Aliment Pharmacol Ther 2011; 34: 335–343
Summary
Background Treatment failure occurs in 20% of autoimmune hepatitis patients on prednisolone and azathioprine (AZA). There is no established second ...line treatment.
Aim To assess the efficacy of mycophenolate mofetil as second line treatment after AZA‐intolerance or AZA‐nonresponse in autoimmune hepatitis and overlap syndromes.
Methods Consecutive patients from the Dutch Autoimmune Hepatitis Group cohort, consisting of 661 patients, with autoimmune hepatitis or overlap syndromes, AZA‐intolerance or AZA‐nonresponse and past or present use of mycophenolate mofetil were included. Primary endpoint of mycophenolate mofetil treatment was biochemical remission. Secondary endpoints were biochemical response (without remission), treatment failure and prevention of disease progression.
Results Forty‐five patients treated with mycophenolate mofetil were included. In autoimmune hepatitis remission or response was achieved in 13% and 27% in the AZA‐nonresponse group compared to 67% and 0% in the AZA‐intolerance group (P = 0.008). In overlap‐syndromes remission or response was reached in 57% and 14% in the AZA‐nonresponse group and 63% and 25% of the AZA‐intolerance group (N.S.); 33% had side effects and 13% discontinued mycophenolate mofetil. Overall 38% had treatment failure; this was 60% in the autoimmune hepatitis AZA‐nonresponse group. Decompensated liver cirrhosis, liver transplantations and death were only seen in the autoimmune hepatitis AZA‐nonresponse group (P < 0.001).
Conclusions Mycophenolate mofetil induced response or remission in a majority of patients with autoimmune hepatitis and azathioprine‐intolerance and with overlap syndromes, irrespective of intolerance or nonresponse for azathioprine. In autoimmune hepatitis with azathioprine nonresponse mycophenolate mofetil is less often effective.
Antidepressant use has been associated with increased fall risk. Antidepressant-related adverse drug reactions (e.g. orthostatic hypotension) depend partly on genetic variation. We hypothesized that ...candidate genetic polymorphisms are associated with fall risk in older antidepressant users.
The association between antidepressant use and falls was cross-sectionally investigated in a cohort of Dutch older adults by logistic regression analyses. In case of significant interaction product term of antidepressant use and candidate polymorphism, the association between the variant genotype and fall risk was assessed within antidepressant users and the association between antidepressant use and fall risk was investigated stratified per genotype. Secondly, a look-up of the candidate genes was performed in an existing genome-wide association study on drug-related falls in antidepressant users within the UK Biobank. In antidepressant users, genetic associations for our candidate polymorphisms for fall history were investigated.
In antidepressant users(n = 566), for rs28371725 (CYP2D6*41) fall risk was decreased in TC/variant allele carriers compared to CC/non-variant allele carriers (OR = 0.45, 95% CI 0.26-0.80). Concerning rs1057910 (CYP2C9*3), fall risk was increased in CA/variant allele carriers compared to AA/non-variant allele carriers (OR = 1.95, 95% CI 1.17-3.27). Regarding, rs1045642 (ABCB1), fall risk was increased in AG/variant allele carriers compared to GG/non-variant allele carriers (OR = 1.69, 95% CI 1.07-2.69). Concerning the ABCB1-haplotype (rs1045642/rs1128503), fall risk was increased in AA-AA/variant allele carriers compared to GG-GG/non-variant allele carriers (OR = 1.86, 95% CI 1.05-3.29). In the UK Biobank, in antidepressant users(n = 34,000) T/variant-allele of rs28371725 (CYP2D*41) was associated with increased fall risk (OR = 1.06, 95% CI 1.01-1.12). G/non-variant-allele of rs4244285 (CY2C19*2) was associated with decreased risk (OR = 0.96, 95% CI 0.92-1.00).
