Vero cells obtained from WHO (10-87) originally derived Raf inhibitor from ATCC (CCL-81) were used as host for poliovirus production. Poliovirus seeds [1] Sabin type 1 (LSc 2ab KP2; SO + 3), Sabin type 2 (P712 Ch2ab-KP2; SO + 3) and Sabin type 3 (Lot 457-III-Pfizer; RSO3) were used. Vero cells were cultured in

T-flasks and Hyperflasks (Corning) in VP-SFM (Libraries Invitrogen) to expand the cell number. After trypisinization (TrypLE Select; Invitrogen) cells were resuspended in VP-SFM and added to the bioreactor. Different cultivation methods have been applied where Vero cells were grown adherent to microcarriers (3 g L−1 Cytodex 1; GE Healthcare). The cultures were maintained

at pH 7.2, 37 °C, 50% dissolved oxygen (DO) by headspace aeration only (1 L min−1) and sampled at least once a day. Cell cultures were carried out in standard glass stirred-tank type bioreactors, optionally equipped with a spin filter (70 μm) to retain cells on microcarriers in the bioreactor when needed (perfusion and recirculation culture mode). Alternatively, a harvest pipe with a 75 μm sieve was used to remove media while retaining microcarriers. Cultivations were controlled using Sartorius DCU-3 this website control units and MFCS-win software (Sartorius AG, Melsungen, Germany). Batch cultivations were carried out at 4 L working volume with inoculation densities of 0.1 × 106 cells mL−1.

During cultivation, glucose and glutamine were added by bolus feeding to 10 mM glucose and 2 mM glutamine when concentrations were below 5 mM and 0.5 mM respectively. Semi-batch cultivations were essentially performed as described by Mendonça (1998) [8] at 3 L working volume with an inoculation density of 0.1 × 106 cells mL−1. From day two onwards, daily 1 L culture medium (1/3 culture volume) was replaced with fresh medium. Media replacement Calpain was done after sedimentation of the microcarriers without agitation. In addition, bolus feeding of glucose and glutamine was done once 4 days after the start of cultivation to obtain concentrations of 20 mM glucose and 2 mM glutamine. Perfusion cultivations were carried out using 1.5 L working volume. Cells were inoculated at 0.1 × 106 cells mL−1 and retained in the bioreactor. After 2 days of batch cultivation, continuous media feed was started at 1.5 L day−1 (1 culture volume per day). Media feed rate was kept constant for the remainder of the perfusion cultures. Recirculation cultures, where cells are retained in the bioreactor (3 L working volume) while medium (15 L total volume = culture volume + circulated volume) is circulated, were carried out essentially as described previously [9]. Cells were inoculated at a cell density of 0.6 × 106 cells mL−1.

Furthermore,

BCG Luminespib has been shown to act non-specifically as a primer for other vaccines [29]. Here we were able to conduct a broad analysis of the effect of BCG Libraries strain by comparing type 1 (IFN-γ), type 2 (IL-5 and IL-13) and regulatory (IL-10) responses to both mycobacteria-specific (cCFP and Ag85) and non-specific (TT and PHA) stimuli. The results revealed three significant patterns of strain-dependent variability of immune responses to both mycobacteria-specific and non-specific stimuli: higher IFN-γ and IL-13 responses in the BCG-Denmark group; lower IL-5 responses in the BCG-Bulgaria group; and higher IL-10 responses in both the BCG-Denmark and BCG-Bulgaria group compared to BCG-Russia.

Consistent with being at the greatest genetic distance from the other two strains [9], the cytokine responses of the BCG-Denmark group were the most divergent. selleck compound Surprisingly however, they were also the highest overall, despite being most distantly related to the original M. bovis strain [37]. It is also interesting that BCG-Bulgaria and BCG-Russia behaved slightly differently in this cohort, despite being genetically identical, except for possible single nucleotide changes [38]. As all infants were immunised with BCG, it is uncertain how these findings would relate to non-specific responses (such as the response to TT) amongst BCG-unvaccinated infants, however, differences between strains in non-specific effects were clearly demonstrated. It is possible that the greater immunogenicity of BCG-Denmark may lead to better protection against TB. However, IFN-γ alone 3-mercaptopyruvate sulfurtransferase is an insufficient protective marker and it is feasible

