Miracle-dz/UniFAR-FTUs huggingface dataset:
Management of Crohn's Disease in the New Era of Gut Rehabilitation and Intestinal Transplantation

Abstract:Despite recent therapeutic advances, patients with Crohn's disease (CD) continue to experience high recurrence with cumulative structural damage and ultimate loss of nutritional autonomy. With short bowel syndrome, strictures, and enteric fistulae being the underlying pathology, CD is the second common indication for home parenteral nutrition (HPN). With development of intestinal failure, nutritional management including HPN is required as a rescue therapy. Unfortunately, some patients do not escape the HPN-associated complications. Therefore, the concept of gut rehabilitation has evolved as part of the algorithmic management of these patients, with transplantation being the ultimate life-saving therapy. With type 2 intestinal failure, comprehensive rehabilitative measures including nutritional care, pharmacologic manipulation, autologous reconstruction, and bowel lengthening is often successful, particularly in patients with quiescent disease. With type 3 intestinal failure, transplantation is the only life-saving treatment for patients with HPN failure and intractable disease. With CD being the second common indication for transplantation in adults, survival outcome continues to improve because of surgical innovation, novel immunosuppression, and better postoperative care. Despite being a rescue therapy, the procedure has achieved survival rates similar to other solid organs, and comparable to those who continue to receive HPN therapy. With similar technical, immunologic, and infectious complications, survival is similar in the CD and non-CD recipients. Full nutritional autonomy is achievable in most survivors with better quality of life and long-term cost-effectiveness. CD recurrence is rare with no impact on graft function. Further progress is anticipated with new insights into the pathogenesis of CD and mechanisms of transplant tolerance.
Evaluation of a new orthodontic bonding system (Beauty Ortho Bond)

Background: The purpose of the current study was to evaluate the efficacy of a new orthodontic bonding system (Beauty Ortho Bond) involving the shear bond strength in dry and wet environments, and adhesion remnant index (ARI) scores evaluation in regard to other bonding systems (Heliosit and Resilience Orthodontic Adhesives). Materials and methods: Sixty defect free extracted premolars were randomly divided into six groups of 10 teeth each, mounted in acrylic resin, three groups for a dry environment and three for a wet one. Shear bond strength test was performed with a cross head speed of 0.5 mm/min, while surfaces of enamel and bracket-adhesive-enamel surfaces were examined with stereomicroscope For ARI scores evaluation. Data were analyzed by one way analysis of variance, least significant difference, student's t-test, and Fisher exact test. Results: The mean shear bond strength showed highest values for Resilience adhesive followed by Beauty Ortho Bond and Heliosit adhesives respectively both in dry and wet environments. Interestingly, there was a non-significant difference (P<0.05) between Resilience and Beauty Ortho Bond adhesives using least significant difference at dry environment. In wet environment the Beauty Ortho Bond showed an acceptable mean shear bond strength value (6.39 Mpa) which is considered as a clinically acceptable value. Adhesive remnant index scores demonstrated a tendency towards score 1 in dry environment, and towards score 3 in wet environment, the scores also showed a non-significant difference (P<0.05) between Resilience and Beauty Ortho Bond adhesives using Fischer exact test. Conclusion: Beauty Ortho Bond is less sensitive to wet environment than Resilience and Heliosit adhesives, therefore it has an advantage during clean up, as it reduces the risk of enamel damage during debonding procedure.
A Novel Dual-cre Motif Enables Two-Way Autoregulation of CcpA in Clostridium acetobutylicum

