Comparing obstetricians' and neonatologists' approaches to periviable counseling

OBJECTIVE: To compare the management options, risks and thematic content that obstetricians and neonatologists discuss in periviable counseling. STUDY DESIGN: Sixteen obstetricians and 15 neonatologists counseled simulated patients portraying a pregnant woman with ruptured membranes at 23 weeks of gestation. Transcripts from video-recorded encounters were qualitatively and quantitatively analyzed for informational content and decision-making themes. RESULT: Obstetricians more frequently discussed antibiotics (P=0.005), maternal risks (<0.001) and cesarean risks (<0.005). Neonatologists more frequently discussed neonatal complications (P=0.044), resuscitation (P=0.015) and palliative options (P=0.023). Obstetricians and neonatologists often deferred questions about steroid administration to the other specialty. Both specialties organized decision making around medical information, survival, quality of life, time and support. Neonatologists also introduced themes of values, comfort or suffering, and uncertainty. CONCLUSION: Obstetricians and neonatologists provided complementary counseling content to patients, yet neither specialty took ownership of steroid discussions. Joint counseling and/or family meetings may minimize observed redundancy and inconsistencies in counseling

A Pilot Study of Neonatologists' Decision-Making Roles in Delivery Room Resuscitation Counseling for Periviable Births

BACKGROUND: Relatively little is known about neonatologists' roles in helping families navigate the difficult decision to attempt or withhold resuscitation for a neonate delivering at the threshold of viability. Therefore, we aimed to describe the "decision-making role" of neonatologists in simulated periviable counseling sessions. METHODS: We conducted a qualitative content analysis of audio-recorded simulation encounters and post-encounter debriefing interviews collected as part of a single-center simulation study of neonatologists' resuscitation counseling practices in the face of ruptured membranes at 23 weeks gestation. We trained standardized patients to request a recommendation if the physician presented multiple treatment options. We coded each encounter for communication behaviors, applying an adapted, previously developed coding scheme to classify physicians into four decision-making roles (informative, facilitative, collaborative, or directive). We also coded post-simulation debriefing interviews for responses to the open-ended prompt: "During this encounter, what did you feel was your role in the management decision-making process?" RESULTS: Fifteen neonatologists (33% of the division) participated in the study; audio-recorded debriefing interviews were available for 13. We observed 9 (60%) take an informative role, providing medical information only; 2 (13%) take a facilitative role, additionally eliciting the patient's values; 3 (20%) take a collaborative role, additionally engaging the patient in deliberation and providing a recommendation; and 1 (7%) take a directive role, making a treatment decision independent of the patient. Almost all (10/13, 77%) of the neonatologists described their intended role as informative. CONCLUSIONS: Neonatologists did not routinely elicit preferences, engage in deliberation, or provide treatment recommendations-even in response to requests for recommendations. These findings suggest there may be a gap between policy recommendations calling for shared decision making and actual clinical practice

Potential Unintended Consequences Of Recent Shared Decision Making Policy Initiatives

Shared decision making (SDM)-when clinicians and patients make medical decisions together-is moving swiftly from an ethical ideal toward widespread clinical implementation affecting millions of patients through recent policy initiatives. We argue that policy initiatives to promote SDM implementation in clinical practice carry the risk of several unintended negative consequences if limitations in defining and measuring SDM are not addressed. We urge policy makers to include prespecified definitions of desired outcomes, offer guidance on the tools used to measure SDM in the multitude of contexts in which it occurs, evaluate the impact of SDM policy initiatives over time, review that impact at regular intervals, and revise SDM measurement tools as needed

Structure and Function of the Hair Cell Ribbon Synapse

Faithful information transfer at the hair cell afferent synapse requires synaptic transmission to be both reliable and temporally precise. The release of neurotransmitter must exhibit both rapid on and off kinetics to accurately follow acoustic stimuli with a periodicity of 1 ms or less. To ensure such remarkable temporal fidelity, the cochlear hair cell afferent synapse undoubtedly relies on unique cellular and molecular specializations. While the electron microscopy hallmark of the hair cell afferent synapse — the electron-dense synaptic ribbon or synaptic body — has been recognized for decades, dissection of the synapse’s molecular make-up has only just begun. Recent cell physiology studies have added important insights into the synaptic mechanisms underlying fidelity and reliability of sound coding. The presence of the synaptic ribbon links afferent synapses of cochlear and vestibular hair cells to photoreceptors and bipolar neurons of the retina. This review focuses on major advances in understanding the hair cell afferent synapse molecular anatomy and function that have been achieved during the past years

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts