Ethical Responsibilities for Companies That Process Personal Data.

It has become increasingly difficult for individuals to exercise meaningful control over the personal data they disclose to companies or to understand and track the ways in which that data is exchanged and used. These developments have led to an emerging consensus that existing privacy and data protection laws offer individuals insufficient protections against harms stemming from current data practices. However, an effective and ethically justified way forward remains elusive. To inform policy in this area, we propose the Ethical Data Practices framework. The framework outlines six principles relevant to the collection and use of personal data-minimizing harm, fairly distributing benefits and burdens, respecting autonomy, transparency, accountability, and inclusion-and translates these principles into action-guiding practical imperatives for companies that process personal data. In addition to informing policy, the practical imperatives can be voluntarily adopted by companies to promote ethical data practices.

How Should Clinicians Own Their Roles as Past and Present Exacerbators of Health Inequity and as Present and Future Contributors to Health Equity?

To improve health outcomes, the science and practice of medicine must move quickly in response to new information. Yet, in other important ways, health professionals must operate slowly and in a mode of intentional stillness to center empathy and light a path from empathy to solidarity. Solidarity, or standing with, prompts efforts to create circumstances in which disadvantaged communities can achieve health equity. This article argues for intentional stillness and solidarity to inspire ethical conduct and structural change. In the case presented, inaction and delay, which are neither virtuous nor antiracist forms of stillness in this context, would leave intact the status quo of disparity and inequity in cardiac medicine.

KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells.

Histone lysine methylation is generally performed by SET domain methyltransferases and regulates chromatin structure and gene expression. Here, we identify human C21orf127 (HEMK2, N6AMT1, PrmC), a member of the seven-ß-strand family of putative methyltransferases, as a novel histone lysine methyltransferase. C21orf127 functions as an obligate heterodimer with TRMT112, writing the methylation mark on lysine 12 of histone H4 (H4K12) in vitro and in vivo. We characterized H4K12 recognition by solving the crystal structure of human C21orf127-TRMT112, hereafter termed 'lysine methyltransferase 9' (KMT9), in complex with S-adenosyl-homocysteine and H4K12me1 peptide. Additional analyses revealed enrichment for KMT9 and H4K12me1 at the promoters of numerous genes encoding cell cycle regulators and control of cell cycle progression by KMT9. Importantly, KMT9 depletion severely affects the proliferation of androgen receptor-dependent, as well as that of castration- and enzalutamide-resistant prostate cancer cells and xenograft tumors. Our data link H4K12 methylation with KMT9-dependent regulation of androgen-independent prostate tumor cell proliferation, thereby providing a promising paradigm for the treatment of castration-resistant prostate cancer.

Lsd1 regulates skeletal muscle regeneration and directs the fate of satellite cells.

Satellite cells are muscle stem cells required for muscle regeneration upon damage. Of note, satellite cells are bipotent and have the capacity to differentiate not only into skeletal myocytes, but also into brown adipocytes. Epigenetic mechanisms regulating fate decision and differentiation of satellite cells during muscle regeneration are not yet fully understood. Here, we show that elevated levels of lysine-specific demethylase 1 (Kdm1a, also known as Lsd1) have a beneficial effect on muscle regeneration and recovery after injury, since Lsd1 directly regulates key myogenic transcription factor genes. Importantly, selective Lsd1 ablation or inhibition in Pax7-positive satellite cells, not only delays muscle regeneration, but changes cell fate towards brown adipocytes. Lsd1 prevents brown adipocyte differentiation of satellite cells by repressing expression of the novel pro-adipogenic transcription factor Glis1. Together, downregulation of Glis1 and upregulation of the muscle-specific transcription program ensure physiological muscle regeneration.

KDM4 Inhibition Targets Breast Cancer Stem-like Cells.

Traditional treatments for breast cancer fail to address therapy-resistant cancer stem-like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here, we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. To assess the antitumor properties of QC6352, we established a method to isolate and propagate breast cancer stem-like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy. Limiting-dilution orthotopic xenografts of these BCSCs regenerated original patient tumor histology and gene expression. QC6352 blocked BCSC proliferation, sphere formation, and xenograft tumor formation. QC6352 also abrogated expression of EGFR, which drives the growth of therapy-resistant triple-negative breast cancer cells. Our findings validate a unique BCSC culture system for drug screening and offer preclinical proof of concept for KDM4 inhibition as a new strategy to treat triple-negative breast cancer. Cancer Res; 77(21); 5900-12. ©2017 AACR.

