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Objective To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10 and 15 µg bimatoprost implant in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods This randomized, 20-month, multicenter, masked, parallel-group, phase 3 trial enrolled 528 patients with OAG or OHT and an open iridocorneal angle inferiorly in the study eye. Study eyes were administered 10 or 15 µg bimatoprost implant on day 1, week 16, and week 32, or twice-daily topical timolol maleate 0.5%. Primary endpoints were IOP and IOP change from baseline through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). Results Both 10 and 15 µg bimatoprost implant met the primary endpoint of noninferiority to timolol in IOP lowering through 12 weeks. Mean IOP reductions from baseline ranged from 6.2–7.4, 6.5–7.8, and 6.1–6.7 mmHg through week 12 in the 10 µg implant, 15 µg implant, and timolol groups, respectively. IOP lowering was similar after the second and third implant administrations. Probabilities of requiring no IOP-lowering treatment for 1 year after the third administration were 77.5% (10 µg implant) and 79.0% (15 µg implant). The most common TEAE was conjunctival hyperemia, typically temporally associated with the administration procedure. Corneal TEAEs of interest (primarily corneal endothelial cell loss, corneal edema, and corneal touch) were more frequent with the 15 than the 10 µg implant and generally were reported after repeated administrations. Loss in mean CECD from baseline to month 20 was ~ 5% in 10 µg implant-treated eyes and ~ 1% in topical timolol-treated eyes. Visual field progression (change in the mean deviation from baseline) was reduced in the 10 µg implant group compared with the timolol group. Conclusions The results corroborated the previous phase 3 study of the bimatoprost implant. The bimatoprost implant met the primary endpoint and effectively lowered IOP. The majority of patients required no additional treatment for 12 months after the third administration. The benefit-risk assessment favored the 10 over the 15 µg implant. Studies evaluating other administration regimens with reduced risk of corneal events are ongoing. The bimatoprost implant has the potential to improve adherence and reduce treatment burden in glaucoma. Clinicaltrials.gov Identifier NCT02250651. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-021-01624-9.

Background/aims Clostridioides difficile infection (CDI) remains a diagnostic challenge in patients with inflammatory bowel disease (IBD). We tested novel biomarkers to differentiate CDI from colonization in patients without (CDI-only) and with IBD (IBD-CDI). Methods Samples were enzyme immunoassay (EIA)-tested for glutamate dehydrogenase (GDH) and toxin, followed by reflex PCR. Quantitative GDH [(qGDH) - a novel indicator of Clostridium difficile load] and stool lactoferrin were tested at days 0, 3 and 10 during antibiotic treatment. Samples were also analyzed for toxin B cytotoxicity neutralization assay (CNA) and toxigenic culture, gold standards to detect free toxin and virulent bacteria, respectively. Results Forty-five symptomatic patients (28 CDI-only, 13 with Crohn's disease, 4 with ulcerative colitis) were recruited with 3 sequential samples available for 36 (21 CDI-only, 15 IBD-CDI). Thirty-nine of 45 (87%) cases were toxigenic culture-positive. In the CDI-only group, 78.6% were positive for EIA-toxin, 21.4% were PCR-positive while 82.1% were CNA-positive. In the IBD-CDI group, only one patient (6%) was EIA-toxin positive and 17.6% CNA-positive. The median qGDH level at day 0 was higher in CNA-positive patients compared to CNA-negative patients (1111 vs. 146 ng/g, P = 0.004) and dropped together with lactoferrin from day 0 to 10. CDI eradication improved symptoms in 72.2% of patients with CDI-only. In 60% of patients with IBD-CDI, eradication was ineffective, with symptoms improving in 89% of them after IBD therapy intensification. Conclusion In patients with IBD-CDI, PCR-only positivity might mainly reflect colonization rather than disease. C. difficile load by qGDH correlates with CNA-detected toxin and together with stool lactoferrin might differentiate CDI from colonization in patients with IBD.

Despite aggressive medical therapy, many patients with Crohn’s disease require surgical intervention over time. After surgical resection, disease recurrence is common. Ileo-colonoscopy and the Rutgeerts score are commonly used for diagnosis and monitoring of post-operative endoscopic recurrence. The latter is the precursor of clinical recurrence and therefore it impacts prognosis and patient management. However, due to the limited length of bowel assessed by ileo-colonoscopy, this procedure can miss out-of-reach, more proximal lesions in the small bowel. This limitation introduces an important uncertainty when evaluating post-operative relapse by ileo-colonoscopy. In addition, the Rutgeerts score ‘per se’ bears a number of ambiguities. Here we will discuss the pros and cons of ileo-colonoscopy and other imaging studies including wireless capsule endoscopy to diagnose and manage post-operative recurrence of Crohn’s disease. A number of studies provide evidence that wireless capsule endoscopy is a potentially more accurate as well as less invasive and less costly alternative to conventional techniques including ileo-colonoscopy. Published version

