Osteoporosis is the cause of spontaneous humeral fracture in dairy cows from New Zealand.

Outbreaks of humeral fractures in dairy cows have been reported in New Zealand for several years. Gross, histologic, and histomorphometric findings in the humerus from primiparous cows with spontaneous humeral fracture were compared to age-matched control cows. Affected cows had a complete nonarticular spiral fracture of the humerus. Histologically affected humeri had a thicker growth plate with abnormal architecture, thinner cortex with increased abnormal resorption, increased resorption in the distal humerus, decreased trabecular density, abnormal trabecular architecture, presence of growth arrest lines and woven bone formation. Histomorphometry showed reduction in bone volume, trabecular perimeter, and trabecular width. Cows grazed on fodder beet had thicker growth plates with an abnormal appearance compared with cows grazed on pasture, and cows with low/marginal liver copper concentration had more resorption cavities in the distal humerus and thinner cortical bone compared with cows with adequate liver copper concentration. Decreased trabecular density (OR = 249.5), abnormal cortical resorption (OR = 54.2), presence of woven bone formation in the proximal metaphysis (OR = 37.2), and the number of resorption cavities in the distal humerus were significantly associated with a high probability of fracture. Ribs had enlargement of the costochondral junction with fractures in different stages of healing. Histology of the ribs revealed abnormal growth plate appearance, presence of fracture lines, callus tissue, fibrosis, and microfractures. Cows with humeral fracture have osteoporosis due to decreased bone formation and increased bone resorption, likely associated with inadequate feed quality and perhaps copper deficiency leading to a reduction in bone strength and fracture.

Hedgehogs as Amplifying Hosts of Severe Fever with Thrombocytopenia Syndrome Virus, China.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tickborne bandavirus mainly transmitted by Haemaphysalis longicornis ticks in East Asia, mostly in rural areas. As of April 2022, the amplifying host involved in the natural transmission of SFTSV remained unidentified. Our epidemiologic field survey conducted in endemic areas in China showed that hedgehogs were widely distributed, had heavy tick infestations, and had high SFTSV seroprevalence and RNA prevalence. After experimental infection of Erinaceus amurensis and Atelerix albiventris hedgehogs with SFTSV, we detected robust but transitory viremias that lasted for 9-11 days. We completed the SFTSV transmission cycle between hedgehogs and nymph and adult H. longicornis ticks under laboratory conditions with 100% efficiency. Furthermore, naive H. longicornis ticks could be infected by SFTSV-positive ticks co-feeding on naive hedgehogs; we confirmed transstadial transmission of SFTSV. Our study suggests that the hedgehogs are a notable wildlife amplifying host of SFTSV in China.

Rapid Spread of Severe Fever with Thrombocytopenia Syndrome Virus by Parthenogenetic Asian Longhorned Ticks.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is spreading rapidly in Asia. This virus is transmitted by the Asian longhorned tick (Haemaphysalis longicornis), which has parthenogenetically and sexually reproducing populations. Parthenogenetic populations were found in ≥15 provinces in China and strongly correlated with the distribution of severe fever with thrombocytopenia syndrome cases. However, distribution of these cases was poorly correlated with the distribution of populations of bisexual ticks. Phylogeographic analysis suggested that the parthenogenetic population spread much faster than bisexual population because colonization is independent of sexual reproduction. A higher proportion of parthenogenetic ticks was collected from migratory birds captured at an SFTSV-endemic area, implicating the contribution to the long-range movement of these ticks in China. The SFTSV susceptibility of parthenogenetic females was similar to that of bisexual females under laboratory conditions. These results suggest that parthenogenetic Asian longhorned ticks, probably transported by migratory birds, play a major role in the rapid spread of SFTSV.

Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1.

Post-traumatic OA (PTOA) is often triggered by injurious, high-impact loading events which result in rapid, excessive chondrocyte cell death and a phenotypic shift in residual cells toward a more catabolic state. As such, the identification of a disease-modifying OA drug (DMOAD) that can protect chondrocytes from death following impact injury, and thereby prevent cartilage degradation and progression to PTOA, would offer a novel intervention. We have previously shown that urocortin-1 (Ucn) is an essential endogenous pro-survival factor that protects chondrocytes from OA-associated pro-apoptotic stimuli. Here, using a drop tower PTOA-induction model, we demonstrate the extent of Ucn's chondroprotective role in cartilage explants exposed to excessive impact load. Using pathway-specific agonists and antagonists, we show that Ucn acts to block load-induced intracellular calcium accumulation through blockade of the non-selective cation channel Piezo1 rather than TRPV4. This protective effect is mediated primarily through the Ucn receptor CRF-R1 rather than CRF-R2. Crucially, we demonstrate that the chondroprotective effect of Ucn is maintained whether it is applied pre-impact or post-impact, highlighting the potential of Ucn as a novel DMOAD for the prevention of injurious impact overload-induced PTOA.