that higher regulatory IL-10 production in the same group may counteract its effects [39]. The observation that IL-10 production differed between strains is contrary to a recent study [28] that found that BCG did not stimulate an IL-10 response. This analysis suggests that the ability of BCG to stimulate an IL-10 response may be strain-dependent, although a study that compared BCG-Denmark to BCG-Brazil and BCG-Japan, found no such differences [16]. Importantly, the differences across groups were observed in response to TT and PHA as well as to mycobacterial antigens, suggesting that the non-specific effects of BCG immunisation are likely to be dependent on the strain administered. The finding for TT specifically indicates that BCG strain differences can modulate the infant response to subsequent, unrelated exposures to antigens, including vaccines (and presumably, pathogens). There was striking disparity in BCG scar frequency between groups, with an almost two-fold increase in scarring frequency in the BCG-Denmark group compared to the BCG-Russia group. The overall proportion with scars was 59%, despite 100% immunisation coverage at birth.

21 However, we were unable to find a previous report regarding selleck screening library thromboembolic events after splenectomy in patients with hemophilia A. Compared to other surgical interventions, the postoperative thrombotic risk in patients

after splenectomy has specific features. The spleen obviously has an important function in the clearing of prothrombotic factors, although yet undefined well. Therefore, the removal of spleen is associated with an elevated long-lasting thrombotic risk, even in patients without an underlying disease such as splenectomy after splenic traumatic injuries.22,23 Post operative thrombocytosis is much more pronounced after splenectomy, and may increase the thrombotic Inhibitors,research,lifescience,medical risk per se, however, this has not been proven yet. Thrombosis of the portal venous system is a unique and potentially life-threatening complication after splenectomy. Since,

post-operative thrombocytosis can occur low dose aspirin should be considered when the platelet counts is more than 1,500,000/µl to minimize the risks of thrombosis or embolism.24 It has been well documented Inhibitors,research,lifescience,medical that in normal subject chronic elevation of plasma factor VIII levels to more than 150 IU/dl is associated Inhibitors,research,lifescience,medical with an increased risk of thrombosis. However, in the present case and other hemophilic patients the elevations to more than 150 IU/dl after replacement therapy are usually transient, and it is unlikely that levels more than 150 IU/dl are sustained for periods greater than a few hours in every 24-hour period. This is in contrast with the Inhibitors,research,lifescience,medical situation in a nonhemophilic patient where the elevated levels, if raised to more than 150 IU/dl as an acute phase response, would be persistent.25-27 Although these high factor VIII levels are unlikely to be the major risk factor, inevitably these high factor VIII levels may well have contributed to the risk of thromboembolism in the present Inhibitors,research,lifescience,medical patient. Therefore, to prevent under or over treatment in hemophilic

patients, we suggest the regular measurement of factor VIII levels after replacement therapy for surgeries, especially after splenectomy. In addition, since splenectomy is associated with an insult to hemostasis systems in the body, it may be associated with a hypercoagulable state leading Thymidine kinase to thromboembolic accidents even in hemophilic patients undergoing replacement therapy. Conclusion The findings surrounding the present case indicate that in patients with hemophilia A receiving factor VIII for replacement therapy who are candidate for splenectomy, formal risk assessment for thromboembolism, pharmacological thromboprophylaxis, intermittent pneumatic compression or inferior vena cava filter should be seriously considered. Acknowledgment We would like to thank to Dr. Kh. Ghasemieh of Kashan Forensic Office for performing the autopsy of the case. Conflict of Interest: None declared
Background: The use of mobile phone by children is increasing drastically. Children are likely to accumulate many years of exposure during their lives.

Figure 4. Summary of splice variants of CLCN1-RNA in the m-RNA region between exons 5 and 8 comparing different studies with our data (9,10). The positions of the pre-mature stop codons of the splicing variants are indicated. The last line, “other variants”, refers … In our study, ClC1236X does not seem to exert a truly dominant-negative effect on co-expressed ClC1, but only a slightly suppressive effect when over-expressed. While confocal laser microscopy suggests that a ClC1236X

association with ClC1 occurs in the membrane, an additional potential trafficking problem or decreased formation of ClC1-ClC1236X heterodimers cannot be excluded. Even so, our results would be compatible with the idea Inhibitors,research,lifescience,medical that ClC1- ClC1236X heterodimers may be 50%-functional and conduct chloride through the pore of the ClC1 part of the dimer. In agreement with this view Inhibitors,research,lifescience,medical of the functional effect of the prematurely terminated channel, nonsense mutations of ClC1 resulting in early truncations nearby such as fs231X (29), fs258X (30), or fs289X (31) are all inherited in a recessive and not dominant manner and produce myotonia by a lossof- function mechanism instead of a dominant-negative mechanism. However, in DM1, two splice variants, i) D6/ i6b-7a, resulting in a 256 amino acid protein, and ii) i6b- 7a (variant including exons 6b and 7a), resulting in a 282 amino

