Authors’ ContributionsYang Wang and Chengping Lu designed the stu

Authors’ ContributionsYang Wang and Chengping Lu designed the study. Yang Wang and Li Yi performed most of the experiments, analysed the data, provided figures and tables, and writing the paper. Zhicheng Zhang and Xiangchao Cheng did some experiments and analysed data. Hongjie Fan and Chengping Lu supervised the study and contributed to writing the paper. Both authors read and approved the final paper. Yang Wang and Li Yi contributed equally to this work.AcknowledgmentsThis work was supported by the National Natural Science Foundation of China (31201910), the Science and Technology Research Foundation of Henan Province Educational Committee (13A230261), Foundation for University Key Teacher by the Ministry of Education of Henan Province, State Key Laboratory of Veterinary Etiological Biology, Henan provincial science and technology department (122102310335), Major project of Nanjing Science and Technology Committee (201201026), and the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

The global epidemic of obesity is irrefutably a major public health issue largely because of its comorbidities, namely, cardiovascular disease, type II diabetes, and cancer. Nevertheless, the prevalence of obesity has drastically escalated by nearly 57% over the previous two decades [1, 2]. The National Health and Nutrition Examination Survey (NHANES 2009-2010) reported that 36% of US adults are currently classified as obese (BMI �� 30kg/m2), while 16% represent incidences of severe cases (BMI �� 35kg/m2) [2].

Based on projections derived from previous NHANES data, 86% of U.S adults will be overweight (BMI �� 25kg/m2) or obese (obesity accounting for 51.1%) by 2030 if this epidemiological trend remains unresolved [3�C5]. Over the past two decades, adipose tissue has been established as a multifunctional organ playing a critical role not only in lipid/energy storage but also in endocrine and immune functions [6�C8]. The confirmed presence of secretory molecules derived from adipocytes, such as proinflammatory cytokines (e.g., tumor necrosis factor-alpha [TNF-��] and interleukin-6 [IL-6]), constitutes the unique endocrine function of adipose and provides valuable pathophysiological insight regarding obesity and its comorbidities [7]. During unhealthy weight gain, the influx and storage of excess lipids in adipocytes perturbs normal cell function, which Cilengitide consequently induces the overexpression and hyper-secretion of inflammatory peptides into circulation [9]. As a result, obesity is now recognized as a state of low-grade systemic inflammation characterized by high circulating levels of inflammatory molecules, such as TNF-��, IL-6, and C-reactive protein (CRP) [10, 11].

Central slices of right lung tissue were cut, collected in cryotu

Central slices of right lung tissue were cut, collected in cryotubes, quick-frozen by immersion in liquid nitrogen and stored at -80��C. Total RNA was extracted from Tofacitinib Citrate CP-690550 frozen tissue using the SV Total RNA Isolation System (Promega, Madison, WI, USA), following the manufacturer��s recommendations. RNA concentration was measured by spectrophotometry in a NanoDrop ND-1000 System (NanoDrop Products, Wilmington, DE, USA). First-strand cDNA was synthesized from total RNA using the GoTaq 2-Step RT-qPCR System (Promega). Relative mRNA levels were measured by SYBR Green�Cbased detection using the ABI 7500 Real-Time PCR System (Applied Biosystems, Foster City, CA, USA). Samples were measured in triplicate.

For each sample, the expression of each gene was normalized to housekeeping gene expression (acidic ribosomal phosphoprotein P0, 36B4) using the 2-����Ct method, where ��Ct = Ct (reference gene) – Ct (target gene).Table 1Target gene primersaStatistical analysisData were tested for normal distribution (Kolmogorov-Smirnov test with Lilliefors correction) and homogeneity of variances (Levene median test). If both conditions were met, the effects of different ventilatory strategies on ALI groups were analyzed by means of one-way analysis of variance (ANOVA) followed by Tukey��s test. Otherwise, one-way ANOVA on ranks followed by Dunn��s post hoc test was employed. The significance level was always set at 5%. Parametric data were expressed as means �� SD, and nonparametric data were expressed as medians (IQR). All tests were performed using SigmaStat 3.1 software (Jandel Corp, San Raphael, CA, USA).

