Development and validation of a theory-based questionnaire examining barriers and facilitators to discontinuing long-term benzodiazepine receptor agonist use.

BACKGROUND: Long-term use of benzodiazepine receptor agonists (BZRAs) is a persistent healthcare challenge and poses patient safety risks. Interventions underpinned by behaviour change theory are needed to support discontinuation of long-term BZRA use. The aim of this study was to develop and validate a questionnaire based on the Theoretical Domains Framework (TDF) to examine mediators of behaviour change relating to the discontinuation of long-term BZRA use. METHODS: An initial 52 item questionnaire was developed using the 14 domains of TDF version 2 and iteratively refined over two rounds. The questionnaire was disseminated online via online support groups that focused on BZRAs to community-based adults with either current or previous experience of taking BZRAs on a long-term basis (≥3 months). Confirmatory factor analysis was undertaken to assess the questionnaire's reliability, discriminant validity and goodness of fit. The Standardized Root Mean Square Residual (SRMR), Root Mean Square Error of Approximation (RMSEA) and Comparative Fit Index (CFI) were calculated. RESULTS: Following an iterative process of adjustment, the results obtained from confirmatory factor analysis resulted in the final questionnaire consisting of 29 items across nine theoretical domains. The internal consistency reliability values across these domains ranged from 0.62 to 0.85. For the final model, the SRMR was 0.23, the RMSEA was 0.11 and the CFI was 0.6. CONCLUSIONS: The questionnaire offers a potential tool that could be used to identify domains that need to be targeted as part of a behaviour change intervention at an individual patient level. Further research is needed to assess the questionnaire's acceptability and usability, and to develop a scoring system so that domains can be prioritised and subsequently targeted as part of an intervention.

Long-term consequences of benzodiazepine-induced neurological dysfunction: A survey.

BACKGROUND: Acute benzodiazepine withdrawal has been described, but literature regarding the benzodiazepine-induced neurological injury that may result in enduring symptoms and life consequences is scant. OBJECTIVE: We conducted an internet survey of current and former benzodiazepine users and asked about their symptoms and adverse life events attributed to benzodiazepine use. METHODS: This is a secondary analysis of the largest survey ever conducted with 1,207 benzodiazepine users from benzodiazepine support groups and health/wellness sites who completed the survey. Respondents included those still taking benzodiazepines (n = 136), tapering (n = 294), or fully discontinued (n = 763). RESULTS: The survey asked about 23 specific symptoms and more than half of the respondents who experienced low energy, distractedness, memory loss, nervousness, anxiety, and other symptoms stated that these symptoms lasted a year or longer. These symptoms were often reported as de novo and distinct from the symptoms for which the benzodiazepines were originally prescribed. A subset of respondents stated that symptoms persisted even after benzodiazepines had been discontinued for a year or more. Adverse life consequences were reported by many respondents as well. LIMITATIONS: This was a self-selected internet survey with no control group. No independent psychiatric diagnoses could be made in participants. CONCLUSIONS: Many prolonged symptoms subsequent to benzodiazepine use and discontinuation (benzodiazepine-induced neurological dysfunction) have been shown in a large survey of benzodiazepine users. Benzodiazepine-induced neurological dysfunction (BIND) has been proposed as a term to describe symptoms and associated adverse life consequences that may emerge during benzodiazepine use, tapering, and continue after benzodiazepine discontinuation. Not all people who take benzodiazepines will develop BIND and risk factors for BIND remain to be elucidated. Further pathogenic and clinical study of BIND is needed.

Enduring neurological sequelae of benzodiazepine use: an Internet survey.

Introduction: Benzodiazepine tapering and cessation has been associated with diverse symptom constellations of varying duration. Although described in the literature decades ago, the mechanistic underpinnings of enduring symptoms that can last months or years have not yet been elucidated. Objective: This secondary analysis of the results from an Internet survey sought to better understand the acute and protracted withdrawal symptoms associated with benzodiazepine use and discontinuation. Methods: An online survey (n = 1207) was used to gather information about benzodiazepine use, including withdrawal syndrome and protracted symptoms. Results: The mean number of withdrawal symptoms reported by a respondent in this survey was 15 out of 23 symptoms. Six percent of respondents reported having all 23 listed symptoms. A cluster of least-frequently reported symptoms (whole-body trembling, hallucinations, seizures) were also the symptoms most frequently reported as lasting only days or weeks, that is, short-duration symptoms. Symptoms of nervousness/anxiety/fear, sleep disturbances, low energy, and difficulty focusing/distractedness were experienced by the majority of respondents (⩾85%) and, along with memory loss, were the symptoms of longest duration. Prolonged symptoms of anxiety and insomnia occurred in many who have discontinued benzodiazepines, including over 50% who were not originally prescribed benzodiazepines for that indication. It remains unclear if these symptoms might be caused by neuroadaptive and/or neurotoxic changes induced by benzodiazepine exposure. In this way, benzodiazepine withdrawal may have acute and long-term symptoms attributable to different underlying mechanisms, which is the case with alcohol withdrawal. Conclusions: These findings tentatively support the notion that symptoms which are acute but transient during benzodiazepine tapering and discontinuation may be distinct in their nature and duration from the enduring symptoms experienced by many benzodiazepine users.

