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Comprehensive characterization of somatic genomic alterations has led to fundamental shifts in our understanding of tumor biology. In clinical practice, these studies can lead to modifications of diagnosis and/or specific treatment implications, fulfilling the promise of personalized medicine. Herein, we describe a 78-yr-old woman under surveillance for long-standing untreated chronic lymphocytic leukemia (CLL). Molecular studies from a peripheral blood specimen revealed a TP53 p.V157F mutation, whereas karyotype and fluorescence in situ hybridization (FISH) identified a 17p deletion, trisomy 12, and no evidence of IGH-CCND1 rearrangement. Positron emission tomography-computed tomography scan identified multistation intra-abdominal lymphadenopathy and a pulmonary nodule, and subsequent pulmonary wedge resection confirmed the presence of a concurrent lung adenocarcinoma. Targeted next-generation sequencing of the lung tumor identified an EGFR in-frame exon 19 deletion, two TP53 mutations (p.P152Q, p.V157F), and, unexpectedly, a IGH-CCND1 rearrangement. Follow-up immunohistochemistry (IHC) studies demonstrated a cyclin D1-positive lymphoid aggregate within the lung adenocarcinoma. The presence of the TP53 p.V157F mutation in the lung resection, detection of an IGH-CCND1 rearrangement, and cyclin D1 positivity by IHC led to revision of the patient's hematologic diagnosis and confirmed the extranodal presence of mantle cell lymphoma within the lung mass, thus representing a "tumor in tumor." Manual review of the sequencing data suggested the IGH-CCND1 rearrangement occurred via an insertional event, whose size precluded detection by original FISH studies. Thus, routine imaging for this patient's known hematologic malignancy led to detection of an unexpected solid tumor, whose subsequent precision medicine studies in the solid tumor redefined the original hematological diagnosis.

In this study, Al₂O₃-based composites strengthened with Ti were manufactured. High-energy milling was used to mix and grind the raw materials (450rpm during 40min). These powders were compacted (300MPa) into cylindrical samples and sintered at 1500 °C for 2h. Scanning electron microscopy observations show dense, fine and homogeneous microstructures, with a uniform distribution of metal particles throughout the ceramic matrix. A significant effect on the composite micro-hardness can be observed (as the titanium percentage is increased, micro-hardness is also increased). In other words, composites have a significant surface hardness, which diminishes towards the center of the piece. This attribute is highly useful for solid elements exposed to extreme strain and shearing conditions since hardness allows withstanding wear, corrosion, and friction, but the soft center allows withstanding vertical loads in the piece cross section. The fracture toughness, estimated by the indentation fracture method, showed that the manufactured composites here present higher values up to 100% than the control sample s average (0.0% Ti). Hence, it can be inferred that titanium particles in a ceramic matrix can disperse the energy of cracks spreading.

ObjectiveVarious models of peer support may be implemented in mental health settings. This randomized trial assessed the effectiveness of a telephone-delivered mutual peer support intervention.MethodsA total of 443 patients receiving ongoing depression treatment from the U.S. Department of Veterans Affairs were enrolled in either enhanced usual care (N=243) or the peer support intervention (N=200). Intent-to-treat analyses assessed outcomes at six months postenrollment, excluding 56 patients who experienced an unplanned telephone platform shutdown.ResultsAt baseline, patients had substantial depressive symptoms, functional limitations, and low quality of life. Both groups showed significant clinical improvements at six months, with no significant differences by group.ConclusionsTelephone-delivered mutual peer support for patients with depression did not improve outcomes beyond those observed with enhanced usual care. Other peer support models, with more "professionalized" peers delivering a structured curriculum, may be more effective.

"El Escalafon" is the process for appointing school directors and "el Doble Turno" is the double shift of morning and afternoon session in Mexican schools. These two concepts open the door to examine more general issues in the appointment of school directors and the structure of the school day. Director appointment and school time are rooted in local culture but can have implications across national borders. This study reports interviews of six first-year school directors in the state of Sonora, Mexico and six principals in Texas, USA. It is part of a larger international study that includes Australia, Canada, England, Jamaica, Scotland, South Africa, and Turkey. The purpose is to look at the appointment, preparation, and challenges of first-year school directors. School directors in both countries wrestled with parent expectations and relations with teachers. The systems for appointing school directors and the structure of the school day were different. These differences were based in cultural orientations and suggested contradictions and shortcomings in each educational system. These issues are important to consider in planning programs of educational administration preparation.