ResultsMean arterial pressure was higher than 70 mmHg throughout the experiments in both ALI groups, but was significantly lower during PCV than during BIVENT (Figure 4). In the ALIexp group, animals required additional fluid administration to keep MAP higher than 70 mmHg (P < 0.05).Figure 4Mean arterial pressure of animals with pulmonary and extrapulmonary acute respiratory distress syndrome. ALIexp: extrapulmonary acute lung injury; ALIp: pulmonary acute lung injury; BIVENT: biphasic positive airway pressure; MAP: mean arterial pressure; ...At baseline, the overall respiratory mechanics parameters were comparable among groups, except for PTP, which was lower for BIVENT-100 in the ALIp group (Table 2).

At the end of the experiment, minutes on ventilation, mean Vt and peak airway pressure were comparable in the PCV and BIVENT groups, regardless of ALI etiology. The RR of spontaneous breaths, minutes on ventilation, PTP/min and P0.1 during Plow were significantly increased for BIVENT-50 compared to BIVENT-75 and BIVENT-100. Inspiratory pressure and mean airway pressure were similar in all assisted ventilation modes (Table 3). However, with regard to spontaneous breaths Brefeldin_A during Plow, P0.1 was higher for BIVENT-50 than for BIVENT-75 and BIVENT-100.

Miller and colleagues

Miller and colleagues Ganetespib Sigma [4] found that the overall mortality rate was 22% with the majority of patients dying from MOF. Age was the only significant predictor of mortality. In both these studies, pre-existing conditions were not analyzed. Goins and colleagues [5] reported a mortality rate of 17% for 87 trauma patients spending more than 30 days in the ICU. There was no comparison to a control group.In contrast to the above-mentioned studies, our study was unique in that we analyzed differences in pre-existing conditions and acquired complications. We found that ILOS>30 patients constituted only a small percentage of all trauma admissions to the ICU but consumed a disproportionately large amount of ICU resources. These findings are similar to a prospective study by Martin and colleagues where in a heterogeneous population, prolonged-stay patients represented 5.

6% of ICU admissions and accounted for almost 40% of bed days [6]. Similarly, medical-surgical ICU patients with ICU LOS of more than 30 days accounted for 8% of total ICU admissions but 48% of occupied beds [7] in another study.Not surprisingly, age and injury severity were associated with prolonged ICU stay and mortality, but after multivariate analysis, age was not found to be an independent predictor of prolonged stay, and neither were pre-existing conditions or admission GCS. Instead, sepsis, ARDS and other infectious complications were found to be powerful predictors.That age or pre-existing conditions did not independently predict prolonged stay could simply be attributed to selection bias: older patients and those with significant pre-existing conditions may not have survived to the 30-day mark.

This is suggested by comparing those who died before 30 days to the ILOS>30 patients: patients who died before 30 days of admission were older, and more likely to have a significant head injury, pre-existing cardiac or neurological condition and be on warfarin. Notably, in ILOS<30 non-survivors, 61% were aged 65 years or older versus 39% in the ILOS>30 group.Within the ILOS>30 group, similar to the previous studies on trauma patients, we found that age was still an independent predictor of mortality. In addition, pre-existing renal conditions and the need for renal replacement therapy during the ICU stay also predicted mortality. The high mortality rates associated with dialysis have been reported in other institutions [2,7,8].

The study by Eachempati and colleagues [8] demonstrated a mortality rate of 61% in patients requiring dialysis compared with an overall mortality of 45% for all patients with acute renal failure. Patients who required dialysis in our study had a mortality rate of 33%.The Dacomitinib mortality rate in the ILOS>30 trauma patients (12%) was consistent with the previously published studies on trauma patients.

Camporota and colleagues’ study is interesting and confirms previ

Camporota and colleagues’ study is interesting and confirms previous observations that no additional anticoagulation Kyprolis is necessary during simultaneous DrotAA infusion and CRRT. The only information that should be interpreted with caution is the authors’ finding that no difference in red blood cell requirements was found, either between DrotAA filters and post-DrotAA filters or between medical patients and surgical patients. It should be remembered that, among the 4,459 patients included in the International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy study, the bleeding incidence in surgical patients was about 10 times higher in the DrotAA group than in the placebo group (4.9% vs. 0.5%), and the incidence in medical patients was about 2.

