"Time Saved" Calculations to Improve Decision-Making in Progressive Disease Studies.

BACKGROUND: Disease modifying therapies (DMTs) may be most beneficial in early disease, when progression is slow and changes small, with clinical relevance difficult to interpret. OBJECTIVES: Time component tests (TCTs) translate differences between treatments from mean change, vertical distance between longitudinal trajectories, into intuitively understood time saved, horizontal distance between trajectories, which can be readily combined across endpoints in a global TCT (gTCT). DESIGN: The value of composites, time savings estimates, and combination scores to optimize measurement and interpretation of DMTs are demonstrated, along with construction details and simulation studies. SETTING: TCT methods were applied to a randomized phase II clinical trial. PARTICIPANTS: Patients with early Alzheimer's disease (N=332). INTERVENTION: Three treatment groups with AFFITOPE® AD02 and two control groups with aluminum oxyhydroxide, AD04. MEASUREMENTS: The co-primary efficacy outcomes were an adapted ADAS-Cog (aADAS) and adapted ADCS-ADL (aADL), which were optimized composite scales specific to cognitive and functional domains. A composite based on these two scores was the study's prespecified primary outcome. The CDR-sb and standard non-adapted ADCS-ADL and ADAS-Cog scales were prespecified secondary outcomes. RESULTS: The AD04 2 mg group showed some statistically significant effects compared with other study arms. It is unclear whether the observed 3.8-point difference on the composite is clinically meaningful. TCT results show a time savings of 11 months in an 18-month study with AD04 2 mg. CONCLUSION: The relevance of 11 months saved is more universally understood than a mean difference of 3.8 points in the composite outcome. These results suggest that a combination of a composite approach and a time savings interpretation offers a powerful approach for detecting and interpreting disease modifying effects.

Long-term experience on assisted suicide in Switzerland: dementia, mental disorders, age-related polymorbidity and the slippery slope argument.

OBJECTIVES: According to the Swiss medico-ethical guidelines valid between 2004 and 2018, the key criterion for assisted suicide (AS) was that the patients who wished to die suffered with a disease leading to death in the foreseeable future. Critics of AS fears that broadening of the medical indications will lead to an uncontrolled expansion to persons who are not terminally ill (slippery slope argument). We evaluated to what extent this broadening took place in practice over time. STUDY DESIGN: Retrospective national cohort study. METHODS: By using data of the Swiss Federal Statistical Office, we analyzed the long-term development of AS in Switzerland over a 20-year period (1999-2018; n = 8738 cases). We classified the cases into one of three categories regarding the aforementioned key criterion for AS. RESULTS: In 43.6% of AS cases, the criterion 'end of life is near' was met. In 5.3% of cases, this criterion was not met (4.7%: mental disorders; 0.6%: dementia). In 51.1% of cases, the reason underlying AS comprised several, mostly age-related diseases and/or functional impairments; the aforementioned key criterion, however, was probably not met in most of the cases. Over time, the number of cases doubled over each 5-year period; this increase occurred similarly for the three categories. CONCLUSION: The fact that many AS cases took place outside the valid medico-ethical guidelines might be interpreted as a development in the idea of the slippery slope argument. The fact that the percentage distribution of these cases remained unchanged over time argues against it.

Assisted suicide in patients with cancer.

BACKGROUND: There are limited data on the long-term development and trends of assisted suicide (AS) among cancer patients. PATIENTS AND METHODS: Using data of the Swiss Federal Statistical Office, we analyzed AS trends over an 18-year period (1999-2016; total number of cases = 6553). RESULTS: Among patients who underwent AS, cancer was the most common underlying disease (n = 2704, 41.3% of all AS cases). The most common cancer types were lung (14.0% of cancer-related AS cases), breast (11.0%) and prostate (10.1%). There was a slight preponderance of men compared with women (51.5% versus 48.5%). The proportion of AS cases within cancer types did not change over time. The ratio of cancer-related AS cases in relationship with all cancer-related deaths increased from 0.3% at the beginning of the study period (1999-2003) to 2.1% from 2014 to 2016 (change of age-standardized rates for men: +488%; for women: +417%). At the end of the study period (2014-2016), there were only minor differences between cancer-specific ratios, highest and lowest range: 1.1% (liver cancer) and 2.8% (breast, esophageal and lip/oral cavity/oropharynx cancer). Individuals who underwent AS because of cancer were considerably younger than those who choose AS on account of other diseases (73 years versus 80 years). The median age of people with cancer-related AS was similar to that of all cancer-related deaths (74 years): for women, the median age of cancer-related AS was 72, whereas for men it was 75. The median age at which AS took place increased over time. CONCLUSIONS: During the study period, the proportion of people who chose cancer-related AS has approximately sextupled. However, AS among cancer patients remains rare and represents only ∼2% of all cancer-related deaths.

