Quantifying biogenic bias in screening libraries.

In lead discovery, libraries of 10(6) molecules are screened for biological activity. Given the over 10(60) drug-like molecules thought possible, such screens might never succeed. The fact that they do, even occasionally, implies a biased selection of library molecules. We have developed a method to quantify the bias in screening libraries toward biogenic molecules. With this approach, we consider what is missing from screening libraries and how they can be optimized

Ligand-based virtual screening using binary kernel discrimination

This paper discusses the use of a machine-learning technique called binary kernel discrimination (BKD) for virtual screening in drug- and pesticide-discovery programmes. BKD is compared with several other ligand-based tools for virtual screening in databases of 2D structures represented by fragment bit-strings, and is shown to provide an effective, and reasonably efficient, way of prioritising compounds for biological screening

Intraoperative fluid restriction in pancreatic surgery : a double blinded randomised controlled trial

Background : Perioperative fluid restriction in a variety of operations has shown improvement of: complications, recovery of gastrointestinal function and length of stay (LOS). We investigated effects of crystalloid fluid restriction in pancreatic surgery. Our hypothesis: enhanced recovery of gastrointestinal function. Methods : In this double-blinded randomized trial, patients scheduled to undergo pancreatoduodenectomy (PD) were randomized: standard (S: 10ml/kg/hr) or restricted (R:5ml/kg/hr) fluid protocols. Primary endpoint: gastric emptying scintigraphically assessed on postoperative day 7. Results : In 66 randomized patients, complications and 6-year survival were analyzed. 54 patients were analyzed in intention to treat: 24 S-group and 30 R-group. 32 patients actually underwent a PD and 16 patients had a palliative gastrojejunostomy bypass operation in the full protocol analysis. The median gastric emptying time (T1/2) was 104 minutes (S-group, 95% confidence interval: 74-369) versus 159 minutes (R-group, 95% confidence interval: 61-204) (P = 0.893, NS). Delayed gastric emptying occurred in 10 patients in the S-group and in 13 patients in the R-group (45% and 50%, P = 0.779, NS). The primary outcome parameter, gastric emptying time, did not show a statistically significant difference between groups. Conclusion : A fluid regimen of 10ml/kg/hr or 5ml/kg/hr during pancreatic surgery did not lead to statistically significant differences in gastric emptying. A larger study would be needed to draw definite conclusions about fluid restriction in pancreatic surgery

No alignment of cattle along geomagnetic field lines found

This paper presents a study of the body orientation of domestic cattle on free pastures in several European states, based on Google satellite photographs. In sum, 232 herds with 3412 individuals were evaluated. Two independent groups participated in our study and came to the same conclusion that, in contradiction to the recent findings of other researchers, no alignment of the animals and of their herds along geomagnetic field lines could be found. Several possible reasons for this discrepancy should be taken into account: poor quality of Google satellite photographs, difficulties in determining the body axis, selection of herds or animals within herds, lack of blinding in the evaluation, possible subconscious bias, and, most importantly, high sensitivity of the calculated main directions of the Rayleigh vectors to some kind of bias or to some overlooked or ignored confounder. This factor could easily have led to an unsubstantiated positive conclusion about the existence of magnetoreception.Comment: Added electronic supplement with source dat

Multimorbidity in bipolar disorder and under-treatment of cardiovascular disease: a cross sectional study

