Increased diagnostic yield from negative whole genome-slice panels using automated reanalysis.

We evaluated the diagnostic yield using genome-slice panel reanalysis in the clinical setting using an automated phenotype/gene ranking system. We analyzed whole genome sequencing (WGS) data produced from clinically ordered panels built as bioinformatic slices for 16 clinically diverse, undiagnosed cases referred to the Pediatric Mendelian Genomics Research Center, an NHGRI-funded GREGoR Consortium site. Genome-wide reanalysis was performed using Moon™, a machine-learning-based tool for variant prioritization. In five out of 16 cases, we discovered a potentially clinically significant variant. In four of these cases, the variant was found in a gene not included in the original panel due to phenotypic expansion of a disorder or incomplete initial phenotyping of the patient. In the fifth case, the gene containing the variant was included in the original panel, but being a complex structural rearrangement with intronic breakpoints outside the clinically analyzed regions, it was not initially identified. Automated genome-wide reanalysis of clinical WGS data generated during targeted panels testing yielded a 25% increase in diagnostic findings and a possibly clinically relevant finding in one additional case, underscoring the added value of analyses versus those routinely performed in the clinical setting.

Pediatric medical genetics house call: Telemedicine for the next generation of patients and providers.

In an era of increasing technology and interaction with the patient bedside, we explore the role of relocating the bedside from the hospital to the home using telemedicine. The COVID-19 pandemic pushed telemedicine from small and pilot programs to widespread practice at an unprecedented rate. With the rapid implementation of telemedicine, it is important to consider how to create a telehealth system that provides both good care for patients and families while maintaining an excellent education environment for trainees of all levels. To this end, we developed telemedicine educational milestones to describe novel skills required to provide high quality telemedicine care, and allow trainees and clinical educators a metric by which to assess trainee progress. We also created methods and tools to help trainees learn and families feel comfortable in their new role as virtual collaborators. We envision a time when safety does not set the venue; instead the needs of the patient will dictate whether a virtual or in-person visit is the right choice for a family. We expect that pediatric medical genetics and metabolism groups across the country will continue to set a standard of a hybrid care system to meet the unique needs of each individual patient, using telemedicine technology.

Biomechanical Analysis of Laparoscopic Incisional Gastropexy With Intracorporeal Suturing Using Knotless Polyglyconate.

OBJECTIVE: To evaluate load to failure of laparoscopic incisional gastropexy performed with intracorporeal suturing using knotless polyglyconate (KP). STUDY DESIGN: Cadaveric study. ANIMALS: Canine cadavers (n = 12). METHODS: Laparoscopic incisional gastropexy using 2 strands of KP was performed in 6 canine cadavers and by an open approach in 6 cadavers. Length of the gastropexy, number of suture bites on each side of the gastropexy, and number of inadvertent full thickness gastric suture bites were recorded. Load to failure was measured. RESULTS: There was no significant difference in mean (±SD) gastropexy load to failure for the open (46.3 ± 19.6 N) and laparoscopic (69.0 ± 26.0 N) approaches (P = .123). No significant differences between laparoscopic and open approaches were detected for mean stomach (3.1 ± 0.1 cm; 3.0 ± 0.2 cm; P = .353) or abdominal wall (3.1 ± 0.2 cm; 3.0 ± 0.2 cm; P = .553) incision lengths. There was no significant difference between groups for number of suture bites medially (P = .448) or laterally (P = .363). There were 3 instances of a single gastric intraluminal suture for the laparoscopic group and none for the open approach (P = .023). CONCLUSION: Incisional gastropexy performed with laparoscopic intracorporeal suturing and KP has a load to failure that is comparable with an open method. Load to failure was similar to reported values for open incisional gastropexy with knotless glycomer 631.

Using a chat-based informed consent tool in large-scale genomic research.

OBJECTIVE: We implemented a chatbot consent tool to shift the time burden from study staff in support of a national genomics research study. MATERIALS AND METHODS: We created an Institutional Review Board-approved script for automated chat-based consent. We compared data from prospective participants who used the tool or had traditional consent conversations with study staff. RESULTS: Chat-based consent, completed on a user's schedule, was shorter than the traditional conversation. This did not lead to a significant change in affirmative consents. Within affirmative consents and declines, more prospective participants completed the chat-based process. A quiz to assess chat-based consent user understanding had a high pass rate with no reported negative experiences. CONCLUSION: Our report shows that a structured script can convey important information while realizing the benefits of automation and burden shifting. Analysis suggests that it may be advantageous to use chatbots to scale this rate-limiting step in large research projects.

