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ABSTRACT: Dairy cows usually store more milk in the rear quarters of the udder than the front quarters. With conventional machine milking, this leads to an earlier cessation of milk flow in front quarters than the rear quarters and hence unavoidable milking on empty front teats. We tested the hypothesis that an increased pulsation ratio in rear quarters reduces milking on empty front teats as well as machine-on time. We have also tested if the different amplitude of cyclic vacuum fluctuations during milking with simultaneous versus alternate pulsation within front and rear quarters, respectively, impacts milking characteristics. Ten Holstein dairy cows were milked twice daily at 14-h and 10-h milking intervals. The pulsation ratio in the front quarters was 65:35, but was set at 65:35, 70:30, 75:25, or 80:20 in the rear quarters. Whole udder milk flow, claw vacuum, and mouthpiece chamber vacuum of all 4 quarters were recorded during milking. Teat tissue thickness of all 4 teats was measured with a cutimeter at 5 and 30 min after cluster detachment. Total milk yield did not differ among treatments, indicating complete udder emptying. The time of quarter milk flow of the front quarters did not differ among treatments but decreased with increasing pulsation ratio in rear quarters. In addition, faster milking of the rear quarters at a higher pulsation ratio caused higher peak and average milk flow rates, a shorter duration of milk flow decline, and a reduced machine-on time. The increased milk flow at a higher pulsation ratio did not cause a significant reduction of the claw vacuum at the used sample size. Teat tissue thickness did not significantly differ among treatments, likely because milking on empty teats did almost not occur in the rear quarters, and treatment settings did not differ in the front quarters. Simultaneous pulsation caused higher amplitudes of cyclic vacuum fluctuation than alternate pulsation. However, milking characteristics did not differ between simultaneous and alternate pulsation. Overall, an increased pulsation ratio in rear quarters reduces machine-on time, increases milking performance, and reduces the time of milking on empty teats in front quarters, without an increased impact on teat tissue thickness.

Background: Myocardial injury is strongly associated with excess morbidity and mortality after noncardiac surgery. Higher heart rate may result in perioperative myocardial injury through demand–supply mismatch. Alternatively, higher heart rates may reflect autonomic dysfunction that promotes myocardial injury independently of heart rate. The specific hyperpolarisation-activated, cyclic nucleotide-gated (HCN)-4 (funny) channel inhibitor ivabradine slows the heart rate without altering autonomic control, blood pressure, or myocardial contractility. We hypothesise that individuals with autonomic dysfunction may benefit most from ivabradine reducing heart rate control to minimise myocardial injury-associated morbidity. Methods: This triple-blind, international, multicentre, randomised, placebo-controlled, parallel group randomised trial will recruit 350 patients, aged ≥55 yr, with cardiovascular risk factors for myocardial injury during elective noncardiac surgery. To achieve the target heart rate

Background: Increasing awareness of the potential environmental impact of volatile anaesthetic agents has stimulated increased use of total i.v. anaesthesia. However, consolidated comparative evidence of the environmental impact of anaesthetic agents across the whole life cycle is lacking. Methods: We performed a systematic review and narrative evidence synthesis of the environmental impact of anaesthetic agents stratified by drug life cycle. We searched MEDLINE (PubMed), Excerpta Medica dataBASE (EMBASE), Cumulative index to nursing and allied health literature (CINAHL), and DrugBank, from inception until 05 March 2023, for studies describing the environmental impact of anaesthetic drugs on the WHO essential medicine list. Independent review and data extraction were performed by pairs of reviewers. Data on any aspect of cradle-to-grave life cycle analysis were reported, with narrative synthesis grouped according to life cycle domains. Results: From 15 229 records, 42 unique reports met our inclusion criteria. The predominant environmental impact of inhalation anaesthetic agents is atmospheric release, contributing to global warming. This may be improved with the emergence of more efficacious scavenging and capture systems. Packaging and waste contributed most to the environmental impact of i.v. anaesthetic agents. There is increasing concern over the ecological impact of i.v. agents entering water sources, either by disposal of unused medication or through the excretion of drug post-administration. Conclusions: There is increasing concern about the global warming impact of inhalation anaesthetic agents. However, there are insufficient ‘cradle-to-grave’ comparative analyses of the environmental impact of i.v. and inhalation anaesthesia to form evidence-based conclusions. Further research is urgently needed to guide clinical practice.

ABSTRACT: Our objectives were to determine the effect of oxytocin use during colostrum harvest on colostrum yield and IgG concentration in Holstein dairy cows on a commercial dairy in New York and to describe associations of cow characteristics with these outcomes. Animals were enrolled between July and October 2023 using a randomized block design, with day of enrollment as the unit of randomization. A median (range) of 10 (3–19) cows were enrolled per day. Treatments were (1) 40 IU oxytocin (OXY40), (2) 20 IU oxytocin (OXY20), and (3) an untreated control group (CNTR). Oxytocin was administered i.m. ∼45 s before unit attachment in a rotary parlor. Colostrum weight was measured using the colostrum bucket-embedded scale or a platform scale when the yield was less than the smallest bucket scale. The concentration of IgG ([IgG]) in colostrum was determined using radial immunodiffusion and used to calculate total IgG, and DM (%) was determined by oven drying. Individual cow characteristics such as parity, calf sex, weight, dystocia score, stillbirth, and milk production in wk 4 of lactation; additionally, for multiparous cows, dry period length and previous lactation dry-off linear SCS were collected. Data were analyzed separately for primiparous and multiparous cows using backward stepwise elimination. To produce final mixed effects ANOVA models, primiparous cows (n = 201) were randomized to 35.8% (n = 72) OXY40, 32.8% (n = 66) OXY20, and 31.3% (n = 63) CNTR. Multiparous groups (n = 435) were randomized to 34.7% (n = 151) OXY40, 29.7% (n = 129) OXY20, and 35.6% (n = 155) CNTR. The median (range) colostrum yield was 6.0 (0–20.6) kg and [IgG] was 98.5 (0.1–293.6) g/L in the study population. In primiparous cows, OXY40 had a higher colostrum yield (LSM [95% CI]) of 5.4 (4.9–5.9) kg compared with both OXY20 (4.1 [3.5–4.7] kg) and CNTR (3.8 [3.3–4.3] kg). In multiparous cows, OXY40, OXY20, and CNTR did not differ in colostrum yield (5.9 [5.3–6.5], 5.7 [5.1–6.3], and 5.4 [4.8–6.0] kg, respectively), but colostrum yield was greater in parity 2 compared with all other parities, cows giving birth to male calves, cows with the highest milk production at wk 4 of lactation, and cows with a dry period of >65 d. Oxytocin use did not affect [IgG] in either primiparous or multiparous cows, but [IgG] was highest in cows in parity ≥4 and lowest in cows dry >65 d. In summary, oxytocin use at 40 IU i.m. was associated with a higher colostrum yield in primiparous cows only and no change in [IgG]. Oxytocin use likely addressed disturbed milk ejection and therefore increased colostrum yield in heifers milked for the first time in a rotary parlor. This study confirms cow characteristics associated with colostrum production within a single herd.

SUMMARY: In-ovo sexing opens the door to on-farm hatching in the laying hen sector, but knowledge on the implications of different hatching system factors remains limited. This study addressed the influence of continuous light exposure during the last 3 d of incubation, posthatch feed and water access, and posthatch litter access on stress responsivity and body weight gain in laying hen chicks. Through a pilot experiment and two replicated experiments, we investigated the influence of these factors on physiological stress responsivity and body weight gain up to 8 wk of age. Short-term stress responsivity was evaluated by serum corticosterone and cloacal temperatures during processing procedures (e.g., sexing, sorting, vaccinating). Additionally, cumulative stress responsivity until 8 wk of age was assessed through corticosterone analysis in feather samples, and chick weights were recorded throughout. The presence of continuous lighting during the last 3 d of incubation affected stress responsivity, potentially by disrupting the circadian release of melatonin and thus corticosterone secretion. Immediate access to posthatch feed and water affected serum corticosterone levels, indicating a relationship between early feeding and stress responsivity. However, the underlying mechanisms remain unclear. Posthatch feed and water access did not have long-term effects on body weight gain, as fully deprived chicks were able to catch up within a day. Despite our study's exploratory nature, a complex relationship between stress responsivity and the hatching environment was shown, highlighting the need for future research to focus on disentangling and optimizing hatching system factors to minimize early life stress.