Enteropathogenic Escherichia coli infection triggers host phospholipid metabolism perturbations.

Enteropathogenic Escherichia coli (EPEC) specifically recognizes phosphatidylethanolamine (PE) on the outer leaflet of host epithelial cells. EPEC also induces apoptosis in epithelial cells, which results in increased levels of outer leaflet PE and increased bacterial binding. Consequently, it is of interest to investigate whether EPEC infection perturbs host cell phospholipid metabolism and whether the changes play a role in the apoptotic signaling. Our findings indicate that EPEC infection results in a significant increase in the epithelial cell PE level and a corresponding decrease in the phosphatidylcholine (PC) level. PE synthesis via both the de novo pathway and the serine decarboxylation pathway was enhanced, and de novo synthesis of phosphatidylcholine via CDP-choline was reduced. The changes were transitory, and the maximum change was noted after 4 to 5 h of infection. Addition of exogenous PC or CDP-choline to epithelial cells prior to infection abrogated EPEC-induced apoptosis, suggesting that EPEC infection inhibits the CTP-phosphocholine cytidylyltransferase step in PC synthesis, which is reportedly inhibited during nonmicrobially induced apoptosis. On the other hand, incorporation of exogenous PE by the host cells enhanced EPEC-induced apoptosis and necrosis without increasing bacterial adhesion. This is the first report that pathogen-induced apoptosis is associated with significant changes in PE and PC metabolism, and the results suggest that EPEC adhesion to a host membrane phospholipid plays a role in disruption of host phospholipid metabolism.

Enteropathogenic Escherichia coli virulence factor bundle-forming pilus has a binding specificity for phosphatidylethanolamine.

The bundle-forming pilus (BFP) of enteropathogenic Escherichia coli (EPEC), an established virulence factor encoded on the EPEC adherence factor (EAF) plasmid, has been implicated in the formation of bacterial autoaggregates and in the localized adherence of EPEC to cultured epithelial cells. While understanding of the pathogenic mechanism of this organism is rapidly improving, a receptor ligand for BFP has not yet been identified. We now report, using both solid-phase and liposome binding assays, that BFP expression correlates with phosphatidylethanolamine (PE) binding. In a thin-layer chromatogram overlay assay, specific recognition of PE was documented for BFP-expressing strains, including E2348/69, a wild-type EPEC clinical isolate, as well as a laboratory strain, HB101, transformed with a bfp-carrying plasmid. Strains which did not express BFP did not bind PE, including a bfpA disruptional mutant of E2348/69, EAF plasmid-cured E2348/69, and HB101. E2348/69 also aggregated PE-containing liposomes but not phosphatidylcholine- or phosphatidylserine-containing liposomes, while BFP-negative strains did not produce aggregates with any tested liposomes. Purified BFP preparations bound commercial PE standards as well as a PE-containing band within lipid extracts from human epithelial cells and from E2348/69. Our results therefore indicate a specific interaction between BFP and PE and suggest that PE may serve as a BFP receptor for bacterial autoaggregation and may promote localized adherence to host cells, both of which contribute to bacterial pathogenesis.

A comparison of the effects of verocytotoxin-1 on primary human renal cell cultures.