ABSTRACT The master regulator CcpA (catabolite control protein A) manages a large and complex regulatory network that is essential for cellular physiology and metabolism in Gram-positive bacteria. Although CcpA can affect the expression of target genes by binding to a cis-acting catabolite-responsive element (cre), whether and how the expression of CcpA is regulated remain poorly explored. Here, we report a novel dual-cre motif that is employed by the CcpA in Clostridium acetobutylicum, a typical solventogenic Clostridium species, for autoregulation. Two cre sites are involved in CcpA autoregulation, and they reside in the promoter and coding regions of CcpA. In this dual-cre motif, creP, in the promoter region, positively regulates ccpA transcription, whereas creORF, in the coding region, negatively regulates this transcription, thus enabling two-way autoregulation of CcpA. Although CcpA bound creP more strongly than creORF in vitro, the in vivo assay showed that creORF-based repression dominates CcpA autoregulation during the entire fermentation. Finally, a synonymous mutation of creORF was made within the coding region, achieving an increased intracellular CcpA expression and improved cellular performance. This study provides new insights into the regulatory role of CcpA in C. acetobutylicum and, moreover, contributes a new engineering strategy for this industrial strain. IMPORTANCE CcpA is known to be a key transcription factor in Gram-positive bacteria. However, it is still unclear whether and how the intracellular CcpA level is regulated, which may be essential for maintaining normal cell physiology and metabolism. We discovered here that CcpA employs a dual-cre motif to autoregulate, enabling dynamic control of its own expression level during the entire fermentation process. This finding answers the questions above and fills a void in our understanding of the regulatory network of CcpA. Interference in CcpA autoregulation leads to improved cellular performance, providing a new useful strategy in genetic engineering of C. acetobutylicum. Since CcpA is widespread in Gram-positive bacteria, including pathogens, this dual-cre-based CcpA autoregulation would be valuable for increasing our understanding of CcpA-based global regulation in bacteria.
Progression patterns under BRAF inhibitor treatment and treatment beyond progression in patients with metastatic melanoma

Despite markedly improved treatment options for metastatic melanoma, resistance to targeted therapies such as BRAF inhibitors (BRAFi) or BRAFi plus MEK inhibitors (MEKi) remains a major problem. Our aim was to characterize progression on BRAFi therapy and outcome of subsequent treatment. One hundred and eighty patients with BRAF‐mutant metastatic melanoma who had progressed on treatment with single‐agent BRAFi from February 2010 to April 2015 were included in a retrospective data analysis focused on patterns of progression, treatment beyond progression (TBP) and subsequent treatments after BRAFi therapy. Analysis revealed that 51.1% of patients progressed with both new and existing metastases opposed to progression of only preexisting (28.3%) or only new (20.6%) metastases. Exclusive extracranial progression occurred in 50.6% of patients compared to both extra‐ and intracranial (29.4%) or sole cerebral progression (20%). Multivariable analyses demonstrated that single site progression and primary response to BRAFi were associated with improved progression‐free survival. Progression with exclusively new or only existing metastases and a baseline Eastern Cooperative Oncology Group (ECOG) of 0 were associated with prolonged overall survival (OS). TBP had no significant impact on OS. Other subsequent treatments showed low efficacy with the exception of anti‐PD‐1 antibodies. In conclusion we identified specific patterns of progression which significantly correlate with further prognosis after progression on BRAFi treatment. In contrast to previously published data, we could not demonstrate a significant survival benefit for BRAFi TBP. Subsequent therapies had strikingly low efficacy except for PD‐1 inhibitors.
Management of inflammatory bowel disease-related anemia and iron deficiency with specific reference to the role of intravenous iron in current practice

ABSTRACT Introduction: Anemia is a common extraintestinal manifestation in patients with inflammatory bowel disease, impacting disease prognosis, morbidity, hospitalization rates and time lost from work. While iron deficiency anemia and anemia of chronic inflammation predominate, combinations of hematimetric and biochemical markers facilitate the diagnosis and targeted therapy of other etiologies according to their underlying pathophysiological causes. Intravenous iron replacement is currently recommended in IBD patients with moderate to severe anemia or intolerance to oral iron. Areas covered: This review examines the impact, pathophysiology and diagnostics of iron deficiency and anemia, compares the characteristics and safety profiles of available oral and intravenous iron preparations, and highlights issues which require consideration in decision making for therapy administration and monitoring. Expert opinion: Modern intravenous iron formulations have been shown to be safe and effective in IBD patients, allowing rapid anemia correction and repletion of iron stores. While traditional oral iron preparations are associated with increased inflammation, negative effects on the microbiome, and poor tolerance and compliance, first clinical trial data indicate that newer oral compounds such as ferric maltol and sucrosomial iron offer improved tolerability and may thus offer a viable alternative for the future.
Effect of electroconvulsive therapy on hippocampal and amygdala volumes: systematic review and meta-analysis

