Patient decision aid based on multi-criteria decision analysis for disease-modifying drugs for multiple sclerosis: prototype development.

BACKGROUND: Since decision making about treatment with disease-modifying drugs (DMDs) for multiple sclerosis (MS) is preference sensitive, shared decision making between patient and healthcare professional should take place. Patient decision aids could support this shared decision making process by providing information about the disease and the treatment options, to elicit the patient's preference and to support patients and healthcare professionals in discussing these preferences and matching them with a treatment. Therefore, a prototype of a patient decision aid for MS patients in the Netherlands-based on the principles of multi-criteria decision analysis (MCDA) -was developed, following the recommendations of the International Patient Decision Aid Standards. MCDA was chosen as it might reduce cognitive burden of considering treatment options and matching patient preferences with the treatment options. RESULTS: After determining the scope to include DMDs labelled for relapsing-remitting MS and clinically isolated syndrome, users' informational needs were assessed using focus groups (N = 19 patients) and best-worst scaling surveys with patients (N = 185), neurologists and nurses (N = 60) to determine which information about DMDs should be included in the patient decision aid. Next, an online format and computer-based delivery of the patient decision aid was chosen to enable embedding of MCDA. A literature review was conducting to collect evidence on the effectiveness and burden of use of the DMDs. A prototype was developed next, and alpha testing to evaluate its comprehensibility and usability with in total thirteen patients and four healthcare professionals identified several issues regarding content and framing, methods for weighting importance of criteria in the MCDA structure, and the presentation of the conclusions of the patient decision aid ranking the treatment options according to the patient's preferences. Adaptations were made accordingly, but verification of the rankings provided, validation of the patient decision aid, evaluation of the feasibility of implementation and assessing its value for supporting shared decision making should be addressed in further development of the patient decision aid. CONCLUSION: This paper aimed to provide more transparency regarding the developmental process of an MCDA-based patient decision aid for treatment decisions for MS and the challenges faced during this process. Issues identified in the prototype were resolved as much as possible, though some issues remain. Further development is needed to overcome these issues before beta pilot testing with patients and healthcare professionals at the point of clinical decision-making can take place to ultimately enable making conclusions about the value of the MCDA-based patient decision aid for MS patients, healthcare professionals and the quality of care.

The influence of immune activation at early vs late gestation on fetal NRG1-ErbB4 expression and behavior in juvenile and adult mice offspring.

Maternal inflammation during pregnancy is associated with a higher incidence of mental disorders (e.g. schizophrenia and autism) in the offspring. In our study, we investigate the involvement of the NRG-ErbB signaling pathway in rodent fetal brains four hours following maternal immune activation (MIA) insult at two different gestational days (i.e. early vs late). Furthermore, we test the long-term behavioral alteration of the exposed MIA mice at juvenile and adulthood. We demonstrate that MIA at late, but not at early gestation day, altered the expression of NRG1, its receptor ErbB4, and the dopamine D2 receptor four hours post injection of viral or bacterial mimic material in fetal brain. At the behavioral levels, adult late-MIA-exposed female offspring, but not juvenile, display lack preference to a novel object. While working memory alteration observed only in adult male MIA-exposed offspring at late gestation day. In addition, we found that adult females MIA-exposed mice spent more time in the center of the open field than female-saline groups. On the other hand, juvenile male offspring exposed to MIA at early, but not late, gestation day displayed a significant alteration in social interaction. Our results suggest that MIA during late gestation immediately influences the expression levels of the NRG1 and ErbB4 genes, and affects long-term behavioral changes at adulthood. These behavioral changes are time related and sex-specific. Thus, immune activation at late stages of the embryonic brain development initiates the activation of the NRG1-ErbB4 pathway and this disturbance might result in cognitive dysfunction in adulthood.

Standardizing Electronic Health Record Data on AD/ADRD to Accelerate Health Equity in Prevention, Detection, and Treatment.