Entrustable professional activities have emerged as a means for the evaluation of resident competency that is expressed in terms of the assessed need for supervision. Recently, 19 physical medicine and rehabilitation-specific entrustable professional activities were published (Am J Phys Med Rehabil. 2017;96:762-764). The electrodiagnostic entrustable professional activity and six new electrodiagnostic entrustable professional activities subcategories (observable practice activities) were piloted as an entrustable professional activities/observable practice activities set within five residency programs. Survey-based (quantitative) and open-ended (qualitative) feedback was collected from participants. Participating attendings found this method feasible and generally reported satisfaction with the entrustable professional activities/observable practice activities as a means of providing feedback to residents. Residents were less clear on the added value of this approach. Qualitative data supported the need for adjustments to the entrustment scale to allow for more gradations within supervisory levels, a standardized orientation of residents to the use of observable practice activities and an increased quantity of assessments for each observable practice activities category to allow for demonstration of resident progress toward independence. Use of the electrodiagnostic entrustable professional activity/observable practice activities set shows promise as a means for observational competency assessment in the outpatient setting. However, feedback acquired through this pilot study suggests changes that could be made to improve future implementation.

Objectives: Targeting tumor necrosis factor (TNF) with biologic agents, such as infliximab and adalimumab, is a widely used and effective therapeutic strategy in inflammatory bowel disease (IBD). Unfortunately, a significant number of patients fail to respond or lose response over time to these agents. Previous studies have defined multiple complex roles for canonical NF-kappa B signaling in the pathogenesis of IBD. However, preliminary evidence suggests that the lesser defined noncanonical NF-kappa B signaling pathway also contributes to disease pathogenesis and response to anti-TNF agents. The objective of this study was to evaluate this hypothesis in Crohn's disease (CD) and ulcerative colitis (UC) patients. Design: A total of 27 subjects with IBD (19 with CD and 8 with UC) and 15 control subjects were tested. Clinical criteria, patient history, and endoscopic disease activity were factors used to categorize patients and define therapeutic response. Biopsy specimens were collected during colonoscopy and expression was determined for 88 target genes known to be associated with noncanonical NF-kappa B signaling and IBD. Results: Noncanonical NF-kappa B signaling was significantly upregulated in IBD patients and was associated with increased gastrointestinal inflammation, epithelial cell death, lymphocyte migration, and Nod-like receptor signaling. Furthermore, noncanonical NF-kappa B signaling was further upregulated in patients unresponsive to anti-TNF agents and was suppressed in responsive patients. MAP3K14, NFKB2, CCL19, CXCL12, and CXCL13 were significantly dysregulated, as were genes that encode pathway regulators, such as CYLD, NLRP12, and BIRC2/3. Conclusion: Our study identifies a previously uncharacterized role for the understudied noncanonical NF-kappa B signaling pathway in the pathogenesis of IBD and anti-TNF therapy responsiveness. The genes and pathways identified may ultimately prove useful in IBD management and could potentially be used as biomarkers of drug response. Carilion Research Advancement Program (RAP) Grant 13 Role of the Non-Canonical NFkB Inflammatory Cascade in Therapeutic Response and Pathogenesis of IBD Published version Carilion Research Advancement Program (RAP) Grant 13 Role of the Non-Canonical NFkB Inflammatory Cascade in Therapeutic Response and Pathogenesis of IBD.

Introduction: Fecal lactoferrin (FL) is a timely and accurate marker of inflammation in ulcerative colitis (UC) and Crohn’s disease (CD). The aim of this study was to verify whether FL can predict primary nonresponse (PNR) to biologic agents during induction. Methods: Retrospective outcome review in 27 patients (13 with CD and 14 with UC) tested for baseline FL and retested within a week after the first and second induction doses. Clinical/biochemical outcomes were evaluated at end of induction and at follow-up (3–24 months). Results: Compared to baseline, changes of the Harvey-Bradshaw (CD) and Partial Mayo Scoring (UC) indices at end of induction separated responders (18/27 or 67%) from nonresponders (9/17 or 33%). In all patients, the initial FL value at induction decreased compared to baseline, continuing to decrease after the following dose in clinical responders while bouncing back in the others. Models targeting the 2 consecutively decreased FL values or the second FL value compared to baseline or the second FL value compared to the first were able to accurately predict response at end of induction. Follow-up assessment confirmed clinical remission in initial responders (with FL values reduced on the average by 94 ± 10% compared to baseline). Conclusions: In CD and UC patients during induction with biologic agents, early FL measurements accurately separate clinical responders from those experiencing PNR. The method described here offers several potential advantages over other strategies to assess and manage these patients.