"Development and Implementation of Novel Chatbot-based Genomic Research Consent".

Objective: To conduct a retrospective analysis comparing traditional human-based consenting to an automated chat-based consenting process. Materials and Methods: We developed a new chat-based consent using our IRB-approved consent forms. We leveraged a previously developed platform (GiaⓇ, or "Genetic Information Assistant") to deliver the chat content to candidate participants. The content included information about the study, educational information, and a quiz to assess understanding. We analyzed 144 families referred to our study during a 6-month time period. A total of 37 families completed consent using the traditional process, while 35 families completed consent using Gia. Results: Engagement rates were similar between both consenting methods. The median length of the consent conversation was shorter for Gia users compared to traditional (44 vs. 76 minutes). Additionally, the total time from referral to consent completion was faster with Gia (5 vs. 16 days). Within Gia, understanding was assessed with a 10-question quiz that most participants (96%) passed. Feedback about the chat consent indicated that 86% of participants had a positive experience. Discussion: Using Gia resulted in time savings for both the participant and study staff. The chatbot enables studies to reach more potential candidates. We identified five key features related to human-centered design for developing a consent chat. Conclusion: This analysis suggests that it is feasible to use an automated chatbot to scale obtaining informed consent for a genomics research study. We further identify a number of advantages when using a chatbot.

Optimizing community and stakeholder engagement in a merger of community health centres.

Community Health Centres (CHCs) are grounded in a model of care that includes engagement with the community and have a history of working with communities to respond to emerging needs. Although most CHCs consider themselves to be integrated, mergers in this sector are uncommon. In Ontario, the first voluntary merger of CHCs showed the importance of community engagement to realize the intended benefits of the integration and to effectively manage change.

Developing an actionable patient taxonomy to understand and characterize high-cost Medicare patients.

BACKGROUND: Improving care for high-cost patients requires a better understanding of their characteristics and the ability to effectively target interventions. We developed an actionable taxonomy with clinically meaningful patient categories for high-cost Medicare patients-those in the top 10% of total costs. METHODS: A cross-sectional study of a Medicare fee-for-service (FFS) patient cohort in the New York metropolitan area. We merged claims and neighborhood social determinants of health data to map patients into actionable categories. RESULTS: Among 428,024 Medicare FFS patients, we mapped the 42,802 high-cost patients into ten overlapping categories, including: multiple chronic conditions, seriously ill, frail, serious mental illness, single condition with high pharmacy cost, chronic pain, end-stage renal disease (ESRD), single high-cost chronic condition, opioid use disorder, and socially vulnerable. Most high-cost patients had multiple chronic conditions (97.4%), followed by serious illness (53.7%) and frailty (48.9%). Patients with ESRD, who were seriously ill, and who were frail were more likely to be high-cost compared to patients in other categories. 72.7% of high-cost patients fell into multiple categories. CONCLUSIONS: High-cost patients are highly heterogeneous. A patient taxonomy incorporating medical, behavioral, and social characteristics may help providers better understand their characteristics and health needs. IMPLICATIONS: Mapping high-cost patients into clinically meaningful and actionable categories that incorporate medical, behavioral, and social factors could help health systems target interventions. Integrated approaches, including medical care, behavioral health, and social services may be needed to effectively and efficiently care for high-cost patients.

Coping With Trauma, Celebrating Life: Reinventing Patient And Staff Support During The COVID-19 Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic presented unprecedented challenges to the New York City Health + Hospitals system. In addition to ramping up capacity and adapting operations quickly to handle the patient surge, NYC Health + Hospitals had to find new ways to provide emotional and psychological support for patients, families, and staff. To help families keep in touch, dedicated staff members provided daily updates by telephone and used tablets for virtual visits. An expanded palliative care team held virtual consultations with families to discuss advance care planning and end-of-life decisions. Bereavement hotlines were set up for families who lost loved ones. Enhanced staff support included one-on-one and group sessions with behavioral health specialists, a behavioral health hotline, a webinar series, and respite rooms, as well as complimentary lodging and child care. NYC Health + Hospitals created new rituals to celebrate recoveries and mourn losses. As regular operations resume, NYC Health + Hospitals plans to sustain and build on emotional and psychological support initiatives developed during the surge.

Chemical, Biological, Radiological, Nuclear, and Explosive (CBRNE) Science and the CBRNE Science Medical Operations Science Support Expert (CMOSSE).