Detailing the effects of polypharmacy in psychiatry: longitudinal study of 320 patients hospitalized for depression or schizophrenia.

Current treatment standards in psychiatry are oriented towards polypharmacy, that is, patients receive combinations of several antidepressants, antipsychotics, mood stabilizers, anxiolytics, hypnotics, antihistamines, and anticholinergics, along with other somatic treatments. In tandem with the beneficial effects of psychopharmacological drug treatment, patients experience significant adverse reactions which appear to have become more frequent and more severe with the rise of ubiquitous polypharmacy. In this study, we aimed to assess today's acute inpatient treatment of depressive and schizophrenic disorders with focus on therapeutic strategies, medications, adverse side effects, time course of recovery, and efficacy of treatments. Of particular interest was the weighing of the benefits and drawbacks of polypharmacy regimens. We recruited a total of 320 patients hospitalized at three residential mental health treatment centers with a diagnosis of either schizophrenic (ICD-10: "F2x.x"; n = 94; "F2 patients") or depressive disorders (ICD-10: "F3x.x"; n = 226; "F3 patients"). The study protocol included (1) assessment of previous history by means of the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medications and adverse side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. Polypharmacy was by far the most common treatment regimen (85%) in this study. On average, patients received 4.50 ± 2.68 medications, consisting of 3.30 ± 1.84 psychotropic drugs, plus 0.79 ± 1.13 medications that alleviate adverse side effects, plus 0.41 ± 0.89 other somatic medications. The treating psychiatrists appeared to be the main determining factor in this context, while «previous history¼ and «severity at baseline¼ played a minor role, if at all. Adverse drug reactions were found to be an inherent component of polypharmacy and tended to have a 2-3 times higher incidence compared to monotherapy. Severe adverse reactions could not be attributed to a particular drug or drug combination. Rather, the empirical data suggested that severe side effects can be triggered by virtually all combinations of drugs, provided patients have a respective vulnerability. In terms of efficacy, there were no advantages of polypharmacy over monotherapy. The results of this study underlined the fact that polypharmacy regimens are not equally suited for every patient. Specifically, such regimens appeared to have a negative impact on treatment outcome and to obfuscate the "natural" time course of recovery through a multitude of interfering factors. Evidence clearly speaks against starting just every therapeutic intervention in psychiatry with a combination of psychopharmaceuticals. We think that it is time for psychiatry to reconsider its treatment strategies, which are far too one-sidedly fixated on psychopharmacology and pay far too little attention to alternative approaches, especially in mild cases where psychotherapy without concurrent medication should still be an option. Also, regular exercises and sports can definitely be an effective therapeutic means in a considerable number of cases. General practitioners (GPs) are particularly in demand here.

Inflammatory processes linked to major depression and schizophrenic disorders and the effects of polypharmacy in psychiatry: evidence from a longitudinal study of 279 patients under therapy.

