A pan-cancer analysis implicates human NKIRAS1 as a tumor-suppressor gene.

The NF-κB family of transcription factors and the Ras family of small GTPases are important mediators of proproliferative signaling that drives tumorigenesis and carcinogenesis. The κB-Ras proteins were previously shown to inhibit both NF-κB and Ras activation through independent mechanisms, implicating them as tumor suppressors with potentially broad relevance to human cancers. In this study, we have used two mouse models to establish the relevance of the κB-Ras proteins for tumorigenesis. Additionally, we have utilized a pan-cancer bioinformatics analysis to explore the role of the κB-Ras proteins in human cancers. Surprisingly, we find that the genes encoding κB-Ras 1 (NKIRAS1) and κB-Ras 2 (NKIRAS2) are rarely down-regulated in tumor samples with oncogenic Ras mutations. Reduced expression of human NKIRAS1 alone is associated with worse prognosis in at least four cancer types and linked to a network of genes implicated in tumorigenesis. Our findings provide direct evidence that loss of NKIRAS1 in human tumors that do not carry oncogenic RAS mutations is associated with worse clinical outcomes.

Activity Measure for Post-Acute Care "6-Clicks" for the Prediction of Short-term Clinical Outcomes in Individuals Hospitalized With COVID-19: A Retrospective Cohort Study.

OBJECTIVE: To determine the ability of the Activity Measure for Post-Acute Care (AM-PAC) "6-Clicks" assessments of mobility and activity to predict key clinical outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19). DESIGN: Retrospective cohort study. SETTING: An academic health system in the United States consisting of 5 inpatient hospitals. PARTICIPANTS: Adult patients (N=1486) urgently or emergently admitted who tested positive for COVID-19 and had at least 1 AM-PAC assessment. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Discharge destination, hospital length of stay, in-hospital mortality, and readmission. RESULTS: A total of 1486 admission records were included in the analysis. After controlling for covariates, initial and final mobility (odds ratio, 0.867 and 0.833, respectively) and activity scores (odds ratio, 0.892 and 0.862, respectively) were both independent predictors of discharge destination with a high accuracy of prediction (area under the curve [AUC]=0.819-0.847). Using a threshold score of 17.5, sensitivity ranged from 0.72-0.79, whereas specificity ranged from 0.74-0.83. Both initial AM-PAC mobility and activity scores were independent predictors of mortality (odds ratio, 0.885 and 0.877, respectively). Initial mobility, but not activity, scores were predictive of prolonged length of stay (odds ratio, 0.957 and 0.980, respectively). However, the accuracy of prediction for both outcomes was weak (AUC=0.659-0.679). AM-PAC scores did not predict rehospitalization. CONCLUSIONS: Functional status as measured by the AM-PAC "6-Clicks" mobility and activity scores are independent predictors of key clinical outcomes individual hospitalized with COVID-19.

TIGER Team: Rapid Response at the University of Missouri.

By the end of the 20th century, health care organizations worldwide were recognizing the benefits of a quick response when patients were experiencing a clinical decline and the difficulty in achieving that goal. The University of Missouri STAT Nurse program, developed in 1989, was an early innovation to deliver the "right care" at the "right time" every time. Over the years, the STAT Nurse program evolved and became the core component of a Rapid Response System. Today Rapid Response at University of Missouri Health Care is called the Targeted Interventional Group Emergency Response Team, also known as the TIGER Team after the much beloved University mascot.

Reevaluating Rehabilitation Practice for Patients Who Were Critically Ill After COVID-19 Infection: An Administrative Case Report.

OBJECTIVE: The goal of this case report is to describe the process, challenges, and opportunities of implementing rehabilitation for individuals who were critically ill and required both mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO) support following a coronavirus 2019 (COVID-19) infection in an academic medical center. METHODS: This administrative case report is set in a heart and vascular intensive care unit, a 35-bed critical care unit that provides services for patients with various complex cardiovascular surgical interventions, including transplantation. Patients were admitted to the heart and vascular intensive care unit with either COVID-19 acute respiratory distress syndrome or pulmonary fibrosis for consideration of bilateral orthotropic lung transplantation. The authors describe the process of establishing rehabilitation criteria for patients who, by previously established guidelines, would be considered too ill to engage in rehabilitation. RESULTS: The rehabilitation team, in coordination with an interprofessional team of critical care providers including physicians, respiratory care providers, perfusionists, and registered nurses, collaborated to implement a rehabilitation program for patients with critical COVID-19 being considered for bilateral orthotropic lung transplantation. This was accomplished by (1) reviewing previously published guidelines and practices; (2) developing an interdisciplinary framework for the consideration of rehabilitation treatment; and (3) implementing the framework for patients in our heart and vascular intensive care unit. CONCLUSION: In response to the growing volume of patients admitted with critical COVID-19, the team initiated and developed an interprofessional framework and successfully provided rehabilitation services to patients who were critically ill. While resource-intensive, the process demonstrates that rehabilitation can be implemented on a case-by-case basis for select patients receiving extracorporeal membrane oxygenation and MV, who would previously have been considered too critically ill for rehabilitation services. IMPACT: Rehabilitating patients with end-stage pulmonary disease on extracorporeal membrane oxygenation and MV support is challenging but feasible with appropriate interprofessional collaboration and knowledge sharing.

APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential.

Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBECs) are cytosine deaminases involved in innate and adaptive immunity. However, some APOBEC family members can also deaminate host genomes to generate oncogenic mutations. The resulting mutations, primarily signatures 2 and 13, occur in many tumor types and are among the most common mutational signatures in cancer. This review summarizes the current evidence implicating APOBEC3s as major mutators and outlines the exogenous and endogenous triggers of APOBEC3 expression and mutational activity. The review also discusses how APOBEC3-mediated mutagenesis impacts tumor evolution through both mutagenic and non-mutagenic pathways, including by inducing driver mutations and modulating the tumor immune microenvironment. Moving from molecular biology to clinical outcomes, the review concludes by summarizing the divergent prognostic significance of APOBEC3s across cancer types and their therapeutic potential in the current and future clinical landscapes.

Analysis of Several Common APOBEC-type Mutations in Bladder Tumors Suggests Links to Viral Infection.

FGFR3 and PIK3CA are among the most frequently mutated genes in bladder tumors. We hypothesized that recurrent mutations in these genes might be caused by common carcinogenic exposures such as smoking and other factors. We analyzed 2,816 bladder tumors with available data on FGFR3 and/or PIK3CA mutations, focusing on the most recurrent mutations detected in ≥10% of tumors. Compared to tumors with other FGFR3/PIK3CA mutations, FGFR3-Y375C was more common in tumors from smokers than never-smokers (P = 0.009), while several APOBEC-type driver mutations were enriched in never-smokers: FGFR3-S249C (P = 0.013) and PIK3CA-E542K/PIK3CA-E545K (P = 0.009). To explore possible causes of these APOBEC-type mutations, we analyzed RNA sequencing (RNA-seq) data from 798 bladder tumors and detected several viruses, with BK polyomavirus (BKPyV) being the most common. We then performed IHC staining for polyomavirus (PyV) Large T-antigen (LTAg) in an independent set of 211 bladder tumors. Overall, by RNA-seq or IHC-LTAg, we detected PyV in 26 out of 1,010 bladder tumors with significantly higher detection (P = 4.4 × 10-5), 25 of 554 (4.5%) in non-muscle-invasive bladder cancers (NMIBC) versus 1 of 456 (0.2%) of muscle-invasive bladder cancers (MIBC). In the NMIBC subset, the FGFR3/PIK3CA APOBEC-type driver mutations were detected in 94.7% (18/19) of PyV-positive versus 68.3% (259/379) of PyV-negative tumors (P = 0.011). BKPyV tumor positivity in the NMIBC subset with FGFR3- or PIK3CA-mutated tumors was also associated with a higher risk of progression to MIBC (P = 0.019). In conclusion, our results support smoking and BKPyV infection as risk factors contributing to bladder tumorigenesis in the general patient population through distinct molecular mechanisms. PREVENTION RELEVANCE: Tobacco smoking likely causes one of the most common mutations in bladder tumors (FGFR3-Y375C), while viral infections might contribute to three others (FGFR3-S249C, PIK3CA-E542K, and PIK3CA-E545K). Understanding the causes of these mutations may lead to new prevention and treatment strategies, such as viral screening and vaccination.

Acute Rehabilitation of a Patient With COVID-19 Myocarditis: A Case Report.

