severe itching (45.6% vs. 27.8%), pain (23.0% vs. 10.6%), and scaling (54.8% vs. 36.1%), and had lower current biologics use (27.0% vs. 42%) (all p<0.05). The misaligned group was associated with reduced HRQoL (lower EQ-5D score: 0.86 vs. 0.91; higher DLQI score: 7.06 vs. 4.23) and greater work productivity loss (higher WPAI scores: 18.27 vs. 11.43) (all p<0.05). Multivariate analyses confirmed these results (p<0.05). Almost 1 in 5 patients were misaligned with their dermatologist's level of satisfaction with their psoriasis treatment; misalignment was associated with increased disease and symptom severity, reduced HRQoL, and reduced work productivity.

Patient satisfaction with current psoriasis treatment: a real-world study in the USA.

Psoriasis patients often report dissatisfaction with treatment. However, it is less clear how the severity of key psoriasis symptoms (painful skin, itching, and scaling) as well as overall disease severity influence patient dissatisfaction levels. Using the Adelphi 2011/2013 Psoriasis Disease Specific Programmes, two "real world" surveys of US dermatologists and their patients, patient satisfaction was evaluated. Dermatologists provided data on disease characteristics, while patients indicated their satisfaction with existing treatment. Physician-reported severity (none, mild, moderate/severe) of psoriasis-related itching, pain, and scaling, overall disease severity (mild, moderate and severe) and therapy type were compared by patient satisfaction levels (satisfied vs. dissatisfied). Multivariate regressions examined the relationship between patient satisfaction, clinical symptoms, and psoriasis overall disease severity, controlling for differences in patient demographics and comorbidities. The sample comprised 633 psoriasis patients (56% male) with a mean age of 45. Overall, 18% of patients reported dissatisfaction with their psoriasis treatment. Dissatisfied patients were more likely to have moderate (65% vs. 40%) or severe (21% vs 3%) psoriasis compared to patients who were satisfied (both p<0.05). Dissatisfied patients were also more likely to have more severe pain (30% moderate-to-severe pain vs. 9%), more severe itching (61% moderate-to-severe itching vs. 25%), and more severe scaling (68% moderate-to-severe scaling vs. 33%) than satisfied patients (all p< 0.05). Multivariate analyses confirmed these results. Clinicians should be aware that some psoriasis patients, especially those with severe overall disease or symptoms, may be dissatisfied and are in need of better treatment.

Population pharmacokinetics of linezolid in critically ill patients on renal replacement therapy: comparison of equal doses in continuous venovenous haemofiltration and continuous venovenous haemodiafiltration.

OBJECTIVES: Few data are available to guide linezolid dosing during renal replacement therapy. The objective of this study was to compare the population pharmacokinetics of linezolid during continuous venovenous haemofiltration (CVVHF, 30 mL/kg/h) and continuous venovenous haemodiafiltration (CVVHDF, 15 mL/kg/h + 15 mL/kg/h). METHODS: Patients requiring linezolid 600 mg iv every 12 h and CVVHF or CVVHDF were eligible for this prospective study. Seven blood samples were collected over one dosing interval and analysed by a validated chromatographic method. Population pharmacokinetic analysis was undertaken using Pmetrics. Monte Carlo simulations evaluated achievement of a pharmacodynamics target of an AUC from 0-24 h to MIC (AUC0-24/MIC) of 80. RESULTS: Nine CVVHDF and eight CVVHF treatments were performed in 13 patients. Regimens of CVVHDF and CVVHF were similar. A two-compartment linear model best described the data. CVVHDF was associated with a 20.5% higher mean linezolid clearance than CVVHF, without statistical significance (P = 0.39). Increasing patient weight and decreasing SOFA score were associated with increasing linezolid clearance. The mean (SD) parameter estimates were: clearance (CL), 3.8 (2.2) L/h; volume of the central compartment, 26.5 (10.3) L; intercompartmental clearance constants from central to peripheral, 8.1 (12.1) L/h; and peripheral to central compartments, 3.6 (4.0) L/h. Achievement of pharmacodynamic targets was poor for an MIC of 2 mg/L with the studied dose. CONCLUSIONS: During CVVHF and CVVHDF, there is profound pharmacokinetic variability of linezolid. Suboptimal achievement of therapeutic targets occurs at the EUCAST breakpoint MIC of 2 mg/L using 600 mg iv every 12 h.

