The novel Mechanical Ventilator Milano for the COVID-19 pandemic.

This paper presents the Mechanical Ventilator Milano (MVM), a novel intensive therapy mechanical ventilator designed for rapid, large-scale, low-cost production for the COVID-19 pandemic. Free of moving mechanical parts and requiring only a source of compressed oxygen and medical air to operate, the MVM is designed to support the long-term invasive ventilation often required for COVID-19 patients and operates in pressure-regulated ventilation modes, which minimize the risk of furthering lung trauma. The MVM was extensively tested against ISO standards in the laboratory using a breathing simulator, with good agreement between input and measured breathing parameters and performing correctly in response to fault conditions and stability tests. The MVM has obtained Emergency Use Authorization by U.S. Food and Drug Administration (FDA) for use in healthcare settings during the COVID-19 pandemic and Health Canada Medical Device Authorization for Importation or Sale, under Interim Order for Use in Relation to COVID-19. Following these certifications, mass production is ongoing and distribution is under way in several countries. The MVM was designed, tested, prepared for certification, and mass produced in the space of a few months by a unique collaboration of respiratory healthcare professionals and experimental physicists, working with industrial partners, and is an excellent ventilator candidate for this pandemic anywhere in the world.

Preoperative methylprednisolone increases plasma Pentraxin 3 early after total knee arthroplasty: a randomized, double-blind, placebo-controlled trial.

Preoperative glucocorticoid administration reduces the systemic inflammatory response. Pentraxin 3 (PTX3) is a novel inflammatory marker belonging to the humoral arm of innate immunity exerting a potentially protective host response. This study evaluated PTX3 and other complement marker changes after preoperative methylprednisolone (MP) early after total knee arthroplasty (TKA). Seventy patients were randomized (1 : 1) to preoperative intravenous (i.v.) MP 125 mg (group MP) or isotonic saline i.v. (group C). The outcomes included change in plasma PTX3, mannose-binding lectin (MBL), ficolins (ficolin-1, -2 and -3), complement components (C4 and C3), terminal complement complex (TCC) and C-reactive protein (CRP) concentrations. Blood samples were analysed at baseline and 2, 6, 24 and 48 h after surgery with complete sampling from 63 patients for analyses. MP resulted in an increase in circulating PTX3 compared to saline from baseline to 24 h postoperatively (P < 0·001), while MP reduced the systemic inflammatory response (CRP) 24 and 48 h postoperatively (P < 0·001). However, the small postoperative changes in MBL, ficolin-1, -2 and -3, C4, C3 and TCC concentrations did not differ between groups (P > 0·05). In conclusion, preoperative MP 125 mg increased circulating PTX3 and reduced the general inflammatory response (CRP) early after TKA, but did not affect other complement markers.

Impaired beta cell sensitivity to incretins in type 2 diabetes is insufficiently compensated by higher incretin response.

BACKGROUND AND AIMS: The incretin effect is impaired in type 2 diabetes (T2D), but the underlying mechanisms are only partially understood. We investigated the relationships between the time course of the incretin effect and that of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during oral glucose tolerance tests (OGTTs), thereby estimating incretin sensitivity of the beta cell, and its associated factors. METHODS AND RESULTS: Eight patients with T2D and eight matched subjects with normal glucose tolerance (NGT) received 25, 75, and 125 g OGTTs and corresponding isoglycemic glucose infusions (IIGI). The time course of the incretin effect, representing potentiation of insulin secretion by incretins (PINCR), was determined by mathematical modelling as the time-dependent fold increase in insulin secretion during OGTT compared to IIGI. The time course of PINCR was correlated with that of both GIP and GLP-1 in each subject (median r = 0.67 in NGT and 0.45 in T2D). We calculated an individual beta cell sensitivity to incretins (SINCR) using a weighted average of GIP and GLP-1 (pooled incretin concentration, PIC), as the slope of the relationship between PINCR and PIC. SINCR was reduced in T2D (p < 0.01). In the whole group, mean PIC, GIP and GLP-1 concentrations during the OGTT were inversely correlated with SINCR, but T2D had lower PIC, GIP and GLP-1 levels at the same SINCR (p < 0.05). CONCLUSION: Relative incretin insensitivity is partly compensated for by higher incretin secretory responses. However, T2D shows both impairment in incretin sensitivity and abnormal compensation by incretin secretion.