The neuronal transcription factor NPAS4 is a strong inducer of sprouting angiogenesis and tip cell formation.

RATIONALE: Regarding branching morphogenesis, neurogenesis and angiogenesis share common principle mechanisms and make use of the same molecules. Therefore, the investigation of neuronal molecules involved in vascular morphogenesis provides new possibilities for pro-angiogenic approaches in cardiovascular diseases. OBJECTIVE: In this study, we investigated the role of the neuronal transcription factor NPAS4 in angiogenesis. METHODS AND RESULTS: Here, we demonstrate that the neuronal transcription factor NPAS4 is expressed in endothelial cells of different origin using reverse transcription PCR and western blot analysis. To investigate how NPAS4 affects endothelial cell function, NPAS4 was overexpressed by plasmid transfection or depleted from human umbilical vein endothelial cells (HUVECs) by specific siRNAs. In vitro HUVEC sprouting assays showed that sprouting and branching of endothelial cells was enhanced by NPAS4 overexpression. Consistently, silencing of NPAS4 resulted in reduced HUVEC sprouting and branching. Mechanistically, we identified as target gene vascular endothelial adhesion molecule VE-cadherin to be involved in the pro-angiogenic function of NPAS4. In endothelial cell mosaic spheroid sprouting assays, NPAS4 was involved in tip cell formation. In vivo experiments in mouse and zebrafish confirmed our in vitro findings. NPAS4-deficient mice displayed reduced ingrowth of endothelial cells in the Matrigel plug assay. Consistent with a regulatory role of NPAS4 in endothelial cell function silencing of NPAS4 in zebrafish by specific morpholinos resulted in perturbed intersegmental vessels growth. CONCLUSIONS: NPAS4 is expressed in endothelial cells, regulates VE-cadherin expression and regulates sprouting angiogenesis.

Cognitive Enhancement and Beyond: Recommendations from the Bioethics Commission.

Media outlets are reporting that cognitive enhancement is reaching epidemic levels, but evidence is lacking and ethical questions remain. The US Presidential Commission for the Study of Bioethical Issues (Bioethics Commission) has examined the issue, and we lay out the commission's findings and their relevance for the scientific community.

Paroxysmal alpha activity in Rett syndrome: a case report.

BACKGROUND: Rett syndrome is a severe neurodevelopmental disorder that primarily affects females. Classically the disorder is characterized by early normal development, followed by a period of regression and later recovery or stagnation. Typical features include a loss of purposeful hand skills, development of hand stereotypies, loss of spoken language, gait abnormalities, and acquired microcephaly. Epilepsy affects between 70% and 90% of individuals with Rett syndrome. A number of stereotypical electroencephalography findings have been reported in Rett syndrome. PATIENT DESCRIPTION: We report a 9-year-old girl with Rett syndrome and epilepsy with a unique electroencephalography finding consisting of intermittent paroxysms of alpha activity in both wakefulness and sleep without clinical signs. RESULTS: This unique electroencephalography signature has not previously been reported in the English literature. CONCLUSIONS: Knowledge of this unique electroencephalography pattern of diffuse paroxysmal alpha activity represents an additional distinct feature of the electroencephalogram in Rett syndrome and expands the spectrum of electroencephalography abnormalities in Rett syndrome.

Epilepsy transition: challenges of caring for adults with childhood-onset seizures.

