ORF virus causes tumor-promoting inflammation in sheep and goats.

ORF virus (ORFV) causes contagious ecthyma ("ORF"), a disease of sheep and goats characterized by lesions ranging from vesicles and pustules to atypical papilloma-like and angiomatous lesions in the skin and mucosae. The authors investigated the molecular factors leading to the ORF-associated atypical tumor-like changes. Fifteen lambs, 15 kids, and an adult ram clinically affected by natural ORFV infection were enrolled in the study and examined by several methods. ORFV was detected by viral culture or real-time polymerase chain reaction (RT-PCR) in the lesioned tissues and in the blood of the clinically affected sheep and goats. Surprisingly, ORFV was also detected in the blood of healthy goats from an affected herd. Microscopically, they found a pseudo-papillomatous proliferation of the epithelium, while the dermis and lamina propria were expanded by a proliferating neovascular component that highly expressed the viral vascular endothelial growth factor (vVEGF) and its host receptor vascular endothelial growth factor receptor 2 (VEGFR2). Immunohistochemistry, immunofluorescence, and in situ hybridization for mRNA showed that epidermal growth factor receptor (EGFR) was expressed in the fibrovascular component, in the infiltrating CD163+ macrophages, and in the basal stratum of the epidermis. Confocal immunofluorescence microscopy demonstrated that CD163+ macrophages were associated with VEGF and VEGFR2. Finally, they found by quantitative RT-PCR the overexpression of the interleukin-6 and VEGFR2 genes in the lesioned tissues. These findings suggest that ORFV activates an inflammatory reaction characterized by CD163+ macrophages expressing EGFR and VEGFR2, which might play an oncogenic role through synergistic action with vVEGF signaling.

Milk proteins as mastitis markers in dairy ruminants - a systematic review.

Mastitis is one of the most impacting diseases in dairy farming, and its sensitive and specific detection is therefore of the greatest importance. The clinical evaluation of udder and mammary secretions is typically combined with the milk Somatic Cell Count (SCC) and often accompanied by its bacteriological culture to identify the causative microorganism. In a constant search for improvement, several non-enzymatic milk proteins, including milk amyloid A (M-SAA), haptoglobin (HP), cathelicidin (CATH), and lactoferrin (LF), have been investigated as alternative biomarkers of mastitis for their relationship with mammary gland inflammation, and immunoassay techniques have been developed for detection with varying degrees of success. To provide a general overview of their implementation in the different dairy species, we carried out a systematic review of the scientific literature using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. Our review question falls within the type "Diagnostic test accuracy questions" and aims at answering the diagnostic question: "Which are the diagnostic performances of mastitis protein biomarkers investigated by immunoassays in ruminant milk?". Based on 13 keywords combined into 42 searches, 523 manuscripts were extracted from three scientific databases. Of these, 33 passed the duplicate removal, title, abstract, and full-text screening for conformity to the review question and document type: 78.8% investigated cows, 12.1% sheep, 9.1% goats, and 6.1% buffaloes (some included more than one dairy species). The most frequently mentioned protein was M-SAA (48.5%), followed by HP (27.3%), CATH (24.2%) and LF (21.2%). However, the large amount of heterogeneity among studies in terms of animal selection criteria (45.5%), index test (87.9%), and standard reference test (27.3%) resulted in a collection of data not amenable to meta-analysis, a common finding illustrating how important it is for case definitions and other criteria to be standardized between studies. Therefore, results are presented according to the SWiM (Synthesis Without Meta-analysis) guidelines. We summarize the main findings reported in the 33 selected articles for the different markers and report their results in form of comparative tables including sample selection criteria, marker values, and diagnostic performances, where available. Finally, we report the study limitations and bias assessment findings.

Thrombocytosis during Stable State Predicts Mortality in Bronchiectasis.

