Interventions for preventing and reducing the use of physical restraints for older people in all long-term care settings.

BACKGROUND: Physical restraints (PR), such as bedrails and belts in chairs or beds, are commonly used for older people receiving long-term care, despite clear evidence for the lack of effectiveness and safety, and widespread recommendations that their use should be avoided. This systematic review of the efficacy and safety of interventions to prevent and reduce the use of physical restraints outside hospital settings, i.e. in care homes and the community, updates our previous review published in 2011. OBJECTIVES: To evaluate the effects of interventions to prevent and reduce the use of physical restraints for older people who require long-term care (either at home or in residential care facilities) SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE (Ovid Sp), Embase (Ovid SP), PsycINFO (Ovid SP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), ClinicalTrials.gov and the World Health Organization's meta-register, the International Clinical Trials Registry Portal, on 3 August 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and controlled clinical trials (CCTs) that investigated the effects of interventions intended to prevent or reduce the use of physical restraints in older people who require long-term care. Studies conducted in residential care institutions or in the community, including patients' homes, were eligible for inclusion. We assigned all included interventions to categories based on their mechanisms and components. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the publications for inclusion, extracted study data, and assessed the risk of bias of all included studies. Primary outcomes were the number or proportion of people with at least one physical restraint, and serious adverse events related to PR use, such as death or serious injuries. We performed meta-analyses if necessary data were available. If meta-analyses were not feasible, we reported results narratively. We used GRADE methods to describe the certainty of the evidence. MAIN RESULTS: We identified six new studies and included 11 studies with 19,003 participants in this review update. All studies were conducted in long-term residential care facilities. Ten studies were RCTs and one study a CCT. All studies included people with dementia. The mean age of the participants was approximately 85 years. Four studies investigated organisational interventions aiming to implement a least-restraint policy; six studies investigated simple educational interventions; and one study tested an intervention that provided staff with information about residents' fall risk. The control groups received usual care only in most studies although, in two studies, additional information materials about physical restraint reduction were provided. We judged the risk of selection bias to be high or unclear in eight studies. Risk of reporting bias was high in one study and unclear in eight studies. The organisational interventions intended to promote a least-restraint policy included a variety of components, such as education of staff, training of 'champions' of low-restraint practice, and components which aimed to facilitate a change in institutional policies and culture of care. We found moderate-certainty evidence that organisational interventions aimed at implementation of a least-restraint policy probably lead to a reduction in the number of residents with at least one use of PR (RR 0.86, 95% CI 0.78 to 0.94; 3849 participants, 4 studies) and a large reduction in the number of residents with at least one use of a belt for restraint (RR 0.54, 95% CI 0.40 to 0.73; 2711 participants, 3 studies). No adverse events occurred in the one study which reported this outcome. There was evidence from one study that organisational interventions probably reduce the duration of physical restraint use. We found that the interventions may have little or no effect on the number of falls or fall-related injuries (low-certainty evidence) and probably have little or no effect on the number of prescribed psychotropic medications (moderate-certainty evidence). One study found that organisational interventions result in little or no difference in quality of life (high-certainty evidence) and another study found that they may make little or no difference to agitation (low-certainty evidence). The simple educational interventions were intended to increase knowledge and change staff attitudes towards PR. As well as providing education, some interventions included further components to support change, such as ward-based guidance. We found pronounced between-group baseline imbalances in PR prevalence in some of the studies, which might have occurred because of the small number of clusters in the intervention and control groups. One study did not assess bedrails, which is the most commonly used method of restraint in nursing homes. Regarding the number of residents with at least one restraint, the results were inconsistent. We found very-low certainty evidence and we are uncertain about the effects of simple educational interventions on the number of residents with PR. None of the studies assessed or reported any serious adverse events. We found moderate-certainty evidence that simple educational interventions probably result in little or no difference in restraint intensity and may have little or no effect on falls, fall-related injuries, or agitation (low-certainty evidence each). Based on very low-certainty evidence we are uncertain about the effects of simple educational interventions on the number of participants with a prescription of at least one psychotropic medication. One study investigated an intervention that provided information about residents' fall risk to the nursing staff. We found low-certainty evidence that providing information about residents' fall risk may result in little or no difference in the mean number of PR or the number of falls. The study did not assess overall adverse events. AUTHORS' CONCLUSIONS: Organisational interventions aimed to implement a least-restraint policy probably reduce the number of residents with at least one PR and probably largely reduce the number of residents with at least one belt. We are uncertain whether simple educational interventions reduce the use of physical restraints, and interventions providing information about residents' fall risk may result in little to no difference in the use of physical restraints. These results apply to long-term care institutions; we found no studies from community settings.