ABSTRACT: We investigated the suitability of the quarter mouthpiece chamber vacuum (MPCV) as an indicator for cessation of quarter milk flow to potentially adjust the teat end vacuum at a quarter level. We tested the hypothesis that a MPCV increase is a clear indicator of quarter milk flow cessation. In addition, we tested if a quarter-individual vacuum reduction at MPCV increase reduces the mechanical effect on the teat. Ten dairy cows were milked twice daily with a quarter-specific vacuum supply with continuously high (51 kPa; TRT51) or low vacuum setting (41 kPa; TRT41), or high vacuum setting combined with a quarter-specific vacuum reduction by 10 kPa immediately after the quarter-specific MPCV increase (TRT51/41). Whole udder milk flow was continuously recorded. Each treatment was repeated at 4 subsequent milkings. The high vacuum settings (TRT51; TRT51/41) reached higher values in peak flow rate and average milk flow and consequently shorter machine-on time. The time from start of milking until the steep increase of the MPCV was shorter in front than rear quarters, and hence the time from start of MPCV increase until end of milking was longer in front than rear teats. Teat condition of the right front teats was measured for teat wall diameter by ultrasound and teat tissue thickness by cutimeter at 5 and 20 min after each experimental milking. The teat measurements were taken at the teat tip (distal barrel) and 2 cm above the teat tip (proximal barrel). The proximal teat wall diameter tended to be higher in TRT51 than in TRT41, both 5 and 20 min after milking. The distal teat wall diameter at 5 min was greater in TRT51 than in TRT41. In TRT51/41 the teat wall diameter at both locations was intermediate, not significantly different from either TRT51 or TRT41. The distal teat tissue thickness was greater in TRT51 than in TRT41, and tended to be greater in TRT51/41 than in TRT41 at 5 min. The proximal teat tissue thickness at 5 min was higher in TRT51 and TRT51/41 than in TRT41. The teat tissue thickness decreased from 5 to 20 min only in the proximal barrel. The quarter-individual MPCV increase appears to be a suitable indicator of the cessation of milk flow. The lack of a significant reduction of mechanical effect on the teat by a reduced vacuum of 41 kPa indicates that the vacuum level chosen may be still too high under conditions of a separate vacuum supply for each quarter, which prevents a vacuum drop caused by the whole udder milk flow.

(1) Background: Danaparoid sodium is a heparinoid antithrombotic that has been used for over 40 years for prophylaxis of DVT in non-HIT patients and for the treatment of heparin-induced thrombocytopenia (HIT) with and without thrombosis. This update summarises current information on its pharmacology and reviews danaparoid dose management in a broad spectrum of clinical situations, including off-label indications. (2) Methods: Evidence from published clinical studies, case reports, compassionate use of danaparoid, and spontaneously reported serious adverse events is summarised and analysed by an interdisciplinary expert group to develop a consensus on dosing regimens of danaparoid for complex clinical situations, including vulnerable patient populations. (3) Results: Dosing regimens are proposed, together with monitoring recommendations and target anti-factor Xa ranges. (4) Conclusion: In a comprehensive summary detailed interdisciplinary dosing recommendations are described to provide a basis for safe and effective use of danaparoid.

IntroductionThe glutaraldehyde test (GAT) allows for animal-side semi-quantitative estimation of fibrinogen and gamma-globulin concentrations in blood samples of adult cattle and therefore detection of inflammatory disease conditions. However, the test has potential limitations, especially due to the latency period until sufficiently high fibrinogen and/or gamma-globulin concentrations are reached. The aim of the present study was therefore to assess the association between results of GAT with other inflammatory markers including hematologic variables, fibrinogen, plasma haptoglobin and serum amyloid A (SAA) concentrations.MethodsFor the purpose of this prospective observational study, a convenience sample of 202 cows with a broad range of inflammatory and non-inflammatory clinical conditions was included. The GAT was run on EDTA blood, fibrinogen was measured using the Clauss and the heat precipitation method, and commercially available ELISA tests were used for determination of plasma haptoglobin and SAA concentrations.ResultsShortened GAT coagulation times were more closely correlated to serum globulin (rs = −0.72) than to plasma fibrinogen concentrations measured with the heat precipitation (rs = −0.64) and the Clauss method (rs = −0.70). Cows with a markedly (≤3 min) or moderately (4–6 min) shortened coagulation time had higher (p

Background The VOYAGER PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) trial compared rivaroxaban (2.5 mg twice a day) plus aspirin with aspirin alone in patients with symptomatic peripheral artery disease requiring endovascular or surgical limb revascularization, with 50% receiving clopidogrel background therapy. The New Drug Indication application includes benefit–risk assessments using clinical judgment to balance benefits against risks. During its review, the US Food and Drug Administration requested additional quantitative benefit–risk analyses with formal weighting approaches. Methods and Results Benefits and risks were assessed using rate differences between treatment groups (unweighted analysis). To account for clinical importance of the end points, a multi‐criteria decision analysis was conducted using health state utility values as weights. Monte Carlo simulations incorporated statistical uncertainties of the event rates and utility weights. Intent‐to‐treat and on‐treatment analyses were conducted. For unweighted intent‐to‐treat analyses, rivaroxaban plus aspirin would result in 120 (95% CI, −208 to −32) fewer events of the primary composite end point (per 10 000 patient‐years) compared with aspirin alone. Rivaroxaban caused an excess of 40 (95% CI, 8–72) Thrombolysis in Myocardial Infarction major bleeding events, which was largely driven by nonfatal, nonintracranial hemorrhage Thrombolysis in Myocardial Infarction major bleeding events. For weighted analyses, rivaroxaban resulted in the utility equivalent of 13.7 (95% CI, −85.3 to 52.6) and 68.1 (95% CI, 7.9–135.7) fewer deaths per 10 000 patient‐years (intent‐to‐treat and on‐treatment, respectively), corresponding to probabilities of 64.4% and 98.7%, respectively, that benefits outweigh risks favoring rivaroxaban per Monte Carlo simulation. Conclusions These analyses show a favorable benefit–risk profile of rivaroxaban therapy in the VOYAGER PAD trial, with findings generally consistent between the unweighted and weighted approaches.

Abstract Introduction Postoperative morbidity and mortality in patients undergoing major emergency gastrointestinal surgery are a major burden on healthcare systems. Optimal management of perioperative intravenous fluids may reduce mortality rates and improve outcomes from surgery. Previous small trials of cardiac-output guided haemodynamic therapy algorithms in patients undergoing gastrointestinal surgery have suggested this intervention results in reduced complications and a modest reduction in mortality. However, this existing evidence is based mainly on elective (planned) surgery, with little evaluation in the emergency setting. There are fundamental clinical and pathophysiological differences between the planned and emergency surgical setting which may influence the effects of this intervention. A large definitive trial in emergency surgery is needed to confirm or refute the potential benefits observed in elective surgery and to inform widespread clinical practice. Methods The FLO-ELA trial is a multi-centre, parallel-group, open, randomised controlled trial. 3138 patients aged 50 and over undergoing major emergency gastrointestinal surgery will be randomly allocated in a 1:1 ratio using minimisation to minimally invasive cardiac output monitoring to guide protocolised administration of intra-venous fluid, or usual care without cardiac output monitoring. The trial intervention will be carried out during surgery and for up to 6 h postoperatively. The trial is funded through an efficient design call by the National Institute for Health and Care Research Health Technology Assessment (NIHR HTA) programme and uses existing routinely collected datasets for the majority of data collection. The primary outcome is the number of days alive and out of hospital within 90 days of randomisation. Participants and those delivering the intervention will not be blinded to treatment allocation. Participant recruitment started in September 2017 with a 1-year internal pilot phase and is ongoing at the time of publication. Discussion This will be the largest contemporary randomised trial examining the effectiveness of perioperative cardiac output-guided haemodynamic therapy in patients undergoing major emergency gastrointestinal surgery. The multi-centre design and broad inclusion criteria support the external validity of the trial. Although the clinical teams delivering the trial interventions will not be blinded, significant trial outcome measures are objective and not subject to detection bias. Trial registration ISRCTN 14729158. Registered on 02 May 2017.