Mechanism-Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake.

Bile acids released postprandially modify the rate and extent of absorption of lipophilic compounds. The present study aimed to predict gastric emptying (GE) rate and gallbladder emptying (GBE) patterns in response to caloric intake. A mechanism-based model for GE, cholecystokinin plasma concentrations, and GBE was developed on data from 33 patients with type 2 diabetes and 33 matched nondiabetic individuals who were administered various test drinks. A feedback action of the caloric content entering the proximal small intestine was identified for the rate of GE. The cholecystokinin concentrations were not predictive of GBE, and an alternative model linking the nutrients amount in the upper intestine to GBE was preferred. Relative to fats, the potency on GBE was 68% for proteins and 2.3% for carbohydrates. The model predictions were robust across a broad range of nutritional content and may potentially be used to predict postprandial changes in drug absorption.

Physics at the [Formula: see text] linear collider.

A comprehensive review of physics at an [Formula: see text] linear collider in the energy range of [Formula: see text] GeV-3 TeV is presented in view of recent and expected LHC results, experiments from low-energy as well as astroparticle physics. The report focusses in particular on Higgs-boson, top-quark and electroweak precision physics, but also discusses several models of beyond the standard model physics such as supersymmetry, little Higgs models and extra gauge bosons. The connection to cosmology has been analysed as well.

Reduced postprandial GLP-1 responses in women with gestational diabetes mellitus.

AIM: We investigated postprandial glucagon-like peptide-1 (GLP-1) responses in pregnant women with and without gestational diabetes mellitus (GDM) and again following delivery when normal glucose tolerance (NGT) was re-established. METHODS: Eleven women with GDM [plasma glucose (PG) concentration at 120 min after a 75-g oral glucose tolerance test (OGTT): 10.0 ± 0.9 mM (mean ± SD); age: 31 ± 6 years; body mass index (BMI): 31.6 ± 6.4 kg/m(2) ; haemoglobin A1c (HbA1c): 5.6 ± 0.5%] and eight pregnant women with NGT (PG(120 min), OGTT : 5.7 ± 0.7 mM; age: 28 ± 3 years; BMI: 29.7 ± 5.4 kg/m(2) ; HbA1c: 5.4 ± 0.3%) were investigated with a 4-h liquid meal test during third trimester (TT) and 3-4 months postpartum (PP). All patients with GDM re-established NGT following delivery. RESULTS: Pregnancy was associated with low postprandial GLP-1 responses. Patients with GDM exhibited reduced postprandial GLP-1 responses compared to their PP levels [area under curve (AUC): 5.5 ± 1.3 vs. 8.4 ± 3.2 nM × min, p=0.005], but the difference among NGT women (7.3 ± 2.8 vs. 8.8 ± 2.0 nM × min, p=0.066) was not statistically significant. Pregnancy did not influence postprandial responses of the other incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in any of the groups, but GDM patients were characterized by greater postprandial GIP responses during both TT and PP compared to NGT subjects. CONCLUSIONS: Pregnancy is associated with reduced postprandial GLP-1 responses (most pronounced in patients with GDM) that normalize after delivery. In contrast, postprandial GIP responses seem unaffected by pregnancy but is increased in GDM patients.

Effect of breeding strategy and feeding system on the within-herd variation of lean meat percents in Danish slaughter pigs.