Rationale: Although platelets are considered key inflammatory mediators in respiratory diseases, their role in bronchiectasis has not been fully explored. Objectives: We hypothesized that thrombocytosis in stable state may be associated with bronchiectasis severity and worse clinical outcomes. Methods: Patients with bronchiectasis have been enrolled from 10 centers in Europe and Israel, with platelet count recorded during stable state. The primary outcome was 5-year all-cause mortality. Secondary outcomes included exacerbations, hospitalizations, and mortality at 1, 2, and 3-year follow-up. Analyses were conducted using logistic regression after adjustment for confounding variables. Results: Among the 1,771 patients (median age, 67 yr; 63.4% female) included, 136 (7.7%) had thrombocytosis. Patients with thrombocytosis had a significantly higher disease severity, worse quality of life, higher number of exacerbations and hospitalizations, and higher mortality rate at both 3-year (23 [22.8%] vs. 83 [8.5%], respectively; P < 0.01) and 5-year (26 [35.1%] vs. 116 [15.9%], respectively; P < 0.01) in comparison with those with normal platelet count. Thrombocytosis was significantly associated with hospitalizations because of severe exacerbations (odds ratio [OR], 1.83; 95% confidence interval [CI], 1.20-2.79; P = 0.01) after 1-year follow-up, as well as increased 3-year (OR, 3.06; 95% CI, 1.74-5.39; P < 0.01) and 5-year (OR, 2.46; 95% CI, 1.39-4.37; P < 0.01) mortality. Conclusions: Platelets represent a cheap and easy-to-evaluate biomarker, and the presence of thrombocytosis during stable state is associated with disease severity, hospitalizations because of exacerbations, poor quality of life, and mortality in adults with bronchiectasis.

Comparison of Intra- and Postoperative Complications between Bilateral Simultaneous and Staged Tibial Plateau Levelling Osteotomy with Arthroscopy in 176 Cases.

OBJECTIVE: The aim of this study was to compare the resulting short-term complications after simultaneous (SIM) or staged (ST) tibial plateau levelling osteotomy (TPLO) in patients that presented with bilaterally torn cranial cruciate ligaments. STUDY DESIGN: This was a retrospective study. MATERIALS AND METHODS: Medical records of dogs diagnosed with bilateral cranial cruciate ligament disease that underwent bilateral SIM or ST TPLO surgery with arthroscopy (2005-2015) were reviewed to evaluate the intra- and postoperative complications. Data were analysed and major and minor complications were compared between the two groups. RESULTS: A total of 176 client-owned dogs (352 stifles) that had TPLO performed bilaterally with SIM or ST procedures were included for analysis. The overall complication rate was 47.5% for the SIM group and 19.5% for the ST group. The incidence of major complications was 10.1 and 3.8% in the SIM and ST groups respectively. Minor complications were 38.4 and 15.6% in the SIM and ST groups respectively. Tibial tuberosity fractures requiring revision were noted in 2% of the SIM group and none of the ST group. CLINICAL SIGNIFICANCE: Although no significant difference was noted in major complication rate or tibial tuberosity fractures in our cohort of patients, a Type II statistical error was found. The complication rate in the SIM group is numerically greater by a factor of 2-3× or more for nearly all categories. Surgeons should consider the risks and benefits of SIM versus ST procedures as well as relevant individual patient and client factors before electing either alternative.

Combined oral contraceptives modify the effect of smoking on inflammatory cellular indexes and endothelial function in healthy subjects.

Little information is available on the influence of sex in combination with smoking habits and combined oral contraceptives (COC) use on cellular inflammatory indexes such as neutrophil/lymphocyte ratio (NLR), derived NRL (dNLR), platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR), mean platelet volume/platelet count (MPV/PLT), aggregate inflammation systemic index (AISI), and systemic inflammation response index (SIRI), which are cost-effective biomarkers to assessing inflammation. Therefore, the effect of COC was studied alone or in association with smoking and compared with results from healthy COC-free women and men. Furthermore, the association of cellular inflammatory indexes with endothelial function (arginine (Arg), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and lipid peroxidation (malondialdehyde MDA) biomarkers was evaluated. Blood was collected for hematological and biochemical analysis, which were used to calculate PLR, NLR, dNLR, MLR, MPV/PLT, AISI, and SIRI. Serum samples were assayed for Arg, ADMA, SDMA, and MDA. Monocytes, MLR, SIRI, and MPV/PLT were higher in men, while PLT count was higher in women. COC use increased lymphocytes and lowered PLR and MLR. Smoking reduced sexually divergent parameters, especially in COC users: smoking and non-smoking COC-free women displayed six divergent parameters, while COC users displayed only two (monocytes and MPV). In addition, COC affected endothelial function, reducing ADMA and Arg. Moreover, COC-free women had lower Arg levels than men. In conclusion, COC use strongly influence the effects of tobacco smoking, which are sex and parameter specific. Further, these data stress that COC use and smoking attitude select different cohorts indicating that sex and gender studies need intersectionality.

Influence of Sex on Urinary Organic Acids: A Cross-Sectional Study in Children.

