Mutation Profile and Fluorescence In Situ Hybridization Analyses Increase Detection of Malignancies in Biliary Strictures.

BACKGROUND & AIMS: It is a challenge to detect malignancies in biliary strictures. Various sampling methods are available to increase diagnostic yield, but these require additional procedure time and expertise. We evaluated the combined accuracy of fluorescence in situ hybridization (FISH) and polymerase chain reaction-based DNA mutation profiling (MP) of specimens collected using standard brush techniques. METHODS: We performed a prospective study of 107 consecutive patients treated for biliary strictures by endoscopic retrograde cholangiopancreatography from June 2012 through June 2014. We performed routine cytology and FISH analyses on cells collected by standard brush techniques, and analyzed supernatants for point mutations in KRAS and loss-of-heterozygosity mutations in tumor-suppressor genes at 10 loci (MP analysis was performed at Interpace Diagnostics). Strictures were determined to be nonmalignant based on repeat image analysis or laboratory test results 12 months after the procedure. Malignant strictures were identified based on subsequent biopsy or cytology analyses, pathology analyses of samples collected during surgery, or death from biliary malignancy. We determined the sensitivity and specificity with which FISH and MP analyses detected malignancies using the exact binomial test. RESULTS: Our final analysis included 100 patients; 41% had biliary malignancies. Cytology analysis identified patients with malignancies with 32% sensitivity and 100% specificity. Addition of FISH or MP results to cytology results increased the sensitivity of detection to 51% (P < .01) without reducing specificity. The combination of cytology, MP, and FISH analyses detected malignancies with 73% sensitivity (P < .001). FISH identified an additional 9 of the 28 malignancies not detected by cytology analysis, and MP identified an additional 8 malignancies. FISH and MP together identified 17 of the 28 malignancies not detected by cytology analysis. CONCLUSIONS: Addition of FISH and mutation analyses to cytology analysis significantly increased the level of sensitivity with which we detected malignancy in biliary strictures, with 100% specificity. These techniques can be performed using standard brush samples collected during endoscopic retrograde cholangiopancreatography, with mutations detected in free DNA in supernatant fluid of samples. The tests are complementary and therefore should be used sequentially in the diagnostic evaluation of biliary strictures.

Nonvariceal upper gastrointestinal bleeding.

PURPOSE OF REVIEW: Acute upper gastrointestinal bleeding is one of the most common medical emergencies. It is important to recognize potential etiologies of upper gastrointestinal bleeding and understand therapeutic modalities available in achieving hemostasis. This article summarizes guidelines in management of acute nonvariceal upper gastrointestinal bleeding and reviews recent advances in the field. RECENT FINDINGS: Recent study showed that patients who received blood transfusion with threshold hemoglobin below 7 g/dl rather than below 9 g/dl had significantly lower mortality at 45 days. Endoscopic therapy should be performed on actively bleeding ulcers and ulcers with visible vessel or adherent clot. An over-the-scope clip is a novel device that can be used to achieve hemostasis. It may be a useful tool for achieving hemostasis for patients who failed endoscopic therapy with epinephrine injection, clip, or thermal therapy. Doppler ultrasound probe can evaluate arterial flow to the ulcer and identify ulcers that are at high risk of rebleeding. SUMMARY: Upper gastrointestinal bleeding from peptic ulcer disease is not a new clinical problem. Yet, the approach to management continues to evolve with the accumulation of data and well designed studies on the subject.

Development and Iterative Design of Peer-based Discussions about Heart Health for Women.

Objective: To support women in their health journeys around cardiovascular risk reduction, providing: access to information; space to discuss complex and personal issues that may factor into decision making; and skills to support conversations with healthcare providers. Methods: We used a participatory design approach to develop peer sessions led by a non-clinical facilitator and a cardiologist, for women to learn, think, and discuss information and decision-making around cardiovascular risk. These sessions took place in-person and over video. A host invited her friends, family or network to the events. Sessions were designed to bring information to women at all stages of cardiovascular risk, including women with no prior experiences with heart health and women with established cardiovascular disease. The sessions provided information about cardiovascular risk and facilitated discussion around risk factors and treatment. Sessions were recorded, transcribed and analyzed using a grounded theory approach to identify emerging themes. Results: We conducted 12 groups, with an average of 6 women per group. Women were of all ages and spectrums of cardiovascular risk. The three major themes that emerged were: Starting Place (attitudes, beliefs, and behaviors toward cardiovascular care are informed by a blend of one's family history, personal interactions with their health and the health system, and approach to managing uncertainty); Lack of Sense-Making (seemingly simple recommendations to support heart health were much more complicated when related to their own risk and experience), and Self-Judgement and Judgement by Others (without support or validation, women may feel judged by others for not doing enough). Conclusion: Peer sessions can illuminate the complicated issues women face when approaching decisions regarding cardiovascular health. These sessions may offer an alternative to the healthcare setting, for women to wrestle with complex issues that relate to their risk, and better prepare for visits with their healthcare providers.

Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection.

OBJECTIVES: Clostridium difficile infection (CDI) has increased to epidemic proportions over the past 15 years, and recurrence rates of 30-65% with failure to respond to multiple courses of antimicrobials are common. The aim of this study was to report the efficacy of fecal microbiota transplantation (FMT) in patients with recurrent CDI in five geographically disparate medical centers across the United States. METHODS: A multicenter long-term follow-up study was performed on the use of FMT for recurrent CDI. We were able to contact 77 of 94 eligible patients who had colonoscopic FMT for recurrent CDI ≥ 3 months before. Respondents completed a 36-item questionnaire via mail and/or phone that solicited pre-FMT, post-FMT, and donor data. Study outcomes included primary cure rate (resolution of symptoms without recurrence within 90 days of FMT) and secondary cure rate (resolution of symptoms after one further course of vancomycin with or without repeat FMT). RESULTS: Seventy-three percent of patients were women and the average age was 65 years. The long-term follow-up period ranged from 3 to 68 months between FMT and data collection (mean: 17 months). The majority of patients were living independently at the time of FMT; however, 40% were ill enough to be hospitalized, homebound, or living in a skilled nursing facility. Spouses and partners accounted for 60% of donors and 27% were either first-degree relatives or otherwise related to the patient. The average symptom duration before FMT was 11 months and patients had failed an average of five conventional antimicrobial regimens; nonetheless, 74% of patients had resolution of their diarrhea in ≤ 3 days. Diarrhea resolved in 82% and improved in 17% of patients within an average of 5 days after FMT. The primary cure rate was 91%. Seven patients either failed to respond or experienced early CDI recurrence (≤ 90 days) after FMT. Four of these patients were successfully treated with vancomycin with or without probiotics; two patients were treated unsuccessfully with vancomycin, but subsequent FMT was successful; one patient was not treated and died in hospice care of unclear cause. The secondary cure rate was 98%. All late recurrences of CDI occurred in the setting of antimicrobial therapy for treatment of infections unrelated to C. difficile. In all, 53% of patients stated they would have FMT as their preferred first treatment option if CDI were to recur. While no definite adverse effects of FMT were noted, two patients had improvement in a pre-existing medical condition and four patients developed diseases of potential interest after FMT. CONCLUSIONS: FMT is a rational, durable, safe, and acceptable treatment option for patients with recurrent CDI.

Solutions to Address Inequity in Diabetes Technology Use in Type 1 Diabetes: Results from Multidisciplinary Stakeholder Co-creation Workshops.

Background: Racial-ethnic inequity in type 1 diabetes technology use is well documented and contributes to disparities in glycemic and long-term outcomes. However, solutions to address technology inequity remain sparse and lack stakeholder input. Methods: We employed user-centered design principles to conduct workshop sessions with multidisciplinary panels of stakeholders, building off of our prior study highlighting patient-identified barriers and proposed solutions. Stakeholders were convened to review our prior findings and co-create interventions to increase technology use among underserved populations with type 1 diabetes. Stakeholders included type 1 diabetes patients who had recently onboarded to technology; endocrinology and primary care physicians; nurses; diabetes educators; psychologists; and community health workers. Sessions were recorded and analyzed iteratively by multiple coders for common themes. Results: We convened 7 virtual 2-h workshops for 32 stakeholders from 11 states in the United States. Patients and providers confirmed prior published studies highlighting patient barriers and generated new ideas by co-creating solutions. Common themes of proposed interventions included (1) prioritizing more equitable systems of offering technology, (2) using visual and hands-on approaches to increase accessibility of technology and education, (3) including peer and family support systems more, and (4) assisting with insurance navigation and social needs. Discussion: Our study furthers the field by providing stakeholder-endorsed intervention ideas that propose feasible changes at the patient, provider, and system levels to reduce inequity in diabetes technology use in type 1 diabetes. Multidisciplinary stakeholder engagement in disparities research offers unique insight that is impactful and acceptable to the target population.

ORF30 and ORF34 are essential for expression of late genes in murine gammaherpesvirus 68.

