Evaluating Mental Health Outcomes in COVID-19 ICU Survivors: A Scoping Review of Measurement Tools.

Objective: The objective of this scoping review was to map the range of measurement tools used to study the prevalence of common mental health conditions in COVID-19 ICU survivors. Introduction: Increased rates of admission to and survivorship from intensive care units (ICUs) have been observed in recent years, particularly during the global pandemic. ICU patients are at a higher risk of developing depressive, anxiety, and PTSD symptoms. Due to the high burden of disease, an accurate understanding of long-term mental health challenges for this population is key. Unfortunately, there is significant variability in reported prevalence rates. Heterogeneity in measurement tools potentially contribute to this. Inclusion criteria: Studies were eligible if they (a) reported mental health outcomes of adult patients diagnosed with COVID-19 and admitted to an ICU, (b) used standardised mental health outcome measures, and (3) were peer-reviewed. Methods: Searches were conducted in PubMed, PsycInfo, and Scopus. The initial search retrieved 1234 publications. After de-duplication and title and abstract screening, 72 full-text articles were examined for eligibility and 44 articles were excluded, leaving 28 eligible studies. Reference lists of the eligible studies were screened, and four other studies were added. 32 studies were ultimately included in this review. Results: Significant heterogeneity of measurement tools and clinical thresholds were observed. Only 6.25% of the studies compared changes in mental health outcomes to baseline measurements. Between five and nine unique measurement tools were used to study depression, anxiety, and PTSD, respectively. Studies were also observed to use up to 19 different thresholds to establish the prevalence of PTSD. Conclusions: The heterogeneity of measurement tools and thresholds continues to confound prevalence rate estimations of mental health complications post-ICU admission. Future research will benefit from consistency in the use of recommended outcome measures and the use of psychometrically comparable cut-off points between key measures.

Co-surgeon versus Single-surgeon Outcomes in Free Tissue Breast Reconstruction: A Meta-analysis.

BACKGROUND: Autologous breast reconstruction offers superior long-term patient reported outcomes compared with implant-based reconstruction. Universal adoption of free tissue transfer has been hindered by procedural complexity and long operative time with microsurgery. In many specialties, co-surgeon (CS) approaches are reported to decrease operative time while improving surgical outcomes. This systematic review and meta-analysis synthesizes the available literature to evaluate the potential benefit of a CS approach in autologous free tissue breast reconstruction versus single-surgeon (SS). METHODS: A systematic review and meta-analysis was conducted using PubMed, Embase, and MEDLINE from inception to December 2022. Published reports comparing CS to SS approaches in uni- and bilateral autologous breast reconstruction were identified. Primary outcomes included operative time, postoperative outcomes, processes of care, and financial impact. Risk of bias was assessed and outcomes were characterized with effect sizes. RESULTS: Eight retrospective studies reporting on 9,425 patients were included. Compared with SS, CS approach was associated with a significantly shorter operative time (SMD -0.65, 95% confidence interval [CI] -1.01 to -0.29, p < 0.001), with the largest effect size in bilateral reconstructions (standardized mean difference [SMD] -1.02, 95% CI -1.37 to -0.67, p < 0.00001). CS was also associated with a significant decrease in length of hospitalization (SMD -0.39, 95% CI -0.71 to -0.07, p = 0.02). Odds of flap failure or surgical complications including surgical site infection, hematoma, fat necrosis, and reexploration were not significantly different. CONCLUSION: CS free tissue breast reconstruction significantly shortens operative time and length of hospitalization compared with SS approaches without compromising postoperative outcomes. Further research should model processes and financial viability of its adoption in a variety of health care models.

Evaluation of Real-World Vancomycin Dosing and Attainment of Therapeutic Drug Monitoring Targets.

