Designing Trials of Disease Modifying Agents for Early and Preclinical Alzheimer's Disease Intervention: What Evidence is Meaningful to Patients, Providers, and Payers?

BACKGROUND: Drug development for disease modifying agents in Alzheimer's disease (AD) is focused increasingly on targeting underlying pathology in very early stages of AD or in cognitively normal patients at elevated risk of developing dementia due to Alzheimer's. Very early interventional studies of this type have many uncertainties, including whether they can provide the clinical results that payers, providers, and patients will wish to see for decisions. This paper describes an initiative to create greater transparency for researchers to anticipate these decision needs. OBJECTIVE: To create multi-stakeholder-vetted recommendations for the design of studies in later phases of drug development to evaluate the ability of disease modifying agents to delay or prevent the onset of dementia due to Alzheimer's disease (AD). DESIGN: A multi-stakeholder expert workgroup and overseeing steering group were convened to discuss current advances in early interventional clinical trial design and the evidence needs of patients, providers, and payers. Eight teleconferences and one in-person all-day meeting were held. Meetings were recorded and summary notes prepared between sessions. Final conclusions were consolidated by the project team with the workgroup Chair based on these discussions and were reviewed by group members. SETTING: The in-person meeting was held in Baltimore, MD. PARTICIPANTS: In total, 36 stakeholders representing life sciences industry, payers or health technology assessors, patient advocates and research advocacy organizations, regulators, clinical experts and academic or NIH researchers. INTERVENTION: N/A. MEASUREMENTS: N/A. RESULTS: Certain aspects of clinical trial design were deemed important to address stakeholder decision needs for future Alzheimer's prevention drugs even as the field rapidly progresses. These include the need for more robust behavioral and psychological outcome data in early symptomatic disease and the need to update activities of daily living measures to include "digital independence." CONCLUSIONS: Amyloid, tau, and biomarkers of neurodegeneration should be included in trials and studied in relation to other early measures of change meaningful to individuals with AD, their families, and health plans. These measures include early sensitive changes in behavioral and psychological measures and ability to navigate the contemporary digital landscape. Additional work is needed to generate more robust behavioral and psychological outcome data in early symptomatic disease, and to generate multi-stakeholder consensus on early measures of change and magnitudes of change that will be meaningful to patients, providers, and payers.

Foster children's attachment security and behavior problems in the first six months of placement: associations with foster parents' stress and sensitivity.

Both traumatic experiences in their birth families and multiple placement histories lead to increased mental health problems in foster children. The formation of secure attachments to new caregivers could be a protective factor for foster children. The current study focused on the associations between foster parents' sensitivity, parenting stress and foster children's attachment behavior as well as behavior problems. The sample consists of 48 children (aged from 1 to 6 years) and their foster caregivers. Attachment behavior and sensitivity were observed during home visits. Furthermore, caregiver reports were used to assess parenting stress and children's behavior problems. Compared to normative data, foster children showed lower levels of attachment security and more behavior problems. Foster children's attachment security and behavior problems were predicted significantly or marginally by foster parents' stress and supportive presence.

Successful reduction of clinical relevant neovascularization with a modified crossectomy combined with a barrier technique after 10-year follow-up.

OBJECTIVE: The aim of this retrospective study was to assess the long-term results of stripping the insufficient great saphenous vein (GSV) with stump coagulation, closure of the cribriform fascia and some additional measures, which will be described in detail. METHODS: Patients treated from 1998 to 1999 for varicose veins had been invited in 2009 for follow-up colour-coded duplex sonography and had been asked to answer a quality-of-life questionnaire. In 2009, the examinations for the study were conducted at a clinic of angiology by an independent and experienced sonographer. RESULTS: From a total of 165 patients, 91 (136 limbs) had been willing to participate in the study. Duplex ultrasound after a mean follow-up of 10.7 years revealed only clinically non-relevant (∅ < 0.3 cm) neovascularizations in 1.5% of all treated legs. No clinical relevant varicosities from the groin had developed. CONCLUSION: The crossectomy combined with stump coagulation and suture of the fossa ovalis, completed with some additional measures, is a successful method to reduce neovascularization and recurrent varicosities, even for redo-crossectomies, without increasing the risk of perioperative complications.