This work presents a method for calculating the contributions of sea-level rise and urban growth to flood risk in coastal flood plains. The method consists of hydraulic/hydrological, urban growth and flood-damage quantification modules. The hydraulic/hydrological module estimates peak annual flows to generate flood stages impacted by sea-level rise within flood plains. A model for urban growth predicts patterns of urbanization within flood plains over the period 2010-2050. The flood-damage quantification module merges flood maps and urbanization predictions to calculate the expected annual flood damage (EAFD) for given scenarios of sea-level rise. The method is illustrated with an application to the Tijuana River of southern California, USA, and northwestern Mexico, where the EAFD is predicted to increase by over US$100 million because of sea-level rise of 0.25-1.0 m and urban growth by the year 2050. It is shown that urbanization plays a principal role in increasing the EAFD in the study area for the range of sea-level rise considered. © 2013 IAHS Press.

Environmental regulations frequently mandate the use of "best available" science, but ensuring that it is used in decisions around the use and protection of natural resources is often challenging. In the Western US, this relationship between science and management is at the forefront of post-fire land management decisions. Recent fires, post-fire threats (e.g. flooding, erosion), and the role of fire in ecosystem health combine to make post-fire management highly visible and often controversial. This paper uses post-fire management to present a framework for understanding why disconnects between science and management decisions may occur. We argue that attributes of agencies, such as their political or financial incentives, can limit how effectively science is incorporated into decision-making. At the other end of the spectrum, the lack of synthesis or limited data in science can result in disconnects between science-based analysis of post-fire effects and agency policy and decisions. Disconnects also occur because of the interaction between the attributes of agencies and the attributes of science, such as their different spatial and temporal scales of interest. After offering examples of these disconnects in post-fire treatment, the paper concludes with recommendations to reduce disconnects by improving monitoring, increasing synthesis of scientific findings, and directing social-science research toward identifying and deepening understanding of these disconnects.

This study presents a method to assess the contributions of 21st-century sea-level rise and groundwater extraction to sea water intrusion in coastal aquifers. Sea water intrusion is represented by the landward advance of the 10,000 mg/L iso-salinity line, a concentration of dissolved salts that renders groundwater unsuitable for human use. A mathematical formulation of the resolution of sea water intrusion among its causes was quantified via numerical simulation under scenarios of change in groundwater extraction and sea-level rise in the 21st century. The developed method is illustrated with simulations of sea water intrusion in the Seaside Area sub-basin near the City of Monterey, California (USA), where predictions of mean sea-level rise through the early 21st century range from 0.10 to 0.90 m due to increasing global mean surface temperature. The modeling simulation was carried out with a state-of-the-art numerical model that accounts for the effects of salinity on groundwater density and can approximate hydrostratigraphic geometry closely. Simulations of sea water intrusion corresponding to various combinations of groundwater extraction and sea-level rise established that groundwater extraction is the predominant driver of sea water intrusion in the study aquifer. The method presented in this work is applicable to coastal aquifers under a variety of other scenarios of change not considered in this work. For example, one could resolve what changes in groundwater extraction and/or sea level would cause specified levels of groundwater salinization at strategic locations and times.

The California Department of Water Resources (2006) estimated a rise in mean sea level along California’s coastline ranging from 10 to 90 cm over the 21st century due to rising global mean surface temperature. This range of sea-level rise is consistent with the Intergovernmental Panel for Climate Change (2007) estimates. The rise in sea level threatens coastal aquifers by exacerbating the risk of saline intrusion. This study simulated the effect of sea-level rise on the Seaside Area sub-basin near the City of Monterey, California. The simulation was carried out with a state-of-art, finite-element, variable-density, numerical model that accounts for the effects of salinity on groundwater density and viscosity. Seawater intrusion was simulated for various scenarios of sea-level rise, varying from 0 m to 1 m assuming a linear increase of sea level through the 21st century. Each scenario contemplated the same level of predicted groundwater extraction through the 21st century in the study aquifers. The numerical simulations of seawater intrusion indicate that one meter of sea-level rise would contribute an additional 10 to 15 meters of inland spread of the 1,000 mg/L saline front and 20 to 30 meters of the 10,000 mg/L saline front. The effect of sea-level rise on seawater intrusion in the Seaside Area sub-basin, therefore, appears minor when compared with historical measurements of seawater intrusion caused primarily by groundwater pumping since the early 1900s. Other aquifers with less topographical relief and more complex hydrostratigraphy could be more vulnerable to sea-level rise, however. One such possibility is posed by the Oxnard Plain groundwater sub-basin, in Ventura County, California. This study compiled a hydrogeologic database and structured the basic elements of a sea-water intrusion numerical simulation model for the Oxnard Plain aquifer. The Oxnard Plain sub-basin is a complex, multi-formation, aquifer that has undergone several decades of groundwater extraction, and, which is known to experience seawater intrusion in several of its coastal areas. The Oxnard Plain sub-basin features an important offshore hydrogeologic section that encompasses its boundary under seawater. Time limitations prevented calibration and validation of the numerical simulation model for seawater intrusion in the Oxnard Plain sub-basin. Nevertheless, the elements needed to complete the Oxnard Plain sub-basin’s seawater-intrusion simulation model in the near future (with additional funding) have been assembled and are presented in this report. The approach presented in this report for the relatively assessment of groundwater extraction and sea-level rise effects on seawater intrusion into coastal aquifers holds potential for wide-ranging applicability in a variety of hydrogeologic settings. In particular, the finite-element spatial grid provides distinct capabilities to represent accurately the geographical layout of an aquifer.