In 2020, the Infectious Diseases Society of America (IDSA) recommended a change in vancomycin therapeutic drug monitoring from trough-based to AUC/MIC-based to optimize vancomycin's efficacy and reduce nephrotoxicity. Many hospitals have not implemented this change due to barriers such as the cost of AUC/MIC software and lack of provider familiarity. The purpose of this study was to determine the rate of AUC/MIC ratio target attainment using current trough-based vancomycin dosing practices at a city hospital. The rates of acute kidney injury (AKI) were also evaluated. Vancomycin orders were reviewed retrospectively to determine the expected AUC/MIC ratios using first-order pharmacokinetic equations over a 7-month period. Orders were excluded if they were written for a one-time dose, for individuals less than 18 years of age, or for those on hemodialysis. A total of 305 vancomycin orders were included in this review. Overall, 27.9% (85/305) of vancomycin orders attained the AUC/MIC ratio target of 400-600 mg·h/L as recommended by the guidelines. Nearly 35% (106/305) achieved AUC/MIC ratios below 400 mg·h/L and 37.4% (114/305) achieved AUC/MIC ratios above 600 mg·h/L. Orders for obese patients were significantly more likely to have below the target AUC/MIC ratios (68% vs. 23.9%, X2 48.48, p < 0.00001) and non-obese patients were significantly more likely to have above the target AUC/MIC ratios (45.7% vs. 12%, X2 27.36, p < 0.00001). The overall rate of acute kidney injury observed was 2.6%. Most vancomycin orders did not attain therapeutic drug monitoring targets, reflecting the ongoing clinical challenge of optimizing vancomycin doses and implementing new guideline recommendations.

Gender disparity in prestigious speaking roles: A study of 10 years of international conference programming in the field of gambling studies.

The objective of this study was to examine the distribution of prestigious speaking roles by gender at gambling studies conferences to better understand the state of gender representation within the field. Keyword searches were conducted in the fall of 2019. A total of 16 conferences that occurred between 2010-2019 and comprising 882 prestigious speaking opportunities were included. Quantitative analysis (i.e., t-tests, chi-squared posthoc tests) was undertaken to evaluate the representation of women speakers and if proportions were the same across genders for speakers. There were significantly less women than men within prestigious speaking roles at gambling studies conferences with only 30.2% of speakers being women (p < .001). This underrepresentation of women was consistent across conference location, speaker continent, speaker role, time, and across the majority of conferences. Women held prestigious speaking roles less frequently than men (M = 1.48 vs. 1.76; p < .001). A 9 to 1 (p < .001) ratio of men to women was found among top 10 most frequent prestigious speakers. While there was a higher proportion of women than men among student speakers and there was no significant gender disparity among early career researchers, there was a significantly lower proportion of women than men among speakers who hold more senior academic positions. There is an issue of gender disparity in prestigious speaking roles at conferences within the gambling studies field. This study highlights the need to counteract gender disparities and make room for diversity within the field.

Pharmacy student perceptions of remote learning and wellness during the pandemic: Lessons learned from a metropolitan commuter city.

INTRODUCTION: The purpose of this study was to assess pharmacy student perceptions of remote learning experiences and personal well-being during the COVID-19 pandemic in a metropolitan commuter city. METHODS: A survey was developed and sent to pharmacy students from the three pharmacy colleges in New York City in January 2021. The survey domains consisted of demographics, personal well-being, classroom experiences, and pandemic and post-pandemic preferred learning modalities and reasons. RESULTS: From a total of 1354 students from professional years one, two, and three across the three colleges, completed responses were received from 268 students (20% response rate). More than half of the respondents (55.6%) reported a negative impact of the pandemic on their well-being. More than half of the respondents (58.6%) reported more time to study. When students were asked their preferred mode of pharmacy education delivery during the pandemic and post-pandemic, a quarter (24.5%) preferred remote learning for all courses during the pandemic, and only a quarter (26.8%) preferred traditional classrooms for all courses post-pandemic. Approximately 60% of the respondents preferred some type of remote learning post-pandemic. CONCLUSIONS: Pharmacy student learning has been and continues to be impacted by the COVID-19 pandemic, especially for pharmacy students in New York City. This study sheds light on the remote learning experiences and preferences of pharmacy students in a commuter city. Future studies could assess pharmacy student learning experiences and preferences after return to campus.

Use of a Structured Method of Antimicrobial Stewardship at a City Hospital by Pharmacy Students.

The objective of this study was to determine the utility of a structured method of antimicrobial stewardship by Advanced Pharmacy Practice Experience students and assess student perceptions of the tool. Pharmacy students on rotation were trained to utilize a structured team antibiotic review form (TARF) as a tool to participate in antimicrobial stewardship. Students completed anonymous evaluations regarding their confidence in performing stewardship after completing their rotation, and preceptors quantified total student interventions. Data analysis was conducted using descriptive statistics. The Fisher's Exact Test was used to compare students' confidence before and after using TARFs. Twenty-six students participated in antimicrobial stewardship using TARFs, resulting in 889 interventions. Nearly 96% of students reported that TARFs helped them evaluate patient antibiotics in a way that was easy to follow and that TARFs provided them with an organized and structured way to systematically evaluate antibiotics. All students felt that the TARFs increased their knowledge on how to evaluate antibiotics. Significantly more students were confident in participating in antimicrobial stewardship after using the TARF. TARF use allowed students to substantially contribute to stewardship, and provided them with a structured guide allowing for improved student knowledge and confidence.

