Real-time evaluation and adaptation to facilitate rapid recruitment in a large, prospective cohort study.

BACKGROUND: Recruiting large cohorts efficiently can speed the translation of findings into care across a range of scientific disciplines and medical specialties. Recruitment can be hampered by factors such as financial barriers, logistical concerns, and lack of resources for patients and clinicians. These and other challenges can lead to underrepresentation in groups such as rural residents and racial and ethnic minorities. Here we discuss the implementation of various recruitment strategies for enrolling participants into a large, prospective cohort study, assessing the need for adaptations and making them in real-time, while maintaining high adherence to the protocol and high participant satisfaction. METHODS: While conducting a large, prospective trial of a multi-cancer early detection blood test at Geisinger, an integrated health system in central Pennsylvania, we monitored recruitment progress, adherence to the protocol, and participants' satisfaction. Tracking mechanisms such as paper records, electronic health records, research databases, dashboards, and electronic files were utilized to measure each outcome. We then reviewed study procedures and timelines to list the implementation strategies that were used to address barriers to recruitment, protocol adherence and participant satisfaction. RESULTS: Adaptations to methods that contributed to achieving the enrollment goal included offering multiple recruitment options, adopting group consenting, improving visit convenience, increasing the use of electronic capture and the tracking of data and source documents, staffing optimization via leveraging resources external to the study team when appropriate, and integrating the disclosure of study results into routine clinical care without adding unfunded work for clinicians. We maintained high protocol adherence and positive participant experience as exhibited by a very low rate of protocol deviations and participant complaints. CONCLUSION: Recruiting rapidly for large studies - and thereby facilitating clinical translation - requires a nimble, creative approach that marshals available resources and changes course according to data. Planning a rigorous assessment of a study's implementation outcomes prior to study recruitment can further ground study adaptations and facilitate translation into practice. This can be accomplished by proactively and continuously assessing and revising implementation strategies.

Similar success rate in proximal and distal colonic stent placement: a retrospective multi-center study.

OBJECTIVES: Stenting of malignant colon obstruction is used as a bridge to surgery or as an alternative to surgical colostomy in a palliative setting. Current guidelines recommend stent placement as the first line of treatment in colonic obstruction in both curative and palliative settings. However, it is unclear whether the location of the malignant obstruction influences the outcome of the stenting procedure. The goal of this study was to compare the outcomes of colonic stents between proximal and distal colonic strictures with regard to technical and clinical success and the risk of adverse events. METHODS: A multi-center retrospective cohort was composed of patients who underwent a colonic stent placement at two tertiary hospitals between 2013 and 2021. The technical and clinical outcome, stent type used, duration of post-procedural hospital stay and complications were noted. RESULTS: A total of 148 patients who underwent colonic stenting were identified. 41 patients underwent stent placement in the proximal colon and 107 patients underwent a distal stent placement. There was no difference in technical success (100% vs 96.3%, p = 0.209), clinical success (97.0% vs 89.6%, p = 0.199) or complications (24.4% vs 37.4%, p = 0,135). CONCLUSION: Technical success and clinical success rates are high and do not differ between stent locations. There is no significant difference in complication rates between proximal and distal colonic stents.

What can the Interventional Endoscopist Offer in the Management of Upper Gastrointestinal Malignancies?

The therapeutic possibilities of endoscopy have rapidly increased in the last decades and now allow organ-sparing treatment of early upper gastrointestinal malignancy as well as an increasing number of options for symptom palliation. This review contains an overview of the interventional endoscopic procedures in upper gastrointestinal malignancies. It describes endoscopic treatment of early oesophageal and gastric cancers, and the palliative options in managing dysphagia and gastric outlet obstruction. It also provides an overview of the therapeutic possibilities of biliary endoscopy, such as retrograde stenting and radiofrequency biliary ablation. Endoscopic ultrasound-guided therapeutic options are discussed, including biliary drainage, gastrojejunostomy and coeliac axis block. To aid in clinical decision making, the procedures are described in the context of their indication, efficacy, risks and limitations.

Liver Retransplantation: The Changing Scenario in a Tertiary Medical Center.

