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يضم الكتاب ثلاث قصص طويلة مترجمة، واثنتين قصيرتين، منهم الذبابة لـ جورج لانجيلان ترجمة محمد عبد العزيز، ميمنتو لـ جوناثان نولان ترجمة محمد عبد العزيز، جميعكم أيها الموتى الأحياء لـ روبرت هينلاين ترجمة محمد الدواخلي، الحارس لـ آرثر سي كلارك ترجمة نادر أسامة، حيث شكلت الأعمال السابقة مصدر وحي لأعمال سينمائية عديدة، تنوعت بين الخيال العلمي والرعب، ومرفق بكل قصة مقال إنبطاعي عن الفيلم المستوحى منها، ومدى إشتباكه مع النص الأصلي.

Background Policy responses to COVID-19 in Victoria, Australia over 2020–2021 have been supported by evidence generated through mathematical modelling. This study describes the design, key findings, and process for policy translation of a series of modelling studies conducted for the Victorian Department of Health COVID-19 response team during this period. Methods An agent-based model, Covasim, was used to simulate the impact of policy interventions on COVID-19 outbreaks and epidemic waves. The model was continually adapted to enable scenario analysis of settings or policies being considered at the time (e.g. elimination of community transmission versus disease control). Model scenarios were co-designed with government, to fill evidence gaps prior to key decisions. Results Understanding outbreak risk following incursions was critical to eliminating community COVID-19 transmission. Analyses showed risk depended on whether the first detected case was the index case, a primary contact of the index case, or a ‘mystery case’. There were benefits of early lockdown on first case detection and gradual easing of restrictions to minimise resurgence risk from undetected cases. As vaccination coverage increased and the focus shifted to controlling rather than eliminating community transmission, understanding health system demand was critical. Analyses showed that vaccines alone could not protect health systems and need to be complemented with other public health measures. Conclusions Model evidence offered the greatest value when decisions needed to be made pre-emptively, or for questions that could not be answered with empiric data and data analysis alone. Co-designing scenarios with policy-makers ensured relevance and increased policy translation.

Chronic diarrhea caused by primary bile acid diarrhea (PBAD) is a common condition. We have previously shown PBAD is associated with low fasting serum levels of the ileal hormone, fibroblast growth factor 19 (FGF19). FGF19 is a negative regulator of hepatic bile acid synthesis and is stimulated by farnesoid X receptor agonists, which produce symptomatic improvement in PBAD. We aimed to assess possible causes for low serum FGF19 in patients with PBAD. Patients with PBAD, defined by reduced (75)Se-labelled homocholic acid taurine (SeHCAT) retention, and idiopathic diarrhea controls had measurements of fasting lipids and fasting/post-prandial FGF19 serum profiles. Specific functional variants in candidate genes were investigated in exploratory studies. In further groups, basal and bile acid-stimulated transcript expression was determined in ileal biopsies and explant cultures by quantitative PCR. FGF19 profiles in PBAD patients included low fasting and meal-stimulated responses, which were both strongly correlated with SeHCAT. A subgroup of 30% of PBAD patients had fasting hypertriglyceridemia and higher FGF19. No clear significant differences were found for any genetic variant but there were borderline associations with FGFR4 and KLB. SeHCAT retention significantly correlated with the basal ileal transcript expression of FGF19 (rs=0.59, P=0.03) and apical sodium-dependent bile acid transporter (ASBT) (rs=0.49, P=0.04), and also with the degree of stimulation by chenodeoxycholic acid at 6 h for transcripts of FGF19 (median 184-fold, rs=0.50, P=0.02) and ileal bile acid binding protein (IBABP) (median 2.2-fold, rs=0.47, P=0.04). Median stimulation of FGF19 was lower in patients with SeHCAT retention <10% (P=0.01). These studies demonstrate a complex, multifactorial etiology of PBAD, including impairments in ileal FGF19 expression and responsiveness.