Over the past 2 decades, polypharmacy has become the de-facto standard of acute treatment in psychiatry where patients with psychiatric disorders receive a multiple medication regimen. There is growing evidence for a potential link between major psychiatric disorders and inflammatory processes. Combining these two aspects aims at avoiding polypharmacy attempts among patients with inflammatory activation through alternative treatment strategies. In this study, we addressed the following questions: (1) to what extent can polypharmacy be explained through the factors "diagnosis", "previous history", "severity at baseline", "age", "gender", and "psychiatrist in charge"; (2) what are the differences between polypharmacy and monotherapy regarding efficacy and side effect profiles; and (3) what amount of between-patient variance is explainable by the natural antibody immunoglobulin M (IgM) within each diagnostic group. This naturalistic longitudinal study was comprised of 279 patients under therapy with a clinical diagnosis of depressive (ICD-10: "F3x.x"; n = 195) or schizophrenic disorders (ICD-10: "F2x.x"; n = 84). The study protocol included (1) assessment of previous history by the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medication and unwanted side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. The association between inflammatory response system and psychiatric disorders was detailed by fitting multi-layer Neural Net (NN) models to the observed data ("supervised learning"). The same approach was used to set up prediction models of side effects. Our data showed that polypharmacy was omnipresent. Yet the various polypharmacy regimens had no advantage over monotherapy: we even found slightly larger baseline score reductions under monotherapy, independent of primary diagnoses and for comparable baseline severities. Most patients experienced unwanted side effects. The close link between side effects and treatment regimen was revealed by a linear model in which the mere number of drugs explained a significant (p < 0.001) proportion of the observed variance. As to the inflammatory response system: For the F2 patients, our NN model identified a 22.5% subgroup exhibiting a significant correlation of r = 0.746 (p = 0.0004) between global schizophrenia scores and IgM levels, along with a correct prediction of response of 94.4%, thus explaining 55.7% of the observed between-patient variance. For the F3 patients, our NN model identified a 19.6% subgroup exhibiting a significant correlation of r = 0.644 (p = 0.00003) between global depression scores and IgM levels, along a correct prediction of response of 89.6%, thus explaining 41.4% of the observed between-patient variance. Polypharmacy is omnipresent in today's acute treatment of psychiatric disorders. Given the large proportion of patients with unwanted side effects and the strong correlation between side effects and the number of drugs, polypharmacy approaches are not equally suited for every patient. In terms of efficacy, there are no advantages of polypharmacy over monotherapy. Most notably, our study appears to have cleared the way for the reliable identification of a subgroup of patients for whom the inflammatory response system is a promising target of therapeutic intervention.

Long-term reduction of seclusion and forced medication on a hospital-wide level: Implementation of an open-door policy over 6 years.

BACKGROUND: Psychiatric inpatient treatment is increasingly performed in settings with locked doors. However, locked wards have well-known disadvantages and are ethically problematic. In addition, recent data challenges the hypothesis that locked wards provide improved safety over open-door settings regarding suicide, absconding and aggression. Furthermore, there is evidence that the introduction of an open-door policy may lead to short-term reductions in involuntary measures. The aim of this study was to assess if the introduction of an open-door policy is associated with a long-term reduction of the frequency of seclusion and forced medication. METHOD: In this 6-year, hospital-wide, longitudinal, observational study, we examined the frequency of seclusion and forced medication in 17,359 inpatient cases admitted to the Department of Adult Psychiatry, Universitäre Psychiatrische Kliniken (UPK) Basel, University of Basel, Switzerland. In an approach to enable a less restrictive policy, six previously closed psychiatric wards were permanently opened beginning from August 2011. During this process, a systematic change towards a more patient-centered and recovery-oriented care was applied. Statistical analysis consisted of generalized estimating equations (GEE) models. RESULTS: In multivariate analyses controlling for potential confounders, the implementation of an open-door policy was associated with a continuous reduction of seclusion (from 8.2 to 3.5%; ηp2=0.82; odds ratio: 0.88) and forced medication (from 2.4 to 1.2%; ηp2=0.70; odds ratio: 0.90). CONCLUSION: This underlines the potential of the introduction of an open-door policy to attain a long-term reduction in involuntary measures.

Mosquitoes (Diptera: Culicidae) from crepuscular period in an Atlantic Forest area in Southern Brazil / Mosquitos (Diptera: Culicidae) do período crepuscular em área de Floresta Atlântica no sul do Brasil

Abstract Crepuscular period is one of the factors that may influence the biting activity of mosquitoes. Many of these insects have a peak activity in this period. The purpose of this study was to investigate the afternoon crepuscular activity of Culicidae in a remaining area of Atlantic Forest in western Santa Catarina, southern Brazil. Moreover, the possible influence of abiotic factors, the abundance and species richness were verified. In order to better analyze the influence of crepuscular period in specific composition and abundance of mosquitoes, the dusk was divided into three periods: pre-sunset, sunset and post-sunset. At the end of the study, nine hundred and eight four specimens distributed in 12 genera and 23 species were collected. Trichoprosopon pallidiventer (Lutz, 1905) (59.76%), Aedes crinifer (Theobald, 1903) (8.13%), Ae. scapularis (Rondani, 1848) (5.89%) were the most abundant species. Spring time presented the greatest abundance and species richness. During the study, among the three periods evaluated, pre-sunset had the greatest abundance and post-sunset the lowest. Pre-sunset and sunset had the greatest similarity between species. Regarding to the abiotic factors evaluated seven and 15 days before sampling, they did not present significant correlation for the three most abundant species. However, temperature had a positive correlation to these species. Moreover, the correlation between collected species and its possible role as vectors of etiological agents of diseases was discussed.

