Optimizing Best Practice Advisory alerts in electronic medical records with a multi-pronged strategy at a tertiary care hospital in Singapore.

Objective: Clinical decision support (CDS) alerts can aid in improving patient care. One CDS functionality is the Best Practice Advisory (BPA) alert notification system, wherein BPA alerts are automated alerts embedded in the hospital's electronic medical records (EMR). However, excessive alerts can change clinician behavior; redundant and repetitive alerts can contribute to alert fatigue. Alerts can be optimized through a multipronged strategy. Our study aims to describe these strategies adopted and evaluate the resultant BPA alert optimization outcomes. Materials and Methods: This retrospective single-center study was done at Jurong Health Campus. Aggregated, anonymized data on patient demographics and alert statistics were collected from January 1, 2018 to December 31, 2021. "Preintervention" period was January 1-December 31, 2018, and "postintervention" period was January 1-December 31, 2021. The intervention period was the intervening period. Categorical variables were reported as frequencies and proportions and compared using the chi-square test. Continuous data were reported as median (interquartile range, IQR) and compared using the Wilcoxon rank-sum test. Statistical significance was defined at P < .05. Results: There was a significant reduction of 59.6% in the total number of interruptive BPA alerts, despite an increase in the number of unique BPAs from 54 to 360 from pre- to postintervention. There was a 74% reduction in the number of alerts from the 7 BPAs that were optimized from the pre- to postintervention period. There was a significant increase in percentage of overall interruptive BPA alerts with action taken (8 [IQR 7.7-8.4] to 54.7 [IQR 52.5-58.9], P-value < .05) and optimized BPAs with action taken (32.6 [IQR 32.3-32.9] to 72.6 [IQR 64.3-73.4], P-value < .05). We estimate that the reduction in alerts saved 3600 h of providers' time per year. Conclusions: A significant reduction in interruptive alert volume, and a significant increase in action taken rates despite manifold increase in the number of unique BPAs could be achieved through concentrated efforts focusing on governance, data review, and visualization using a system-embedded tool, combined with the CDS Five Rights framework, to optimize alerts. Improved alert compliance was likely multifactorial-due to decreased repeated alert firing for the same patient; better awareness due to stakeholders' involvement; and less fatigue since unnecessary alerts were removed. Future studies should prospectively focus on patients' clinical chart reviews to assess downstream effects of various actions taken, identify any possibility of harm, and collect end-user feedback regarding the utility of alerts.

Imprint cytology: Invaluable technique to evaluate fresh specimens received in the pathology department for lymphoma workup.

At the time of intraoperative consultation, cytologic preparations including smears and imprints can be used in combination with frozen sections to increase diagnostic yield; however, these simple and rapid techniques are not adopted by all pathologists and their use varies considerably between institutions. In patients under investigation for suspected lymphoma, optimal triaging of tissue received fresh in pathology for lymphoma workup is paramount to maximize the odds of obtaining an accurate and clinically meaningful diagnosis and to avoid the need for additional procedures and delays in management, particularly in the current context in which core biopsies have become common practice as a first attempt to attain this goal. Imprint cytology is invaluable in this regard, also as these patients may not have a lymphoma but rather one of its clinical mimics. Herein, imprint cytology is used to approach fresh specimens received intraoperatively for lymphoma workup. More specifically, how these specimens are triaged for ancillary studies, such as flow cytometry, florescence in situ hybridization, or molecular analyses based on an interpretation of the touch imprints, is described. Detailed imprint cytological findings of typical benign and malignant lymphoid and nonlymphoid lesions are discussed and illustrated.

Effect of a Real-Time Risk Score on 30-day Readmission Reduction in Singapore.

OBJECTIVE: To develop a risk score for the real-time prediction of readmissions for patients using patient specific information captured in electronic medical records (EMR) in Singapore to enable the prospective identification of high-risk patients for enrolment in timely interventions. METHODS: Machine-learning models were built to estimate the probability of a patient being readmitted within 30 days of discharge. EMR of 25,472 patients discharged from the medicine department at Ng Teng Fong General Hospital between January 2016 and December 2016 were extracted retrospectively for training and internal validation of the models. We developed and implemented a real-time 30-day readmission risk score generation in the EMR system, which enabled the flagging of high-risk patients to care providers in the hospital. Based on the daily high-risk patient list, the various interfaces and flow sheets in the EMR were configured according to the information needs of the various stakeholders such as the inpatient medical, nursing, case management, emergency department, and postdischarge care teams. RESULTS: Overall, the machine-learning models achieved good performance with area under the receiver operating characteristic ranging from 0.77 to 0.81. The models were used to proactively identify and attend to patients who are at risk of readmission before an actual readmission occurs. This approach successfully reduced the 30-day readmission rate for patients admitted to the medicine department from 11.7% in 2017 to 10.1% in 2019 (p < 0.01) after risk adjustment. CONCLUSION: Machine-learning models can be deployed in the EMR system to provide real-time forecasts for a more comprehensive outlook in the aspects of decision-making and care provision.