Background: Individuals with serious mental disorders experience poor physical health, especially increased rates of cardiometabolic morbidity and premature morbidity. Recent evidence suggests that individuals with schizophrenia have numerous comorbid physical conditions which may be under-recorded and under-treated but to date very few studies have explored this issue for bipolar disorder. Methods:We conducted a cross-sectional analysis of a dataset of 1,751,841 registered patients within 314 primary-care practices in Scotland, U.K. Bipolar disorder was identified using Read Codes recorded within electronic medical records. Data on 32 common chronic physical conditions were also assessed. Potential prescribing inequalities were evaluated by analyzing prescribing data for coronary heart disease (CHD) and hypertension. Results: Compared to controls, individuals with bipolar disorder were significantly less likely to have no recorded physical conditions (OR 0.59, 95% CI 0.54-0.63) and significantly more likely to have one physical condition (OR 1.27, 95% CI 1.16-1.39), two physical conditions (OR 1.45, 95% CI 1.30-1.62) and three or more physical conditions (OR 1.44, 95% CI 1.30-1.64). People with bipolar disorder also had higher rates of thyroid disorders, chronic kidney disease, chronic pain, chronic obstructive airways disease and diabetes but, surprisingly, lower recorded rates of hypertension and atrial fibrillation. People with bipolar disorder and comorbid CHD or hypertension were significantly more likely to be prescribed no antihypertensive or cholesterol-lowering medications compared to controls, and bipolar individuals with CHD or hypertension were significantly less likely to be on 2 or more antihypertensive agents. Conclusions: Individuals with bipolar disorder are similar to individuals with schizophrenia in having a wide range of comorbid and multiple physical health conditions. They are also less likely than controls to have a primary-care record of cardiovascular conditions such as hypertension and atrial fibrillation. Those with a recorded diagnosis of CHD or hypertension were less likely to be treated with cardiovascular medications and were treated less intensively. This study highlights the high physical healthcare needs of people with bipolar disorder, and provides evidence for a systematic under-recognition and under-treatment of cardiovascular disease in this group

Pharmacological Treatment of Ambulatory Schizophrenic Patients in Belgium

peer reviewedBACKGROUND: the objective of this study was twofold:1) Describe the use of antipsychotic treatments in ambulatory patients suffering from schizophrenia in Belgium.2) Evaluate to which extend antipsychotic treatment prescribing patterns are in accordance with published treatment guidelines. METHOD: A cross-sectional survey was carried out in 16 Belgian hospitals selected from a sample of 67 hospitals. The hospitals were equally distributed between the north and south part of the country and were representative of Belgian practice. During 2 months, participating psychiatrists were asked to record the medication use as well as demographic parameters of all consecutive ambulatory patients seen at their consultation or attending a day-hospital. Data concerning 1000 ambulatory patients with schizophrenia or schizoaffective disorder were collected. RESULTS: In Belgium, the use of atypical antipsychotics is frequent (69%) in ambulatory patients with schizophrenia. In the overall sample, 73% receive only one antipsychotic drug. The majority of patients are treated with drugs of only one antipsychotic drug group, either first- typical (29.8%) or second-generation, atypical antipsychotics (53.2%). 15.8% of patients combine different types of antipsychotics. Antipsychotic dosing is adequate for the majority of patients but about one fifth receives a higher than recommended dose as per package inserts. Polypharmacy remains within reasonable limits. The use of concomitant medication varies according the antipsychotic treatment: patients who take second-generation antipsychotics only, receive the least additional drugs. CONCLUSION: Atypical antipsychotics appear to be the first line treatment for schizophrenic psychosis. Psychiatrists working with ambulatory patients are well aware of treatment guidelines and follow them quite adequately

Evaluation of a Bayesian inference network for ligand-based virtual screening

Background Bayesian inference networks enable the computation of the probability that an event will occur. They have been used previously to rank textual documents in order of decreasing relevance to a user-defined query. Here, we modify the approach to enable a Bayesian inference network to be used for chemical similarity searching, where a database is ranked in order of decreasing probability of bioactivity. Results Bayesian inference networks were implemented using two different types of network and four different types of belief function. Experiments with the MDDR and WOMBAT databases show that a Bayesian inference network can be used to provide effective ligand-based screening, especially when the active molecules being sought have a high degree of structural homogeneity; in such cases, the network substantially out-performs a conventional, Tanimoto-based similarity searching system. However, the effectiveness of the network is much less when structurally heterogeneous sets of actives are being sought. Conclusion A Bayesian inference network provides an interesting alternative to existing tools for ligand-based virtual screening

Evaluation of machine-learning methods for ligand-based virtual screening

Machine-learning methods can be used for virtual screening by analysing the structural characteristics of molecules of known (in)activity, and we here discuss the use of kernel discrimination and naive Bayesian classifier (NBC) methods for this purpose. We report a kernel method that allows the processing of molecules represented by binary, integer and real-valued descriptors, and show that it is little different in screening performance from a previously described kernel that had been developed specifically for the analysis of binary fingerprint representations of molecular structure. We then evaluate the performance of an NBC when the training-set contains only a very few active molecules. In such cases, a simpler approach based on group fusion would appear to provide superior screening performance, especially when structurally heterogeneous datasets are to be processed