Resumo O período crepuscular é um dos fatores que pode influenciar na atividade hematofágica dos mosquitos. Muitos desses insetos iniciam ou terminam suas atividades nesse período. O objetivo deste trabalho foi estudar os Culicidae que ocorrem no crepúsculo vespertino em uma área de Floresta Atlântica no oeste de Santa Catarina, sul do Brasil. Além disso, foi analisada a possível influência de fatores abióticos, bem como abundância e riqueza de espécies. Para melhor avaliar a influência do período crepuscular na composição das espécies e na abundância destas, o crepúsculo foi dividido em três períodos: pré-crepúsculo, crepúsculo e pós-crepúsculo. Ao final do estudo foram coletados 984 exemplares distribuídos em 12 gêneros e 23 espécies. Trichoprosopon pallidiventer (Lutz, 1905) (59,76%), Aedes crinifer (Theobald, 1903) (8,13%) e Ae. scapularis (Rondani, 1848) (5,89%) foram as espécies mais abundantes. A maior abundância e riqueza de espécies se deram na primavera. Dentre os três períodos estudados, o pré-crepúsculo apresentou a maior abundância de mosquitos, em contrapartida, o pós-crepúsculo apresentou a menor abundância. Os períodos pré-crepuscular e crepuscular apresentaram maior similaridade entre si com relação à composição das espécies. Relacionando os fatores abióticos e as três espécies mais abundantes, não foi observada correlação significativa nos dados avaliados nos sete e 15 dias anteriores às coletas. Entretanto, a temperatura apresentou uma correlação positiva para estas três espécies. A relação entre as espécies coletadas e a potencial transmissão de agentes etiológicos causadores de doenças foi comentada.

Mosquitoes (Diptera: Culicidae) from crepuscular period in an Atlantic Forest area in Southern Brazil.

Crepuscular period is one of the factors that may influence the biting activity of mosquitoes. Many of these insects have a peak activity in this period. The purpose of this study was to investigate the afternoon crepuscular activity of Culicidae in a remaining area of Atlantic Forest in western Santa Catarina, southern Brazil. Moreover, the possible influence of abiotic factors, the abundance and species richness were verified. In order to better analyze the influence of crepuscular period in specific composition and abundance of mosquitoes, the dusk was divided into three periods: pre-sunset, sunset and post-sunset. At the end of the study, nine hundred and eight four specimens distributed in 12 genera and 23 species were collected. Trichoprosopon pallidiventer (Lutz, 1905) (59.76%), Aedes crinifer (Theobald, 1903) (8.13%), Ae. scapularis (Rondani, 1848) (5.89%) were the most abundant species. Spring time presented the greatest abundance and species richness. During the study, among the three periods evaluated, pre-sunset had the greatest abundance and post-sunset the lowest. Pre-sunset and sunset had the greatest similarity between species. Regarding to the abiotic factors evaluated seven and 15 days before sampling, they did not present significant correlation for the three most abundant species. However, temperature had a positive correlation to these species. Moreover, the correlation between collected species and its possible role as vectors of etiological agents of diseases was discussed.

Methodological Aspects of the Phase II Study AFF006 Evaluating Amyloid-beta -Targeting Vaccine AFFITOPE® AD02 in Early Alzheimer's Disease - Prospective Use of Novel Composite Scales.