The effect of calcium supplementation on blood pressure in non-pregnant women with previous pre-eclampsia: An exploratory, randomized placebo controlled study.

BACKGROUND: Epidemiological findings suggest that the link between poverty and pre-eclampsia might be dietary calcium deficiency. Calcium supplementation has been associated with a modest reduction in pre-eclampsia, and also in blood pressure (BP). METHODS: This exploratory sub-study of the WHO Calcium and Pre-eclampsia (CAP) trial aims to determine the effect of 500mg/day elemental calcium on the blood pressure of non-pregnant women with previous pre-eclampsia. Non-pregnant women with at least one subsequent follow-up trial visit at approximately 12 or 24weeks after randomization were included. RESULTS: Of 836 women randomized by 9 September 2014, 1st visit data were available in 367 women of whom 217 had previously had severe pre-eclampsia, 2nd visit data were available in 201 women. There was an overall trend to reduced BP in the calcium supplementation group (1-2.5mmHg) although differences were small and not statistically significant. In the subgroup with previous severe pre-eclampsia, the mean diastolic BP change in the calcium group (-2.6mmHg) was statistically larger than in the placebo group (+0.8mmHg), (mean difference -3.4, 95% CI -0.4 to -6.4; p=0.025). The effect of calcium on diastolic BP at 12weeks was greater than in those with non-severe pre-eclampsia (p=0.020, ANOVA analysis). CONCLUSIONS: There is an overall trend to reduced BP but only statistically significant in the diastolic BP of women with previous severe pre-eclampsia. This is consistent with our hypothesis that this group is more sensitive to calcium supplementation, however results need to be interpreted with caution.

Risk factors for target non-attainment during empirical treatment with ß-lactam antibiotics in critically ill patients.

PURPOSE: Risk factors for ß-lactam antibiotic underdosing in critically ill patients have not been described in large-scale studies. The objective of this study was to describe pharmacokinetic/pharmacodynamic (PK/PD) target non-attainment envisioning empirical dosing in critically ill patients and considering a worst-case scenario as well as to identify patient characteristics that are associated with target non-attainment. METHODS: This analysis uses data from the DALI study, a prospective, multi-centre pharmacokinetic point-prevalence study. For this analysis, we assumed that these were the concentrations that would be reached during empirical dosing, and calculated target attainment using a hypothetical target minimum inhibitory concentration (MIC), namely the susceptibility breakpoint of the least susceptible organism for which that antibiotic is commonly used. PK/PD targets were free drug concentration maintained above the MIC of the suspected pathogen for at least 50 % and 100 % of the dosing interval respectively (50 % and 100 % f T (>MIC)). Multivariable analysis was performed to identify factors associated with inadequate antibiotic exposure. RESULTS: A total of 343 critically ill patients receiving eight different ß-lactam antibiotics were included. The median (interquartile range) age was 60 (47-73) years, APACHE II score was 18 (13-24). In the hypothetical situation of empirical dosing, antibiotic concentrations remained below the MIC during 50 % and 100 % of the dosing interval in 66 (19.2 %) and 142 (41.4 %) patients respectively. The use of intermittent infusion was significantly associated with increased risk of non-attainment for both targets; creatinine clearance was independently associated with not reaching the 100 % f T( >MIC) target. CONCLUSIONS: This study found that-in empirical dosing and considering a worst--case scenario--19 % and 41 % of the patients would not achieve antibiotic concentrations above the MIC during 50 % and 100 % of the dosing interval. The use of intermittent infusion (compared to extended and continuous infusion) was the main determinant of non-attainment for both targets; increasing creatinine clearance was also associated with not attaining concentrations above the MIC for the whole dosing interval. In the light of this study from 68 ICUs across ten countries, we believe current empiric dosing recommendations for ICU patients are inadequate to effectively cover a broad range of susceptible organisms and need to be reconsidered.