De novo TANGLED1 recruitment from the phragmoplast to aberrant cell plate fusion sites in maize.

Division plane positioning is crucial for proper growth and development in many organisms. In plants, the division plane is established before mitosis, by accumulation of a cytoskeletal structure called the preprophase band (PPB). The PPB is thought to be essential for recruitment of division site-localized proteins, which remain at the division site after the PPB disassembles. Here, we show that the division site-localized protein TANGLED1 (TAN1) is recruited independently of the PPB to the cell cortex by the plant cytokinetic machinery, the phragmoplast, from experiments using both the PPB-defective mutant discordia1 (dcd1) and chemical treatments that disrupt the phragmoplast in maize. TAN1 recruitment to de novo sites on the cortex is partially dependent on intact actin filaments and the myosin XI motor protein OPAQUE1 (O1). These data imply a yet unknown role for TAN1 and possibly other division site-localized proteins during the last stages of cell division when the phragmoplast touches the cell cortex to complete cytokinesis.

The Development of the Oncology Center of Excellence Patient-Friendly Language Glossary of Oncology Clinical Trial Terms.

Oncology clinical trials terms and definitions have become increasingly complex, which has led to shortcomings among research staff and healthcare providers in informing clinical trial participants with the study results and consenting procedures in simple language. Understanding oncology clinical trial terms is of critical importance to assist patients and caregivers in making cancer treatment decisions, including enrollment into clinical trials. The U.S. Food and Drug Administration's (FDA) Oncology Center of Excellence (OCE) organized a physician and patient advocate-led focus group, with the primary goal of publishing a patient-centric public glossary of select cancer clinical trial terms for healthcare providers, patients, and caregivers. This commentary reports the results of the focus group sessions that gave FDA OCE valuable insights into how patients perceive clinical trial terms and how oncology clinical trial definitions can be improved to effectively communicate information to the patients to make better informed decisions about their treatment options.

IL-17C regulates the innate immune function of epithelial cells in an autocrine manner.

Interleukin 17C (IL-17C) is a member of the IL-17 family that is selectively induced in epithelia by bacterial challenge and inflammatory stimuli. Here we show that IL-17C functioned in a unique autocrine manner, binding to a receptor complex consisting of the receptors IL-17RA and IL-17RE, which was preferentially expressed on tissue epithelial cells. IL-17C stimulated epithelial inflammatory responses, including the expression of proinflammatory cytokines, chemokines and antimicrobial peptides, which were similar to those induced by IL-17A and IL-17F. However, IL-17C was produced by distinct cellular sources, such as epithelial cells, in contrast to IL-17A, which was produced mainly by leukocytes, especially those of the T(H)17 subset of helper T cells. Whereas IL-17C promoted inflammation in an imiquimod-induced skin-inflammation model, it exerted protective functions in dextran sodium sulfate-induced colitis. Thus, IL-17C is an essential autocrine cytokine that regulates innate epithelial immune responses.

Cardiovascular Impact of Androgen Deprivation Therapy: from Basic Biology to Clinical Practice.

PURPOSE OF THE REVIEW: There have been increasing reports of cardiovascular complications of androgen deprivation therapy (ADT) leading to worse outcomes among patients with prostate cancer. While this may result from the direct effects of androgen suppression in the cardiovascular systems, there are ADT-type-specific distinct cardiovascular complications suggestive of mechanisms beyond androgen-mediated. Thus, it is critical to understand the biological and clinical impact of ADT on the cardiovascular system. RECENT FINDINGS: Gonadotropin-releasing hormone (GnRH) agonists cause increased cardiovascular events compared to GnRH antagonists. Androgen receptor antagonists are linked to an increased risk of long QT syndrome, torsades de pointes, and sudden cardiac death. Androgen synthesis inhibitors are associated with increased rates of hypertension, atrial tachyarrhythmia, and, in rare incidences, heart failure. ADT increases the risk of cardiovascular disease. The risk among ADT drugs differs and must be evaluated to develop a medically optimal plan for prostate cancer patients.

Management of traumatic globe subluxation with optic nerve and extraocular muscle transection.