BACKGROUND: Optimized scales and composite outcomes have been proposed as a way to more accurately measure Alzheimer's disease related decline. AFFITOPE® AD02, is an amyloid-beta (Aß)-targeting vaccine to elicit anti-Aß antibodies. IMM-AD04, commonly known as Alum, originally designated as a control agent, appeared to have disease-modifying activity in a multicenter, parallel group phase II study in early AD patients. OBJECTIVES: To develop adapted outcomes for cognition, function and a composite scale with improved sensitivity to decline and treatment effects in early AD (mild plus prodromal AD) based on historical data and to assess these adapted outcomes in this phase II study. DESIGN: Data from public datasets was analyzed using a partial least squares model in order to identify an optimally weighted cognitive outcome, Adapted ADAS-cog, and an optimally weighted ADL outcome, Adapted ADCS-ADL which were prospectively defined as co-primary endpoints for the study and were also combined into a composite scale. Data from 162 patients in the placebo groups of ADCS studies and 156 mild patients in the ADNI I study were pooled for this analysis. The Adapted ADAS-cog scale considered 13 ADAS-cog items as well as several Neuropsychological test items and CogState items, the Adapted ADCS-ADL considered all ADCS-ADL items. After the pre-specified analyses were complete, additional adapted and composite scales were investigated in a post-hoc manner. Evaluation of the adapted and composite scales was performed on Phase II trial data for AFFITOPE® AD02 (AFF006, Clinical Trial Identifier: NCT01117818) and historic data in early AD. Least square means, standard deviations, and least squares mean to standard deviation ratios were compared among adapted and composite scales and traditional scales for the 5 treatment groups in the phase II study and overall for the historic data. Treatment effect sizes and p-values were also compared for the phase II study. RESULTS: Cognitive items that were selected for the adapted cognitive scale (aADAS-cog) and had the highest weights were Word Recall, Word Recognition, and Orientation. Delayed Word Recall and Digit Cancellation were among the items excluded due to lack of improved sensitivity to decline. Highly weighted ADL items included in the adapted functional scale (aADCS-ADL) were using the telephone, traveling, preparing a meal/snack, selecting clothing, shopping and using appliances. Excluded items were primarily basic ADLs such as eating, walking, toileting and bathing. Comparisons between traditional scales and primary outcome adapted scales show improved sensitivity to group differences with the adapted scales in the phase II trial. Most of the improvement in the sensitivity of the aADAS-cog and the aADCS-ADL is due to a larger treatment difference observed rather than the improved sensitivity to decline in the comparison groups. CONCLUSION: To our knowledge, this is the first study to prospectively use optimized scales as primary endpoints and to demonstrate the superior power of optimized scales and composites in early disease. Although it is possible that the treatment difference between randomized groups is due to a factor other than the treatment itself, for instance baseline imbalance, the improved power to detect these differences still argues in favor of the adapted scales. The issue of oversensitivity to detect treatment effects is controlled by selection of the alpha level for significance, and in our case will happen less than 5% of the time. Clinical relevance of the treatment difference should be assessed separately from statistical significance, and in this phase II study, is supported by significant or similar sizes of effect on function, behaviour and quality of life outcomes, which are important to patients and caregivers.

Results from a Phase II Study to Assess the Clinical and Immunological Activity of AFFITOPE® AD02 in Patients with Early Alzheimer's Disease.

OBJECTIVES: The primary objective of this clinical trial was to assess the clinical activity of various doses and formulations of AFFITOPE® AD02 following its repeated s.c. administration to patients with early Alzheimer´s disease (AD), based on the evaluation of cognitive and functional domains. DESIGN: It was designed as a randomized, placebo-controlled, parallel group, double blind, multicenter phase II trial with 10 regular outpatient visits and 6 telephone interviews. SETTING: The trial was performed at 32 sites in six countries. PARTICIPANTS: A total of 332 patients were enrolled and 265 patients completed the trial in 3 treatment groups with AD02 and 2 control groups with aluminum oxihydroxide, here named IMM-AD04. Patients were randomly assigned to 5 groups: two doses of IMM-AD04, 25µg AD02 (in two different formulations) and 75µg AD02. INTERVENTION: At months 0, 1, 2, 3, 9 and 15, each patient received a single s.c. injection of the corresponding preparations of AFFITOPE® AD02 or the control, IMM-AD04. MEASUREMENTS: Co-primary efficacy outcomes included a measure of cognition (adapted AD Assessment Scale cognitive [aADAS cog]), and a measure of function (adapted AD Cooperative Trial Activities of Daily Living [aADCS-ADL]). A primary composite score was the sum of these two scores. RESULTS: Treatments were generally well tolerated and adverse events (AEs) were seen at similar rates across all treatment groups, with the exception that more injection site reactions were seen in the groups with a higher level of adjuvant. None of the AD02 groups showed a benefit over the IMM-AD04 controls for primary or exploratory efficacy outcomes. The control groups differed on aADCS-ADL and therefore couldn't be pooled (p=0.039). Unexpectedly, the 2mg IMM-AD04 showed statistically significant effects over the other groups on several clinical outcomes including: aADAS-cog, aADL, Composite, ADAS-cog, CDR-sb, and QOL-AD Caregiver as well as two biomarker outcomes: right and total hippocampal volume (all p<0.05). 48% of patients in the IMM-AD04 2mg group had no decline in the composite outcome over 18 months compared to 17%-31% in the other groups, which is consistent with historical placebo groups. CONCLUSION: No significant treatment effects were seen for the investigational compound AD02. However, the IMM-AD04 2mg group showed statistically significant effects over all other groups on several clinical outcomes as well as a slowing of decline on right hippocampal volume. The data support further development of IMM-AD04 as a disease modifying agent in line with EMA/FDA definitions.