The characterization of urinary metabolome, which provides a fingerprint for each individual, is an important step to reach personalized medicine. It is influenced by exogenous and endogenous factors; among them, we investigated sex influences on 72 organic acids measured through GC-MS analysis in the urine of 291 children (152 males; 139 females) aging 1-36 months and stratified in four groups of age. Among the 72 urinary metabolites, in all age groups, 4-hydroxy-butirate and homogentisate are found only in males, whereas 3-hydroxy-dodecanoate, methylcitrate, and phenylacetate are found only in females. Sex differences are still present after age stratification being more numerous during the first 6 months of life. The most relevant sex differences involve the mitochondria homeostasis. In females, citrate cycle, glyoxylate and dicarboxylate metabolism, alanine, aspartate, glutamate, and butanoate metabolism had the highest impact. In males, urinary organic acids were involved in phenylalanine metabolism, citrate cycle, alanine, aspartate and glutamate metabolism, butanoate metabolism, and glyoxylate and dicarboxylate metabolism. In addition, age specifically affected metabolic pathways, the phenylalanine metabolism pathway being affected by age only in males. Relevantly, the age-influenced ranking of metabolic pathways varied in the two sexes. In conclusion, sex deeply influences both quantitatively and qualitatively urinary organic acids levels, the effect of sex being age dependent. Importantly, the sex effects depend on the single organic acid; thus, in some cases the urinary organic acid reference values should be stratified according the sex and age.

Relationship of Late Lactation Milk Somatic Cell Count and Cathelicidin with Intramammary Infection in Small Ruminants.

Late lactation is a critical moment for making mastitis management decisions, but in small ruminants the reliability of diagnostic tests is typically lower at this stage. We evaluated somatic cell counts (SCC) and cathelicidins (CATH) in late lactation sheep and goat milk for their relationship with intramammary infections (IMI), as diagnosed by bacteriological culture (BC). A total of 315 sheep and 223 goat half-udder milk samples collected in the last month of lactation were included in the study. IMI prevalence was 10.79% and 15.25%, respectively, and non-aureus staphylococci were the most common finding. Taking BC as a reference, the diagnostic performance of SCC and CATH was quite different in the two species. In sheep, receiver operating characteristic (ROC) analysis produced a higher area under the curve (AUC) value for CATH than SCC (0.9041 versus 0.8829, respectively). Accordingly, CATH demonstrated a higher specificity than SCC (82.92% versus 73.67%, respectively) at comparable sensitivity (91.18%). Therefore, CATH showed a markedly superior diagnostic performance than SCC in late lactation sheep milk. In goats, AUC was <0.67 for both parameters, and CATH was less specific than SCC (61.90% versus 65.08%) at comparable sensitivity (64.71%). Therefore, both CATH and SCC performed poorly in late lactation goats. In conclusion, sheep can be screened for mastitis at the end of lactation, while goats should preferably be tested at peak lactation. In late lactation sheep, CATH should be preferred over SCC for its higher specificity, but careful cost/benefit evaluations will have to be made.

Cardiac Abnormalities in Alzheimer Disease: Clinical Relevance Beyond Pathophysiological Rationale and Instrumental Findings?

OBJECTIVES: This case control study sought to assess the presence and characteristics of cardiac abnormalities in patients with Alzheimer disease (AD). BACKGROUND: Protein misfolding is involved in the pathophysiology of neurodegenerative disorders such as AD. Recently, amyloid-beta (Aß) aggregates were identified within the cardiomyocytes and interstitium of patients with AD, suggesting that Aß oligomers may reach and damage the heart. METHODS: The authors studied 32 patients with AD and 34 controls matched by age and sex, all of whom were free from cardiac or systemic diseases. A clinical evaluation, an electrocardiogram, and an echocardiogram were performed in all subjects. Furthermore, patients with AD underwent genetic analyses (of the PSEN1, PSEN2, APP, and APOE genes). RESULTS: Compared to the control group, patients with AD had a higher prevalence of low-voltage electrocardiographic QRS complexes (28% vs. 3%, respectively; p = 0.004), a lower voltage/mass ratio (p = 0.05), a greater echocardiographic interventricular septum (10.1 ± 1.3 mm vs. 9.3 ± 1.1 mm, respectively; p = 0.01), a greater maximum wall thickness (10.8 ± 1.7 mm vs. 9.3 ± 1.1 mm, respectively; p = 0.0001), and a 2-fold higher prevalence of diastolic dysfunction (70% vs. 35%, respectively; p = 0.007). Symptoms and signs of heart failure were absent in all patients with AD. CONCLUSIONS: This study shows that electrocardiographic and echocardiographic abnormalities, including diastolic dysfunction, are present in patients with AD and that these studies reproduce the pattern of cardiac amyloidosis. These findings suggest that, in AD, there may be subclinical cardiac involvement likely associated with Aß amyloid deposition. The clinical relevance of these cardiac abnormalities should be evaluated in larger prospective studies.