ABSTRACT: Energy and nutrient deficiency in dairy cows in early lactation is considered to contribute to their increased susceptibility to mastitis. We have tested the hypothesis that feeding diets with high contents of either nitrogenic, glucogenic, or lipogenic components in early lactation affects both the endocrine and metabolic status, as well as the mammary immune competence. After calving, cows were fed increasing amounts of concentrate up to 10 kg/d rich in crude protein (nitrogenic, n = 10), glucogenic precursors (glucogenic, n = 11), or lipids (lipogenic, n = 11). In wk 3, one udder quarter was challenged with lipopolysaccharide (LPS) from Escherichia coli. Blood and milk were sampled on the day before LPS challenge (d −1), and on d 0, 1, 2, 3, and 9 after LPS challenge. On the day of LPS challenge additional samples were taken hourly for quarter milk and every 3 h for blood. Urea concentrations were higher in plasma and milk of cows fed the nitrogenic diet. However, plasma concentrations of glucose, cholesterol, triglycerides, β-hydroxybutyrate, nonesterified fatty acids, as well as insulin, glucagon, and insulin-like growth factor-1 were not affected by the different diets. The mammary immune challenge induced a substantial increase of somatic cell count (SCC) in the treated quarter, and a transient decrease of total milk yield and white blood cells similar in all diet groups for one day. The absolute phagocytosis of blood leukocytes was decreased; however, the phagocytosis per cell was increased in glucogenic-fed cows at 6 h after LPS challenge. During mammary inflammation an insulin resistance, shown by increased plasma glucose, insulin, and glucagon, developed similarly in all diet groups. β-hydroxybutyrate and nonesterified fatty acids were decreased at 1 d after LPS challenge in glucogenic-fed cows only. Cholesterol did not change, and triglycerides only decreased significantly in lipogenic-fed cows 6 h after challenge. On d 9 after LPS challenge, SCC and milk yield and metabolic factors were recovered in all groups. In conclusion, the endocrine and metabolic situation, and the immune response to intramammary LPS of dairy cows during early lactation was not substantially influenced by the elevated supply of nitrogenic, glucogenic, or lipogenic components due to the provided feed in this study.

ABSTRACT: This study aimed to investigate the effect of the different dry-off strategies based on reducing feeding level (normal vs. reduced energy density), reducing milking frequency (twice vs. once daily), and administration of a dopamine agonist after last milking (i.e. saline vs. cabergoline injection) on blood metabolites, hormones, and minerals around dry-off. In this experiment, 119 Holstein dairy cows were used in a 2 × 2 × 2 factorial arrangement. In the last week before dry-off, cows were allocated to 1 of the 4 possible dry-off strategies based on feeding level and milking frequency. Within 3 h after last milking, cows were injected with either saline or a D2 dopamine agonist (cabergoline; Velactis, Ceva Santé Animale, Libourne, France; labeled for use only with abrupt dry-off, e.g., no preceding reduction in feeding level or milking frequency before last milking). After dry-off, all cows were fed the same dry cow diet and data collection continued for a week. Blood samples were collected from the coccygeal vein on d −9, −6, −5, −2, 1, 2, 5, and 7 relative to dry-off. Additionally, blood was sampled at 0, 3, and 6 h relative to injection of either cabergoline or saline, equivalent to d 0.125, 0.250, and 0.375 relative to last milking (dry-off). The reduced feeding level before dry-off caused reduced glucose and insulin concentrations as well as increased free fatty acid concentrations, particularly when reduced feeding level was combined with milking the cows 2× daily. The intramuscular injection of cabergoline caused the expected reduction in circulating prolactin concentrations. In addition, dopamine-agonist cabergoline induced an atypical simultaneous pattern of plasma metabolites (i.e., increased glucose and free fatty acid concentrations), hormones (i.e., reduced insulin and increased cortisol concentrations), and minerals (i.e., reduced calcium concentration), indicating that normal metabolic and mineral homeostatic regulations were hindered after the injection of ergot alkaloid cabergoline. In conclusion, reducing milking frequency seems the best management strategy to reduce milk production at dry-off among those tested in this study.

ABSTRACT: Drying-off practices to reduce milk production before dry-off are gaining attention because high milk yields at dry-off are becoming more common and increase the risk to cow health and welfare during the dry period. Incomplete milking for the last days before dry-off is one approach for reducing milk production. We conducted an online survey to determine the currently used drying-off practices on Swiss dairy farms and to identify the adoption potential of integrating incomplete milking before dry-off. In March 2021, the online survey was sent to a representative sample of 1,974 Swiss dairy farmers. A total of 518 completed questionnaires were analyzed. The mean number of dairy cows per farm was 39 (range: 11–140 cows). Thirty-five percent of cows produced considerable quantities of milk (>15 kg/d) at dry-off, and milk yield at dry-off increased with increasing annual milk yield. Abrupt dry-off was applied on 45% of the farms. The participants reported observing behavioral changes of cows such as increased vocalizations and decreased lying time associated with dry-off. Selective dry cow therapy was applied on 74% of the farms, and 44% of the participants indicated the use of antibiotics at dry-off as being “rather often,” “often,” or “always.” Correlation analysis revealed that with increasing annual milk yields, the frequency of observed behavioral changes and antibiotic use at dry-off increased as well. Therefore, drying-off approaches that reduce milk production while supporting cow welfare are needed. We found that farmers showed an interest in testing the presented drying-off approach of incomplete milking. In addition, the farmers indicated that they would be more willing to test incomplete milking before dry-off if it became available for automated use in milking parlors or robots. Uncertainties regarding udder health appeared to be the main barrier for the adoption potential of this approach.

Background: Postoperative complications are associated with reduced long-term survival. We characterise healthcare use changes after sentinel postoperative complications. Methods: We linked primary and secondary care records of patients undergoing elective surgery at four East London hospitals (2012–7) with at least 90 days follow-up. Complication codes (wound infection, urinary tract infection, pneumonia, new stroke, and new myocardial infarction) recorded within 90 days of surgery were identified from primary or secondary care. Outcomes were change in healthcare contact days in the 2 yr before and after surgery, and 2 yr mortality. We report rate ratios (RaR) with 95% confidence intervals and adjusted for baseline healthcare use and confounders using negative binomial regression. Results: We included 49 913 patients (median age 49 yr [inter-quartile range {IQR}: 34–64]), 27 958 (56.0%) were female. Amongst 3883 (7.8%) patients with complications (median age 58 [IQR: 43–72]), there were 18.4 days per year in contact with healthcare before surgery and 25.3 days after surgery (RaR: 1.38 [1.37–1.39]). Patients without complications (median age 48 [IQR: 33–63]) had 12.3 days per year in contact with healthcare before surgery and 14.0 days after surgery (RaR: 1.14 [1.14–1.15]). The adjusted incidence rate ratio of days in contact with healthcare associated with complications was 1.67 (1.49–1.87). More patients (391; 10.1%) with complications died within 2 yr than those without (1428; 3.1%). Conclusions: Patients with postoperative complications are older with greater healthcare use before surgery. However, their absolute and relative increases in healthcare use after surgery are greater than patients without complications.

ABSTRACT: Adequate prestimulation is considered a requirement for a fast, gentle, and complete udder emptying at machine milking. Reduced vacuum or reduced liner-open phase of pulsation (or both) may replace prestimulation and consequently reduce work load of the milker and increase parlor efficiency. In the present study we compared 2 milking routines (MR) with manual prestimulation (LPrep = long preparation: 15 s of forestripping, teat cleaning, and stimulation; SPrep = short preparation: 5 s of teat cleaning) followed by 1-min latency period and milking at standard vacuum and pulsation settings (claw vacuum 44 kPa, pulsation rate 60 cycles/min, pulsation ratio 65/35) with 2 MR consisting of 5 s of teat cleaning, immediate cluster attachment and milking at reduced vacuum with or without shortened liner-open phase of pulsation until milk flow exceeded 400 g/min (RP = reduced pulsation: pulsation ratio 30/70, pulsation rate 50 cycles/min, claw vacuum 44 kPa; RPV = reduced pulsation and vacuum: pulsation ratio 30/70, pulsation rate 50 cycles/min, claw vacuum 34 kPa). Cluster detachment was performed at 400 g/min in all MR. Ten Holstein dairy cows were milked twice daily at 14-h and 10-h milking intervals. Milk flow and electrical conductivity (EC) were recorded throughout milking. During the first 2 min of each milking ultrasound cross-section images of the gland cistern of one front quarter were recorded, and 5 min after the end of milking teat tissue thickness of both front teats was measured by using a cutimeter. Most milking characteristics such as total milk yield, average milk flow, and machine-on time reached higher values at 14-h than 10-h milking intervals, but did not differ among MR. However, the occupancy time (time from the first touch of the udder until cluster detachment) was considerably shorter in RP and RPV compared with LPrep and SPrep. Ultrasound cross section areas of the gland cistern were larger in LPrep than in RP and RPV indicating that milk ejection already occurred at cluster attachment in LPrep. This assumption is also supported by the lower EC at cluster attachment in LPrep than in RP and RPV, which was caused by the presence of alveolar milk in the gland cistern after milk ejection. The MR RP and RPV increase parlor efficiency and are work-saving alternatives to MR, which include an adequate prestimulation (LPrep). However, shortening prestimulation to a 5-s teat cleaning followed by a latency period and milking at regular vacuum and pulsation is not adequate to save occupancy time. Because milking was performed at a relatively low vacuum (44 kPa) and at a detachment level of 400 g/min, teat tissue thickness did not differ among MR, and the vacuum reduction in RPV did not cause an additional advantage for teat condition compared with RP.