A national need is to prepare for and respond to accidental or intentional disasters categorized as chemical, biological, radiological, nuclear, or explosive (CBRNE). These incidents require specific subject-matter expertise, yet have commonalities. We identify 7 core elements comprising CBRNE science that require integration for effective preparedness planning and public health and medical response and recovery. These core elements are (1) basic and clinical sciences, (2) modeling and systems management, (3) planning, (4) response and incident management, (5) recovery and resilience, (6) lessons learned, and (7) continuous improvement. A key feature is the ability of relevant subject matter experts to integrate information into response operations. We propose the CBRNE medical operations science support expert as a professional who (1) understands that CBRNE incidents require an integrated systems approach, (2) understands the key functions and contributions of CBRNE science practitioners, (3) helps direct strategic and tactical CBRNE planning and responses through first-hand experience, and (4) provides advice to senior decision-makers managing response activities. Recognition of both CBRNE science as a distinct competency and the establishment of the CBRNE medical operations science support expert informs the public of the enormous progress made, broadcasts opportunities for new talent, and enhances the sophistication and analytic expertise of senior managers planning for and responding to CBRNE incidents.

Significance of green granules in neutrophils and monocytes.

Intracytoplasmic green granules in neutrophils have been the subject of conjecture and discussion. Sometimes nicknamed "death cells," these granules are often associated with severe liver disease and have been said to predict acute bad outcomes in severely ill patients. Some recommend that the laboratory community report these granules to treating clinicians as an indication of poor prognosis. We report two patients presenting with secondary liver disease who were found to have blue-green neutrophilic inclusions on the peripheral blood smear. One patient died, while the other patient recovered. We propose that this morphologic finding is likely transient and is related to liver disease and that recovery is possible. Additionally, prognosis in intensive care units continues to be determined by a number of variables, such as age, comorbidities, and severity of illness.

Dense Semantic 3D Reconstruction.

Both image segmentation and dense 3D modeling from images represent an intrinsically ill-posed problem. Strong regularizers are therefore required to constrain the solutions from being 'too noisy'. These priors generally yield overly smooth reconstructions and/or segmentations in certain regions while they fail to constrain the solution sufficiently in other areas. In this paper, we argue that image segmentation and dense 3D reconstruction contribute valuable information to each other's task. As a consequence, we propose a mathematical framework to formulate and solve a joint segmentation and dense reconstruction problem. On the one hand knowing about the semantic class of the geometry provides information about the likelihood of the surface direction. On the other hand the surface direction provides information about the likelihood of the semantic class. Experimental results on several data sets highlight the advantages of our joint formulation. We show how weakly observed surfaces are reconstructed more faithfully compared to a geometry only reconstruction. Thanks to the volumetric nature of our formulation we also infer surfaces which cannot be directly observed for example the surface between the ground and a building. Finally, our method returns a semantic segmentation which is consistent across the whole dataset.

Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome.

In addition to mutations in genes, aberrant enhancer element activity at non-coding regions of the genome is a key driver of tumorigenesis. Here, we perform epigenomic enhancer profiling of a cohort of more than forty genetically diverse human colorectal cancer (CRC) specimens. Using normal colonic crypt epithelium as a comparator, we identify enhancers with recurrently gained or lost activity across CRC specimens. Of the enhancers highly recurrently activated in CRC, most are constituents of super enhancers, are occupied by AP-1 and cohesin complex members, and originate from primed chromatin. Many activate known oncogenes, and CRC growth can be mitigated through pharmacologic inhibition or genome editing of these loci. Nearly half of all GWAS CRC risk loci co-localize to recurrently activated enhancers. These findings indicate that the CRC epigenome is defined by highly recurrent epigenetic alterations at enhancers which activate a common, aberrant transcriptional programme critical for CRC growth and survival.

Modeling disease risk through analysis of physical interactions between genetic variants within chromatin regulatory circuitry.

SNPs associated with disease susceptibility often reside in enhancer clusters, or super-enhancers. Constituents of these enhancer clusters cooperate to regulate target genes and often extend beyond the linkage disequilibrium (LD) blocks containing risk SNPs identified in genome-wide association studies (GWAS). We identified 'outside variants', defined as SNPs in weak LD with GWAS risk SNPs that physically interact with risk SNPs as part of a target gene's regulatory circuitry. These outside variants further explain variation in target gene expression beyond that explained by GWAS-associated SNPs. Additionally, the clinical risk associated with GWAS SNPs is considerably modified by the genotype of outside variants. Collectively, these findings suggest a potential model in which outside variants and GWAS SNPs that physically interact in 3D chromatin collude to influence target transcript levels as well as clinical risk. This model offers an additional hypothesis for the source of missing heritability for complex traits.

UNITED STATES DEPARTMENT OF HEALTH AND HUMAN SERVICES BIODOSIMETRY AND RADIOLOGICAL/NUCLEAR MEDICAL COUNTERMEASURE PROGRAMS.