Psychosocial interventions for reducing antipsychotic medication in care home residents.

BACKGROUND: Antipsychotic medications are regularly prescribed in care home residents for the management of behavioural and psychological symptoms of dementia (BPSD) despite questionable efficacy, important adverse effects, and available non-pharmacological interventions. Prescription rates are related to organisational factors, staff training and job satisfaction, patient characteristics, and specific interventions. Psychosocial intervention programmes aimed at reducing the prescription of antipsychotic drugs are available. These programmes may target care home residents (e.g. improving communication and interpersonal relationships) or target staff (e.g. by providing skills for caring for people with BPSD). Therefore, this review aimed to assess the effectiveness of these interventions, updating our earlier review published in 2012. OBJECTIVES: To evaluate the benefits and harms of psychosocial interventions to reduce antipsychotic medication use in care home residents compared to regular care, optimised regular care, or a different psychosocial intervention. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 14 July 2022. SELECTION CRITERIA: We included individual or cluster-randomised controlled trials comparing a psychosocial intervention aimed primarily at reducing the use of antipsychotic medication with regular care, optimised regular care, or a different psychosocial intervention. Psychosocial interventions were defined as non-pharmacological intervention with psychosocial components. We excluded medication withdrawal or substitution interventions, interventions without direct interpersonal contact and communication, and interventions solely addressing policy changes or structural interventions. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Critical appraisal of studies addressed risks of selection, performance, attrition and detection bias, as well as criteria related to cluster randomisation. We retrieved data on the complex interventions on the basis of the TIDieR (Template for Intervention Description and Replication) checklist. Our primary outcomes were 1. use of regularly prescribed antipsychotic medication and 2. ADVERSE EVENTS: Our secondary outcomes were 3. mortality; 4. BPSD; 5. quality of life; 6. prescribing of regularly psychotropic medication; 7. regimen of regularly prescribed antipsychotic medication; 8. antipsychotic medication administered 'as needed'; 9. physical restraints; 10. cognitive status; 11. depression; 12. activities of daily living; and 13. COSTS: We used GRADE to assess certainty of evidence. MAIN RESULTS: We included five cluster-randomised controlled studies (120 clusters, 8342 participants). We found pronounced clinical heterogeneity and therefore decided to present study results narratively. All studies investigated complex interventions comprising, among other components, educational approaches. Because of the heterogeneity of the results, including the direction of effects, we are uncertain about the effects of psychosocial interventions on the prescription of antipsychotic medication. One study investigating an educational intervention for care home staff assessed the use of antipsychotic medication in days of use per 100 resident-days, and found this to be lower in the intervention group (mean difference 6.30 days, 95% confidence interval (CI) 6.05 to 6.66; 1152 participants). The other four studies reported the proportion of participants with a regular antipsychotic prescription. Of two studies implementing an intervention to promote person-centred care, one found a difference in favour of the intervention group (between-group difference 19.1%, 95% CI 0.5% to 37.7%; 338 participants), while the other found a difference in favour of the control group (between-group difference 11.4%, 95% CI 0.9% to 21.9%; 862 participants). One study investigating an educational programme described as "academic detailing" found no difference between groups (odds ratio 1.06, 95% CI 0.93 to 1.20; 5363 participants). The fifth study used a factorial design to compare different combinations of interventions to supplement person-centred care. Results showed a positive effect of medication review, and no clear effect of social interaction or exercise. We considered that, overall, the evidence about this outcome was of low certainty. We found high-certainty evidence that psychosocial interventions intended primarily to reduce antipsychotic use resulted in little to no difference in the number of falls, non-elective hospitalisations, or unplanned emergency department visits. Psychosocial interventions intended primarily to reduce antipsychotic use also resulted in little to no difference in quality of life (moderate-certainty evidence), and BPSD, regular prescribing of psychotropic medication, use of physical restraints, depression, or activities of daily living (all low-certainty evidence). We also found low-certainty evidence that, in the context of these interventions, social interaction and medication review may reduce mortality, but exercise does not. AUTHORS' CONCLUSIONS: All included interventions were complex and the components of the interventions differed considerably between studies. Interventions and intervention components were mostly not described in sufficient detail. Two studies found evidence that the complex psychosocial interventions may reduce antipsychotic medication use. In addition, one study showed that medication review might have some impact on antipsychotic prescribing rates. There were no important adverse events. Overall, the available evidence does not allow for clear generalisable recommendations.

Informed decision-making with and for people with dementia - efficacy of the PRODECIDE education program for legal representatives: protocol of a randomized controlled trial (PRODECIDE-RCT).