Fondaparinux sodium is a chemically synthesized selective factor Xa inhibitor approved for the prevention and treatment of venous thromboembolic events, that is, deep vein thrombosis, pulmonary embolism, and superficial vein thrombosis, in acutely ill (including those affected by COVID-19 or cancer patients) and those undergoing surgeries. Since its approval in 2002, the efficacy and safety of fondaparinux is well demonstrated by many clinical studies, establishing the value of fondaparinux in clinical practice. Some of the advantages with fondaparinux are its chemical nature of synthesis, minimal risk of contamination, 100% absolute bioavailability subcutaneously, instant onset of action, a long half-life, direct renal excretion, fewer adverse reactions when compared with direct oral anticoagulants, and being an ideal alternative in conditions where oral anticoagulants are not approved for use or in patients intolerant to low molecular weight heparins (LMWH). In the last decade, the real-world use of fondaparinux has been explored in other conditions such as acute coronary syndromes, bariatric surgery, in patients developing vaccine-induced immune thrombotic thrombocytopenia (VITT) and in pregnant women with heparin-induced thrombocytopenia (HIT), or those intolerant to LMWH. The emerging data from these studies have culminated in recent updates in the guidelines that recommend the use of fondaparinux under various conditions. This paper aims to review the recent data and the subsequent updates in the recommendations of various guidelines on the use of fondaparinux sodium.

Recently, we observed that lipopolysaccharide (LPS) suppresses corpus luteum (CL) function in isolated perfused ovaries. It remained unclear if this suppression was due to increased luteal PGF2α secretion or LPS-induced apoptosis. Therefore, possible impacts of PGF2α and LPS were inhibited by a non-steroidal anti-inflammatory drug (flunixin) and an endotoxin-binding agent (polymyxin B), respectively. Bovine ovaries with a mid-cycle CL were collected immediately after slaughter and perfused for 240 min. After 50 min of equilibration, either flunixin or polymyxin B (5 μg/ml of each) were added to the perfusion medium of six ovaries, respectively. All ovaries (n = 12) were treated with E. coli LPS (0.5 μg/ml) 60 min after the onset of perfusion, and received 500 I.U. of hCG after 210 min of perfusion. Progesterone and PGF2α were measured in the effluent perfusate every 10 and 30 min, respectively. Biopsies of the CL were collected every 60 min to determine the mRNA expression of the cytokine TNFA and factors of apoptosis (CASP3, -8). Flunixin-treatment inhibited the increase of PGF2α after LPS-challenge that was observed in the polymyxin B-treated (PX-LPS) ovaries. After hCG-stimulation, progesterone secretion increased (P < 0.05) in group PX-LPS but not in the flunixin-treated (F-LPS) ovaries. Compared to initial values before LPS-challenge, luteal mRNA expression of TNFA and CASP3 was increased (P < 0.05) in group F-LPS at 120 and 180 min, respectively, and those of CASP8 was decreased (P < 0.05) in PX-LPS at 60 and 120 min after LPS-treatment. In conclusion, although flunixin managed to inhibit PGF2α, it did not suffice to successfully prevent LPS-induced apoptosis. However, endotoxin-binding polymyxin B resulted in luteal responsiveness to hCG after LPS-challenge.

Background: Improving women's health is a critical component of the sustainable development goals. Although obstetric outcomes in Africa have received significant focus, non-obstetric surgical outcomes for women in Africa remain under-examined. Methods: We did a secondary analysis of the African Surgical Outcomes Study (ASOS) and International Surgical Outcomes Study (ISOS), two 7-day prospective observational cohort studies of outcomes after adult inpatient surgery. This sub-study focuses specifically on the analysis of the female, elective, non-obstetric, non-gynaecological surgical data collected during these two large multicentre studies. The African data from both cohorts are compared with international (non-African) outcomes in a risk-adjusted logistic regression analysis using a generalised linear mixed-effects model. The primary outcome was severe postoperative complications including in-hospital mortality in Africa compared with non-African outcomes. Results: A total of 1698 African participants and 18 449 international participants met the inclusion criteria. The African cohort were younger than the international cohort with a lower preoperative risk profile. Severe complications occurred in 48 (2.9%) of 1671, and 431 (2.3%) of 18 449 patients in the African and international cohorts, respectively, with in-hospital mortality after severe complications of 23/48 (47.9%) in Africa and 78/431 (18.1%) internationally. Women in Africa had an adjusted odds ratio of 2.06 (95% confidence interval, 1.17–3.62; P=0.012) of developing a severe postoperative complication after elective non-obstetric, non-gynaecological surgery, compared with the international cohort. Conclusions: Women in Africa have double the risk adjusted odds of severe postoperative complications (including in-hospital mortality) after elective non-obstetric, non-gynaecological surgery compared with the international incidence.

Abstract Background It is uncertain whether the association of the intraoperative driving pressure (ΔP) with postoperative pulmonary complications (PPCs) depends on the surgical approach during abdominal surgery. Our primary objective was to determine and compare the association of time–weighted average ΔP (ΔPTW) with PPCs. We also tested the association of ΔPTW with intraoperative adverse events. Methods Posthoc retrospective propensity score–weighted cohort analysis of patients undergoing open or closed abdominal surgery in the ‘Local ASsessment of Ventilatory management during General Anaesthesia for Surgery’ (LAS VEGAS) study, that included patients in 146 hospitals across 29 countries. The primary endpoint was a composite of PPCs. The secondary endpoint was a composite of intraoperative adverse events. Results The analysis included 1128 and 906 patients undergoing open or closed abdominal surgery, respectively. The PPC rate was 5%. ΔP was lower in open abdominal surgery patients, but ΔPTW was not different between groups. The association of ΔPTW with PPCs was significant in both groups and had a higher risk ratio in closed compared to open abdominal surgery patients (1.11 [95%CI 1.10 to 1.20], P

Abstract Background Treatment decisions on critically ill patients with circulatory shock lack consensus. In an international survey, we aimed to evaluate the indications, current practice, and therapeutic goals of inotrope therapy in the treatment of patients with circulatory shock. Methods From November 2016 to April 2017, an anonymous web-based survey on the use of cardiovascular drugs was accessible to members of the European Society of Intensive Care Medicine (ESICM). A total of 14 questions focused on the profile of respondents, the triggering factors, first-line choice, dosing, timing, targets, additional treatment strategy, and suggested effect of inotropes. In addition, a group of 42 international ESICM experts was asked to formulate recommendations for the use of inotropes based on 11 questions. Results A total of 839 physicians from 82 countries responded. Dobutamine was the first-line inotrope in critically ill patients with acute heart failure for 84% of respondents. Two-thirds of respondents (66%) stated to use inotropes when there were persistent clinical signs of hypoperfusion or persistent hyperlactatemia despite a supposed adequate use of fluids and vasopressors, with (44%) or without (22%) the context of low left ventricular ejection fraction. Nearly half (44%) of respondents stated an adequate cardiac output as target for inotropic treatment. The experts agreed on 11 strong recommendations, all of which were based on excellent (> 90%) or good (81–90%) agreement. Recommendations include the indications for inotropes (septic and cardiogenic shock), the choice of drugs (dobutamine, not dopamine), the triggers (low cardiac output and clinical signs of hypoperfusion) and targets (adequate cardiac output) and stopping criteria (adverse effects and clinical improvement). Conclusion Inotrope use in critically ill patients is quite heterogeneous as self-reported by individual caregivers. Eleven strong recommendations on the indications, choice, triggers and targets for the use of inotropes are given by international experts. Future studies should focus on consistent indications for inotrope use and implementation into a guideline for circulatory shock that encompasses individualized targets and outcomes.

The COVID-19 pandemic has had a major impact on global healthcare systems, has drastically affected patient care, and has had widespread effects upon medical education. As plans are being devised to reinstate elective surgical services, it is important to consider the impact that the pandemic has had and will continue to have on surgical training. We describe the effect COVID-19 has had at all levels of training in the UK within trauma and orthopaedics and evaluate how training might change in the future. We found that the COVID-19 pandemic has significantly impacted trainees within trauma and orthopaedics at all levels of training. It had led to reduced operative exposure, cancellations of examinations and courses, and modifications to speciality recruitment and annual appraisals. This cohort of trainees is witnessing novel methods of delivering orthopaedic services, which will continue to develop and become part of routine practice even once the pandemic has resolved. It will be important to observe the extent to which the rapid changes currently being introduced will impact the personal health, safety, and career progression of current trainees.