A care algorithm for partial globe subluxation cases with optic nerve and at least one extraocular muscle (EOM) transection is presented after a literature review was performed using key term variations of globe, ocular, subluxation, optic nerve evulsion or transection, and trauma. Partial globe subluxation cases with transection of the optic nerve and at least 1 EOM were included. Exclusion criteria included globe rupture, complete enucleation defined by a globe without at least 1 EOM attachment, or unclear details confirming optic nerve transection. Including the patient presented herein, a total of 24 patients with 26 eyes were analyzed. About 73.08% of cases underwent initial repositioning (n = 19), with 11.54% of those requiring secondary enucleation or evisceration (n = 3). Of the secondarily managed cases, 2 of the 3 cases listed pain (n = 2) and inadequate cosmesis (n = 1) as rationale. We found that 26.92% of cases underwent initial enucleation (n = 7), citing lack of visual potential and limiting later complications. Most cases favored repositioning, which was typically sustainable. Initial repositioning can improve cosmetic outcome and psychological impact. Given the low risk of later management, cases of traumatic partial subluxation with EOM and optic nerve transections should attempt initial repositioning.

Clinical Trial Diversity in Oncology: FDA Takes Action with Post-Marketing Requirements or Commitments.

In recent years, there has been a renewed focus on promoting the inclusion of patients from racial and ethnic minority groups in oncology clinical trials. FDA Oncology has long pointed to the underrepresentation of racial minorities in registration trials leading to approval. US FDA's Guidance on diversity discusses how diversity could be handled within clinical trials, giving recommendations on broadening eligibility criteria, inclusive trial practices, and alternative trial designs. While there is no specific guidance from the FDA on cancer clinical trials, the recommendation is to include a representative population applicable to the US population. With the recent renewed focus on diversity in oncology clinical trials, FDA Oncology has recently asked for the completion of a Diversity Plan during drug development and has issued post-marketing commitments and requirements at the time of approval. As FDA has started to issue post-marketing requirements or commitments regarding diversity in 2020, we sought to analyze the post-marketing studies asking for a study of racial and ethnic minorities issued by the FDA's Office of Oncologic Diseases (OOD). The analysis demonstrated the need to increase the enrollment of a diverse patient population in cancer clinical trials.

Burkholderia cepacia complex outbreak linked to a no-rinse cleansing foam product, United States - 2017-2018.

In March 2018, the US Food and Drug Administration (FDA), US Centers for Disease Control and Prevention, California Department of Public Health, Los Angeles County Department of Public Health and Pennsylvania Department of Health initiated an investigation of an outbreak of Burkholderia cepacia complex (Bcc) infections. Sixty infections were identified in California, New Jersey, Pennsylvania, Maine, Nevada and Ohio. The infections were linked to a no-rinse cleansing foam product (NRCFP), produced by Manufacturer A, used for skin care of patients in healthcare settings. FDA inspected Manufacturer A's production facility (manufacturing site of over-the-counter drugs and cosmetics), reviewed production records and collected product and environmental samples for analysis. FDA's inspection found poor manufacturing practices. Analysis by pulsed-field gel electrophoresis confirmed a match between NRCFP samples and clinical isolates. Manufacturer A conducted extensive recalls, FDA issued a warning letter citing the manufacturer's inadequate manufacturing practices, and federal, state and local partners issued public communications to advise patients, pharmacies, other healthcare providers and healthcare facilities to stop using the recalled NRCFP. This investigation highlighted the importance of following appropriate manufacturing practices to minimize microbial contamination of cosmetic products, especially if intended for use in healthcare settings.

Nearly all thirty most frequently used emergency department drugs experienced shortages from 2006-2019.

BACKGROUND: Drug shortages contribute to avoidable medication error and patient harm; these shortages are exacerbated in the Emergency Department due to the time-sensitive nature of acute care. METHODS: We performed a cross-sectional study to describe the frequency and duration of drug shortages associated with the most frequent medications administered in the ED. We identified the most frequently used ED medications and calculated number of visits associated with these medications using the 2006-2019 National Hospital Ambulatory Medical Care Survey. We obtained the frequency and duration of shortages associated with these medications from the University of Utah Drug Information System. We calculated duration and total ED visits associated with shortages of the most frequently used ED medications. RESULTS: From 2006 through 2019, the most frequently used drugs were ondansetron (255.1 million ED visits), 0.9% normal saline (251.3 million ED visits), and ibuprofen (188.5 million ED visits). All but two of the top thirty most frequently used medications experienced a shortage. The median shortage duration was 425 days, while the longest were for injectable morphine (3,202 days). The number of ED visits associated with drugs experiencing shortages increased from 2,564,425 (2.2% of U.S. ED visits) in 2006 to 67,221,968 (60.4%) in 2019. The most common reasons for shortage include manufacturing delays and increased demand. CONCLUSIONS AND RELEVANCE: Drug shortages were more frequent and persistent from 2006 through 2019. Further studies on the clinical impact of these shortages are needed, in addition to policy interventions to mitigate shortages.