Introduction: Management of inflammatory bowel diseases (IBDs) – both Crohn’s disease (CD) and ulcerative colitis (UC) – during pregnancy can be challenging since most monitoring tools available in nonpregnant patients are contraindicated. Objectives: The aim of the study was to test whether fecal inflammatory markers – specifically fecal lactoferrin – physiologically change during normal pregnancy as a prerequisite to use them to monitor IBD activity during pregnancy. Methods: Fecal lactoferrin was tested in healthy pregnant and nonpregnant women from the same geographic area and age range (18–40 years) – all negative for clinical gastrointestinal tract inflammation. A retrospective review of fecal lactoferrin levels contrasted with the Simple Endoscopic Score for CD, and the Disease Activity Index for UC was also performed in women with active IBDs within the same age range and geographical area. Results: In 30 nonpregnant subjects, fecal lactoferrin levels were 0.87 ± 1.08 μg/g. In 49 pregnant subjects, levels were 0.59 ± 0.83, 0.87 ± 1.13, and 0.85 ± 1.06 μg/g during the first, second, and third trimester, respectively (p = 0.64), with average levels for the 3 trimesters of 0.81 ± 1.04 μg/g (p = 0.61 compared to nonpregnant subjects). Sequential fecal lactoferrin levels (n = 26) did not differ from one trimester to the other in the individual subjects (p = 0.80). In 45 female IBD patients (27 with CD and 18 with UC), fecal lactoferrin levels were correlated with disease activity as defined by the endoscopic scores: 218, 688, and 1,175 μg/g for CD and 931, 2,088, and 2,509 μg/g for UC, respectively, for mild, moderate, and severe activity. Conclusions: Fecal lactoferrin levels during normal pregnancy are superimposable to those of nonpregnant women and significantly below levels in women of the same childbearing age with active IBDs. Additional published data – reviewed in this atricle – and our own indicate that fecal lactoferrin and other markers can be potentially used to monitor disease activity in pregnant IBD patients.

The H2A.Z histone variant, a genome-wide hallmark of permissive chromatin, is enriched near transcription start sites in all eukaryotes. H2A.Z is deposited by the SWR1 chromatin remodeler and evicted by unclear mechanisms. We tracked H2A.Z in living yeast at single-molecule resolution, and found that H2A.Z eviction is dependent on RNA Polymerase II (Pol II) and the Kin28/Cdk7 kinase, which phosphorylates Serine 5 of heptapeptide repeats on the carboxy-terminal domain of the largest Pol II subunit Rpb1. These findings link H2A.Z eviction to transcription initiation, promoter escape and early elongation activities of Pol II. Because passage of Pol II through +1 nucleosomes genome-wide would obligate H2A.Z turnover, we propose that global transcription of noncoding RNAs prior to premature termination, in addition to transcription of mRNAs, are responsible for eviction of H2A.Z. Such usage of yeast Pol II suggests a general mechanism coupling eukaryotic transcription to erasure of the H2A.Z epigenetic signal.

Inflammatory bowel disease (IBD) patients are at increased risk of developing Clostridioides difficile infection (CDI). Common methods to diagnose CDI involve a combination of tests including the toxin A/B enzyme immunoassay (Toxin) and toxin gene polymerase chain reaction assay (PCR). Disease outcomes in Toxin+ versus Toxin-PCR+ IBD patients remain unclear. This study aimed to examine the response to antibiotics and risk of IBD therapy escalation in Toxin+ versus Toxin-PCR+ patients. IBD patients at an academic center with CDI diagnosis based on Toxin+ or Toxin-PCR+ from 2012 to 2017 were identified. Comparisons of response to antibiotics within 30 days and escalation of IBD therapy within 90 days of CDI diagnosis between these two groups were analyzed by Chi-square analysis. Multivariable regression analysis examined factors associated with antibiotic response. Among 92 patients included, 61% had Crohn’s disease and 39% had ulcerative colitis. 70% tested Toxin-PCR+. 60% received vancomycin or fidaxomicin to treat CDI. 82% of Toxin+ patients responded to antibiotics compared to 25% of Toxin-PCR+ patients (p

Background In Crohn's disease (CD) a small bowel study-in addition to colonoscopy-is considered necessary for diagnosis/staging. In this study we re-examined the role of capsule endoscopy (CE), colonoscopy, imaging tests [magnetic resonance enterography/computed tomographic enterography (MRE/CTE)], and inflammatory markers [fecal lactoferrin and C-reactive protein (FL/CRP)] in CD patients who had undergone intestinal resection and in those who never had surgery. Methods In this retrospective study 43 consecutive patients underwent CE because of staging/symptoms unexplained by colonoscopy/imaging. We compared colonoscopy, imaging, and FL/CRP with CE and evaluated the impact of the latter on clinical management and outcomes. Results In patients who never had surgery imaging was negative with a positive CE in 8/15 (53%) of cases. Colonoscopy was insufficient for disease staging in 10/20 (50%) cases. CRP and FL were normal with a positive CE in 35% and 28% of cases, respectively. CE findings changed the management in 6/20 (30%) of cases, with 83% showing clinical/biochemical improvement after up to 15 months of follow-up. In postoperative patients CE was positive with negative imaging in 6/8 (75%) cases. Colonoscopy was insufficient for disease staging in 13/22 (59%) cases. CRP and FL were normal in 42% and 31.8% of patients with positive CE. In these patients CE findings changed the management in 12/23 (52%) cases with 83% of them showing clinical/biochemical improvement after up to 18 months of follow-up. Conclusions Omitting CE from diagnostic/staging algorithms in CD tends to underdiagnose clinically significant small bowel lesions, thus impacting on patients' management and outcomes. 10.1093/ibd/izy048_video1izy048.video15794820403001.