BACKGROUND: In Germany, the guardianship system provides adults who are no longer able to handle their own affairs a court-appointed legal representative, for support without restriction of legal capacity. Although these representatives only rarely are qualified in healthcare, they nevertheless play decisive roles in the decision-making processes for people with dementia. Previously, we developed an education program (PRODECIDE) to address this shortcoming and tested it for feasibility. Typical, autonomy-restricting decisions in the care of people with dementia-namely, using percutaneous endoscopic gastrostomy (PEG) or physical restrains (PR), or the prescription of antipsychotic drugs (AP)-were the subject areas trained. The training course aims to enhance the competency of legal representatives in informed decision-making. In this study, we will evaluate the efficacy of the PRODECIDE education program. METHODS: A randomized controlled trial with a six-month follow-up will be conducted to compare the PRODECIDE education program with standard care, enrolling legal representatives (N = 216). The education program lasts 10 h and comprises four modules: A, decision-making processes and methods; and B, C and D, evidence-based knowledge about PEG, PR and AP, respectively. The primary outcome measure is knowledge, which is operationalized as the understanding of decision-making processes in healthcare affairs and in setting realistic expectations about benefits and harms of PEG, PR and AP in people with dementia. Secondary outcomes are sufficient and sustainable knowledge and percentage of persons concerned affected by PEG, FEM or AP. A qualitative process evaluation will be performed. Additionally, to support implementation, a concept for translating the educational contents into e-learning modules will be developed. DISCUSSION: The study results will show whether the efficacy of the education program could justify its implementation into the regular training curricula for legal representatives. Additionally, it will determine whether an e-learning course provides a valuable backup or even alternative learning strategy. TRIAL REGISTRATION: TRN: ISRCTN17960111 , Date: 01/06/2017.

Informed Decision-Making with and for People with Dementia-Efficacy of the PRODECIDE Education Program for Legal Representatives: A Randomized Controlled Trial (PRODECIDE-RCT) and Process Evaluation.

Legal representatives take a major role in healthcare decisions with and for people with dementia, but only a minority has a qualification in this field. The aim was to evaluate the efficacy of the PRODECIDE education program for legal representatives. In a prospective randomized controlled trial, legal representatives (volunteers and professionals, representing at least one person with dementia) were allocated (1:1 computer-generated block randomization) to the intervention (PRODECIDE education program) and control (standard care) groups. The primary outcome measure was knowledge, operationalized as the understanding of decision-making processes and in setting realistic expectations. Only data entry and analyses were blinded. A process evaluation in a mixed methods design was performed. We enrolled 218 legal representatives, and 216 were included in the primary analysis (intervention n = 109, control n = 107). The percentage of correct answers in the knowledge test post intervention was 69.0% in the intervention and 43.4% in the control group (difference 25.6%; CI 95%, 21.3 to 29.8; p < 0.001). In the comparison of professional and voluntary representatives, professionals had 13.6% (CI 95%, 8.0 to 19.2; p < 0.001) more correct answers. The PRODECIDE education program can improve the knowledge of legal representatives, an important prerequisite for evidence-based, informed decision-making.

Psychosocial interventions for reducing antipsychotic medication in care home residents.

BACKGROUND: Antipsychotic medication is regularly prescribed in care homes to control 'behavioural and psychological symptoms of dementia' despite moderate efficacy, significant adverse effects, and available non-pharmacological alternatives. OBJECTIVES: To evaluate the effectiveness of psychosocial interventions to reduce antipsychotic medication in care home residents. SEARCH METHODS: The Cochrane Dementia and Cognitive Improvement Group's Specialized Register, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, a number of trial registers and grey literature sources were searched on 19th December 2011. SELECTION CRITERIA: Individual or cluster-randomised controlled trials comparing a psychosocial intervention aimed at reducing antipsychotic medication with usual care in care home residents or comparing two different approaches. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the retrieved articles for relevance and methodological quality and extracted data. Critical appraisal of studies addressed risk of bias through selection bias, performance bias, attrition bias, and detection bias, as well as criteria related to cluster design. Authors of relevant studies were contacted for additional information.Owing to clinical heterogeneity of interventions, statistical heterogeneity was not assessed and no meta-analysis performed. Study results are presented in a narrative form. MAIN RESULTS: Four cluster-randomised controlled studies met the inclusion criteria. All of them investigated complex interventions comprising educational approaches. Three studies offered education and training for nursing staff, one study offered multidisciplinary team meetings as main component of the intervention. There was one high-quality study, but overall the methodological quality of studies was moderate. The studies revealed consistent results for the primary end point. All studies documented a decrease of the proportion of residents with antipsychotic drug use or a reduction in days with antipsychotic use per 100 days per resident, respectively. In summary, the reviewed evidence on psychosocial interventions targeting professionals is consistent with a reduction of antipsychotic medication prescription in care home residents. However, owing to heterogeneous approaches, summary effect sizes cannot be determined. AUTHORS' CONCLUSIONS: There is evidence to support the effectiveness of psychosocial interventions for reducing antipsychotic medication in care home residents. However, the review was based on a small number of heterogeneous studies with important methodological shortcomings. The most recent and methodologically most rigorous study showed the most pronounced effect.