OBJECTIVE: The purpose of this case report is to describe the acute rehabilitation of an individual with severe COVID-19 complicated by myocarditis, focusing on both facility-wide and patient-specific strategies. METHODS: A 50-year-old male presented to the emergency department with progressive dyspnea and confirmed COVID-19. He developed hypoxic respiratory failure and heart failure requiring prolonged mechanical ventilation. Mobility was limited by severe impairments in strength, endurance, balance, and cognition. The referral, screening, and rehabilitation of this patient were guided by a COVID-19 Service Delivery Plan designed to maximize the effectiveness and efficiency of care delivery while minimizing staff exposure to the virus. Coordinated physical and occupational therapy sessions focused on progressive mobility and cognitive retraining. Progress was monitored using a series of standardized outcome measures, including the Activity Measure for Post-Acute Care, Timed Up and Go test, and the Saint Louis University Mental Status examination. RESULTS: Rehabilitation was initiated on day 18, and the patient participated in 19 treatment sessions, each approximately 30 minutes, over the remaining 30 days of his hospital stay. His Activity Measure for Post-Acute Care mobility and function scores both improved from 100% to 0% disability, he experienced substantial improvements in both Timed Up and Go (Δ = 4.2 seconds) and Saint Louis University Mental Status (discharge score = 25). There were no adverse events. He was discharged to home with his family and home rehabilitation services. CONCLUSION: COVID-19 contributed to severe declines in mobility and function in this middle-aged man. He experienced substantial gains in his function, mobility, and cognition during his in-hospital rehabilitation, which was guided by a facility-wide plan to prevent virus transmission. IMPACT: The rehabilitation of individuals with severe COVID-19 presents significant challenges, both at the level of the individual patient and the whole facility. This report describes clinical decision-making required to manage these individuals in the setting of a global pandemic.

Quantitative peripheral muscle ultrasound in sepsis: Muscle area superior to thickness.

PURPOSE: The objective of this study is to describe the relationship between two quantitative muscle ultrasound measures, the rectus femoris cross-sectional area (RF-CSA) and quadriceps muscle thickness, with volitional measures of strength and function in critically ill patients with sepsis. MATERIALS AND METHODS: We performed a prospective study of patients admitted to a medical ICU with sepsis and shock or respiratory failure. We examined the association of two ultrasound measurements - the RF-CSA and quadriceps muscle thickness - with strength and function at day 7. Strength was determined using the Medical Research Council Score and function using Physical Function in the ICU Test, scored. RESULTS: Twenty-nine patients were enrolled; 19 patients had outcome testing performed. Over 7days, RF-CSA and thickness decreased by an average of 23.2% and 17.9%, respectively. The rate of change per day of RF-CSA displayed a moderate correlation with strength (ρ 0.51, p-value 0.03) on day 7. Baseline and day 7 RF-CSA did not show a significant correlation with either outcome. Quadriceps muscle thickness did not significantly correlate with either outcome. CONCLUSIONS: Muscle atrophy as detected by the rate of change in RF-CSA moderately correlated with strength one week after sepsis admission.

Autosomal recessive severe combined immunodeficiency of Jack Russell terriers.

Because of unexplained mortality among 33 sibling offspring of a single pair of dogs, a family of Jack Russell Terriers was investigated. Twelve pups, 5 male and 7 female, died between 8 and 14 weeks of age. Six of those animals died in the field within 50 hours following vaccination with modified live vaccines. Subsequent histopathologic examination revealed the absence of splenic white pulp in 4 dogs and hepatic inclusions diagnostic for adenoviral infection in 2 dogs. Two additional litters yielded 2 pups with the same splenic and hepatic lesions. These observations led to a detailed study of 7 siblings whelped specifically for this investigation. Four of these 7 siblings had a profound lymphopenia and a decrease in serum immunoglobulins. Six of these dogs were necropsied at 7 weeks of age, and 4 of them had marked hypoplasia of all lymphoid tissue. The affected pups had an 86% decrease in mean thymic weight, with poor corticomedullary differentiation, and very few CD3-positive (T cell) thymocytes were detected immunohistochemically. However, the affected thymic tissue stained intensely with a immunochemical stain for cytokeratin. The other affected lymphoid tissues were identified histologically only by stromal architectural characteristics. Lymph nodes lacked both CD3 and CD79a (B cell) positive cells. The analyzed breeding data were consistent with an autosomal recessive mode of inheritance. This canine severe combined immunodeficiency has immunologic and pathologic features similar to those observed in immunodeficient C.B-17 mice and Arabian horses.

Adherence of pediatric asthma patients with oral corticosteroid prescriptions following pediatric emergency department visit or hospitalization.