While much progress has been made in the last two decades in the treatment and the management of inflammatory bowel diseases (IBD)—both ulcerative colitis (UC) and Crohn’s Disease (CD)—as of today these conditions are still diagnosed only after they have become symptomatic. This is a major drawback since by then the inflammatory process has often already caused considerable damage and the disease might have become partially or totally unresponsive to medical therapy. Late diagnosis in IBD is due to the lack of accurate, non-invasive indicators that would allow disease identification during the pre-clinical stage—as it is often done in many other medical conditions. Here, we will discuss what is known about the biologic onset and pre-clinical CD with an emphasis on studies conducted in patients’ first degree relatives. We will then review the possible strategies to diagnose IBD very early in time including screening, available disease markers and imaging, and the possible clinical implications of treating these conditions at or close to their biologic onset. Later, we will review the potential impact of conducting translational research in IBD during the pre-clinical stage, especially focusing on the role of the microbiome in disease etiology and pathogenesis. Finally, we will highlight possible future developments in the field and how they can impact IBD management and our scientific knowledge of these conditions.

BACKGROUND Studies have demonstrated a potential role for fecal biomarkers such as fecal calprotectin (FC) and fecal lactoferrin (FL) in monitoring inflammatory bowel diseases (IBD) - Crohn’s disease (CD) and ulcerative colitis (UC). However, their correlation to endoscopic scores, disease severity and affected intestinal surface has not been extensively investigated. AIM To correlate FL, and for comparison white blood cell (WBC) and C-reactive protein (CRP), with endoscopic scores, disease extent and location in CD and UC. METHODS Retrospective analysis in 188 patients who had FL, CRP and WBC determined within 30 d of endoscopy. Disease location, disease extent (number of intestinal segments involved), disease severity (determined by endoscopic scores), timing of FL testing in relation to colonoscopy, as well as the use of effective fast acting medications (steroids and biologics) between colonoscopy and FL measurement, were recorded. RESULTS In 131 CD and 57 UC patients, both CRP and FL - but not WBC - distinguished disease severity (inactive, mild, moderate, severe). In patients receiving fast-acting (steroids or biologics) treatment in between FL and colonoscopy, FL showed a higher correlation to endoscopic scores when tested before vs after the procedure (r = 0.596, P < 0.001, vs r = 0.285, P = 0.15 for the Simple Endoscopic Score for CD; and r = 0.402, P = 0.01 vs r = 0.054 P = 0.84 for Disease Activity Index). Finally, FL was significantly correlated with the diseased mucosal surface (colon-ileocolon > small bowel) and the number of inflamed colon segments. CONCLUSION FL and CRP separated disease severity categories with FL showing lower discriminating P-values. FL showed a close correlation with the involved mucosal surface and with disease extent and was more closely correlated to endoscopy when determined before the procedure – this indicating that inflammatory activity changes associated with therapy might be rapidly reflected by FL levels. FL can accurately and timely characterize intestinal inflammation in IBD.

Introduction: Postoperative recurrence (POR) of Crohn’s disease is common after surgical resection. How to best manage POR remains uncertain.Areas covered: In this review, we will first describe the natural course and the best modalities to diagnose this surgical sequela. We will then focus on the potential risk factors for relapse and highlight the main shortcomings in the current study designs and endoscopic and clinical scoring systems, which may partly explain the unexpected outcomes of recent clinical trials. Finally, we will propose a strategy to address the management of POR.Expert commentary: Anti-tumor necrosis factor (Anti-TNF) agents are the most effective therapy to prevent POR in Crohn’s disease. Patient risk stratification and active monitoring with scheduled ileocolonoscopy are cornerstones of optimal POR management. Further studies are needed to address areas of uncertainty including timing and duration of therapy and the role of therapeutic drug monitoring in this setting.

Entrustable professional activities are observable units of professional practice that can potentially provide a link between competency-based medical education and clinical practice. The authors, part of a subcommittee of the Association of Academic Physiatrists Education Committee, identified a set of entrustable professional activities that would serve residency training programs in the specialty of physical medicine and rehabilitation. Using a modified Delphi process, residency program directors in the field reviewed and validated a set of entrustable professional activities. The final set of 19 entrustable professional activities is presented in this article.

The impact of diagnostic delay in inflammatory bowel disease, including Crohn's disease (CD) and ulcerative colitis (UC), on disease course remains uncertain. This study examines factors that may influence time to diagnosis and disease outcomes in a U.S. patient cohort.We retrospectively collected data on patient characteristics, time to diagnosis, disease phenotype, and complications in 177 patients with inflammatory bowel disease (110 CD and 67 UC) diagnosed at our institution from 2008 to 2015. Factors potentially affecting time to diagnosis were analyzed. Association between disease complications (perianal disease, intestinal strictures, surgery, fistula, abscess, and perforation) and time to diagnosis was tested by multivariable analysis.The median time to diagnosis was longer for patients with CD compared with patients with UC (median 9.5 versus 3.1 months; P0.001). The median time from symptom onset to initial physician visit was similar for patients with CD and patients with UC (1 month). However, the median time from symptom onset to specialist evaluation was longer for patients with CD compared with patients with UC: 7 months (interquartile range: 3-23) versus 3 months (interquartile range: 1-8), respectively (P0.001). In CD, ileal disease and hematochezia were positively and negatively correlated, respectively, with longer time to diagnosis (P0.05). Compared with patients with time to diagnosis ≤4 months, patients with time26 months had increased overall complications (odds ratio, 8.22; P = 0.007) and intestinal strictures (odds ratio, 8.96; P = 0.012) at time of diagnosis. Such correlation persisted at follow-up.Time to diagnosis was long in CD. Physician-related delay in diagnosing CD was associated with increased overall complications and intestinal strictures (See Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B646).

