Attention challenges in Kabuki syndrome.

BACKGROUND: Understanding the specific neurobehavioural profile of rare genetic diseases enables clinicians to provide the best possible care for patients and families, including prognostic and treatment advisement. Previous studies suggested that a subset of individuals with Kabuki syndrome (KS), a genetic disorder causing intellectual disability and other neurodevelopmental phenotypes, have attentional deficits. However, these studies looked at relatively small numbers of molecularly confirmed cases and often used retrospective clinical data instead of standardised assessments. METHODS: Fifty-five individuals or caregivers of individuals with molecularly confirmed KS completed assessments to investigate behaviour and adaptive function. Additionally, information was collected on 23 unaffected biological siblings as controls. RESULTS: Attention Problems in children was the only behavioural category that, when averaged, was clinically significant, with the individual scores of nearly 50% of the children with KS falling in the problematic range. Children with KS scored significantly higher than their unaffected sibling on nearly all behavioural categories. A significant correlation was found between Attention Problems scores and adaptive function scores (P = 0.032), which was not explained by lower general cognitive ability. CONCLUSIONS: We found that the rates of children with attentional deficits are much more elevated than would be expected in the general population, and that attention challenges are negatively correlated with adaptive function. When averaged across KS participants, none of the behavioural categories were in the clinically significant range except Attention Problems for children, which underscores the importance of clinicians screening for attention deficit hyperactivity disorder (ADHD) in children with KS.

The Cost-Effectiveness of Three Prevention Strategies in Alzheimer's Disease: Results from the Multidomain Alzheimer Preventive Trial (MAPT).

BACKGROUND: To date, no curative treatment is available for Alzheimer's disease (AD). Therefore, efforts should focus on prevention strategies to improve the efficiency of healthcare systems. OBJECTIVE: Our aim was to assess the cost-effectiveness of three preventive strategies for AD compared to a placebo. DESIGN: The Multidomain Alzheimer Preventive Trial (MAPT) study was a multicenter, randomized, placebo-controlled superiority trial with four parallel groups, including three intervention groups (one group with Multidomain Intervention (MI) plus a placebo, one group with Polyunsaturated Fatty Acids (PFA), one group with a combination of PFA and MI) and one placebo group. SETTING: Participants were recruited and included in 13 memory centers in France and Monaco. PARTICIPANTS: Community-dwelling subject aged 70 years and older were followed during 3 years. INTERVENTIONS: We used data from the MAPT study which aims to test the efficacy of a MI along PFA, the MI plus a placebo, PFA alone, or a placebo alone. MEASUREMENT: Direct medical and non-medical costs were calculated from a payer's perspective during the 3 years of follow-up. The base case incremental Cost-Effectiveness Ratio (ICER) represents the cost per improved cognitive Z-score point. Sensitivity analyses were performed using different interpretation of the effectiveness criteria. RESULTS: Analyses were conducted on 1,525 participants. The ICER at year 3 that compares the MI + PFA and the MI alone to the placebo amounted to €21,443 and €21,543 respectively, per improved Z score point. PFA alone amounted to €111,720 per improved Z score point. CONCLUSION: Our study shows that ICERS of PFA combined with MI and MI alone amounted to €21,443 and €21,543 respectively per improved Z score point compared to the placebo and are below the WTP of €50,000 while the ICER of PFA alone amounted to €111,720 per improved Z score point. This information may help decision makers and serve as a basis for the implementation of a lifetime decision analytic model.

FRAILTY, SARCOPENIA AND LONG TERM CARE UTILIZATION IN OLDER POPULATIONS: A SYSTEMATIC REVIEW.