Improving the prevention, detection, and treatment of Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD) across racial, ethnic, and other diverse populations is a national priority. To this end, this paper proposes the development of the Standard Health Record for Dementia (SHRD, pronounced "shared") for collecting and sharing AD/ADRD real-world data (RWD). SHRD would replace the current unstandardized, fragmented, or missing state of key RWD with an open source, consensus-based, and interoperable common data standard. This paper describes how SHRD could leverage the best practices of the Minimal Common Oncology Data Elements (mCODETM) initiative to advance prevention, detection, and treatment; gain adoption by clinicians and electronic health record (EHR) vendors; and establish sustainable business and governance models. It describes a range of potential use cases to advance equity, including strengthening public health surveillance by facilitating AD/ADRD registry reporting; improving case detection and staging; and diversifying participation in clinical trials.

Protective self-presentation style: association with disordered eating and anorexia nervosa mediated by sociocultural attitudes towards appearance.

OBJECTIVE: We tested the hypothesis that a protective self-presentation style (Lennox and Wolfe, 1984) is associated with eating pathology and anorexia nervosa (AN) and that this association is mediated by sociocultural attitudes towards appearance emphasizing the thin ideal. METHOD: We compared the protective-presentation style of women with AN (N=17), partially recovered women (N=110), fully recovered women (N=73), and female controls (N=374). RESULTS: Ill women had a more protective self-presentation style than partially or fully recovered women, who in turn had a more protective self-presentation style than controls. Sociocultural attitudes towards appearance fully mediated the association between protective self-presentation and disordered eating. CONCLUSIONS: Protective self-presentation may therefore be a risk factor for AN and/or a prognostic factor. Implications for therapy and prevention are discussed.

Health benefits of a physical exercise program for inpatients with mental health; a pilot study.

The positive effect of exercise on human health and the relationship between physical activity, health, and wellbeing are well studied and extensively documented in the literature. However, considerably less attention is devoted to the impact of exercise on mental health and wellbeing for people experiencing a mental illness, in general, and in particular for inpatients in the mental health care system. Here, we determine the clinical feasibility and effects of short-term (up to three months) vs long-term (up to six months) group-based exercise program for inpatients with chronic mental health. Changes in psychiatric symptoms, well-being, empathy, and physiological fitness factor (e.g., fasting blood glucose, lipid profile, hemoglobin A1C, and BMI) were monitored before, during and following the physical exercise program. Here, we demonstrated that long-term physical activity improved negative symptoms, but not positive symptoms, while improvement in the severity of the illness as measured by the BPRS questionnaire was found to be independent of the training time. We additionally showed that the empathic ability of patients who exercised for more than three months was significantly improved as compared to the other experimental groups. No significant differences were found in wellbeing, mood, satisfaction, and functioning between exercise groups and the control group. Furthermore, physical activity did not improve any of the physiological parameters that were measured in this study. Together, these data indicate that exercise for at least 3 months seems to improve the overall patient mental state, but not his or her physiological parameters, while improvement in negative symptoms and patient's empathy may occur only after a long-term physical exercise activity.

Effect of peripheral retinal ablation with cryotherapy versus diode laser photocoagulation on axial length in the growing rabbit eye.

