Search

n/a

The common marmoset (Callithrix jacchus), a New World NHP, has emerged as important animal model in multiple areas of translational biomedical research. The quality of translational research in marmosets depends on early diagnosis, treatment, and prevention of their spontaneous diseases. Here, we characterize an outbreak of infectious cholangiohepatitis that affected 7 adult common marmosets in a single building over a 10-mo period. Marmosets presented for acute onset of lethargy, dull mentation, weight loss, dehydration, hyporexia, and hypothermia. Blood chemistries at presentation revealed markedly elevated hepatic and biliary enzymes, but mild neutrophilia was detected in only 1 of the 7. Affected marmosets were unresponsive to rigorous treatment and died or were euthanized within 48 h of presentation. Gross and histopathologic examinations revealed severe, necrosuppurative cholangiohepatitis and proliferative cholecystitis with bacterial colonies and an absence of gallstones. Perimortem and postmortem cultures revealed single or dual isolates of Escherichia coli and Pseudomonas aeruginosa. Other postmortem findings included bile duct hyperplasia, periportal hepatitis, bile peritonitis, ulcerative gastroenteritis, and typhlitis. Environmental contamination of water supply equipment with Pseudomonas spp. was identified as the source of infection, but pathogenesis remains unclear. This type of severe, infectious cholangiohepatitis with proliferative cholecystitis with Pseudomonas spp. had not been reported previously in marmosets, and we identified and here describe several contributing factors in addition to contaminated drinking water.

Marmosets are becoming more utilized in biomedical research due to multiple advantages including (1) a nonhuman primate of a smaller size with less cost for housing, (2) physiologic similarities to humans, (3) translatable hepatic metabolism, (4) higher numbers of litters per year, (5) genome is sequenced, molecular reagents are available, (6) immunologically similar to humans, (7) transgenic marmosets with germline transmission have been produced, and (8) are naturally occurring hematopoietic chimeras. With more use of marmosets, disease surveillance over a wide range of ages of marmosets has been performed. This has led to a better understanding of the disease management of spontaneous diseases that can occur in colonies. Knowledge of clinical signs and histologic lesions can assist in maximizing the colony’s health, allowing for improved outcomes in translational studies within biomedical research. Here, we describe some basic husbandry, biology, common spontaneous diseases, and animal model applications for the common marmoset in biomedical research.

The impact of neurosurgical resident hospital coverage system, performed via a night float (12-hour shifts overnight) or a 24-hour call, on neurological surgery resident training and patient care is unknown.Retrospective review comparing night float and 24-hour call coverage on trainee surgical experience, elective time, annual program surveys, patient outcomes, and length of stay.The Ohio State Wexner Medical Center Neurosurgery residency program, Columbus, Ohio.The neurosurgical residents from 2016 to 2019.Monthly cases performed by junior residents significantly increased after transitioning to a 24-hour call schedule (18 versus 30, p0.001). There were no differences for total cases among program graduates during this time (p = 0.7). Trainee elective time significantly increased after switching to 24-hour call coverage (18 versus 24 months after the transition; p = 0.004). Risk-adjusted mortality and length of stay indices were not different (0.5 versus 0.3, p = 0.1; 0.9 versus 0.9; p = 0.3). Program surveys had minimal change after the transition to 24-hour call.Transitioning from a night float to a 24-hour call coverage system led to improved junior resident case volume and elective time without detrimental effect on patient-related outcomes.

Recent studies suggest that B cells could play an important role in the tumor microenvironment. However, the role of humoral responses in endometrial cancer remains insufficiently investigated. Using a cohort of 107 patients with different histological subtypes of endometrial carcinoma, we evaluated the role of coordinated humoral and cellular adaptive immune responses in endometrial cancer. Concomitant accumulation of T, B, and plasma cells at tumor beds predicted better survival. However, only B-cell markers corresponded with prolonged survival specifically in high-grade endometrioid type and serous tumors. Immune protection was associated with class-switched IgA and, to a lesser extent, IgG. Expressions of polymeric immunoglobulin receptor (pIgR) by tumor cells and its occupancy by IgA were superior predictors of outcome and correlated with defects in methyl-directed DNA mismatch repair. Mechanistically, pIgR-dependent, antigen-independent IgA occupancy drove activation of inflammatory pathways associated with IFN and TNF signaling in tumor cells, along with apoptotic and endoplasmic reticulum stress pathways, while thwarting DNA repair mechanisms. Together, these findings suggest that coordinated humoral and cellular immune responses, characterized by IgA:pIgR interactions in tumor cells, determine the progression of human endometrial cancer as well as the potential for effective immunotherapies. Significance: This study provides new insights into the crucial role of humoral immunity in human endometrial cancer, providing a rationale for designing novel immunotherapies against this prevalent malignancy. See related commentary by Osorio and Zamarin, p. 766