Vaccination for Parkinson's disease.

Idiopathic Parkinson's disease (PD) is, like other neurodegenerative diseases such as Alzheimer's disease (AD) considered a proteinopathy. Thus, a disease that is driven by the accumulation and aggregation of misfolded proteins, in case of PD α-synuclein (aSyn) is incriminated. Accordingly, removal of aSyn is assumed of having the potential to modify the course of the disease. Both active and passive aSyn targeting immunotherapy were found to modify disease in mice overexpressing human aSyn and recapitulating various aspects of synucleopathies. Translating immunotherapy to humans needs to consider the issue of potential autoimmunity. PD vaccines developed by AFFiRiS integrate the safety concept as applied for the company's AD vaccine candidates. This includes the use of short antigens, precluding activation of aSyn-specific T cells and, thus, cellular autoimmunity. Moreover, the selection of AFFITOPES® for clinical development is based on the principle of exclusive aSyn reactivity of vaccine-induced Abs excluding crossreactivity to ß-synuclein (bSyn), which is ensured by the AFFITOME® platform technology. PD01, the first in class aSyn vaccine developed by AFFiRiS is about to enter the clinical phase of development.

[Cementless femoral neck prosthesis CUT--clinical and radiological results after 5 years]. / Die zementfreie Schenkelhalsprothese CUT--klinisch-radiologische Ergebnisse nach 5 Jahren.

AIM: With regard to total replacement of the hip, revision arthroplasty poses a challenge especially for younger patients. In spite of substantial improvements, new materials and operation techniques are still not able to prevent a shorter running life of prostheses in this group. The present work aims at evaluating clinical and radiological mid-term results of the femoral neck prosthesis CUT (ESKA Orthodynamics Lübeck) to answer the question of whether this implant is recommendable for younger patients. METHOD: Between 2001 and 2005 a consecutive series of 99 CUT prostheses was performed in 86 patients (50 female, 36 male) with a mean age of 50 (17-72) years and again evaluated clinically and radiologically after 5.4 (1.7-6.5) years. 84 cases were operated using a posterior approach and 15 cases were operated according to the anterolateral Watson-Jones approach. For clinical evaluation the Harris hip score and the visual analogue scale (VAS) for pain measurement were applied. Standard anteroposterior radiographs of the pelvis and lateral radiographs of the operated hip were compared to radiographs taken in the recovery room by two independent observers. Interobserver measurement discrepancy of the implant angle was 2.6 +/- 1.4 degrees. With 4 degrees being the maximum discrepancy, it was defined as the threshold of the normal range of 145 degrees (141-149 degrees). Additionally, the amount of femoral neck resection, the contact of the medial corticalis with the proximal stem, and the contact of the lateral corticalis with the distal part of the stem, periarticular ossifications and stable fixation by bone ingrowth according to Engh et al. were evaluated. Five delineated sections around the femoral component for evaluation of looseness or progressive loosening were used according to Gruen et al. Radiological evaluation of the cup was performed according to Charnley and DeLee. RESULTS: The survival rate according to Kaplan-Meier was 98 % after on average 6.6 years. The Harris hip score significantly improved from 50 (16-83) points preoperatively to 98 (40-100) points at the time of follow-up (p < or = 0.05). 82 % achieved an excellent result (91-100 points), 10% a good (91-90 points), 4% had a moderate (71-80 points) and 4% had a bad (< 70 points) result. Six prostheses had to be revised. One of them had to be changed to a cementless standard stem after 5 years because of aseptic loosening. Another one had to be revised after 2.7 years because of chronic thigh pain. Two painful hips had a capsular revision. In one case the liner had to be changed and one case had an exchange of the femoral ball for a better femoral offset. The VAS revealed a significant reduction of pain in rest and under load (p < or = 0.05). 92% had a correct subcapital neck resection. The recommended implant angle of 145 degrees was seen in 72% while a valgus alignment in 18% and a varus alignment in 10% was measured. Undersizing of the CUT-prosthesis was seen in 27 cases. Nine of these cases developed a varus alignment. Osseous integration of the cup and stem was seen in 100% and in 95%, respectively. CONCLUSION: This study demonstrates the CUT prosthesis as a bone-preserving prosthesis with good functional and radiological results and therefore as an alternative joint replacement in younger patients.