Concurrent development of HIV-negative Kaposi's sarcoma and mycosis fungoides in an elderly Inuit from Canada.

An 88-year-old Inuit man from Northern Canada presented with an extensive skin rash associated with numerous violaceous skin nodules on his palms and lower extremities. Biopsy of a skin nodule revealed Kaposi's sarcoma (KS), a human herpesvirus 8 (HHV8)-associated malignancy, whereas biopsy of the erythematous skin showed an atypical infiltrate of CD4-positive T-cells that, together with TCR gene rearrangement and presence of clonal T-cells in peripheral blood by flow cytometry, was consistent with a T-cell lymphoma, mycosis fungoides (MF) subtype. Serology was negative for HIV and HTLV-I/II and no immunodeficiency syndrome was identified. The patient was successfully treated with an oral retinoid for KS, and with topical hydrocortisone and ultraviolet B (UVB) phototherapy for MF. This case highlights the existence of HHV8-related lesions in native persons of Northern Canada, and also that MF-induced immunosuppression combined with immunosenescence may play a role in the development of non-HIV-related KS.

Extracavitary primary effusion lymphoma recurring with syphilis in an HIV-infected patient.

A 59-year-old Caucasian man infected with HIV, in remission from human herpes virus-8-positive extracavitary primary effusion lymphoma (EC-PEL), presented to a sexual health clinic with fever and rectal pain 10 weeks after a single episode of receptive anal sexual intercourse with another man. He was initially treated for a presumptive diagnosis of lymphogranuloma venereum proctitis, then for syphilis on positive serology. Rectosigmoidoscopy revealed a single ulcerated rectal mass; endoscopic biopsies confirmed the recurrence of EC-PEL. The patient received chemotherapy and went into remission. This is the first reported case of EC-PEL occurring synchronously with early syphilis, and specifically at the site of inoculation, which can be a major diagnostic challenge since both conditions may present with lymphadenopathy, mucosal involvement and constitutional symptoms. We reviewed the literature for similar cases and hypothesised that syphilis may have triggered the recurrence of this rare lymphoma.

Structural insights into the putative bacterial acetylcholinesterase ChoE and its substrate inhibition mechanism.

Mammalian acetylcholinesterase (AChE) is well-studied, being important in both cholinergic brain synapses and the peripheral nervous systems and also a key drug target for many diseases. In contrast, little is known about the structures and molecular mechanism of prokaryotic acetylcholinesterases. We report here the structural and biochemical characterization of ChoE, a putative bacterial acetylcholinesterase from Pseudomonas aeruginosa Analysis of WT and mutant strains indicated that ChoE is indispensable for P. aeruginosa growth with acetylcholine as the sole carbon and nitrogen source. The crystal structure of ChoE at 1.35 Å resolution revealed that this enzyme adopts a typical fold of the SGNH hydrolase family. Although ChoE and eukaryotic AChEs catalyze the same reaction, their overall structures bear no similarities constituting an interesting example of convergent evolution. Among Ser-38, Asp-285, and His-288 of the catalytic triad residues, only Asp-285 was not essential for ChoE activity. Combined with kinetic analyses of WT and mutant proteins, multiple crystal structures of ChoE complexed with substrates, products, or reaction intermediate revealed the structural determinants for substrate recognition, snapshots of the various catalytic steps, and the molecular basis of substrate inhibition at high substrate concentrations. Our results indicate that substrate inhibition in ChoE is due to acetate release being blocked by the binding of a substrate molecule in a nonproductive mode. Because of the distinct overall folds and significant differences of the active site between ChoE and eukaryotic AChEs, these structures will serve as a prototype for other prokaryotic acetylcholinesterases.

Breast implant-associated anaplastic large cell lymphoma and effusions: A review with emphasis on the role of cytopathology.