US Food and Drug Administration regulatory updates in neuro-oncology.

OBJECTIVE: Contemporary management of patients with neuro-oncologic disease requires an understanding of approvals by the US Food and Drug Administration (FDA) related to nervous system tumors. To summarize FDA updates applicable to neuro-oncology practitioners, we sought to review oncology product approvals and Guidances that were pertinent to the field in the past year. METHODS: Oncology product approvals between January 1, 2020, and December 31, 2020, were reviewed for clinical trial outcomes involving tumors of the nervous system. FDA Guidances relevant to neuro-oncology were also reviewed. RESULTS: Five oncology product approvals described outcomes for nervous system tumors in the year 2020. These included the first regulatory approval for neurofibromatosis type 1: selumetinib for children with symptomatic, inoperable plexiform neurofibromas. Additionally, there were 4 regulatory approvals for non-central nervous system (CNS) cancers that described clinical outcomes for patients with brain metastases. These included the approval of tucatinib for metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer including patients with brain metastases, brigatinib for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), and pralsetinib and selpercatinib for RET fusion-positive NSCLC. Finally, two FDA Guidances for Industry, "Cancer Clinical Trial Eligibility Criteria: Brain Metastases" and "Evaluating Cancer Drugs in Patients with Central Nervous System Metastases" were published to facilitate drug development for and inclusion of patients with CNS metastases in clinical trials. CONCLUSIONS: Despite the challenges of the past year brought on by the COVID-19 pandemic, progress continues to be made in neuro-oncology. These include first-of-their-kind FDA approvals and Guidances that are relevant to the management of patients with nervous system tumors.

Patient-Reported Outcomes After Treatment Discontinuation: Commercial Clinical Trial Data From Four Cancer Types.

OBJECTIVES: How frequently patient-reported outcome (PRO) data are collected in commercial cancer clinical trials after treatment discontinuation and the quality of that data are poorly understood. We reviewed treatment discontinuation follow-up PRO data collection to learn about trials collecting these data and understand data quality. The review included 4 cancer types representing potential for long- (prostate cancer), medium-/long- (breast cancer), and short-term (pancreatic cancer and hepatocellular carcinoma) follow-up owing to disease trajectory. METHODS: We reviewed registration trials in US Food and Drug Administration databases between January 2010 and January 2019. Protocols were reviewed to determine whether PROs were collected and, if so, whether these included the follow-up phase. Clinical study reports were reviewed when follow-up PROs were collected to determine completion rates. Results were summarized using descriptive analyses. RESULTS: Of the 46 trials containing PRO data, 46% had at least 1 follow-up PRO assessment. Follow-up schedules of assessment were wide ranging; the first assessment occurred between 30 days and 6 months after stopping treatment with follow-up for as long as 3 years. PRO completion rates were reported in 57% of 21 trials; at the first follow-up assessment, completion rates for the treatment arm ranged from 38% to 91% and from 41% to 100% in the control arm. CONCLUSIONS: The quality of the follow-up PRO data, based on completion rates, was variable, as was the duration of follow-up. A clear research objective should be developed for follow-up PRO data, accounting for patient burden. If PRO data are collected, monitoring should be implemented to improve completion because poor completion limits data use in the benefit-risk assessment.

Novel antibody-antibiotic conjugate eliminates intracellular S. aureus.

Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S. aureus within host cells may provide a reservoir relatively protected from antibiotics, thus enabling long-term colonization of the host and explaining clinical failures and relapses after antibiotic therapy. Here we confirm that intracellular reservoirs of S. aureus in mice comprise a virulent subset of bacteria that can establish infection even in the presence of vancomycin, and we introduce a novel therapeutic that effectively kills intracellular S. aureus. This antibody-antibiotic conjugate consists of an anti-S. aureus antibody conjugated to a highly efficacious antibiotic that is activated only after it is released in the proteolytic environment of the phagolysosome. The antibody-antibiotic conjugate is superior to vancomycin for treatment of bacteraemia and provides direct evidence that intracellular S. aureus represents an important component of invasive infections.

When cardiomyopathy, cancer, and COVID-19 collide: A case report.

Malignancy has historically prohibited solid organ transplant; however, patients with effectively treated, favorable-risk cancers should not necessarily be eliminated as transplant candidates. These cases require careful review by a multidisciplinary team. Here, we report the case of a woman with end-stage heart failure undergoing heart transplant evaluation during the COVID pandemic who was found to have early-stage, hormone receptor-positive breast cancer. Given her favorable cancer-related prognosis, a multidisciplinary committee recommended lumpectomy, accelerated partial breast irradiation, and adjuvant aromatase inhibitor therapy for definitive treatment to allow for consideration of orthotopic heart transplant.