Borrelia burgdorferi genes, bb0639-0642, encode a putative putrescine/spermidine transport system, PotABCD, that is spermidine specific and essential for cell survival.

Polyamines are an essential class of metabolites found throughout all kingdoms in life. Borrelia burgdorferi harbors no enzymes to synthesize or degrade polyamines yet does contain a polyamine uptake system, potABCD. In this report, we describe the initial characterization of this putative transport system. After several unsuccessful attempts to inactivate potABCD, we placed the operon under the control of an inducible LacI promoter expression system. Analyses of this construct confirmed that potABCD was required for in vitro survival. Additionally, we demonstrated that the potABCD operon were upregulated in vitro by low osmolarity. Previously, we had shown that low osmolarity triggers the activation of the Rrp2/RpoN/RpoS regulatory cascade, which regulates genes essential for the transmission of spirochetes from ticks to mammalian hosts. Interestingly, induction of the pot operon was only affected in an rpoS mutant but not in a rpoN mutant, suggesting that the genes were RpoS dependent and RpoN independent. Furthermore, potABCD was upregulated during tick feeding concomitant with the initiation of spirochete replication. Finally, uptake experiments determined the specificity of B. burgdorferi's PotABCD for spermidine.

Assessing the accuracy of ICD-10 codes for identifying acute thromboembolic events among patients receiving anticoagulation therapy.

International classification of disease (ICD) codes can improve the efficiency of epidemiological research provided the codes accurately identify outcomes of interest. The purpose of this retrospective cross-sectional study is to evaluate the accuracy of ICD-10 codes for identifying thromboembolic events occurring during anticoagulation therapy. Medical charts of patients hospitalized for any reason while receiving anticoagulant therapy between September 1, 2017 and December 31, 2017 were reviewed by two reviewers blinded to ICD-10 code status. Following identification of confirmed acute thromboembolic events, ICD-10 codes were unblinded and sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) along with 95% confidence intervals (CI) were calculated for coding in any diagnosis position ("principal" or "other"). There were 661 hospitalizations identified among 487 anticoagulated patients. There were 27 thromboembolic events identified during chart review. Stroke and venous thromboembolism were the most common thromboembolic event types. Overall thromboembolic ICD-10 coding sensitivity was 100.0% (95% CI 87.2-100.0); specificity was 79.3% (75.9-82.4). PPV was 17.1% (11.6-23.9%), and NPV was 100% (99.3-100.0). ICD-10 codes can reliably be used for ruling out hospitalizations for thromboembolic events in patients receiving anticoagulation therapy but should not be used for identifying thromboembolic complications without confirmatory chart review.

Two Different Virulence-Related Regulatory Pathways in Borrelia burgdorferi Are Directly Affected by Osmotic Fluxes in the Blood Meal of Feeding Ixodes Ticks.

Lyme disease, caused by Borrelia burgdorferi, is a vector-borne illness that requires the bacteria to adapt to distinctly different environments in its tick vector and various mammalian hosts. Effective colonization (acquisition phase) of a tick requires the bacteria to adapt to tick midgut physiology. Successful transmission (transmission phase) to a mammal requires the bacteria to sense and respond to the midgut environmental cues and up-regulate key virulence factors before transmission to a new host. Data presented here suggest that one environmental signal that appears to affect both phases of the infective cycle is osmolarity. While constant in the blood, interstitial fluid and tissue of a mammalian host (300 mOsm), osmolarity fluctuates in the midgut of feeding Ixodes scapularis. Measured osmolarity of the blood meal isolated from the midgut of a feeding tick fluctuates from an initial osmolarity of 600 mOsm to blood-like osmolarity of 300 mOsm. After feeding, the midgut osmolarity rebounded to 600 mOsm. Remarkably, these changes affect the two independent regulatory networks that promote acquisition (Hk1-Rrp1) and transmission (Rrp2-RpoN-RpoS) of B. burgdorferi. Increased osmolarity affected morphology and motility of wild-type strains, and lysed Hk1 and Rrp1 mutant strains. At low osmolarity, Borrelia cells express increased levels of RpoN-RpoS-dependent virulence factors (OspC, DbpA) required for the mammalian infection. Our results strongly suggest that osmolarity is an important part of the recognized signals that allow the bacteria to adjust gene expression during the acquisition and transmission phases of the infective cycle of B. burgdorferi.