Background Despite high female prevalence of peripheral artery disease (PAD), little is known about sex‐based outcomes after lower extremity revascularization (LER) for symptomatic PAD. The effects of rivaroxaban according to sex following LER have not been fully reported. Methods and Results In VOYAGER PAD (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease), low‐dose rivaroxaban versus placebo on a background of aspirin reduced the composite primary efficacy outcome of cardiovascular and limb events in patients with PAD undergoing LER. Unplanned index limb revascularization was prespecified and prospectively ascertained. The primary safety outcome was Thrombolysis in Myocardial Infarction major bleeding. Analyses of outcomes and treatment effects by sex were performed using Cox proportional hazards models. Among 6564 randomly assigned patients followed for a median of 28 months, 1704 (26.0%) were women. Among patients administered placebo, women were at similar risk for the primary efficacy outcome (hazard ratio [HR], 0.90; [95% CI, 0.74–1.09]; P=0.29) as men, while female sex was associated with a trend toward higher risk of unplanned index limb revascularization (HR, 1.18; [95% CI, 1.00–1.40]; P=0.0499). Irrespective of sex, effects of rivaroxaban were consistent for the primary efficacy outcome (P‐interaction=0.22), unplanned index limb revascularization (P‐interaction=0.64), and bleeding (P‐interaction=0.61). Women were more likely than men to discontinue study treatment (HR, 1.13; [95% CI, 1.03–1.25]; P=0.0099). Conclusions Among >1700 women with PAD undergoing LER, women and men were at similar risk for the primary outcome, but a trend for greater risk of unplanned index limb revascularization among women was observed. Effects of rivaroxaban were consistent by sex, though women more often discontinued treatment. Better understanding of sex‐based outcomes and treatment adherence following LER is needed. Registration URL: http://clinicaltrials.gov; Unique identifier: NCT02504216.

Prolonged cow-calf contact (CCC) could potentially improve dairy calf welfare. However, it is currently unknown how different types of CCC affect animals' biological functions. We evaluated health and performance parameters of dairy calves and their dams, where calves: (i) had no contact with their dam (NC), in which the calf was removed from the dam directly after birth (n = 10); (ii) were allowed to have partial contact (PC) with their dam, in which the calf was housed in a calf pen adjacent to the cow area allowing physical contact on the initiative of the dam but no suckling (n = 18); (iii) were allowed to have full contact (FC) with their dam, including suckling, in which calves were housed together with their dams in a free-stall barn (n = 20). Throughout the first 7 weeks postpartum, data were collected on the health status, fecal microbiota, hematological profile, immune and hormonal parameters, and growth rates of calves, and on the health status, metabolic responses, and performance of dams. Overall, FC calves had more health issues (P = 0.02) and a tendency for higher antibiotic usage (P = 0.07) than NC calves. Additionally, FC calves showed elevated levels of erythrocytes, hematocrit, hemoglobin, and leukocytes on day 49 compared to NC calves (P < 0.001). Calf fecal microbiota changed over time, and we found preliminary evidence that fecal microbiota is affected by the type of CCC, as reflected by differences in relative abundances of taxa including Lactobacillus in FC calves compared to NC and PC calves except on days 7 and 66. The FC calves had a greater average daily gain in body weight than NC and PC calves (P = 0.002). Cow health was not affected by the type of CCC, although in the first 7 weeks of lactation FC cows had a lower machine-gained milk yield accompanied by a lower fat percentage than NC and PC cows (P < 0.001). These results indicate that full contact posed a challenge for calf health, presumably because the housing conditions of FC calves in this experimental context were suboptimal. Secondly, ad libitum suckling leads to higher weight gains and negatively affected milk fat content besides machine-gained yields. More research into strategies to improve cow-calf housing and management in CCC systems is warranted.

AimThis study aimed to examine the effects of feeding or abdominal brushing on the release of the hormones oxytocin, ACTH and cortisol during milking in dairy cows.MethodsTwelve cows in early lactation were used (2 × 2 factorial experimental design), testing the effects of two types of sensory stimulation during milking over a 3 day period; feeding concentrate or manual abdominal brushing (1 stroke/s). Blood samples for hormone analyses were collected at time at −15, −1, 0 (onset of cluster), every min for 8 min, at 10, 12, 14, 16, 30, and 60 min. Hormone levels were assayed and AUC was calculated.ResultsMilking was associated with an immediate and significant rise of oxytocin. When milking was combined with feeding, significantly higher levels of oxytocin were observed at 2 and 4 mins (p < 0.05). No effect of brushing on oxytocin levels was observed. Milking alone was associated with a significant rise of ACTH levels. Feeding in connection with milking reduced the immediate rise of ACTH levels (p < 0.05) and AUC (p < 0.02), whereas no effects of brushing were found. Milking caused a progressive rise of cortisol levels. Concomitant feeding did not influence cortisol levels, whereas brushing significantly decreased cortisol levels at 1, 5 and 14 mins after onset of milking (p < 0.05).ConclusionFeeding increases oxytocin release in response to milking and decreases ACTH levels. Abdominal brushing did not influence these variables, but decreased cortisol levels. These data demonstrate that activation of afferent vagal nerve fibres and of cutaneous sensory nerves originating from the abdominal skin in front of the udder influence milking related hormone release differently.

Ultra- and circadian activity rhythms of animals can provide important insights into animal welfare. The consistency of behavioral patterns is characteristic of healthy organisms, while changes in the regularity of behavioral rhythms may indicate health and stress-related challenges. This pilot study aimed to examine whether dairy cows in free-stall barns with an automatic milking system (AMS) and free cow traffic can develop ultra- and circadian activity rhythms. On 4 dairy farms, pedometers recorded the activity of 10 cows each over 28 days. Based on time series calculation, the Degree of Functional Coupling (DFC) was used to determine the cows' activity rhythms. The DFC identified significant rhythmic patterns in sliding 7-day periods and indicated the percentage of activity (0–100%) that was synchronized with the 24-h day-night rhythm. As light is the main factor influencing the sleep-wake cycle of organisms, light intensity was recorded in the AMS, at the feed alley and in the barn of each farm. In addition, feeding and milking management were considered as part of the environmental context. Saliva samples of each cow were taken every 3 h for 1 day to determine the melatonin concentration. The DFC approach was successfully used to detect activity rhythms of dairy cows in commercial housing systems. However, large inter- and intra-individual variations were observed. Due to a high frequency of 0 and 100%, a median split was used to dichotomize into “low” (

Background: The effects of ethnic and social inequalities on patient outcomes in acute healthcare remain poorly understood.Methods: Prospectively-defined analysis of registry data from four acute NHS hospitals in east London including all patients ≥ 18 years with a first emergency admission between 1st January 2013 and 31st December 2018. We calculated adjusted one-year mortality risk using logistic regression. Results are presented as n (%), median (IQR), and odds ratios (OR) with 95% confidence intervals.Findings: We included 203,182 patients. 43,101 (21%) patients described themselves as Asian, 21,388 (10.5%) Black, 2,982 (1.4%) Mixed, 13,946 (6.8%) Other ethnicity, and 100,065 (49%) White. We excluded 21,700 (10.7%) patients with undisclosed ethnicity. 16,054 (7.9%) patients died within one year. Non-white patients were younger (Asian: 43 [31–62] years; Black: 48 [33–63] years; Mixed 36 [26–52] years) than White patients (55 [35–75] years), with a higher incidence of comorbid disease. In each age-group, non-white patients were more likely to be admitted to hospital. This effect was greatest in the ≥ 80 years age-group (32% non-white admitted to hospital versus 23% non-white in community population). Deprivation was associated with increased mortality in all ethnic groups (OR 1.41 [1.33–1.50]; p