In several countries slaughter pigs are paid for individually, according to slaughter weight and lean meat percent (LMP). Production of uniform batches of pigs within the optimal weight and LMP limits will obtain the best price. Therefore, all pigs should have a similar growth rate (average daily gain, ADG) and reach an appropriate slaughter weight within the same time period. LMP may serve as a proxy for ADG since pigs with low LMP have significantly higher ADG than pigs with high LMP and vice versa. Both breeding strategy and feeding system may influence the range of variation among pigs. The aim of this study was to test the two following hypotheses: (1) Herds purchasing breeding gilts have a higher mean value and a lower variation (standard deviation) in LMP than herds producing their own breeding gilts and (2) Herds using restricted feeding of finishers have a higher mean value and a lower variation (standard deviation) in LMP than herds with ad libitum feeding of finishers. The study included 72 herds and a total of 345,132 pigs slaughtered during one year. Among the 72 herds, 40 were home-breeders and 32 purchased breeding gilts from a breeding company. Nineteen herds used restricted feeding, of which 8 (42%) were home-breeders. Fifty-three herds used ad libitum feeding, of which 32 (60%) were home-breeders. Breeding strategy had a significant effect on SDLMP (p=0.003), where purchase of breeding gilts resulted in a significantly lower standard deviation of the monthly LMP compared to home-bred gilts (a difference in median SDLMP of 0.2 percentage points or 8% difference between groups). Feeding system had a significant effect on the meanLMP (p<0.001), with a significantly higher meanLMP in herds using restrictive feeding compared to ad libitum feeding (60.7% versus 60.0%). Restrictive feeding also resulted in a significantly lower SDLMP (p<0.001) compared to ad libitum feeding (2.2% versus 2.5% or a 12% difference between groups).

Glucagon antagonism as a potential therapeutic target in type 2 diabetes.

Glucagon is a hormone secreted from the alpha cells of the pancreatic islets. Through its effect on hepatic glucose production (HGP), glucagon plays a central role in the regulation of glucose homeostasis. In patients with type 2 diabetes mellitus (T2DM), abnormal regulation of glucagon secretion has been implicated in the development of fasting and postprandial hyperglycaemia. Therefore, new therapeutic agents based on antagonizing glucagon action, and hence blockade of glucagon-induced HGP, could be effective in lowering both fasting and postprandial hyperglycaemia in patients with T2DM. This review focuses on the mechanism of action, safety and efficacy of glucagon antagonists in the treatment of T2DM and discusses the challenges associated with this new potential antidiabetic treatment modality.

Association between lean meat percentage and average daily weight gain in Danish slaughter pigs.

Danish pigs that are within optimal weight limits and have a high lean meat percentage (LMP) obtain the best prices at slaughter. Another reason to consider the variation in LMP is the assumed association between LMP and average daily weight gain (ADG) at the individual level. The aim of this study was to test whether high ADG was associated with low LMP and vice versa. A cohort of 99 pigs from a conventional Danish herd was followed from 30kg to slaughter. The data included days in the herd, start- and end-weights, calculated ADG and LMP, reported from the abattoir. The study also included existing data from 13,057 boars from a Danish boar test station. The results of the study demonstrated a significant negative association between LMP and ADG: Pearson's correlation coefficient (r)=-0.42 (95% CI: -0.57; -0.24) (p<0.0001) for the cohort and r=-0.42 (95% CI: -0.48; -0.36) (p<0.0001) for the boars.

Reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high-calorie diet impairs the incretin effect in healthy subjects.