Anti-tumor necrosis factor (TNF)-α agents like Infliximab (IFX) are effective in the treatment of inflammatory bowel diseases (IBDs) and are widely used. However, a considerable number of patients do not respond or lose response to this therapy. Preliminary evidence suggests that transmembrane TNF-α (tmTNF-α) might be linked to response to IFX by promoting reverse signaling-induced apoptosis in inflammatory cells. The main aim of this study was the evaluation of this hypothesis in primary IFX non-responders.A total of 47 IFX naive IBD patients were included in the study. Blood samples were taken before the start of IFX therapy (at week 0) and after induction therapy (at week 14). Endoscopic disease activity and markers of inflammation at baseline and at week 14 were used to evaluate response. Baseline soluble TNF-α (sTNF-α), percentage of circulating TNF-α positive cells, mean fluorescence intensity (MFI) of tmTNF-α, and apoptosis rate at week 14 in the peripheral blood mononuclear cells (PBMCs) were evaluated in IFX responders and non-responders.Mean sTNF-α was not significantly different in responders compared to non-responders (P=0.13). Mean percentage of tmTNF-α bearing lymphocytes and monocytes was higher in the PBMCs of responders (P=0.05 and P=0.014, respectively). Mean MFI of tmTNF-α in circulating lymphocytes and monocytes was greater in responders (P=0.002 and P0.001, respectively). Moreover, the mean percentage of apoptosis in PBMCs was significantly greater in responders compared to non-responders (P=0.002).The percentage of tmTNF-α bearing lymphocytes and monocytes and the intensity of tmTNF-α in the circulating leukocyte population of IBD patients was directly related to primary response to IFX. This was likely due-as assessed by the apoptosis rate-to promotion of inflammatory cell death. Thus, our data suggest that peripheral leukocytes could in principle be used for predicting primary response to IFX in IBD patients.

Postoperative recurrence (POR) of Crohn's disease (CD) is common. Guidelines on POR management have recently been issued, but clinical practice may vary.To examine the current clinical practice of POR management in the USA METHODS: A web-based survey was sent to all members of the American Gastroenterological Association and the American College of Gastroenterology. The survey consisted of multiple-choice questions with clinical scenarios to assess how participants manage POR.A total of 189 responses were received from practices in 34 states. 44% of participants were from academic settings. The median number of CD patients seen each month was 20-30 patients per participant. The majority of participants considered smoking, prior intestinal surgery, penetrating disease, perianal fistula, early disease onset, and long extent of disease as high-risk factors for POR. To diagnose and grade endoscopic recurrence, 57% of participants used an endoscopic scoring system; 86% defined clinical recurrence using a combination of symptoms and endoscopic findings; and 79% of participants routinely performed colonoscopy after surgery. In high-risk patients, 65% offered medical prophylaxis-most often biologics and/or immunomodulators-immediately after surgery, while 34% offered medical prophylaxis regardless of the patient's risk of POR. 64% of participants never stopped medical prophylaxis once initiated.Most gastroenterologists routinely perform colonoscopy to guide POR management. The majority of these providers continue medical prophylaxis indefinitely regardless of subsequent endoscopic findings. Further research is needed to determine the risks and benefits of continuing versus deescalating therapy in patients with potentially surgically induced remission.

Summary Hepatitis D virus (HDV) infection is acquired as a co- /superinfection of Hepatitis B virus (HBV) and can modulate the pathophysiology of chronic hepatitis B and related liver diseases including hepatocellular carcinoma. Among the eight distinct HDV genotypes reported, relatively few studies have attempted to investigate the prevalence of HDV mixed genotypes and RNA recombination of HDV. With a recorded prevalence of 10–20% HBV infection in Vietnam, this study investigated the HDV variability, HDV genotypes and HDV recombination among twenty-one HDV isolates in Vietnamese HBsAg-positive patients. HDV subgenomic and full-length genome sequences were obtained using newly established HDV-specific RT-PCR techniques. The nucleotide homology was observed from 74.6% to 99.4% among the investigated full-length genome of the HDV isolates. We observed HDV genotype 1 and HDV genotype 2 in the investigated Vietnamese patients. Although no HDV genotype mixtures were observed, we report here a newly identified recombinant of HDV genotypes (HDV 1 and HDV 2). The identified recombinant HDV isolate C03 revealed sequence homology to both HDV genotype 1 (nt1 to nt907) and HDV genotype 2 (nt908 to nt1675; HDAg coding region) with a breakpoint at nt908. Our findings demonstrate the prevalence of intergenotypic recombination between HDV genotypes 1 and 2 in a Vietnamese HBsAg-positive patient. Extended investigation on the distribution and prevalence of HDV, HDV mixed genotypes and recombinant HDV genotypes in a larger Vietnamese population offers vital insights into understanding of the micro-epidemiology of HDV and subsequent pathophysiology in chronic HBV- /HDV-related liver diseases.

