The role of GammaTile in the treatment of brain tumors: a technical and clinical overview.

Malignant and benign brain tumors with a propensity to recur continue to be a clinical challenge despite decades-long efforts to develop systemic and more advanced local therapies. GammaTile (GT Medical Technologies Inc., Tempe AZ) has emerged as a novel brain brachytherapy device placed during surgery, which starts adjuvant radiotherapy immediately after resection. GammaTile received FDA clearance in 2018 for any recurrent brain tumor and expanded clearance in 2020 to include upfront use in any malignant brain tumor. More than 1,000 patients have been treated with GammaTile to date, and several publications have described technical aspects of the device, workflow, and clinical outcome data. Herein, we review the technical aspects of this brachytherapy treatment, including practical physics principles, discuss the available literature with an emphasis on clinical outcome data in the setting of brain metastases, glioblastoma, and meningioma, and provide an overview of the open and pending clinical trials that are further defining the efficacy and safety of GammaTile.

mTOR inhibition abrogates human mammary stem cells and early breast cancer progression markers.

BACKGROUND: Mammary physiology is distinguished in containing adult stem/progenitor cells that are actively amending the breast tissue throughout the reproductive lifespan of women. Despite their importance in both mammary gland development, physiological maintenance, and reproduction, the exact role of mammary stem/progenitor cells in mammary tumorigenesis has not been fully elucidated in humans or animal models. The implications of modulating adult stem/progenitor cells in women could lead to a better understanding of not only their function, but also toward possible breast cancer prevention led us to evaluate the efficacy of rapamycin in reducing mammary stem/progenitor cell activity and malignant progression markers. METHODS: We analyzed a large number of human breast tissues for their basal and luminal cell composition with flow cytometry and their stem and progenitor cell function with sphere formation assay with respect to age and menopausal status in connection with a clinical study (NCT02642094) involving a low-dose (2 mg/day) and short-term (5-7 days) treatment of the mTOR inhibitor sirolimus. The expression of biomarkers in biopsies and surgical breast samples were measured with quantitative analysis of immunohistochemistry. RESULTS: Sirolimus treatment significantly abrogated mammary stem cell activity, particularly in postmenopausal patients. It did not affect the frequency of luminal progenitors but decreased their self-renewal capacity. While sirolimus had no effect on basal cell population, it decreased luminal cell population, particularly in postmenopausal patients. It also significantly diminished prognostic biomarkers associated with breast cancer progression from ductal carcinoma in situ to invasive breast cancer including p16INK4A, COX-2, and Ki67, as well as markers of the senescence-associated secretary phenotype, thereby possibly functioning in preventing early breast cancer progression. CONCLUSION: Overall, these findings indicate a link from mTOR signaling to mammary stem and progenitor cell activity and cancer progression. Trial registration This study involves a clinical trial registered under the ClinicalTrials.gov identifier NCT02642094 registered December 30, 2015.

Hydroxychloroquine-Chloroquine, QT-Prolongation, and Major Adverse Cardiac Events: A Meta-analysis and Scoping Review.

OBJECTIVES: We aimed to evaluate the high-quality literature on the frequency and nature of major adverse cardiac events (MACE) associated with either hydroxychloroquine (HCQ) or chloroquine (CQ). DATA SOURCES: We searched Medline, Embase, International Pharmaceutical Abstracts, and Cochrane Central from 1996 onward using search strategies created in collaboration with medical science librarians. STUDY SELECTION AND DATA EXTRACTION: Randomized controlled trials (RCTs) published in English language from January 1996 to September 2022, involving adult patients at least 18 years of age, were selected. Outcomes of interest were death, arrhythmias, syncope, and seizures. Random-effects meta-analyses were performed with a Treatment Arm Continuity Correction for single and double zero event studies. DATA SYNTHESIS: By study drug, there were 31 HCQ RCTs (n = 6677), 9 CQ RCTs (n = 622), and 1 combined HCQ-CQ trial (n = 105). Mortality was the most commonly reported MACE at 220 of 255 events (86.3%), with no reports of torsades de pointes or sudden cardiac death. There was no increased risk of MACE with exposure to HCQ-CQ compared with control (risk ratio [RR] = 0.90, 95% CI = 0.69-1.17, I2 = 0%). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: These findings have important implications with respect to patient reassurance and updated guidance for prescribing practices of these medications. CONCLUSIONS: Despite listing as QT-prolonging meds, HCQ-CQ did not increase the risk of MACE.