Supplementary Figure from Olfactory Receptor OR2H1 Is an Effective Target for CAR T Cells in Human Epithelial Tumors

Supplementary Data from Olfactory Receptor OR2H1 Is an Effective Target for CAR T Cells in Human Epithelial Tumors

Recent studies suggest that B cells could play an important role in the tumor microenvironment. However, the role of humoral responses in endometrial cancer remains insufficiently investigated. Using a cohort of 107 patients with different histological subtypes of endometrial carcinoma, we evaluated the role of coordinated humoral and cellular adaptive immune responses in endometrial cancer. Concomitant accumulation of T, B, and plasma cells at tumor beds predicted better survival. However, only B-cell markers corresponded with prolonged survival specifically in high-grade endometrioid type and serous tumors. Immune protection was associated with class-switched IgA and, to a lesser extent, IgG. Expressions of polymeric immunoglobulin receptor (pIgR) by tumor cells and its occupancy by IgA were superior predictors of outcome and correlated with defects in methyl-directed DNA mismatch repair. Mechanistically, pIgR-dependent, antigen-independent IgA occupancy drove activation of inflammatory pathways associated with IFN and TNF signaling in tumor cells, along with apoptotic and endoplasmic reticulum stress pathways, while thwarting DNA repair mechanisms. Together, these findings suggest that coordinated humoral and cellular immune responses, characterized by IgA:pIgR interactions in tumor cells, determine the progression of human endometrial cancer as well as the potential for effective immunotherapies.Significance:This study provides new insights into the crucial role of humoral immunity in human endometrial cancer, providing a rationale for designing novel immunotherapies against this prevalent malignancy.See related commentary by Osorio and Zamarin, p. 766

Supplementary Figure from IgA-Dominated Humoral Immune Responses Govern Patients' Outcome in Endometrial Cancer

Supplementary Data from Treatment of Chronic Lymphocytic Leukemia with a Hypomethylating Agent Induces Expression of NXF2, an Immunogenic Cancer Testis Antigen

Purpose: Critical to the success of active immunotherapy against cancer is the identification of immunologically recognized cancer-specific proteins with low tolerogenic potential. Cancer testis antigens (CTA), in particular, fulfill this requirement as a result of their aberrant expression restricted to cancer cells and lack of expression in normal tissues bypassing tolerogenic mechanisms against self. Although CTAs have been extensively studied in solid malignancies, little is known regarding their expression in chronic lymphocytic leukemia (CLL).Experimental Design: Using a two-pronged approach we evaluated the immunogenicity of 29 CTAs in 22 patients with CLL and correlated these results to reverse transcriptase PCR data from CLL cell lines and patient cells.Results: We identified IgG-specific antibodies for one antigen, NXF2, and confirmed this response by ELISA and Western blot. We found that treatment of CLL with 5-aza-2′-deoxycytidine can induce expression of NXF2 that lasted for several weeks after treatment. Treatment also increased levels of MHC and costimulatory molecules (CD80, CD86, and CD40) necessary for antigen presentation. In addition, we identified other promising antigens that may have potential immunotherapeutic application.Conclusions: Our findings suggest that NXF2 could be further pursued as an immunotherapeutic target in CLL, and that treatment with demethylating agents could be exploited to specifically modulate CTA expression and effective antigen presentation in malignant B cells.