AIM: To analyze the causes of liver retransplantation (LRT), which mostly depend on recipient factors. MATERIALS AND METHODS: A descriptive, observational, and unicentric study including patients who underwent an LRT in a tertiary medical center between April 2002 and December 2018. Recipient, donor, and liver transplant data were collected. RESULTS: During the period under review a total of 468 transplants were made; among them, 32 (6.8%) were LRT. The most common indication (25%) was hepatic artery thrombosis (HAT) developing ischemic cholangiopathy followed by chronic rejection (21.8%). Late LRT was performed in 71.8%. A total of 96.8% of donations were after brain death with a donor median age of 65 years. Six patients (18.7%) had HAT as a postoperative complication. The recipients' 3-, 6-, and 12-month overall survival was 72.7%, 54.6%, and 51.5%, respectively, and the 5-year was 46.8%. Leading cause of death was septic shock (42.1%). CONCLUSION: In our patients, the most common cause of LRT is HAT. We had an LRT rate of 6.8%, which is consistent with national and international registers.

A Model for Genome-First Care: Returning Secondary Genomic Findings to Participants and Their Healthcare Providers in a Large Research Cohort.

There is growing interest in communicating clinically relevant DNA sequence findings to research participants who join projects with a primary research goal other than the clinical return of such results. Since Geisinger's MyCode Community Health Initiative (MyCode) was launched in 2007, more than 200,000 participants have been broadly consented for discovery research. In 2013 the MyCode consent was amended to include a secondary analysis of research genomic sequences that allows for delivery of clinical results. Since May 2015, pathogenic and likely pathogenic variants from a set list of genes associated with monogenic conditions have prompted "genome-first" clinical encounters. The encounters are described as genome-first because they are identified independent of any clinical parameters. This article (1) details our process for generating clinical results from research data, delivering results to participants and providers, facilitating condition-specific clinical evaluations, and promoting cascade testing of relatives, and (2) summarizes early results and participant uptake. We report on 542 participants who had results uploaded to the electronic health record as of February 1, 2018 and 291 unique clinical providers notified with one or more participant results. Of these 542 participants, 515 (95.0%) were reached to disclose their results and 27 (5.0%) were lost to follow-up. We describe an exportable model for delivery of clinical care through secondary use of research data. In addition, subject and provider participation data from the initial phase of these efforts can inform other institutions planning similar programs.

Analysis of Indications and Results in Liver Retransplantation: Is Late Retransplantation Worthwhile?

BACKGROUND: Liver retransplantation (LrT) is the only therapeutic option for irreversible hepatic graft failure. Despite various improvements, its technical complexity entails a greater morbidity in the short and long term. The main goal of the study was to analyze the activity of LrT at our center, as well as its indications, timing, postoperative evolution, and the long-term survival of patients. METHODS: We designed a descriptive study of a cohort of patients who underwent LrT in a Spanish Hepatic Transplant Unit, between April 1, 2002 and December 31, 2015. RESULTS: A total of 366 primary orthotopic liver transplantations were performed, 20 of which were LrTs, resulting in a 5.5% retransplantation rate. The most frequent indication for LrT was hepatic artery thrombosis (HAT) (35%). Twenty-five percent of the LrTs were early retransplantations and 75% were late retransplantations. After LrT, 35% of the grafts showed liver dysfunction. The overall mortality rate was 45%: in early LrT this was 25% and in late LrT it was 46.7%. Graft actuarial survival at 1 month post-LrT was 75% and at 5 years it was 63.6%. The overall actuarial survival after LrT at month 1, year 1, year 3, and year 5 was 80%, 69.6%, 58.9%, and 50.5%, respectively. In the late LrT group, the results proved less favorable, so it is necessary to define the minimum acceptable result before proceeding to a second graft. CONCLUSION: Our LrT rate was lower than that reported by other groups in our country. The actuarial survival rates for graft and patient are comparable to those obtained by other groups.

Analysis of the Predictive Ability for Graft Loss and Mortality of Two Criteria for Early Allograft Dysfunction After Liver Transplantation.

INTRODUCTION: The current imbalance between available donors and potential recipients for orthotopic liver transplantation (OLT) has led to a liberalization of organ acceptance criteria, increasing the risk of post-transplant complications such as early allograft dysfunction (EAD). Consequently, we need accurate criteria to detect patients with early poor graft function to guide the strategies of management. We evaluated the usefulness of two frequently used criteria: the definition from Olthoff et al and the Model for Early Allograft Function (MEAF) scoring. PATIENTS AND METHODS: Unicentric cohort study of patients undergoing OLT between January 1, 2010, and November 20, 2016. We performed a univariate study to detect donor, recipient, and transplant factors favoring EAD, defined both by Olthoff criteria and a MEAF score higher than 7. Finally, we developed a comparative survival analysis for cases having or not EAD. RESULTS: In all, 201 transplants met inclusion criteria. According to the stated cutoff for MEAF score, the frequency of EAD was 9.3%, with a significant association to low recipient body mass index and prolonged total graft ischemia time, resulting in lower patient 3-month postoperative survival. According to Olthoff criteria, EAD incidence was 22.1% and was associated with younger donor and recipient ages and higher Model for End-stage Liver Disease and Child-Pugh recipient scores. Its development resulted in lower graft and recipient survival at 3 months after OLT. CONCLUSION: MEAF score and Olthoff criteria are useful tools for detection of EAD. The latter could select more appropriately patients at risk, but its calculation cannot be done until the seventh day after OLT, unlike MEAF score, available on third day.