Spatial datasets of 30-year (1991-2020) average monthly total precipitation and minimum/maximum temperature for Canada and the United States.

Thin plate smoothing spline models, covering Canada and the continental United States, were developed using ANUSPLIN for 30-year (1991-2020) monthly mean maximum and minimum temperature and precipitation. These models employed monthly weather station values from the North American dataset published by National Oceanic and Atmospheric Administration's (NOAA's) National Centers for Environmental Information (NCEI). Maximum temperature mean absolute errors (MAEs) ranged between 0.54 °C and 0.64 °C (approaching measurement error), while minimum temperature MAEs were slightly higher, varying from 0.87 °C to 1.0 °C. On average, thirty-year precipitation estimates were accurate to within approximately 10 % of total precipitation levels, ranging from 9.0 % in the summer to 12.2 % in the winter. Error rates were higher in Canada compared to estimates in the United States, consistent with a less dense station network in Canada relative to the United States. Precipitation estimates in Canada exhibited MAEs representing 14.7 % of mean total precipitation compared to 9.7 % in the United States. The datasets exhibited minimal bias overall; 0.004 °C for maximum temperature, 0.01 °C for minimum temperature, and 0.5 % for precipitation. Winter months showed a greater dry bias (0.8 % of total winter precipitation) compared to other seasons (-0.4 % of precipitation). These 30-year gridded datasets are available at ∼2 km resolution.

An Assessment of the Epidemiology and Herd-Level Impact of the Fractured Humerus Epidemic in New Zealand Dairy Cattle, 2007-2015: Results from Four Studies.

A multi-method approach integrating data from four independent sources was used to describe some key features of the epidemiology and estimate the herd and within-herd incidence of fractured humeri in New Zealand dairy cattle for the period 2007-2015. The first dataset was from a national case series where cases of humeral fractures in dairy cattle were identified by veterinarians across New Zealand between the 2007/2008 and 2011/2012 lactation seasons. The second dataset was from a pet food company based in the Waikato region, which collated the number of casualty first- and second-lactation cows found to have a fractured humerus post-slaughter in the 2014/2015 lactation season, and the third dataset was a case series conducted by veterinarians employed in a Waikato veterinary business, also from the 2014/2015 lactation season. For the final dataset, 505 randomly selected New Zealand dairy farmers completed a phone survey on the incidence of non-responsive, non-weight-bearing forelimb lameness in first- and second-lactation cows in the 2014/2015 lactation season. Using the telephone survey results, the within-herd and herd-level incidence of cases for first- and second-lactation dairy animals was calculated. The national case series reported 149 cases of humeral fractures in 22 dairy herds; the pet food case series identified 61 cases from 41 farms; and the practice-based case series found 14 cases from 10 farms. Humeral fractures exclusively affected first- and second-lactation dairy cows and had a peak incidence between calving and early mating. The national telephone survey found that non-weight-bearing forelimb lameness requiring euthanasia of first- or second-lactation cows occurred in 11.7% of herds, with a mean within-herd incidence of 2.6% for first lactation cows and 2.8% for second-lactation cows for affected herds. These combined datasets demonstrate that humeral fractures in young, lactating dairy cattle are more common than previously suspected and that they occur nationally and over multiple years on some farms. Further work on this condition is urgently required in New Zealand to establish cost-effective management practices that will reduce unnecessary animal suffering and waste.

Admission Frailty Score Are Associated With Increased Risk of Acute Respiratory Failure and Mortality in Burn Patients 50 and Older.