Background Prior studies demonstrated reduced risk for venous thromboembolism (VTE) in neurosurgical patients secondary to prophylaxis with both heparin and low-molecular-weight heparin. The ability to monitor low-molecular-weight heparin by obtaining anti–factor Xa (anti-Xa) serum levels provides an opportunity to evaluate safety and efficacy. The aim of this study was to describe characteristics of patients who have anti-Xa levels outside of the goal range (0.2–0.4/0.5 IU/mL) and investigate incidence of major bleeding and VTE. Methods A single-center, retrospective, observational study was conducted on neurosurgical patients receiving enoxaparin for VTE prophylaxis between August 2019 and December 2020. Significance testing was conducted via Fisher exact test and independent samples t test. Results The study included 85 patients. Patients were less likely to have an anti-Xa level in the goal range if they were male, had a higher weight, or were morbidly obese. Three neuroendovascular patients (3.5%) experienced a major bleed. Serum anti-Xa levels were significantly higher in patients who experienced major bleeds compared with patients who did not (0.45 ± 0.16 IU/mL vs. 0.28 ± 0.09 IU/mL, P = 0.003). Patients with a supraprophylactic anti-Xa level (>0.5 IU/mL) were more likely to experience a major bleed (P = 0.005). One VTE event occurred: the patient experienced a pulmonary embolism with anti-Xa level at goal. Conclusions Anti-Xa–guided enoxaparin dosing for VTE prophylaxis in neurosurgical patients may help prevent major bleeding. These data suggest that a higher anti-Xa level may predispose patients to major bleeding. Further evaluation is needed to identify the goal anti-Xa level for VTE prophylaxis in this population.

The purpose of this study was to quantify disparities in the utilization of outpatient pediatric surgical care and to examine the extent to which neighborhood-level socioeconomic disadvantage is associated with access to care among children.Clinic "no-shows" were examined among children scheduled from 2017 to 2019 at seven pediatric surgery clinics associated with a tertiary care children's hospital. The association between Area Deprivation Index, a neighborhood-level measure of socioeconomic disadvantage, and other patient factors with clinic no-shows was examined using multivariable logistic regression models. Difficulties in accessing postoperative care in particular were explored in a subgroup analysis of postoperative (within 90 days) clinic visits after appendectomy or inguinal/umbilical hernia repairs.Among 10,162 patients, 16% had at least 1 no-show for a clinic appointment. Area Deprivation Index (most deprived decile adjusted odds ratio 3.17, 95% confidence interval 2.20-4.58, P.001), Black race (adjusted odds ratio 3.30, 95% confidence interval 2.70-4.00, P.001), and public insurance (adjusted odds ratio 2.75, 95% confidence interval 2.38-3.31, P.001) were associated with having at least 1 no-show. Similar associations were identified among 2,399 children scheduled for postoperative clinic visits after undergoing appendectomy or inguinal/umbilical hernia repair, among whom 20% were a no-show.Race, insurance type, and neighborhood-level socioeconomic disadvantage are associated with disparities in utilization of outpatient pediatric surgical care. Challenges accessing routine outpatient care among disadvantaged children may be one mechanism through which disparate outcomes result among children requiring surgical care.

In the United States, acute low back pain, with or without radiculopathy, is the leading cause of years lived with disability and the third ranking cause of disability-adjusted life-years. Uncomplicated acute low back pain and/or radiculopathy is a benign, self-limited condition that does not warrant any imaging studies. Imaging is considered in those patients who have had up to 6 weeks of medical management and physical therapy that resulted in little or no improvement in their back pain. It is also considered for those patients presenting with red flags, raising suspicion for a serious underlying condition, such as cauda equina syndrome, malignancy, fracture, or infection. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Cerebrovascular disease is a broad topic. This document focuses on the imaging recommendations for the varied clinical scenarios involving intracranial aneurysms, vascular malformations, and vasculitis, which all carry high risk of morbidity and mortality. Additional imaging recommendations regarding complications of these conditions, including subarachnoid hemorrhage and vasospasm, are also covered. While each variant presentation has unique imaging recommendations, the major focus of this document is neurovascular imaging techniques. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

In an effort, to curtail rising health care costs, government and private payers have begun to focus on measuring quality of care. Along with quality improvement initiatives, clinical practice guidelines may also be utilized to provide better care. Clinical practice guidelines are recommendations for clinicians about the care of patients with specific conditions. This review provides an overview of clinical practice guidelines and quality improvement initiatives to highlight strategies to optimize patient outcomes.