AIMS: To evaluate and compare the effects of peripheral retinal cryotherapy and diode laser photocoagulation on axial length, anterior chamber depth, and lens thickness in developing rabbit eyes. METHODS: 26 eyes of 6 week old Abbit rabbits were randomly assigned to undergo laser photocoagulation or cryotherapy of the peripheral retina. Eight eyes of four untreated rabbits served as controls. Biometric and intraocular pressure measurements were performed at 0, 5, and 10 weeks after treatment. RESULTS: Five rabbits died, leaving 10 rabbits (20 eyes) in the study group and two (four eyes) in the control group. Average axial lengths for the control, laser treated, and cryo treated eyes were 15.72 mm, 16.08 mm, and 16.11 mm, respectively, at baseline and 17.48 mm, 18.09 mm, and 19.4 mm, respectively, at 10 weeks after treatment (p = 0.028, paired Wilcoxon test). Anterior chamber depth increased from 2.2 mm to 2.5 mm in both treatment groups, and from 2.14 mm to 2.28 mm in the control group. Lens thickness averaged 5.11 mm in the control group and 5.38 mm in the treatment groups before treatment, and 6.34 mm, 6.31 mm, and 6.38 mm, respectively, 10 weeks after treatment. CONCLUSIONS: Peripheral retinal cryotherapy causes a significantly greater elongation of the eye compared to diode laser photocoagulation in a rabbit model.

Risk factors for development of diabetic nephropathy and retinopathy in Jewish IDDM patients.

Risk factors associated with diabetic microvascular complications, with special reference to ethnic origin, were looked for in 231 young Jewish insulin-dependent diabetes mellitus (IDDM) patients with duration of diabetes greater than or equal to 10 yr. Median age at diagnosis of diabetes was 9.2 yr (range 0.04-26.2 yr), and median duration of the disease was 15.3 yr (range 10.0-37.2 yr). Sixty-three percent of the patients were Ashkenazi Jews, and 37% were non-Ashkenazi Jews. HbA1 was evaluated every 3 mo in the last 10 yr of follow-up, and albumin excretion rate was tested in three 24-h urine collections. Direct and indirect ophthalmoscopy was performed every year since diagnosis of diabetes, and if retinal pathology was suspected, color photographs were taken. Microalbuminuria was detected in 31% and macroalbuminuria in 7% of the patients. Nonproliferative and proliferative retinopathy was found in 44 and 12% of the patients, respectively. On logistic regression analysis, two variables were significantly and independently associated with diabetic nephropathy--non-Ashkenazi origin and mean HbA1 values over the first 5 of 10 yr of follow-up. Variables significantly and independently related to diabetic retinopathy were non-Ashkenazi origin, mean HbA1 values over the last 10 yr of follow-up, and duration of diabetes. Because non-Ashkenazi Jews in Israel are of lower socioeconomic status than Ashkenazi Jews, we stratified our patients according to their socioeconomic parameters, median HbA1 values, and duration of diabetes. Non-Ashkenazi patients were at a higher risk to develop complications in all strata.(ABSTRACT TRUNCATED AT 250 WORDS)

Despite the presence of UVB-induced DNA damage, HLA-DR+ cells from ex vivo UVB-exposed human skin are able to migrate and show no impaired allostimulatory capacity.

In this study, we investigated the effect of ultraviolet B radiation on human Langerhans cell function. Normal human skin was irradiated ex vivo with single doses of ultraviolet B. For assessment of T-cell stimulatory function, cells that spontaneously migrated from epidermal sheets were used, whereas full-thickness skin biopsies were used to investigate alterations in migratory properties. The cells migrating from ultraviolet B-exposed epidermal sheets demonstrated a decrease in the percentage of HLA-DR positive Langerhans cells, as well as a reduced capacity to induce proliferation of allogeneic T cells, when compared with cells migrating from nonexposed sheets. When a correction was made for the decreased number of HLA-DR positive Langerhans cells migrating from ultraviolet B-exposed epidermis, however, it appeared that the capacity to induce T-cell proliferation was identical for Langerhans cells migrating from ultraviolet B-exposed and nonexposed epidermis. The presence of ultraviolet B-induced DNA damage could be demonstrated in the Langerhans cells from ultraviolet B-treated skin, indicating that the cells had received significant doses of ultraviolet B. As regards the effect of ultraviolet B on migratory properties of Langerhans cells, we found not only that reduced numbers of CD1a-positive Langerhans cells migrated from the ultraviolet B-exposed full-thickness skin, but also that there was a reduction in CD1a-positive Langerhans cells in the epidermis. This implies that ultraviolet B induces death of Langerhans cells as well as loss of cell surface molecules rather than altering Langerhans cells migration, whereas the Langerhans cells that were still able to migrate fully retained the capacity to activate allogeneic T cells.