Objective To describe outcomes within different ethnic groups of a cohort of hospitalised patients with confirmed COVID-19 infection. To quantify and describe the impact of a number of prognostic factors, including frailty and inflammatory markers.Setting Five acute National Health Service Hospitals in east London.Design Prospectively defined observational study using registry data.Participants 1737 patients aged 16 years or over admitted to hospital with confirmed COVID-19 infection between 1 January and 13 May 2020.Main outcome measures The primary outcome was 30-day mortality from time of first hospital admission with COVID-19 diagnosis during or prior to admission. Secondary outcomes were 90-day mortality, intensive care unit (ICU) admission, ICU and hospital length of stay and type and duration of organ support. Multivariable survival analyses were adjusted for potential confounders.Results 1737 were included in our analysis of whom 511 had died by day 30 (29%). 538 (31%) were from Asian, 340 (20%) black and 707 (40%) white backgrounds. Compared with white patients, those from minority ethnic backgrounds were younger, with differing comorbidity profiles and less frailty. Asian and black patients were more likely to be admitted to ICU and to receive invasive ventilation (OR 1.54, (95% CI 1.06 to 2.23); p=0.023 and OR 1.80 (95% CI 1.20 to 2.71); p=0.005, respectively). After adjustment for age and sex, patients from Asian (HR 1.49 (95% CI 1.19 to 1.86); p

Previous grazing experience on high alpine pastures may help cows to optimise feed selection and minimise impairments in milk production. Eight inexperienced and eight experienced Aosta Red Pied cows were compared (primiparous:multiparous = 1:1). Measurements were performed when cows grazed sites at 600, 1800 and 2100 m a.s.l. The statistical model included experience, parity and site as fixed effects. The longest ingestion time was recorded for primiparous inexperienced cows at 1800 m a.s.l. Milk yield remained unaffected by experience, but the main milking time was shorter in inexperienced cows in the lowlands. Milk of inexperienced cows had a higher urea content than experienced cows. Somatic cell score remained unaffected by experience, but inexperienced cows had more incidences of clinical mastitis on alpine pastures. Compared with experienced cows, proportions of the fatty acids ΣC16:1 and ΣC17:1 in milk fat of inexperienced cows were higher and proportions of C18:1 t9 and C18:1 t6–8 lower. Overall, alpine grazing had substantial effects on milk yield and composition coinciding with results from previous studies. There were interactions between experience and site in milking characteristics and milk composition, and for the latter also between experience and parity. In conclusion, experience had effects on several of the variables tested, effects which were sometimes exhibited already on lowland pasture. Still, the effects of experience were much lower than those of the transhumance system.Highlights The advantages of previous site-specific and age experience of cows were studied on alpine pasture. Lack of experience had mostly minor effects on economically relevant traits. Experience helped to maintain udder health in this alpine environment.

Abstract Perioperative fluid and hemodynamic management have been much-debated topics over the last few years. Recently, a number of large trials have been published to help inform this debate. The Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery (RELIEF) study is the largest trial to date of perioperative fluid management. The 3000-patient trial comparing 2 different fluid regimes showed that a restrictive fluid regimen during and up to 24 h after surgery was associated with an increase in acute kidney injury (AKI). This result is at odds with a recent trend to a more restrictive fluid approach during major surgery and suggests that practice may have become too restrictive. A moderately liberal (aiming for 1–2 l positive) or goal-directed approach is therefore recommended.

Summary: Background: Maternal and neonatal mortality is high in Africa, but few large, prospective studies have been done to investigate the risk factors associated with these poor maternal and neonatal outcomes. Methods: A 7-day, international, prospective, observational cohort study was done in patients having caesarean delivery in 183 hospitals across 22 countries in Africa. The inclusion criteria were all consecutive patients (aged ≥18 years) admitted to participating centres having elective and non-elective caesarean delivery during the 7-day study cohort period. To ensure a representative sample, each hospital had to provide data for 90% of the eligible patients during the recruitment week. The primary outcome was in-hospital maternal mortality and complications, which were assessed by local investigators. The study was registered on the South African National Health Research Database, number KZ_2015RP7_22, and on ClinicalTrials.gov, number NCT03044899. Findings: Between February, 2016, and May, 2016, 3792 patients were recruited from hospitals across Africa. 3685 were included in the postoperative complications analysis (107 missing data) and 3684 were included in the maternal mortality analysis (108 missing data). These hospitals had a combined number of specialist surgeons, obstetricians, and anaesthetists totalling 0·7 per 100 000 population (IQR 0·2–2·0). Maternal mortality was 20 (0·5%) of 3684 patients (95% CI 0·3–0·8). Complications occurred in 633 (17·4%) of 3636 mothers (16·2–18·6), which were predominantly severe intraoperative and postoperative bleeding (136 [3·8%] of 3612 mothers). Maternal mortality was independently associated with a preoperative presentation of placenta praevia, placental abruption, ruptured uterus, antepartum haemorrhage (odds ratio 4·47 [95% CI 1·46–13·65]), and perioperative severe obstetric haemorrhage (5·87 [1·99–17·34]) or anaesthesia complications (11·47 (1·20–109·20]). Neonatal mortality was 153 (4·4%) of 3506 infants (95% CI 3·7–5·0). Interpretation: Maternal mortality after caesarean delivery in Africa is 50 times higher than that of high-income countries and is driven by peripartum haemorrhage and anaesthesia complications. Neonatal mortality is double the global average. Early identification and appropriate management of mothers at risk of peripartum haemorrhage might improve maternal and neonatal outcomes in Africa. Funding: Medical Research Council of South Africa.

Abstract Background The majority of critically ill patients do not suffer from acute respiratory distress syndrome (ARDS). To improve the treatment of these patients, we aimed to identify potentially modifiable factors associated with outcome of these patients. Methods The PRoVENT was an international, multicenter, prospective cohort study of consecutive patients under invasive mechanical ventilatory support. A predefined secondary analysis was to examine factors associated with mortality. The primary endpoint was all-cause in-hospital mortality. Results 935 Patients were included. In-hospital mortality was 21%. Compared to patients who died, patients who survived had a lower risk of ARDS according to the ‘Lung Injury Prediction Score’ and received lower maximum airway pressure (P max), driving pressure (ΔP), positive end-expiratory pressure, and FiO2 levels. Tidal volume size was similar between the groups. Higher P max was a potentially modifiable ventilatory variable associated with in-hospital mortality in multivariable analyses. ΔP was not independently associated with in-hospital mortality, but reliable values for ΔP were available for 343 patients only. Non-modifiable factors associated with in-hospital mortality were older age, presence of immunosuppression, higher non-pulmonary sequential organ failure assessment scores, lower pulse oximetry readings, higher heart rates, and functional dependence. Conclusions Higher P max was independently associated with higher in-hospital mortality in mechanically ventilated critically ill patients under mechanical ventilatory support for reasons other than ARDS. Trial Registration ClinicalTrials.gov (NCT01868321).

Abstract Background Mildly elevated lactate levels (i.e., 1–2 mmol/L) are increasingly recognized as a prognostic finding in critically ill patients. One of several possible underlying mechanisms, microcirculatory dysfunction, can be assessed at the bedside using sublingual direct in vivo microscopy. We aimed to evaluate the association between relative hyperlactatemia, microcirculatory flow, and outcome. Methods This study was a predefined subanalysis of a multicenter international point prevalence study on microcirculatory flow abnormalities, the Microcirculatory Shock Occurrence in Acutely ill Patients (microSOAP). Microcirculatory flow abnormalities were assessed with sidestream dark-field imaging. Abnormal microcirculatory flow was defined as a microvascular flow index (MFI) 1.5 mmol/L was independently associated with a MFI

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Objectives: The objectives were to assess whether or not the QI programme improves 90-day survival after emergency abdominal surgery; to assess effects on 180-day survival, hospital stay and hospital readmission; and to better understand these findings through an integrated process evaluation, ethnographic study and cost-effectiveness analysis. Design: This was a stepped-wedge cluster randomised trial. Hospitals were organised into 15 geographical clusters, and commenced the QI programme in random order over 85 weeks. Analyses were performed on an intention-to-treat basis. The primary outcome was analysed using a mixed-effects parametric survival model, adjusting for time-related effects. Ethnographic and economics data were collected in six hospitals. The process evaluation included all hospitals. Setting: The trial was set in acute surgical services of 93 NHS hospitals. Participants: Patients aged ≥ 40 years who were undergoing emergency abdominal surgery were eligible. Intervention: The intervention was a QI programme to implement an evidence-based care pathway. Main outcome measures: The primary outcome measure was mortality within 90 days of surgery. Secondary outcomes were mortality within 180 days, length of hospital stay and hospital readmission within 180 days. The main economic measure was the quality-adjusted life-years. Data sources: Data were obtained from the National Emergency Laparotomy Audit database; qualitative interviews and ethnographic observations; quality-of-life and NHS resource use data were collected via questionnaires. Results: Of 15,873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 participants in the usual care group and 7374 in the QI group. The primary outcome occurred in 1393 participants in the usual care group (16%), compared with 1210 patients in the QI group (16%) [QI vs. usual care hazard ratio (HR) 1.11, 95% confidence interval (CI) 0.96 to 1.28]. No differences were found in mortality at 180 days or hospital readmission; there was a small increase in hospital stay in the QI group (HR for discharge 0.90, 95% CI 0.83 to 0.97). There were only modest improvements in care processes following QI implementation. The ethnographic study revealed good QI engagement, but limited time and resources to implement change, affecting which processes teams addressed, the rate of change and eventual success. In some sites, there were challenges around prioritising the intervention in busy environments and in obtaining senior engagement. The intervention is unlikely to be cost-effective at standard cost-effectiveness thresholds, but may be cost-effective over the lifetime horizon. Limitations: Substantial delays were encountered in securing data access to national registries. Fewer patients than expected underwent surgery and the mortality rate was lower than anticipated. Conclusions: There was no survival benefit from a QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. The modest impact of the intervention on process measures, despite good clinician engagement, may have been limited by the time and resources needed to improve patient care. Future work: Future QI programmes must balance intervention complexity with the practical realities of NHS services to ensure that such programmes can be delivered with the resources available. Trial registration: Current Controlled Trials ISRCTN80682973 and The Lancet protocol 13PRT/7655. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 7, No. 32. See the NIHR Journals Library website for further project information.

