Off-label prescribing for allergic diseases in pre-school children

BACKGROUND: Several studies have demonstrated that medication is commonly used off-label in children with allergic diseases. The aim of this study was to characterise off-label use of prescriptions for allergic diseases in pre-school children from an allergology outpatient unit. METHODS: The clinical files of children aged ≤6 years seen in a reference allergology consultation with asthma, allergic rhinitis, and/or atopic eczema were reviewed. A total of 500 patients were consecutively observed from January to June 2012. The data collected included gender, age, diagnosis, and prescriptions with the respective daily dosage. RESULTS: A total of 1224 prescriptions were registered. The most prescribed medications were oral antihistamines (34.6%), antileukotrienes (22.6%), topical nasal corticosteroids (20.3%), and inhaled corticosteroids (17.7%). From all prescriptions, 422 (34.5%) were considered off-label for age (62.6%), dosage (31.7%), or clinical indication (5.7%). Off-label use was more frequent in children aged <2 years, with 73.5% prescribed for children of this age. CONCLUSIONS: Off-label use of drugs for the treatment of paediatric allergic diseases is high. However, these prescriptions are not necessarily wrong, and are recommended in many guidelines. Randomised controlled studies are limited by methodological difficulties creating the need for more observational studies in order to further evaluate the safety and efficacy of drugs used in children

Targeting SxIP-EB1 interaction: An integrated approach to the discovery of small molecule modulators of dynamic binding sites

End binding protein 1 (EB1) is a key element in the complex network of protein-protein interactions at microtubule (MT) growing ends, which has a fundamental role in MT polymerisation. EB1 is an important protein target as it is involved in regulating MT dynamic behaviour, and has been associated with several disease states, such as cancer and neuronal diseases. Diverse EB1 binding partners are recognised through a conserved four amino acid motif, (serine-X-isoleucine-proline) which exists within an intrinsically disordered region. Here we report the use of a multidisciplinary computational and experimental approach for the discovery of the first small molecule scaffold which targets the EB1 recruiting domain. This approach includes virtual screening (structure- and ligand-based design) and multiparameter compound selection. Subsequent studies on the selected compounds enabled the elucidation of the NMR structures of the C-terminal domain of EB1 in the free form and complexed with a small molecule. These structures show that the binding site is not preformed in solution, and ligand binding is fundamental for the binding site formation. This work is a successful demonstration of the combination of modelling and experimental methods to enable the discovery of compounds which bind to these challenging systems

Persistent Non-pharmacological Pain Management and Brain-Predicted Age Differences in Middle-Aged and Older Adults With Chronic Knee Pain

Chronic pain has been associated with changes in pain-related brain structure and function, including advanced brain aging. Non-pharmacological pain management is central to effective pain management. However, it is currently unknown how use of non-pharmacological pain management is associated with pain-related brain changes. The objective of the current study was to examine the association between brain-predicted age difference and use of non-pharmacological pain management (NPM) in a sample of middle-aged and older adults with and without chronic knee pain across two time points. One-hundred and 12 adults (mean age = 57.9 ± 8.2 years) completed sociodemographic measures, clinical pain measures, structural T1-weighted brain magnetic resonance imaging, and self-reported non-pharmacological pain management. Using a validated approach, we estimated a brain-predicted age difference (brain-PAD) biomarker, calculated as brain-predicted age minus chronological age, and the change in brain-PAD across 2 years. Repeated measures analysis of covariance was conducted to determine associations of non-pharmacological pain management and brain-PAD, adjusting for age, sex, study site, and clinical pain. There was a significant time*pain/NPM interaction effect in brain-PAD (p < 0.05). Tests of simple main effects indicated that those persistently using NPM had a “younger” brain-PAD over time, suggesting a potential protective factor in persistent NPM use. Future studies are warranted to determine the influence of NPM in brain aging and pain-related neurological changes

Decreasing Atmospheric CO2 During the Late Miocene Cooling

A pronounced late Miocene cooling (LMC) from ~7 to 5.7 Ma has been documented in extratropical and tropical sea surface temperature records, but to date, available proxy evidence has not revealed a significant pCO2 decline over this event. Here, we provide a new, high‐resolution pCO2 proxy record over the LMC based on alkenone carbon isotopic fractionation (εp) measured in sediments from the South Atlantic at Ocean Drilling Program (ODP) Site 1088. We apply a recent proxy calibration derived from a compilation of laboratory cultures, which more accurately reflects the proxy sensitivity to pCO2 changes during late Quaternary glacial‐interglacial cycles, together with new micropaleontological proxies to reconstruct past variations in algal growth rate, an important secondary influence on the εp. Our resulting pCO2 record suggests an approximately twofold to threefold decline over the LMC and confirms a strong coupling between climate and pCO2 through the late Miocene. Within this long‐term trend are pCO2 variations on sub‐myr timescales that may reflect 400‐kyr long‐eccentricity cycles, in which pCO2 minima coincide with several orbital‐scale maxima in published high‐resolution benthic δ18O records. These may correspond to ephemeral glaciations, potentially in the Northern Hemisphere. Our temperature and planktonic δ18O records from Site 1088 are consistent with substantial equatorward movement of Southern Ocean frontal systems during the LMC. This suggests that potential feedbacks between cooling, ocean circulation and deep ocean CO2 storage may warrant further investigation during the LMC

