Estimated mortality with early empirical antibiotic coverage of methicillin-resistant Staphylococcus aureus in hospitalized patients with bacterial infections: a systematic review and meta-analysis.

OBJECTIVES: We performed a systematic review and meta-analysis to estimate the effect of early active empirical antibiotics for MRSA on mortality, both in patients admitted with MRSA infections and in patients admitted with common infectious syndromes, for whom the causative pathogen may not have been MRSA. METHODS: A systematic literature search was conducted using Embase, MEDLINE, PubMed, Web of Science, Cochrane, Scopus and Google Scholar from the earliest entry through to 26 April 2022. We included studies of patients hospitalized with culture-proven MRSA infections that compared mortality rates depending on whether patients received active empirical antibiotics. The primary outcome was the adjusted OR for mortality with early active empirical antibiotics. After performing random-effects meta-analysis, we estimated the absolute risk reduction in mortality with initial empirical MRSA coverage for common infectious syndromes based on the prevalence of MRSA and baseline mortality rate for each syndrome, as reported in the medical literature. RESULTS: Of an initial 2136 unique manuscripts, 37 studies (11 661 participants) met our inclusion criteria. Fifteen studies (6066 participants) reported adjusted OR of mortality. The pooled adjusted OR for mortality was 0.64 (95% CI, 0.48-0.84), favouring active empirical antibiotics. The estimated absolute mortality benefit was 0% for patients with pneumonia, 0.1% (95% CI, 0.04-0.2) for non-critically ill patients with soft tissue infections, 0.04% (95% CI, 0.01-0.05) for non-critically ill patients with urinary tract infections, 0.6% (95% CI, 0.2-1.0) for patients with septic shock, and 1.0% (95% CI, 0.3-1.4) for patients with catheter-related infections admitted to ICUs. CONCLUSIONS: For the three most common infections in the hospital, the absolute benefit on mortality of empirical antibiotics against MRSA is 0.1% or less. Meaningful benefit of empirical antimicrobials against MRSA is limited to patients with approximately 30% mortality and 10% prevalence of MRSA. Avoiding empirical antibiotics against MRSA for low-risk infections would substantially reduce the use of anti-MRSA therapy.

Nonutility of procalcitonin for diagnosing bacterial pneumonia in patients with severe COVID-19.

Background: Patients hospitalized with COVID-19 are at significant risk for superimposed bacterial pneumonia. However, diagnosing superinfection is challenging due to its clinical resemblance to severe COVID-19. We therefore evaluated whether the immune biomarker, procalcitonin, could facilitate the diagnosis of bacterial superinfection. Methods: We retrospectively identified 185 patients hospitalized with severe COVID-19 who underwent lower respiratory culture; 85 had evidence of bacterial superinfection. Receiver operating characteristic curve and area under the curve (AUC) analyses were performed to assess the utility of procalcitonin for diagnosing superinfection. Results: This approach demonstrated that procalcitonin measured at the time of culture was incapable of distinguishing patients with bacterial infection (AUC, 0.52). The AUC not affected by exposure to antibiotics, treatment with immunomodulatory agents, or timing of procalcitonin measurement. Conclusion: Static measurement of procalcitonin does not aid in the diagnosis of superinfection in severe COVID-19.

Ulnar Artery Aneurysm in a 6-Month-Old: A Case Report.

BACKGROUND: Pediatric ulnar aneurysms are rare and, unlike their adult counterparts, cannot be explained by repetitive trauma to the palm. A small number of case reports describe diagnostic difficulty with these lesions and different treatments. METHODS: We present the case of a 6-month-old with an ulnar artery aneurysm of unknown cause. The diagnosis was supported with magnetic resonance imaging, and the lesion was resected. RESULTS: Because the hand remained well perfused, the ulnar artery was not reconstructed. CONCLUSIONS: Although the early result was good, the long-term outcome of this approach is unknown.

Expression and mutational analysis of c-CBL and its relationship to the MET receptor in head and neck squamous cell carcinoma.

MET is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and degraded by c-CBL E3-ubiquitin ligase. We investigated genetic variations of c-CBL in HNSCC and the relationship between c-CBL and MET expression. High MET, low c-CBL expression was detected in 10 cell lines and 73 tumor tissues. Two novel mutations (L254S, L281F), and the single nucleotide polymorphism (SNP) P782L were identified from archival tumor tissues. 27.3% of loss of heterozygosity was found at CBL locus. Ectopic expression of wild-type c-CBL in SCC-35 cells downregulated MET expression and decreased cell viability. These results suggest MET overexpression is related to altered c-CBL expression, which may influence tumorigenesis.