Bladder cancer is a genetically heterogeneous disease, and novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes. Here, we identified a unique subset of urothelial tumors with focal amplification of the RAF1 (CRAF) kinase gene. RAF1-amplified tumors had activation of the RAF/MEK/ERK signaling pathway and exhibited a luminal gene expression pattern. Genetic studies demonstrated that RAF1-amplified tumors were dependent upon RAF1 activity for survival, and RAF1-activated cell lines and patient- derived models were sensitive to available and emerging RAF inhibitors as well as combined RAF plus MEK inhibition. Furthermore, we found that bladder tumors with HRAS- or WRAS-activating mutations were dependent on RAF1-mediated signaling and were sensitive to RAF1-targeted therapy. Together, these data identified RAF1 activation as a dependency in a subset making up nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rational therapeutic strategy., Introduction Bladder cancer accounts for approximately 80,000 new cancer diagnoses and nearly 20,000 deaths annually in the United States (1). Approximately 25% of patients present with muscle-invasive bladder cancer (MIBC), [...]

Similar to the early phases of the COVID-19 pandemic, New York City was the national epicenter of the ongoing 2022 mpox (formerly monkeypox) outbreak. Cases quickly began to rise in July 2022, primarily in gay, bisexual, or other men who have sex with men. Tools in the form of a reliable diagnostic test, an effective vaccine, and a viable treatment option have been available from the onset, although logistically complex to roll out. The special pathogens program at NYC Health + Hospitals/Bellevue, the flagship facility for the largest public hospital system in the United States, collaborated with multiple departments within Bellevue, the hospital system, and the NYC Department of Health and Mental Hygiene, to swiftly establish ambulatory testing, immunizations, patient-centered inpatient care, and outpatient therapeutics. With the ongoing mpox outbreak, hospitals and local health departments must prepare a systemwide response to identify and isolate patients and provide high-quality care. Findings from our experience can help guide institutions in developing a multipronged, comprehensive response to the ongoing mpox outbreak. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD, eczema) is driven by a combination of skin barrier defects, immune dysregulation, and extrinsic stimuli such as allergens, irritants, and microbes. The role of environmental allergens (aeroallergens) in triggering AD remains unclear. We systematically synthesized evidence regarding the benefits and harms of allergen immunotherapy (AIT) for AD. As part of the 2022 American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters AD Guideline update, we searched the MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, Global Resource for Eczema Trials, and Web of Science databases from inception to December 2021 for randomized controlled trials comparing subcutaneous immunotherapy (SCIT), sublingual immunotherapy (SLIT), and/or no AIT (placebo or standard care) for guideline panel–defined patient-important outcomes: AD severity, itch, AD-related quality of life (QoL), flares, and adverse events. Raters independently screened, extracted data, and assessed risk of bias in duplicate. We synthesized intervention effects using frequentist and Bayesian random-effects models. The GRADE approach determined the quality of evidence. Twenty-three randomized controlled trials including 1957 adult and pediatric patients sensitized primarily to house dust mite showed that add-on SCIT and SLIT have similar relative and absolute effects and likely result in important improvements in AD severity, defined as a 50% reduction in SCORing Atopic Dermatitis (risk ratio [95% confidence interval] 1.53 [1.31-1.78]; 26% vs 40%, absolute difference 14%) and QoL, defined as an improvement in Dermatology Life Quality Index by 4 points or more (risk ratio [95% confidence interval] 1.44 [1.03-2.01]; 39% vs 56%, absolute difference 17%; both outcomes moderate certainty). Both routes of AIT increased adverse events (risk ratio [95% confidence interval] 1.61 [1.44-1.79]; 66% with SCIT vs 41% with placebo; 13% with SLIT vs 8% with placebo; high certainty). AIT's effect on sleep disturbance and eczema flares was very uncertain. Subgroup and sensitivity analyses were consistent with the main findings. SCIT and SLIT to aeroallergens, particularly house dust mite, can similarly and importantly improve AD severity and QoL. SCIT increases adverse effects more than SLIT. These findings support a multidisciplinary and shared decision-making approach to optimally managing AD. [Display omitted] [ABSTRACT FROM AUTHOR]