Infection with verocytotoxin-producing Escherichia coli causes haemolytic uraemic syndrome (HUS). Verocytotoxin-1 (VT1) is cytopathic to renal microvascular endothelial cells in culture, supporting the hypothesis that the vasculopathy of HUS is caused directly by the toxic action of VT1 on cells. We provide evidence that VT1 inhibits protein synthesis in primary cultures of glomerular epithelial cells (GE), cortical tubular epithelial cells (CTE) and mesangial cells (MC). Using 100 pg/ml of VT1 we saw a decrease in protein synthesis to 14.3+/-1.9% in vero cells (a primate cell line), 1.7+/-0.3% in GE, 0.9+/-0.4% in CTE and 74.8+/-1.3% in MC at 24 h. The human renal epithelial cells are at least as sensitive as vero cells to the protein synthesis inhibitory effects of VT1 if not more so. Cell viability decreased in all cultures as measured by MTT reduction, neutral red incorporation and lactate dehydrogenase release and followed the same pattern of susceptibility as for protein synthesis inhibition. However, unlike vero cells, death occurred without DNA fragmentation. Cell sensitivity was greatest in cells which bound more VT1.

The critical care nurse practitioner: an advanced practice role for the critical care nurse.

Research provides compelling evidence that supports the current and future utilization of critical care nurse practitioners (CCNPs) in pivotal roles as providers of cost-effective, quality patient-centered care for critically ill and technology-dependent adults. This paper gives a historical perspective and describes the current national need for CCNPs to practice in expanded roles both within and outside the boundaries of intensive care. An existing CCNP program is described. In addition, guidelines for CCNP program development and role implementation are discussed.

Verapamil in the treatment of maternal paroxysmal supraventricular tachycardia.

Paroxysmal supraventricular tachycardia (PSVT) is seen somewhat frequently in the emergency department but less frequently during pregnancy. Although verapamil is widely used as the drug of choice for PSVT with a narrow QRS complex in a hemodynamically stable patient, the acute IV use of verapamil during pregnancy has not been well studied. Only a limited number of case reports document its safety and efficacy in the treatment of maternal or fetal PSVT. In general, the use of medication during pregnancy requires careful assessment of both the maternal and fetal risks versus benefits and documentation of patient consent. Because it crosses the placenta, one of the major concerns with the acute use of IV verapamil centers around the drug's potential effect on fetal heart rate. The case we present describes the occurrence of PSVT on two separate occasions in a woman in the third trimester of pregnancy. In both episodes, as much as 10 mg IV verapamil was given with resulting successful conversion to normal sinus rhythm. Fetal heart monitoring during drug administration failed to show significant change in fetal heart rate.

The direct lateral approach to the hip for arthroplasty. Advantages and complications.

The direct lateral approach to the hip as described by Hardinge in 1982 was used in the performance of 83 hip arthroplasties. This approach was found to give excellent visualization of the proximal femur and acetabulum and was found to have comparable operative time, blood loss, time to ambulation, and range of motion to other approaches. The postoperative dislocation rate was very low (2.5%) and redislocations have not occurred. The incidence of heterotopic ossification was high (61%) and this may limit the use of this approach in some cases.

Update on external fixators in the treatment of wrist fractures.

Fifty fractures of the distal radius in 49 patients were treated by either a Roger Anderson device or a Hoffman C-series external fixator. The radiographic and clinical results were evaluated for comparison of the use of the two fixators. The follow-up period for the entire group averaged 15.9 months. For 12 patients personally examined and 12 returning a questionnaire, the follow-up period averaged 27.7 months. The Hoffman fixator and Roger Anderson device gave predictably good results in the treatment of comminuted intra-articular fractures of the distal radius when used in the active age group. Neither was found to yield superior functional results over the other, although the Hoffman fixator had a more rigid configuration. Serious complications may result from the use of external fixators, but these can be minimized by proper technique and care.

Lateral humeral condylar fractures in children.

Fifty-three patients with 56 fractures of the lateral humeral condyle were reviewed and the results were assessed to determine the amount of displacement that could be relied on to produce satisfactory results. Closed treatment resulted in satisfactory results if the initial displacement did not exceed 2 mm. This required close follow-up for detection of displacement. Percutaneous pinning of nondisplaced and minimally displaced fractures is an acceptable alternative in any situation in which close scrutiny cannot be ensured. Those fractures with greater than 2 mm of displacement should be reduced, pinned, and immobilized for 6-8 weeks. Evidence of delayed union after 8 weeks is an indication for internal fixation and possibly bone grafting. Established nonunions in good position are best treated by open reduction and bone grafting. In this series, varus deformity was the most common deviation from a normal carrying angle. The functional results were invariably good regardless of the radiographic or clinical findings.

Cost-benefit evaluation of house fly (Diptera:Muscidae) control in caged layer poultry houses.