Interventions for preventing and reducing the use of physical restraints in long-term geriatric care - a Cochrane review.

AIMS AND OBJECTIVES: To evaluate the effectiveness of interventions to prevent and reduce the use of physical restraints in older people requiring long-term nursing care. BACKGROUND: Physical restraints are commonly used in geriatric long-term care. However, they are associated with adverse outcomes. Therefore, freedom from physical restraints should be the aim of high-quality nursing care. DESIGN: Systematic review of randomised controlled trials. METHODS: This review followed the methods of the Cochrane Handbook of systematic reviews of interventions. The systematic search (September 2009) covered the Cochrane Dementia and Cognitive Improvement Group's Specialized Register, MEDLINE, EMBASE, CINAHL, PsycINFO and LILACS. RESULTS: Six cluster-randomised controlled trials met the inclusion criteria. All studies investigated educational approaches targeting nursing staff. In addition, two studies offered consultation, two guidance and one support and free access to technical aids. Five studies examined nursing home residents and one study residents in group dwelling units. No studies in community settings were included. Overall, the methodological quality of studies was low. Their results were inconsistent. One study with good methodological quality in the nursing home setting documented an increase in physical restraints use in both groups, while the other four studies with lower quality found reduced use of physical restraints in the intervention group. The single study in group dwelling units found no change in physical restraints use in the intervention group but a significant increase in the control group. CONCLUSIONS: There is insufficient evidence supporting the effectiveness of educational interventions targeting nursing staff for preventing or reducing the use of physical restraints in geriatric long-term care. Relevance to clinical practice. Our findings indicate that educational programmes targeting nursing staff might not be effective in reducing the use of physical restraints in geriatric long-term care. It remains unclear which components should be included in educational programmes aiming to reduce physical restraints.

Interventions for preventing and reducing the use of physical restraints in long-term geriatric care.

BACKGROUND: Physical restraints (PR) are commonly used in geriatric long-term care. Restraint-free care should be the aim of high quality nursing care. OBJECTIVES: To evaluate the effectiveness of interventions to prevent and reduce the use of physical restraints in older people who require long-term nursing care (either in community nursing care or in residential care facilities). SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement Group's Specialized Register, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, a number of trial registers and grey literature sources were searched on 7 September 2009. The following search terms were used: "physical restraint*", bedrail*, bedchair*, "containment measure*, elderly, "old people", geriatric*, aged, "nursing home*", "care home*", "geriatric care", "residential facilit*". SELECTION CRITERIA: Individual or cluster-randomised controlled trials comparing an intervention aimed at reducing the use of physical restraints with usual care in long-term geriatric care settings. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the retrieved articles for relevance and methodological quality and extracted data. Critical appraisal of studies addressed risk of bias through selection bias, performance bias, attrition bias, and detection bias, as well as critera related to cluster designa. We contacted study authors for additional information where necessary. PR were defined heterogeneously throughout the studies. Not all studies offered sufficient data for aggregated data meta-analysis, and therefore study results are presented in a narrative form. MAIN RESULTS: Five cluster-randomised controlled studies met the inclusion criteria. All of them investigated educational approaches. Two studies offered consultation in addition and two other studies offered guidance for nursing staff in addition. Four studies examined nursing home residents and one study residents in group dwelling units. No studies in community settings were included. Three studies included only one or two nursing homes per study condition. Overall, methodological quality of studies was low.The studies revealed inconsistent results. One study in the nursing home setting documented an increase of PR use in both groups after eight months, while the other three studies found reduced use of PR in the intervention groups after seven and 12 months of follow up respectively. The single study examining residents in group dwelling units found no change in PR use in the intervention group after six months whereas PR use increased significantly in the control group. AUTHORS' CONCLUSIONS: There is insufficient evidence supporting the effectiveness of educational interventions targeting nursing staff for preventing or reducing the use of physical restraints in geriatric long-term care.