OBJECTIVES: Children with severe chronic epilepsy are living longer, and they eventually transition to the adult health care system. Additional research is required to better define the population that is being transferred and the qualifications of those who are assuming their care. We aimed to evaluate the complexity of epilepsy patients transitioning between tertiary centers, and to evaluate neurologists' confidence in dealing with childhood-onset epilepsies. METHODS: Patients aged from 18 to 25 years were divided into two groups: Group 1 comprised patients referred from the pediatric tertiary center; and Group 2 comprised patients referred from the community. Clinical data were retrospectively studied and groups were compared using appropriate statistics. We also created a survey to evaluate neurologists' levels of confidence in diagnosing and treating childhood-onset epilepsies. Differences among responders were compared. RESULTS: Group 1 comprised 170 patients, whereas group 2 had 132. Patients in group 1 had earlier seizure onset, longer epilepsy duration (p < 0.001), and more patients with symptomatic etiologies, epileptic encephalopathy, and cognitive delay (p < 0.001). Group 1 patients required more referrals to other specialties (p = 0.001). Treatment with polytherapy (p = 0.003), epilepsy surgery (p < 0.001), ketogenic diet (p < 0.001), and vagus nerve stimulator were more common in group 1 (p < 0.001). In addition, our survey applied to adult (n = 86) and pediatric (n = 29) neurologists indicated that adult neurologists have lower levels of confidence in diagnosing and treating severe forms of childhood-onset epilepsies (p < 0.001), as well as epilepsy associated with cognitive delay (p < 0.001). SIGNIFICANCE: These findings suggest that patients from tertiary centers present more complex health care needs and require more resources than age-matched patients from the community; and that adult neurologists may not feel prepared to diagnose and treat adult patients with some childhood-onset epilepsies.

A Pou5f1/Oct4 dependent Klf2a, Klf2b, and Klf17 regulatory sub-network contributes to EVL and ectoderm development during zebrafish embryogenesis.

In mammalian ES cells, the transcription factors Klf4 and Klf2 contribute to maintenance of pluripotency and self-renewal and are regulated by Pou5f1/Oct4. In the early zebrafish embryo Pou5f1/Oct4 is necessary for expression of three Klf2/4 family members, klf2a, klf2b and klf17 (previously klf4b), similar to the regulation reported for mammalian ES cells. In this study, we analyzed blastula and gastrula stage Klf regulatory networks and their influence on zebrafish embryonic patterning. We show that Pou5f1 acts in combination with region-specific factors to activate klf2a, klf2b, and klf17 in the superficial cell layer of the embryo. In addition, Pou5f1 acts together with the BMP signaling pathway to activate and maintain expression of klf2a and klf2b in a ventral ectodermal domain. We used microarray expression profiles of klf2a, klf2b and klf17 knockdown and overexpression embryos to identify Klf target genes, which reveals that Klfs participate in specification of the extraembryonic enveloping layer (EVL). We discuss mechanistic implications of simultaneous activation of transcriptional targets by ubiquitous, like Pou5f1, and region-specific inducers, emerging as a common regulatory motif in early development.

The pediatric stroke outcome measure: a validation and reliability study.

BACKGROUND AND PURPOSE: The Pediatric Stroke Outcome Measure (PSOM) is an objective, disease-specific outcome measure containing 115 test items suitable for newborn to adult ages. The PSOM measures neurological deficit and function across 5 subscales: right sensorimotor, left sensorimotor, language production, language comprehension, and cognitive/behavior yielding a final 10-point deficit score. The goal of this study was to examine PSOM construct validity in measuring neurological outcome in pediatric stroke survivors and interrater reliability (IRR) for both prospective and retrospective scoring. METHODS: For construct validity, PSOM subscale scores were correlated with scores on standardized neuropsychological measures matched by functional domain. We assessed IRR by comparing same-day "live" PSOM scores from 2 independent raters in 10 children (prospective IRR) and by comparing PSOM scores estimated from medical dictations across 5 raters in another 10 children (retrospective IRR). RESULTS: We analyzed PSOM scores from 203 children with ischemic stroke. PSOM subscales show good construct validity (ρ=0.2-0.4; P<0.05). PSOM subscale scores of normal/abnormal demonstrate strong agreement for domain-matched neuropsychology scores (alternative chance-corrected statistic=0.4-0.8). IRR was excellent with the 2 prospective raters' scores in almost perfect agreement (intraclass correlation coefficient, 0.93; 95% CI, 0.76-0.98). Retrospective IRR demonstrated strong agreement with an intraclass correlation coefficient of 0.77 (95% CI, 0.56-0.92). CONCLUSIONS: The PSOM is a valid and reliable outcome measure for pediatric stroke. It is useful for retrospective scoring from health records and prospective serial longitudinal outcome assessments and is ideally suited for prospective clinical trials in pediatric stroke.

Nursing issues in caring for children with moyamoya vasculopathy and their families.

Moyamoya vasculopathy is a rare, progressive neurovascular condition that may cause recurrent transient ischemic attacks, ischemic strokes, hemorrhagic strokes, or neurologic decline in children. Children with moyamoya disease have no clear contributing etiology, but children with moyamoya syndrome have contributory diagnoses such as Down syndrome or neurofibromatosis. The concerns and lived experiences of children affected by this disease and their families have not been well explored or addressed in the nursing literature. Nurses who understand this lived experience increase their own knowledge of the disease so they can manage the complex medical issues, educate families about the disease, and provide emotional support.