5 times higher than that in surgical patients (2.6% vs. 1%) [29,30].AbbreviationsAKI: acute kidney injury; AKIN: Acute Kidney Injury Network; CRRT: continuous renal replacement therapy; DrotAA: drotrecogin A activated; HIT: heparin-induced thrombocytopenia; ICU: intensive care unit; OR: odds ratio; RIFLE: Risk, Injury, Failure, Loss of kidney function, and End-stage; RRT: renal replacement therapy.Competing interestsThe authors declare that they have no competing interests.
ALI and acute respiratory distress syndrome (ARDS) are major causes of morbidity and mortality, and account for a large proportion of intensive care unit (ICU) bed use. Many pharmacological interventions for these entities have been evaluated, but none has clearly been shown to decrease mortality [1].

To help develop novel treatment strategies for patients with ALI/ARDS, the Irish Critical Care Trials Group conducted a study in a cohort of patients with ALI/ARDS in the Irish adult ICU population [2]. The investigators Drug_discovery described the epidemiology and management of ALI/ARDS in order to identify factors associated with outcome, and to identify whether standardized care is being delivered across participating centres in a research network. There were 1,029 admissions during a 10-week study period in 14 participating centres. A total of 196 (19%) patients had ALI/ARDS; of these 141 (72%) had ALI/ARDS on admission. The most common predisposing risk factors were pneumonia (50%) and extrapulmonary sepsis (26%). Although protective lung ventilation (mean tidal volume 7.0 �� 1.7 ml/kg) was used commonly throughout participating centres, the overall ICU mortality for ALI/ARDS was 32.3%. Lower arterial oxygen tension (PaO2)/fractional inspired oxygen (FiO2) ratios and higher Sequential Organ Failure Assessment scores at admission were associated with increased mortality. These data are helpful in planning future multicentre clinical trials in patients with ALI/ARDS.

Despite advancing technology in surface cooling devices and the i

Despite advancing technology in surface cooling devices and the introduction of endovascular catheters for core cooling, somehow average periods of 2 to 3 hours are still required to reach temperatures of 32��C to 34��C [71]. The currently available surface cooling devices are also relatively large and cumbersome. This coupled with the need for staff with specialist knowledge of the management of induced hypothermia may prevent its use outside of the intensive care unit [71].A recent study examined the feasibility, speed, and complication rates of infusing refrigerated fluids intravenously to quickly induce hypothermia in patients with various neurological injuries [71]. Results showed that a 1,500 mL infusion of 0.9% saline, administered over the course of 30 minutes in patients without cardiogenic shock, reduced core temperature from 36.

9��C �� 1.9��C to 34.6��C �� 1.5��C at 30 minutes and to 32.9��C �� 0.9��C at 60 minutes. Continuous monitoring of arterial blood pressure, heart rhythm, central venous pressure, arterial blood gasses, and serum levels of electrolytes, platelets, and white blood cells showed no significant adverse events [71].When hypothermia develops, the body will immediately try to counteract the temperature drop to maintain homeostasis [72]. One of the key mechanisms of heat production is shivering, which can lead to an increased oxygen consumption of 40% to 100%, which may be detrimental in this patient population. Sedation drugs are known to increase peripheral blood flow and, in turn, increase the transfer of heat from the core to the peripheries, thus reducing core temperature [72].

Therefore, shivering may be counteracted by the administration of sedatives, anaesthetic agents, opiates, and/or paralysing agents [72].It should be noted, however, that the capacity and effectiveness of the mechanisms of controlling body temperature decrease with age. Younger patients will therefore react earlier and with greater intensity than older patients. For this reason, induction of hypothermia in younger patients often requires high doses of sedation drugs to neutralise the counter-regulatory mechanisms [72].Meta-analysesEight meta-analyses have been published between the years 2000 and 2009 [73-80]. These include various numbers of trials, with varying quality of randomisation and blinding procedures.

All have found a trend to positive effects of hypothermia on neurological outcome, although statistical significance was reached in only two reviews: RR of improved neurological outcome of 0.78 (95% CI 0.63 to 0.98) [73] and RR of 0.68 (95% CI 0.52 to 0.89) [74]. Since submission of this manuscript, two Cochrane systematic reviews (issue 1 [79] and updated issue 2 [80] from 2009) have been published (Figure (Figure1).1). The authors found that hypothermia may Anacetrapib be effective in reducing death and unfavourable outcomes, but significant benefit was found only in low-quality trials.