Knocking out C9ORF72 Exacerbates Axonal Trafficking Defects Associated with Hexanucleotide Repeat Expansion and Reduces Levels of Heat Shock Proteins.

In amyotrophic lateral sclerosis (ALS) motor neurons (MNs) undergo dying-back, where the distal axon degenerates before the soma. The hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of ALS, but the mechanism of pathogenesis is largely unknown with both gain- and loss-of-function mechanisms being proposed. To better understand C9ORF72-ALS pathogenesis, we generated isogenic induced pluripotent stem cells. MNs with HRE in C9ORF72 showed decreased axonal trafficking compared with gene corrected MNs. However, knocking out C9ORF72 did not recapitulate these changes in MNs from healthy controls, suggesting a gain-of-function mechanism. In contrast, knocking out C9ORF72 in MNs with HRE exacerbated axonal trafficking defects and increased apoptosis as well as decreased levels of HSP70 and HSP40, and inhibition of HSPs exacerbated ALS phenotypes in MNs with HRE. Therefore, we propose that the HRE in C9ORF72 induces ALS pathogenesis via a combination of gain- and loss-of-function mechanisms.

Disaster response to the release of biohazardous agent: instrument development and evaluation of a firefighter's exercise.

INTRODUCTION: The release of biohazardous agents could affect many people. Preparedness is crucial for adequate responses to accidental or deliberate release of biohazardous agents. It is believed that exercises based on simulated incident scenes are effective methods for the training of firefighters and biohazard response teams. Structured evaluations are important methods used to identify areas of ineffectiveness and to assure the quality of responses to releases of biohazards. METHODS: A local fire department conducted a full-scale biohazard exercise in an elementary school. The firefighters practiced prohibiting entry to the area, establishing security zones, evacuating victims, assessing hazards, preventing further dissemination, and sampling and keeping the suspicious material in safe custody. Trained observers systematically evaluated the exercise following a standardized evaluation protocol. A set of data collection templates were created based on standard operating procedures extracted from current guidelines. RESULTS: There were 60 firefighters, eight members of the incident command, 16 simulated victims, and 18 trained observers that participated in the exercise. Out of 31 standard operating procedures, 20 were in accordance with the guidelines, 10 were performed incorrectly, and one was not applicable. Major problems related to the assessment and handling of the suspicious material, the use of protective equipment, and decontamination of victims. Reasons for incomplete and/or conflicting documentation included insufficient knowledge and training of observers, imprecise instructions about documentation, and the size of observation zones. CONCLUSIONS: Intensive education and training of response activities is necessary. Each fire department should perpetually reassess their technical equipment and specific skills and their communication and command structures. The applied documentation system performed well in disclosing discrepancies between observed response activities and current recommendations. Using external observers provided transparent and independent data. However, intensive observer training is necessary. Observer training should include detailed, written instructions and short guidelines that could be available during the exercise.

Mosaic genome-wide maternal isodiploidy: an extreme form of imprinting disorder presenting as prenatal diagnostic challenge.

BACKGROUND: Uniparental disomy of certain chromosomes are associated with a group of well-known genetic syndromes referred to as imprinting disorders. However, the extreme form of uniparental disomy affecting the whole genome is usually not compatible with life, with the exception of very rare cases of patients with mosaic genome-wide uniparental disomy reported in the literature. RESULTS: We here report on a fetus with intrauterine growth retardation and malformations observed on prenatal ultrasound leading to invasive prenatal testing. By cytogenetic (conventional karyotyping), molecular cytogenetic (QF-PCR, FISH, array), and methylation (MS-MLPA) analyses of amniotic fluid, we detected mosaicism for one cell line with genome-wide maternal uniparental disomy and a second diploid cell line of biparental inheritance with trisomy X due to paternal isodisomy X. As expected for this constellation, we observed DNA methylation changes at all imprinted loci investigated. CONCLUSIONS: This report adds new information on phenotypic outcome of mosaic genome-wide maternal uniparental disomy leading to an extreme form of multilocus imprinting disturbance. Moreover, the findings highlight the technical challenges of detecting these rare chromosome disorders prenatally.

Inhibition of human CYP2B6 by N,N',N''-triethylenethiophosphoramide is irreversible and mechanism-based.