AIMS/HYPOTHESIS: The loss of incretin effect in patients with type 2 diabetes mellitus may be secondary to impaired glucose homeostasis. We investigated whether reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high-calorie diet in healthy young males would impair the incretin effect. METHODS: The incretin effect was measured using 75 g oral glucose tolerance test (OGTT) and isoglycemic iv glucose infusion (IIGI) in 10 healthy Caucasian normal glucose-tolerant male subjects without any family history of diabetes [age 24 + or - 3 yr (mean + or - sd); body mass index 23 + or - 2 kg/m(2); glycosylated hemoglobin 5.4 + or - 0.1%] before and at the end of a 12-d period with oral administration of prednisolone (37.5 mg once daily), high-calorie diet, and relative physical inactivity. RESULTS: The 12-d intervention period resulted in significant increases in body weight [79 + or - 5 vs. 80 + or - 6 kg (mean + or - sd), P = 0.03] and fasting plasma glucose (5.1 + or - 0.1 vs. 5.6 + or - 0.2 mm, P = 0.016), whereas insulin sensitivity (Matsuda index 17.6 + or - 1.7 vs. 9.2 + or - 1.0, P = 0.0001) decreased. Glucose tolerance [as assessed by the 120-min plasma glucose value after OGTT (4.9 + or - 1.1 vs. 7.8 + or - 2.5 mm, P < 0.0001) and area under curve (AUC) (152 + or - 45 vs. 384 + or - 53 mm.4 h, P = 0.002)] during the OGTT deteriorated. Also, the incretin effect [incretin effect (percent) = 100% x (AUC(insulin,OGTT) - AUC(insulin,IIGI))/AUC(insulin,OGTT))] deteriorated (72 + or - 5 vs. 43 + or - 7%, P = 0.002). An increase in glucose-dependent insulinotropic polypeptide response during OGTT, but no significant changes in glucagon-like peptide-1 or glucagon responses, was observed after glucose homeostatic dysregulation. CONCLUSIONS/INTERPRETATION: Impairment of the incretin effect can be elicited by a short period of reduced glucose tolerance and insulin resistance in healthy male subjects not disposed for type 2 diabetes.

Influence of socioeconomic status on survival after primary aortic or mitral valve replacement.

OBJECTIVES: We sought to evaluate whether socioeconomic status influences outcome after first-time single aortic or mitral valve replacement. SETTING: National Heart Valve registry. DESIGN AND PATIENTS: Between 1 January 1986 and 31 December 2001, 51 844 consecutive patients who underwent primary aortic or mitral valve replacement were registered on the United Kingdom (UK) Heart Valve Registry. Data included age, gender, valve position, type of valve implant, postcode, follow-up time, date and cause of death. The Carstairs deprivation score (1991 Census data for the UK) was used to stratify cases by level of social deprivation according to postcodes. RESULTS: Both 30-day and 1-year survival/mortality rates were similar across all socioeconomic levels. However, long-term survival rate (up to 15 years) was significantly higher in the least deprived socioeconomic level than in the two most deprived levels. There was an 18% lower survival rate amongst women in the most deprived levels (35.9%, 95% CI: 32.4 to 39.4) versus the least deprived level (43.7%, 95% CI: 38.1 to 49.2, p<0.004). In men, survival in the most deprived levels (39.5%, 95% CI: 36.4 to 42.5) was 7% lower than in the least deprived level (42.7%, 95% CI: 37.7 to 47.7, p<0.005). Biological valve, mitral position, female gender, and low socioeconomic status were all associated with long-term mortality. CONCLUSIONS: A disadvantaged social background has a negative influence on long-term survival after aortic or mitral valve replacement, especially among women.

Survival of Escherichia coli and Salmonella Typhimurium in slurry applied to clay soil on a Danish swine farm.

A pilot study was carried out on a Danish swine farm infected with multi-resistant Salmonella Typhimurium DT104 (MRDT104). We aimed to (1) investigate to which degree the decline of Escherichia coli and Salmonella in swine slurry applied to farmland depended on the application method; (2) estimate the survival times of E. coli and Salmonella in the soil surface following deposition of naturally contaminated pig slurry; and (3) simulate survival of Salmonella in different infection levels using E. coli data as input estimates. Slurry was deposited by four different methods: (1) hose applicator on black soil followed by ploughing and harrowing; (2) hose applicator on black soil followed only by harrowing; (3) hose applicator on a field with winter-wheat seedlings without further soil treatment; (4) slurry injector on a field with winter-wheat seedlings without further soil treatment. E. coli and Salmonella could not be detected at all in soil following treatment 1. Following the other treatments, E. coli was not detected in soil samples after day 21 and Salmonella was no longer detected after day 7. Simulation results showed that clinical (4 log CFU g(-1)) and sub-clinical Salmonella levels (2500 CFU g(-1)) would fall below the detection limit within 10 or 5 days, respectively. Analysis of samples from 62 Danish MRDT104-infected swineherds showed that nearly 75% of these herds had low levels of MRDT104 (< 10 CFU g(-1)) in their slurry. Our results show that ploughing and harrowing of soil amended with contaminated pig slurry was an effective means to reduce environmental exposure to E. coli and Salmonella on this clay-soil farm.