Exposure to Family Member Deaths Across the Life Course for Hispanic Individuals.

The present study documents differences in exposure to family member deaths among foreign-born and U.S.-born Hispanic individuals compared with non-Hispanic Black and non-Hispanic White individuals. We use data from the Health and Retirement Study (HRS; 1992-2016, ages 51+; N = 23,228) and the National Longitudinal Study of Adolescent to Adult Health (Add Health; Waves I-V, ages 12-43; N = 11,088) to estimate the risk of exposure to the death of a mother, father, spouse, sibling, and child across the life course. HRS results show more inequities in exposure to family deaths compared with Add Health results, suggesting differences by age or birth cohort. Compared with non-Hispanic Whites, U.S.-born Hispanic individuals in the HRS have a higher risk of experiencing a child's death throughout adulthood and a sibling's death in later life; the latter is explained by larger sibship size, indicating a greater lifetime risk of bereavement experiences. The higher risk of parental death during childhood for U.S.-born and foreign-born Hispanic individuals is explained by covariates (e.g., lower levels of educational attainment). Hispanic individuals generally have a lower risk of family deaths than non-Hispanic Black individuals, but at times a higher risk of exposure relative to non-Hispanic White individuals.

Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche.

We have described multipotent progenitor-like cells within the major pancreatic ducts (MPDs) of the human pancreas. They express PDX1, its surrogate surface marker P2RY1, and the bone morphogenetic protein (BMP) receptor 1A (BMPR1A)/activin-like kinase 3 (ALK3), but not carbonic anhydrase II (CAII). Here we report the single-cell RNA sequencing (scRNA-seq) of ALK3bright+-sorted ductal cells, a fraction that harbors BMP-responsive progenitor-like cells. Our analysis unveiled the existence of multiple subpopulations along two major axes, one that encompasses a gradient of ductal cell differentiation stages, and another featuring cells with transitional phenotypes toward acinar tissue. A third potential ducto-endocrine axis is revealed upon integration of the ALK3bright+ dataset with a single-cell whole-pancreas transcriptome. When transplanted into immunodeficient mice, P2RY1+/ALK3bright+ populations (enriched in PDX1+/ALK3+/CAII- cells) differentiate into all pancreatic lineages, including functional ß-cells. This process is accelerated when hosts are treated systemically with an ALK3 agonist. We found PDX1+/ALK3+/CAII- progenitor-like cells in the MPDs of types 1 and 2 diabetes donors, regardless of the duration of the disease. Our findings open the door to the pharmacological activation of progenitor cells in situ.

Provider- and Facility-Level Variation in Precancerous Cervical Biopsy Diagnoses.

OBJECTIVES: Reproducibility of cervical biopsy diagnoses is low and may vary based on where the diagnostic test is performed and by whom. Our objective was to measure multilevel variation in diagnoses across colposcopists, pathologists, and laboratory facilities. METHODS: We cross-sectionally examined variation in cervical biopsy diagnoses within the 5 sites of the Population-Based Research Optimizing Screening through Personalized Regimens (PROSPR I) consortium within levels defined by colposcopists, pathologists, and laboratory facilities. Patients aged 18 to 65 years with a colposcopy with biopsy performed were included, with diagnoses categorized as normal, cervical intraepithelial neoplasia grade 1 (CIN1), grade 2 (CIN2), and grade 3 (CIN3). Using Markov Chain Monte-Carlo methods, we fit mixed-effects logistic regression models for biopsy diagnoses and presented median odds ratios (MORs), which reflect the variability within each level. Median odds ratios can be interpreted as the average increased odds a patient would have for a given outcome (e.g., CIN2 or CIN3 vs normal or CIN1) when switching to a provider with higher odds of diagnosing that outcome. The MOR is always 1 or greater, and a value of 1 indicates no variation in outcome for that level, with higher values indicating greater variation. RESULTS: A total of 130,110 patients were included who received care across 82 laboratory facilities, 2,620 colposcopists, and 489 pathologists. Substantial variation in biopsy diagnoses was found at each level, with the most occurring between laboratory facilities, followed by pathologists and colposcopists. Substantial variation in biopsy diagnoses of CIN2 or CIN3 (vs normal or CIN1) was present between laboratory facilities (MOR: 1.26; 95% credible interval = 1.19-1.36). CONCLUSIONS: Improving consistency in cervical biopsy diagnoses is needed to reduce underdiagnosis, overdiagnosis, and unnecessary treatment resulting from variation in cervical biopsy diagnoses.