This is the first study showing that certain genetic variants modify antidepressant-related fall risk. The results were not always consistent across the studies and should be validated in a study with a prospective design. However, pharmacogenetics might have value in antidepressant (de)prescribing in falls prevention.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Laparoscopic total mesorectal excision (TME) surgery for rectal cancer has important technical limitations. Robot-assisted and transanal TME (TaTME) may overcome these limitations, potentially ...leading to lower conversion rates and reduced morbidity. However, comparative data between the three approaches are lacking. The aim of this study was to compare short-term outcomes for laparoscopic TME, robot-assisted TME and TaTME in expert centres.
Patients undergoing rectal cancer surgery between 2015 and 2017 in expert centres for laparoscopic, robot-assisted or TaTME were included. Outcomes for TME surgery performed by the specialized technique in the expert centres were compared after propensity score matching. The primary outcome was conversion rate. Secondary outcomes were morbidity and pathological outcomes.
A total of 1078 patients were included. In rectal cancer surgery in general, the overall rate of primary anastomosis was 39.4, 61.9 and 61.9 per cent in laparoscopic, robot-assisted and TaTME centres respectively (P < 0.001). For specialized techniques in expert centres excluding abdominoperineal resection (APR), the rate of primary anastomosis was 66.7 per cent in laparoscopic, 89.8 per cent in robot-assisted and 84.3 per cent in TaTME (P < 0.001). Conversion rates were 3.7 , 4.6 and 1.9 per cent in laparoscopic, robot-assisted and TaTME respectively (P = 0.134). The number of incomplete specimens, circumferential resection margin involvement rate and morbidity rates did not differ.
In the minimally invasive treatment of rectal cancer more primary anastomoses are created in robotic and TaTME expert centres.
•We developed a PBK model for occupational diisocyanate exposure.•Sensitivity analysis quantified the impact of factors on modelled urinary levels.•This PBK model helps define relevant factors for ...interpreting biomonitoring data.•Sampling time relative to task and frequency of urination are important.
Diisocyanates are highly reactive substances and known causes of occupational asthma. Exposure occurs mainly in the occupational setting and can be assessed through biomonitoring which accounts for inhalation and dermal exposure and potential effects of protective equipment. However the interpretation of biomonitoring data can be challenging for chemicals with complex kinetic behavior and multiple exposure routes, as is the case for diisocyanates. To better understand the relation between external exposure and urinary concentrations of metabolites of diisocyanates, we developed a physiologically based kinetic (PBK) model for methylene bisphenyl isocyanate (MDI) and toluene di-isocyanate (TDI). The PBK model covers both inhalation and dermal exposure, and can be used to estimate biomarker levels after either single or chronic exposures. Key parameters such as absorption and elimination rates of diisocyanates were based on results from human controlled exposure studies. A global sensitivity analysis was performed on model predictions after assigning distributions reflecting a mixture of parameter uncertainty and population variability.
Although model-based predictions of urinary concentrations of the degradation products of MDI and TDI for longer-term exposure scenarios compared relatively well to empirical results for a limited set of biomonitoring studies in the peer-reviewed literature, validation of model predictions was difficult because of the many uncertainties regarding the precise exposure scenarios that were used. Sensitivity analyses indicated that parameters with a relatively large impact on model estimates included the fraction of diisocyanates absorbed and the binding rate of diisocyanates to albumin relative to other macro molecules.We additionally investigated the effects of timing of exposure and intermittent urination, and found that both had a considerable impact on estimated urinary biomarker levels. This suggests that these factors should be taken into account when interpreting biomonitoring data and included in the standard reporting of isocyanate biomonitoring studies.