The Implications of COVID-19 for Early Childhood Education in Ethiopia: Perspectives from Parents and Caregivers.

Recent research on the effects of COVID-19 on school closures has mainly focused on primary and secondary education, with extremely limited attention to early childhood education (ECE). To address this gap, we identify the extent to which parents and caregivers with pre-primary school-aged children were engaged in their children's learning during school closures in Ethiopia. Our focus on Ethiopia is of particular relevance given that ECE provision has expanded dramatically in recent years, aimed at ensuring children are prepared for primary school. Using data collected through a phone survey with 480 parents and caregivers, the results revealed that learning disruption due to COVID-19 school closures is likely to be substantial and will probably widen existing inequalities further. Many poorer households and those where parents or caregivers are not literate, are less likely to have child-oriented learning resources, and home learning activities between parents and children in these households are limited. The study highlights that greater attention needs to be paid to mitigate the threats of COVID-19 on Ethiopia's recent gains in ECE, to prevent the pandemic from further reinforcing inequalities between children from advantaged and disadvantaged households.

Evaluation of Serious Postmarket Safety Signals Within 2 Years of FDA Approval for New Cancer Drugs.

BACKGROUND: We examined how often new serious safety signals were identified by the U.S. Food and Drug Administration within the first 2 years after approval for new molecular entities (NMEs) for treatment of cancer that required specific regulatory actions described here. METHODS: We identified, for all NMEs approved for treatment of cancer or malignant hematology indications between 2010 and 2016, substantial safety-related changes within the first 2 years after approval, which included a new Boxed Warning or Warning and Precaution; requirement for (or modification of existing) Risk Evaluation and Mitigation Strategies (REMS); and withdrawal from the market because of safety concerns. RESULTS: Fifty-five NMEs were approved between 2010 and 2016: 32 (58%) under regular approval (RA) and 23 (42%) under accelerated approval (AA). Of these 55 NMEs, 9 (16%) had substantial safety-related changes after approval. Across all 55 NMEs, one was temporarily withdrawn from the market for safety reasons (1.8%); one (1.8%) required a new REMS; nine required labeling revisions-new Boxed Warnings were required for two NMEs (3.6%), and new Warnings and Precautions subsections were required for eight (14.6%). One drug (ponatinib) was responsible for several of the substantial safety-related changes (withdrawal, REMS, Boxed Warnings). One of 32 NMEs approved under RA required a new Warning and Precaution, whereas 7 of 23 NMEs approved under AA had substantial safety-related changes in the first 2 years after approval. CONCLUSION: Based on our analysis we conclude that although there was a greater incidence of substantial safety-related changes to AA drugs versus RA drugs, the majority of these were changes to the Warnings and Precautions and did not substantially alter the benefit-risk profile of the drug. IMPLICATIONS FOR PRACTICE: The majority of new cancer drugs (84%) approved in the U.S. do not have new substantial safety information being added to the label within the first 2 years of approval. Unprecedented efficacy seen in contemporary cancer drug development has led to early availability of effective cancer therapies based on large effects in smaller populations. More limited premarket safety data require diligent postmarketing safety surveillance as we continue to learn and update drug labeling throughout the product lifecycle.

Outbreak of Norovirus Illness Among Wildfire Evacuation Shelter Populations - Butte and Glenn Counties, California, November 2018.

The Camp Fire, California's deadliest wildfire, began November 8, 2018, and was extinguished November 25 (1). Approximately 1,100 evacuees from the fire sought emergency shelter. On November 10, acute gastroenteritis (AGE) was reported in two evacuation shelters; norovirus illness was suspected, because it is commonly detected in shelter-associated AGE outbreaks. Norovirus is highly contagious and resistant to several disinfectants. Butte County Public Health Department (BCPHD), assisted by the California Department of Public Health (CDPH), initiated active surveillance to identify cases, confirm the etiology, and assess shelter infection prevention and control (IPC) practices to guide recommendations. During November 8-30, a total of 292 patients with AGE were identified among nine evacuation shelters; norovirus was detected in 16 of 17 unique patient stool specimens. Shelter IPC assessments revealed gaps in illness surveillance, isolation practices, cleaning, disinfection, and handwashing. CDPH and BCPHD collaborated with partner agencies to implement AGE screening, institute isolation protocols and 24-hour cleaning services, and promote proper hand hygiene. During disasters with limited resources, damaged infrastructure, and involvement of multiple organizations, establishing shelter disease surveillance and IPC is difficult. However, prioritizing effective surveillance and IPC at shelter activation is necessary to prevent, identify, and contain outbreaks.