Tuberculosis transmission among children and adolescents in schools and other congregate settings: a systematic review.

Children, especially those aged <5 years, and adolescents are at increased risk of progression to active TB disease when infected. Management of childhood TB outbreaks is crucial for TB elimination especially in low burden countries. We searched the electronic databases MEDLINE-CINHAL-EMBASE up to July 2017 for primary studies reporting on TB incidents which involved teacher/child-caregiver, relative or students diagnosed with TB in a school/childcare setting or in other congregate settings attended by children and adolescents. Out of 10,481 citations, 74 studies, published mostly in low TB burden countries from 1950 to 2017, describing 128 incident investigations, were included. Overall 5025 (14.2%) LTBI and 811 (2.3%) TB cases were diagnosed among 35,331 screened individuals. Incidents occurred mainly in schools (89.1%) where index cases were more frequently students (63.3%) than teachers/caregivers; almost all of the incidents exposing children aged 2-5 were attributable to a teacher/caregiver index case. In 68 individual contact investigations the pooled proportions of TB and LTBI among those exposed were 0.03 (95%CI 0.02-0.04) and 0.15 (95%CI 0.13- 0.18). The overall risk of developing TB disease in school-congregate settings seems slightly lower than in high-income country household settings. Public health interventions targeting school-congregate settings may be critical to overall TB control and towards TB elimination in low-burden countries.

Intravitreal Dexamethasone in Patients with Wet Age-Related Macular Degeneration Resistant to Anti-VEGF: A Prospective Pilot Study.

PURPOSE: To evaluate the efficacy and safety of a single intravitreal dexamethasone implant (DXI) combined with intravitreal antivascular endothelial growth factor (anti-VEGF) therapy, in patients with neovascular age-related macular degeneration (wet-AMD) resistant to conventional treatment. METHODS: In this randomized, controlled pilot study, 16 eyes of 15 patients, unresponsive to anti-VEGF therapy, were enrolled and randomly assigned to two groups: DXI + anti-VEGF (treatment group: 11 eyes) and monthly anti-VEGF alone (control group: 5 eyes). Patients were treated at baseline and followed for 6 months. Best corrected visual acuity (BCVA), optical coherence tomography (OCT) parameters, and fluorescein angiography (FA) were evaluated. RESULTS: Eight eyes (72.7%) in the treatment group and 2 eyes in the control group (40%) showed complete retinal fluid resorption (p=0.049). BCVA showed no significant change from baseline in both the treatment group and the control group (p=0.40 and p=0.29, respectively). Both median central foveal thickness (CFT) and median macular volume showed a greater reduction from baseline in the treatment group. CONCLUSION: In patients showing an incomplete response to anti-VEGF therapy, DXI combined with intravitreal anti-VEGF seems to improve retinal fluid resorption without functional advantage. This trial is registered with ACTRN12618001102268.

Sheep embryonic stem-like cells engrafted into sheep femoral condyle osteochondral defects: 4-year follow-up.

BACKGROUND: Articular cartilage lacks a regenerative response. Embryonic stem cells (ESCs) are a source of pluripotent cells for cartilage regeneration. Their use, however, is associated with a risk of teratoma development, which depends on multiple factors including the number of engrafted cells and their degree of histocompatibility with recipients, the immunosuppression of the host and the site of transplantation. Colonies of sheep embryonic stem-like (ES-like) cells from in vitro-produced embryos, positive for stage-specific embryonic antigens (SSEAs), alkaline phosphatase (ALP), Oct 4, Nanog, Sox 2 and Stat 3 gene expression, and forming embryoid bodies, were pooled in groups of two-three, embedded in fibrin glue and engrafted into osteochondral defects in the left medial femoral condyles of 3 allogeneic ewes (ES). Empty defects (ED) and defects filled with cell-free glue (G) in the condyles of the controlateral stifle joint served as controls. After euthanasia at 4 years post-engraftment, the regenerated tissue was evaluated by macroscopic, histological and immunohistochemical (collagen type II) examinations and fluorescent in situ hybridization (FISH) assay to prove the ES-like cells origin of the regenerated tissue. RESULTS: No teratoma occurred in any of the ES samples. No statistically significant macroscopic or histological differences were observed among the 3 treatment groups. FISH was positive in all the 3 ES samples. CONCLUSIONS: This in vivo preclinical study allowed a long-term evaluation of the occurrence of teratoma in non-immunosuppressed allogeneic adult sheep engrafted with allogeneic ES-like cells, supporting the safe and reliable application of ES cells in the clinic.