Spinal cord injury is associated with changes in synaptic properties of the mouse major pelvic ganglion.

Spinal cord injury (SCI) has substantial impacts on autonomic function. In part, SCI results in loss of normal autonomic activity that contributes to injury-associated pathology such as neurogenic bladder, bowel, and sexual dysfunction. Yet little is known of the impacts of SCI on peripheral autonomic neurons that directly innervate these target organs. In this study, we measured changes in synaptic properties of neurons of the mouse major pelvic ganglion (MPG) associated with acute and chronic SCI. Our data show that functional and physiological properties of synapses onto MPG neurons are altered after SCI and differ between acute and chronic injury. After acute injury excitatory postsynaptic potentials (EPSPs) show increased rise and decay time constants leading to overall broader and longer EPSPs, whereas in chronic-injured animals EPSPs are reduced in amplitude and show faster rise and decay leading to shorter EPSPs. Synaptic depression and low-pass filtering are also altered in injured animals. Finally, cholinergic currents are smaller in acute-injured animals but larger in chronic-injured animals relative to control animals. These changes in synaptic properties are associated with differences in nicotinic receptor subunit expression as well. MPG CHRNA3 mRNA levels decreased after injury, whereas CHRNA4 mRNAs increased. Furthermore, changes in the correlations of α- and ß-subunit mRNAs suggest that nicotinic receptor subtype composition is altered after injury. Taken together, our data demonstrate that peripheral autonomic neurons are fundamentally altered after SCI, suggesting that longer-term therapeutic approaches could target these neurons directly to potentially help ameliorate neurogenic target organ dysfunction.NEW & NOTEWORTHY Spinal cord injury (SCI) has substantial impacts on autonomic function, yet little is known of the impacts of SCI on autonomic neurons that directly innervate effectors impacted by injury. Here we investigated changes at the cellular level associated with SCI in neurons that are "downstream" of the central injury. An understanding of these off-target impacts of SCI ultimately will be critical in the context of effective restoration of function through neuromodulation of pharmacological therapeutic approaches.

Severe Acute Respiratory Syndrome Coronavirus 2 and Respiratory Virus Sentinel Surveillance, California, USA, May 10, 2020-June 12, 2021.

State and local health departments established the California Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Respiratory Virus Sentinel Surveillance System to conduct enhanced surveillance for SARS-CoV-2 and other respiratory pathogens at sentinel outpatient testing sites in 10 counties throughout California, USA. We describe results obtained during May 10, 2020‒June 12, 2021, and compare persons with positive and negative SARS-CoV-2 PCR results by using Poisson regression. We detected SARS-CoV-2 in 1,696 (19.6%) of 8,662 specimens. Among 7,851 specimens tested by respiratory panel, rhinovirus/enterovirus was detected in 906 (11.5%) specimens and other respiratory pathogens in 136 (1.7%) specimens. We also detected 23 co-infections with SARS-CoV-2 and another pathogen. SARS-CoV-2 positivity was associated with male participants, an age of 35-49 years, Latino race/ethnicity, obesity, and work in transportation occupations. Sentinel surveillance can provide useful virologic and epidemiologic data to supplement other disease monitoring activities and might become increasingly useful as routine testing decreases.

Evaluation of two-stage designs of Phase 2 single-arm trials in glioblastoma: a systematic review.

