Precision or personalized cancer medicine is a clinical approach that strives to customize therapies based upon the genomic profiles of individual patient tumors. Machine learning (ML) is a ...computational method particularly suited to the establishment of predictive models of drug response based on genomic profiles of targeted cells. We report here on the application of our previously established open-source support vector machine (SVM)-based algorithm to predict the responses of 175 individual cancer patients to a variety of standard-of-care chemotherapeutic drugs from the gene-expression profiles (RNA-seq or microarray) of individual patient tumors. The models were found to predict patient responses with >80% accuracy. The high PPV of our algorithms across multiple drugs suggests a potential clinical utility of our approach, particularly with respect to the identification of promising second-line treatments for patients failing standard-of-care first-line therapies.
A panel of experts was convened by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) to update the 2010 clinical practice guideline on ...Clostridium difficile infection (CDI) in adults. The update, which has incorporated recommendations for children (following the adult recommendations for epidemiology, diagnosis, and treatment), includes significant changes in the management of this infection and reflects the evolving controversy over best methods for diagnosis. Clostridium difficile remains the most important cause of healthcare-associated diarrhea and has become the most commonly identified cause of healthcare-associated infection in adults in the United States. Moreover, C. difficile has established itself as an important community pathogen. Although the prevalence of the epidemic and virulent ribotype 027 strain has declined markedly along with overall CDI rates in parts of Europe, it remains one of the most commonly identified strains in the United States where it causes a sizable minority of CDIs, especially healthcare-associated CDIs. This guideline updates recommendations regarding epidemiology, diagnosis, treatment, infection prevention, and environmental management.
A panel of experts was convened by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) to update the 2010 clinical practice guideline on ...Clostridium difficile infection (CDI) in adults. The update, which has incorporated recommendations for children (following the adult recommendations for epidemiology, diagnosis, and treatment), includes significant changes in the management of this infection and reflects the evolving controversy over best methods for diagnosis. Clostridium difficile remains the most important cause of healthcare-associated diarrhea and has become the most commonly identified cause of healthcare-associated infection in adults in the United States. Moreover, C. difficile has established itself as an important community pathogen. Although the prevalence of the epidemic and virulent ribotype 027 strain has declined markedly along with overall CDI rates in parts of Europe, it remains one of the most commonly identified strains in the United States where it causes a sizable minority of CDIs, especially healthcare-associated CDIs. This guideline updates recommendations regarding epidemiology, diagnosis, treatment, infection prevention, and environmental management.
We examined the risk of sepsis within 90 days after discharge from a previous hospital stay by type of antibiotic received during the previous stay.
We retrospectively identified a cohort of ...hospitalized patients from the Truven Health MarketScan Hospital Drug Database. We examined the association between the use of certain antibiotics during the initial hospital stay, determined a priori, and the risk of postdischarge sepsis controlling for potential confounding factors in a multivariable logistic regression model. Our primary exposure was receipt of antibiotics more strongly associated with clinically important microbiome disruption. Our primary outcome was a hospital stay within 90 days of the index stay that included an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) discharge diagnosis of severe sepsis (ICD-9-CM code 995.92) or septic shock (785.52).
Among 516 hospitals, we randomly selected a single stay for eligible patients. In 0.17% of these patients, severe sepsis/septic shock developed within 90 days after discharge. The risk of sepsis associated with exposure to our high-risk antibiotics was 65% higher than in those without antibiotic exposure.
Our study identified an increased risk of sepsis within 90 days of discharge among patients with exposure to high-risk antibiotics or increased quantities of antibiotics during hospitalization. Given that a significant proportion of inpatient antimicrobial use may be unnecessary, this study builds on previous evidence suggesting that increased stewardship efforts in hospitals may not only prevent antimicrobial resistance, Clostridium difficile infection, and other adverse effects, but may also reduce unwanted outcomes potentially related to disruption of the microbiota, including sepsis.
Despite considerable amount of research, the poor prognosis of patients diagnosed with glioblastoma multiforme (GBM) critically needs new drug development to improve clinical outcomes. The ...development of an inflammatory microenvironment has long been considered important in the initiation and progression of glioblastoma; however, the success of developing therapeutic approaches to target inflammation for GBM therapy has yet been limited. Here, we summarize the accumulating evidence supporting a role for inflammation in the pathogenesis of glioblastoma, discuss anti‐inflammatory targets that could be relevant for GBM treatment and provide a perspective on the challenges faced in the development of drugs that target GBM inflammation. In particular, we will review the function of IL‐1β, IL‐6 and IL‐8 as well as the potential of kinase inhibitors targeting key players in inflammatory cell signalling cascades such as JAK, JNK and p38 MAPK.
Background. This report compares the clinical characteristics, epidemiologic investigations, infection-control evaluations, and microbiologic findings of all 7 of the cases of vancomycin-resistant ...Staphylococcus aureus (VRSA) infection in the United States during the period 2002–2006. Methods. Epidemiologic, clinical, and infection-control information was collected. VRSA isolates underwent confirmatory identification, antimicrobial susceptibility testing, pulsed-field gel electrophoresis, and typing of the resistance genes. To assess VRSA transmission, case patients and their contacts were screened for VRSA carriage. Results. Seven cases were identified from 2002 through 2006; 5 were reported from Michigan, 1 was reported from Pennsylvania, and 1 was reported from New York. All VRSA isolates were vanA positive and had a median vancomycin minimum inhibitory concentration of 512 µg/mL. All case patients had a history of prior methicillin-resistant S. aureus and enterococcal infection or colonization; all had several underlying conditions, including chronic skin ulcers; and most had received vancomycin therapy prior to their VRSA infection. Person-to-person transmission of VRSA was not identified beyond any of the case patients. Infection-control precautions were evaluated and were consistent with established guidelines. Conclusions. Seven patients with vanA-positive VRSA have been identified in the United States. Prompt detection by microbiology laboratories and adherence to recommended infection control measures for multidrug-resistant organisms appear to have prevented transmission to other patients.