Determination of minimum alveolar concentration and cardiovascular effects of desflurane in positive-pressure ventilated sheep.

OBJECTIVE To determine the minimum alveolar concentration of desflurane (MACDES) and effects on cardiovascular variables in positive-pressure ventilated sheep. ANIMALS 13 adult female sheep. PROCEDURES Anesthesia was induced with desflurane. After a 30-minute equilibration at an end-tidal concentration of desflurane (etDES) of 10.5%, an electrical stimulus (5 Hz/ms and 50 mA) was applied for 1 minute or until gross purposeful movement occurred. The etDES was then changed by 0.5% (modified up-down method), depending on whether a positive motor response had been elicited, and stimulation was repeated. The MACDES was the etDES midway between a positive and negative response. After MACDES was determined, etDES was increased to 1.3 and 1.6 MACDES. Animals were allowed to equilibrate for 15 minutes, and cardiovascular, blood gas, acid-base, and hematologic variables were measured. Times to induction of anesthesia, extubation, attainment of sternal position, and standing and duration of anesthesia were recorded. RESULTS Mean ± SD MACDES was 9.81 ± 0.79%. Times to intubation, extubation, and standing were 4.81 ± 2.21 minutes, 14.09 ± 4.05 minutes, and 32.4 ± 12.5 minutes, respectively. Duration of anesthesia was 226 ± 22 minutes. Heart rate increased significantly at induction of anesthesia but otherwise remained at preanesthetic rates. Arterial blood pressures progressively decreased with increasing etDES; pressures increased slightly only in response to noxious stimulation. CONCLUSIONS AND CLINICAL RELEVANCE The MACDES determined here compared favorably with that determined for other sheep populations and indicated similar anesthetic potency as in other species. Desflurane caused dose-dependent arterial hypotension, which indicated the need for careful blood pressure monitoring.

Correction to: Long-acting bronchodilators improve exercise capacity in COPD patients: a systematic review and meta-analysis.

In the original publication [1] is an incorrect sentence in the abstract under Conclusions.

Long-acting bronchodilators improve exercise capacity in COPD patients: a systematic review and meta-analysis.

Background: We carried out a systematic review and meta-analysis with the aim to evaluate the efficacy of longacting bronchodilators on exercise capacity in COPD patients. Methods: The endpoints were the efficacy of long-acting bronchodilators (altogether, and by single classes) vs. placebo in modifying endurance time (ET), inspiratory capacity (IC) and dyspnea during exercise, taking into consideration the outcomes according to different patients' inclusion criteria and exercise methodology. Results: Twenty-two studies were deemed eligible for analysis. Weighted mean increase in ET resulted of 67 s (95% CI ranges from 55 to 79). For isotime IC and dyspnea during exercise, weighted improvements were 195 ml (162­229), and − 0.41 units (− 0.56 to − 0.27), respectively. The increase in trough IC was 157 ml (138­175). We found a trend in favour of LAMA compared to LABA in terms of ET. In the 11 studies which reported a value of functional residual capacity > 120% as inclusion criterion, weighted mean increase in endurance time was 94 s (65 to 123); however we did not find any significant correlation between ET and mean trough IC (P: 0.593). The improvement of ET in the 5 studies using walking as exercise methodology resulted of 58 s (− 4 to 121). Conclusions: Long-acting bronchodilators improve exercise capacity in COPD. The main effect of long-acting bronchodilators seems to be a increase of basal IC rather than a modification of dynamic hyperinflation during exercise. The efficacy in terms of endurance time seems higher in studies which enrolled patients with hyperinflation, with a similar efficacy on walking or cycling.

Intramammary infusion of a live culture of Lactococcus lactis in ewes to treat staphylococcal mastitis.