This systematic literature review documents the link between frailty or sarcopenia, conceptualized as dimensions of physical health, and the use of long-term care services by older individuals. Long-term care services include formal and informal care provided at home as well as in institutions. A systematic review was performed according to PRISMA requirements using the following databases: PubMed-Medline, Embase, CINAHL, Web of Science, and Academic Search Premier. We included all quantitative studies published in English between January 2000 and December 2018 focusing on individuals aged 50 or more, using a relevant measurement of sarcopenia or physical frailty and a long-term care related outcome. A quality assessment was carried out using the questionnaire established by the Good Practice Task Force Report of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Five subsets of long-term care outcome were considered: 1/ nursing home placement (NHP), 2/ nursing home short stay (NHSS), 3/ formal personal care (FPC), 4/ formal home help (FHH), 5/ informal care (IC). Out of 1943 studies, 17 were finally included in the review. With some studies covering several LTC outcomes, frailty and / or sarcopenia were associated with increased LTC use in 17 out of 26 cases (NHP: 5/6, NHSS: 3/4, FPC: 5/7, FHH: 1/4, IC: 3/5) The association was not consistent in 5 cases (NHP: 1/6, NHSS: 1/4, FPC: 2/7, FHH: 0/4, IC: 1/5) and the association was either not significant or the results inconclusive in the remaining 9 cases. Overall, while results on sarcopenia are scarce, evidence support a positive association between frailty and LTC use. The evidence is stronger for the association of physical frailty with nursing home placement / short stay as well as on FPC. There is less (more heterogeneous) evidence regarding the correlation between physical frailty and FHH or IC use. Results need to be confirmed by more advanced statistical methods or design based on longitudinal data.

Quality of diabetes follow-up care and hospital admissions.

Diabetes may lead to severe complications. For this reason, disease prevention and improvement of medical follow-up represent major public health issues. The aim of this study was to measure the impact of adherence to French follow-up guidelines on hospitalization of people with diabetes. We used insurance claims data from the years 2010 to 2013 collected for 52,027 people aged over 18, affiliated to a French social security provider and treated for diabetes. We estimated panel data models to explore the association between adherence to guidelines and different measures of hospitalization, controlling for socioeconomic characteristics, diabetes treatment and density of medical supply. The results show that adherence to four guidelines was associated with a significant decrease in hospital admissions, up to approximatively 30% for patients monitored for a complete lipid profile or microalbuminuria during the year. In addition, our analyses confirmed the strong protective effect of income and a significant positive correlation with good supply of hospital care. In conclusion, good adherence to French diabetes guidelines seems to be in line with the prevention of health events, notably complications, that could necessitate hospitalization.

The impact of economic conditions on the disablement process: A Markov transition approach using SHARE data.

A growing number of studies underline the relationship between socioeconomic status and health at older ages. Following that literature, we explore the impact of economic conditions on changes in functional health overtime. Frailty, a state of physiological instability, has been identified in the public health literature as a candidate for disability prevention but received little attention from health economists. Using SHARE panel data, respondents aged 50 and over from ten European countries were categorised as robust, frail and dependent. The determinants of health states' changes between two interviews were analysed using multinomial Probit models accounting for potential sample attrition. A particular focus was made on initial socioeconomic status, proxied by three alternative measures. Concentration indices were computed for key transition probabilities. Across Europe, poorer and less educated elders were substantially more likely to experience health degradations and also less likely to experience health improvements. The economic gradient for the recovery from frailty was steeper than that of frailty onset, but remained lower than that of dependency onset. The existing social programs in favour of deprived and dependent elders could be widened to those diagnosed as frail to reduce the onset of dependency and economic inequalities in health at older ages.

Ruthenium-Caged Antisense Morpholinos for Regulating Gene Expression in Zebrafish Embryos.

Photochemical approaches afford high spatiotemporal control over molecular structure and function, for broad applications in materials and biological science. Here, we present the first example of a visible light responsive ruthenium-based photolinker, Ru(bipyridine)2(3-ethynylpyridine)2 (RuBEP), which was reacted stoichiometrically with a 25mer DNA or morpholino (MO) oligonucleotide functionalized with 3' and 5' terminal azides, via Cu(I)-mediated [3+2] Huisgen cycloaddition reactions. RuBEP-caged circular morpholinos (Ru-MOs) targeting two early developmental zebrafish genes, chordin and notail, were synthesized and tested in vivo. One-cell-stage zebrafish embryos microinjected with Ru-MO and incubated in the dark for 24 h developed normally, consistent with caging, whereas irradiation at 450 nm dissociated one 3-ethynylpyridine ligand (ϕ = 0.33) and uncaged the MO to achieve gene knockdown. As demonstrated, Ru photolinkers provide a versatile method for controlling structure and function of biopolymers.

Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas.