Model amphipathic peptide coupled with tacrine to improve its antiproliferative activity

Drug repurposing and drug combination are two strategies that have been widely used to overcome the traditional development of new anticancer drugs. Several FDA-approved drugs for other indications have been tested and have demonstrated beneficial anticancer effects. In this connection, our research group recently reported that Tacrine, used to treat Alzheimer’s Disease, inhibits the growth of breast cancer MCF-7 cells both alone and in combination with a reference drug. In this view, we have now coupled Tacrine with the model amphipathic cell-penetrating peptide (CPP) MAP, to ascertain whether coupling of the CPP might enhance the drug’s antiproliferative properties. To this end, we synthesized MAP through solid-phase peptide synthesis, coupled it with Tacrine, and made a comparative evaluation of the parent drug, peptide, and the conjugate regarding their permeability across the blood-brain barrier (BBB), ability to inhibit acetylcholinesterase (AChE) in vitro, and antiproliferative activity on cancer cells. Both MAP and its Tacrine conjugate were highly toxic to MCF-7 and SH-SY5Y cells. In turn, BBB-permeability studies were inconclusive, and conjugation to the CPP led to a considerable loss of Tacrine function as an AChE inhibitor. Nonetheless, this work reinforces the potential of repurposing Tacrine for cancer and enhances the antiproliferative activity of this drug through its conjugation to a CPP.This work was financed by FEDER–Fundo Europeu de Desenvolvimento Regional through the COMPETE 2020—Operational Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT–Fundação para a Ciência e a Tecnologia, in a framework of CINTESIS, R&D Unit (reference UIDB/4255/2020), iMed.ULisboa (UID/DTP/04138/ 2013), LAQV-REQUIMTE (UIDB/50006/2020), and the “Institute for Research and Innovation in Health Sciences” (UID/BIM/04293/2019)

Methodological strengths and weakness of cohorts and administrative data for developing population estimates of dementia

Background: There are three main methods of obtaining population data on the incidence and/or prevalence of dementia: cross-sectional surveys (which may be repeated over time); cohort studies that follow people initially without dementia and count newly diagnosed cases over time; and administrative health records (including linkage of records from multiple sources). The major challenges for all these methods are: how well the study sample represents the target population, the accuracy of diagnoses, and the costs of maintaining the data collection over time. Method: In a project to improve Australia’s dementia statistics, we conducted a series of studies to compare population estimates of dementia obtained using different methods. Firstly, we used existing general health studies of community-based cohorts, supplemented by linkage to administrative records of hospital and emergency department admissions, assessments for aged care support, medication prescriptions, and death certificates to estimate the cumulative incidence of dementia. Secondly, we created cohorts based on administrative records for entire populations. Thirdly, we assessed the validity of the identification of people with dementia in the record linkage cohorts in various ways, including linkage with studies that had obtained clinical diagnosis through the standardised assessment of participants. Result: We will present empirical results illustrating the strengths and limitations of these different approaches. In summary, community-based cohort studies lack representativeness of national or regional populations due to recruitment biases and differential loss to follow-up. Cohort studies are also costly to maintain over the long time needed for participants to develop dementia. In contrast, the use of administrative records is relatively inexpensive, but is subject to policy changes that impact on the continuity of data coverage and quality. Population coverage may also be problematic for administrative data if important sources of care for people with dementia are not included; for example, in Australia linkable primary care data are not available. The validation studies showed that accuracy was highly dependent on data sources, and identification of dementia type was unreliable. Conclusion: Prevalence and trends data of dementia obtained from multiple sources are needed to provide accurate population estimates, together with detailed contextual knowledge and careful analysis

Differing Methodologies Are Required to Estimate Prevalence of Dementia: Single Study Types Are No Longer Reliable

Abstract: Population-based surveys were used to estimate community prevalence of dementia, but have low response fractions due, among other things, to difficulties in obtaining informed consent from people with diminished capacity. Cohort studies of younger people are subject to recruitment bias and non-random drop-outs. Dementia registries can delineate sub-types of dementia but have limited population coverage and are costly to maintain. Administrative datasets have low costs but may be subject to selection bias and uncertain sensitivity. We propose that astute combination of methodologies, including assessment of coverage and validity of administrative datasets, is the most cost-effective process to estimate and monitor community prevalence