The Chicago Thoracic Oncology Database Consortium: A Multisite Database Initiative.

OBJECTIVE: An increasing amount of clinical data is available to biomedical researchers, but specifically designed database and informatics infrastructures are needed to handle this data effectively. Multiple research groups should be able to pool and share this data in an efficient manner. The Chicago Thoracic Oncology Database Consortium (CTODC) was created to standardize data collection and facilitate the pooling and sharing of data at institutions throughout Chicago and across the world. We assessed the CTODC by conducting a proof of principle investigation on lung cancer patients who took erlotinib. This study does not look into epidermal growth factor receptor (EGFR) mutations and tyrosine kinase inhibitors, but rather it discusses the development and utilization of the database involved. METHODS:  We have implemented the Thoracic Oncology Program Database Project (TOPDP) Microsoft Access, the Thoracic Oncology Research Program (TORP) Velos, and the TORP REDCap databases for translational research efforts. Standard operating procedures (SOPs) were created to document the construction and proper utilization of these databases. These SOPs have been made available freely to other institutions that have implemented their own databases patterned on these SOPs. RESULTS: A cohort of 373 lung cancer patients who took erlotinib was identified. The EGFR mutation statuses of patients were analyzed. Out of the 70 patients that were tested, 55 had mutations while 15 did not. In terms of overall survival and duration of treatment, the cohort demonstrated that EGFR-mutated patients had a longer duration of erlotinib treatment and longer overall survival compared to their EGFR wild-type counterparts who received erlotinib. DISCUSSION: The investigation successfully yielded data from all institutions of the CTODC. While the investigation identified challenges, such as the difficulty of data transfer and potential duplication of patient data, these issues can be resolved with greater cross-communication between institutions of the consortium. CONCLUSION: The investigation described herein demonstrates the successful data collection from multiple institutions in the context of a collaborative effort. The data presented here can be utilized as the basis for further collaborative efforts and/or development of larger and more streamlined databases within the consortium.

Medical student opinions on character development in medical education: a national survey.

BACKGROUND: Recently United States (US) medical schools have implemented curricular reforms to address issues of character in medical education. Very few studies have examined students' opinions about the importance of character development in medical school. This cross-sectional study assessed US medical students' opinions regarding character-focused education and their experiences receiving character feedback from educators. We mailed a questionnaire to 960 third year medical students from 24 medical schools. Respondents received a second questionnaire during their fourth year. Students answered three items that assessed their opinions regarding character development in medical education. They also indicated the frequency of positive/negative feedback regarding their character traits. We also tested associations between these opinions and various demographic, religious and spiritual characteristics. We used the χ(2) test to examine bivariate associations between each demographic/religious characteristic and students' opinions on character development or feedback. RESULTS: Excluding 41 ineligible respondents, the adjusted response rate for the first questionnaire was 61 % (n = 564/919) and 84 % (n = 474/564) for the follow-up questionnaire. Twenty-eight percent of students agreed that one could be a good physician without being a good person; 39 % agreed that educators should focus on science instead of students' characters; 72 % agreed that it was educators' responsibility to train students to have good character; 1 % of students reported no positive feedback from faculty regarding character traits; 50 % reported no negative feedback. CONCLUSIONS: US students in clinical clerkships receive predominately positive feedback from educators regarding character traits. A majority of medical students, regardless of demographic and religious characteristics, are receptive to the role of character development in medical education. This finding suggests that character-based approaches toward ethics and professionalism training may find renewed receptivity among medical students despite recent "professionalism movement" fatigue.

Tumor genome analysis includes germline genome: are we ready for surprises?

We sought to describe the spectrum of potential and confirmed germline genomic events incidentally identified during routine medium-throughput somatic tumor DNA sequencing, and to provide a framework for pre- and post-test consent and counseling for patients and families. Targeted tumor-only next-generation sequencing (NGS) had been used to evaluate for possible druggable genomic events obtained from consecutive new patients with metastatic gastroesophageal, hepatobiliary or colorectal cancer seen at the University of Chicago. A panel of medical oncologists, cancer geneticists and genetic counselors retrospectively grouped these patients (N = 111) based on probability of possessing a potentially inherited mutation in a cancer susceptibility gene, both prior to and after incorporating tumor-only NGS results. High-risk patients (determined from NGS results) were contacted and counseled in person by a genetic counselor (N = 21). When possible and indicated, germline genetic testing was offered. Of 8 evaluable high-risk patients, 7 underwent germline testing. Three (37.5%) had confirmed actionable germline mutations (all in the BRCA2 gene). NGS offers promise, but poses significant challenges for oncologists who are ill prepared to handle incidental findings that have clinical implications for at risk family members. In this relatively small cohort of patients undergoing tumor genomic testing for gastrointestinal malignancies, we incidentally identified 3 BRCA2 mutations carriers. This report underscores the need for oncologists to develop a framework for pre- and post-test communication of risks to patients undergoing routine tumor-only sequencing.