Tumors are thought to be sustained by a reservoir of self-renewing cells, termed tumor-initiating cells or cancer stem cells. Osteosarcomas are high-grade sarcomas derived from osteoblast progenitor cells and are the most common pediatric bone malignancy. In this report we show that the stem cell transcription factor Sox2 is highly expressed in human and murine osteosarcoma (mOS) cell lines as well as in the tumor samples. Osteosarcoma cells have increased ability to grow in suspension as osteospheres, that are greatly enriched in expression of Sox2 and the stem cell marker, Sca-1. Depletion of Sox2 by short-hairpin RNAs in independent mOS-derived cells drastically reduces their transformed properties in vitro and their ability to form tumors. Sox2-depleted osteosarcoma cells can no longer form osteospheres and differentiate into mature osteoblasts. Concomitantly, they exhibit decreased Sca-1 expression and upregulation of the Wnt signaling pathway. Thus, despite other mutations, these cells maintain a requirement for Sox2 for tumorigenicity. Our data indicate that Sox2 is required for osteosarcoma cell self renewal, and that Sox2 antagonizes the pro-differentiation Wnt pathway that can in turn reduce Sox2 expression. These studies define Sox2 as a survival factor and a novel biomarker of self renewal in osteosarcomas, and support a tumor suppressive role for the Wnt pathway in tumors of mesenchymal origin. Our findings could provide the basis for novel therapeutic strategies based on inhibiting Sox2 or enhancing Wnt signaling for the treatment of osteosarcomas.

Differences in resource use and costs of dementia care between European countries: baseline data from the ICTUS study.

OBJECTIVES: This study aimed to estimate the costs of formal and informal care of patients with Alzheimer's disease, to compare care costs across European countries and identify potential differences in cost patterns between countries and regions. SETTING: The ICTUS study is a prospective, naturalistic observational study conducted in specialised memory clinics in 12 European countries. In total, 1385 patients diagnosed with Alzheimer's disease were enrolled at baseline. All subjects had a reliable informant (primary caregiver) and informed consent was obtained from patients or their primary caregiver. MAIN OUTCOME MEASURES: Resource utilization data was captured with the RUD Lite (Resource Utilization in Dementia) instrument and caregiver burden with the Zarit Burden Interview (ZBI). Patient disease severity was measured with the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog), Katz´ index (PADL), Instrumental activities of daily living (IADL) scale and Neuropsychiatric inventory (NPI). RESULTS: The mean annual cost of care per patient was estimated to €7,820 (95% CI: €7,194-€8,446), whereof 54% were costs of informal care, 16% direct medical costs and 30% community care costs. There were substantial differences in total resource utilization and also in the balance between formal and informal care between Northern, Western and Southern Europe. PADL scores were strongly associated with formal care costs while IADL scores correlated strongly with informal care costs. CONCLUSIONS: Costs of Alzheimer's disease are high across European countries. Activities of daily living is an important determinant of care costs. Formal care service use is lower and informal care higher in Southern Europe compared to Western and Northern Europe. Differences in resource utilization patterns are important to consider in international studies of dementia care costs as well as in economic evaluations of new treatments for dementia.

[Hygienic requirements on materials in contact with drinking water]. / Gesundheitliche Anforderungen an Werkstoffe und Materialien im Kontakt mit Trinkwasser.

In Germany the hygienic requirements on materials used to supply drinking water are a part of the technical standards. These regulations have to ensure that legal requirements on drinking water are met at the tap. The hygienic harmlessness is assured by requirements on the composition of materials and by test procedures including parametric limits. Historically, the requirements on different types of materials are a part of different technical standards.

Nonoperative management of dens fracture nonunion in elderly patients without myelopathy.

