Safety and efficacy of liraglutide in patients with type 2 diabetes with elevated liver enzymes: individual patient data meta-analysis of the LEAD programme

BackgroundFatty liver disease has reached epidemic proportions in type 2 diabetes. Glucagon-like peptide-1 (GLP-1) analogues are licensed for treatment of type 2 diabetes, yet little data exist on efficacy and safety in liver injury. We aimed to assess the safety and efficacy of 26 weeks' liraglutide on liver function compared with an active placebo.MethodsIndividual patient data meta-analysis was done with patient level data combined from six 26-week, phase 3, double-blind randomised controlled trials on type 2 diabetes, which comprise the Liraglutide Effect and Action in Diabetes (LEAD) programme. In addition, the LEAD-2 sub-study was analysed to assess the effect on CT-measured hepatic steatosis.FindingsOf 4442 patients analysed, 2241 (50·8%) had an abnormal alanine aminotransferase (ALT) at baseline (mean 33·8 IU/L [SD 14·9] in female participants; 47·3 [18·3] in male participants). Liraglutide 1·8 mg reduced ALT in these patients compared with placebo (?8·20 vs ?5·01 IU/L, p=0·003), and was dose dependent (no significant differences vs placebo with liraglutide 0·6 or 1·2 mg). This effect was lost after adjustment for liraglutide's effect on reduction of weight (corrected mean ALT difference vs placebo ?1·41 IU/L, p=0·21) and HbA1c (corrected mean ALT difference vs placebo 0·57 IU/L, p=0·63). Adverse effects with 1·8 mg liraglutide were similar between patients with and without baseline abnormal ALT. In the LEAD-2 sub-study, liraglutide 1·8 mg (26 weeks) improved hepatic steatosis (CT-measured liver:spleen attenuation ratio) from baseline (0·10, p=0·001) and showed a trend towards improvement compared with placebo (0.10 vs 0·00, p=0·07).Interpretation26 weeks of liraglutide (1·8 mg) is safe, well tolerated, and improves liver enzymes compared with placebo in patients with type 2 diabetes.FundingWellcome Trust.     

Duration and predictors of emergency surgical operations - basis for medical management of mass casualty incidents

Background

Hospitals have a critically important role in the management of mass causality incidents (MCI), yet there is little information to assist emergency planners. A significantly limiting factor of a hospital''s capability to treat those affected is its surgical capacity. We therefore intended to provide data about the duration and predictors of life saving operations.

Methods

The data of 20,815 predominantly blunt trauma patients recorded in the Trauma Registry of the German-Trauma-Society was retrospectively analyzed to calculate the duration of life-saving operations as well as their predictors. Inclusion criteria were an ISS ≥ 16 and the performance of relevant ICPM-coded procedures within 6 h of admission.

Results

From 1,228 patients fulfilling the inclusion criteria 1,793 operations could be identified as life-saving operations. Acute injuries to the abdomen accounted for 54.1% followed by head injuries (26.3%), pelvic injuries (11.5%), thoracic injuries (5.0%) and major amputations (3.1%). The mean cut to suture time was 130 min (IQR 65-165 min). Logistic regression revealed 8 variables associated with an emergency operation: AIS of abdomen ≥ 3 (OR 4,00), ISS ≥ 35 (OR 2,94), hemoglobin level ≤ 8 mg/dL (OR 1,40), pulse rate on hospital admission < 40 or > 120/min (OR 1,39), blood pressure on hospital admission < 90 mmHg (OR 1,35), prehospital infusion volume ≥ 2000 ml (OR 1,34), GCS ≤ 8 (OR 1,32) and anisocoria (OR 1,28) on-scene.

Conclusions

The mean operation time of 130 min calculated for emergency life-saving surgical operations provides a realistic guideline for the prospective treatment capacity which can be estimated and projected into an actual incident admission capacity. Knowledge of predictive factors for life-saving emergency operations helps to identify those patients that need most urgent operative treatment in case of blunt MCI.     

The Human Phenotype Ontology

Robinson PN, Mundlos S. The Human Phenotype Ontology. A standardized, controlled vocabulary allows phenotypic information to be described in an unambiguous fashion in medical publications and databases. The Human Phenotype Ontology (HPO) is being developed in an effort to provide such a vocabulary. The use of an ontology to capture phenotypic information allows the use of computational algorithms that exploit semantic similarity between related phenotypic abnormalities to define phenotypic similarity metrics, which can be used to perform database searches for clinical diagnostics or as a basis for incorporating the human phenome into large‐scale computational analysis of gene expression patterns and other cellular phenomena associated with human disease. The HPO is freely available at http://www.human‐phenotype‐ontology.org .     