In the 2003 Toronto SARS outbreak, SARS-CoV was transmitted in hospitals despite adherence to infection control procedures. Considerable controversy resulted regarding which procedures and behaviours ...were associated with the greatest risk of SARS-CoV transmission.
A retrospective cohort study was conducted to identify risk factors for transmission of SARS-CoV during intubation from laboratory confirmed SARS patients to HCWs involved in their care. All SARS patients requiring intubation during the Toronto outbreak were identified. All HCWs who provided care to intubated SARS patients during treatment or transportation and who entered a patient room or had direct patient contact from 24 hours before to 4 hours after intubation were eligible for this study. Data was collected on patients by chart review and on HCWs by interviewer-administered questionnaire. Generalized estimating equation (GEE) logistic regression models and classification and regression trees (CART) were used to identify risk factors for SARS transmission.
45 laboratory-confirmed intubated SARS patients were identified. Of the 697 HCWs involved in their care, 624 (90%) participated in the study. SARS-CoV was transmitted to 26 HCWs from 7 patients; 21 HCWs were infected by 3 patients. In multivariate GEE logistic regression models, presence in the room during fiberoptic intubation (OR = 2.79, p = .004) or ECG (OR = 3.52, p = .002), unprotected eye contact with secretions (OR = 7.34, p = .001), patient APACHE II score > or = 20 (OR = 17.05, p = .009) and patient Pa0(2)/Fi0(2) ratio < or = 59 (OR = 8.65, p = .001) were associated with increased risk of transmission of SARS-CoV. In CART analyses, the four covariates which explained the greatest amount of variation in SARS-CoV transmission were covariates representing individual patients.
Close contact with the airway of severely ill patients and failure of infection control practices to prevent exposure to respiratory secretions were associated with transmission of SARS-CoV. Rates of transmission of SARS-CoV varied widely among patients.
This research explores if poor grammaticality judgments of late (age of arrival
⩾
12) second language learners often attributed to being beyond the critical period for language acquisition can be ...better explained by processing difficulties due to (1) low L2 working memory capacity, (2) poor L2 decoding, and/or (3) inadequate L2 processing speed. In Experiment 1, late L2 learners and native speakers performed measures of English working memory, decoding, and speed, and a grammaticality judgment task. Compared to native speakers, late L2 learners were poorer on all measures. L2 span, L2 decoding ability, and arrival age correlated with L2 judgment accuracy. Late L2 learners had less difficult judging some structures (e.g., word order, questions) than others (e.g., articles, regular past). To simulate these deficits, Experiment 2 placed native speakers under stressors relevant to memory (low or high digit load), decoding (noise), or speed (response deadline, compressed speech) during grammaticality judgment. Span and decoding scores correlated with judgment under relevant stressors. The stressors caused native speakers to show selective deficits in judgment, with some structures (e.g., word order) being less vulnerable to stress than others (e.g., regular past). Performance of natives under noise or memory stress paralleled that of late L2 learners, indicating a role for decoding and memory abilities in explaining poor grammaticality judgment.
A
bstract
There exist tree-level generalizations of the Type-I and Type-III seesaw mechanisms that realize neutrino mass via low-energy effective operators with
d >
5. However, these generalizations ...also give radiative masses that can dominate the seesaw masses in regions of parameter space — i.e. they are not purely seesaw models, nor are they purely radiative models, but instead they are something in between. A recent work detailed the remaining minimal models of this type. Here we study the remaining model with
d
= 9 and investigate the collider phenomenology of the exotic quadruplet fermions it predicts. These exotics can be pair produced at the LHC via electroweak interactions and their subsequent decays produce a host of multi-lepton signals. Furthermore, the branching fractions for events with distinct charged-leptons encode information about both the neutrino mass hierarchy and the leptonic mixing phases. In large regions of parameter-space discovery at the LHC with a 5
σ
significance is viable for masses approaching the TeV scale.
The protein folding capacity of the endoplasmic reticulum (ER) is regulated by the unfolded protein response (UPR). The UPR senses unfolded proteins in the ER lumen and transmits that information to ...the cell nucleus, where it drives a transcriptional program that is tailored to re-establish homeostasis. Using thin section electron microscopy, we found that yeast cells expand their ER volume at least 5-fold under UPR-inducing conditions. Surprisingly, we discovered that ER proliferation is accompanied by the formation of autophagosome-like structures that are densely and selectively packed with membrane stacks derived from the UPR-expanded ER. In analogy to pexophagy and mitophagy, which are autophagic processes that selectively sequester and degrade peroxisomes and mitochondria, the ER-specific autophagic process described utilizes several autophagy genes: they are induced by the UPR and are essential for the survival of cells subjected to severe ER stress. Intriguingly, cell survival does not require vacuolar proteases, indicating that ER sequestration into autophagosome-like structures, rather than their degradation, is the important step. Selective ER sequestration may help cells to maintain a new steady-state level of ER abundance even in the face of continuously accumulating unfolded proteins.
PDF