STUDY DESIGN: A retrospective review of elderly patients treated without surgery for chronic mobile nonunions of the odontoid process. Patients were observed on an annual basis with clinical examinations and flexion/extensions plain film radiographs. OBJECTIVES: To evaluate the clinical and radiographic results of elderly patients without myelopathy treated without surgery for dens fracture nonunion. SUMMARY OF BACKGROUND DATA: Because of the risk of progressive myelopathy or sudden neurologic injury, many surgeons recommend operative stabilization for patients with mobile dens nonunions who are able to withstand an operation. There is, however, a lack of information about the radiographic and neurologic progression of dens nonunions. Although a less aggressive surgical approach has been recommended by some authors for elderly or medically compromised patients with acute fractures, long-term follow-up evaluation of patients with resulting nonunions has not been reported. METHODS: A series of elderly patients with chronic, unstable, dens nonunions without myelopathy were treated with a nonoperative treatment protocol. Patients were informed of the nature of their lesion, including the risk of acute or chronic spinal cord injury and the options for operative treatment. Patients were evaluated yearly for clinical and radiographic progression. No intervention to slow progression of atlantoaxial instability was undertaken. RESULTS: None of the patients developed myelopathic symptoms during the follow-up period, and no patient experienced more than a 1 mm radiographic increase in atlantoaxial excursion. None of the reported patients had less than 14 mm available for the spinal cord in either flexion or extension at the start of clinical monitoring. CONCLUSIONS: Although further follow-up evaluation is needed, the authors believe on the basis of this review that this treatment protocol may be considered for patients who are poor candidates for surgical fusion.

An aluminum heat sink and radiator for electrophoresis capillaries.

An aluminum heat sink and radiator are used with forced air cooling of an electrophoresis capillary. Theoretical analyses of the operating limits and heat dissipation characteristics are presented. A system designed for power dissipation as high as 5 W is shown to dissipate heat efficiently and to operate without arcing at voltages higher than 30 kV.

Variable frequency modulation in DNA separations using field inversion capillary gel electrophoresis.

Variable frequency pulsed field capillary gel electrophoresis of nucleic acid restriction fragment mobility and resolution is reported. The frequency of the sine wave superimposed on the dc driving field was randomly varied throughout the duration of the electrophoresis in order to enhance the fragment separations. By frequent changes of frequency, fragments of various sizes experienced optimum conditions for separation sometime during the electrophoresis. The mobilities of phi X 174 HaeIII fragments in 9% T linear polyacrylamide were primarily dependent on power dissipation in the capillary, independent of whether the driving field was dc only or modulated. Resolution of long fragments exhibited a strong modulation frequency dependence. Modulated driving fields provided better resolution of the 603-1353 base pair fragments than dc only fields. Modulation protocols with center frequencies near 100 Hz gave the highest resolution.

Acrylamide polymerization kinetics in gel electrophoresis capillaries. A Raman microprobe study.

The formation of 3.5% T, 3.3% C cross-linked polyacrylamide is monitored in 75-microns-i.d. electrophoresis capillaries by Raman microprobe spectroscopy. The disappearance of the acrylamide 1292-cm-1 band is followed with 60-s time resolution for 30 min, and 2-4 min resolution for up to 10 h. Polymerization is 98% complete in 1.5 h and greater than 99% complete after 2 h. In the 900-1700-cm-1 region no bands attributable to cross-linking are observable. Reaction in the capillary follows second-order kinetics. The reaction is faster in the bulk system because heat dissipation is not sufficient to maintain a constant temperature.

[Vipoma. 9-year observations using currently available therapy methods]. / Vipom. Verlaufsbeobachtung über 9 Jahre unter Einsatz der bisher vorgeschlagenen Therapiemöglichkeiten.

A now 61-year old man with hypersecretion of vasoactive intestinal polypeptide (VIP) due to carcinoma of the tail of the pancreas was treated and followed for nine years. Combined administration of lomustin (2.5 mg/kg on day 1) and 5-fluorouracil (30 mg/kg on days 2-6) over eight courses at six-week intervals achieved clinical remission for 13 months. No clinical improvement was observed with streptozocin (500 mg/m2 on days 1-5) for two courses four weeks apart. Treatment had to be discontinued after the second course because of the onset of (rarely observed) neurotoxic side-effect of bilateral peroneal paresis. High doses of somatostatin (6.9 micrograms/kg hourly intravenously) immediately and markedly reduced stool quantity. But at a lower dose (3.4 micrograms/kg hourly i.v.) there was no noticeable effect. In the further course of the disease, massive attacks of diarrhoea at varying intervals were best controlled in intensity and duration by prednisolone (50-60 mg daily). Other drugs which have been recommended for such cases (indometacin, lithium, trifluoperazine, nicotinic acid and clonidine) had no worth-while effect. In future long-acting somatostatin analogues may provide better prospects for long-term treatment.