Child Abuse and Neglect: Screening for Risks During the Perinatal Period.

Purpose: Currently, there is a claim for earlier interventions for families in order to prevent child maltreatment. Here, a screening instrument to assess risk indicators for child abuse and neglect already in the context of maternity clinics is introduced. The present study is the first report on the psychometric properties of this instrument, the "short questionnaire for risk indices around birth" (RIAB). Material and Methods: Data were collected in the context of three different studies conducted at Ulm University Hospital. To examine interrater reliability eight case vignettes were rated by n = 90 study participants (50 students and 40 experts working at a maternity clinic). Criterion validity was examined in two studies applying the German version of the child abuse potential inventory CAPI (n = 96 families at risk and n = 160 additional families). Results: Both laymen and experts were able to understand and use the screening instrument correctly, leading to a high agreement with the sample solutions given. A high concordance was found between parents' and experts' ratings: In case of no reported risk factors applying the screening instrument RIAB, parents themselves reported significantly less stressors and burdens, compared to those parents with an indication for a thorough examination as pointed out in the RIAB. Conclusion: In the context of maternity clinics the RIAB is a useful, broadly applicable instrument, screening for existing risk factors at the earliest and thus allowing for the initiation of specific interventions when needed.

German primary care doctors' awareness of osteoporosis and knowledge of national guidelines.

AIMS: With the aging of populations in industrialized countries, managing osteoporosis in the primary care setting becomes increasingly important. General practitioners (GPs) are in an ideal position to identify and manage patients who are at an increased risk of osteoporosis and fracture. In a cross-sectional survey we studied whether German GPs (1) are aware of osteoporosis as an urgent health problem, (2) felt competent to manage patients with osteoporosis, (3) knew and used the national guideline for osteoporosis treatment and if not, (4) which barriers prevented them from doing so. PARTICIPANTS AND METHODS: A representative random sample of German GPs were sent a 30-item standardized questionnaire by mail. Chi-square statistics and multiple logistic regression were used to detect associations between knowledge of guidelines and explanatory variables. RESULTS: Of 2,194 doctors addressed, 892 (41.1%) answered the questionnaire. The majority of doctors (82.7%) felt competent in osteoporosis management (95% confidence interval: 80.2 - 85.2) and only 11.2% (8.2 - 13.1) did not consider osteoporosis an important problem in their practice. About half (459/892) reported knowing the national osteoporosis guideline well (51.7%; 48.4 - 55.0), whereas 22.6% (19.9 - 25.4) admitted to not being familiar with it at all. Knowledge of the guideline was positively associated with being a female doctor (OR=1.36; 1.01-1.85), having Internet access (OR=1.40, 1.06 - 1.85), seeing institutionalized patients (OR=1.67; 1.03 -2.69), and caring for patients with osteoporosis at a higher frequency (OR=2.60; 1.93 - 3.50). Nearly 43% (39.7 - 46.2) used the guideline in their practice without problems. In free-text fields, GPs reported most frequently that budgetary restrictions preventing the prescription of appropriate medication represented a severe problem for osteoporosis management. CONCLUSION: Although most GPs are aware of osteoporosis as an important health problem and felt competent in the management of this disease, only half of the respondents knew and used the national guideline. This may explain deficits in diagnosis and therapy of osteoporosis in Germany. Since guideline knowledge and frequency of consultations for osteoporosis strongly correlate, proper dissemination of the guideline may further enhance awareness of, and evidence-based treatment for, osteoporosis.

Comparación psicométrica transcultural de la depresión mayor entre Chile y Alemania / Cross cultural psychometric comparison of major depression in inpatients from Chile and Germany

Background: Depressive symptoms and personality features of patients with mood disorders are supposed to have a strong variability in cross cultural studies. The clinical profile, the outcome and the treatment response seem to be different across the world. Aim: To investigate the differences and similarities of major depressive disorders in Chile and Germany. Material and methods: Sixty seven Chilean and German depressive inpatients, without comorbidity on axis I or II were studied. Diagnosis of depression was based on DSM IV and ICD 10 criteria for major depression. Symptomatology was assessed using the self reporting questionnaire (SRQ-20), the Symptom checklist-90-revisited (SCL 90-R), the Beck inventory for Depression (BDI), and the Hamilton scale for depression (HAM-D). Personality was assessed with the Munich Personality Scale. Results: Only the SRQ-20 shows significantly higher tendency towards depression among Chilean patients. At the personality level, Chileans exhibited higher scores in extroversion, neuroticism, esoteric and isolating tendencies. Conclusions: These results help to understand differences and similarities between depressive syndromes across cultures. They suggest that the relation between symptomatology, some personality traits and severe major depression has little variability across cultures

E1B 55-kilodalton-associated protein: a cellular protein with RNA-binding activity implicated in nucleocytoplasmic transport of adenovirus and cellular mRNAs.