Inhibitors,research,lifescience,medical acid protein, have been studied functionally. They both exert a dominant-negative effect on co-expressed ClC1 channel in Xenopus oocytes (14). Possibly, this effect may be sequence specific as they are the only two truncations containing PVPVLQMSTPLSPVAPHGDRAWAAX, the sequence encoded by exons 6b-7a, a proline

rich peptide Inhibitors,research,lifescience,medical that might affect the pore of the co-expressed ClC1 wt (32). Therefore, the Inhibitors,research,lifescience,medical truncation variants in DM1 may explain why the chloride conductance is more Gefitinib reduced in DM1 than in DM2 and, therefore, why clinical myotonia is more prominent in DM1 than in DM2 (2). For both types of DM, the clinical variability of myotonia may depend on the degree of nonsense-mediated mRNA decay (NMD) of mRNAs containing premature stop codons. Previous reports have suggested that up to 27% of CLCN1-RNA result in alternatively spliced forms that generate premature termination codons (11, 12) which are subject to NMD; this has been shown especially for CLCN1-RNA variants that contain a premature termination codon in exon 7 (33). The most frequent variants Mannose-binding protein-associated serine protease in both DM1 (D6/i6b-7a) and DM2 (D6-7) have their stop codons in this RNA region, being in exons 7a and exon 8 respectively. Therefore, the respective degree of NMD may be similar and contribute to the reduced quantity of CLCN1 mRNA in DM (34). Because chloride current is reduced but not abolished in DM muscle (35), it seems reasonable to assume that at least a portion of transcripts coding for R894X is not degraded and can contribute to reduced chloride conductance and myotonia in DM2.

Pfizer was recently fined US$2.3 billion for off-licence marketing of four of its medicines including the antipsychotic agent ziprasidone (Geodon) [Ratner, 2009]. Some have argued that restrictions on advertising are in effect a restriction of commercial free expression, and that the regulatory systems should be sufficiently flexible to recognize ‘real-world’ prescribing practices [Stafford, 2008], which are often driven

by patient need and expectation. Of course if such real-world practices are not supported by any real evidence then they should be challenged. A major incentive for novel drug investigation is the opportunity to secure a patent, granting the holder a 20-year sales #PARP inhibitor keyword# monopoly [French, 2005]. Inhibitors,research,lifescience,medical However, once the patent has expired, pharmaceutical companies have little or no further incentive to establish new indications,

given competition from low-cost generic suppliers, so any such work beyond that time will almost inevitably fall to independent academics [Devulapalli and Nasrallah, 2009]. The availability and licensed indications for drugs differs between countries and is often based on marketing decisions, as well as but also different national regulation Inhibitors,research,lifescience,medical requirements. For example the atypical antipsychotic ziprasidone, was approved in a variety of countries including the USA in 2001[Nemeroff et al. 2005]. It is indicated for schizophrenia, as monotherapy or adjunctive therapy for Inhibitors,research,lifescience,medical acute mania, and maintenance therapy for mania and bipolar disorder. But more than 10% of patients prescribed the drug have developed modest QTc interval prolongation, and so the launch of the atypical antipsychotic ziprasidone continues to be delayed

in the UK in part due to the request for mandatory cardiovascular monitoring that may have limited sales and influenced requirement in other jurisdictions [Abdelmawla and Mitchell, 2006]. Prescriber practices, safeguards and checks Off-licence prescribing can involve the purposeful prescription of a medicine, outside its licensed target Inhibitors,research,lifescience,medical group or dose, but justified on the basis of the best available evidence and discussed collaboratively with a consenting patient; or it may be unintentional, used by a physician who is unaware that the licensed parameters have been breached [Uzoechina et al. 2011] or that the evidence is scant or nonexistant. In fact prescribers who are aware of the off-label status of a product often overestimate the strength from and quality of the evidence to support their practice, and rely on personal experience as justification. A study of psychotropic prescribing in two large UK medium secure units found less than 30% of all off-label prescriptions were supported by meta-analyses or well-designed RCTs, while lesser quality experimental evidence supported about 30%, expert opinion about 40%, while 5% was unsupported by any evidence [Haw and Stubbs, 2010].