Breast implants are surgically implanted by the hundreds of thousands every year worldwide for reconstructive or aesthetic purposes. Complications related to breast implants include early and late effusions that are often submitted for cytopathological analysis, particularly to exclude the possibility of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), a rare disease that generally follows an indolent clinical course, although it is becoming clearer that a subset of patients with adverse features have a poorer prognosis. Since a late-onset breast implant-associated effusion is the most common initial presentation of BIA-ALCL, cytopathological analysis of these effusions is considered the cornerstone and gold standard for rapid, efficient, reliable diagnosis and is critical for appropriate management and treatment. The National Comprehensive Cancer Network recently published clinical guidelines for the diagnosis and management of BIA-ALCL and stresses the essential role of cytopathological analysis, although it remains a matter of debate if all seromas should undergo immunocytochemistry or flow cytometry, particularly for assessment of expression of CD30 irrespective of morphological appearance on cytology. Herein, we review the current knowledge on BIA-ALCL, review the key cytological findings of reactive and malignant effusions related to breast implants, and present a comprehensive cytopathological workup with the presence of atypical cells as the key and pivotal element triggering further ancillary studies. We believe this approach will ensure appropriate and cost-effective management of effusion specimens from breast implants.

A Novel Approach of Promoting Adhesion of Reinforcing Cord to Elastomers by Plasma Polymerization.

Adhesion of cords to elastomers is crucial for many elastomeric products, such as tires and V-belts. The best adhesion system so far is based on a combination of resorcinol, formaldehyde, and a latex (RFL). However, this cord treatment has serious disadvantages in terms of processing and toxicity. A promising alternative is a plasma treatment of the cords prior to be embedded in the elastomer. For rayon cords, a plasma polymerization of sulfur-containing precursors results in adhesion levels close to RFL treatment. However, for polyethylene terephthalate (PET) cords, this treatment is not satisfactory. For this type of cords, a water-plasma activation followed by a silane dip is more promising, as 72% of the adhesion level of RFL treatment could be achieved. For rayon, an even higher adhesion level was realized.

Association of Piriform Cortex Resection With Surgical Outcomes in Patients With Temporal Lobe Epilepsy.

Importance: A functional area associated with the piriform cortex, termed area tempestas, has been implicated in animal studies as having a crucial role in modulating seizures, but similar evidence is limited in humans. Objective: To assess whether removal of the piriform cortex is associated with postoperative seizure freedom in patients with temporal lobe epilepsy (TLE) as a proof-of-concept for the relevance of this area in human TLE. Design, Setting, and Participants: This cohort study used voxel-based morphometry and volumetry to assess differences in structural magnetic resonance imaging (MRI) scans in consecutive patients with TLE who underwent epilepsy surgery in a single center from January 1, 2005, through December 31, 2013. Participants underwent presurgical and postsurgical structural MRI and had at least 2 years of postoperative follow-up (median, 5 years; range, 2-11 years). Patients with MRI of insufficient quality were excluded. Findings were validated in 2 independent cohorts from tertiary epilepsy surgery centers. Study follow-up was completed on September 23, 2016, and data were analyzed from September 24, 2016, through April 24, 2018. Exposures: Standard anterior temporal lobe resection. Main Outcomes and Measures: Long-term postoperative seizure freedom. Results: In total, 107 patients with unilateral TLE (left-sided in 68; 63.6% women; median age, 37 years [interquartile range {IQR}, 30-45 years]) were included in the derivation cohort. Reduced postsurgical gray matter volumes were found in the ipsilateral piriform cortex in the postoperative seizure-free group (n = 46) compared with the non-seizure-free group (n = 61). A larger proportion of the piriform cortex was resected in the seizure-free compared with the non-seizure-free groups (median, 83% [IQR, 64%-91%] vs 52% [IQR, 32%-70%]; P < .001). The results were seen in left- and right-sided TLE and after adjusting for clinical variables, presurgical gray matter alterations, presurgical hippocampal volumes, and the proportion of white matter tract disconnection. Findings were externally validated in 2 independent cohorts (31 patients; left-sided TLE in 14; 54.8% women; median age, 41 years [IQR, 31-46 years]). The resected proportion of the piriform cortex was individually associated with seizure outcome after surgery (derivation cohort area under the curve, 0.80 [P < .001]; external validation cohorts area under the curve, 0.89 [P < .001]). Removal of at least half of the piriform cortex increased the odds of becoming seizure free by a factor of 16 (95% CI, 5-47; P < .001). Other mesiotemporal structures (ie, hippocampus, amygdala, and entorhinal cortex) and the overall resection volume were not associated with outcomes. Conclusions and Relevance: These results support the importance of resecting the piriform cortex in neurosurgical treatment of TLE and suggest that this area has a key role in seizure generation.