Bone remodeling in proximal HA-coated versus uncoated cementless SL-Plus((R)) femoral components: a 5-year follow-up study.

BACKGROUND AND PURPOSE: Bone resorption at the femoral stem due to stress shielding has been particularly observed secondary to cementless hip replacement. This prospective study of 126 total-hip replacements was performed to examine clinical outcomes and changes in peri-prosthetic bone density after implantation of a double-tapered cementless femoral component manufactured with versus without hydroxyapatite (HA) coating. METHODS: Sixty-seven femoral components with and 59 femoral components without proximal HA coating were implanted and examined after a mean follow-up of 5.8 (SD 1.1, 2.8-7.8) years. The Harris hip score (HHS) and plain radiographs were used for clinical and radiological follow-up evaluations. Possible changes in peri-prosthetic bone mineral density (BMD) were measured by dual-energy X-ray absorptiometry (DEXA). RESULTS: Clinical outcome, measured by HHS, was similar in both groups. On plain radiographs, significantly less radiolucent lines were observed for the coated implants. DEXA revealed a significant increase in BMD at the proximal zones, along the medial side, and at the stem tips in the coated compared with the non-coated implants. INTERPRETATION: Hydroxyapatite-coated implants yield favorable radiographic characteristics, but no greater clinical benefit after 5 years' implantation.

Development of AFFITOPE vaccines for Alzheimer's disease (AD)--from concept to clinical testing.

Based on the notion that cerebral accumulation of certain Abeta species is central to AD pathogenesis and endowed with the knowledge that emerged during clinical testing of the first human Alzheimer vaccine, AN1792, we designed a new generation of Alzheimer vaccines. Rather than relying on full-length Abeta itself or fragments thereof, AFFITOPE vaccines use short peptides, mimicking parts of the native Abeta sequence, as their antigenic component. The technology created to identify these peptides, termed AFFITOPE-technology, at the same time provides the basis for the multi-component safety concept realized in AFFITOPE vaccines. First, as they are nonself, AFFITOPES don't need to break tolerance typically established against self proteins. This allows us to use aluminium hydroxide, the agent first approved as immunological adjuvant for human use and, thus, exhibiting an excellent safety profile. Second, AFFITOPES employed in Alzheimer vaccines are only 6 amino acids in length, which precludes the activation of Abeta-specific autoreactive T cells. Third, and above all, the AFFITOPE technology allows for controlling the specificity of the vaccine-induced antibody response focusing it exclusively on Abeta and preventing crossreactivity with APP. In a program based on two AFFITOPES allowing neoepitope targeting of Abeta (free N-terminus), this approach was taken all the way from concept to clinical application. Early clinical data support the safety concept inherent to AFFITOPE Alzheimer vaccines. Further clinical testing will focus on the identification of the optimal vaccine dose and immunization schedule. Together, result of these trials will provide a solid basis for clinical POC studies.

Apheresis products of the Amicus and the AS.TEC 204 cell separators are comparable with regard to dendritic cells derived from the mononuclear cell collection.

BACKGROUND: In this study, we investigated the quality of autologous mononuclear cells (MNC) collected with two different cell separators using standard MNC-apheresis procedure modalities. MNCs were purified by density gradient centrifugation and cultured according to standard protocols to generate dendritic cells (DC) and 1 x 10(7)/ml immature DCs were pulsed with tumour lysate for 3 days and subsequently characterized by fluorescent-activated cell sorter analysis. RESULTS: No difference was found in the monocyte content of either apheresis product (P = 0.07) and in the overall yield of MNCs (P = 0.7). Mature DCs as defined by their phenotype revealed also no significant difference: Amicus, 118 x 10(6) cells +/- 91 vs. AS.TEC 204, 128 x 10(6) cells +/- 137 (P = 0.55), respectively, although the contamination with platelets (threefold) and red cells (twofold) was significantly higher in the AS.TEC 204 group (P < 0.05) than in the Amicus group. CONCLUSION: The Amicus and the AS.TEC 204 are equally capable in providing MNCs for the generation of DCs and the amount of concomitantly collected red cells and platelets had no impact on the final DC yield.

Defects of camera covers after arthroscopic surgery.