(A) Intrahippocampal … Repeated measures analysis of the effects within each group revealed a concentration-dependent effect on the evoked population spike. First, infusion of the lowest concentration of ISO, 0.1 μmol/L (n = 6) produced

a transient depression of the dentate gyrus evoked population spike from baseline responses (F41,205 = 1.555, P < 0.025; see Fig. 2B). Post hoc analysis revealed that this decrease began at the termination of infusion and was maximal at 46% of the baseline spike amplitude. The depression lasted for four 5-min samples (20 min) and Inhibitors,research,lifescience,medical then returned to baseline. The remaining concentrations of intrahippocampal ISO (1, 10, and 100 μmol/L) produced a potentiation of the perforant path—dentate gyrus evoked population spike (see Fig. 2C–E). The potentiation observed at the 1 μmol/L concentration (F41,205 = 3.3424; P < 0.0001; n = 6) began following infusion termination and was significantly different ~75 min later with a maximal mean potentiation from

baseline Inhibitors,research,lifescience,medical of 133%. The response returned to baseline before 3 h of recording had elapsed. Application of ISO at 10 μmol/L concentration produced the largest and most enduring increases in population spike amplitude (F41,205 = 4.9210; P < 0.00001; n = 6). The potentiation began during infusion and was significantly different Inhibitors,research,lifescience,medical ~60 min following infusion termination. The mean maximal GSK1210151A cell line increase was 185% and persisted for the duration of the 3-h recording period. Finally, intrahippocampal infusion of the 100 μmol/L concentration produced a small and variable potentiation of the Inhibitors,research,lifescience,medical evoked population spike (F41,205 = 1.97; P < 0.001; n = 6), with the first significant

increase at ~70 min postinfusion but then returning to baseline, a second elevation occurred 2 h later and lasted Inhibitors,research,lifescience,medical 35 min, returning to baseline prior to termination of recording. The maximal mean increase occurred in the second period of potentiation and was 124% of baseline. A two-way repeated measures ANOVA (concentration × time at 15 min preinfusion and 15, 110, and 180 min postinfusion) was used to assess between-group effects of varying ISO concentrations. A significant interaction was found for the effects of varying concentrations Phosphatidylinositol diacylglycerol-lyase of ISO on the population spike amplitude (F12,78 = 2.4123; P < 0.01). Post hoc analysis showed no differences between groups in the 15-min period prior to infusion; however, 15 min after the start of the infusion of 0.1 μmol/L ISO, the population spike was depressed compared to aCSF-infused control rats (see Fig. 2F). The population spike amplitude in rats receiving 10 μmol/L ISO was greater than that of rats receiving infusions of either aCSF or any other ISO concentration. By 110 min after the start of infusions, the spike amplitude of rats infused with 10 μmol/L was still elevated, compared to all other groups.

The Selleck MLN2238 HCUP-NIS contains data from 1,050 hospitals and represents a 20% stratified sample of US community hospitals (9). Since the HCUP-NIS is a discharge-level database, each line represents a single unique hospitalization. Institutional Review Board approval is not required when using this database, since it is made available to researchers in a de-identified format. Study design and sample A retrospective cross-sectional design was used for this study. Discharges with LOS greater than 365 days or total charges greater than $1 million were excluded from the analysis. Patients hospitalized with any listed diagnosis of GISTs were identified using the International

Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes including 171.5, 171.8, 171.9, 215.1 or 238.1 (10). A control group consisting of patients without any diagnosis of GISTs or other cancers was identified. Cases and controls were matched based on age and gender in a 1:4 ratio using a greedy match algorithm (11). Statistical analysis All analyses were performed using PROCSURVEY procedures in Statistical Analysis System (SAS) version 9.2 to account for the

