The reliability and validity of the Seasonal Pattern Assessment Questionnaire: a comparison between patient groups

Background: The Seasonal Pattern Assessment Questionnaire (SPAQ) is a frequently used screening instrument in the research on Seasonal Affective Disorder (SAD). Nevertheless, studies on its reliability and validity are relatively scarce. In the present study the reliability and the contrast validity of the SPAQ are investigated. Methods: SAD patients, selected by means of a clinical interview, non-seasonal depressed out-patients, non-depressed out-patients, and a control group, are contrasted to estimate the discriminating power of the SPAQ. Also, the reliability and factor structure of the seasonality and the climate subscales are investigated. To study food intake the Seasonal Food Preference Questionnaire (SFPQ) was developed. Results: The SAD criterion of the SPAQ shows good specificity (94%), but a low sensitivity (44%). Discriminant analysis shows sufficient ability to classify subjects (81% correctly classified). The Global Seasonality Scale has a good internal consistency. It consists of two factors, a psychological factor and a food factor. The SFPQ is sensitive for carbohydrate intake by SAD patients. Limitations: Most SAD patients had received treatment and completed the SPAQ while they were not depressed, which may have influenced the sensitivity. Conclusions: The SPAQ is not sensitive enough to be considered a diagnostic instrument for SAD. Nevertheless, it is accurate enough to be used as a screenings instrument. The only false positives were found in the depressive group. The accuracy of prevalence Figs. can be improved by completion of the SPAQ in the summer months, combined with the completion of a depression scale.     

A European consensus statement on the use of four-factor prothrombin complex concentrate for cardiac and non-cardiac surgical patients

Modern four-factor prothrombin complex concentrate was designed originally for rapid targeted replacement of the coagulation factors II, VII, IX and X. Dosing strategies for the approved indication of vitamin K antagonist-related bleeding vary greatly. They include INR and bodyweight-related protocols as well as fixed dose regimens. Particularly in the massively bleeding trauma and cardiac surgery patient, four-factor prothrombin complex concentrate is used increasingly for haemostatic resuscitation. Members of the Transfusion and Haemostasis Subcommittee of the European Association of Cardiothoracic Anaesthesiology performed a systematic literature review on four-factor prothrombin complex concentrate. The available evidence has been summarised for dosing, efficacy, drug safety and monitoring strategies in different scenarios. Whereas there is evidence for the efficacy of four-factor prothrombin concentrate for a variety of bleeding scenarios, convincing safety data are clearly missing. In the massively bleeding patient with coagulopathy, our group recommends the administration of an initial bolus of 25 IU.kg^-1. This applies for: the acute reversal of vitamin K antagonist therapy; haemostatic resuscitation, particularly in trauma; and the reversal of direct oral anticoagulants when no specific antidote is available. In patients with a high risk for thromboembolic complications, e.g. cardiac surgery, the administration of an initial half-dose bolus (12.5 IU.kg^-1) should be considered. A second bolus may be indicated if coagulopathy and microvascular bleeding persists and other reasons for bleeding are largely ruled out. Tissue-factor-activated, factor VII-dependent and heparin insensitive point-of-care tests may be used for peri-operative monitoring and guiding of prothrombin complex concentrate therapy.     

The use of natural interferon alpha conjugated to a monoclonal antibody anti mammary epithelial mucin (Mc5) for the treatment of human breast cancer xenografts

Summary An immunoconjugate composed of natural interferon (nIFN) bound in a noncleavable fashion to a monoclonal antibody (MoAb) recognizing a breast epithelial membrane mucin (Mc5) was used to treat xenografts of a human mammary carcinoma cell line (MCF-7) growing in nude mice. The immunoconjugate (nIFN/Mc5) was administered as 20 intralesional (i.l.) injections to 1 of 2 xenografts in each animal. It was found that nIFN/Mc5 produced a significant enhancement of the growth inhibitory actions of nIFN on the injected tumors. Further enhancement was obtained when nIFN or nIFN together with Mc5 (at a dose 10 times larger than that present in nIFN/Mc5) were added to the immunoconjugate. Biodistribution experiments showed that the uptake of¹²⁵I-nIFN/Mc5 by the tumors was greater and its elimination slower than for¹²⁵I-nIFN alone or conjugated to irrelevant mouse IgG₁. In addition, the immunoconjugate up-regulated the antigenic expression of a breast epithelial membrane mucin by the carcinoma cells, an up-regulation which was not significantly different from that produced by nIFN alone. The contralateral noninjected tumors exposed to systemic levels of the immunoconjugate showed an enhancement of antitumor effects, but to a lesser extent than the injected tumors. These findings suggest that the enhancement of the growth inhibitory action of the immunoconjugate was related to the specific binding of Mc5 which targeted the IFN to the carcinoma cells and impeded its elimination. It is likely that the targeting was favored by the IFN-mediated up-regulation of antigenic expression by the carcinoma cells, thereby producing a cascade of interrelated effects. The results of this study point out the feasibility and potential usefulness of IFN treatment by means of immunoconjugates as well as the worth of pursuing and improving this form of therapy.     

