798 research outputs found
Pilot Validation of the Tuberous Sclerosis-Associated Neuropsychiatric Disorders (TAND) Checklist
AbstractBackgroundTuberous sclerosis complex is a multisystem disorder that includes a range of tuberous sclerosisâassociated neuropsychiatric disorders (TAND). The lifetime prevalence rates of TAND are very high; yet surveys suggest that the majority of individuals with tuberous sclerosis never receive appropriate assessment or treatment for TAND. To aid systematic enquiry, a TAND Checklist was developed. Here, we performed pilot validation of the TAND Checklist.MethodMixed methods were used across two stages. In stage 1, we gathered feedback on the Checklist from tuberous sclerosis âexpert professionalsâ and âexpert parents and caregivers.â The aim was to examine face and content validity. Stage 2 involved the administration of the refined TAND Checklist to 20 parents of individuals with tuberous sclerosis concurrently with four widely used validated rating scales, to examine external validity and obtain qualitative feedback on face-to-face administration of the TAND Checklist.ResultsTwenty professionals and 62 parents and caregivers from 28 countries participated in the pilot. The TAND Checklist demonstrated good face and content validity with high overall mean and median scores. Qualitative analysis highlighted concerns about the likely use of the TAND Checklist, suggesting that family members and individuals with tuberous sclerosis should drive usage. Stage 2 results showed moderate-to-very good external validity across TAND domain and key subdomains. Internal consistency of domains and subdomains was acceptable to very good. Ninety-three percent of all participants (93%) reported four or more lifetime TAND behavioral difficulties.ConclusionThe pilot validation suggested that the TAND Checklist could provide a useful screening tool in clinical settings
Multiscale modeling of molecular structure and optical properties of complex supramolecular aggregates
Supramolecular aggregates of synthetic dye molecules offer great perspectives to prepare biomimetic functional materials for light-harvesting and energy transport. The design is complicated by the fact that structure-property relationships are hard to establish, because the molecular packing results from a delicate balance of interactions and the excitonic properties that dictate the optics and excited state dynamics, in turn sensitively depend on this packing. Here we show how an iterative multiscale approach combining molecular dynamics and quantum mechanical exciton modeling can be used to obtain accurate insight into the packing of thousands of cyanine dye molecules in a complex double-walled tubular aggregate in close interaction with its solvent environment. Our approach allows us to answer open questions not only on the structure of these prototypical aggregates, but also about their molecular-scale structural and energetic heterogeneity, as well as on the microscopic origin of their photophysical properties. This opens the route to accurate predictions of energy transport and other functional properties
Sex-specific difference in cardiac function in patients with systemic sclerosis: association with cardiovascular outcomes
BACKGROUND
Cardiovascular involvement is one of the leading causes of mortality in systemic sclerosis (SSc) and is reported to be higher in men as compared with women. However, the cause of this difference is largely unknown. The objective of this study was to assess sex differences in echocardiographic characteristics, including left ventricular global longitudinal strain (LV GLS), as a potential explanation of sex differences in outcomes.
METHODS
A total of 746 patients with SSc from four centres, including 628 (84%, 54±13 years) women and 118 (16%, 55±15 years) men, were evaluated with standard and advanced echocardiographic examinations. The independent association of the echocardiographic parameters with the combined endpoint of cardiovascular events-hospitalisation/death was evaluated.
RESULTS
Men and women with SSc showed significant differences in disease characteristics and cardiac function. After adjusting for the most important clinical characteristics, while LV ejection fraction and diastolic function were not significantly different anymore, men still presented with more impaired LV GLS as compared with women (-19% (IQR -20% to -17%) vs -21% (IQR: -22% to -19%), p<0.001). After a median follow-up of 48 months (IQR: 26-80), the combined endpoint occurred in 182 patients. Men with SSc experienced higher cumulative rates of cardiovascular events-hospitalisation/mortality (Ï=8.648; Log-rank=0.003), and sex differences were maintained after adjusting for clinical confounders, but neutralised when matching the groups for LV GLS.