complex sampling design of the HCUP-NIS. Hospitalization rates for GISTs were reported by patient-, Inhibitors,research,lifescience,medical hospital-, and discharge-level characteristics. Rates were calculated by dividing the number of weighted hospitalizations associated with GISTs in each category by the total number of hospitalizations in that category. In addition, common comorbid diagnoses and procedures performed among patients with GISTs were assessed. Hospitalization Inhibitors,research,lifescience,medical characteristics among patients with GISTs were compared to Inhibitors,research,lifescience,medical the control group using χ2 test and t-test. Linear regression (PROC SURVEYREG) was used to determine the factors predicting total charges among patients with GISTs. Factors predicting mortality among patients with GISTs were determined using logistic regression (PROC SURVEYLOGISTIC). Results reported in the study are weighted estimates. Results Table 1 describes the hospitalization

rates for GISTs and compares the patient-, hospital-, and discharge-level characteristics among patients with and without a diagnosis of GISTs. In 2009, there were a total of 14,562 hospitalizations among patients with GISTs in the US. The overall hospitalization Calpain rate of patients with GISTs was 44/100,000 admissions. In terms of patient-level characteristics, the highest rates for GISTs were among patients aged 50-64 years, males, having household income of $63,000 or more, and with private insurance, respectively. As per hospital-level characteristics, rates were the highest for hospitalizations that took place in small hospitals, urban hospitals, hospitals located in the South, and teaching hospitals, respectively.

84 Leonard et al92 found a specific SNP genetic mutation in the promoter region of the α7-subunit of the nicotinic gene, which seems to account for the P50 findings listed above. Thus, P50 suppression represents the most “complete” “DNA to RNA to protein” story of an endophenotype–genetic abnormality linkage. The P50 suppression findings represent an example of how endophenotypes can be utilized as neurobiologically meaningful markers that contribute to our understanding of the genetics and potentially the treatment of schizophrenia. Importantly, these types of studies do not merely identify a “schizophrenia Inhibitors,research,lifescience,medical endophenotype,” but

rather the linkage of deficits (P50 suppression) in schizophrenia patients

to a specific chromosomal region. Conundrums Inhibitors,research,lifescience,medical and caveats, and the use of endophenotypes in the genetics of schizophrenia Although there are many click here candidate endophenotypes in schizophrenia, imposing challenges still exist. First, since some endophenotypes are at least partially normalized by current second-generation antipsychotic medications, the statistical genetic approach to these data sets presents many daunting challenges. For example, the fact that clozapine improves P50 suppression deficits93-95 suggests that Inhibitors,research,lifescience,medical patients on clozapine cannot be utilized in studies of P50 suppression as a candidate Inhibitors,research,lifescience,medical endophenotype. It would be optimal to use never-medicated schizophrenia patients in studies of endophenotypes in schizophrenia. Unfortunately, given the power demands of such studies, finding enough never-medicated patients, even in a multisite study such as the Consortium on the Genetics of Schizophrenia (COGS) would seem to be virtually Inhibitors,research,lifescience,medical impossible. Family studies that rely on identifying probands with endophenotypic deficits then become difficult to interpret. Where significant

endophenotypic normalization occurs with antipsychotic treatment, statistical strategies will have to be utilized that allow us to “exclude” or “account for” the (partially) “normalized” schizophrenia patients or to utilize only clinically unaffected family members in genetic studies. This reliance on clinically unaffected family members is what Braff and Freedman7 Adenosine referred to as the “null-proband” strategy. Medicated probands must either be excluded from analyses or a complex “adjustment” on a phenotypic value must be made in order to utilize them in the genetic analysis. One could posit that a temporary withdrawal of antipsychotic medication would allow us to identify these trait-related endophenotypic markers, but this is ethically and practically unfeasible.

2009a) Study: Semistructured questionnaire (20 items) survey to all Polish psychiatric inpatient facilities N= 58 responded facilities (100% response rate) N= 25 confirmed use of ECT, but only N= 20 (34%) facilities administered ECT

buy Afatinib during study period N= 435 ECT-treated patients in period Date: 2005 Time span: One year Diagnoses: Inhibitors,research,lifescience,medical Depression, mania, schizophrenia and schizoaffective, and other disorders Gender: 65% women Age: >18 years (but six units offered to patients <18 years) Conditions: Written informed consent obligatory For involuntary approval from court necessary Legal: Requires specialist in anesthesiologist Other: Only one-third of facilities treated patients with ECT during study period. ECT administered under pregnancy in 10 settings