BACKGROUND: Due to economical and ethical reasons, the two-stage designs have been widely used for Phase 2 single-arm trials in oncology because the designs allow us to stop the trial early if the proposed treatment is likely to be ineffective. Nonetheless, none has examined the usage for published articles that had applied the two-stage designs in Phase 2 single-arm trials in brain tumor. A complete systematic review and discussions for overcoming design issues might be important to better understand why oncology trials have shown low success rates in early phase trials. METHODS: We systematically reviewed published single-arm two-stage Phase 2 trials for patients with glioblastoma and high-grade gliomas (including newly diagnosed or recurrent). We also sought to understand how these two-stage trials have been implemented and discussed potential design issues which we hope will be helpful for investigators who work with Phase 2 clinical trials in rare and high-risk cancer studies including Neuro-Oncology. The systematic review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-statement. Searches were conducted using the electronic database of PubMed, Google Scholar and ClinicalTrials.gov for potentially eligible publications from inception by two independent researchers up to May 26, 2022. The followings were key words for the literature search as index terms or free-text words: "phase II trials", "glioblastoma", and "two-stage design". We extracted disease type and setting, population, therapeutic drug, primary endpoint, input parameters and sample size results from two-stage designs, and historical control reference, and study termination status. RESULTS: Among examined 29 trials, 12 trials (41%) appropriately provided key input parameters and sample size results from two-stage design implementation. Among appropriately implemented 12 trials, discouragingly only 3 trials (10%) explained the reference information of historical control rates. Most trials (90%) used Simon's two-stage designs. Only three studies have been completed for both stages and two out of the three completed studies had shown the efficacy. CONCLUSIONS: Right implementation for two-stage design and sample size calculation, transparency of historical control and experimental rates, appropriate selection on primary endpoint, potential incorporation of adaptive designs, and utilization of Phase 0 paradigm might help overcoming the challenges on glioblastoma therapeutic trials in Phase 2 trials.

Association between Troponin I Levels during Sepsis and Postsepsis Cardiovascular Complications.

Rationale: Sepsis commonly results in elevated serum troponin levels and increased risk for postsepsis cardiovascular complications; however, the association between troponin levels during sepsis and cardiovascular complications after sepsis is unclear.Objectives: To evaluate the association between serum troponin levels during sepsis and 1 year after sepsis cardiovascular events.Methods: We analyzed adults aged ⩾40 years without preexisting cardiovascular disease within 5 years, admitted with sepsis across 21 hospitals from 2011 to 2017. Peak serum troponin I levels during sepsis were grouped as normal (⩽0.04 ng/ml) or tertiles of abnormal (>0.04 to ⩽0.09 ng/ml, >0.09 to ⩽0.42 ng/ml, or >0.42 ng/ml). Multivariable adjusted cause-specific Cox proportional hazards models with death as a competing risk were used to assess associations between peak troponin I levels and a composite cardiovascular outcome (atherosclerotic cardiovascular disease, atrial fibrillation, and heart failure) in the year following sepsis. Models were adjusted for presepsis and intrasepsis factors considered potential confounders.Measurements and Main Results: Among 14,046 eligible adults with troponin I measured, 2,012 (14.3%) experienced the composite cardiovascular outcome, including 832 (10.9%) patients with normal troponin levels, as compared with 370 (17.3%), 376 (17.6%), and 434 (20.3%) patients within each sequential abnormal troponin tertile, respectively (P < 0.001). Patients within the elevated troponin tertiles had increased risks of adverse cardiovascular events (adjusted hazard ratio [aHR]troponin0.04-0.09 = 1.37; 95% confidence interval [CI], 1.20-1.55; aHRtroponin0.09-0.42 = 1.44; 95% CI, 1.27-1.63; and aHRtroponin>0.42 = 1.77; 95% CI, 1.56-2.00).Conclusions: Among patients without preexisting cardiovascular disease, troponin elevation during sepsis identified patients at increased risk for postsepsis cardiovascular complications. Strategies to mitigate cardiovascular complications among this high-risk subset of patients are warranted.

FASN inhibition as a potential treatment for endocrine-resistant breast cancer.