Solitary pulmonary metastasis from intracranial meningiothelial meningioma

Although known, histologically proven pulmonary metastasis from a benign intracranial meningioma is exceedingly rare. We report a case of meningiothelial meningioma producing a solitary pulmonary deposit.     

Fetal iron status in maternal anemia

Hemoglobin, serum iron, transferrin saturation and ferritin were measured on paired maternal and cord blood samples in 54 anemic (hemoglobin < 110 g/L) and 22 non-anemic (hemoglobin ≥ 110 g/L) pregnant women at term gestation. The levels of hemoglobin, serum iron, transferrin saturation and ferritin were significantly low in the cord blood of anemic women, suggesting that iron supply to the fetus was reduced in maternal anemia. The linear relationships of these parameters with both maternal hemoglobin and maternal serum ferritin indicated that the fetus extracted iron in amounts proportional to the levels available in the mother. Infants of mothers with moderate and severe anemia had significantly lower cord serum ferritin levels and hence poor iron stores at birth. It is concluded that iron deficiency anemia during pregnancy adversely affects the iron endowment of the infant at birth.     

棉酚对体外家兔精子顶体酶类的抑制作用

本文对棉酚体外抑制１０种家兔精子顶体酶活性进行了测定。当醋酸棉酚浓度为１２～７６μｍｏｌ／Ｌ时，可完全或明显抑制顶体酶（ａｃｒｏｓｉｎ）、Ａｚｏｃｏｌｌ蛋白酶、芳香基硫酸酯酶和神经氨酸苷酶活性；而当浓度高达３８０μｍｏｌ／Ｌ时才能抑制透明质酸酶、β－葡糖苷酸酶和酸性磷酸酶，但不抑制磷酸酯酶Ｃ、碱性磷酸；酶和β－Ｎ－乙酰氨基葡糖苷酶。棉酚对芳香基硫酸酯酶的抑制作用是一种非竞争性抑制作用，Ｋｉ为１２０μｍｏｌ／Ｌ。其抑制作用是可逆的，呈剂量依赖关系。由于抑制家兔精子顶体酶所需棉酚浓度比精子糖酵解或能量代谢酶要低，因此，这些敏感酶似可作为监护棉酚引起不育的指标。     

Does intramuscular vitamin K1 act as an unintended depot preparation?

Objective : To propose a hypothesis that the long duration of effect of intramuscular (i.m.) vitamin K₁ in preventing late onset haemorrhagic disease results from a depot effect after i.m. injection.
Methodology : Review of scientific literature relating to the pharmacology of vitamin K, and the aetiology of late onset haemorrhagic disease.
Results : A single i.m. dose of vitamin K₁ is effective for at least 2 months, whereas the duration of effect of a single oral dose is about 3-4 weeks. The known pharmacological properties of vitamin K₁ are seemingly at variance with the long duration of effect of an i.m. dose. Menaquinones (vitamins K₂) are absent in the newborn liver, but gradually accumulate after birth. This, together with the low concentrations of vitamin K₁ in human breast milk, may explain the peak frequency of late onset haemorrhagic disease at 4-8 weeks. We hypothesize that after i.m. injection, vitamin K₁ acts as a depot preparation by forming a viscous mass in muscle tissue which is slowly absorbed over many weeks. This hypothesis is supported by reports indicating significantly higher plasma vitamin K₁ levels several weeks after i.m., as compared to oral vitamin K₁.
Conclusions : The prolonged efficacy of i.m. vitamin K₁, compared to oral preparations may be due to a depot effect New oral preparations of vitamin K₁, despite greatly improved bioavailability, may have a shorter duration of effect than i.m. vitamin K₁, and therefore be less effective for long-term prophylaxis.     

Routine microbiological testing in sudden and unexpected infant death

Objective : To evaluate the significance of microbiological test results in a series of infants who had died suddenly and unexpectedly.
Methodology : Following a review of all cases of sudden natural death in infants presenting to the Adelaide Children's Hospital (ACH) division of the Women's and Children's Hospital (WCH) over the 10 year period between 1983 and 1992, specific evaluation of microbiological test results was undertaken.
Results : There were 329 cases of sudden infant death syndrome (SIDS) and 23 cases in which sudden infant death was either attributed to other conditions or was unclassifiable. Positive microbiological results were recorded in the majority of cases, most being considered to be due to postmortem overgrowth or to contamination at autopsy. Of the remaining cases, microbiological results were essential to the establishment of the diagnosis in three cases, and were a useful adjunct to the diagnosis in a further six cases.
Conclusions : Routine microbiological testing in cases presenting as SIDS did not reveal occult sepsis in most instances. Such testing did, however, add support to the diagnosis of SIDS where no pathogens were isolated and, if not undertaken, would have resulted in a small percentage of cases of sudden infant death due to infections remaining undiagnosed.