This study aimed to (1) investigate effects of reducing postpartum dietary energy level for cows after a 0-d dry period (DP) on resumption of ovarian cyclicity and reproductive performance, (2) relate days open with other reproductive measures, and (3) relate onset of luteal activity (OLA) and days open with metabolic status in early lactation. Holstein-Friesian dairy cows were randomly assigned to 1 of 3 transition treatments: no DP and low postpartum dietary energy level from 22 days in milk( DIM )onwards (0-d DP (LOW)) (n = 42), no DP and standard postpartum dietary energy level (0-d DP (STD)) (n = 43), and a short DP and standard postpartum dietary energy level (30-d DP (STD)) (n = 43). Milk progesterone concentration was determined three times per week until 100 DIM. Plasma metabolite and hormone concentrations were measured weekly until week 7 postpartum. Reducing postpartum dietary energy level in older cows (parity ≥ 3) after no DP and 22 DIM did not affect milk production but prevented a positive energy balance and shortened the interval from calving to OLA. In addition, services per pregnancy and days open were reduced in cows of parity ≥ 3 on 0-d DP (LOW), compared with cows of parity ≥ 3 with 0-d DP (STD), but not in cows of parity 2.

BackgroundImpaired cardiac vagal function, quantified preoperatively as slower heart rate recovery (HRR) after exercise, is independently associated with perioperative myocardial injury. Parasympathetic (vagal) dysfunction may also promote (extra-cardiac) multi-organ dysfunction, although perioperative data are lacking. Assuming that cardiac vagal activity, and therefore heart rate recovery response, is a marker of brainstem parasympathetic dysfunction, we hypothesized that impaired HRR would be associated with a higher incidence of morbidity after noncardiac surgery.MethodsIn two prospective, blinded, observational cohort studies, we established the definition of impaired vagal function in terms of the HRR threshold that is associated with perioperative myocardial injury (HRR ≤ 12 beats min-1 (bpm), 60 seconds after cessation of cardiopulmonary exercise testing. The primary outcome of this secondary analysis was all-cause morbidity three and five days after surgery, defined using the Post-Operative Morbidity Survey. Secondary outcomes of this analysis were type of morbidity and time to become morbidity-free. Logistic regression and Cox regression tested for the association between HRR and morbidity. Results are presented as odds/hazard ratios [OR or HR; (95% confidence intervals).Results882/1941 (45.4%) patients had HRR≤12bpm. All-cause morbidity within 5 days of surgery was more common in 585/822 (71.2%) patients with HRR≤12bpm, compared to 718/1119 (64.2%) patients with HRR>12bpm (OR:1.38 (1.14-1.67); p = 0.001). HRR≤12bpm was associated with more frequent episodes of pulmonary (OR:1.31 (1.05-1.62);p = 0.02)), infective (OR:1.38 (1.10-1.72); p = 0.006), renal (OR:1.91 (1.30-2.79); p = 0.02)), cardiovascular (OR:1.39 (1.15-1.69); pConclusionsMulti-organ dysfunction is more common in surgical patients with cardiac vagal dysfunction, defined as HRR ≤ 12 bpm after preoperative cardiopulmonary exercise testing.Clinical trial registryISRCTN88456378.

[This corrects the article DOI: 10.1371/journal.pone.0221277.].

Background Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are the most commonly prescribed antihypertensive medications in higher-risk surgical patients. However, there is no clinical consensus on their use in the perioperative period, in part, due to an inconsistent evidence-base. To help inform the design of a large multi-centre randomized controlled trial (ISRCTN17251494), we undertook a questionnaire-based survey exploring variability in ACEi/ARB prescribing in perioperative practice. Methods The online survey included perioperative scenarios to examine how consistent respondents were with their stated routine preoperative practice. Clinicians with an academic interest in perioperative medicine were primarily targeted between July and September 2017. STROBE guidelines for observational research and ANZCA Trials Group Survey Reporting recommendations were adhered to. Results 194 responses were received, primarily from clinicians practicing in the UK. A similar minority of respondents continue ACEi (n = 57; 30%) and ARBs (n = 62; 32%) throughout the perioperative period. However, timing of preoperative cessation was highly variable, and rarely influenced by the pharmacokinetics of individual ACE-i/ARBs. Respondents’ stated routine practice was frequently misaligned with their management of common pre- and postoperative scenarios involving continuation or restarting ACE-i/ARBs. Discussion This survey highlights many inconsistencies amongst clinicians’ practice in perioperative ACE-i/ARB management. Studies designed to reveal an enhanced understanding of perioperative mechanisms at play, coupled with randomised controlled trials, are required to rationally inform the clinical management of ACE-i/ARBs in patients most at risk of postoperative morbidity.

INTRODUCTION:Post-operative infections occur frequently following major surgery. The magnitude of the post-operative immune response is associated with an increased risk of post-operative infections, although the mechanisms driving post-operative immune-dysfunction and the potential reversibility of this response with immune stimulants are not well understood. This study aims to describe the immediate immune response to major surgery and establish links to both post-operative infection and functional aspects of immune dysregulation. We also investigate the potential of clinically available immune stimulants to reverse features of post-operative immune-dysfunction. METHODS:Patients over 45 years old undergoing elective gastro-intestinal surgery with planned post-operative surgical ICU admission were recruited. The expression of selected genes was determined pre-operatively and at 2, 24 and 48 hours post-operatively using qRT-PCR. Circulating levels of Interleukin-10 protein were determined by ELISA. Peri-operative cell surface monocyte HLA-DR (mHLA-DR) expression was determined using flow cytometry. Gene expression and mHLA-DR levels were determined in healthy monocytes cultured in peri-operative serum with and without neutralising antibodies and immune stimulants. RESULTS:119 patients were recruited; 44 developed a post-operative infection. Interleukin-10 mRNA and protein increased 4-fold post-operatively (P

Serotonin is known to regulate energy and calcium homeostasis in several mammalian species. The objective of this study was to determine if pre-partum infusions of 5-hydroxytryptophan (5-HTP), the immediate precursor to serotonin synthesis, could modulate energy homeostasis at the level of the hepatocyte in post-partum Holstein and Jersey dairy cows. Twelve multiparous Holstein cows and twelve multiparous Jersey cows were intravenously infused daily for approximately 7 d pre-partum with either saline or 1 mg/kg bodyweight of 5-HTP. Blood was collected for 14 d post-partum and on d30 post-partum. Liver biopsies were taken on d1 and d7 post-partum. There were no changes in the circulating concentrations of glucose, insulin, glucagon, non-esterified fatty acids, or urea nitrogen in response to treatment, although there were decreased beta-hydroxybutyrate concentrations with 5-HTP treatment around d6 to d10 post-partum, particularly in Jersey cows. Cows infused with 5-HTP had increased hepatic serotonin content and increased mRNA expression of the serotonin 2B receptor on d1 and d7 post-partum. Minimal changes were seen in the hepatic mRNA expression of various gluconeogenic enzymes. There were no changes in the mRNA expression profile of cell-cycle progression marker cyclin-dependent kinase 4 or apoptotic marker caspase 3, although proliferating cell nuclear antigen expression tended to be increased in Holstein cows infused with 5-HTP on d1 post-partum. Immunofluorescence assays showed an increased number of CASP3- and Ki67-positive cells in Holstein cows infused with 5-HTP on d1 post-partum. Given the elevated hepatic serotonin content and increased mRNA abundance of 5HTR2B, 5-HTP infusions may be stimulating an autocrine-paracrine adaptation to lactation in the Holstein cow liver.