Wavelength selected for simultaneous estimation of two drugs was

Wavelength selected for simultaneous estimation of two drugs was 270 nm. The column was saturated with the selleck screening library mobile phase for about an hour at a flow rate of 1.0 ml/min, monitoring the eluent at 270 nm so as to obtain a steady base line. After the chromatographic conditions were set and the instrument was stabilized to obtain a steady baseline, 20 ��L of standard drug solution each of BH (25 ��g/ ml) and TB (25 ��g/ml) made in the mobile phase were loaded into the injection port of the instrument and injected after filtration through a 0.2 ��m membrane filter. The injection was repeated three times. This was done to check retention times of the individual drugs. The mean retention time for BT and TB were found to be 15.50 min and 9.85 min, respectively [Figure 1].

Figure 1 Chromatogram of BT and TB Standard stock solutions of pure drugs were made separately in the mobile phase containing 100 ��g/ml of BH and TB, filtered through a 0.2 ��m membrane filter. In a 10 ml volumetric flask, 2.5 ml standard stock solution of BH with 2.5 ml standard stock solution of TB was taken and volume made to the mark with the mobile phase. This mixed standard solution was loaded in the injector port of the instrument. The solution was injected and a chromatogram was recorded. This was done to check the resolution of two drugs. The two drugs were found to be perfectly resolved. Calibration curve In a series of a 10 ml volumetric flask, several dilutions of BH (15�C55 ��g/ml) and TB (6�C36 ��g/ml) were prepared in the mobile phase. Each solution was injected and a chromatogram was recorded.

The peak area of a drug was calculated for each concentration level of two drugs and a graph was plotted between drug concentrations against the peak area. The linearity was observed in the concentration range of 15�C55 ��g/ml for BH and 6�C36 ��g/ml for TB. Method validation Linearity A series of standard curves were prepared over a concentration range of 15�C55 ��g/ml for BH and 6�C36 ��g/ml for TB from a stock solution of BH Carfilzomib and TB (100 ��g/ml) in the mobile phase. Dilutions were prepared in the mobile phase, phosphate buffer: acetonitrile (70:30% v/v). The data from peak area vs. drug concentration plots were treated by linear least square regression analysis. The standard curves were evaluated for intra-day and inter-day reproducibility. The experiment was performed in triplicate [Table 1]. Table 1 Validation parameters Accuracy Recovery studies by the standard addition method were performed with a view to justify the accuracy of the proposed method. Previously analyzed samples of BH and TB were spiked with known amounts of BH and TB standard drugs and the mixtures were analyzed by the proposed method. The experiment was performed in triplicate.

The surgery was performed under general anesthesia with a double-

The surgery was performed under general anesthesia with a double-lumen endotracheal tube protocol inserted for ipsilateral lung collapse and single lung ventilation. A close watch on all hemodynamic and respiratory parameters was maintained. The patients were placed in the right/left lateral decubitus position, depending on the radiologic findings (i.e., bulk of abscess and caseating tissue and destruction of body) and the relevant part was draped and prepared for a standard posterolateral thoracotomy (for conversion to standard thoracotomy in circumstance of intraoperative complication or the presence of severe pleural adhesion). With selective collapse of right/left lung, the initial trocar incision (2cm) was made usually at the fifth or sixth intercostal space (ICS) or higher along the anterior axillary line depending upon the site of lesion.

An 11-mm trocar was used to introduce the operating thoracoscope and an exploratory thoracoscopy was performed. The lesion site was identified and displayed on the video monitor. Two other stab incisions, the extended manipulating channels, usually 3-4cm in length, were done 2-3 intercostal spaces above and below the first port, slightly posterior to the posterior axillary line. We encountered difficulty in making portals due to overcrowding of ribs in two patients. Visualization of the spine was enhanced by tilting the patient forward so that the collapsed lung fell anteriorly and, if required, a fan retractor for further retraction of ipsilateral lung was inserted. The correct level of diseased vertebrae was determined by counting the ribs as seen through the endoscope.