Background Electroconvulsive therapy (ECT) is one of the most effective treatments for depression, although the underlying mechanisms remain unclear. Animal studies have shown that electroconvulsive shock induced neuroplastic changes in the hippocampus. Aims To summarise volumetric magnetic resonance imaging studies investigating the effects of ECT on limbic brain structures. Method A systematic review and meta-analysis was conducted to assess volumetric changes of each side of the hippocampus and amygdala before and after ECT. Standardised mean difference (SMD) was calculated. Results A total of 8 studies (n = 193) were selected for our analyses. Both right and left hippocampal and amygdala volumes increased after ECT. Meta-regression analyses revealed that age, percentage of those responding and percentage of those in remission were negatively associated with volume increases in the left hippocampus. Conclusions ECT increased brain volume in the limbic structures. The clinical relevance of volume increase needs further investigation. Declaration of interest None.
The underlying inflammatory chronic disease influences infliximab pharmacokinetics

ABSTRACT Infliximab is an anti-tumor necrosis factor monoclonal antibody approved in chronic inflammatory diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD) and ulcerative colitis (UC). Infliximab pharmacokinetics is variable between patients, but influence of the underlying disease was never assessed. This study aimed at assessing this influence using a cohort of patients monitored in a single center and with the same assay. Infliximab trough concentrations were determined on samples collected between weeks 0 and 22 after treatment initiation in 218 patients treated for RA, PsA, AS, CD or UC. Infliximab pharmacokinetics was analyzed by a one-compartment population model with first-order elimination rate constant. In AS patients, volume of distribution (V) and elimination clearance (CL) were 5.4 L and 0.24 L/day, respectively. In CD and UC patients, V was 49% and 52% higher than in AS, respectively, and CL was 47% and 60% higher than in AS, respectively. In RA patients, CL was 49% higher than in AS patients. Simulations showed that without methotrexate, a 3 mg/kg dosing regimen would lead only 16% of RA patients to reach the target concentration (2.5 mg/L) at week 22, whereas target concentrations would be reached in approximately half of RA patients cotreated with methotrexate, as well as half of CD (3.5 mg/L) and UC (3.7 mg/L) patients. The suboptimality of approved dosing regimens supports the development of dosing optimization based on concentration measurements.
An event-triggered design scheme for spacecraft attitude control

In this paper, to reduce the communication burden between the controller and the actuator, we propose an event-triggered control design scheme for the spacecraft attitude stabilization problem. The main idea is that we design the controller and the triggering event simultaneously such that the controller can effectively compensate for the measurement errors caused by the event-triggering mechanism. Two different kinds of triggering events, i.e. the fixed threshold strategy and the relative threshold strategy, are considered according to practical situations. Through Lyapunov analysis, it is shown that the proposed event-trigger control schemes guarantee that the spacecraft attitude tracking error and the angular velocity error will exponentially converge towards an adjustable set around zero.
Alopecia areata and Affected Skin CRH Receptor Upregulation Induced by Acute Emotional Stress

Background: Recent evidence indicates that acute stress can precipitate a number of dermatological conditions, including alopecia areata. This effect may be mediated by corticotropin-releasing hormone (CRH) released locally in the skin from dorsal root ganglia or immune cells. CRH typically acts through activation of specific receptors that are either type 1 or types 2α and 2β. CRH, or related peptides such as urocortin, could have proinflammatory effects directly or through activation of mast cells leading to destruction of the hair root. Objectives: To investigate the expression of CRH receptors on the affected skin of patients who developed alopecia areata following acute emotional stress. Methods: Scalp skin biopsies were obtained from 1 normal volunteer and 3 patients after ring infiltration of the relevant site with lidocaine. The biopsies were frozen and were later processed for in situ hybridization for CRH receptors type 1 or types 2α and 2β. Sections showing positive results were photographed. Results: The skin from the normal volunteer showed weak background expression of all three receptor types. However, skin from the affected sites of all 3 patients studied showed intense expression only on the type 2β receptor around the hair follicles. Conclusion: Acute emotional stress may precipitate alopecia areata by activation of overexpressed type 2β CRH receptors around the hair follicles leading to intense local inflammation.
Association Between HIV Infection and the Risk of Heart Failure With Reduced Ejection Fraction and Preserved Ejection Fraction in the Antiretroviral Therapy Era: Results From the Veterans Aging Cohort Study