Syncope and presyncope lead to well over one million emergency room visits in the United States each year. Elucidating the cause of syncope or presyncope, which are grouped together given similar etiologies and outcomes, can be exceedingly difficult given the diverse etiologies. This becomes more challenging as some causes, such as vasovagal syncope, are relatively innocuous while others, such as cardiac-related syncope, carry a significant increased risk of death. While the mainstay of syncope and presyncope assessment is a detailed history and physical examination, imaging can play a role in certain situations. In patients where a cardiovascular etiology is suspected based on the appropriate history, physical examination, and ECG findings, resting transthoracic echocardiography is usually considered appropriate for the initial imaging. While no imaging studies are considered usually appropriate when there is a low probability of cardiac or neurologic pathology, chest radiography may be appropriate in certain clinical situations. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

The deployment of molten salt reactors requires validation of the computational tools used to support the licensing process. The Molten Salt Reactor Experiment (MSRE), built and operated in the 196...

Having been awarded the 2019 British Nutrition Foundation Annual Prize I had looked forward to delivering a lecture to assembled guests at the BNF Annual Day at the Royal College of Physicians in London, in 2020 Unfortunately, this was not to be;the COVID‐19 global pandemic prevented a face‐to‐face meeting, and my talk was delivered remotely In the paper, I shall summarise some of the research that I have carried out during my career as a nutrition scientist I shall not dwell in much detail on any single aspect of my work but rather I shall attempt to show how my research interests developed over the decades, how one thing led to another, so to speak The elements of my work that I have selected, in order to make this short walk together, commence with vitamin B2, riboflavin and a consideration of two particular aspects of function I then move on to folate in the context of homocysteine metabolism and cardiovascular disease and finally consider the role of this vitamin and other methyl donors in cancer risk and outcome [ABSTRACT FROM AUTHOR] Copyright of Nutrition Bulletin is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission However, users may print, download, or email articles for individual use This abstract may be abridged No warranty is given about the accuracy of the copy Users should refer to the original published version of the material for the full abstract (Copyright applies to all Abstracts )

European Snacks Association (ESA) data on acrylamide in potato crisps from 2002 to 2019 (99704 observations) were analysed. Acrylamide levels have plateaued since 2011, although the lowest mean so far was attained in 2018 at 353 ± 2.7 ng g-1: a 54% reduction since 2002. The 85th, 90th and 95th quantiles did show evidence of continued downward progress, the 90th quantile being lower than the 750 ng g-1 European Benchmark Level from 2017 to 2019. A smaller dataset from the European Food Safety Authority (2124 observations) for 2011-2018, was also analysed. The yearly means were higher than those of the ESA data, but showed a fall in average acrylamide from 715 ± 40.5 ng g-1 in 2015 to 505 ±28.5 ng g-1 in 2018, as well as steep falls in the 85th, 90th and 95th quantiles. Nevertheless, even the 85th quantile remained above the 750 ng g-1 Benchmark Level. The ESA data showed a reduction in the proportion of samples with acrylamide exceeding 750 ng g-1, from over 40 % in 2002 to 7.75 % in 2019. Seasonality was evident, with highest acrylamide levels from November to May. Crisp type had little effect except that thicker types had a higher proportion of samples containing >750 ng g-1 acrylamide. Analysis of the region of origin in Europe of the final product revealed improvements in the east and north. Geographical factors combined with seasonality continued to be problematic but was also an aspect in which progress was most evident. The findings show that improvements have been made in reducing the number of samples with very high levels of acrylamide, but do not suggest that mean acrylamide levels could be reduced substantially below where they have been since 2011, or that levels could be kept consistently below the current Benchmark Level.