Arthroscopic cameras are used either sterilized or in an unsterile manner enveloped in a sterile cover. The goal of this investigation was to determine the integrity of camera covers after arthroscopic procedures, as defects of camera covers have been occasionally observed by us. Such defects might be a potential cause of infection. Six different types of camera covers were tested in a prospective randomized study involving 90 consecutive shoulder arthroscopies. After surgery, the covers were tested by filling them with water up to a level of 20 cm. Any water leaks were recorded. Of all tested camera covers, 74% had 1 to 9 holes involving all types of covers. Of the holes, 17% were larger than 1 mm. In addition, 37% of the covers leaked at the junction between the cover and the arthroscope. The type of cover with the lowest number of leaks had the largest diameter of all tested covers and included an arthroscope adapter, in contrast to the others, which were only sealed off from the arthroscope by adhesive tape. One cover with tape sealing leaked more frequently than the others at the junction (93% of cases, P < .003). The tested camera covers are fragile and tend to leak. This might be a potential risk factor for infection. Mechanically more resistant camera covers or sterilized cameras without the need for covers should be used instead.

Successful use of acitretin in conjunction with narrowband ultraviolet B phototherapy in a child with severe pustular psoriasis, von Zumbusch type.

Severe pustular psoriasis von Zumbusch type is a therapeutic challenge not only in adults, but even more in children. We report a 3(1/2)-year-old boy who developed a generalized flare of diffusely scattered pustules on erythematous skin which rapidly progressed to large exuding areas. The clinical presentation and investigations including histopathological examination of a biopsy and negative bacterial cultures were consistent with the diagnosis of pustular psoriasis von Zumbusch type. Upon initial treatment with methylprednisolone, acitretin and antibiotics the extent of the disease declined. However, several attempts to reduce the dose of the oral corticosteroid were followed by immediate severe flares. Additional treatment with narrowband ultraviolet B (NB-UVB, 311-313 nm UVB) resulted in a rapid arrest of disease activity and allowed the corticosteroid to be tapered off. After 10 irradiations the patient was both off steroid and disease free. NB-UVB therapy was subsequently reduced to twice-weekly exposures and acitretin gradually diminished to a maintenance dose of 0.3 mg kg(-1) daily. We conclude that NB-UVB in conjunction with acitretin is a potent therapeutic regimen for the treatment of severe pustular psoriasis von Zumbusch type in childhood.

Effect of tendon release and delayed repair on the structure of the muscles of the rotator cuff: an experimental study in sheep.

BACKGROUND: Ruptures of the tendons of the rotator cuff lead to profound and possibly irreversible changes in the structure and physiological properties of the rotator cuff muscles. Muscle atrophy and fatty infiltration are important prognostic factors that affect the natural history and outcome of treatment. The purpose of this study was to examine the amount of muscle atrophy and fatty infiltration in an animal model and to determine whether the repair of a long-standing tendon tear can reverse these changes. METHODS: The infraspinatus tendon in six sheep was released and encased in a silicone tube to prevent spontaneous healing. The musculotendinous unit was allowed to retract for forty weeks. Throughout this period, the muscular changes were studied with use of computed tomography, histological analysis, and electron microscopy. At forty weeks, the elasticity, intramuscular pressure, and perfusion were measured intraoperatively and a tendon repair was carried out. The structural changes of the muscle were studied for thirty-five weeks after the repair. The animals were then killed, and the musculotendinous units were examined macroscopically and by computed tomography, histological analysis, and electron microscopy. RESULTS: At the time of the tendon release, the infraspinatus showed no fatty changes. The force needed to cause a tendon excursion of 1 cm was a mean (and standard deviation) of 6.8 +/- 1 N. The application of tension on the tendon did not alter the perfusion and decreased the intramuscular pressure. After the tendon release, muscular atrophy developed and there was a significant increase (p < 0.001) in interfascicular and intrafascicular fat, representing fatty infiltration rather than fatty degeneration. Furthermore, there was an increase of interstitial connective tissue. At the time of the tendon repair, between forty and forty-two weeks after the release, there was a sevenfold poorer elasticity of the musculotendinous unit but preserved muscle perfusion. The structural changes increased six weeks after the repair and then recovered partially at twelve and thirty-five weeks thereafter but only to the amount demonstrated before the repair. CONCLUSIONS: Musculotendinous retraction induced by tendon release is associated with profound changes in the structure and function of the affected muscle. Vascularization, intramuscular pressure, and individual fiber composition are not markedly affected, and muscle fibers do not appear to degenerate. However, muscle atrophy, infiltration by fat cells, and an increase of interstitial connective tissue lead to impairment of the physiological properties of the muscle. These changes were irreversible under the conditions of this experiment with the repair technique used.