Stroke remains one of the leading causes of death in the United States. However, due to advancements in medical care, more and more Americans are surviving the acute event and living with disability of varying degrees. One factor that has been shown to decrease functional recovery and quality of life in this population is hemiplegic shoulder pain (HSP). Due to the diverse nature of possible etiologies, the exact cause of HSP in a patient is often obscure, thus making effective treatment equally as elusive. Therapy remains a mainstay of treatment in HSP of any etiology, especially when coupled with functional electrical stimulation. Both corticosteroid and botulinum toxin A injections have been show to be efficacious in certain subpopulations experiencing HSP and studies centered around new technology in the realm of implantable microstimulators show promising results.

As the incidence of inflammatory bowel diseases and the number of patients treated with anti-TNF agents keep on increasing so are the phenomena of primary non response (PNR) and secondary loss of response (SLR) to these medications. Traditionally PNR and SLR have been managed empirically-that is, switching medications for PNR and increasing the anti-TNF dose for SNR. More recently an approach based on testing drug levels and antibodies to the drug (therapeutic drug monitoring) has gained increasing popularity in the management of inflammatory bowel diseases. However, while this strategy might offer an insight into the mechanisms leading to PNR/SLR it often falls short of providing a simple, reproducible method to manage these issues in clinical practice. Here, we will review the currently recommended therapeutic strategies when using therapeutic drug monitoring; the evidence for and against such approach and the current standard strategies in Rheumatology (the specialty with the largest and longest experience with anti-TNF agents). We will then discuss the possible reasons of the shortcomings of therapeutic drug monitoring and the rationale and need to move the therapeutic target to the disease burden in inflammatory bowel diseases-along with the supporting preliminary evidence. Finally, we will focus on future crucial studies that need to be done to make approaches to PNR/SLR more rigorous and at the same time user-friendly for the practicing gastroenterologist.

Extraintestinal manifestations are common in inflammatory bowel disease; however, muscular involvement in Crohn disease is rarely reported. We present a case of a 26-year-old male with ileocolonic Crohn disease who developed sudden tenderness in both calves. Doppler ultrasound was negative for deep vein thrombosis. Magnetic resonance imaging of the gastrocnemius muscle showed high intensity signal in the muscle fibers, and muscle biopsy demonstrated nonspecific lymphocytic myositis. Other relevant laboratory results included normal antineutrophil cytoplasmic antibodies and creatine kinase as well as elevated C-reactive protein, erythrocyte sedimentation rate, and anti-Saccharomyces cerevisiae IgG titer. The patient was in clinical remission, being treated with azathioprine 2.5 mg/kg. Prednisone 60 mg/day was initiated with rapid resolution of calf tenderness; however, tenderness soon returned when the dose was tapered to 10 mg/day. Subsequently, prednisone and azathioprine were discontinued, and adalimumab was started at standard induction and maintenance doses. The patient’s symptoms resolved shortly after the first induction dose. A repeat magnetic resonance imaging of the calves – 3 months after starting adalimumab – showed complete resolution of muscle inflammation. To our knowledge, this is the first case of gastrocnemius myositis – a rare extraintestinal manifestation of Crohn disease – successfully treated with anti-tumor necrosis factor agents.

According to the National Health and Nutrition Examination Survey in 2007, nearly half of all American children are either overweight or obese. Retrospective chart review identified patients with the diagnostic codes for overweight, obese, and/or excessive weight gain. Inclusion criteria were current age between 2 and 20 years, a minimum of 5 visits with weight and height measurements, and a body mass index (BMI) at or above the 85th percentile. A total of 184 patients met inclusion criteria. More than half the children became overweight before age 2, and all patients were obese or overweight by age 10. The rate of gain is approximately 1 excess BMI unit/year, therefore causing most children to be overweight by age 2 ( R2= .53). This study indicates that the critical period for preventing childhood obesity in this subset of identified patients is during the first 2 years of life and for many by 3 months of age.

We evaluated whether sex affects the steady-state pharmacokinetics of the antimalarial drugs, primaquine and doxycycline, in healthy subjects. Seventeen male and 17 female healthy Vietnamese subjects were administered 30 mg (base) of primaquine daily for 14 days. After a 2-week washout period, 14 male and 14 female subjects were administered 100 mg (base) of doxycycline daily for 14 days. Women had significantly higher median values of C(max) (212 versus 122 ng/mL, P< 0.001) and AUC(0-24) (1,909 versus 917 ng . h/mL, P < 0.001) of primaquine compared with men. Other than a longer t(max) in women, no sex-related differences were seen in the pharmacokinetics of doxycycline. The primaquine pharmacokinetic data suggest that women have increased exposure to primaquine, which may put them at increased risk for toxicity when administered the same maintenance dose as men. The similar pharmacokinetics of doxycycline between the two sexes justifies the same maintenance dose.