OBJECTIVE: To determine caregiver adherence to oral corticosteroids prescribed in the emergency department for pediatric patients with an acute asthma exacerbation and to identify caregivers' perceived barriers to adherence with prescribed oral corticosteroids. METHOD: We conducted telephone interviews 7 to 9 days following a patient's presentation to an urban children's hospital emergency department for an acute asthma exacerbation. The telephone interview conducted with caregivers of pediatric asthma patients included questions regarding whether caregivers filled a prescription for an oral corticosteroid, the number of days the caregiver gave the medication, and the perceived barriers to adherence by the caregiver. RESULTS: During the study period, oral corticosteroid prescriptions were written for 161 of 172 patients completing the phone interview (93.6%). Of these patients, 98.7% reported filling the prescription, with caregivers of female patients and adolescent patients less likely to fill prescriptions than caregivers of male and younger patients. Asthma patient caregivers, however, reported adherence to the prescribed length of oral corticosteroid therapy only 64% of the time. Caregivers worried about the side effects of oral corticosteroids 60% of the time. CONCLUSIONS: Efforts to increase corticosteroid adherence in children with acute asthma exacerbations should consider the causes for variation in caregiver adherence with length of therapy as well as caregiver perceptions regarding corticosteroid side effects.

Influence of plant-earthworm interactions on SOM chemistry and p,p'-DDE bioaccumulation.

Laboratory experiments assessed how bioaccumulation of weathered p,p'-DDE from soil and humic acid (HA) chemistry are affected by interactions between the plants Cucurbita pepo ssp. pepo and ssp. ovifera and the earthworms Eisenia fetida, Lumbricus terrestris, and Apporectodea caliginosa. Total organochlorine phytoextraction by ssp. pepo increased at least 25% in the presence of any of the earthworm species (relative to plants grown in isolation). Uptake of the compound by ssp. ovifera was unaffected by earthworms. Plants influenced earthworm bioaccumulation as well. When combined with pepo, p,p'-DDE levels in E. fetida decreased by 50%, whereas, in the presence of ovifera, bioconcentration by L. terrestris increased by more than 2-fold. Spectral analysis indicated a decrease in hydrophobicity of HA in each of the soils in which both pepo and earthworms were present. However, HA chemistry from ovifera treatments was largely unaffected by earthworms. Risk assessments of contaminated soils should account for species interactions, and SOM chemistry may be a useful indictor of pollutant bioaccumulation.

Theory into practice: implementing ecosystem management objectives in the USDA Forest Service.

In the United States and around the world, scientists and practitioners have debated the definition and merits of ecosystem management as a new approach to natural resource management. While these debates continue, a growing number of organizations formally have adopted ecosystem management. However, adoption does not necessarily lead to successful implementation, and theories are not always put into practice. In this article, we examine how a leading natural resource agency, the United States Department of Agriculture Forest Service, has translated ecosystem management theory into concrete policy objectives and how successfully these objectives are perceived to be implemented throughout the national forest system. Through document analysis, interviews, and survey responses from 345 Forest Service managers (district rangers, forest supervisors, and regional foresters), we find that the agency has incorporated numerous ecosystem management components into its objectives. Agency managers perceive that the greatest attainment of such objectives is related to collaborative stewardship and integration of scientific information, areas in which the organization has considerable prior experience. The objectives perceived to be least attained are adaptive management and integration of social and economic information, areas requiring substantial new resources and a knowledge base not traditionally emphasized by natural resource managers. Overall, success in implementing ecosystem management objectives is linked to committed forest managers.

Pentachlorophenol Residues in Porcine Tissue Following Preslaughter Exposure to Treated Wood Shavings.

Sixty market hogs originating from one producer and finished in a concrete and steel facility were divided into two groups of 30 and housed for approximately 60 h on either straw (control group) or pentachlorophenol (PCP) treated wood shavings (test group). Feed, straw, and shavings were analyzed for PCP residues. Both feed and straw yielded nondetectable levels of PCP residues, while shavings ranged from 0.03 to 12.0 ppm. The hogs were shipped to slaughter without bedding, and liver, fat and muscle (muscle from the test group only) samples were collected postmortem. The mean level of PCP residue in control (straw) hog livers was 0.037 ppm, while that of livers of hogs bedded with contaminated shavings was 0.342 ppm, a highly significant difference. The t-value using Welch's approximation equalled 9.77 using 28.5 degrees of freedom, indicating the mean PCP residue level was higher for the treated than the control group at a 0.01% level of significance.