TPR: 0.11 iP: Inhibitors,research,lifescience,medical 0.79% (up to 6.46%) AvE: 9 C-ECT: 25% A-ECT: ECT not performed in Polish outpatient clinics Modified Anesthesia: 58% thiopenthal 23% propofol 15% etomidate 4% midazolam Devices: Mecta JR-1, Mecta SR-1 & Spectrum 5000, Thymatron IV, Pabel ES and Siemens E2077 Type: 30% sine wave 70% brief pulse Placement: All BL Two facilities used UL or BF as second choice Germany (L) Muller U (Muller et al. 1998) Study: Questionnaire survey to psychiatric hospitals and university clinics. N= 451 Inhibitors,research,lifescience,medical clinics (Response rate 64%) Inhibitors,research,lifescience,medical N= 1050 patients ECT treated Clinics (59%) providing ECT were: 82% university clinics 74% state hospitals 48% special hospitals 68% psychiatric wards Date: April to October 1995 Time span: Seven months

Diagnoses (diagnostic indication for ECT given by clinics): 79% catatonia 58% depression 24% malignant neuroleptic syndrome 2% neurological disorders Inhibitors,research,lifescience,medical Gender: No information Age: 18–64 years, seldom elderly patients Side effects reported (common to rare): amnesia, headache, cognitive problems, organic psychoses, dental injuries, neurologic disease Conditions: 20% involuntary (nonconsent) Patient information: 43% oral 42% oral and written 15% written Other: Reasons for not providing ECT: No equipment and not enough knowledge or for political reasons Attitudes: 96% positive TPR, East Germany: 0.15 TPR, West Germany: 0.36 (between Rolziracetam 1992 &1994) TPR total: 0.26 C-ECT:14% Modified Anesthesia: 64% barbiturate 38% etomidate 20% propofol Devices: 21%Thymatron DG 39% Siemens konvulsator 2077S 2% other machines Type: 21% brief pulse 39% sine wave Dose: 39% titration 18% fixed Placement: 21% UL 19% BL 18% both BL & UL 39% no data Spain (L) Bertolin-Guillen JM (Bertolin-Guillen et al. 2006) Study: Questionnaire survey to all hospitals with psychiatric unit in Spain.

These observational studies have now sparked the conduct of large-scale randomized controlled trials currently ongoing in cancer. We show in this paper that the spectacular effects on new indications or new outcomes reported in many observational studies in chronic obstructive pulmonary disease (COPD), HRT, and cancer are the result of time-related biases, such as immortal time bias, that tend to seriously exaggerate the benefits of a drug and that eventually disappear with the proper statistical analysis. In all, while observational studies are central to selleck products assess the effects of drugs, their proper Inhibitors,research,lifescience,medical design and analysis are essential to avoid bias. The scientific

evidence on the potential beneficial effects in new indications Inhibitors,research,lifescience,medical of existing drugs will need to

be more carefully assessed before embarking on long and expensive unsubstantiated trials. Keywords: Cohort studies, drug effectiveness, drug indications, observational studies, randomized controlled trials, scientific evidence INTRODUCTION The randomized controlled trial is the fundamental paradigm to evaluate the effectiveness of medications in the clinical setting. It is the essential study Inhibitors,research,lifescience,medical design required by regulatory agencies to approve the marketing of a drug or a new indication for an existing drug. Despite extensive pre-approval trials, medications can have important unintended side-effects even if used properly. The epidemiological approach of observational studies has been recognized as an essential tool to address post-marketing drug safety issues and study the actual effects of medications as used in the population, a different Inhibitors,research,lifescience,medical situation from the experimental setting in which the drugs were developed and approved. This approach is particularly important for less frequent but severe adverse events or long-term adverse effects that cannot and could not be detected by the randomized trials required for

initial drug approval. Moreover, the use of existing computerized databases arising from the routine collection of data in the usual care of patients has become essential for the rapid conduct Inhibitors,research,lifescience,medical of these observational studies in this field called pharmacoepidemiology. For example, health care databases worldwide have been used to rapidly assess the risks and benefits of several drugs such as NSAIDs, beta-agonists, anti-depressants, anti-hypertensives, statins, gastric-acid suppressants, corticosteroids, and many others, on major disease GBA3 outcomes.1–9 Another less common situation where observational studies have been used is to uncover new indications for drugs that are already on the market or to assess the effectiveness of such available drugs in the same indication but on new outcomes not studied in pre-approval trials. An example of the effectiveness of a drug on new outcomes is that of hormone replacement therapy (HRT), an effective treatment for menopausal symptoms.