The risks and safety of clopidogrel in pediatric arterial ischemic stroke.

BACKGROUND AND PURPOSE: The purpose of this study was to determine safety and tolerability of clopidogrel in children with arterial ischemic stroke (AIS). Clopidogrel is the alternative antiplatelet medication when aspirin is not tolerated or fails. The possible risks and safety of clopidogrel in children with AIS have not been assessed. METHODS: This is a prospective consecutive cohort study of children with AIS who were started on clopidogrel. Seventeen children were included. RESULTS: Two children developed subdural hematomas while on clopidogrel in conjunction with aspirin. Two others had headache or hand numbness. No other side effects like rash or gastrointestinal upsets were reported. CONCLUSIONS: We found clopidogrel to be relatively well tolerated in the pediatric population. In combination with aspirin and in the presence of other risk factors, intracranial bleeding may be seen.

Use of a telephone nursing line in a pediatric neurology clinic: one approach to the shortage of subspecialists.

OBJECTIVE: There are not enough pediatric neurologists to meet the many needs of pediatric neurology patients. The Hospital for Sick Children has responded by expanding the nursing role in the pediatric neurology outpatient clinic. The objective of this study was to examine the use of a telephone nursing line in this hospital-based pediatric neurology clinic. METHODS: A cross-sectional study was performed on all telephone call records collected during a 2-week study period. Each initial incoming call concerning a patient was counted as an index call. Associations between clinic type or diagnosis and length of telephone calls were assessed using the chi(2) test. RESULTS: A total of 208 index calls were received, generating a total of 597 incoming and outgoing calls. The most common clinic types were Epilepsy clinic (35.6%) and General Neurology clinic (32.7%), and the most common patient diagnoses were epilepsy (63.5%) and developmental delay (45.2%). Most patients were between the ages of 1 and <7 years (33.9%) and 12 and <18 years (32.8%) and male (55.2%). Most calls were made by mothers (57.2%) to ask about medical administrative issues (28.4%) and/or symptoms (27.9%). Physicians were notified for 47.1% of calls; nurses were twice as likely to notify physicians for calls concerning new symptoms (relative risk: 2.1; 95% confidence interval: 1.6-2.7). Most calls required between 1 and 5 minutes (49.0%). Long telephone calls (>10 minutes) were strongly associated with a diagnosis of epilepsy. CONCLUSIONS: There is a high demand for the neurology nursing line in our clinic. Most telephone calls and most long telephone calls concerned patients with epilepsy. Nurses managed more than half of all telephone calls without physician assistance. Use of a nursing line can aid in the provision of care to complicated subspecialty patients. Additional strategies are needed to optimize delivery of care to high-need medical populations.

Risk of mesh erosion with sacral colpopexy and concurrent hysterectomy.

OBJECTIVE: To examine short- and long-term mesh-related complications in women undergoing abdominal sacral colpopexy with concurrent hysterectomy, compared with women with a prior hysterectomy undergoing sacral colpopexy alone. METHODS: Patient characteristics, hospital complications, postoperative clinical course, and long-term graft-related complications were reviewed for all women with genital prolapse who underwent abdominal sacral colopexy between 1996 and 1998. Women with concurrent hysterectomy were compared with women with vaginal prolapse after a prior hysterectomy. RESULTS: One hundred twenty-four patients, 60 with concurrent hysterectomy and 64 with prior hysterectomy, were observed postoperatively for a median of 35.5 (0-74) months. Demographics of the two groups were similar, with a mean age of 65.1 +/- 9.4 years and a mean body mass index of 25.8 +/- 4.2 kg/m(2). Eighty percent of colpopexies used prolene synthetic mesh and 20% allograft material. Initial operative and hospital complications were rare in both groups and included a blood transfusion of 2 U, a ureteral transection, a wound infection, heart block, and an arrhythmia. Delayed graft complications included one mesh erosion in a patient with a prior hysterectomy that was managed by office resection (0.8%). CONCLUSION: Concurrent hysterectomy with abdominal sacral colopopexy has a low incidence of mesh complications and can be used as a first-line treatment for genital prolapse.