The Influence of Radiotherapy on the Mechanical Properties of Silicone Breast Implants.

BACKGROUND: Silicone breast implants have been used for decades for cosmetic breast augmentation or reconstruction after mastectomy. In selected cases, postmastectomy adjuvant radiotherapy is given with the breast implants in situ. Previous clinical studies have shown that radiotherapy may lead to complications such as capsular contracture and infection and that removal of the implant may be required. Yet, the effect of radiotherapy on silicone breast implants themselves is unknown. The aim of this study was to investigate if irradiation of breast implants influences their mechanical properties. METHODS: This was an ex vivo study on 32 ready-to-use silicone breast implants (Mentor and Silimed). Half of the implants of each brand were irradiated with 1 × 60 Gy, the other half were not irradiated. Tensile, mechanical hysteresis, and rheology tests were performed. Differences in mechanical properties between the irradiated and nonirradiated implants were determined. RESULTS: No significant differences were found in tensile strength, mechanical hysteresis, and rheological properties between irradiated and nonirradiated implants. CONCLUSIONS: Breast implants' mechanical properties for these 2 brands were not significantly affected after single-dose irradiation in an ex vivo setting.

ICN_Atlas: Automated description and quantification of functional MRI activation patterns in the framework of intrinsic connectivity networks.

Generally, the interpretation of functional MRI (fMRI) activation maps continues to rely on assessing their relationship to anatomical structures, mostly in a qualitative and often subjective way. Recently, the existence of persistent and stable brain networks of functional nature has been revealed; in particular these so-called intrinsic connectivity networks (ICNs) appear to link patterns of resting state and task-related state connectivity. These networks provide an opportunity of functionally-derived description and interpretation of fMRI maps, that may be especially important in cases where the maps are predominantly task-unrelated, such as studies of spontaneous brain activity e.g. in the case of seizure-related fMRI maps in epilepsy patients or sleep states. Here we present a new toolbox (ICN_Atlas) aimed at facilitating the interpretation of fMRI data in the context of ICN. More specifically, the new methodology was designed to describe fMRI maps in function-oriented, objective and quantitative way using a set of 15 metrics conceived to quantify the degree of 'engagement' of ICNs for any given fMRI-derived statistical map of interest. We demonstrate that the proposed framework provides a highly reliable quantification of fMRI activation maps using a publicly available longitudinal (test-retest) resting-state fMRI dataset. The utility of the ICN_Atlas is also illustrated on a parametric task-modulation fMRI dataset, and on a dataset of a patient who had repeated seizures during resting-state fMRI, confirmed on simultaneously recorded EEG. The proposed ICN_Atlas toolbox is freely available for download at http://icnatlas.com and at http://www.nitrc.org for researchers to use in their fMRI investigations.

A CZT-based blood counter for quantitative molecular imaging.

BACKGROUND: Robust quantitative analysis in positron emission tomography (PET) and in single-photon emission computed tomography (SPECT) typically requires the time-activity curve as an input function for the pharmacokinetic modeling of tracer uptake. For this purpose, a new automated tool for the determination of blood activity as a function of time is presented. The device, compact enough to be used on the patient bed, relies on a peristaltic pump for continuous blood withdrawal at user-defined rates. Gamma detection is based on a 20 × 20 × 15 mm3 cadmium zinc telluride (CZT) detector, read by custom-made electronics and a field-programmable gate array-based signal processing unit. A graphical user interface (GUI) allows users to select parameters and easily perform acquisitions. RESULTS: This paper presents the overall design of the device as well as the results related to the detector performance in terms of stability, sensitivity and energy resolution. Results from a patient study are also reported. The device achieved a sensitivity of 7.1 cps/(kBq/mL) and a minimum detectable activity of 2.5 kBq/ml for 18F. The gamma counter also demonstrated an excellent stability with a deviation in count rates inferior to 0.05% over 6 h. An energy resolution of 8% was achieved at 662 keV. CONCLUSIONS: The patient study was conclusive and demonstrated that the compact gamma blood counter developed has the sensitivity and the stability required to conduct quantitative molecular imaging studies in PET and SPECT.

Methods and utility of EEG-fMRI in epilepsy.