Importance With improved survival, heart failure (HF) has become a major complication for individuals with human immunodeficiency virus (HIV) infection. It is unclear if this risk extends to different types of HF in the antiretroviral therapy (ART) era. Determining whether HIV infection is associated with HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), or both is critical because HF types differ with respect to underlying mechanism, treatment, and prognosis. Objectives To investigate whether HIV infection increases the risk of future HFrEF and HFpEF and to assess if this risk varies by sociodemographic and HIV-specific factors. Design, Setting, and Participants This study evaluated 98 015 participants without baseline cardiovascular disease from the Veterans Aging Cohort Study, an observational cohort of HIV-infected veterans and uninfected veterans matched by age, sex, race/ethnicity, and clinical site, enrolled on or after April 1, 2003, and followed up through September 30, 2012. The dates of the analysis were October 2015 to November 2016. Exposure Human immunodeficiency virus infection. Main Outcomes and Measures Outcomes included HFpEF (EF≥50%), borderline HFpEF (EF 40%-49%), HFrEF (EF<40%), and HF of unknown type (EF missing). Results Among 98 015 participants, the mean (SD) age at enrollment in the study was 48.3 (9.8) years, 97.0% were male, and 32.2% had HIV infection. During a median follow-up of 7.1 years, there were 2636 total HF events (34.6% were HFpEF, 15.5% were borderline HFpEF, 37.1% were HFrEF, and 12.8% were HF of unknown type). Compared with uninfected veterans, HIV-infected veterans had an increased risk of HFpEF (hazard ratio [HR], 1.21; 95% CI, 1.03-1.41), borderline HFpEF (HR, 1.37; 95% CI, 1.09-1.72), and HFrEF (HR, 1.61; 95% CI, 1.40-1.86). The risk of HFrEF was pronounced in veterans younger than 40 years at baseline (HR, 3.59; 95% CI, 1.95-6.58). Among HIV-infected veterans, time-updated HIV-1 RNA viral load of at least 500 copies/mL compared with less than 500 copies/mL was associated with an increased risk of HFrEF, and time-updated CD4 cell count less than 200 cells/mm3 compared with at least 500 cells/mm3 was associated with an increased risk of HFrEF and HFpEF. Conclusions and Relevance Individuals who are infected with HIV have an increased risk of HFpEF, borderline HFpEF, and HFrEF compared with uninfected individuals. The increased risk of HFrEF can manifest decades earlier than would be expected in a typical uninfected population. Future research should focus on prevention, risk stratification, and identification of the mechanisms for HFrEF and HFpEF in the HIV-infected population.
The Relationship between Sociodemographic Characteristics and Recruitment, Retention, and Health Improvements in a Worksite Health Promotion Program

Background. Recruitment, retention, and success in a worksite health promotion program was examined among various demographic groups of employees (n = 11,830) of the Dallas, Texas Independent School District. Methods. Enrolled employees (n =3,873) were given a health screen consisting of health habit assessment, measurement of clinical variables, physical fitness testing, and a medical examination. Results. Thirty-three percent of employees were successfully recruited into the program. Recruitment rates were virtually identical for men and women (32 % and 33%, respectively), but varied across ethnic, age, and education groups. Blacks, younger employees, and noncollege graduates were less likely to be recruited. Sixtynine percent of the employees were retained in the program, as defined by participation in the second screen, and women were more likely to be retained than men (71 % versus 64%, respectively). Retention rates throughout the 10-week program were higher for whites and Hispanics, and were virtually identical for each age group and education level. Overall, participants in the program showed an improvement in physical fitness and general well-being, lost weight, and smoked less. These changes were relatively consistent across the various demographic groups. Discussion. Data suggest demographic characteristics are related to recruitment and retention in a health promotion program.
Recurrent bloody dialysate during upper respiratory tract infection in mesangial IgA glomerulonephritis.