Background Mesenchymal stem cell treatment (MST) has emerged as a new therapeutic strategy for Crohn's perianal fistulas. It has been demonstrated that a fibrotic tract on MRI with a MAGNIFI-CD score ...less than or equal to 6 is the best predictor for long-term clinical closure. Therefore, the aim of the current study was to analyse the effectiveness of MST for complex Crohn's perianal fistulas based on MRI. Methods Consecutive patients with complex Crohn's perianal fistulas, previously failing both anti-TNF treatment and surgical closure, who had surgical closure of the internal opening with MST were included. The primary endpoint was radiological remission of the fistula(s) defined as a MAGNIFI-CD less than or equal to 6 on MRI, read by an experienced radiologist. Results Between December 2019 and March 2023, 30 patients (15 males) with 48 fistula tracts were included with a median follow-up of 16.5 months. Radiological remission was achieved in thirteen patients (43.3%) after a median follow-up of 5.0 months (IQR 3.0-6.0). The median MAGNIFI-CD at baseline was 15.0 (IQR 7.0-20.0) which significantly decreased to 8.0 (IQR 3.0-15.0) after treatment (p = 0.001). Clinical closure was achieved in 21 patients (70.0%). Three patients (14.3%) developed a recurrence during long-term FU, all with clinically closed fistula(s), but no radiological remission. The median PDAI decreased significantly from 10.5 (IQR 7.0-14.0) to 4.0 (IQR 0.0-7.3) (p = 0.001). Conclusion MST is a promising treatment strategy for therapy refractory Crohn's perianal fistulas, resulting in > 40% radiological remission, clinical closure in 70% and a significant improvement in quality of life. No recurrences were seen in patients with radiological remission. Keywords: Perianal fistulas, Crohn's disease, Mesenchymal stem cells
The COVID-19 pandemic has created ethical challenges for intensive care unit (ICU) professionals, potentially causing moral distress. This study explored the levels and causes of moral distress and ...the ethical climate in Dutch ICUs during COVID-19. An extended version of the Measurement of Moral Distress for Healthcare Professionals (MMD-HP) and Ethical Decision Making Climate Questionnaire (EDMCQ) were online distributed among all 84 ICUs. Moral distress scores in nurses and intensivists were compared with the historical control group one year before COVID-19. Three hundred forty-five nurses (70.7%), 40 intensivists (8.2%), and 103 supporting staff (21.1%) completed the survey. Moral distress levels were higher for nurses than supporting staff. Moral distress levels in intensivists did not differ significantly from those of nurses and supporting staff. "Inadequate emotional support for patients and their families" was the highest-ranked cause of moral distress for all groups of professionals. Of all factors, all professions rated the ethical climate most positively regarding the culture of mutual respect, ethical awareness and support. "Culture of not avoiding end-of-life-decisions" and "Self-reflective and empowering leadership" received the lowest mean scores. Moral distress scores during COVID-19 were significantly lower for ICU nurses (p < 0.001) and intensivists (p < 0.05) compared to one year prior. Levels and causes of moral distress vary between ICU professionals and differ from the historical control group. Targeted interventions that address moral distress during a crisis are desirable to improve the mental health and retention of ICU professionals and the quality of patient care.
The fatigue life of an asphalt mix is defined as the number of load repetitions at which the crack initiation phase ends and macro cracks start to grow (crack propagation/failure phase). The problem ...is how to determine in an objective way this number of repetitions. Three different definitions for the fatigue life were applied and compared to each other using three different Polish asphalt mixes. Twelve beams of SBS-modified asphalt mix (mix A), 12 beams of the HiMA mix (mix B) and 14 beams of an ordinary Polish asphalt mix (mix C) were tested in a four-point bending (4PB) device in controlled deflection (strain) mode at 10 Hz and 10°C. During fatigue development, three different phases typically may be indicated (plus so-called transition zone). Based on the locations of the fatigue life (obtained on the basis of three different definitions) with respect to the characteristic fatigue phases a proposal for a new fatigue life definition was made. The location of this fatigue life definition will always fall in the transition zone between the fatigue initiation phase and the failure phase. The main advantage of this definition is that it can be used in automatic processing of fatigue data.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Carrying building materials into remote cold regions makes construction in these regions difficult and rather expensive. The need for such materials can be reduced by the use of both ice and ice-soil ...composites. In cold regions ice is abundant and cheap. However, using ice as a building material has some limitations. It is a relatively weak material and shows an extreme creep behavior compared to conventional building materials; mechanical properties are strongly temperature dependent and melt protection is necessary even in the coldest areas. The behavior of ice can be improved by reinforcement. Ice composites have been applied successfully in engineering structures. In this paper the classification of various methods of ice (-soil) reinforcement is presented. Despite the fact that there are many studies on ice reinforcement, ice composites have a very limited application. At present there are only three types of reinforced ice structures: (i) ice roads reinforced by geomaterials, (ii) watertight elements in the dam of Irelyakh hydro system in Siberia and (iii) ice structures on an inflatable mold constructed in the winters of 2014 and 2015 in Finland. Currently ice reinforcement methods are not widely used in construction. The aim of this paper is to carry out research to further introduce ice reinforcement into the practice of construction when feasible. The authors show that there is a need to stimulate the development of a building method for ice composites.