PURPOSE: The majority of breast cancers are estrogen receptor (ERα) positive making endocrine therapy a mainstay for these patients. Unfortunately, resistance to endocrine therapy is a common occurrence. Fatty acid synthase (FASN) is a key enzyme in lipid biosynthesis and its expression is commensurate with tumor grade and resistance to numerous therapies. METHODS: The effect of the FASN inhibitor TVB-3166 on ERα expression and cell growth was characterized in tamoxifen-resistant cell lines, xenografts, and patient explants. Subcellular localization of ERα was assessed using subcellular fractionations. Palmitoylation and ubiquitination of ERα were assessed by immunoprecipitation. ERα and p-eIF2α protein levels were analyzed by Western blotting after treatment with TVB-3166 with or without the addition of palmitate or BAPTA. RESULTS: TVB-3166 treatment leads to a marked inhibition of proliferation in tamoxifen-resistant cells compared to the parental cells. Additionally, TVB-3166 significantly inhibited tamoxifen-resistant breast tumor growth in mice and decreased proliferation of primary tumor explants compared to untreated controls. FASN inhibition significantly reduced ERα levels most prominently in endocrine-resistant cells and altered its subcellular localization. Furthermore, we showed that the reduction of ERα expression upon TVB-3166 treatment is mediated through the induction of endoplasmic reticulum stress. CONCLUSION: Our preclinical data provide evidence that FASN inhibition by TVB-3166 presents a promising therapeutic strategy for the treatment of endocrine-resistant breast cancer. Further clinical development of FASN inhibitors for endocrine-resistant breast cancer should be considered.

Outcomes of Patients With Coronavirus Disease 2019 Receiving Organ Support Therapies: The International Viral Infection and Respiratory Illness Universal Study Registry.

OBJECTIVES: To describe the outcomes of hospitalized patients in a multicenter, international coronavirus disease 2019 registry. DESIGN: Cross-sectional observational study including coronavirus disease 2019 patients hospitalized with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection between February 15, 2020, and November 30, 2020, according to age and type of organ support therapies. SETTING: About 168 hospitals in 16 countries within the Society of Critical Care Medicine's Discovery Viral Infection and Respiratory Illness University Study coronavirus disease 2019 registry. PATIENTS: Adult hospitalized coronavirus disease 2019 patients who did and did not require various types and combinations of organ support (mechanical ventilation, renal replacement therapy, vasopressors, and extracorporeal membrane oxygenation). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was hospital mortality. Secondary outcomes were discharge home with or without assistance and hospital length of stay. Risk-adjusted variation in hospital mortality for patients receiving invasive mechanical ventilation was assessed by using multilevel models with hospitals as a random effect, adjusted for age, race/ethnicity, sex, and comorbidities. Among 20,608 patients with coronavirus disease 2019, the mean (± sd) age was 60.5 (±17), 11,1887 (54.3%) were men, 8,745 (42.4%) were admitted to the ICU, and 3,906 (19%) died in the hospital. Hospital mortality was 8.2% for patients receiving no organ support (n = 15,001). The most common organ support therapy was invasive mechanical ventilation (n = 5,005; 24.3%), with a hospital mortality of 49.8%. Mortality ranged from 40.8% among patients receiving only invasive mechanical ventilation (n =1,749) to 71.6% for patients receiving invasive mechanical ventilation, vasoactive drugs, and new renal replacement therapy (n = 655). Mortality was 39% for patients receiving extracorporeal membrane oxygenation (n = 389). Rates of discharge home ranged from 73.5% for patients who did not require organ support therapies to 29.8% for patients who only received invasive mechanical ventilation, and 8.8% for invasive mechanical ventilation, vasoactive drugs, and renal replacement; 10.8% of patients older than 74 years who received invasive mechanical ventilation were discharged home. Median hospital length of stay for patients on mechanical ventilation was 17.1 days (9.7-28 d). Adjusted interhospital variation in mortality among patients receiving invasive mechanical ventilation was large (median odds ratio 1.69). CONCLUSIONS: Coronavirus disease 2019 prognosis varies by age and level of organ support. Interhospital variation in mortality of mechanically ventilated patients was not explained by patient characteristics and requires further evaluation.

Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3.

PURPOSE: Variants in genes encoding sarcomeric proteins are the most common cause of inherited cardiomyopathies. However, the underlying genetic cause remains unknown in many cases. We used exome sequencing to reveal the genetic etiology in patients with recessive familial cardiomyopathy. METHODS: Exome sequencing was carried out in three consanguineous families. Functional assessment of the variants was performed. RESULTS: Affected individuals presented with hypertrophic or dilated cardiomyopathy of variable severity from infantile- to early adulthood-onset and sudden cardiac death. We identified a homozygous missense substitution (c.170C>A, p.[Ala57Asp]), a homozygous translation stop codon variant (c.106G>T, p.[Glu36Ter]), and a presumable homozygous essential splice acceptor variant (c.482-1G>A, predicted to result in skipping of exon 5). Morpholino knockdown of the MYL3 orthologue in zebrafish, cmlc1, resulted in compromised cardiac function, which could not be rescued by reintroduction of MYL3 carrying either the nonsense c.106G>T or the missense c.170C>A variants. Minigene assay of the c.482-1G>A variant indicated a splicing defect likely resulting in disruption of the EF-hand Ca2+ binding domains. CONCLUSIONS: Our data demonstrate that homozygous MYL3 loss-of-function variants can cause of recessive cardiomyopathy and occurrence of sudden cardiac death, most likely due to impaired or loss of myosin essential light chain function.