Patient-Friendly Language to Facilitate Treatment Choice for Patients with Cancer.

Resources are needed to assist patients in understanding their diagnoses and considering treatment options. This commentary focuses on improving the language used to communicate disease and treatment information so that patients can make informed decisions.

Sepsis Attributed to Bacterial Contamination of Platelets Associated with a Potential Common Source - Multiple States, 2018.

During May-October 2018, four patients from three states experienced sepsis after transfusion of apheresis platelets contaminated with Acinetobacter calcoaceticus-baumannii complex (ACBC) and Staphylococcus saprophyticus; one patient died. ACBC isolates from patients' blood, transfused platelet residuals, and two environmental samples were closely related by whole genome sequencing. S. saprophyticus isolates from two patients' blood, three transfused platelet residuals, and one hospital environmental sample formed two whole genome sequencing clusters. This whole genome sequencing analysis indicated a potential common source of bacterial contamination; investigation into the contamination source continues. All platelet donations were collected using apheresis cell separator machines and collection sets from the same manufacturer; two of three collection sets were from the same lot. One implicated platelet unit had been treated with pathogen-inactivation technology, and two had tested negative with a rapid bacterial detection device after negative primary culture. Because platelets are usually stored at room temperature, bacteria in contaminated platelet units can proliferate to clinically relevant levels by the time of transfusion. Clinicians should monitor for sepsis after platelet transfusions even after implementation of bacterial contamination mitigation strategies. Recognizing adverse transfusion reactions and reporting to the platelet supplier and hemovigilance systems is crucial for public health practitioners to detect and prevent sepsis associated with contaminated platelets.

Left ventricular perforation with catheter decompression.

Thoracostomy tube placement is one of the more common procedures performed in the Emergency Department, most commonly for treatment of pneumothorax or hemothorax but occasionally for drainage of empyema or pleural effusion. Thoracostomy may be a life-saving procedure with a wide range of complication rates reported, ranging from 19.4-37%, most commonly extrathoracic placement. Most recent meta-analyses showed a relatively stable complication rate of 19% over the past three decades with the vast majority being benign in nature. We present a case with the rare complication of thoracostomy in which of a small-caliber thoracostomy tube was placed in the left ventricle. Although thoracotomy was performed to remove the catheter, the patient remained virtually asymptomatic and had an uneventful course.

Evaluating the Effect of a Video Education Curriculum for First Time Breast Cancer Patients: a Prospective RCT Feasibility Study.

Newly diagnosed breast cancer patients seek information through a variety of sources. In this small pilot study, we evaluated the feasibility of providing personalizable breast cancer video education prior to the first oncology consultation and compared outcomes to patients receiving standard of care educational materials. Personalized videos included detailed information on a patient's specific grade, stage, and tumor subtype (e.g., grade 2, stage 3, triple negative breast cancer) in addition to general videos that defined the terms of grade, stage, and cancer subtype. Newly diagnosed breast cancer patients who were scheduled for an initial oncology appointment at two sites were enrolled in this prospective, randomized control trial. Twenty-eight patients were assigned to receive either video education (experimental group) with the possibility of personalization or a video explaining how to view cancer education materials at the cancer center website (control group). Sixteen oncologists at the two centers also participated in evaluating patient outcomes. Pre- and post-education surveys queried patient-perceived understanding of breast cancer and treatment, perceived ability for decision-making, confidence in providers, and anxiety and depression symptoms. We observed that patients given video education had greater improvements in some of these areas, with the biggest improvement seen in patients who received a personalized video on their specific tumor subtype (based on tumor receptor status). Overall, however, there were no statistically significant differences between the study groups. We conclude that providing personalized video education during the time prior to first oncologic consultation is feasible and may provide benefit for patients, especially for explaining complex components of a diagnosis, such as a cancer subtype. Further research is needed to determine how to optimally provide education tailored to a given patient and tumor type, and how to leverage patients' electronic devices as an education delivery vehicle.

Correction to: Evaluating the Effect of a Video Education Curriculum for First Time Breast Cancer Patients: a Prospective RCT Feasibility Study.

The original version of this article unfortunately contained a mistake. The name of "Eric Gelfand" was omitted.