House fly (Musca domestica L.) control was determined in small-unit, commercial, caged layer poultry houses. Cyromazine was the most cost effective treatment (4 per bird per season) and provided the highest level of control. Larviciding and adulticiding with dimethoate, fenthion and dimethoate, permethrin and dimethoate, and stirofos provided good fly control, and these treatments were moderately cost effective. The use of dichlorvos-stirofos provided only marginal fly control and was not cost effective. Early-season manure removal, combined with more selective insecticide use would provide the caged layer producer with a more effective management strategy for controlling house flies in small-unit operations.

The effect of fragment B of staphylococcal protein A on the binding of rabbit IgG to human granulocytes and monocytes.

The effect of fragment B of staphylococcal protein A on the binding of rabbit IgG to human granulocytes has been examined. When rabbit IgG sensitized sheep erythrocytes (EA) were preincubated with increasing amounts of fragment B, a dose dependent inhibition of rosette formation between the human granulocytes and the treated EA was observed. In contrast, rosette formation between human monocytes and fragment B treated EA was not impaired. These results confirm previous findings which revealed differences in the specificities of the human Fc receptors of these cells. Rabbit IgG was used in place of human IgG for the preparation of the sensitized erythrocytes since human IgG coated human erythrocytes were agglutinated by fragment B, indicating the possibility of a secondary binding site for human IgG in this fragment.

The interaction of the Facb fragment of rabbit anti-sheep red cell IgG with guinea pig macrophages, and human monocytes and granulocytes.

Yasmeen et al. (J. Immun. 110, 1706-1709, 1973) have previously reported on the binding requirements of the guinea pig peritoneal macrophage Fc receptor. The C gamma 3 domain fragments of human IgG1, in contrast to the C gamma 2 domain fragment, were able to bind to these macrophages, as demonstrated by both direct and indirect rosette tests. We now report that we have been unable to show binding by the C gamma 2-bearing rabbit Facb fragment to either peritoneal or alveolar macrophages of the guinea pig. This evidence is therefore in agreement with the hypothesis proposed by Yasmeen et al. (1973) that the C gamma 2 homology region does not contribute directly to the binding requirements for this cell type. The same protein, rabbit anti-sheep erythrocyte Facb, when coated on sheep erythrocytes, did not form rosettes with human granulocytes, but did form some rosettes with human monocytes.

Structure and function of immunoglobulin domains. VIII. An analysis of the structural requirements in human IgG1 for binding to the Fc receptor of human monocytes.

A human mononuclear cell population, enriched with monocytes by adhering them to microexudate on Petri dishes previously used for fibroblast cultures was used in a homologous human system to form EA rosettes. IgG1, Fc, and subfragments of Fc representing the C gamma 2 and C gamma 3 domains were tested for their ability to inhibit rosette formation. Although Fc and IgG were equally effective in inhibiting rosette formation over the concentration range 10(-6) to 10(-5) M, all subfragments were inactive at these concentrations. At 10-fold higher concentrations the C gamma 2 fragment was still inactive; however, both the C gamma 3 fragments, pFc' and at C gamma 3, did show significant activity at this higher level. Reduction and alkylation diminished the inhibitory capacity of IgG 10-fold but had a lesser effect on Fc. In a parallel series of experiments the ability of IgG and Fc to inhibit granulocyte rosettes was found to be markedly diminished by reduction and alkylation in both cases. These experiments reveal differences between Fc receptors in different cells, confirm a role for the C gamma 3 homology region in monocyte Fc receptor recognition, but do suggest a requirement, either direct or indirect, for the C gamma 2 domain.

Structure and function of immunoglobulin domains. VII. Studies on the structural requirements of human immunoglobulin G for granulocyte binding.

The ability of various fragments of human myeloma IgG1 to inhibit rosette formation between human anti-D-coated human red blood cells and human polymorphonuclear leukocytes has been investigated. Although IgG and Fc showed a dose-dependent inhibition of rosettes and Fc showed a dose-dependent inhibition of rosettes at equimolar concentrations, neither of the fragments corresponding to the Cgamma2 and Cgamma3 homology regions obtained by acid-tryptic cleavage of Fc was able to inhibit rosette formation. The pepsin fragment of Fc, pFc', which represents the complete Cgamma3 domain, was also unable to prevent rosette formation. Reduction and alkylation of IgG or Fc markedly diminished cytophilic activity as measured by this system. These data indicate that the site in human IgG1 bound by granulocytes is dependent on the full quaternary structure of Fc, a requirement in marked contrast to that noted for binding by macrophages and monocytes.