CONCLUSION
In patients with SSc, male sex is associated with worse cardiovascular outcomes even after adjusting for important clinical characteristics. LV GLS was more impaired in men as compared with women and potentially explains the sex difference in cardiovascular outcomes
Lipid-DNAs as Solubilizers of mTHPC
Hydrophobic drug candidates require innovative
formulation agents. We designed and synthesized lipidDNA polymers containing varying numbers of hydrophobic alkyl chains. The hydrophobicity of these amphiphiles
is easily tunable by introducing a defined number of alkyl
chain-modified nucleotides during standard solid-phase
synthesis of DNA using an automated DNA synthesizer.
We observed that the resulting self-assembled micelles
solubilize the poorly water-soluble drug, meta-tetra-hydroxyphenyl-chlorin (mTHPC) used in photodynamic therapy (PDT) with high loading concentrations and loading
capacities. A cell viability study showed that mTHPCloaded micelles exhibit good biocompatibility without irradiation, and high PDT efficacy upon irradiation. LipidDNAs provide a novel class of drug-delivery vehicle, and
hybridization of DNA offers a potentially facile route for
further functionalization of the drug-delivery system with,
for instance, targeting or imaging moieties
Steroid hormones affect binding of the sigma ligand C-11-SA4503 in tumour cells and tumour-bearing rats
PURPOSE: Sigma receptors are implicated in memory and cognitive functions, drug addiction, depression and schizophrenia. In addition, sigma receptors are strongly overexpressed in many tumours. Although the natural ligands are still unknown, steroid hormones are potential candidates. Here, we examined changes in binding of the sigma-1 agonist (11)C-SA4503 in C6 glioma cells and in living rats after modification of endogenous steroid levels. METHODS: (11)C-SA4503 binding was assessed in C6 monolayers by gamma counting and in anaesthetized rats by microPET scanning. C6 cells were either repeatedly washed and incubated in steroid-free medium or exposed to five kinds of exogenous steroids (1Â h or 5Â min before tracer addition, respectively). Tumour-bearing male rats were repeatedly treated with pentobarbital (a condition known to result in reduction of endogenous steroid levels) or injected with progesterone. RESULTS: Binding of (11)C-SA4503 to C6 cells was increased (~50%) upon removal and decreased (~60%) upon addition of steroid hormones (rank order of potency: progesterone > allopregnanolone = testosterone = androstanolone > dehydroepiandrosterone-3-sulphate, IC(50) progesterone 33Â nM). Intraperitoneally administered progesterone reduced tumour uptake and tumour-to-muscle contrast (36%). Repeated treatment of animals with pentobarbital increased the PET standardized uptake value of (11)C-SA4503 in tumour (16%) and brain (27%), whereas the kinetics of blood pool radioactivity was unaffected. CONCLUSIONS: The binding of (11)C-SA4503 is sensitive to steroid competition. Since not only increases but also decreases of steroid levels affect ligand binding, a considerable fraction of the sigma-1 receptor population in cultured tumour cells or tumour-bearing animals is normally occupied by endogenous steroids
The continuum of fetal alcohol spectrum disorders in four rural communities in south africa: Prevalence and characteristics
Prevalence and characteristics of the continuum of diagnoses within fetal alcohol spectrum disorders (FASD) were researched in previously unstudied rural, agricultural, lower socioeconomic populations in South Africa (ZA)
Immunogenicity of a bivalent BA.1 COVID-19 booster vaccine in people with HIV in the Netherlands