The Coronary Artery Revascularisation in Diabetes (CARDia) trial: background, aims, and design.

BACKGROUND: Patients with diabetes have an increased incidence and severity of ischemic heart disease, which leads to an increased requirement for coronary revascularization. Comparative information regarding mode of revascularization--coronary artery bypass graft surgery surgery (CABG) or percutaneous coronary intervention (PCI)--is limited, mainly confined to a subanalysis of the Bypass Angioplasty Revascularization (BARI) trial, suggesting a mortality benefit of CABG over PCI. No prospective trial has specifically compared these modes of revascularization in patients with diabetes. OBJECTIVE: The Coronary Artery Revascularisation in Diabetes (CARDia) trial is designed to address the hypothesis that optimal PCI is not inferior to modern CABG as a revascularization strategy for diabetics with multivessel or complex single-vessel coronary disease. The primary end point is a composite of death, nonfatal myocardial infarction, and cerebrovascular accident at 1 year. METHOD: A total of 600 patients with diabetes are to be randomized to either PCI or CABG, with few protocol restrictions on operative techniques or use of new technology. This gives a power of 80% to detect non-inferiority of PCI assuming that the PCI 1-year event rate is 9%. A cardiac surgeon and a cardiologist must agree that a patient is suitable for revascularization by either technique prior to recruitment into the study. Twenty-one centers in the United Kingdom and Ireland are recruiting patients. Data on cost effectiveness, quality of life, and neurocognitive function are being collected. Long-term (3-5 year) follow-up data will also be collected.

A prospective study of long term prognosis in young myocardial infarction survivors: the prognostic value of angiography and exercise testing.

OBJECTIVES: To define the ability of early exercise testing and coronary angiography to predict prognosis in young survivors of myocardial infarction (MI). METHODS: 255 consecutive patients (210 men) aged 55 years or less (mean 48 years) admitted to hospital (1981-85) were eligible. Of these, 150 patients (130 men) who were able to exercise early after MI and underwent coronary angiography within six months constituted the study group and were followed up for up to 15 years. Survival data up to 18 years was obtained for the whole cohort. RESULTS: Survival at a median of 16 years was 52% for the whole cohort, 62% for the study group, and 48% for the excluded group. From nine years onwards survival deteriorated significantly in the study group compared with an age matched background population. Fifteen years after MI, 121 patients (81%) in the study group had had at least one event (death, MI, revascularisation, cardiac readmission, stroke) leaving 29 (19%) event-free. The number of diseased vessels was the major determinant of time to first event (p = 0.001) and event-free survival (p = 0.04). Exercise duration was also important in the prediction of time to first event (p = 0.003). Death was influenced by a history of prior MI. CONCLUSION: The favourable initial survival was followed by significant deterioration after nine years. This late attrition is an important treatment target. Furthermore, this study supports risk stratification early after MI combining angiography with non-invasive tools.

Improved interobserver variation after training of doctors in the Neer system. A randomised trial.

We investigated whether training doctors to classify proximal fractures of the humerus according to the Neer system could improve interobserver agreement. Fourteen doctors were randomised to two training sessions, or to no training, and asked to categorise 42 unselected pairs of plain radiographs of fractures of the proximal humerus according to the Neer system. The mean kappa difference between the training and control groups was 0.30 (95% CI 0.10 to 0.50, p = 0.006). In the training group the mean kappa value for interobserver variation improved from 0.27 (95% CI 0.24 to 0.31) to 0.62 (95% CI 0.57 to 0.67). The improvement was particularly notable for specialists in whom kappa increased from 0.30 (95% CI 0.23 to 0.37) to 0.79 (95% CI 0.70 to 0.88). These results suggest that formal training in the Neer system is a prerequisite for its use in clinical practice and research.