Exome Sequencing-Based Screening for BRCA1/2 Expected Pathogenic Variants Among Adult Biobank Participants.

Importance: Detection of disease-associated variants in the BRCA1 and BRCA2 (BRCA1/2) genes allows for cancer prevention and early diagnosis in high-risk individuals. Objectives: To identify pathogenic and likely pathogenic (P/LP) BRCA1/2 variants in an unselected research cohort, and to characterize the features associated with P/LP variants. Design, Setting, and Participants: This is a cross-sectional study of adult volunteers (n = 50 726) who underwent exome sequencing at a single health care system (Geisinger Health System, Danville, Pennsylvania) from January 1, 2014, to March 1, 2016. Participants are part of the DiscovEHR cohort and were identified through the Geisinger MyCode Community Health Initiative. They consented to a research protocol that included sequencing and return of actionable test results. Clinical data from electronic health records and clinical visits were correlated with variants. Comparisons were made between those with (cases) and those without (controls) P/LP variants in BRCA1/2. Main Outcomes: Prevalence of P/LP BRCA1/2 variants in cohort, proportion of variant carriers not previously ascertained through clinical testing, and personal and family history of relevant cancers among BRCA1/2 variant carriers and noncarriers. Results: Of the 50 726 health system patients who underwent exome sequencing, 50 459 (99.5%) had no expected pathogenic BRCA1/2 variants and 267 (0.5%) were BRCA1/2 carriers. Of the 267 cases (148 [55.4%] were women and 119 [44.6%] were men with a mean [range] age of 58.9 [23-90] years), 183 (68.5%) received clinically confirmed results in their electronic health record. Among the 267 participants with P/LP BRCA1/2 variants, 219 (82.0%) had no prior clinical testing, 95 (35.6%) had BRCA1 variants, and 172 (64.4%) had BRCA2 variants. Syndromic cancer diagnoses were present in 11 (47.8%) of the 23 deceased BRCA1/2 carriers and in 56 (20.9%) of all 267 BRCA1/2 carriers. Among women, 31 (20.9%) of 148 variant carriers had a personal history of breast cancer, compared with 1554 (5.2%) of 29 880 noncarriers (odds ratio [OR], 5.95; 95% CI, 3.88-9.13; P < .001). Ovarian cancer history was present in 15 (10.1%) of 148 variant carriers and in 195 (0.6%) of 29 880 variant noncarriers (OR, 18.30; 95% CI, 10.48-31.4; P < .001). Among 89 BRCA1/2 carriers without prior testing but with comprehensive personal and family history data, 44 (49.4%) did not meet published guidelines for clinical testing. Conclusions and Relevance: This study found that compared with previous clinical care, exome sequencing-based screening identified 5 times as many individuals with P/LP BRCA1/2 variants. These findings suggest that genomic screening may identify BRCA1/2-associated cancer risk that might otherwise remain undetected within health care systems and may provide opportunities to reduce morbidity and mortality in patients.

Diagnostic imaging in Crohn's disease: what is the new gold standard?

Historically Barium and isotope studies been used for imaging of inflammatory bowel disease (IBD) but carry risk of radiation exposure. Use of Barium is declining resulting in fewer radiologists that have the necessary expertise. Isotopes studies lack anatomical definition but 18F - fludeoxyglucose (FDG) positron emission tomography (PET) shows promise in accurate assessment of disease compared to endoscopy. Computerised tomography (CT) is particularly useful in assessment of complications of Crohn's disease (CD) but radiation exposure is high. CT enterography (CTE) has improved visualisation of small bowel mucosal disease and allows assessment of disease activity. Ultrasound is increasingly used for preliminary assessment of patients with potential IBD. Although widely available and economically attractive, the expertise required is not widespread. Finally magnetic resonance imaging (MRI) is proving to be the most accurate tool for assessment of disease extent and distribution. MRI of the pelvis has superseded other techniques in assessment of peri-anal fistulation.