Prof. Dr. E. Ritz, Klinikum der Universität Heidelberg, Sektion Nephrologie, Bergheimer Strasse 56a, D-6900 Heidelberg 1 (FRG) bir, Bloody dialysate is a known complication of CAPD, e.g. secondary to endometriosis, rupture of Graaf s follicle, trauma, tumor, etc. Recently we had the opportunity to examine a patient with mesangial IgA glomerulonephritis (IgA-GN) who was on CAPD and presented with recurrent bloody dialysate in temporal relationship to upper respiratory tract infections. 37-year-old patient; since 1975, known microhematuria and proteinuria, serum creatinine 2.5 mg/dl. Renal biopsy at that stage showed mesangial IgA-GN. Biopsy of uninvolved skin showed no IgA deposits suggestive of vasculitis. The patient was admitted to our unit and put on CAPD in October 1983. In the following 2 years he complained of 6 bouts of bloody dialysate (erythrocytes 500,000/ml) without evidence of peritonitis (leukocytes 10,000/ml; negative bacterial cultures). The bouts lasted for 3–5 days and were not associated with abdominal symptoms. Bleeding time and coagulation tests (Quick, PTT, factor VIII) were repeatedly normal. Abdominal CAT scan was unremarkable. Scintigraphy with 99mTc-Nano-Coll® showed no localized source of bleeding. Gastrointestinal X-rays were repeatedly normal. In every single instance, intraperitoneal bleeding was preceded by an upper respiratory tract infection several days prior to onset of bloody dialysate. The episodes were afebrile but associated with headache, rhinitis and on some occasions with painful swallowing. Upon intensive questioning and check-up because of the episodes, the patient volunteered that in 1966 he had a bout of nonbloody gastroenteritis accompanied by arthralgia and a fine macu-lar and possibly petechial rash on the lower and upper extremities compatible with the diagnosis of Schònlein-Henoch’s purpura (SHP). After 5 episodes, tonsillectomy was performed in January 1985, after which only one minor episode occurred to date. The proportion of B cells expressing IgA versus IgG in the tonsils was within the normal range. The observation documents asymptomatic bleeding into the peritoneal space as another clinical manifestation of IgA-GN/SHP. The case adds another differential diagnosis for bloody dialysate on CAPD. The observation also illustrates that the peritoneum is a potential target organ for the IgA-GN/SHP complex. A fortuitous association is unlikely in view of the occurence of the
Activities of a Nitrofurazone-Containing Urinary Catheter and a Silver Hydrogel Catheter against Multidrug-Resistant Bacteria Characteristic of Catheter-Associated Urinary Tract Infection

ABSTRACT The in vitro inhibitory activity of a nitrofurazone-coated urinary catheter (NFC) against 86 recently obtained susceptible and multidrug-resistant (MDR) clinical isolates of Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Staphylococcus aureus, coagulase-negativestaphylococci, and Enterococcus faecium, which are species implicated in catheter-associated urinary tract infection and which traditionally have been susceptible to nitrofuran derivatives, was determined using an agar diffusion assay. In a subset of these strains, the activity of the NFC was compared with that of a silver hydrogel urinary catheter (SHC), and the durability of each catheter’s inhibitory activity was assessed during serial daily transfers of catheter segments to fresh culture plates. Except for vancomycin-resistant E. faecium, the NFC was active against all isolates tested and showed comparable inhibition zones with susceptible and MDR strains of each species. In contrast, the SHC inhibited only certain staphylococci (P < 0.01 versus the NFC), and among these strains, the SHC produced smaller inhibition zones than did the NFC (P < 0.01). Inhibition was evident for up to 5 days with the NFC, but for only 1 day (if at all) with the SHC (P < 0.01). These data document that, for most genera which traditionally have been susceptible to nitrofuran derivatives, the NFC remains active against contemporary MDR isolates. They also demonstrate that the in vitro antibacterial activity of the NFC is markedly superior to that of the SHC in several respects. Thus, the NFC shows promise for clinical use in the current era of MDR bacteria.