Context.--The analysis of somatic mutations across multiple genes in cancer specimens may be used to aid clinical decision making. The analytical validation of targeted next-generation sequencing panels is important to assess accuracy and limitations. Objective.--To report the development and validation of OncoPanel, a custom targeted next-generation sequencing assay for cancer. Design.--OncoPanel was designed for the detection of single-nucleotide variants, insertions and deletions, copy number alterations, and structural variants across 282 genes with evidence as drivers of cancer biology. We implemented a validation strategy using formalin-fixed, paraffin-embedded, fresh or frozen samples compared with results obtained by clinically validated orthogonal technologies. Results.--OncoPanel achieved 98% sensitivity and 100% specificity for the detection of single-nucleotide variants, and 84% sensitivity and 100% specificity for the detection of insertions and deletions compared with single-gene assays and mass spectrometry-based genotyping. Copy number detection achieved 86% sensitivity and 98% specificity compared with array comparative genomic hybridization. The sensitivity of structural variant detection was 74% compared with karyotype, fluorescence in situ hybridization, and polymerase chain reaction. Sensitivity was affected by inconsistency in the detection of FLT3 and NPM1 alterations and IGH rearrangements due to design limitations. Limit of detection studies demonstrated 98.4% concordance across triplicate runs for variants with allele fraction greater than 0.1 and at least 50X coverage. Conclusions.--The analytical validation of OncoPanel demonstrates the ability of targeted next-generation sequencing to detect multiple types of genetic alterations across a panel of genes implicated in cancer biology. (Arch Pathol Lab Med. 2017; 141:751-758; doi: 10.5858/arpa.2016-0527-OA), The understanding of cancer as a genomic disease, coupled with the introduction of targeted therapeutic agents to treat cancer, has propelled the genomic profiling of tumor samples to aid in [...]

Synaptojanin is a nerve terminal protein that belongs to the inositol-5-phosphatase family. It has 5-phosphatase activity and an amino-terminal domain that matches the yeast protein Sac1 (Rsd1). Aside from dynamin, synaptojanin is the only other major brain protein that binds the SH3 domain of the presynaptic protein amphiphysin. The results of an analysis indicate a relationship between phosphoinositide metabolism and synaptic vesicle recycling.

To identify recent ataxia interventions and investigate cost-utility for patients with ataxia. Bibliographical searches conducted using electronic databases: PubMed, Scopus, EBSCO, PEDro, CINAHL. Time restriction to publications since 2008 to represent modern practice. Indexing terms: physical therapy, ataxia, robot-assisted gait training, optokinetic training, quality of life, cerebellar ataxia, physiotherapy, incoordination, modalities, Frenkel, heat OR cold therapy. Inclusion criteria: Adults with lower extremity incoordination or ataxia. Systematic reviews, RCTs, quasi-experimental studies, and meta-analyses were included. Targets: interventions to manage or improve ataxia, quality of life improvements, fall reduction or management. Multiple reviewers (three total) to apply consensus for inclusion. Initial selection found 19 papers for full review. Independent extraction by multiple readers; JBI Reviewer's Manual. Positive findings and negative findings included, regardless of recovery phase. Variation across outcome measures and drop-out rates. Costs of treatment options over 1 year were compared, using a program cost analysis from the perspective of a rehab program director. Rehabilitation outcome measures used to assess effectiveness relative to direct costs, particularly quality of life measures and program administration costs. Although preliminary, the same best practice recommendations from APTA for overground gait training for patients with SCI, CVA, and TBI may also apply to conditions of ataxia as the most effective form of physical therapy. Other interventions may provide benefit as well, although concerns about cost impact remain. No disclosures. [ABSTRACT FROM AUTHOR]

The U.S. Coast Guard Academy Naval Architecture and Marine Engineering Program is accredited by the Engineering Accreditation Commission (EAC) of ABET. For the 2019 ABET general review, the program's transition to the new ABET Criteria is described. This includes program interpretation of the updated ABET Criteria, specifically Criterion 3, Student Outcomes, and newly revised ABET language and definitions. Concurrently, evidence-based changes were applied to assessment. A performance vector was implemented to categorize the quality of student work as Excellent, Adequate, Marginal or Unsatisfactory (EAMU Vector), both increasing the fidelity of the assessment data and creating meaningful student performance data trends. [ABSTRACT FROM AUTHOR]