The chemotherapeutic agent N,N',N''-triethylenethiophosphoramide (thioTEPA) is frequently used in high-dose chemotherapy regimens including cyclophosphamide. Previous studies demonstrated partial inhibition by thioTEPA of the cytochrome P4502B6 (CYP2B6)-catalyzed 4-hydroxylation of cyclophosphamide, which is required for its bioactivation. The aim of our study was to investigate the detailed mechanism of CYP2B6 inhibition by thioTEPA. Using human liver microsomes and recombinant P450 enzymes we confirmed potent inhibition of CYP2B6 enzyme activity determined with bupropion as substrate. ThioTEPA was found to inhibit CYP2B6 activity in a time- and concentration-dependent manner. The loss of CYP2B6 activity was NADPH-dependent and could not be restored by extensive dialysis. The maximal rates of inactivation (K(inact)) were 0.16 min(-1) in human liver microsomes and 0.17 min(-1) in membrane preparations expressing recombinant CYP2B6. The half-maximal inactivator concentrations (K(I)) were 3.8 microM in human liver microsomes and 2.2 microM in recombinant CYP2B6. Inhibition was attenuated by the presence of alternative active site ligands but not by nucleophilic trapping agents or reactive oxygen scavengers, further supporting mechanism-based action. Inactivated CYP2B6 did not lose its ability to form a CO-reduced complex suggesting a modification of the apoprotein, which is common for sulfur-containing compounds. Pharmacokinetic consequences of irreversible inactivation are more complicated than those of reversible inactivation, because the drug's own metabolism can be affected and drug interactions will not only depend on dose but also on duration and frequency of application. These findings contribute to better understanding of drug interactions with thioTEPA.

Impact of genetic polymorphism in relation to other factors on expression and function of human drug-metabolizing p450s.

A major cause for unpredictable drug response is the enormous variability of drug-metabolizing cytochrome P450s (CYPs) in human liver in which genetic polymorphisms, regulation of gene expression, and physiological factors, including sex, may play a role. To dissect these different factors, we established a large human liver bank with extensive clinical documentation. Recent work concentrated on CYPs 2D6, 2B6, and the 3A family. CYP2D6 expression is highly polymorphic with over 70 alleles. Using liver samples and DNA from phenotyped patients, we further elucidated the genetic basis of phenotypic differences and demonstrated a novel role of alternative splicing, leading to decreased enzyme activity. These studies further emphasize the intricacy of genetic regulation at the CYP2D6 locus. In contrast, CYP2B6, the human orthologue of the rodent phenobarbital-inducible P450 2B, is known to be inducible by a range of substances, but our recent studies also show a high degree of genetic polymorphism. However, the role of polymorphism in determining CYP2B6 expression and function is less decisive as compared with CYP2D6. Thus, with respect to the balance between genetic and nongenetic factors controlling expression, CYP2B6 appears to take an intermediate position. CYP3A4 is the major P450 of human liver and contributes critically to the metabolism of at least half of all drugs. CYP3A4 expression variability is not influenced much by genetic polymorphism. Studies in our liver bank confirm that both induction and down-regulation occur as a consequence of drug treatment. As a further major determinant of hepatic CYP3A4 expression, we found sexual dimorphism, with women expressing at least twice the amount of CYP3A4 protein than men. This surprising result explains the many pharmacokinetic findings of faster metabolism of CYP3A4 drug substrates in women. In conclusion, these data illustrate how various factors contribute to the individual CYP profile in human liver.

Differential expression and function of CYP2C isoforms in human intestine and liver.

This study aimed to characterize the intestinal and hepatic expression and function of CYP2C enzymes in the same set of subjects. CYP2C isoform-specific quantitative reverse transcription-polymerase chain reaction assays, Western immunoblotting and marker reactions of CYP2C8, CYP2C9 and CYP2C19 activities were employed to investigate expression and activity of the CYP2C isoforms in samples of small intestine and liver obtained from 15 patients undergoing gastrectomy or pancreatoduodenectomy. The rank order for CYP2C mRNA expression in the intestine was CYP2C9 = CYP2C18 > CYP2C19 > CYP2C8, whereas that in the liver was CYP2C9 > CYP2C8 > CYP2C18 > CYP2C19. The rank order for expression of CYP2C protein in the intestine was CYP2C9 > CYP2C19 > CYP2C8 (content below limit of quantification) > CYP2C18 (not detected) and that in the liver was CYP2C9 > CYP2C8 > CYP2C19 > CYP2C18 (not detected). The CYP2C9 protein content was approximately 10-fold higher in the liver than in the intestine (P < 0.001). The CLint for the formation of D-703 from verapamil (marker of CYP2C8 activity) was 7.6-fold higher (P < 0.001) and that for the diclofenac 4'-hydroxylation (marker of CYP2C9 activity) was 6.1-fold higher (P < 0.001) in the liver than in the intestine. Apart from a borderline positive correlation (r = 0.58, P = 0.0504) between the intestinal and hepatic CLint for the diclofenac 4'-hydroxylation, no intra-individual relationships between these tissues with respect to expression or activity of different CYP2C isoforms were found. Collectively, these results show that CYP2C8, CYP2C9 and CYP2C19 are expressed as functional enzymes in the human small intestine, and further suggest that CYP2C genes are independently regulated in human intestine and liver. Although, overall, the expression and activity of CYP2C enzymes is lower in the gut than in the liver, the surface area of the proximal small intestine is large and intestinal CYP2C9 and CYP2C19 may well contribute to the first-pass metabolism of their substrate drugs.