O-6-methylguanine-deoxyribonucleic acid methyltransferase methylation enhances response to temozolomide treatment in esophageal cancer.

BACKGROUND: World-wide, esophageal cancer is a growing epidemic and patients frequently present with advanced disease that is surgically inoperable. Hence, chemotherapy is the predominate treatment. Cytotoxic platinum compounds are mostly used, but their efficacy is only moderate. Newer alkylating agents have shown promise in other tumor types, but little is known about their utility in esophageal cancer. METHODS: We utilized archived human esophageal cancer samples and esophageal cancer cell lines to evaluate O-6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) hypermethylation status and determined sensitivity to the alkylating drug temozolomide (TMZ). Immunoblot analysis was performed to determine MGMT protein expression in cell lines. To assess and confirm the effect of TMZ treatment in a methylated esophageal cancer cell line in vivo, a mouse flank xenograft tumor model was utilized. RESULTS: Nearly 71% (12/17) of adenocarcinoma and 38% (3/8) of squamous cell carcinoma (SCC) patient samples were MGMT hypermethylated. Out of four adenocarcinoma and nine SCC cell lines tested, one of each histology was hypermethylated. Immunoblot analyses confirmed that hypermethylated cell lines did not express the MGMT protein. In vitro cell viability assays showed the methylated Kyse-140 and FLO cells to be sensitive to TMZ at an IC50 of 52-420 µM, whereas unmethylated cells Kyse-410 and SKGT-4 did not respond. In an in vivo xenograft tumor model with Kyse-140 cells, which are MGMT hypermethylated, TMZ treatment abrogated tumor growth by more than 60%. CONCLUSION: MGMT methylation may be an important biomarker in subsets of esophageal cancers and targeting by TMZ may be utilized to successfully treat these patients.

Paxillin mutations affect focal adhesions and lead to altered mitochondrial dynamics: relevance to lung cancer.

Cytoskeletal and focal adhesion abnormalities are observed in several types of cancer, including lung cancer. We have previously reported that paxillin (PXN) was mutated, amplified, and overexpressed in a significant number of lung cancer patient samples, that PXN protein was upregulated in more advanced stages of lung cancer compared with lower stages, and that the PXN gene was also amplified in some pre-neoplastic lung lesions. Among the mutations investigated, we previously found that PXN variant A127T in lung cancer cells enhanced cell proliferation and focal adhesion formation and colocalized with the anti-apoptotic protein B Cell Lymphoma 2 (BCL-2), which is known to localize to the mitochondria, among other sites. To further explore the effects of activating mutations of PXN on mitochondrial function, we cloned and expressed wild-type PXN and variants containing the most commonly occurring PXN mutations (P46S, P52L, G105D, A127T, P233L, T255I, D399N, E423K, P487L, and K506R) in a GFP-tagged vector using HEK-293 human embryonic kidney cells. Utilizing live-cell imaging to systematically study the effects of wild-type PXN vs. mutants, we created a model that recapitulates the salient features of the measured dynamics and conclude that compared with wild-type, some mutant clones confer enhanced focal adhesion and lamellipodia formation (A127T, P233L, and P487L) and some confer increased association with BCL-2, Dynamin-related Protein-1 (DRP-1), and Mitofusion-2 (MFN-2) proteins (P233L and D399N). Further, PXN mutants, through their interactions with BCL-2 and DRP-1, could regulate cisplatin drug resistance in human lung cancer cells. The data reported herein suggest that mutant PXN variants play a prominent role in mitochondrial dynamics with direct implications on lung cancer progression and hence, deserve further exploration as therapeutic targets.

Pathobiological implications of MUC4 in non-small-cell lung cancer.