Purpose A clinical testing cohort was used to gain a broader understanding of the spectrum of tumors associated with germline p53 mutations to aid clinicians in identifying high-risk families. Patients and Methods Full sequencing of the coding exons (2 to 11) and associated splice junctions of the p53 gene was performed on 525 consecutive patients whose blood samples were submitted for diagnostic testing. Clinical features of p53 germline carriers in this cohort were characterized, clinical referral schemes based on reported p53-associated family phenotypes were evaluated, and practical mutation prevalence tables were generated. Results Mutations were identified in 91 (17%) of 525 patients submitted for testing. All families with a p53 mutation had at least one family member with a sarcoma, breast, brain, or adrenocortical carcinoma (ACC). Every individual with a choroid plexus tumor (eight of eight) and 14 of 21 individuals with a childhood ACC had a mutation regardless of family history. Based on reported personal and family history, 95% of patients (71 of 75) with a mutation met either classic Li Fraumeni syndrome (LFS) or Chompret criteria. A simplified prevalence table provides a concise summary of individual and family characteristics associated with p53 mutations. Conclusion This is, to our knowledge, the largest single report of diagnostic testing for germline p53 mutations, yielding practical mutation prevalence tables and suggesting clinical utility of classic LFS and Chompret criteria for identifying a subset of cancer-prone families with p53 germline mutations, with important implications for diagnosis and management.

Purpose To compare the clinical, subjective, and objective outcomes of the use of 2 topical nonsteroidal antiinflammatory drugs—ketorolac tromethamine LS 0.4% (Acular) and nepafenac 0.1% (Nevanac)—in patients having cataract surgery. Setting Single-center private practice, Las Vegas, Nevada, USA. Methods One hundred eighty-three patients (193 eyes) with visually significant cataract were recruited for the study. Consenting patients were randomized to a standard regimen of Acular, gatifloxacin 0.3% (Zymar), and prednisolone acetate 1% (Pred Forte) (ketorolac group) or Nevanac, moxifloxacin hydrochloride 0.5% (Vigamox), and prednisolone acetate (Econopred) (nepafenac group). Analysis included subjective complaints (burning, itching, foreign-body sensation, pain level after surgery) and objective findings (visual function, degree of inflammation in the anterior segment, complications). Results The ketorolac group consisted of 94 patients (100 eyes) and the nepafenac group, 89 patients (93 eyes). The between-group differences in visual outcomes and anterior chamber inflammation were not statistically significant (mean P = .33). There was a higher incidence of posterior capsule opacification in the nepafenac group ( P = 0.019). Patient satisfaction, patient compliance, and postoperative pain control were statistically significantly better in the ketorolac group ( P = .022, P = .023, and P = .025, respectively). Conclusion Ketorolac tromethamine was statistically significantly better than nepafenac in terms of patient satisfaction, compliance, and postoperative pain control.

In vivo imaging of thymocytes has not been accomplished due to their localization deep within opaque body and high susceptibility to surgical stress. To overcome these problems, medaka is useful because of transparency and ex-uterine development. We report the noninvasive detection of thymocytes in transgenic medaka that express fluorescent protein under the control of immature-lymphocyte-specific rag1. We show that lymphoid progenitor cells colonize the thymus primordium in an anterior-to-posterior orientation-specific manner, revealing that extrathymic anterior components guide prevascular thymus colonization. We also show that developing thymocytes acquire “random walk motility” along with the expression of Ag receptors and coreceptors, suggesting that thymocyte walking is initiated at the developmental stage for repertoire selection. Thus, transgenic medaka enables real-time intravital imaging of thymocytes without surgical invasion.

PURPOSE To compare 3 clinical variables, namely, visual recovery, anterior chamber inflammation, and macular edema, between 2 different regimens after uncomplicated cataract surgery. DESIGN Prospective, randomized, single-blind study at a single center, private, teaching practice in Las Vegas, NV. METHODS Patients randomized to group I (nonsteroidal anti-inflammatory drugs, n = 113) received besifloxacin ophthalmic suspension 0.6% and bromfenac 0.09%, whereas those randomized to group II (steroid, n = 109) received besifloxacin ophthalmic suspension 0.6% and prednisolone acetate 1%.Preoperative evaluation included a baseline macular optical coherence tomography. Postoperative data collected included visual acuity, direct visual anterior segment cell and flare counts, and macular optical coherence tomographies. Foveal thickness and total macular volume were used to assess the presence of cystoid macular edema. RESULTS Visual recovery was statistically insignificant with P values at 0.7, 0.10, 0.2, and 0.7 at 1 day, 1 week, 1 month, and 2 months, respectively.The degree of anterior segment inflammation was not statistically significant (P = 0.8) between the studied populations.The foveal thickness (1 week, P = 0.8; 1 month, P = 0.2; 2 months, P = 0.2) and total macular volume (1 week, P = 0.7; 1 month, P = 0.1; 2 months, P = 0.2) were not statistically significant between the groups, and the observed power were 0.902 and 0.666, respectively. CONCLUSIONS This study demonstrated that bromfenac was equally efficacious when compared with a potent topical steroid in restoring visual function, decreasing and resolving anterior chamber inflammation, and preventing the development of macular edema.