[Development of a decision aid on post mortem organ donation - somewhere between evidence uncertainty, fears, and ethical and moral values]. / Entwicklung einer Entscheidungshilfe "Organspende nach dem Tod" - im Spannungsfeld zwischen Evidenz, Ungewissheit, Ängsten und ethisch-moralischen Wertvorstellungen.

The recently revised German transplantation law provides that people are to be supported to make informed decisions on post-mortem organ donation by implementing broad education campaigns. A comprehensive web-based decision aid "organ donation after death" was developed, evaluated and optimised utilising multiple methodological phases. The decision aid comprises 1) factual information in a question-answer format, 2) tools for the individual assessment of this information, and 3) narratives addressing attitudes and emotional aspects. The website content was compiled by participating experts and potential users of the decision aid. Potential users also participated in the usability evaluation. Version 1.0 was made publicly available on the Internet in April 2012. Currently, version 2.0 of the decision aid is being updated step-by-step, based on the results of the evaluation.

Prevalence of psychotropic medication use among German and Austrian nursing home residents: a comparison of 3 cohorts.

BACKGROUND: Despite increasing knowledge about the limited effectiveness and severe adverse effects, the prescription rate of psychotropic medications in frail elderly persons remains high. Prescriptions are mainly made to control behavioral and psychological symptoms of dementia, although factors associated with prescriptions are rarely reported. However, such information is a prerequisite to develop intervention programs aiming to safely reduce psychotropic medication in nursing home residents. METHODS: We report the comparison of cross-sectional data of psychotropic medication prescription rates from 3 large studies including nursing home residents in Germany and Austria. We aimed to compare the prevalence of (1) psychotropic medication, (2) different classes of psychotropic medication, (3) psychotropic medication administered for bedtime use, and (4) associations between prescription of psychotropics and institutional and residents' characteristics. Confidence intervals of prevalences and multiple logistic regression analyses were adjusted for cluster correlation. RESULTS: Data from 5336 residents in 136 long term care facilities were included. In Austria, 74.6% (95% CI 72.0-77.2%) of all residents had a prescription of at least one psychotropic medication compared to Germany with about 51.8% (95% CI 48.3-55.2%) and 52.4% (95% CI 48.7-56.1%). Of all antipsychotics, 66% (Austria) and 47% (Germany) were prescribed for bedtime use. Most prescriptions were conventional, low-potency antipsychotics. In all 3 studies, there was no statistically significant association between psychotropic medication prescription and nursing home characteristics. On the level of residents, consistent positive associations were found for higher level of care dependency and permanent restlessness. Consistent negative associations were found for older age and male gender. CONCLUSION: Frequency of psychotropic and especially antipsychotic medication is substantial in nursing home residents in Germany and Austria. The high number of prescriptions is likely to be an indicator for a perceived or actual lack of strategies to handle behavioral and psychological symptoms of dementia.

Implementation of a patient education program on multiple sclerosis relapse management.

OBJECTIVE: To study the implementation of a patient education program on relapses and relapse therapy into routine care. METHODS: 31 health care professionals took part in a one day train-the-trainer program (TTTP) and subsequently 261 persons with MS (pwMS) took part in the education program. Evaluation was carried out in trainers and pwMS. RESULTS: Participants (health professionals) in the TTTP understood the program's main goals and reported that the TTTP enabled them to successfully perform the program. The majority of participants in the program (pwMS) understood the core messages. Also, they showed increased risk knowledge and increased decision autonomy preferences. Treatment decisions were reported as autonomous or as "informed choice" in 49%, and as "shared decisions" by 45%. Overall, effects were less marked compared to the results of the underlying randomized-controlled trial. CONCLUSION: PwMS! appreciate evidence-based information about relapse management and view the unbiased presentation of scientific uncertainty as a chance for decision autonomy. PRACTICE IMPLICATIONS: The implementation study confirms the program's transferability into clinical practice.

Decision aids for patients.