INTRODUCTION: Altered expression of MUC4 plays an oncogenic role in various cancers, including pancreatic, ovarian, and breast. This study evaluates the expression and role of MUC4 in non-small-cell lung cancer (NSCLC). METHODS: We used a paired system of MUC4-expressing (H292) and MUC4-nonexpressing (A549) NSCLC cell lines to analyze MUC4-dependent changes in growth rate, migration, and invasion using these sublines. We also evaluated the alterations of several tumor suppressor, proliferation, and metastasis markers with altered MUC4 expression. Furthermore, the association of MUC4 expression (by immunohistochemistry) in lung cancer samples with patient survival was evaluated. RESULTS: MUC4-expressing lung cancer cells demonstrated a less proliferative and metastatic phenotype. Up-regulation of p53 in MUC4-expressing lung cancer cells led to the accumulation of cells at the G2/M phase of cell cycle progression. MUC4 expression attenuated Akt activation and decreased the expression of Cyclins D1 and E, but increased the expression of p21 and p27. MUC4 expression abrogated cancer cell migration and invasion by altering N- & E-cadherin expression and FAK phosphorylation. A decrease in MUC4 expression was observed with increasing tumor stage (mean composite score: stage I, 2.4; stage II, 1.8; stage III, 1.4; and metastatic, 1.2; p = 0.0093). Maximal MUC4 expression was associated with a better overall survival (p = 0.042). CONCLUSION: MUC4 plays a tumor-suppressor role in NSCLC by altering p53 expression in NSCLC. Decrease in MUC4 expression in advanced tumor stages also seems to confirm the novel protective function of MUC4 in NSCLC.

Utilisation of a thoracic oncology database to capture radiological and pathological images for evaluation of response to chemotherapy in patients with malignant pleural mesothelioma.

OBJECTIVE: An area of need in cancer informatics is the ability to store images in a comprehensive database as part of translational cancer research. To meet this need, we have implemented a novel tandem database infrastructure that facilitates image storage and utilisation. BACKGROUND: We had previously implemented the Thoracic Oncology Program Database Project (TOPDP) database for our translational cancer research needs. While useful for many research endeavours, it is unable to store images, hence our need to implement an imaging database which could communicate easily with the TOPDP database. METHODS: The Thoracic Oncology Research Program (TORP) imaging database was designed using the Research Electronic Data Capture (REDCap) platform, which was developed by Vanderbilt University. To demonstrate proof of principle and evaluate utility, we performed a retrospective investigation into tumour response for malignant pleural mesothelioma (MPM) patients treated at the University of Chicago Medical Center with either of two analogous chemotherapy regimens and consented to at least one of two UCMC IRB protocols, 9571 and 13473A. RESULTS: A cohort of 22 MPM patients was identified using clinical data in the TOPDP database. After measurements were acquired, two representative CT images and 0-35 histological images per patient were successfully stored in the TORP database, along with clinical and demographic data. DISCUSSION: We implemented the TORP imaging database to be used in conjunction with our comprehensive TOPDP database. While it requires an additional effort to use two databases, our database infrastructure facilitates more comprehensive translational research. CONCLUSIONS: The investigation described herein demonstrates the successful implementation of this novel tandem imaging database infrastructure, as well as the potential utility of investigations enabled by it. The data model presented here can be utilised as the basis for further development of other larger, more streamlined databases in the future.

Adjustment of trendy, gaming and less assimilated tweens in the United States.

Youth transitioning from childhood to adolescence (tweens) are exposed to increasing amounts of media and advertisement. Tweens have also emerged as a major marketing segment for corporate America with increasing buying power.We examine how tweens relate to popular culture messages and the association of different orientations to popular culture on adjustment. A secondary data analysis was conducted on a marketing survey of 3527 tweens, aged 10-14 years, obtained from 49 schools using stratified sampling methods. A sample of children nationwide described their preferences on popular culture and measures of psychosocial adjustment. Using cluster analysis, we identified three main clusters or adaptation styles of tweens: (1) those who enjoyed gaming, (2) trendy youth and (3) youth less assimilated into popular culture. There were differences in clusters based on adjustment indices. Gaming and trendy tweens reported higher self-perceptions of being smart, caring and confident compared to less assimilated tweens. However, gaming and trendy tweens worried more about fitting in than less assimilated tweens. Gaming and trendy tweens also endorsed future goals and traditional values more strongly than less assimilated tweens. Trendy tweens reported the strongest positive feelings about substance use. Results suggest that for each method of adaptation (gamer, trendy and less assimilated), there are unique differences in adjustment that can impact the child's future. Parents and service providers must recognize the complexity of these decisions and be sensitive to the unique needs of youth as they move from childhood to adolescence.