Background: The purpose of this study was to compare the performance of the Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD-4), and Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equations for estimation of glomerular filtration rate (GFR) using 24-hour urine measurements. Secondary objectives included evaluation of such estimations based on age, body mass index (BMI), and pregnancy. Methods: This was a retrospective chart review of 195 patients who were ≥ 18 years of age and who had a 24-hour urine sample collected to determine GFR. Subjects were identified based on an ICD-9 search strategy for 24-hour urine sample. Demographic and laboratory data were collected from medical records and used to calculate GFR estimates. CKD-EPI, CG, MDRD-4 and generated estimates of GFR were calculated for each patient included. Results: Calculated GFR using CG, CKD-EPI, and MDRD-4 resulted in significant underestimation. Reclassification to a higher GFR proved less likely in those who were obese or elderly. As age increased, GFR decreased in both the male and female population for all creatinine based formulas except 24-hour urine collection. CG reported the highest mean average among the creatinine-based equations in all subgroups with a BMI >18.5 while CKD-EPI reported the lowest. Conclusions: While the equations evaluated did not provide an accurate measure of GFR, these methods are considered the least invasive and most convenient. Based on the results of this study, use of a 24-hour urine collection should be used when accurate estimation of GFR is warranted and measurements of inulin clearance is not feasible.

Recently, three distinct genotypes (1, 2 and 3) of human parvovirus B19 (B19) have been identified. However, the characteristics and distribution of B19 genotypes in Vietnam have not been investigated. Phylogenetic analysis using 49 subgenomic NS1/VP1u regions and two coding NS1–VP1/VP2 regions has been applied to investigate the prevalence of B19 genotypes in Vietnamese patients co-infected with Hepatitis B virus. Genetic analysis of the subgenomic NS1/VP1u region of B19 revealed that two genotypes of B19 were identified in these populations, with predominance of genotype 1 (47/49, 96 %) followed by genotype 2 (2/49, 4 %), but not genotype 3. Further, phylogenetic analysis of subgenomic B19 genomes revealed two major subgroups within genotype 1 (B19-1A and B19-1B) with an estimated nucleotide difference of >5 % between each subgroup, forming different branches. The mean percentage of amino acid variation between subgroup B19-1A and B19-1B was >2 % of the NS1, VP1 and VP2 proteins. Our results indicated that two of the three known genotypes of B19 were present in Vietnamese patients, with genotype 1 predominating, and that this genotype can be classified into at least two subgroups, B19-1A and B19-1B.

Aims To evaluate the effects of gender, food and grapefruit juice on the pharmacokinetics of primaquine in healthy subjects. Methods In a randomized, two-phase cross-over study, 10 male and 10 female healthy Vietnamese subjects were administered 30 mg primaquine in the fasting state or with food, followed by administration of primaquine with grapefruit juice. Results The pharmacokinetics of primaquine were comparable between male and female subjects, with geometric mean ratios of Cmax = 0.89 [95% confidence interval (CI) 0.65, 1.22] and AUC = 0.80 (95% CI 0.56, 1.15). The mean CL/F of primaquine was slightly higher in males than in females [0.52 l h−1 kg−1vs. 0.43 l h−1 kg−1, mean difference of 0.09 (95% CI –0.10, 0.28), P = 0.32]. When compared with fasting state values, food increased the geometric mean Cmax of primaquine by 26% (95% CI 12, 40) and the AUC by 14% (95% CI 3, 27). Similarly, grapefruit juice increased the geometric mean Cmax by 23% (95% CI 4, 45) and the AUC by 19% (95% CI 4, 37). Conclusions The disposition of primaquine was comparable between genders, suggesting no need to modify the dose of primaquine for malaria treatment or prophylaxis. Food increased the oral bioavailability of primaquine, which may lead to higher antimalarial efficacy. Grapefruit juice increased the bioavailability of primaquine, with marked interindividual differences suggesting that people should not take primaquine with grapefruit juice.

Mannose-binding lectin (MBL) is a constituent of the human innate immune system which may play an important role in combating a variety of infectious diseases. We investigated the distribution of MBL gene mutations in a Vietnamese population, using polymerase chain reaction and DNA sequence analysis, and sought associations with the outcome of hepatitis B virus (HBV) infection. For this purpose we used samples from a total of 123 patients with confirmed, well-defined HBV infections, representing a full spectrum of clinical presentation from acute to chronic to malignant states, as well as from 112 healthy controls. The only MBL gene mutation found in this population, that at codon 54 of exon 1, was present at an overall frequency of 0.12, with a trend towards a higher frequency in the HBV-infected group compared with controls (0.15 versus 0.08, P = 0.079). Within the HBV-infected group there was a non-significant trend towards higher viral loads in those with this mutation, accompanied by significantly higher serum transaminase levels in the same individuals. Segregation according to clinical presentation showed that the mutation was present at a significantly higher frequency in the group with acute hepatitis B (AHB) compared with the healthy control group (0.25 versus 0.08, P = 0.01), and was associated with higher serum transaminase levels. Our results indicate that a mutation of the MBL gene might influence the clinical outcome of HBV infection in Vietnamese patients.