BACKGROUND: Patients want to be more involved in medical decision-making. To this end, some decision aids are now available. METHODS: We present an overview of this subject, in which we explain the terms "shared decision-making", "decision aid", and "evidence-based patient information" and survey information on the available decision aids in German and other languages on the basis of a literature search in MEDLINE, EMBASE and PsycInfo and a current Cochrane Review. We also searched the Internet for providers of decision aids in Germany. RESULTS: Decision aids exist in the form of brochures, decision tables, videos, and computer programs; they address various topics in the prevention, diagnosis, and treatment of disease. They typically contain information on the advantages and disadvantages of the available options, as well as guidance for personal decision-making. They can be used alone or as a part of structured counseling or patient education. Minimal quality standards include an adequate evidence base, completeness, absence of bias, and intelligibility. Our search revealed 12 randomized controlled trials (RCTs) of decision aids in German and 106 RCTs of decision aids in other languages. These trials studied the outcome of the use of decision aids not just with respect to clinical developments, but also with respect to patient knowledge, adherence to treatment regimens, satisfaction, involvement in decision-making, autonomy preference, and decisional conflicts. CONCLUSION: Only a small fraction of the available decision aids were systematically developed and have been subjected to systematic evaluation. Patients are still not receiving the help in decision-making to which medical ethics entitles them. Structures need to be put in place for the sustainable development, evaluation and implementation of high-quality decision aids.

The morbidity and mortality associated with overweight and obesity in adulthood: a systematic review.

BACKGROUND: Overweight and obesity are generally thought to elevate morbidity and mortality. New data call this supposed association into question. METHODS: The Cochrane, Pubmed, and other databases were systematically searched for a combination of relevant terms and subject headings. Meta-analyses and cohort studies based on the German population were evaluated for possible associations between overweight/ obesity and adult morbidity and mortality. Case-control and cross-sectional studies were excluded. RESULTS: A total of 27 meta-analyses and 15 cohort studies were evaluated. The overall mortality of overweight persons (body mass index [BMI] 25-29.9 kg/m(2)) is no higher than that of persons of normal weight (BMI 18.5-24.9 kg/m(2)), but their mortality from individual diseases is elevated, diminished or unchanged, depending on the particular disease. The overall morbidity is unknown. Both obesity (BMI >30 kg/m(2)) and overweight are associated with increased disease-specific morbidity for some diseases, but decreased or unchanged for others. In general, obesity confers a higher risk than overweight. Morbidity and mortality are markedly influenced by the patient's age, sex, ethnic origin, and social status. The external validity of the comparative predictive performance (c-statistic) of BMI, waist circumference, and ratio of waist to hip circumference cannot be determined from the available analyses. CONCLUSION: The prevailing notion that overweight increases morbidity and mortality, as compared to so-called normal weight, is in need of further specification. Obesity, however, is indeed associated with an elevated risk for most of the diseases studied.

A natural CYP2B6 TATA box polymorphism (-82T--> C) leading to enhanced transcription and relocation of the transcriptional start site.

We investigated the impact of promoter polymorphisms on transcription of the human CYP2B6 gene. In total, 98 DNA samples from white persons from a previously characterized liver bank were sequenced throughout 2.3 kilobases of upstream sequence and haplotype structures were determined using additional coding sequence information. HepG2 cells and primary rat and human hepatocytes were transfected with luciferase reporter gene constructs driven by 2033 base pairs (bp) of the most frequent promoter variants. The novel haplotype *22 (-1848C--> A, -801G--> T, -750T--> C, and -82T--> C) showed 3- to 9-fold enhanced transcriptional activity in all transfected cells. Constructs containing single mutations surprisingly revealed -82T--> C, predicted to disrupt a putative TATA box, to be alone responsible for this effect. In silico analysis and electrophoretic mobility shift assay demonstrated conversion of the putative TATA box into a functional CCAAT/enhancer-binding protein binding site. Analysis of transcriptional start sites showed the mutant promoter to be transcribed from a start site located approximately 30 bp downstream of the wild-type start site, consistent with the use of a noncanonical TATA box at -55 bp. Median CYP2B6 mRNA expression and bupropion hydroxylase activity as a selective marker of CYP2B6 catalytic activity were approximately 2-fold higher in livers genotyped -82TC as in those genotyped -82TT (20.4 versus 9.8 arbitrary units, p = 0.007, and 201.8 versus 106.7 pmol/mg/min, p = 0.042, respectively). This promoter polymorphism thus contributes to CYP2B6 functional variability and represents a novel mechanism by which mutations can enhance transcription. Furthermore, a detailed interspecies comparison of CYP2B promoters and transcriptional start sites provided novel insights into evolutionary relationships.