BackgroundBeneficial response to first-line immunosuppressive azathioprine in patients with inflammatory bowel disease (IBD) is low due to high rates of adverse events. Co-administrating allopurinol has been shown to improve tolerability. However, data on this co-therapy as first-line treatment are scarce.AimRetrospective comparison of long-term effectiveness and safety of first-line low-dose azathioprine-allopurinol co-therapy (LDAA) with first-line azathioprine monotherapy (AZAm) in patients with IBD without metabolite monitoring.MethodsClinical benefit was defined as ongoing therapy without initiation of steroids, biologics or surgery. Secondary outcomes included CRP, HBI/SCCAI, steroid withdrawal and adverse events.ResultsIn total, 166 LDAA and 118 AZAm patients (median follow-up 25 and 27 months) were evaluated. Clinical benefit was more frequently observed in LDAA patients at 6 months (74% vs. 53%, p = 0.0003), 12 months (54% vs. 37%, p = 0.01) and in the long-term (median 36 months; 37% vs. 24%, p = 0.04). Throughout follow-up, AZAm patients were 60% more likely to fail therapy, due to a higher intolerance rate (45% vs. 26%, p = 0.001). Only 73% of the effective AZA dose was tolerated in AZAm patients, while LDAA could be initiated and maintained at its target dose. Incidence of myelotoxicity and elevated liver enzymes was similar in both cohorts, and both conditions led to LDAA withdrawal in only 2%. Increasing allopurinol from 100 to 200–300 mg/day significantly lowered liver enzymes in 5/6 LDAA patients with hepatotoxicity.ConclusionsOur poor AZAm outcomes emphasize that optimization of azathioprine is needed. We demonstrated a long-term safe and more effective profile of first-line LDAA. This co-therapy may therefore be considered standard first-line immunosuppressive.

Background Thioguanine (TG) is a thiopurine which has been used for patients with inflammatory bowel disease (IBD), who have failed azathioprine (AZA) or mercaptopurine (MP) due to adverse events or suboptimal response. Its widespread use has been hampered due to concerns about nodular regenerative hyperplasia (NRH) of the liver. The aim of this study was to investigate the long-term efficacy and safety of low-dose TG therapy in IBD patients failing AZA and MP. Methods A retrospective multicentre study was performed in IBD patients who failed prior treatment with conventional thiopurines with or without following immunomodulation (thiopurine-allopurinol, biologicals, methotrexate, tacrolimus) and were subsequently treated with TG as rescue monotherapy between 2003 and 2019 at three hospitals in the United Kingdom. Clinical response, adverse events, laboratory results, imaging and liver biopsies were retrospectively collected. Results A total of 193 patients (57% female and 64% Crohn’s disease) were included, with a median daily TG dose of 20 mg (range: 20–40 mg), a median treatment duration of 23 months (IQR 10–47) and a median follow-up of 36 months (IQR 22–53). The clinical response rate at 12 months was 65 and 54% remained on TG until the end of follow-up. Adverse events consisted primarily of elevated liver tests (6%), myelotoxicity (7%) and rash (5%). NRH was histologically diagnosed in two patients and two other patients (1%) developed non-cirrhotic portal hypertension. The median 6-TGN and TPMT levels were 953 pmol/8 × 10 8 RBC (IQR 145–1761) and 47 mu/L (IQR 34.5–96). Conclusions Long-term follow-up suggests that TG can be an effective and well-tolerated therapy in more than half of difficult-to-treat and multi-therapy failing IBD patients. Findings of this study indicate that TG can be used safely and the occurrence of hepatotoxicity was low. The incidence rate of NRH was within the background incidence.

BackgroundBile acid diarrhoea (BAD) is a common cause of chronic diarrhoea with a population prevalence of primary BAD around 1%. Previous studies have identified associations with low levels of the ileal hormone fibroblast growth factor 19 (FGF19), obesity and hypertriglyceridaemia. The aim of this study was to identify further associations of BAD.MethodsA cohort of patients with chronic diarrhoea who underwent 75selenohomocholic acid taurate (SeHCAT) testing for BAD was further analysed retrospectively. Additional clinical details available from the electronic patient record, including imaging, colonoscopy, chemistry and histopathology reports were used to calculate the prevalence of fatty liver disease, gallstones, colonic neoplasia and microscopic colitis, which was compared for BAD, the primary BAD subset and control patients with diarrhoea.FindingsOf 578 patients, 303 (52%) had BAD, defined as a SeHCAT 7d retention value <15%, with 179 (31%) having primary BAD. 425 had an alanine aminotransferase (ALT) recorded, 184 had liver imaging and 176 had both. Overall, SeHCAT values were negatively associated with ALT (rs=−0.19, p<0.0001). Patients with BAD had an OR of 3.1 for an ALT >31 ng/mL with imaging showing fatty liver (p<0.001); similar figures occurred in the primary BAD group. FGF19 was not significantly related to fatty liver but low levels were predictive of ALT >40 IU/L. In 176 subjects with gallbladder imaging, 27% had gallstones, 7% had a prior cholecystectomy and 34% either of these. The median SeHCAT values were lower in those with gallstones (3.8%, p<0.0001), or gallstones/cholecystectomy (7.2%, p<0.001), compared with normal gallbladder imaging (14%). Overall, BAD had an OR of 2.0 for gallstones/cholecystectomy (p<0.05). BAD was not significantly associated with colonic adenoma/carcinoma or with microscopic colitis.InterpretationThe diagnosis of BAD is associated with fatty liver disease and with gallstones. The reasons for these associations require further investigation into potential metabolic causes.