Herein, we assessed the utility of the Canadian Study of Health and Aging Clinical Frailty Scale (CSHA-CFS) to predict burn-specific outcomes. We hypothesized that frail patients are at greater risk for burn-related complications and require increased healthcare support at discharge. Patients 50 years and older admitted to our institution for burn injuries between July 2009 and June 2019 were included. Demographics, comorbidities, pre-injury functional status, injury and hospitalization information, complications (graft loss, acute respiratory failure, and acute kidney disease [AKI]), mortality, and discharge disposition were collected. Multivariate analyses were performed to assess the association between admission frailty scored using the CSHA-CFS and outcomes. P < .05 was considered significant. Eight-hundred fifty-one patients were included, 697 were not frail and 154 were frail. Controlling for Baux scores, sex, race, mechanism of injury, 2nd and 3rd degree burn surface, and inhalation injury, frailty was associated with acute respiratory failure (OR = 2.599 [1.460-4.628], P = .001) and with mortality (OR = 6.080 [2.316-15.958]; P < .001). Frailty was also associated with discharge to skilled nursing facility, rehabilitation, or long-term acute care facilities (OR = 3.135 [1.784-5.508], P < .001), and to hospice (OR = 8.694 [1.646-45.938], P = .011) when compared to home without healthcare services. Frailty is associated with increased risk of acute respiratory failure, mortality, and requiring increased healthcare support post-discharge. Our data suggest that frailty can be used as a tool to predict morbidity and mortality and for goals of care discussions for the burn patient.

Heating degree day spatial datasets for Canada.

Heating degree days (HDD) represent a concise measure of heating energy requirements used to inform decision making about the impact of climate change on heating energy demand. This data paper presents spatial datasets of heating degree days (HDD) for Canada for two thirty-year periods, 1951-1980 and 1981-2010, using daily temperature gauge observations over these time periods. Stations with fewer than nine missing days in a year and greater than nine years of data over each thirty-year period were included, resulting in 1339 and 1679 stations for the 1951-1980 and 1981-2010 periods respectively. Mean absolute error (MAE) of the spatial models ranged from 124.2 Celsius degree days (C-days) for the 1951-1980 model (2.4% of the surface mean) to 137.6 C-days for the 1981-2010 model (2.7%). This note presents maps illustrating cross validation errors at a set of representative stations. The grids are available at ∼2 km resolutions.

Bone quality changes as measured by Raman and FTIR spectroscopy in primiparous cows with humeral fracture from New Zealand.

The occurrence of spontaneous humeral fractures in primiparous dairy cows from New Zealand prompted the study of bone material from affected cows to further characterize this condition and to outline a likely pathogenesis. Previous studies indicate that these cows developed osteoporosis due to periods of suboptimal bone formation followed by increased bone resorption during the period of lactation complicated by copper deficiency. We hypothesized that there are significant differences in the chemical composition/bone quality in bones from cows with spontaneous humeral fracture compared to cows without humeral fractures. In this study, Raman and Fourier transform infrared spectroscopy band ratios were, for the first time, measured, calculated, and compared in bone samples from 67 primiparous dairy cows that suffered a spontaneous fracture of the humerus and 14 age-matched post-calving cows without humeral fractures. Affected bone showed a significantly reduced mineral/matrix ratio, increased bone remodeling, newer bone tissue with lower mineralization and, lower carbonate substitution, and reduced crystallinity. As such, is likely that these have detrimentally impacted bone quality and strength in affected cows.

Nitrosative damage to free and zinc-bound cysteine thiols underlies nitric oxide toxicity in wild-type Borrelia burgdorferi.

Borrelia burgdorferi encounters potentially harmful reactive nitrogen species (RNS) throughout its infective cycle. In this study, diethylamine NONOate (DEA/NO) was used to characterize the lethal effects of RNS on B. burgdorferi. RNS produce a variety of DNA lesions in a broad spectrum of microbial pathogens; however, levels of the DNA deamination product, deoxyinosine, and the numbers of apurinic/apyrimidinic (AP) sites were identical in DNA isolated from untreated and DEA/NO-treated B. burgdorferi cells. Strains with mutations in the nucleotide excision repair (NER) pathway genes uvrC or uvrB treated with DEA/NO had significantly higher spontaneous mutation frequencies, increased numbers of AP sites in DNA and reduced survival compared with wild-type controls. Polyunsaturated fatty acids in B. burgdorferi cell membranes, which are susceptible to peroxidation by reactive oxygen species (ROS), were not sensitive to RNS-mediated lipid peroxidation. However, treatment of B. burgdorferi cells with DEA/NO resulted in nitrosative damage to several proteins, including the zinc-dependent glycolytic enzyme fructose-1,6-bisphosphate aldolase (BB0445), the Borrelia oxidative stress regulator (BosR) and neutrophil-activating protein (NapA). Collectively, these data suggested that nitrosative damage to proteins harbouring free or zinc-bound cysteine thiols, rather than DNA or membrane lipids underlies RNS toxicity in wild-type B. burgdorferi.