Early detection of biliary complications and graft rejection in a non-RH Identitical liver transplant recipient from a non-heart-beating donor: a case report.

Because of a shortage of organs, non-heart-beating donors have been proposed to be a possible source of grafts for orthotopic liver transplantation. Herein, we have presented a blood group A+ patient with primary biliary cirrhosis, who underwent orthotopic liver transplantation from a non-heart-beating blood group A- donor. On day 5 after transplantation the patient displayed a low hemoglobin levels as well as an increased total bilirubin with progressive encephalopathy, hypotension, and oligoanuria on day 11. The patient responded to steroid treatment. We assume the main cause of organ dysfunction was a passenger lymphocyte syndrome (ABO-Rh incompatibility). Biliary complications were detected at a 6-month follow-up visit by increased hepatic enzymes. We thus concluded that it is useful to take Rh group into account.

Mast cell densities in bronchial biopsies and small airways are related.

INTRODUCTION: The study sought to determine whether mast cell counts in endobronchial biopsies of large airways are related to mast cell counts in the small airways. METHODS: Lungs, obtained postmortem from 10 subjects who had died of non-respiratory causes, were fixed in inflation. Mast cell densities (cells/mm(3)), determined with an optical disector, were compared on histological sections (30 µm thick) of biopsies and small airways stained with human anti-mast cell tryptase. RESULTS: Mean mast cell density over the inner airway wall in biopsies was significantly related to mean mast cell density over the total airway wall in the small airways (r=∼0.80, p<0.01). A minimum of three biopsies per case was required to demonstrate this relationship. Within relevant count areas, mast cell density was about 1.6-fold higher in the small airways than in the biopsies. CONCLUSIONS: These findings suggest that when mean counts from at least three biopsies per case are used, intersubject comparisons of mast cell density in the inner airway wall in endobronchial biopsies reflect intersubject comparisons of mast cell density over the total airway wall in small airways. This is despite the observation that mast cell densities are generally higher in the small airways.

Colorectal cancer detection: time to abandon barium enema?

OBJECTIVES: To assess the sensitivity of double contrast barium enema (DCBE) for diagnosing colorectal cancer (CRC). DESIGN: Retrospective evaluation of DCBE performed in the 2 years prior to diagnosis of CRC. SETTING: Teaching hospital in Cambridge, UK. PATIENTS: 1310 consecutive cases of CRC identified from cancer registry data. INTERVENTIONS: DCBE and colonoscopy. MAIN OUTCOME MEASURES: Sensitivity of DCBE for diagnosing CRC. RESULTS: 215 patients had undergone a DCBE within the 2 years prior to diagnosis with CRC. After excluding those reported as inadequate, 37 of these were reported as normal, giving a sensitivity of 83% (81-85%). CONCLUSIONS: The performance of DCBE is inadequate for the exclusion of CRC. Expansion of colonoscopy and CT colonography capacity is urgently required nationally so that DCBE can finally be abandoned as a firstline test in patients at risk of CRC.

Service provision and training for endoscopic ultrasound in the UK.

Endoscopic ultrasound (EUS) is a standard procedure that plays an important role in the management of both malignant and benign disease. The development of EUS services in the UK has been haphazard and training inconsistent. The British Society of Gastroenterology has charged a working group with the task of laying down a national framework for how such services might be commissioned, structured and regulated; with particular attention to defining how endoscopist skills might be acquired, assessed and maintained. This report lays out a map for this process and its future revision.

Baseline sputum time to detection predicts month two culture conversion and relapse in non-HIV-infected patients.

BACKGROUND: Few biomarkers are available to identify tuberculosis (TB) patients at risk of delayed sputum conversion and relapse. OBJECTIVES: To investigate whether baseline pre-treatment time to detection (TTD) of culture predicted 2-month bacteriological conversion and TB relapse. METHODS: A total of 263 non-HIV-infected smear-positive previously untreated pulmonary TB patients were prospectively followed from diagnosis until treatment outcome after 6 months' treatment and TB recurrence within 24 months. RESULTS: The median TTD was 3 days (range 1-17). Of 211 (80.2%) patients with favourable treatment outcome, 22 (10.4%) had recurrence, while 12 (5.7%) had confirmed relapse. Culture conversion at 2 months was associated in univariate analysis with the presence and number of cavities, extensive parenchymal involvement, male sex, sputum smear grading and TTD. In multiple logistic regression, TTD or smear grading and extensive parenchymal involvement both predicted month 2 conversion. Relapse was predicted by TTD, sex, body mass index, smear grading and number of cavities in univariate analysis, and in multivariate regression by TTD and sputum smear grading. CONCLUSIONS: Baseline TTD and smear grading predicted month 2 culture conversion, relapse and also recurrence. These markers may be useful to identify non-HIV-infected patients at risk of recurrence, and may be relevant in clinical trials.