Dietary reference values (DRV) are estimates of the daily amounts of nutrients or food energy that meet the needs of healthy people. In the UK, three terms are used to express these estimates, assuming a normal distribution of requirements in a population. These are the estimated average requirement, the lower reference nutrient intake and the reference nutrient intake. DRV are for use in a variety of settings, including the assessment of adequacy and safety of nutrient or energy intake in a population group, in the design of meal provision in care settings, in food labelling and in considering food fortification strategies. DRV, and other expressions of nutrient requirements, assume a relationship between the intake of a nutrient and some criterion of adequacy, the outcome. Estimates of requirements are based on a diverse range of measures of adequacy, according to available evidence. The Scientific Advisory Committee on Nutrition (SACN) is the body responsible for reviewing and setting DRV for the UK population. The work of SACN is guided by a framework of evidence that relates food and nutrients to health. There have been calls for the harmonisation of approaches used in the setting of nutrient requirements, globally, and an increased transparency in the decision-making process. Some progress has been made in this regard, but there is a great deal of work to be done.

Although chimeric antigen receptor (CAR)-expressing T cells have proven success in hematologic malignancies, their effectiveness in solid tumors has been largely unsuccessful thus far. We found that some olfactory receptors are expressed in a variety of solid tumors of different histologic subtypes, with a limited pattern of expression in normal tissues. Quantification of OR2H1 expression by qRT-PCR and Western blot analysis of 17 normal tissues, 82 ovarian cancers of various histologies, eight non–small cell lung cancers (NSCLCs), and 17 breast cancers demonstrated widespread OR2H1 expression in solid epithelial tumors with expression in normal human tissues limited to the testis. CAR T cells recognizing the extracellular domain of the olfactory receptor OR2H1 were generated with a targeting motif identified through the screening of a phage display library and demonstrated OR2H1-specific cytotoxic killing in vitro and in vivo, using tumor cells with spontaneous expression of variable OR2H1 levels. Importantly, recombinant OR2H1 IgG generated with the VH/VL sequences of the CAR construct specifically detected OR2H1 protein signal in 60 human lung cancers, 40 ovarian carcinomas, and 73 cholangiocarcinomas, at positivity rates comparable with mRNA expression and without OR2H1 staining in 58 normal tissues. CRISPR/Cas9-mediated ablation of OR2H1 confirmed targeting specificity of the CAR and the tumor-promoting role of OR2H1 in glucose metabolism. Therefore, T cells redirected against OR2H1-expressing tumor cells represent a promising therapy against a broad range of epithelial cancers, likely with an admissible toxicity profile.

Palm wine alcohol extract of senesced banana leaf material, Musa spp., was tested for its efficacy in open field trapping of the banana weevil, Cosmopolites sordidus in Ghana from June to August 2015. Modified pitfall and bottle traps were baited with either individual treatments, that is palm alcohol extract, C. sordidus aggregation pheromone or pseudostem or with combinations of extract plus aggregation pheromone or extract plus pseudostem. The combination of extract plus aggregation pheromone was able to lure more weevils into traps compared with the respective individual lures. There was a 2.1‐fold increase in mean catch per week when the palm alcohol extract was used in combination with pheromone compared with using pheromone alone, and a corresponding 2.6‐fold increase when the extract was used with pseudostem in traps. There was no statistically significant interaction between the palm alcohol extract (presence or absence) and treatment (pheromone or pseudostem), but the best combination for maximal catches of adult banana weevils was a combination of palm alcohol extract with aggregation pheromone. Management of banana weevils with attractive banana leaf extract has important practical applications in parts of the world where other management options are too expensive or commercial treatments are in short supply, but where leaf material is cheap and readily available for local use by smallholder farmers.

Key Clinical Points Acute Ischemic Stroke Treatment for patients with acute ischemic stroke is guided by the time from the onset of stroke, the severity of neurologic deficit, and findings on neuro...

