BackgroundThe clinical utility of serum procalcitonin levels in guiding antibiotic treatment decisions in patients with sepsis remains unclear. This patient-level meta-analysis based on 11 randomized trials investigates the impact of procalcitonin-guided antibiotic therapy on mortality in intensive care unit (ICU) patients with infection, both overall and stratified according to sepsis definition, severity, and type of infection.MethodsFor this meta-analysis focusing on procalcitonin-guided antibiotic management in critically ill patients with sepsis of any type, in February 2018 we updated the database of a previous individual patient data meta-analysis which was limited to patients with respiratory infections only. We used individual patient data from 11 trials that randomly assigned patients to receive antibiotics based on procalcitonin levels (the “procalcitonin-guided” group) or the current standard of care (the “controls”). The primary endpoint was mortality within 30 days. Secondary endpoints were duration of antibiotic treatment and length of stay.ResultsMortality in the 2252 procalcitonin-guided patients was significantly lower compared with the 2230 control group patients (21.1% vs 23.7%; adjusted odds ratio 0.89, 95% confidence interval (CI) 0.8 to 0.99; p = 0.03). These effects on mortality persisted in a subgroup of patients meeting the sepsis 3 definition and based on the severity of sepsis (assessed on the basis of the Sequential Organ Failure Assessment (SOFA) score, occurrence of septic shock or renal failure, and need for vasopressor or ventilatory support) and on the type of infection (respiratory, urinary tract, abdominal, skin, or central nervous system), with interaction for each analysis being > 0.05. Procalcitonin guidance also facilitated earlier discontinuation of antibiotics, with a reduction in treatment duration (9.3 vs 10.4 days; adjusted coefficient −1.19 days, 95% CI −1.73 to −0.66; p <  0.001).ConclusionProcalcitonin-guided antibiotic treatment in ICU patients with infection and sepsis patients results in improved survival and lower antibiotic treatment duration.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2125-7) contains supplementary material, which is available to authorized users.

Human DHRS6 is a previously uncharacterized member of the short chain dehydrogenases/reductase family and displays significant homologies to bacterial hydroxybutyrate dehydrogenases. Substrate screening reveals sole NAD ؉ -dependent conversion of (R)-hydroxybutyrate to acetoacetate with K m values of about 10 mM, consistent with plasma levels of circulating ketone bodies in situations of starvation or ketoacidosis. The structure of human DHRS6 was determined at a resolution of 1.8 Å in complex with NAD(H) and reveals a tetrameric organization with a short chain dehydrogenases/reductase-typical folding pattern. A highly conserved triad of Arg residues ("triple R" motif consisting of Arg 144 , Arg 188 , and Arg 205 ) was found to bind a sulfate molecule at the active site. Docking analysis of R-␤-hydroxybutyrate into the active site reveals an experimentally consistent model of substrate carboxylate binding and catalytically competent orientation. GFP reporter gene analysis reveals a cytosolic localization upon transfection into mammalian cells. These data establish DHRS6 as a novel, cytosolic type 2 (R)-hydroxybutyrate dehydrogenase, distinct from its well characterized mitochondrial type 1 counterpart. The properties determined for DHRS6 suggest a possible physiological role in cytosolic ketone body utilization, either as a secondary system for energy supply in starvation or to generate precursors for lipid and sterol synthesis.Hepatic ketone body formation and utilization of these compounds by peripheral tissues with high energy demands is essential in humans and other mammals for survival during times of starvation and extended fasting. The compounds categorized as ketone bodies comprise acetoacetate, R-␤-hydroxybutyrate, and acetone, the last being a nonmetabolizable decarboxylation product of acetoacetate. The liver produces and excretes ketone bodies during times when the amount of acetyl-CoA exceeds the oxidative capacity of hepatic mitochondria. Ketone body formation is thus necessary to maintain ␤-oxidation by supplying free CoA. This metabolic situation occurs when high amounts of fatty acids derived from peripheral tissues during starvation or fasting are oxidized by ␤-oxidation pathways. In exacerbated disease states, such as ketoacidotic coma, extremely high amounts of fatty acids are oxidized as a consequence of insulin resistance in diabetes mellitus. In this situation, a potentially life-threatening metabolic acidosis occurs through the high amounts of protons provided by acetoacetate and R-␤-hydroxybutyrate, exceeding the serum bicarbonate buffer capacity. Serum levels of 5-10 mM ketone bodies are reached under these circumstances as compared with levels of 1 mM in normal states. The liver synthesizes acetoacetate through the enzymes thiolase, hydroxymethylglutaryl-CoA synthase, and hydroxymethylglutaryl-CoA lyase from three molecules of acetyl-CoA, thus producing 1 mol of acetoacetate, 1 mol of acetyl-CoA, and 2 mol of free CoA. Acetoacetate is further reduced to R-␤-hydroxybutyrate through mito...