The United States Department of Health and Human Services (HHS) is fully committed to the development of medical countermeasures to address national security threats from chemical, biological, radiological, and nuclear agents. Through the Public Health Emergency Medical Countermeasures Enterprise, HHS has launched and managed a multi-agency, comprehensive effort to develop and operationalize medical countermeasures. Within HHS, development of medical countermeasures includes the National Institutes of Health (NIH), (led by the National Institute of Allergy and Infectious Diseases), the Office of the Assistant Secretary of Preparedness and Response/Biomedical Advanced Research and Development Authority (BARDA); with the Division of Medical Countermeasure Strategy and Requirements, the Centers for Disease Control and Prevention, and the Food and Drug Administration as primary partners in this endeavor. This paper describes various programs and coordinating efforts of BARDA and NIH for the development of medical countermeasures for radiological and nuclear threats.

Acupuncture: role in comprehensive cancer care--a primer for the oncologist and review of the literature.

In recent studies, patients have reported an increased use of complementary and alternative medicine (CAM). Acupuncture is a popular complementary therapy for patients with cancer. This article will provide current cancer treatment providers with information on acupuncture as well as the research conducted on cancer symptoms and side effects of cancer treatments. Antiemetic studies are the most prevalent and contain the most promising results. Several studies have found that acupuncture significantly reduces the number of emesis (vomiting) episodes for patients receiving chemotherapy. While studies on pain control vary due to the heterogeneity of pain, there are few studies investigating pain caused from cancer and the removal of cancerous tumors. These studies, while promising, provide basic results that need further investigation for more definitive results. Although relatively few studies have been done on anxiety and depression, several researchers have found acupuncture to be just as effective as or more effective than antidepressants for patients without cancer. Studies on breathlessness, while small, have shown acupuncture to have a significant positive effect on chronic obstructive pulmonary disease, breathlessness associated with end-stage cancer, and asthma. Researchers studying xerostomic individuals who have received salivary gland irradiation found significant positive results in salivary flow rates compared to baseline. Patients with hot flashes due to hormonal imbalance may benefit from the use of acupuncture. A recent pilot study showed improvement of chronic postchemotherapy fatigue following acupuncture treatments. Many individuals with cancer have turned to acupuncture because their symptoms persisted with conventional treatments or as an alternative or complement to their ongoing treatments. Despite the immense popularity in the community, few large randomized trials have been conducted to determine the effects acupuncture has on cancer symptoms and side effects of treatments. A majority of the current studies have shown beneficial effects that warrant further investigation with large trial sizes.

One-stop shop. The houseworks experience: redefining innovations in private-pay home care.

For more than thirty years, forward-looking gerontologists and entrepreneurs have realized the potential market for private-pay home care services and have proposed creative approaches to meeting the projected demand. Innovative ventures ranging from "life care at home" to "virtual retirement communities" have been launched throughout the country in an attempt to meet a growing need while responding to an unprecedented business opportunity. While these ventures reflect intriguing ideas, the story of an unconventional private-pay home care company in Greater Boston suggests that innovation and creativity are most needed to transform the fundamentals of private-pay service delivery: responsiveness, reliability, customer service, and sales.

Characterizing mutational heterogeneity in a glioblastoma patient with double recurrence.

Human cancers are driven by the acquisition of somatic mutations. Separating the driving mutations from those that are random consequences of general genomic instability remains a challenge. New sequencing technology makes it possible to detect mutations that are present in only a minority of cells in a heterogeneous tumor population. We sought to leverage the power of ultra-deep sequencing to study various levels of tumor heterogeneity in the serial recurrences of a single glioblastoma multiforme patient. Our goal was to gain insight into the temporal succession of DNA base-level lesions by querying intra- and inter-tumoral cell populations in the same patient over time. We performed targeted "next-generation" sequencing on seven samples from the same patient: two foci within the primary tumor, two foci within an initial recurrence, two foci within a second recurrence, and normal blood. Our study reveals multiple levels of mutational heterogeneity. We found variable frequencies of specific EGFR, PIK3CA, PTEN, and TP53 base substitutions within individual tumor regions and across distinct regions within the same tumor. In addition, specific mutations emerge and disappear along the temporal spectrum from tumor at the time of diagnosis to second recurrence, demonstrating evolution during tumor progression. Our results shed light on the spatial and temporal complexity of brain tumors. As sequencing costs continue to decline and deep sequencing technology eventually moves into the clinic, this approach may provide guidance for treatment choices as we embark on the path to personalized cancer medicine.