Novel Assessment of Collagen and Its Crosslink Content in the Humerus from Primiparous Dairy Cows with Spontaneous Humeral Fractures Due to Osteoporosis from New Zealand.

Numerous cases of spontaneous humeral fracture in primiparous dairy cows from New Zealand have prompted the study of the condition to establish probable causes or risk factors associated with the condition. Previous studies identified inadequate protein-calorie malnutrition as an important contributory factor. Earlier case studies also reported that ~50% of cows have low liver and/or serum copper concentration at the time of humeral fracture. Because copper is so closely associated with the formation of collagen cross-links, the aim of this study was to compare collagen and collagen crosslink content in the humerus from primiparous cows with and without humeral fractures and to determine the role of copper in the occurrence of these fractures. Humeri were collected from cows with and without humeral fractures, ground, and the collagen and collagen cross-link content measured using high-performance liquid chromatography. Collagen content was significantly higher in the humeri of cows without humeral fractures, while total collagen crosslink content was significantly higher in the humerus of cows with humeral fractures. These results indicate other factor/s (e.g., protein-calorie undernutrition) might be more important than the copper status in the occurrence of humeral fractures in dairy cows in New Zealand.

A Field Evaluation of the LuciTrap and the Western Australian Trap with Three Different Baits Types for Monitoring Lucilia cuprina and Lucilia sericata in New Zealand.

Flytraps can be used on farms to monitor the populations of primary strike flies (Lucilia cuprina and Lucilia sericata) and, hence, offer a view regarding the incidence of flystrike on sheep. This study aimed to contrast the specificity and effectiveness of the LuciTrap with its combination of three chemical lures (Lucilures) and the Western Australian Trap with three bait types (LuciLure, Sheep liver with 30% sodium sulphide and squid). A mean model and rate model were fitted to the data. The mean model showed no difference (p > 0.05) in the mean weekly catch for L. cuprina between the Western Australian Trap with LuciLures and the Western Australian Trap baited with sheep liver with 30% sodium sulphide (p < 0.05). Whereas, for L. sericata, no difference (p > 0.05) was found between the Western Australian Trap with LuciLures, the Western Australian Trap baited with sheep liver with 30% sodium sulphide and the LuciTrap. The rate model illustrated that the Western Australian Trap with sheep liver with 30% sodium sulphide and LuciTrap did not differ (p > 0.05) for L. cuprina and L. sericata. Combined, these results indicate that New Zealand farmers can use either the LuciTrap or the Western Australian Trap with sheep liver with 30% sodium sulphide to monitor these target species.

Review of the New Zealand Theileria orientalis Ikeda Type Epidemic and Epidemiological Research since 2012.

This article sets out to document and summarise the New Zealand epidemic and the epidemiological research conducted on the epizootic of bovine anaemia associated with Theileria orientalis Ikeda type infection, which began in New Zealand in August 2012. As New Zealand has no other pathogenic tick-borne cattle haemoparasites, the effects of the T. orientalis Ikeda type infection observed in affected herds and individual animals were not confounded by other concurrent haemoparasite infections, as was possibly the case in other countries. This has resulted in an unbiased perspective of a new disease. In addition, as both New Zealand's beef and dairy cattle systems are seasonally based, this has led to a different epidemiological presentation than that reported by almost all other affected countries. Having verified the establishment of a new disease and identified the associated pathogen, the remaining key requirements of an epidemiological investigation, for a disease affecting production animals, are to describe how the disease spreads, describe the likely impacts of that disease at the individual and herd level and explore methods of disease control or mitigation.

CHANGES IN THE LEVELS OF THEILERIA ORIENTALIS IKEDA TYPE INFECTION IN HAEMAPHYSALIS LONGICORNIS NYMPHS OVER A SIX-MONTH PERIOD.

This study aimed to investigate whether the infection intensity of Theileria orientalis Ikeda type organisms within Haemaphysalis longicornis larvae and nymph stages fluctuated over 6 mo after feeding as larvae on infected calves in the field. Naïve larvae, hatched from eggs, were fed on infected calves for 5 days while contained within cotton socks glued over the calves' ears. Larvae were first sampled immediately post-feeding and then sampled every 3 wk for 23 wk in total, after molting to nymphs. All larvae and nymphs were tested for T. orientalis Ikeda organisms using quantitative PCR. The qPCR results showed that the infection intensity of Haemaphysalis longicornis larvae and nymphs was not constant over the sampling period, and after initially dropping after molting to nymphs, it then rose with fasting to a maximum at 17 and 23 wk post-feeding. The significant rise in T. orientalis Ikeda organisms observed at 23 wk postfeeding may explain why more severe clinical cases of bovine theileriosis in New Zealand are seen in the spring when nymphs are the predominant instar questing.

Borrelia burgdorferi bb0426 encodes a 2'-deoxyribosyltransferase that plays a central role in purine salvage.

Borrelia burgdorferi is an obligate parasite with a limited genome that severely narrows its metabolic and biosynthetic capabilities. Thus survival of this spirochaete in an arthropod vector and mammalian host requires that it can scavenge amino acids, fatty acids and nucleosides from a blood meal or various host tissues. Additionally, the utilization of ribonucleotides for DNA synthesis is further complicated by the lack of a ribonucleotide reductase for the conversion of nucleoside-5'-diphosphates to deoxynucleosides-5'-diphosphates. The data presented here demonstrate that B. burgdorferi must rely on host-derived sources of purine bases, deoxypurines and deoxypyrimidines for the synthesis of DNA. However, if deoxyguanosine (dGuo) is limited in host tissue, the enzymatic activities of a 2'-deoxyribosyltransferase (DRTase, encoded by bb0426), IMP dehydrogenase (GuaB) and GMP synthase (GuaA) catalyse the multistep conversion of hypoxanthine (Hyp) to dGMP for DNA synthesis. This pathway provides additional biochemical flexibility for B. burgdorferi when it colonizes and infects different host tissues.

CD4+ lymphocyte adenosine triphosphate determination in sepsis: a cohort study.

INTRODUCTION: Patients suffering from sepsis are currently classified on a clinical basis (i.e., sepsis, severe sepsis, septic shock); however, this clinical classification may not accurately reflect the overall immune status of an individual patient. Our objective was to describe a cohort of patients with sepsis in terms of their measured immune status. METHODS: Fifty-two patients with sepsis (n = 13), severe sepsis (n = 21), or septic shock (n = 18) were studied. The immune status was determined by measuring the CD4+ lymphocyte adenosine triphosphate (ATP) content after mitogen stimulation in whole blood. RESULTS: The measured CD4+ lymphocyte ATP content at the time of ICU admission did not differ among the various groups defined by the sepsis classification system (sepsis = 454 +/- 79 ng/ml; severe sepsis = 359 +/- 54 ng/ml; septic shock = 371 +/- 53 ng/ml; P = 0.44). Furthermore, survivors of sepsis had a significantly higher CD4+ lymphocyte ATP content at the time of ICU admission than did nonsurvivors of sepsis (431 +/- 41 ng/mL vs. 266 +/- 53 ng/mL, respectively; P = 0.04). CONCLUSIONS: The sepsis classification system that is currently used is not representative of the individual immune status as determined by measuring the CD4+ lymphocyte ATP content. Moreover, a lower CD4+ ATP content at the time of ICU admission is associated with a worse clinical outcome in those suffering from sepsis.

Antimicrobial stewardship in the intensive care unit: advances and obstacles.

Antimicrobial stewardship involves a multifaceted approach that strives to combat the emergence of resistance, improve clinical outcomes, and control costs by improving antimicrobial use. Therefore, stewardship is of great importance and relevance in the intensive care unit. Clinical decision support systems, biomarker-derived treatment algorithms, and improved knowledge regarding the different components of antimicrobial therapy represent some of the advances that have been made in stewardship. Yet, significant obstacles have prevented the full achievement of stewardship's goals, and approaches to confronting these obstacles should be appreciated. Clinicians should realize that antimicrobials are important therapeutic agents and strive to use them wisely.