The human hair follicle: a reservoir of CD40+ B7-deficient Langerhans cells that repopulate epidermis after UVB exposure.

The ability of skin to maintain its protective structural and functional integrity depends on both resident and circulating cells. Until now, it was thought that dendritic antigen presenting cells of epidermis (Langerhans cells) were replaced by circulating bone marrow derived precursors. Here we show by immunostaining studies of timed biopsies taken from human skin after ultraviolet exposure, that hair follicle is a critical reservoir of Langerhans cells that repopulate epidermis depleted of Langerhans cells by a single four minimal erythema dose of ultraviolet B. Immunostaining with antibodies to thymidine dimers showed that ultraviolet B only penetrated the superficial hair follicle opening, whereas deeper follicle was relatively protected. Langerhans cells migrating from hair follicle into epidermis 72 h after ultraviolet exposure have a partial deficiency of molecules important to T cell costimulation. We used four color flow cytometry to show that Langerhans cells isolated from epidermis 72 h after ultraviolet B can upregulate CD40 but not B7-1 or B7-2 expression in culture, suggesting a different phenotype of hair follicle Langerhans cells. Therefore, the hair follicle is a specialized immune compartment of the skin that serves as an intermediate reservoir of Langerhans cells between bone marrow and epidermis, and that may play a critical role in immune surveillance.

Oxygen-induced retinopathy in newborn kittens. A model for ischemic vasoproliferative retinopathy.

Fourteen kittens were reared in 80% oxygen for 65-72 hr, after which they were returned to room air. At that time, funduscopic examination of all the kittens showed complete obliteration of the retinal vasculature and even optic disc vessels. In the following 18-21 days, florid preretinal new vessels were found growing into the vitreous from the revascularized retina and from the optic disc itself. Subsequent histologic examinations confirmed the above clinical findings and reinforced the authors to suggest this animal model as a future research tool for ischemic vasoproliferative retinopathy, rather than a model for retinopathy of prematurity (ROP). The similarities and dissimilarities between this animal model and the human ischemic retinal disease are discussed.

The pupillary effects of retrobulbar injection of botulinum toxin A (oculinum) in albino rats.

Botulinum toxin (BoTx) has been clinically used in the treatment of localized dystonic states such as blepharospasm, as well as in strabismus. Reported side effects have included primary excessive weakness of neighboring extraocular muscles. To evaluate possible involvement of the iris, we injected BoTx into the retrobular space of albino rats. Ipsilateral mydriasis with cholinomimetic supersensitivity developed in the treated animals. There was no apparent optic nerve dysfunction. The authors observed these effects using BoTx doses insufficient to cause clinical weakness or electrophysiological evidence of generalized neuromuscular dysfunction. The mydriasis disappeared spontaneously within 2-3 weeks. Higher BoTx doses resulted in severe neuromuscular paralysis and death. These findings were consistent with clinical botulism, which may include autonomic paralysis. The site of BoTx action could be the ciliary ganglion or cholinergic terminals in the iris. The authors concluded that side effects of BoTx were not necessarily limited to striated muscle weakness.

The retinal effects of copper vapor laser exposure.

The copper vapor laser is a pulsed gas laser which emits energy in two wavelengths simultaneously: 510.6 nm (green) and 578.2 nm (yellow). Each pulse has a duration of 15 nsec, maximal energy of 3 mJ and a peak power of more than 100 kW. It is a variably high repetition rate laser, in the range between 1 kHz and more than 20 kHz. We studied its interaction with the rabbit retina, while using two different repetition rates, 4 kHz and 18 kHz. The histological analysis of the lesion produced by 4 kHz repetition rate showed undesired retinal effects, similar to those caused by other pulsed lasers. On the other hand, the histological examination of the lesion produced by the 18 kHz repetition rate showed a desired coagulation effect, limited to the outer retinal layers, and comparable to a lesion produced by a continuous wave (CW) laser.