Brain activity data in general and more specifically in epilepsy can be represented as a matrix that includes measures of electrophysiology, anatomy and behaviour. Each of these sub-matrices has a complex interaction depending upon the brain state i.e., rest, cognition, seizures and interictal periods. This interaction presents significant challenges for interpretation but also potential for developing further insights into individual event types. Successful treatments in epilepsy hinge on unravelling these complexities, and also on the sensitivity and specificity of methods that characterize the nature and localization of underlying physiological and pathological networks. Limitations of pharmacological and surgical treatments call for refinement and elaboration of methods to improve our capability to localise the generators of seizure activity and our understanding of the neurobiology of epilepsy. Simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI), by potentially circumventing some of the limitations of EEG in terms of sensitivity, can allow the mapping of haemodynamic networks over the entire brain related to specific spontaneous and triggered epileptic events in humans, and thereby provide new localising information. In this work we review the published literature, and discuss the methods and utility of EEG-fMRI in localising the generators of epileptic activity. We draw on our experience and that of other groups, to summarise the spectrum of information provided by an increasing number of EEG-fMRI case-series, case studies and group studies in patients with epilepsy, for its potential role to elucidate epileptic generators and networks. We conclude that EEG-fMRI provides a multidimensional view that contributes valuable clinical information to localize the epileptic focus with potential important implications for the surgical treatment of some patients with drug-resistant epilepsy, and insights into the resting state and cognitive network dynamics.

[mTOR, the mammalian target of rapamycin]. / mTOR, la cible fonctionnelle de la rapamycine.

The discovery of rapamycin from a soil sample on Easter Island in the mid 60's marked the beginning of an exciting field of research in cell biology and medicine. While it was first used as an antifungal and as an immunosuppressive drug, more recent studies confirmed rapamycin's antiproliferative properties over a variety of solid tumors. Research aimed at identifying its mechanism of action uncovered mTOR (mammalian target of rapamycin), a protein kinase that regulates mRNA translation and protein synthesis, an essential step in cell division and proliferation. Recent evidence suggests a more complex role for mTOR in the regulation of several growth factor-stimulated protein kinases, including the proto-oncogene Akt. This article reviews mTOR function and regulation, and briefly details the future challenges for anti-cancer therapies based on mTOR inhibition.

mTORC2 can associate with ribosomes to promote cotranslational phosphorylation and stability of nascent Akt polypeptide.

The mechanisms that couple translation and protein processing are poorly understood in higher eukaryotes. Although mammalian target of rapamycin (mTOR) complex 1 (mTORC1) controls translation initiation, the function of mTORC2 in protein synthesis remains to be defined. In this study, we find that mTORC2 can colocalize with actively translating ribosomes and can stably interact with rpL23a, a large ribosomal subunit protein present at the tunnel exit. Exclusively during translation of Akt, mTORC2 mediates phosphorylation of the nascent polypeptide at the turn motif (TM) site, Thr450, to avoid cotranslational Akt ubiquitination. Constitutive TM phosphorylation occurs because the TM site is accessible, whereas the hydrophobic motif (Ser473) site is concealed in the ribosomal tunnel. Thus, mTORC2 can function cotranslationally by phosphorylating residues in nascent chains that are critical to attain proper conformation. Our findings reveal that mTOR links protein production with quality control.

Molecular composition of staufen2-containing ribonucleoproteins in embryonic rat brain.

Messenger ribonucleoprotein particles (mRNPs) are used to transport mRNAs along neuronal dendrites to their site of translation. Numerous mRNA-binding and regulatory proteins within mRNPs finely regulate the fate of bound-mRNAs. Their specific combination defines different types of mRNPs that in turn are related to specific synaptic functions. One of these mRNA-binding proteins, Staufen2 (Stau2), was shown to transport dendritic mRNAs along microtubules. Its knockdown expression in neurons was shown to change spine morphology and synaptic functions. To further understand the molecular mechanisms by which Stau2 modulates synaptic function in neurons, it is important to identify and characterize protein co-factors that regulate the fate of Stau2-containing mRNPs. To this end, a proteomic approach was used to identify co-immunoprecipitated proteins in Staufen2-containing mRNPs isolated from embryonic rat brains. The proteomic approach identified mRNA-binding proteins (PABPC1, hnRNP H1, YB1 and hsc70), proteins of the cytoskeleton (alpha- and beta-tubulin) and RUFY3 a poorly characterized protein. While PABPC1 and YB1 associate with Stau2-containing mRNPs through RNAs, hsc70 is directly bound to Stau2 and this interaction is regulated by ATP. PABPC1 and YB1 proteins formed puncta in dendrites of embryonic rat hippocampal neurons. However, they poorly co-localized with Stau2 in the large dendritic complexes suggesting that they are rather components of Stau2-containing mRNA particles. All together, these results represent a further step in the characterization of Stau2-containing mRNPs in neurons and provide new tools to study and understand how Stau2-containing mRNPs are transported, translationally silenced during transport and/or locally expressed according to cell needs.

mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling.

The mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that forms two functionally distinct complexes important for nutrient and growth factor signaling. While mTOR complex 1 (mTORC1) regulates mRNA translation and ribosome biogenesis, mTORC2 plays an important role in the phosphorylation and subsequent activation of Akt. Interestingly, mTORC1 negatively regulates Akt activation, but whether mTORC1 signaling directly targets mTORC2 remains unknown. Here we show that growth factors promote the phosphorylation of Rictor (rapamycin-insensitive companion of mTOR), an essential subunit of mTORC2. We found that Rictor phosphorylation requires mTORC1 activity and, more specifically, the p70 ribosomal S6 kinase 1 (S6K1). We identified several phosphorylation sites in Rictor and found that Thr1135 is directly phosphorylated by S6K1 in vitro and in vivo, in a rapamycin-sensitive manner. Phosphorylation of Rictor on Thr1135 did not affect mTORC2 assembly, kinase activity, or cellular localization. However, cells expressing a Rictor T1135A mutant were found to have increased mTORC2-dependent phosphorylation of Akt. In addition, phosphorylation of the Akt substrates FoxO1/3a and glycogen synthase kinase 3 alpha/beta (GSK3 alpha/beta) was found to be increased in these cells, indicating that S6K1-mediated phosphorylation of Rictor inhibits mTORC2 and Akt signaling. Together, our results uncover a new regulatory link between the two mTOR complexes, whereby Rictor integrates mTORC1-dependent signaling.

Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation.

BACKGROUND: The mammalian target of rapamycin (mTOR) is a Ser/Thr kinase that controls cell growth in response to mitogens, as well as amino acid and energy sufficiency. The scaffolding protein Raptor binds to mTOR and recruits substrates to the rapamycin-sensitive mTOR complex 1 (mTORC1). Although Raptor has been shown to be essential for mTORC1 activity, the mechanisms regulating Raptor function remain unknown. RESULTS: Here, we demonstrate that Raptor becomes highly phosphorylated on RXRXXpS/T consensus motifs after activation of the Ras/mitogen-activated protein kinase (MAPK) pathway. Using pharmacological inhibitors and RNA interference, we show that the p90 ribosomal S6 kinases (RSKs) 1 and 2 are required for Raptor phosphorylation in vivo and directly phosphorylate Raptor in vitro. Quantitative mass spectrometry and site-directed mutagenesis revealed that RSK specifically phosphorylates Raptor within an evolutionarily conserved region with no previously known function. Interestingly, expression of oncogenic forms of Ras and MEK that elevate mTORC1 activity induced strong and constitutive phosphorylation of Raptor on these residues. Importantly, we demonstrate that expression of Raptor mutants lacking RSK-dependent phosphorylation sites markedly reduced mTOR phosphotransferase activity, indicating that RSK-mediated phosphorylation of Raptor is important for mTORC1 activation by the Ras/MAPK pathway. CONCLUSIONS: We propose a unique mode of mTOR regulation in which RSK-mediated phosphorylation of Raptor regulates mTORC1 activity and thus suggest a means by which the Ras/MAPK pathway might promote rapamycin-sensitive signaling independently of the PI3K/Akt pathway.

Antibiotics used in the ambulatory management of acute COPD exacerbations.

STUDY OBJECTIVES: This study was conducted to describe the different antibiotics that are used in the home management of chronic obstructive pulmonary disease (COPD) exacerbations and to estimate the failure rates following the initiation of the antibiotic. METHODS: A cohort study was conducted. Patients enrolled in a COPD home management program were included in the analysis. Failure rates were defined as an additional prescription of an antibiotic, an emergency room visit, or a hospitalization for a COPD exacerbation in the 30 days following the initiation of the antibiotic. RESULTS: A total of 1180 episodes of antibiotic treatment were analyzed. Overall, 348 episodes led to a failure (29.5%). The most frequently used antibiotics were cefuroxime (45.9%) and ciprofloxacin (21.1%). CONCLUSION: This project demonstrates that a wide range of antibiotics were prescribed to our population of COPD patients with a moderate to severe form of the disease. Many treatment failures (about 30%) occurred in the 30-day period following the initiation of the home therapy with an antibiotic. Clinicians should be aware of this high failure rate when managing mild exacerbations of COPD at home.