OBJECTIVE:Â We evaluated the immunogenicity of a bivalent BA.1 COVID-19 booster vaccine in people with HIV (PWH).DESIGN:Â Prospective observational cohort study.METHODS:Â PWH aged â„45âyears received Wuhan-BA.1 mRNA-1273.214 and those <â45âyears Wuhan-BA.1 BNT162b2. Participants were propensity score-matched 1:2 to people without HIV (non-PWH) by age, primary vaccine platform (mRNA-based or vector-based), number of prior COVID-19 boosters and SARS-CoV-2 infections, and spike (S1)-specific antibodies on the day of booster administration. The primary endpoint was the geometric mean ratio (GMR) of ancestral S1-specific antibodies from day 0 to 28 in PWH compared to non-PWH. Secondary endpoints included humoral responses, T-cell responses, and cytokine responses up to 180âdays post-vaccination.RESULTS:Forty PWH received mRNA-1273.214 (Nâ=â35) or BNT162b2 (Nâ=â5) following mRNA-based (Nâ=â29) or vector-based (Nâ=â11) primary vaccination. PWH were predominantly male (87% vs 26% of non-PWH) and median 57âyears (interquartile range [IQR] 53-59). Their median CD4+ T-cell count was 775 (IQR 511-965) and the plasma HIV-RNA load was <â50âcopies/mL in 39/40. The GMR of S1-specific antibodies by 28âdays post-vaccination was comparable between PWH (4.48, 95% confidence interval [CI] 3.24-6.19) and non-PWH (4.07, 95% CI 3.42-4.83). S1-specific antibody responses were comparable between PWH and non-PWH up to 180âdays, and T-cell responses up to 90âdays post-vaccination. IFN-Îł, IL-2, and IL-4 cytokine concentrations increased 28âdays post-vaccination in PWH.CONCLUSION:Â A bivalent BA.1 booster vaccine was immunogenic in well-treated PWH, eliciting comparable humoral responses to non-PWH. However, T-cell responses waned faster after 90âdays in PWH compared to non-PWH.</p
Immunogenicity of a bivalent BA.1 COVID-19 booster vaccine in people with HIV in the Netherlands
OBJECTIVE:Â We evaluated the immunogenicity of a bivalent BA.1 COVID-19 booster vaccine in people with HIV (PWH).DESIGN:Â Prospective observational cohort study.METHODS:Â PWH aged â„45âyears received Wuhan-BA.1 mRNA-1273.214 and those <â45âyears Wuhan-BA.1 BNT162b2. Participants were propensity score-matched 1:2 to people without HIV (non-PWH) by age, primary vaccine platform (mRNA-based or vector-based), number of prior COVID-19 boosters and SARS-CoV-2 infections, and spike (S1)-specific antibodies on the day of booster administration. The primary endpoint was the geometric mean ratio (GMR) of ancestral S1-specific antibodies from day 0 to 28 in PWH compared to non-PWH. Secondary endpoints included humoral responses, T-cell responses, and cytokine responses up to 180âdays post-vaccination.RESULTS:Forty PWH received mRNA-1273.214 (Nâ=â35) or BNT162b2 (Nâ=â5) following mRNA-based (Nâ=â29) or vector-based (Nâ=â11) primary vaccination. PWH were predominantly male (87% vs 26% of non-PWH) and median 57âyears (interquartile range [IQR] 53-59). Their median CD4+ T-cell count was 775 (IQR 511-965) and the plasma HIV-RNA load was <â50âcopies/mL in 39/40. The GMR of S1-specific antibodies by 28âdays post-vaccination was comparable between PWH (4.48, 95% confidence interval [CI] 3.24-6.19) and non-PWH (4.07, 95% CI 3.42-4.83). S1-specific antibody responses were comparable between PWH and non-PWH up to 180âdays, and T-cell responses up to 90âdays post-vaccination. IFN-Îł, IL-2, and IL-4 cytokine concentrations increased 28âdays post-vaccination in PWH.CONCLUSION:Â A bivalent BA.1 booster vaccine was immunogenic in well-treated PWH, eliciting comparable humoral responses to non-PWH. However, T-cell responses waned faster after 90âdays in PWH compared to non-PWH.</p
- âŠ