PURPOSE: Alternatives to antibiotic therapy for mastitis in ruminants are needed. We present an evaluation, in two trials, of the efficacy of an intramammary infusion of a live culture of Lactococcus lactis for the treatment of subclinical and clinical mastitis in ewes. METHODOLOGY: In total, 67 animals were enrolled: 19 lactating ewes (study 1), including healthy (N=6) and coagulase-negative staphylococci (CNS)-infected ewes (N=13); and 48 lactating ewes (study 2) with either CNS mastitis (N=32), or Staphylococcus aureus mastitis (N=16), for a total of 123 mammary glands. Intramammary infusions were performed with either L. lactis or PBS for 3 (study 1) or 7 (study 2) consecutive days. Antibiotic-treated and untreated control glands were included. Milk samples for microbiology, somatic cell analysis and milk production were collected before and after treatment.Results/Key findings.L. lactis rapidly activated the mammary glands' innate immune response and initiated an inflammatory response as evidenced by the recruitment of polymorphonuclear neutrophils and increased somatic cell counts. But while leading to a transient clearance of CNS in the gland, this response caused mild to moderate clinical cases of mastitis characterized by abnormal milk secretions and udder inflammation. Moreover, S. aureus infections did not improve, and CNS infections tended to relapse. CONCLUSION: Under our experimental conditions, the L. lactis treatment led to a transient clearance of the pathogen in the gland, but also caused mild to moderate clinical cases of mastitis. We believe it is still early to implement bacterial formulations as alternatives in treating mastitis in ruminants and further experimentation is needed.

Beyond pulmonary nontuberculous mycobacteria disease: do extra-pulmonary forms represent an emerging clinical and public health threat?

Pulmonary and extra-pulmonary diseases caused by nontuberculous mycobacteria: new clinical and public health threats http://ow.ly/87Dm30eMFd9.

Cathelicidin production and release by mammary epithelial cells during infectious mastitis.

Cathelicidins are well-characterized antimicrobial peptides (AMPs) that are present in significant amounts in mastitic milk. Neutrophils are believed to be the main producers of these AMPs, while the role of mammary epithelial cells (MECs) in their production and release is still unclear. In this work, cathelicidin production patterns were investigated in mammary tissues of ewes infected by Staphylococcus aureus, Streptococcus uberis, or Mycoplasma agalactiae, with a combined approach including immunohistochemistry, immune-colocalization, and fluorescent in situ hybridization. Our results confirm that MECs produce and release cathelicidins in response to different mastitis pathogens. As opposed to neutrophils, however, MECs do not seem to store the preformed protein precursor in their cytoplasm, but appear to synthesize and release it only upon exposure to the microorganisms. Cathelicidin production by MECs appears to occur before leukocyte influx in the milk, suggesting a role for these cells in the initial response of the mammary epithelium to microbial infection. Once in the milk, infiltrating neutrophils release massive amounts of cathelicidin by degranulation and production of neutrophil extracellular traps, acting as the main contributor for cathelicidin abundance in mastitic milk. Taken together, our results support the active contribution of MECs to cathelicidin production and release, and reinforce the value of cathelicidins as sensitive and pathogen-independent mastitis markers.

Use of the Fluid Challenge in Critically Ill Adult Patients: A Systematic Review.

The fluid challenge (FC) aims at identifying patients in whom fluid administration improves hemodynamics. Although the FC has been extensively studied, the implementation and definition of improvement are not standardized. This systematic review of studies published between January 1, 1994 and December 31, 2014 characterizes these key components of the FC for critically ill adult patients, as described in the medical literature in the last 20 years. A literature search was performed using MEDLINE, Embase, and Cochrane. For each study, data were collected on study design, study size, study setting, patient population, and how the FC was administered. Eligibility criteria for FC were (1) the infusion of a definite quantity of fluid, (2) of a specific type, (3) in a fixed time period (expressed as either span or infusion rate), (4) with a defined hemodynamic variable as the target, and (5) for a predetermined threshold. One hundred fifty-seven full-text manuscripts were extracted from 870 potentially relevant studies. The inclusion criteria were met by 71 studies including 3617 patients. Sixty-six studies were from a single center and 45 were prospective observational in format. The most common amount infused was 500 cc, used by 55 (77.5%) studies. The most commonly infused fluids were colloids (62.0%). In 43 (60.5%) studies, the FC was administered between 20 and 30 minutes. A positive response to fluid administration was defined as an increase ≥15% of cardiac index or cardiac output in 44 (62.6%) studies. Static or dynamic physiologic indices were utilized in a minority of studies (16.9%) and safety limits for interrupting the FC are adopted in 4 (5.6%) studies only. This systematic review indicates that the FC most commonly consists in infusing 500 mL of crystalloids or colloids in 20-30 minutes, and considered an increase in cardiac index ≥15% as a positive response. However, definite standards for FC administration and evaluation remain undefined.