BACKGROUND:Dogs with leptospirosis show similar organ manifestations and disease course as human patients, including acute kidney injury and pulmonary hemorrhage, making this naturally-occurring infection a good animal model for human leptospirosis. Expression patterns of cytokines and enzymes have been correlated with disease manifestations and clinical outcome in humans and animals. The aim of this study was to describe mRNA expression of pro- and anti-inflammatory mediators in canine leptospirosis and to compare it with other renal diseases to identify patterns characterizing the disease and especially its pulmonary form. METHODOLOGY AND PRINCIPAL FINDINGS:The mRNA abundance of cytokines (IL-1α, IL-1β, IL-8, IL-10, TNF-α, TGF-β) and enzymes (5-LO, iNOS) was measured prospectively in blood leukocytes from 34 dogs with severe leptospirosis and acute kidney injury, including 22 dogs with leptospirosis-associated pulmonary hemorrhages. Dogs with leptospirosis were compared to 14 dogs with acute kidney injury of other origin than leptospirosis, 8 dogs with chronic kidney disease, and 10 healthy control dogs. Canine leptospirosis was characterized by high 5-LO and low TNF-α expression compared to other causes of acute kidney injury, although the decreased TNF-α expression was also seen in chronic kidney disease. Leptospirosis-associated pulmonary hemorrhage was not characterized by a specific pattern, with only mild changes noted, including increased IL-10 and decreased 5-LO expression on some days in affected dogs. Fatal outcome from pulmonary hemorrhages was associated with low TNF-α, high IL-1β, and high iNOS expression, a pattern possibly expressed also in dogs with other forms of acute kidney injury. CONCLUSION:The patterns of cytokine and enzyme expression observed in the present study indicate a complex pro- and anti-inflammatory response to the infection with leptospires. The recognition of these signatures may be of diagnostic and prognostic relevance for affected individuals and they may indicate options for newer therapies targeting the identified pathways.

The response of cholesterol metabolism to a negative energy balance (NEB) induced by feed restriction for 3 weeks starting at 100 days in milk (DIM) compared to the physiologically occurring NEB in week 1 postpartum (p.p.) was investigated in 50 dairy cows (25 control (CON) and 25 feed-restricted (RES)). Blood samples, liver biopsies and milk samples were taken in week 1 p.p., and in weeks 0 and 3 of feed restriction. Plasma concentrations of total cholesterol (C), phospholipids (PL), triglycerides (TAG), very low density lipoprotein-cholesterol (VLDL-C) and low density lipoprotein-cholesterol (LDL-C) increased in RES cows from week 0 to 3 during feed restriction and were higher in week 3 compared to CON cows. In contrast, during the physiologically occurring NEB in week 1 p.p., C, PL, TAG and lipoprotein concentrations were at a minimum. Plasma phospholipid transfer protein (PLTP) and lecithin:cholesterol acyltransferase (LCAT) activities did not differ between week 0 and 3 for both groups, whereas during NEB in week 1 p.p. PLTP activity was increased and LCAT activity was decreased. Milk C concentration was not affected by feed restriction in both groups, whereas milk C mass was decreased in week 3 for RES cows. In comparison, C concentration and mass in milk were elevated in week 1 p.p. Hepatic mRNA abundance of sterol regulatory element-binding factor-2 (SREBF-2), 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), and ATP-binding cassette transporter (ABCA1) were similar in CON and RES cows during feed restriction, but were upregulated during NEB in week 1 p.p. compared to the non-lactating stage without a NEB. In conclusion, cholesterol metabolism in dairy cows is affected by nutrient and energy deficiency depending on the stage of lactation.

Background and objectivesVitamin D deficiency and endothelial dysfunction are non-traditional risk factors for cardiovascular events in chronic kidney disease. Previous studies in chronic kidney disease have failed to demonstrate a beneficial effect of vitamin D on arterial stiffness, left ventricular mass and inflammation but none have assessed the effect of vitamin D on microcirculatory endothelial function.Study designWe conducted a randomised controlled trial of 38 patients with non diabetic chronic kidney disease stage 3-4 and concomitant vitamin D deficiency (ResultsTwenty patients received ergocalciferol and 18 patients received placebo. After 6 months, there was a significant improvement in the ergocalciferol group in both endothelium dependent microcirculatory vasodilatation after iontophoresis of acetylcholine (p = 0.03) and a reduction in tissue advanced glycation end products (p = 0.03). There were no changes in sublingual microcirculatory parameters. Pulse pressure (p = 0.01) but not aortic pulse wave velocity was reduced. There were no significant changes in bone mineral parameters, blood pressure or left ventricular mass index suggesting that ergocalciferol improved endothelial function independently of these parameters. In parallel experiments, expression of endothelial nitric oxide synthase and activity were increased in human endothelial cells in a dose dependent manner.ConclusionsErgocalciferol improved microcirculatory endothelial function in patients with chronic kidney disease and concomitant vitamin D deficiency. This process may be mediated through enhanced expression and activity of endothelial nitric oxide synthase.Trial registrationClinical trials.gov NCT00882401.

Staphylococcus aureus is a major mastitis-causing pathogen in dairy cows. The latex agglutination-based Staphaurex test allows bovine S. aureus strains to be grouped into Staphaurex latex agglutination test (SLAT)-negative [SLAT(-)] and SLAT-positive [SLAT(+)] isolates. Virulence and resistance gene profiles within SLAT(-) isolates are highly similar, but differ largely from those of SLAT(+) isolates. Notably, specific genetic changes in important virulence factors were detected in SLAT(-) isolates. Based on the molecular data, it is assumed that SLAT(+) strains are more virulent than SLAT(-) strains. The objective of this study was to investigate if SLAT(-) and SLAT(+) strains can differentially induce an immune response with regard to their adhesive capacity to epithelial cells in the mammary gland and in turn, could play a role in the course of mastitis. Primary bovine mammary epithelial cells (bMEC) were challenged with suspensions of heat inactivated SLAT(+) (n = 3) and SLAT(-) (n = 3) strains isolated from clinical bovine mastitis cases. After 1, 6, and 24 h, cells were harvested and mRNA expression of inflammatory mediators (TNF-α, IL-1β, IL-8, RANTES, SAA, lactoferrin, GM-CSF, COX-2, and TLR-2) was evaluated by reverse transcription and quantitative PCR. Transcription (ΔΔCT) of most measured factors was induced in challenged bMEC for 6 and 24 h. Interestingly, relative mRNA levels were higher (P

Minority enrichment programs play a vitally important role in current efforts to increase the number of health care providers from underrepresented racial and ethnic populations and other disadvantaged groups. However, the existence of minority enrichment programs is challenged by recent changes in the political and economic environment, including the sharp reduction of federal funding support in 2006. This article presents case studies of two longitudinal minority enrichment programs located in Chicago, Illinois: the Urban Health Program (UHP) of the University of Illinois at Chicago, and the Chicago Area Health and Medical Career Program (CAHMCP) at Illinois Institute of Technology. Prior to the cuts in federal funding, in 2005, we conducted in-person interviews with administrative staff of the two programs. The qualitative data were supplemented with follow-up interviews conducted in 2008 with directors of the programs. During the interviews, we discussed how the programs responded to the budget cuts and how the programs viewed their future prospects. The results of the study indicated that adequate funding is crucial for the continued success of these minority enrichment programs in ensuring a viable health professions pipeline.

Objective. Sublingual microcirculatory alterations are associated with an adverse prognosis in several critical illness subgroups. Up to now, single-center studies have reported on sublingual microcirculatory alterations in ICU patient subgroups, but an extensive evaluation of the prevalence of these alterations is lacking. We present the study design of an international multicenter observational study to investigate the prevalence of microcirculatory alterations in critically ill: the Microcirculatory Shock Occurrence in Acutely ill Patients (microSOAP). Methods. 36 ICU’s worldwide have participated in this study aiming for inclusion of over 500 evaluable patients. To enable communication and data collection, a website, an Open Clinica 3.0 database, and image uploading software have been designed. A one-session assessment of the sublingual microcirculation using Sidestream Dark Field imaging and data collection on patient characteristics has been performed in every ICU patient >18 years, regardless of underlying disease. Statistical analysis will provide insight in the prevalence and severity of sublingual alterations, its relation to systemic hemodynamic variables, disease, therapy, and outcome. Conclusion. This study will be the largest microcirculation study ever performed. It is expected that this study will also establish a basis for future studies related to the microcirculation in critically ill.