Dasatinib, paclitaxel, and carboplatin in women with advanced-stage or recurrent endometrial cancer: A pilot clinical and translational study.

PURPOSE: To evaluate the effect of dasatinib therapy on EphA2 signaling in cancers of women with measurable (biopsy amenable) advanced-stage, chemo-naïve primary or recurrent endometrial cancer. Preliminary efficacy was also assessed. PATIENTS AND METHODS: We performed a pilot study of single-agent dasatinib lead-in, followed by triplet dasatinib, paclitaxel, and carboplatin. We measured the downstream effectors of EphA2 signaling in pre- and post-dasatinib treatment biopsy tissue samples; we also determined the severity of adverse events and patients' progression-free survival and overall survival durations. RESULTS: Eighteen patients were recruited and given dasatinib (150 mg orally daily for 14 days), followed by paclitaxel, carboplatin and dasatinib (daily) for six cycles (21-day cycles). Seventeen patients were evaluable for toxicity and 11 patients for response. A reverse phase protein array and proximity ligation assay revealed that CRAF/BRAF dimerization, caveolin-1 level, and Notch pathway signaling were predictive of response and resistance to dasatinib. Overall, the objective response rate was 45% (95% CI: 17%-77%), with median progression-free survival duration of 10.5 months and median overall survival duration of 30.4 months. The most common grade 3 or 4 adverse events were neutropenia (76%), thrombocytopenia (53%), anemia (53%), and fatigue (12%). CONCLUSIONS: Caveolin-1 expression, in combination with CRAF/BRAF heterodimerization, is associated with resistance to EphA2 targeting by dasatinib. The triplet combination showed interesting clinical activity in endometrial cancer with acceptable toxicity. Pretreatment with dasatinib may accentuate combination therapy toxicity.

Predictors to forgo resuscitative effort during Covid-19 critical illness at the height of the pandemic : A retrospective cohort study.

BACKGROUND: Early in the Covid-19 pandemic, there was uncertainty regarding critical illness prognosis and challenges to traditional face-to-face family meetings. Ethnic minority populations have suffered disproportionately worse outcomes during the pandemic, which may in part relate to differences in end-of-life decision-making. AIM: Characterize patterns of and factors associated with decisions to forgo resuscitative efforts, as measured by do-not-resuscitate orders, during critical illness with Covid-19. DESIGN: Retrospective cohort with medical record abstraction. SETTING/PARTICIPANTS: Adult patients diagnosed with SARS-Cov-2 virus via polymerase chain reaction and admitted to the intensive care unit at an academic hospital, which cares for the city's underserved communities, between March 1 and June 7, 2020 who underwent invasive mechanical ventilation for at least 48 hours. RESULTS: In this cohort (n = 155), 45% were black people, and 51% spoke English as their primary language. Median time to first goals-of-care conversation was 3.9 days (IQR 1.9-7.6) after intensive care unit admission. Overall 61/155 patients (39%) transitioned to do-not-resuscitate status, and 50/62 (82%) patients who died had do-not-resuscitate orders. Multivariate analysis shows age and palliative care involvement as the strongest predictors of decision to instate do-not-resuscitate order. There was no association between race, ethnicity, or language and decisions to forego resuscitation. CONCLUSIONS: During this time of crisis and uncertainty with limited resources and strained communication, time to first goals of care conversation was shorter than in pre-pandemic studies, but rates of foregoing resuscitation remained similar, with no differences observed by race, ethnicity, or language. This study suggests that early palliative care involvement and non-traditional communications, including videoconferencing, to facilitate goals of care conversations could have mitigated potential disparities in end-of-life decision making patterns during the pandemic.