Low agreement among 24 doctors using the Neer-classification; only moderate agreement on displacement, even between specialists.

Twenty-four orthopaedic surgeons classified 42 pairs of radiographs according to the Neer system for proximal humeral fractures. Mean kappa value for inter-observer agreement was 0.27 (95% CI 0.26-0.28) with no clinically significant difference between orthopaedic residents ( n=9), fellows ( n=6) and specialists ( n=9). Mean kappa for agreement of displacement versus non-displacement was 0.41 (95% CI 0.39-0.43) overall, and 0.50 (95% CI 0.45-0.56) within the specialist group. The agreement found in our study is unsatisfactory from a clinical perspective.

A new Salmonella surveillance and control programme in Danish pig herds and slaughterhouses.

The Danish Salmonella Surveillance and Control Programme for pigs operates at all stages of the production chain and has been applied nationally since 1995. Due to the program the level of Salmonella in Danish pork has declined from 3.5% in 1993 to 0.7% in the year 2000. Simultaneously, the number of human cases with salmonellosis due to pork has declined from approximately 1,144 in 1993 to 166 in 2000. In year 2001, the programme has been improved at a number of stages. A new classification scheme for the serological surveillance of finisher herds has been developed. The individual test cut-off in the mix-ELISA has been reduced to 20 OD%. Only herds producing more than 200 finishers/year are sampled. Based on the serological result from the last 3 months a new weighted salmonella index is calculated: The Danish Bacon and Meat Council has agreed on a new stricter penalty system. Level 2 and 3 herds get a penalty of 2% and 4% of the value per slaughter carcass, respectively. A new method of Salmonella testing on carcasses has been introduced; 5 carcasses per slaughter day are swabbed at 3 defined areas at 100 cm2 for each sample. This method is more sensitive than the one used previously. Herds infected with multiresistant Salmonella Typhimurium DT104 have to follow special restrictions. These include a requirement for a herd intervention plan, restriction on livestock trade, and a requirement for special slurry handling. Carcasses from DT 104 herds must be heat-treated or decontaminated with hot water.

Admission plasma glucose: an independent risk factor in nondiabetic women after coronary artery bypass grafting.

OBJECTIVE: To investigate the relationship between admission plasma glucose and 30-day mortality after primary isolated coronary artery bypass grafting (CABG) in nondiabetic patients. RESEARCH DESIGN AND METHODS: All nondiabetic patients with admission plasma glucose measurement undergoing primary isolated CABG from 1993 to 1997 were included in this study. RESULTS: In 878 consecutive patients (155 women), overall mortality was 3.4% (95% CI 2.3-4.8). The mortality rate in women (n = 11; 7.1%, 3.6-12.3) was higher than in men (n = 19; 2.6%, 1.6-4.1) (P = 0.01). There was a positive correlation between plasma glucose and 30-day mortality among women only (P = 0.0001). There was a higher mortality rate in the upper two glucose quartiles (11.7%, 5.5-21.0) compared with the lower two quartiles (2.6%, 3.0-8.9) in the female patients (P = 0.03); a plasma glucose of 6.0 mmol/l separated high- and low-mortality groups. Furthermore, women in the upper two glucose quartiles had a fourfold higher mortality rate than men in the similar quartiles (P = 0.002). Among men, there was no difference in mortality rate across glucose quartiles. In a multivariate analysis, admission plasma glucose, history of thyroid disease, left ventricular ejection fraction <0.35, operation bypass time, and perioperative myocardial infarction were independently associated with mortality. CONCLUSIONS: Women with admission plasma glucose < or =6.0 mmol/l and men across the whole range of glucose values had similar mortality rates after CABG. The surplus female mortality was found only in subjects with plasma glucose >6 mmol/l. Further studies are needed to appraise the possible influence of glucose status on outcome from CABG in nondiabetic subjects.