ObjectivesRecently, the Hospital Frailty Risk Score based on a derivation and validation study in the UK has been proposed as a low-cost, systematic screening tool to identify older, frail patients who are at a greater risk of adverse outcomes and for whom a frailty-attuned approach might be useful. We aimed to validate this Score in an independent cohort in Switzerland.DesignSecondary analysis of a prospective, observational study (TRIAGE study).SettingOne 600-bed tertiary care hospital in Aarau, Switzerland.ParticipantsConsecutive medical inpatients aged ≥75 years that presented to the emergency department or were electively admitted between October 2015 and April 2018.Primary and secondary outcome measuresThe primary endpoint was all-cause 30-day mortality. Secondary endpoints were length of hospital stay, hospital readmission, functional impairment and quality of life measures. We used multivariate regression analyses.ResultsOf 4957 included patients, 3150 (63.5%) were classified as low risk, 1663 (33.5%) intermediate risk, and 144 (2.9%) high risk for frailty. Compared with the low-risk group, patients in the moderate risk and high-risk groups had increased risk for 30-day mortality (OR (OR) 2.53, 95% CI 2.09 to 3.06, p<0.001 and OR 4.40, 95% CI 2.94 to 6.57, p<0.001) with overall moderate discrimination (area under the ROC curve 0.66). The results remained robust after adjustment for important confounders. Similarly, we found longer length of hospital stay, more severe functional impairment and a lower quality of life in higher risk group patients.ConclusionOur data confirm the prognostic value of the Hospital Frailty Risk Score to identify older, frail people at risk for mortality and adverse outcomes in an independent patient population.Trial registration numberNCT01768494; Post-results.

Background Whether procalcitonin (PCT)–guided antibiotic management in patients with positive blood cultures is safe remains understudied. We performed a patient-level meta-analysis to investigate effects of PCT-guided antibiotic management in patients with bacteremia. Methods We extracted and analyzed individual data of 523 patients with positive blood cultures included in 13 trials, in which patients were randomly assigned to receive antibiotics based on PCT levels (PCT group) or a control group. The main efficacy endpoint was duration of antibiotic treatment. The main safety endpoint was mortality within 30 days. Results Mean duration of antibiotic therapy was significantly shorter for 253 patients who received PCT-guided treatment than for 270 control patients (–2.86 days [95% confidence interval [CI], –4.88 to –.84]; P = .006). Mortality was similar in both arms (16.6% vs 20.0%; P = .263). In subgroup analyses by type of pathogen, we noted a trend of shorter mean antibiotic durations in the PCT arm for patients infected with gram-positive organisms or Escherichia coli and significantly shorter treatment for subjects with pneumococcal bacteremia. In analysis by site of infection, antibiotic exposure was shortened in PCT subjects with Streptococcus pneumoniae respiratory infection and those with E. coli urogenital infections. Conclusions This meta-analysis of patients with bacteremia receiving PCT-guided antibiotic management demonstrates lower antibiotic exposure without an apparent increase in mortality. Few differences were demonstrated in subgroup analysis stratified by type or site of infection but notable for decreased exposure in patients with pneumococcal pneumonia and E. coli urogenital infections.

The influence that grandparents have on the life history traits of their descendants has been studied extensively. However, no attention has been paid to the potential influence a grandparent's own reproductive history has on the investment they make in their grandchildren. We use data from 658 Swiss grandchildren and 591 of their grandparents to investigate whether grandparents' reproductive scheduling and family size influence the amount of investment grandparents make in a focal grandchild (shared contacts, occasions to meet, activities, discussions, interests, and important roles the grandparent plays). Grandparents who were younger when they had their first child had more children and grandchildren; this relationship strengthened after controlling for grandparental age, sex, lineage, and education (all P < 0.001). Generally, having more children or grandchildren was associated with reduced levels of grandparental investment. After adjustment for a wide range of factors known to influence investment, having more children or grandchildren and having a first child or grandchild at a younger age were associated with reduced investment in 14 of 24 analyses (all P < 0.09). The association between reproductive scheduling and investment was partially mediated by the grandparent's family size. Interestingly, these relationships were only present in data reported from the grandchild's point of view, not the grandparent's. This analysis provides preliminary evidence that grandparents' reproductive strategies have consequences for the amount of investment they make in their grandchildren. These results are examined in terms of the trade-offs between current and future reproduction and offspring quality and quantity. Am. J. Hum. Biol. 21:455-463, 2009. Grandparents can play a crucial role in the lives of their grandchildren. However, as with any relationship, the extent of grandparental investment is highly variable (e.g., Euler and Weitzel, 1996;Laham et al., 2005;Michalski and Shackelford, 2005;Pashos and McBurney, 2008). Studies examining the underlying factors that contribute to this variability have been carried out by behavioral ecologists, psychologists, sociologists, and economists. To date, grandparental investment research has focused on the potential influences of genetic relatedness (e.g., Aldous, 1995), paternity certainty (e.g., Pollet et al., 2006), sex-specific reproductive strategies (e.g., Euler and Weitzel, 1996), the moderating role of parents (e.g., Pashos and McBurney, 2008), including mothers as links maintaining family ties (e.g., Monserud, 2008), grandparental age (Lahdenperä et al., 2004), physical resemblance (e.g., Michalski and Shackelford, 2005), the grandchild's reproductive value (e.g., Smith, 1991), and the grandchild's family size and birth order (Leonetti et al., 2005). Although grandparental investment, like parental investment, is often conceptualized as part of an individual's reproductive strategy (see Coall and Hertwig, submitted for publication), no attention has been pai...