The role of bile acids (BA) extends far beyond lipid digestion and cholesterol metabolism. The transcriptional regulation of multiple genes within the liver and intestine are under their influence. BA exert these effects through binding and activating receptors in much the same way as endocrine hormones. The farnesoid X receptor (FXR) is the intracellular transcription factor for BA; TGR5 is the cell-surface receptor. The main target genes of FXR are those involved in BA and cholesterol metabolism. Yet more recently, FXR has also been shown to influence and promote certain protective pathways within the liver. These pathways are being harnessed by semisynthetic BAs in Phase II and III clinical trials. FXR activation within the intestine is also associated with similar protective pathways. This article examines the consequences of altered FXR activation in the context of BA malabsorption in Crohn's disease and the potential benefits of FXR agonists in Crohn's disease.

Ireland’s health service, the Health Service Executive, provides Mental Health services to the population of Ireland. These services are overseen by the National Mental Health Division. Unlike other parts of the Health Service the Mental Health Division provides services in all settings, for all acuities and all ages. This truly integrated approach is demonstrated in eight abstracts submitted by Irelands Mental Health service. This abstract is a covering abstract which proposes that those submissions which are successful are considered as a body of work – featuring at conference as a Mental Health seminar/stream. This is because each of our abstracts, while addressing a specific topic and theme must be considered as interoperable to appreciate how at national level a whole system national integrated approach operates.The Mental Health abstracts submitted by the Health Service Executive Mental Health Division and partners cover a range of topics which span strategy, clinical care, service user involvement and quality. These include;The development of integrated national quality standards for mental health services (ID 188)Service user and family engagement in integrated service design and delivery (ID 173)An integrated national model of care for eating disorders services in multiple settings (ID 440)Inter-professional education as a building block for collaborative and integrated eating disorder services (ID 443)Assessment and management of self harm in Emergency Departments in Ireland: The National Clinical Programme (ID pending)Developing an integrated approach across government departments for service users with first episode psychosis to achieve employment and educational gaol using an Individual Placement Support model (ID 461)Little Things – making a big difference to promoting positive mental health (ID 492)Advancing Recovery in Ireland – a national initiative aimed at securing the organisational and cultural changes necessary to develop more “Recovery-oriented” services for the population (ID pending)It is proposed that should the above abstracts be accepted by the scientific committee that they would form a body of evidence that in seminar or “Mental Health Stream” format would paint a clear picture of national integration. Integration in this context means integration in a number of senses and the granularity of the meaning of “integration” in the round would be considered (i.e. integration between physical and mental health, between health and other government departments and between components of the health service itself.

IntroductionThe number of IBD patients experiencing a beneficial response from the first-line, low-cost immunosuppressive azathioprine (AZA) is too low due to high rates of adverse events. Co-administration with allopurinol has been reported to improve tolerability and might be an option as first-line therapy.MethodsThe long-term efficacy, side-effects and safety of low-dose azathioprine with allopurinol (LDAA) was compared with AZA monotherapy (AZAm) in thiopurine-naïve IBD patients unguided by metabolite levels. Medical records of patients (identified from pharmacy dispensing records and an IBD database) were reviewed retrospectively. The primary outcome ‘clinical benefit’ was defined as: ongoing use of therapy without initiation of steroids, biologics or IBD-surgery. Secondary outcomes included disease activity scores, endoscopic findings, withdrawal of concomitant therapy (including steroids), CRP and adverse events.Results166 LDAA and 118 AZAm patients (≥ 90% having active disease) were included with a median follow-up of 25 and 27 months, respectively. Clinical benefit was higher in the LDAA cohort at both 6 months (74% vs 53%, p=0.0004) and 12 months (54% vs 37%, p=0.01). The overall median duration of beneficial response since commencement of therapy was 17 months (95%-CI 9 – 25) for LDAA therapy compared to 6 months (95%-CI 1 - 11) for AZAm. The lower efficacy of AZAm was explained by the median dose tolerated of 1.83 mg/kg (73% of most effective dose) and high percentage (45%) of patients discontinuing due to intolerance. Although elevated liver function tests and leukopenia were relatively commonly observed in the LDAA cohort, they only led to treatment withdrawal in 2% for both. Increasing allopurinol dosage from 100 to 200 – 300 mg/day significantly lowered liver enzymes in the majority (83%) of patients who had developed hepatotoxicity on LDAA.ConclusionsOptimisation of AZA therapy for IBD is mandatory as poor outcomes were observed in our AZAm cohort. LDAA without metabolite monitoring should be considered standard first-line immunosuppressive therapy, as we demonstrated a safe and effective profile in the long-term.