The effect of light on oxygen-induced vasoproliferative retinopathy in newborn kittens.

The effect of bright fluorescent light (115 fc) on oxygen-induced retinopathy in newborn kittens was compared with that of complete darkness and cyclic illumination of 12 hr of bright light (115 fc) and 12 hr of complete darkness. No significant difference was found in the extent of preretinal vasoproliferation and retinal ultrastructural findings among the three groups of kittens reared in different levels of illumination and a control group raised in a standard laboratory illumination level of 40 fc. These results confirmed that light is not a required factor for the development of oxygen-induced retinopathy in kittens.

Confirmation of an excess of the high enzyme activity COMT val allele in heroin addicts in a family-based haplotype relative risk study.

A previous case control study by Vandenbergh et al. [1997: Am J Med Genet 74:439-442] showed an association between the high activity catechol O-methyltransferase (COMT) polymorphism and polysubstance abuse in a group of North American subjects. In the current study we confirm these results by genotyping 38 Israeli heroin addicts and both parents using a robust family-based haplotype relative risk (HRR) strategy. There is an excess of the val COMT allele (likelihood ratio = 4.48, P = 0.03) and a trend for an excess of the val/val COMT genotype (likelihood ratio = 4.97, P = 0.08, 2 df) in the heroin addicts compared to the HRR control group. We also genotyped an additional 101 nonrelated heroin addicts and 126 control subjects using a case control design and found no significant difference in COMT val allele frequency (25.4% vs. 29.7%, likelihood ratio = 1.04, P = 0.31). A significant difference is observed in COMT allele frequency among the three principal Israeli ethnic groups (Ashkenazi Jewish, non-Ashkenazi Jewish, and Palestinian Arab) in a large group of control subjects we have so far examined (chi-square = 7.9, P = 0.019, df = 2, n = 1,422 alleles) suggesting that population stratification is responsible for our failure to observe an excess of the COMT val allele when using the case-control design.

Late-onset localized junctional epidermolysis bullosa and mental retardation: a distinct autosomal recessive syndrome.

We present 2 sibs with a local junctional type of epidermolysis bullosa associated with enamel defect of the teeth, dystrophic nails of the feet, and mental retardation. Subluxation of the lenses was evident in 1 of them. This combination found in a brother and a sister seems to represent a distinct autosomal recessive type of epidermolysis bullosa.

No association between the dopamine D3 receptor Bal I polymorphism and schizophrenia in a family-based study of a Palestinian Arab population.

Several recent meta-analyses appear to show a weak but significant effect of both forms of the gly/ser DRD3 polymorphism in conferring risk for schizophrenia. Since most studies have employed the artifact-prone case-control design, we thought it worthwhile to examine the role of this polymorphism using a robust family-based strategy in an ethnic group not previously systematically studied in psychiatric genetics, Palestinian Arabs. We failed to obtain any evidence in 129 Palestinian triads, using the haplotype relative risk (allele frequency: Pearson chi-square = 0.009, P > 0.1, df = 1, n = 258 alleles) or transmission disequilibrium test design (chi-square = 0.38, P > 0.1, n = 86 families) for association/linkage (or increased homozygosity) of the DRD3 Bal I polymorphism to schizophrenia in our sample. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:778-780, 2000.

A family-based study of the Cys23Ser 5HT2C serotonin receptor polymorphism in schizophrenia.