Time to detection of Mycobacterium tuberculosis in BACTEC systems as a viable alternative to colony counting.

OBJECTIVE: To investigate whether time to detection (TTD) of Mycobacterium tuberculosis in BACTEC Mycobacteria Growth Indicator Tube (MGIT) 960 and BACTEC 460 TB systems can be used as an alternative to colony-forming unit (cfu) counting. DESIGN: A single sputum sample recovered from each of 22 patients with tuberculosis (TB) was cultured on Middlebrook 7H11 agar and in BACTEC MGIT 960 and BACTEC 460 to investigate the relationship between cfu/ml and TTD. The relationship between TTD and treatment response was investigated by culturing a single sputum sample from each of 125 patients with TB in the BACTEC 460 system and comparing TTD values with their treatment response. RESULTS: An inverse correlation between TTD and bacterial number, as assessed by inoculum size and cfu/ml, was observed. For the 125 patients followed up during treatment, TTD values at diagnosis correlated with smear conversion rates at 2 months and treatment outcomes. Drug resistance of the infecting strain was associated with decreased killing, as indicated by the delayed increase in TTD during the first few days of treatment. CONCLUSION: The TTD of M. tuberculosis in BACTEC MGIT 960 and BACTEC 460 TB systems is a viable alternative to colony counting. TTD in liquid culture will facilitate mycobacterial quantification, especially in the evaluation of early bactericidal activity.

Prediction of delayed treatment response in pulmonary tuberculosis: use of time to positivity values of Bactec cultures.

New drugs that can shorten tuberculosis (TB) treatment and target drug resistant strains are urgently needed. A test which could predict patients at risk of a delayed response to treatment would facilitate clinical trials of new anti-tuberculosis drugs. A widely-used test for the assessment of response to treatment is sputum smear examination. Patients who are smear positive after 2 and 3 months of treatment are said to have delayed and significantly delayed treatment responses respectively. Time to positivity (TTP) values of Bactec cultures, from the first 2 weeks of treatment were used to predict delayed and significantly delayed treatment responses in patients with first time pulmonary tuberculosis. Changes in TTP values early in treatment were transformed to a response ratio (r). Values of r that were less than a threshold value (r(c)) indicated patients who were at risk of having delayed or significantly delayed response to treatment. Accuracy of prediction was sensitive to the timing of sputum sampling and adherence to therapy in the first 2 weeks. Based on TTP data from the first 2 weeks of treatment, significantly delayed treatment response could be predicted with a sensitivity of 75% and a specificity of 62% while the positive (PPV) and negative predictive values (NPV) were 14% and 97% respectively. While the high NPV indicates that a large proportion of patients with a satisfactory response to treatment can be reliably identified, the low PPV value underlines the need to use TTP in conjunction with other markers of disease activity to predict unfavourable treatment response in tuberculosis treatment.

A clinical algorithm for the assessment of pancreatic lesions: utilization of 16- and 64-section multidetector CT and endoscopic ultrasound.

Pancreatic masses may be solid or cystic, benign or malignant, and their characterization can often be difficult as there is considerable overlap in their imaging features. Multidetector computed tomography (MDCT) with multiplanar reconstructions offers improved resolution and optimum visualization of the peripancreatic vasculature, which has improved the accuracy in predicting surgical resectability. Endoscopic ultrasound (EUS) is valuable in the detection of tumours not identified on CT. It is also accurate in identifying vascular involvement, which complements MDCT in predicting resectability. In cases of diagnostic uncertainty, EUS-guided fine-needle aspiration (FNA) can be used to obtain tissue samples from solid lesions and fluid aspirates from cystic lesions, allowing histological, cytological, and biochemical analysis to determine the nature of the lesion. This article focuses on the MDCT and EUS appearances of common pancreatic malignancies, highlighting their relative advantages and their complementary role in detecting and characterizing pancreatic masses. A clinical algorithm for the assessment of pancreatic malignancy, as practised in our institution, is outlined.