•The behavior of ice as a building material can be improved by reinforcement.•The classification of various methods of ice (-soil) reinforcement is presented.•At present there are 3 types of reinforced ice structures made from ice composites.•Reinforced ice structures: ice roads and ice-soil watertight elements are described.•Wood-fiber-reinforced ice structures on inflatable molds are described.
The paper deals with the processing of the data of the four point bending tests carried out for determination of material properties. The tests are interpreted throughout the Bernoulli's beam theory ...with neglecting dynamical influences at the start of the test. Presented interpretation is done mainly for problems dealing with determination of visco-elastic, thixotropy and fatigue properties of road bituminous materials.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Key summary points
Aim
To summarize the existing knowledge on fall risk associated with antidepressant use in older adults, including the underlying pathophysiology, and assist clinicians in (de-) ...prescribing antidepressants.
Findings
Untreated depression and antidepressant use both increase fall risk in older people. Antidepressants differ in fall-related side effect profile. They contribute to (or cause) falling through orthostatic hypotension, sedation/impaired attention, hyponatremia, movement disorders and cardiac toxicity. Although withdrawal of antidepressants is recommended in fall-prone elderly persons, physicians are frequently reluctant to deprescribe antidepressants. Practical resources and algorithms are available that guide and assist clinicians in deprescribing antidepressants.
Message
Insight in fall-related side effect profile of antidepressants, and clinical decision tools such as the STOPPFalls antidepressant withdrawal algorithm assist prescribers in rational (de-) prescribing decision making.
Purpose
The aim of this clinical review was to summarize the existing knowledge on fall risk associated with antidepressant use in older adults, describe underlying mechanisms, and assist clinicians in decision-making with regard to (de-) prescribing antidepressants in older persons.
Methodology
We comprehensively examined the literature based on a literature search in Pubmed and Google Scholar, and identified additional relevant articles from reference lists, with an emphasis on the most commonly prescribed drugs in depression in geriatric patients. We discuss use of antidepressants, potential fall-related side effects, and deprescribing of antidepressants in older persons.
Results
Untreated depression and antidepressant use both contribute to fall risk. Antidepressants are equally effective, but differ in fall-related side effect profile. They contribute to (or cause) falling through orthostatic hypotension, sedation/impaired attention, hyponatremia, movement disorder and cardiac toxicity. Falling is an important driver of morbidity and mortality and, therefore, requires prevention. If clinical condition allows, withdrawal of antidepressants is recommended in fall-prone elderly persons. An important barrier is reluctance of prescribers to deprescribe antidepressants resulting from fear of withdrawal symptoms or disease relapse/recurrence, and the level of complexity of deprescribing antidepressants in older persons with multiple comorbidities and medications. Practical resources and algorithms are available that guide and assist clinicians in deprescribing antidepressants.
Conclusions
(De-) prescribing antidepressants in fall-prone older adults is often challenging, but detailed insight in fall-related side effect profile of the different antidepressants and a recently developed expert-based decision aid STOPPFalls assists prescribers in clinical decision-making.
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