An Overview of the Changing Landscape of Treatment for Advanced Melanoma.

Melanoma-the deadliest form of skin cancer-leads to thousands of deaths each year. Although melanoma is less common than basal cell and squamous cell skin cancers, melanoma is more dangerous because it is more likely to spread to other parts of the body, such as lymph nodes, if not diagnosed and treated early. Data from the National Cancer Institute indicate a steady rise in new cases of melanoma and, unfortunately, a steady rate in the number of deaths through 2013. Ninety percent of melanomas are linked to inadequate sun protection from ultraviolet rays or the tanning habits of young adults. Over the past 5 years, however, there have been a variety of new pharmacologic treatments for advanced melanoma including immunotherapy, targeted agents (BRAF and MEK inhibitors), and oncolytic viral therapy. In this article, we review the current literature on the treatment of melanoma, with a focus on emerging therapies.

Non-small-cell lung cancer after breast cancer: a population-based study of clinicopathologic characteristics and survival outcomes in 3529 women.

INTRODUCTION: Annually, 1.4 million women worldwide are diagnosed with breast cancer (BC) and are at risk for another common malignancy: non-small-cell lung cancer (NSCLC). No large population-based study has examined subsequent survival. METHODS: Women with histologically confirmed NSCLC after BC (BC-NSCLC, n = 3529) were identified in SEER-18 registries (1988-2009). Clinicopathologic characteristics and survival outcomes were compared among women with first primary NSCLC (NSCLC-1, n = 151,628). Cox regression analyses were adjusted for patient, BC, and NSCLC factors. RESULTS: BC-NSCLC was diagnosed at earlier stages (34% localized, 30% regional, 36% distant) than NSCLC-1 (22%, 28%, and 50%, respectively; p < 0.0001). For localized and regional BC-NSCLC, surgical resection rates were higher than NSCLC-1 (72% versus 69% [p < 0.01] and 56% versus 46% [p < 0.0001]), respectively). Radiotherapy was given less often for BC-NSCLC than NSCLC-1 (localized: 15% versus 18%, p < 0.004; regional: 38% versus 49%, p < 0.0001). Median overall survival (OS) after localized, regional, and distant BC-NSCLC was 5.1 years, 1.9 years, and 5.8 months, respectively. For NSCLC-1, median OS was 4.6 years, 1.5 years, and 4.6 months, respectively. BC history did not affect OS for localized NSCLC, and OS was modestly greater after regional (p = 0.016) and distant (p < 0.0001) BC-NSCLC compared with NSCLC-1. BC radiotherapy to the ipsilateral chest did not unfavorably influence OS. CONCLUSIONS: BC survivors are more likely to be diagnosed with earlier stage NSCLC versus first primary NSCLC patients, perhaps reflecting heightened surveillance compared with the general population. In contrast to prior studies of NSCLC in survivors of lymphopoietic malignancies, BC history does not appear to adversely affect OS after NSCLC.

A genome-wide miRNA screen revealed miR-603 as a MGMT-regulating miRNA in glioblastomas.

MGMT expression is a critical determinant for therapeutic resistance to DNA alkylating agents. We previously demonstrated that MGMT expression is post-transcriptionally regulated by miR-181d and other miRNAs. Here, we performed a genome-wide screen to identify MGMT regulating miRNAs. Candidate miRNAs were further tested for inverse correlation with MGMT expression in clinical specimens. We identified 15 candidate miRNAs and characterized the top candidate, miR-603. Transfection of miR-603 suppressed MGMT mRNA/protein expression in vitro and in vivo; this effect was reversed by transfection with antimiR-603. miR-603 affinity-precipitated with MGMT mRNA and suppressed luciferase activity in an MGMT-3'UTR-luciferase assay, suggesting direct interaction between miR-603 and MGMT 3'UTR. miR-603 transfection enhanced the temozolomide (TMZ) sensitivity of MGMT-expressing glioblastoma cell lines. Importantly, miR-603 mediated MGMT suppression and TMZ resistance were reversed by expression of an MGMT cDNA. In a collection of 74 clinical glioblastoma specimens, both miR-603 and miR-181d levels inversely correlated with MGMT expression. Moreover, a combined index of the two miRNAs better reflected MGMT expression than each individually. These results suggest that MGMT is co-regulated by independent miRNAs. Characterization of these miRNAs should contribute toward strategies for enhancing the efficacy of DNA alkylating agents.

Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma.

Glioblastoma remains one of the deadliest of human cancers, with most patients succumbing to the disease within two years of diagnosis. The available data suggest that simultaneous inactivation of critical nodes within the glioblastoma molecular circuitry will be required for meaningful clinical efficacy. We conducted parallel genome-wide shRNA screens to identify such nodes and uncovered a number of G-Protein Coupled Receptor (GPCR) neurotransmitter pathways, including the Dopamine Receptor D2 (DRD2) signaling pathway. Supporting the importance of DRD2 in glioblastoma, DRD2 mRNA and protein expression were elevated in clinical glioblastoma specimens relative to matched non-neoplastic cerebrum. Treatment with independent si-/shRNAs against DRD2 or with DRD2 antagonists suppressed the growth of patient-derived glioblastoma lines both in vitro and in vivo. Importantly, glioblastoma lines derived from independent genetically engineered mouse models (GEMMs) were more sensitive to haloperidol, an FDA approved DRD2 antagonist, than the premalignant astrocyte lines by approximately an order of magnitude. The pro-proliferative effect of DRD2 was, in part, mediated through a GNAI2/Rap1/Ras/ERK signaling axis. Combined inhibition of DRD2 and Epidermal Growth Factor Receptor (EGFR) led to synergistic tumoricidal activity as well as ERK suppression in independent in vivo and in vitro glioblastoma models. Our results suggest combined EGFR and DRD2 inhibition as a promising strategy for glioblastoma treatment.

Key concepts in glioblastoma therapy.

Glioblastoma is the most common form of primary brain cancer and remains one of the most aggressive forms of human cancer. Current standard of care involves maximal surgical resection followed by concurrent therapy with radiation and the DNA alkylating agent temozolomide. Despite this aggressive regimen, the median survival remains approximately 14 months. Meaningful strategies for therapeutic intervention are desperately needed. Development of such strategies will require an understanding of the therapeutic concepts that have evolved over the past three decades. This article reviews the key principles that drive the formulation of therapeutic strategies in glioblastoma. Specifically, the concepts of tumour heterogeneity, oncogene addiction, non-oncogene addiction, tumour initiating cells, tumour microenvironment, non-coding sequences and DNA damage response will be reviewed.

Genomic profiling of glioblastoma: convergence of fundamental biologic tenets and novel insights.

With advances in genomic profiling and sequencing technology, we are beginning to understand the landscape of the genetic events that accumulated during the neoplastic process. The insights gleamed from these genomic profiling studies with regards to glioblastoma etiology has been particularly satisfying because it cemented the clinical pertinence of major concepts in cancer biology-concepts developed over the past three decades. This article will review how the glioblastoma genomic data set serves as an illustrative platform for the concepts put forward by Hanahan and Weinberg on the cancer phenotype. The picture emerging suggests that most glioblastomas evolve along a multitude of pathways rather than a single defined pathway. In this context, the article will further provide a discussion of the subtypes of glioblastoma as they relate to key principles of developmental neurobiology.

DNA damage response and repair: insights into strategies for radiation sensitization of gliomas.

The incorporation of radiotherapy into multimodality treatment plans has led to significant improvements in glioma patient survival. However, local recurrence from glioma resistance to ionizing radiation remains a therapeutic challenge. The tumoricidal effect of radiation therapy is largely attributed to the induction of dsDNA breaks (DSBs). In the past decade, there have been tremendous strides in understanding the molecular mechanisms underlying DSB repair. The identification of gene products required for DSB repair has provided novel therapeutic targets. Recent studies revealed that many US FDA-approved cancer agents inhibit DSB repair by interacting with repair proteins. This article will aim to provide discussion of DSB repair mechanisms to provide molecular targets for radiation sensitization of gliomas and a discussion of FDA-approved cancer therapies that modulate DSB repair to highlight opportunities for combination therapy with radiotherapy for glioma therapy.

Post-transcriptional regulation of O(6)-methylguanine-DNA methyltransferase MGMT in glioblastomas.