A hallmark of productive infection by DNA viruses is the coupling of viral late gene expression to genome replication. Here we report the identification of open reading frame 30 (ORF30) and ORF34 as viral trans factors crucial for activating late gene transcription following viral DNA replication during lytic infection of murine gammaherpesvirus 68 (MHV-68). The mutant virus lacking either ORF30 or ORF34 underwent normal DNA replication but failed to express viral late gene transcripts, leading to nonproductive infection. In a reporter assay system, ORF30 and ORF34 were required for MHV-68 to activate the viral late gene promoters. Furthermore, studies using chromatin immunoprecipitation assays showed that the recruitment of RNA polymerase II to the viral late promoters during lytic infection was significantly reduced in the absence of ORF30 or ORF34. Together, the results suggest that ORF30 and ORF34 may play an important role in the assembly of the transcription initiation complex at the late gene promoters. Our discovery of the viral mutants that uncouple late gene transcription from DNA replication lays an important foundation to dissect the mechanism of this critical step of gene expression regulation.

Living Profiles: design of a health media platform for teens with special healthcare needs.

Living Profiles is a health media platform in development that aggregates multiple data flows to help teens with special healthcare needs (SHCN), particularly with regard to self-management and independence. A teen-oriented personal health record (PHR) incorporates typical teen behaviors and attitudes about health and wellness, encompasses how teens perceive and convey quality of life, and aligns with data related to their chronic medical condition. We have conceived a secure personalized user interface called the Quality of Life Timeline, which will assist with the transition from pediatric care to an adult provider through modules that include a mood meter, reminder device, and teleport medicine. With this personalized PHR, teens with SHCN can better understand their condition and its effects on daily activities and life goals and vice versa; additionally, use of this PHR allows for better information sharing and communication between providers and patients. The use of a teen-oriented tool such as Living Profiles can impact teens' overall quality of life and disease self-management, important attributes for a successful transition program.

Microscopic colitis: A review of etiology, treatment and refractory disease.

Microscopic colitis is a common cause of chronic, nonbloody diarrhea. Microscopic colitis is more common in women than men and usually affects patients in their sixth and seventh decade. This article reviews the etiology and medical management of microscopic colitis. The etiology of microscopic colitis is unknown, but it is associated with autoimmune disorders, such as celiac disease, polyarthritis, and thyroid disorders. Smoking has been identified as a risk factor of microscopic colitis. Exposure to medications, such as non-steroidal anti-inflammatory drugs, proton pump inhibitors, and selective serotonin reuptake inhibitors, is suspected to play a role in microscopic colitis, although their direct causal relationship has not been proven. Multiple medications, including corticosteroids, anti-diarrheals, cholestyramine, bismuth, 5-aminosalicylates, and immunomodulators, have been used to treat microscopic colitis with variable response rates. Budesonide is effective in inducing and maintaining clinical remission but relapse rate is as high as 82% when budesonide is discontinued. There is limited data on management of steroid-dependent microscopic colitis or refractory microscopic colitis. Immunomodulators seem to have low response rate 0%-56% for patients with refractory microscopic colitis. Response rate 66%-100% was observed for use of anti-tumor necrosis factor (TNF) therapy for refractory microscopic colitis. Anti-TNF and diverting ileostomy may be an option in severe or refractory microscopic colitis.

Orthodontic and surgical management of cleidocranial dysplasia.

Cleidocranial dysplasia (CCD), an autosomal dominant disorder with a prevalence of 1 in 1,000,000 individuals, is mainly caused by mutations in Runx2, a gene required for osteoblastic differentiation. It is generally characterized by hypoplastic clavicles, narrow thorax, and delayed or absent fontanel closure. Importantly, its orofacial manifestations, including midfacial hypoplasia, retained primary teeth, and impacted permanent and supernumerary teeth, severely impede the well-being of affected individuals. Successful treatment of the orofacial problems requires the combined efforts of dental specialists. However, only a few successfully treated cases have been reported because of the rarity of CCD and complexity of the treatment. This article presents the University of California, San Francisco (UCSF) treatment protocol for the dentofacial manifestations of CCD based on two treated and 17 diagnosed cases. The records of two patients with CCD who had been treated at the UCSF School of Dentistry and the treatment options reported in the literature were reviewed. The UCSF treatment protocol produced a successful case and a partially successful one (inadequate oral hygiene in the retention stage resulted in decay and loss of teeth). It provides general guidelines for successfully treating the orofacial manifestations of CCD.