Magnetic Resonance Imaging for the Detection of High Grade Cancer in the Canary Prostate Active Surveillance Study.

PURPOSE: We investigated the ability of prostate magnetic resonance imaging to detect Gleason Grade Group 2 or greater cancer in a standardized, multi-institutional active surveillance cohort. MATERIALS AND METHODS: We evaluated men enrolled in Canary Prostate Active Surveillance Study with Gleason Grade Group less than 2 and who underwent biopsy within 12 months of multiparametric magnetic resonance imaging. Our primary outcome was biopsy reclassification to Gleason Grade Group 2 or greater. We evaluated the performance of magnetic resonance imaging PI-RADS® score and clinical factors. Multivariable logistic regression models were fit with magnetic resonance imaging and clinical factors and used to perform receiver operating curve analyses. RESULTS: There were 361 participants with 395 prostate magnetic resonance imaging studies with a median followup of 4.1 (IQR 2.0-7.6) years. Overall 108 (27%) biopsies showed reclassification. Defining positive magnetic resonance imaging as PI-RADS 3-5, the negative predictive value and positive predictive value for detecting Gleason Grade Group 2 or greater cancer was 83% (95% CI 76-90) and 31% (95% CI 26-37), respectively. PI-RADS was significantly associated with reclassification (PI-RADS 5 vs 1 and 2 OR 2.71, 95% CI 1.21-6.17, p=0.016) in a multivariable model but did not improve upon a model with only clinical factors (AUC 0.768 vs 0.762). In 194 fusion biopsies higher grade cancer was found in targeted cores in 21 (11%) instances, while 25 (13%) had higher grade cancer in the systematic cores. CONCLUSIONS: This study adds the largest cohort data to the body of literature for magnetic resonance imaging in active surveillance, recommending systematic biopsy in patients with negative magnetic resonance imaging and the inclusion of systematic biopsy in patients with positive magnetic resonance imaging.

Functional Consequences of Synapse Remodeling Following Astrocyte-Specific Regulation of Ephrin-B1 in the Adult Hippocampus.

Astrocyte-derived factors can control synapse formation and functions, making astrocytes an attractive target for regulating neuronal circuits and associated behaviors. Abnormal astrocyte-neuronal interactions are also implicated in neurodevelopmental disorders and neurodegenerative diseases associated with impaired learning and memory. However, little is known about astrocyte-mediated mechanisms that regulate learning and memory. Here, we propose astrocytic ephrin-B1 as a regulator of synaptogenesis in adult hippocampus and mouse learning behaviors. We found that astrocyte-specific ablation of ephrin-B1 in male mice triggers an increase in the density of immature dendritic spines and excitatory synaptic sites in the adult CA1 hippocampus. However, the prevalence of immature dendritic spines is associated with decreased evoked postsynaptic firing responses in CA1 pyramidal neurons, suggesting impaired maturation of these newly formed and potentially silent synapses or increased excitatory drive on the inhibitory neurons resulting in the overall decreased postsynaptic firing. Nevertheless, astrocyte-specific ephrin-B1 knock-out male mice exhibit normal acquisition of fear memory but enhanced contextual fear memory recall. In contrast, overexpression of astrocytic ephrin-B1 in the adult CA1 hippocampus leads to the loss of dendritic spines, reduced excitatory input, and impaired contextual memory retention. Our results suggest that astrocytic ephrin-B1 may compete with neuronal ephrin-B1 and mediate excitatory synapse elimination through its interactions with neuronal EphB receptors. Indeed, a deletion of neuronal EphB receptors impairs the ability of astrocytes expressing functional ephrin-B1 to engulf synaptosomes in vitro Our findings demonstrate that astrocytic ephrin-B1 regulates long-term contextual memory by restricting new synapse formation in the adult hippocampus.SIGNIFICANCE STATEMENT These studies address a gap in our knowledge of astrocyte-mediated regulation of learning and memory by unveiling a new role for ephrin-B1 in astrocytes and elucidating new mechanisms by which astrocytes regulate learning. Our studies explore the mechanisms underlying astrocyte regulation of hippocampal circuit remodeling during learning using new genetic tools that target ephrin-B signaling in astrocytes in vivo On a subcellular level, astrocytic ephrin-B1 may compete with neuronal ephrin-B1 and trigger astrocyte-mediated elimination of EphB receptor-containing synapses. Given the role EphB receptors play in neurodevelopmental disorders and neurodegenerative diseases, these findings establish a foundation for future studies of astrocyte-mediated synaptogenesis in clinically relevant conditions that can help to guide the development of clinical applications for a variety of neurological disorders.