Putting a spinal needle from the marker site and visualizing the tip of needle through the thoracoscope further confirmed the correct level. With monopolar electrocautery accompanied by a suction tube the parietal pleura overlying the lesion was divided longitudinally. Dacomitinib The larger intercostal arteries and veins were isolated, ligated, and divided if needed. The biopsy and decompression procedure was then performed with conventional disc roungeurs and elongated bone curettes and was carried out down to the epidural space. Additional procedures like placement of bone graft into the intervertebral space using a conventional bone impactor were done in 3 patients. In 2 patients, conversion to minithoracotomy was undertaken. A larger manipulating channel measuring 5 to 6cm in length was created on the right/left lateral chest after introducing the thoracoscope and a short-segment rib of equal length was removed. The incision was made slightly behind the posterior axillary line at the level of right fifth rib. Then a rib spreader was used to open the intercostal space. Adhesionolysis by blunt dissection using finger was done.

The relationship between NI rates and various extrinsic

The relationship between NI rates and various extrinsic next factors was analyzed using a chi-square test when there was a need to compare proportional data, using a level of 95% confidence interval. 4. Results 4.1. Population Characteristics We collected data of 707 admissions (6561 days of hospitalization) during the study period (Table 1). Fifty-four percent were males with a mean age of 6.9 years (range: 3 months�C15 years; SD = 4 years). The most common neoplastic disease on admission was ALL (59%). Eighty-seven percent of patients had leukopenia, 52.2% had an absolute neutrophil count of less than 500/mm3, and 58.7% had thrombocytopenia. Table 1 Demographic characteristics of study samples. 4.2. Rates of NIs Nosocomial infections were reported among 46 admissions (6.

5/100 admission episodes; 7 episodes/1000 days of hospitalization). There were 13 episodes of urinary tract infections per 1000 days of urinary catheterization, 21 episodes of pneumonia per 1000 days of endotrachial intubation, and no episodes of bacteremia among patients who had central venous catheterization. Episodes of NIs were most frequent among patients with ALL (41.3%), and patients with AML (34.8%). 4.3. Sites of NIs The most common sites of NIs were the blood stream (30.5%) and the ear/nose/throat (19.6%) (Table 2). Table 2 Types of nosocomial infections. 4.4. Causal Organisms of NIs Causal organisms of NIs were identified in 34 episodes (73.9%). The most common were gram-negative bacteria (47.1%), followed by gram-positive bacteria (29.4%), and fungi (14.7%) (Table 3).

Table 3 Causal organisms of nosocomial infections. 4.5. Procedures Related to NIs Patients who developed NIs were more likely to have had endotracheal intubation (mean duration: 10.2 days; range: 1�C15 days), urinary catheterization (mean duration: 5.8 days; range: 1�C10 days), nasogastric tube (mean duration: 4.9 days; range: 1�C17 days), and central venous catheterization (mean duration: 1.7 days; range: 1-2 days) (P < .001) (Table 4). Table 4 Comparison of procedures related to nosocomial infections. 4.6. Outcomes of NIs The mean time from admittance until time of diagnosis of an NI was 22 days (range: 2�C126 days; SD: 23 days). The majority of NIs (74%) occurred between the 2nd and the 30th day of hospitalization. Nine patients died (19.6%): 4 with ALL (44.4%), 4 with AML (44.4%), and 1 with an astrocytoma brain tumor.

Four patients (44.4%) had bacteremia, 3 (33.4%) had soft tissue infections, 1 (11.1%) had pneumonia, and 1 had both bacteremia and pneumonia. Three patients (33.4%) were infected with gram-positive bacteria, 2 (22.2%) with gram-negative bacteria, 2 (22.2%) with Cilengitide fungal organisms, and 1 patient (11.1%) was found to be infected with gram-positive bacteria and a fungal organism. 5. Discussion A total of 707 admission episodes were included in the study. Forty-six episodes of NIs were reported (the incidence of NIs was 6.

This result is consis tent with the immunostaining result of poly

This result is consis tent with the immunostaining result of polytene chromosomes which shows that CP190dBTB still associ ates with polytene chromosomes at many sites. The polytene staining results described above indicate that the CP190dBTB protein does not associate with the Su Mod 67. 2 complex at gypsy, which selleck chem Dovitinib is sup ported by immunoprecipitation assays. We showed pre viously that proteins in the Su complex, such as Su and Mod 67. 2, co precipitated with Cp190. We precipitated the myc CP190dBTB protein with anti MYC from extracts of the y2 w ct6,P, CP1903 TM6B, Tb pupae and detected very weak sig nals of co precipitated Mod 67. 2, in contrast to precipitation of wildtype Cp190. The anti Myc and anti Cp190 immunoprecipitation reactions were specific since neither Cp190 nor Mod 67.