BACKGROUND: The DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) confers therapeutic resistance to DNA alkylating agents, including temozolomide. It is largely believed that MGMT promoter methylation is associated with down regulation of MGMT transcription and corresponding protein expression, thereby predisposing tumor cells to the toxic effect of temozolomide. Here we rigorously examined this underlying assumption. METHODS: We examined the correlation between MGMT promoter methylation, transcription, and protein expression using The Cancer Genome Atlas (TCGA) glioblastoma database as well as an independent collection of glioblastoma specimens. RESULTS: In both analyses, we found that MGMT promoter methylation status correlates well with low MGMT mRNA levels (p = 0.04). On the other hand, glioblastomas with unmethylated MGMT promoters exhibited a wide range of MGMT mRNA expression. Intriguingly, the MGMT mRNA levels correlated poorly with MGMT protein levels by Western blotting (R(2) = 0.04, p = 0.34) or by ImmunoHistoChemical (IHC) stain quantitation (R(2) = 0.02, p = 0.50). To exclude the possibility that the poor correlation was due to substandard specimens, we determined the mRNA and protein levels of Colony Stimulating Factor 1 (CSF1), a gene previously shown to exhibit excellent mRNA/protein correlation. In contrast to MGMT, the mRNA level of CSF1 correlated well with the protein level (R(2) = 0.47, p = 0.001). Importantly, long-term passaged glioblastoma cell lines with comparable MGMT transcript levels differed in MGMT protein levels, suggesting mechanisms of post-transcriptional regulation. Accordingly, the correlation between MGMT promoter methylation and MGMT protein expression was poor (p = 0.27). In silico analysis predicted potential binding sites for several miRNA within the 3'UTR of MGMT, suggesting a mechanism for the post-transcriptional of MGMT. CONCLUSION: Our results suggest mechanisms such as miRNA mediated regulation for post-transcriptional regulation of MGMT. Identification of these mechanisms should enhance the value of MGMT based prognostic or predictive biomarker strategies.

Targeting EGFR induced oxidative stress by PARP1 inhibition in glioblastoma therapy.

Despite the critical role of Epidermal Growth Factor Receptor (EGFR) in glioblastoma pathogenesis, EGFR targeted therapies have achieved limited clinical efficacy. Here we propose an alternate therapeutic strategy based on the conceptual framework of non-oncogene addiction. A directed RNAi screen revealed that glioblastoma cells over-expressing EGFRvIII, an oncogenic variant of EGFR, become hyper-dependent on a variety of DNA repair genes. Among these, there was an enrichment of Base Excision Repair (BER) genes required for the repair of Reactive Oxygen Species (ROS)-induced DNA damage, including poly-ADP ribose polymerase 1 (PARP1). Subsequent studies revealed that EGFRvIII over-expression in glioblastoma cells caused increased levels of ROS, DNA strand break accumulation, and genome instability. In a panel of primary glioblastoma lines, sensitivity to PARP1 inhibition correlated with the levels of EGFR activation and oxidative stress. Gene expression analysis indicated that reduced expression of BER genes in glioblastomas with high EGFR expression correlated with improved patient survival. These observations suggest that oxidative stress secondary to EGFR hyper-activation necessitates increased cellular reliance on PARP1 mediated BER, and offer critical insights into clinical trial design.

Functional genomics to explore cancer cell vulnerabilities.

Our understanding of glioblastoma multiforme (GBM), the most common form of primary brain cancer, has been significantly advanced by recent efforts to characterize the cancer genome using unbiased high-throughput sequencing analyses. While these studies have documented hundreds of mutations, gene copy alterations, and chromosomal abnormalities, only a subset of these alterations are likely to impact tumor initiation or maintenance. Furthermore, genes that are not altered at the genomic level may play essential roles in tumor initiation and maintenance. Identification of these genes is critical for therapeutic development and investigative methodologies that afford insight into biological function. This requirement has largely been fulfilled with the emergence of RNA interference (RNAi) and high-throughput screening technology. In this article, the authors discuss the application of genome-wide, high-throughput RNAi-based genetic screening as a powerful tool for the rapid and cost-effective identification of genes essential for cancer proliferation and survival. They describe how these technologies have been used to identify genes that are themselves selectively lethal to cancer cells, or synthetically lethal with other oncogenic mutations. The article is intended to provide a platform for how RNAi libraries might contribute to uncovering glioma cell vulnerabilities and provide information that is highly complementary to the structural characterization of the glioblastoma genome. The authors emphasize that unbiased, systems-level structural and functional genetic approaches are complementary efforts that should facilitate the identification of genes involved in the pathogenesis of GBM and permit the identification of novel drug targets.