Informed consent, parental awareness, and reasons for participating in a randomised controlled study

BACKGROUND: The informed consent procedure plays a central role in randomised controlled trials but has only been explored in a few studies on children. AIM: To assess the quality of the informed consent process in a paediatric setting. METHODS: A questionnaire was sent to parents who volunteered their child (230 children) for a randomised, double blind, placebo controlled trial of ibuprofen syrup to prevent recurrent febrile seizures. RESULTS: 181 (79%) parents responded. On average, 73% of parents were aware of the major study characteristics. A few had difficulty understanding the information provided. Major factors in parents granting approval were the contribution to clinical science (51%) and benefit to the child (32%). Sociodemographic status did not influence initial participation but west European origin of the father was associated with willingness to participate in future trials. 89% of participants felt positive about the informed consent procedure; however, 25% stated that they felt obliged to participate. Although their reasons for granting approval and their evaluation of the informed consent procedure did not differ, relatively more were hesitant about participating in future. Parents appreciated the investigator being on call 24 hours a day (38%) and the extra medical care and information provided (37%) as advantages of participation. Disadvantages were mainly the time consuming aspects and the work involved (23%). CONCLUSIONS: Parents' understanding of trial characteristics might be improved by designing less difficult informed consent forms and by the investigator giving extra attention and information to non-west European parents. Adequate measures should be taken to avoid parents feeling obliged to participate, rather than giving true informed consent.     

Rearrangement of the T cell receptor gamma-chain gene in childhood acute lymphoblastic leukemia

We analyzed rearrangements of the T cell receptor gamma-chain (T gamma) gene as well as rearrangements of the T cell receptor beta-chain (T beta) gene and immunoglobulin heavy-chain (IgH) gene in 68 children with acute lymphoblastic leukemia (ALL). All 15 patients with T cell ALL showed rearrangements of both T beta and T gamma genes. Twenty-four of 53 non-T, non-B ALL patients (45%) showed T gamma gene rearrangements and only 14 of these also showed T beta gene rearrangements. Only a single patient rearranged the T beta gene in the absence of T gamma gene rearrangement. The rearrangement patterns of the T gamma gene in non-T, non-B ALL were quite different from those observed in T cell ALL, as 20 of 23 patients retained at least one germline band of the T gamma gene. In contrast, all T cell ALL patients showed no retention of germline bands. These data indicate that rearrangement of the T gamma gene is not specific for T cell ALL. Further, the results also suggest that T gamma gene rearrangement precedes T beta gene rearrangement. The combined analysis of rearrangement patterns of IgH, T beta, and T gamma genes provides new criteria for defining the cellular origin of leukemic cells and for further delineation of leukemia cell heterogeneity.     

Fc-Fc interactions of human IgG4 require dissociation of heavy chains and are formed predominantly by the intra-chain hinge isomer

Human IgG4 antibodies are remarkable not only because they can dynamically exchange half-molecules (Fab-arm exchange) but also for their ability to interact with the Fc part of IgG4 and other IgG subclasses. This rheumatoid factor-like binding of IgG4 does not appear to take place spontaneously, because it is only observed to solid-phase or antigen-bound IgG. We hypothesized that Fc-Fc interactions might involve (partial) dissociation of heavy chains. We investigated the molecular basis of these Fc-Fc interactions, and found that the structural features important for the exchange reaction also control the Fc binding activity. In particular, if arginine-409 in the CH(3)-CH(3) interface in IgG4 is mutated to lysine (the equivalent in IgG1), Fc-Fc interactions are formed 3 orders of magnitude less efficiently compared to the wild-type. This mutation was previously found to increase the CH(3)-CH(3) interaction strength in IgG4. Furthermore, of the two hinge isomers of IgG4, the intra-chain (non-covalently linked) form was found to form Fc-Fc interactions, but not the inter-chain form. Together, these results demonstrate that Fc-Fc interactions of IgG4 involve (partial or complete) dissociation of heavy chains. The promiscuity to other IgG subclasses suggests that IgG4 might act as scavenger to IgG molecules with impaired structural integrity.     