2 were precipitated from the y2 w ct6 pupae with anti Myc or with pre immune serum. The results indicate that association of the myc CP190dBTB with the Mod 67. 2 containing complex is significantly weaker than wild type Cp190. Role of BTB domain in the association of Cp190 with multiple types of Cp190 containing insulator complexes Cp190 associates with diverse insulators including Su, CTCF and BEAF32. To more closely investigate the role of the BTB domain in association between Cp190 and the three types of Cp190 containing insulator complexes, we performed chromatin immuno precipitation assays. We tested Su associated gypsy loci, 1A2 and 62D, CTCF associated Fab 8, CTCF2, CTCF12, CTCF13, BXC100 and BXC114 loci, and BEAF32A or BEAF32B associated scs, BEAF A2, BEAF A3, BEAF AB3, BEAF B12, BEAF B13 and BEAF B16 loci.

We included a site in chromosome locus 1A6 as a negative control. Signals from all loci were normalized to the signal of Fab 8 to reveal the relative strength of association of Cp190 with tested sites in comparison with the association of Cp190 with the Fab 8 region. The results indicate that Cp190 associates with Su complexes at gypsy, 1A2 and 62D, but not with the 1A6 negative control region. Cp190 also associates with CTCF sites at Fab 8, CTCF12, BXC100, BXC114, but not at CTCF2 and CTCF13. Cp190 binds to BEAF32 sites at scs, A2, and B16, but not at A3, AB3, B12, and B13. Association with the tested regions is specific and we did not detect these sites in ChIP sam ples precipitated with pre immune serum. We next determined the binding of the myc CP190dBTB Anacetrapib at the Cp190 positive sites and the negative control 1A6 site. The signal of myc CP190dBTB at Fab 8 is significantly higher than the 1A6 negative control region, suggesting that substantial amounts of the myc CP190dBTB protein lacking the BTB domain still associates with the Fab 8 region.

One frequent theory in personalized therapy is that effective tre

One frequent theory in personalized therapy is that effective treatment results from applying treatment across multiple important biological pathways. These pathways generally consist of sequentially activated gene and pro tein nodes acting as a feedback network. Treatment of individual pathways may not be selleck kinase inhibitor sufficient for majority of diseases, so multiple independent parallel pathways must be targeted to create an effective treatment. We believe that one possible approach to the analysis of multiple pathway treatment is to begin with an underlying frame work based on the Boolean interactions of the multiple targets in the pathway architecture. The approach is based on developing families of Boolean equations that describe the multiple treatment combinations capable of acting as an effective intervention strategy.

For the initial step of developing the underlying Boolean functions, an initial binarization of the data set must be performed. However, the resulting model lends itself to numerous continuous approaches to sensitivity prediction which we will explore further in the paper. Binarization of drug targets and conversion of IC50 s to sensitivities In this subsection, we present algorithms for generation of binarized drug targets and continuous sensitivity score of each drug. The inputs for the algorithms in this subsection are the EC50 s of the drug targets and the IC50 s of the drugs when applied to a tumor culture. In order to perform the binarization, we must con sider the nature of the data we are given.

In particular, we are provided with an IC50 for each drug, and an EC50 value for each kinase target inhibited by the drug. Under the assumption that the primary mechanism of tumor eradication is, in fact, the protein kinase inhibition enacted by these targeted drugs, a GSK-3 natural consequence would be the existence of a relationship between the IC50 and EC50 values. This rela tionship is explained as such, suppose for a drug Si the IC50 value of Si and the EC50 of kinase target kj, are of similar value, then it can be reasonably assumed that kinase target kj is possibly a primary mechanism in the effectiveness of the drug. In other words, if 50% inhibition of a kinase target directly correlates with 50% of the tumor cells losing viability, then inhibition of the kinase target is most likely one of the causes of cell death. Hence, the tar get that matches the drug IC50 is binarized as a target hit for the drug. The above assumption of direct correlation for all successful drugs is obviously an extremely restrictive assumption and will be unable to produce high accu racy predictions.