Evaluation of online clinical pharmacology curriculum resources for medical students.

AIMS: To identify and evaluate clinical pharmacology (CP) online curricular (e-Learning) resources that are internationally available for medical students. METHODS: Literature searches of Medline, EMBASE and ERIC databases and an online survey of faculty members of international English language medical schools, were used to identify CP e-Learning resources. Resources that were accessible online in English and aimed to improve the quality of prescribing specific medications were then evaluated using a summary percentage score for comprehensiveness, usability and quality, and for content suitability. RESULTS: Our literature searches and survey of 252 faculty (40.7% response rate) in 219 medical schools identified 22 and 59 resources respectively. After screening and removing duplicates, 8 eligible resources remained for evaluation. Mean total score was 53% (standard deviation = 13). The Australian National Prescribing Curriculum, ranked highest with a score of 77%, based primarily on very good ratings for usability, quality and suitable content. CONCLUSION: Using a novel method and evaluation metric to identify, classify, and rate English language CP e-Learning resources, the National Prescribing Curriculum was the highest ranked open access resource. Future work is required to implement and evaluate its effectiveness on prescribing competence.

Arginase-1 expressing microglia in close proximity to motor neurons were increased early in disease progression in canine degenerative myelopathy, a model of amyotrophic lateral sclerosis.

Toxicity within superoxide dismutase-1 (SOD1)-associated familial amyotrophic lateral sclerosis (ALS) is non-cell autonomous with direct contribution from microglia. Microglia exhibit variable expression of neuroprotective and neurotoxic molecules throughout disease progression. The mechanisms regulating microglial phenotype within ALS are not well understood. This work presents a first study to examine the specific microglial phenotypic response in close association to motor neurons in a naturally occurring disease model of ALS, canine degenerative myelopathy (DM). Microglia closely associated with motor neurons were increased in all stages of DM progression, although only DM Late reached statistical significance. Furthermore, the number of arginase-1 expressing microglia per motor neuron were significantly increased in early stages of DM, whereas the number of inducible nitric oxide synthase (iNOS)-expressing microglia per motor neuron was indistinguishable from aged controls at all stages of disease. Fractalkine, a chemotactic molecule for microglia, was expressed in motor neurons, and the fractalkine receptor was specifically localized to microglia. However, we found no correlation between microglial response and lumbar spinal cord fractalkine levels. Taken together, these data suggest that arginase-1-expressing microglia are recruited to the motor neuron early in DM disease through a fractalkine-independent mechanism.

Palliative radiotherapy near the end of life.

BACKGROUND: A significant proportion of patients with advanced cancer undergo palliative radiotherapy (RT) within their last 30 days of life. This study characterizes palliative RT at our institution and aims to identify patients who may experience limited benefit from RT due to imminent mortality. METHODS: Five hundred and-eighteen patients treated with external beam RT to a site of metastatic disease between 2012 and 2016 were included. Mann-Whitney U and chi-squared tests were used to identify factors associated with RT within 30 days of death (D30RT). RESULTS: Median age at RT was 63 years (IQR 54-71). Median time from RT to death was 74 days (IQR 33-174). One hundred and twenty-five patients (24%) died within 30 days of RT. D30RT was associated with older age at RT (64 vs. 62 years, p = 0.04), shorter interval since diagnosis (14 vs. 31 months, p <  0.001), liver metastasis (p = 0.02), lower KPS (50 vs. 70, p <  0.001), lower BMI (22 vs. 24, p = 0.001), and inpatient status at consult (56% vs. 26%, p < 0.001). Patients who died within 30 days of RT were less likely to have hospice involved in their care (44% vs. 71%, p = 0.001). D30RT was associated with higher Chow and TEACHH scores at consult (p < 0.001 for both). CONCLUSIONS: Twenty-four percent of patients received palliative RT within 30 days of death. Additional tools are necessary to help physicians identify patients who would benefit from short treatment courses or alternative interventions to maximize quality at the end of life.