What Are the Interobserver and Intraobserver Variability of Gap and Stepoff Measurements in Acetabular Fractures?

BackgroundGap and stepoff values in the treatment of acetabular fractures are correlated with clinical outcomes. However, the interobserver and intraobserver variability of gap and stepoff measurements for all imaging modalities in the preoperative, intraoperative, and postoperative phase of treatment is unknown. Recently, a standardized CT-based measurement method was introduced, which provided the opportunity to assess the level of variability.Questions/purposes(1) In patients with acetabular fractures, what is the interobserver variability in the measurement of the fracture gaps and articular stepoffs determined by each observer to be the maximum one in the weightbearing dome, as measured on pre- and postoperative pelvic radiographs, intraoperative fluoroscopy, and pre- and postoperative CT scans? (2) What is the intraobserver variability in these measurements?MethodsSixty patients with a complete subset of pre-, intra- and postoperative high-quality images (CT slices of < 2 mm), representing a variety of fracture types with small and large gaps and/or stepoffs, were included. A total of 196 patients with nonoperative treatment (n = 117), inadequate available imaging (n = 60), skeletal immaturity (n = 16), bilateral fractures (n = 2) or a primary THA (n = 1) were excluded. The maximum gap and stepoff values in the weightbearing dome were digitally measured on pelvic radiographs and CT images by five independent observers. Observers were free to decide which gap and/or stepoff they considered the maximum and then measure these before and after surgery. The observers were two trauma surgeons with more than 5 years of experience in pelvic surgery, two trauma surgeons with less than 5 years of experience in pelvic surgery, and one surgical resident. Additionally, the final intraoperative fluoroscopy images were assessed for the presence of a gap or stepoff in the weightbearing dome. All observers used the same standardized measurement technique and each observer measured the first five patients together with the responsible researcher. For 10 randomly selected patients, all measurements were repeated by all observers, at least 2 weeks after the initial measurements. The intraclass correlation coefficient (ICC) for pelvic radiographs and CT images and the kappa value for intraoperative fluoroscopy measurements were calculated to determine the inter- and intraobserver variability. Interobserver variability was defined as the difference in the measurements between observers. Intraobserver variability was defined as the difference in repeated measurements by the same observer.ResultsPreoperatively, the interobserver ICC was 0.4 (gap and stepoff) on radiographs and 0.4 (gap) and 0.3 (stepoff) on CT images. The observers agreed on the indication for surgery in 40% (gap) and 30% (stepoff) on pelvic radiographs. For CT scans the observers agreed in 95% (gap) and 70% (stepoff) of images. Postoperatively, the interobserver ICC was 0.4 (gap) and 0.2 (stepoff) on radiographs. The observers agreed on whether the reduction was acceptable or not in 60% (gap) and 40% (stepoff). On CT images the ICC was 0.3 (gap) and 0.4 (stepoff). The observers agreed on whether the reduction was acceptable in 35% (gap) and 38% (stepoff). The preoperative intraobserver ICC was 0.6 (gap and stepoff) on pelvic radiographs and 0.4 (gap) and 0.6 (stepoff) for CT scans. Postoperatively, the intraobserver ICC was 0.7 (gap) and 0.1 (stepoff) on pelvic radiographs. On CT the intraobserver ICC was 0.5 (gap) and 0.3 (stepoff). There was no agreement between the observers on the presence of a gap or stepoff on intraoperative fluoroscopy images (kappa -0.1 to 0.2).ConclusionsWe found an insufficient interobserver and intraobserver agreement on measuring gaps and stepoffs for supporting clinical decisions in acetabular fracture surgery. If observers cannot agree on the size of the gap and stepoff, it will be challenging to decide when to perform surgery and study the results of acetabular fracture surgery.Level of EvidenceLevel III, diagnostic study.