Background Increased prevalence of patients on anticoagulants and the advent of new therapies raise concern over how these patients fare if they sustain a traumatic injury. We investigated the role of prehospitalization anticoagulation therapy in trauma-related mortality and postacute disposition. Methods A retrospective analysis was performed on patients who sustained traumatic injury identified in the 2017 National Trauma Data Bank (NTDB). Patients with and without anticoagulation therapy were analyzed to identify differences in demographics, injury type, Injury Severity Score (ISS), and trauma outcomes including hospital length of stay, ER, final hospital disposition, and mortality. Logistic regression was used to correlate anticoagulation to mortality and facility discharge. Results Of the 1 000 596 patients included, 73 602 (7%) patients were on anticoagulants at the time of their trauma. Increased age was the strongest predictor for anticoagulation therapy (odds ratio 5.54, 95% CI 5.44-5.63), but being female and white were also independent predictors of anticoagulation ( P < .001). Patients on anticoagulants had a significantly longer length of stay (5.11 days; 95% CI 5.06-5.15) than those who were not (4.37 days, 95% CI 4.36-4.39), were 2.20 times more likely to die (95% CI 2.12-2.28, P < .001), and were 2.77 times more likely to be discharged to a facility (95% CI 2.73-2.81, P < .001). Anticoagulation remained a significant predictor of worse trauma outcomes even when accounting for age and ISS in multivariate analysis. Discussion Anticoagulation preceding trauma-related admission is associated with higher mortality and an increased likelihood of the need for a posthospital care facility.

Campylobacter jejuni monitors intestinal metabolites produced by the host and microbiota to initiate intestinal colonization of avian and animal hosts for commensalism and infection of humans for diarrheal disease. We previously discovered that C. jejuni has the capacity to spatially discern different intestinal regions by sensing lactate and the short-chain fatty acids acetate and butyrate and then alter transcription of colonization factors appropriately for in vivo growth. In this study, we identified the C. jejuni butyrate-modulated regulon and discovered that the BumSR two-component signal transduction system (TCS) directs a response to butyrate by identifying mutants in a genetic screen defective for butyrate-modulated transcription. The BumSR TCS, which is important for infection of humans and optimal colonization of avian hosts, senses butyrate likely by indirect means to alter transcription of genes encoding important colonization determinants. Unlike many canonical TCSs, the predicted cytoplasmic sensor kinase BumS lacked in vitro autokinase activity, which would normally lead to phosphorylation of the cognate BumR response regulator. Instead, BumS has likely evolved mutations to naturally function as a phosphatase whose activity is influenced by exogenous butyrate to control the level of endogenous phosphorylation of BumR and its ability to alter transcription of target genes. To our knowledge, the BumSR TCS is the only bacterial signal transduction system identified so far that mediates responses to the microbiota-generated intestinal metabolite butyrate, an important factor for host intestinal health and homeostasis. Our findings suggest that butyrate sensing by this system is vital for C. jejuni colonization of multiple hosts.

Movement disorders and neurodegenerative diseases are a variety of conditions that involve progressive neuronal degeneration, injury, or death. Establishing the correct diagnosis of a movement disorder or neurodegenerative process can be difficult due to the variable features of these conditions, unusual clinical presentations, and overlapping symptoms and characteristics. MRI has an important role in the initial assessment of these patients, although a combination of imaging and laboratory and genetic tests is often needed for complete evaluation and management. This document summarizes the imaging appropriateness data for rapidly progressive dementia, chorea, Parkinsonian syndromes, suspected neurodegeneration with brain iron accumulation, and suspected motor neuron disease. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Degenerative disease of the central nervous system is a growing public health concern. The primary role of neuroimaging in the workup of patients with probable or possible Alzheimer disease has typically been to exclude other significant intracranial abnormalities. In general, the imaging findings in structural studies, such as MRI, are nonspecific and have limited potential in differentiating different types of dementia. Advanced imaging methods are not routinely used in community or general practices for the diagnosis or differentiation of forms of dementia. Nonetheless, in patients who have been evaluated by a dementia expert, FDG-PET helps to distinguish Alzheimer disease from frontotemporal dementia. In patients with suspected dementia with Lewy bodies, functional imaging of the dopamine transporter (ioflupane) using SPECT may be helpful. In patients with suspected normal-pressure hydrocephalus, DTPA cisternography and HMPAO SPECT/CT brain may provide assessment. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Background and Purpose— EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine. Methods— Subjects were World Federation of Neurological Surgeons grades 2–4, modified Fisher grades 2–4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6–8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated. Results— The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83–1.22], P =0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P =0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3–4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94–1.58], P =0.13). No safety concerns were identified that halted the study or that preclude further development. Conclusions— There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02790632.

Carole A. Miller, M.D., was born (May 7, 1939) and raised in Kalamazoo, Michigan. She obtained her undergraduate and medical degrees at the Ohio State University. She went on to complete her neurosurgical training at the Ohio State University Medical Center. After her first faculty role at the University of Michigan (1971), she returned to the Ohio State University Medical Center (1975) where she spent nearly 4 decades. She thrived in the specialty, achieving in every facet of academic practice including scientific contributions, graduate medical education, clinical care, and leadership roles within her academic department, locally, and at the national level of organized neurosurgery. Dr. Miller passed away peacefully, on October 28, 2015, after a courageous battle with cancer. Based on her essential programmatic and specialty-related contributions, she is remembered as the 'founding mother' of neurosurgery at the Ohio State University.

Despite repeated associations between T cell infiltration and outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that the hallmarks of tumor recognition in ovarian cancer-infiltrating T cells are primarily restricted to tissue-resident memory (TRM) cells. Single-cell RNA/TCR/ATAC sequencing of 83,454 CD3(+) CD8(+)CD103(+)CD69(+) TRM cells and immunohistochemistry of 122 high-grade serous ovarian cancers shows that only progenitor (TCF1(low)) tissue-resident T cells (TRMstem cells), but not recirculating TCF1(+) T cells, predict ovarian cancer outcome. TRMstem cells arise from transitional recirculating T cells, which depends on antigen affinity/persistence, resulting in oligoclonal, trogocytic, effector lymphocytes that eventually become exhausted. Therefore, ovarian cancer is indeed an immunogenic disease, but that depends on similar to 13% of CD8(+) tumor-infiltrating T cells (similar to 3% of CD8(+) clonotypes), which are primed against high-affinity antigens and maintain waves of effector TRM-like cells. Our results define the signature of relevant tumor-reactive T cells in human ovarian cancer, which could be applicable to other tumors with unideal mutational burden.

The shared-pathway hypothesis offers a cellular explanation for the connection between ketocarotenoid pigmentation and individual quality. Under this hypothesis, ketocarotenoid metabolism shares cellular pathways with mitochondrial oxidative phosphorylation such that red carotenoid-based coloration is inextricably linked mitochondrial function. To test this hypothesis, we exposed Tigriopus californicus copepods to a mitochondrially targeted protonophore, 2,4-dinitrophenol (DNP), to induce proton leak in the inner mitochondrial membranes. We then measured whole-animal metabolic rate and ketocarotenoid accumulation. As observed in prior studies of vertebrates, we observed that DNP treatment of copepods significantly increased respiration and that DNP-treated copepods accumulated more ketocarotenoid than control animals. Moreover, we observed a relationship between ketocarotenoid concentration and metabolic rate, and this association was strongest in DNP-treated copepods. These data support the hypothesis that ketocarotenoid and mitochondrial metabolism are biochemically intertwined. Moreover, these results corroborate observations in vertebrates, perhaps suggesting a fundamental connection between ketocarotenoid pigmentation and mitochondrial function that should be explored further.

Acinetobacter baumannii is an important hospital-associated pathogen that causes antibiotic resistant infections and reoccurring hospital outbreaks. A. baumannii's ability to asymptomatically colonize patients is a risk factor for infection and exacerbates its spread. However, there is little information describing the mechanisms it employs to colonize patients. A. baumannii often colonizes the upper respiratory tract and skin. Antibiotic use is a risk factor for colonization and infection suggesting that A. baumannii likely competes with commensal bacteria to establish a niche. To begin to investigate this possibility, we cocultured A. baumannii and commensal bacteria of the upper respiratory tract and skin. In conditions that mimic iron starvation experienced in the host, we observed that A. baumannii inhibits Staphylococcus epidermidis, Staphylococcus hominis, Staphylococcus haemolyticus and Corynebacterium striatum. Then using an ordered transposon library screen we identified the A. baumannii siderophore acinetobactin as the causative agent of the inhibition phenotype. Using mass spectrometry, we show that acinetobactin is released from A. baumannii under our coculture conditions and that purified acinetobactin can inhibit C. striatum and S. hominis. Together our data suggest that acinetobactin may provide a competitive advantage for A. baumannii over some respiratory track and skin commensal bacteria and possibly support its ability to colonize patients.