The 5HT2C receptor has a high affinity for clozapine, a nontypical neuroleptic, and has therefore been postulated to play a role in mediating negative symptoms and neuroleptic response in schizophrenia. In the current study, the Cys23Ser 5HT2C serotonin receptor polymorphism was examined for linkage to schizophrenia by genotyping 207 nuclear families consisting of both parents and schizophrenic child and using the transmission disequilibrium test to examine possible preferential transmission of these alleles from 68 heterozygous mothers to their ill child. No evidence was obtained for preferential transmission of the Cys23Ser 5HT2C alleles in schizophrenia in either of the two main ethnic groups examined (German and Palestinian Arab) or in the combined cohort (TDT chi-square = 0.00, NS).

No evidence for linkage by transmission disequilibrium test analysis of microsatellite marker D22S278 and schizophrenia in a Palestinian Arab and in a German population.

Linkage for a schizophrenia susceptibility locus on chromosome region 22q12-q13 was initially suggested by independent studies from two groups and confirmed in a combined analysis of data for the microsatellite marker D22S278 in multiply affected schizophrenic families derived from 11 independent research groups worldwide. In addition to these reports of linkage to schizophrenia on chromosome 22, bipolar disorder has also been linked to markers in this chromosomal region. We now report results from an analysis of 223 Palestinian Arab trios from three different centers in Israel and Palestine using the allele-wise extended transmission disequilibrium test for multiallelic markers. No evidence for linkage is observed in the entire group or in any of the three centers (entire group: chi-square = 5.59, P = 0.78, df = 9; Afula: chi-square = 6.51, P = 0.48, df = 7; Bethlehem: chi-square = 14.11, P = 0.12, df = 9; Beersheva: chi-square = 7.04, P = 0.32, df = 6). Additionally, we examined D22S278 in a group of 114 schizophrenic German triads and failed to observe evidence for linkage (chi-square = 8.13, P = 0.42, df = 8df).

Retinopathy of prematurity.

Over the last decade major advances have been made in the understanding of the pathogenesis and evolution of retinopathy of prematurity (ROP). The increased survival of very small premature infants in modern neonatal intensive care units has led to the resurgence of this potentially blinding disease. ROP appears to be a multifactorial disease, the prevention of which is probably impossible even now, with the most accurate methods of blood gas monitoring and oxygen restriction. In addition to oxygen, there are a number of significant risk factors, such as birth weight and gestational age, ventilator hours, hyper and hypocarbia, hypoxia and acidosis, xanthine therapy and probably bright light. Current data suggest that the level of antioxidants in the immature retina is relatively low and therefore oxygen radicals which accumulate in the preterm baby's retina may play an important role in the pathogenesis of ROP. The treatment of the disease in both its "active" and "cicatricial" stages emphasizes the need for a new classification which could serve as a common international language through which results may be compared. Vitamin E was suggested in some studies to be helpful in preventing the severe stages of the disease, but its efficacy has yet to be proved. Treatment modalities such as photocoagulation, cryotherapy and vitrectomy are being tried as a means of therapy in the more advanced stages of the disease. Preliminary results of a large multicenter study support the efficacy of cryotherapy.

Seroepidemiologic study of toxocariasis and strongyloidiasis in institutionalized mentally retarded adults.

Serologic surveys for Toxocara canis and Strongyloides sp., as well as stool examinations for intestinal parasites, were conducted in a home for mentally retarded adults. Evidence of parasitic infection was found in 30 (28.3%) of 106 residents; nine (8.5%) had positive toxocaral serology (enzyme-linked immunosorbent assay[ELISA]), 1 (0.9%) had positive serology for Stronglyoides sp. (ELISA), and 21 (19.8%) had parasites in stool (including Stronglyoides stercoralis in the patient with positive serology). Most of the residents with positive toxocaral serology lived in the same apartment and used to play with dogs. Parameters found to be significantly associated with positive toxocaral serology were pica behavior and eosinophilia (P less than 0.05). Mental retardation requiring institutionalization appears to be a risk factor for toxocariasis and other parasitic infections in adults as it is for children.