The adenovirus type 5 (Ad5) early 1B 55-kDa protein (E1B-55kDa) is a multifunctional phosphoprotein that regulates viral DNA replication and nucleocytoplasmic RNA transport in lytically infected cells. In addition, E1B-55kDa provides functions required for complete oncogenic transformation of rodent cells in cooperation with the E1A proteins. Using the far-Western technique, we have isolated human genes encoding E1B-55kDa-associated proteins (E1B-APs). The E1B-AP5 gene encodes a novel nuclear RNA-binding protein of the heterogeneous nuclear ribonucleoprotein (hnRNP) family that is highly related to hnRNP-U/SAF-A. Immunoprecipitation experiments indicate that two distinct segments in the 55-kDa polypeptide which partly overlap regions responsible for p53 binding are required for complex formation with E1B-AP5 in Ad-infected cells and that this protein interaction is modulated by the adenovirus E4orf6 protein. Expression of E1B-AP5 efficiently interferes with Ad5 E1A/E1B-mediated transformation of primary rat cells. Furthermore, stable expression of E1B-AP5 in Ad-infected cells overcomes the E1B-dependent inhibition of cytoplasmic host mRNA accumulation. These data suggest that E1B-AP5 might play a role in RNA transport and that this function is modulated by E1B-55kDa in Ad-infected cells.

Fitness of twinning.

On the basis of a family reconstitution of the rural Krummhörn population (Ostfriesland, Germany) of the eighteenth and nineteenth centuries, we pursued the question of to what extent the birth of twins contributed to the reproductive fitness of their mothers. The twinning rate was 16.2/1000; the secondary sex ratio among twins was 0.93, and it was 1.16 among their singleton siblings. Mothers of twins were older, had a longer generative life phase, and achieved higher age-specific fertility rates with shorter birth intervals. Parity effects on twinning tendency could not be detected. Twin maternities caused reproductive costs, namely, increased maternal, infant, and child mortality and obviously higher intrafamilial competition, because adult twins had fewer local marriage chances and to a higher degree were forced to emigrate. These reproductive disadvantages mean that the productivity of a male pair of twins, as measured by the number of live-born grandchildren, is clearly less than the productivity of a single boy. On the other hand, the birth of a female pair of twins led to more live-born grandchildren than the birth of a single girl. In sum, mothers of twins achieved greater reproductive success, with 13.5% more live-born grandchildren, than mothers of singletons only. The results are discussed against the background of Anderson's (1990) error hypothesis of twinning.

[Indications-related use of stockings--measuring venous pump function]. / Indikationsgerechte Bestrumpfung--Messung der venösen Pumpfunktion.

In 48 patients (16 healthy persons, 16 patients with venous incompetence and 16 patients with phlebographic proved status after thrombosis) the effect of medical compression stockings of different compression pressure (Sigvaris Thrombo, Sigvaris 503, Sigvaris 504) on venous pumping function was studied by foot volumetry. In patients with varicosis and preexistent reduced pumping function the expelled volume in average ascended from 13.0 to 16.23 (+25%, Sigvaris 503), respectifly to 16.52 (+27%, Sigvaris 504) (p less than 0.05 Wilcox and Wilcoxon test). In patients in status after deep leg vein thrombosis with very reduced pumping function it came to an increase of expelled volume from 8.48 to 11.08 (+31%, Sigvaris 503) and to 12.55 (+48%, Sigvaris 504) (p less than 0.01). The hospital stocking Sigvaris Thrombo did not really improve the venous pumping function. So for the first time the common prescription of medical compression stockings class II in patients with varicosis and in mild cases of chronic venous incompetence and of stockings class III in patients in status after deep leg vein thrombosis is justified by measurement.