Genetic insights into immune mechanisms of Alzheimer's and Parkinson's disease

Microglia, the macrophages of the brain, are vital for brain homeostasis and have been implicated in a broad range of brain disorders. Neuroinflammation has gained traction as a possible therapeutic target for neurodegeneration, however, the precise function of microglia in specific neurodegenerative disorders is an ongoing area of research. Genetic studies offer valuable insights into understanding causality, rather than merely observing a correlation. Genome-wide association studies (GWAS) have identified many genetic loci that are linked to susceptibility to neurodegenerative disorders. (Post)-GWAS studies have determined that microglia likely play an important role in the development of Alzheimer's disease (AD) and Parkinson's disease (PD). The process of understanding how individual GWAS risk loci affect microglia function and mediate susceptibility is complex. A rapidly growing number of publications with genomic datasets and computational tools have formulated new hypotheses that guide the biological interpretation of AD and PD genetic risk. In this review, we discuss the key concepts and challenges in the post-GWAS interpretation of AD and PD GWAS risk alleles. Post-GWAS challenges include the identification of target cell (sub)type(s), causal variants, and target genes. Crucially, the prediction of GWAS-identified disease-risk cell types, variants and genes require validation and functional testing to understand the biological consequences within the pathology of the disorders. Many AD and PD risk genes are highly pleiotropic and perform multiple important functions that might not be equally relevant for the mechanisms by which GWAS risk alleles exert their effect(s). Ultimately, many GWAS risk alleles exert their effect by changing microglia function, thereby altering the pathophysiology of these disorders, and hence, we believe that modelling this context is crucial for a deepened understanding of these disorders

AN INQUIRY INTO THE RELATIONSHIP OF WETLAND REGULATIONS AND PROPERTY VALUES IN MINNESOTA

Ownership in property can be thought of as ownership of the rights to the "incomes" associated with different uses of the property. Each potential use has a separate economic value, which can be ranked if put into money terms. The property's market value is usually held to be the highest income on that ranking. Wetland protection regulations might shift the ownership of some of these rights from private to public entities or restrict the exercise of some rights. This can result in a reduction of the property's market value, if the regulation precludes access to the income from the highest ranking use. A regulation can never increase the economic value of a property from the owner's perspective. Whether or not a reduction in property value is considered "fair" is a question usually left to the courts. If it is determined that a regulation has resulted in a "taking" of property, compensation must be paid. The appropriate level of compensation is the difference between estimated pre- and post-regulation market values. The task of the analyst is to estimate those two values, after first determining if the two uses are feasible given other physical, financial, and legal conditions. Because property prices are not determined until there is a transaction, all such valuations are necessarily estimates based on the professional judgments of the analyst. There are not easy ways to determine these values short of costly individual appraisals or extensive market studies. Wetland regulations in Minnesota do result in reduced values for some property owners--as do all land use regulations. Demonstrating that values went down on regulated properties has policy import, however, only if: (1) the examples are so egregious that the Legislature decides to change the enabling legislation to adjust the distribution of the law's benefits and costs; or (2) the sum of measured property losses exceeds any estimate of total benefits, in which case the Legislature might decide to change the law as not in the broader public interest. Should further property value analyses be conducted? Only if the Legislature is very clear about why it wants to do the study. If the concern is one of fairness, then the distribution of a regulation's costs should be examined by using parcel-by-parcel appraisals or by a careful calculation of the economic benefits and costs among different classes of people, classes of property, or regions of the state. If, on the other hand, the concern is that the aggregate costs of the regulation may exceed its total benefits, then broader economic valuation studies are called for. We are not prepared to recommend either approach at this time, because the Legislature has not yet declared what the problem really is.Land Economics/Use,

Opioid-Ketamine and Norketamine Codrug Combinations for Pain Management

The present invention relates to the field of pain management, and more particularly to synergistic codrugs comprising an opioid and ketamine or norketamine which have been combined to form a single chemical codrug entity. When the codrug is administered it produces a synergistic analgesic response to pain

Opioid-Nornicotine Codrugs Combinations for Pain Management

The present invention relates to the field of pain management, and more particularly to synergistic codrugs comprising an opioid and nornicotine which have been combined to form a single chemical codrug entity. When the codrug is administered it produces a synergistic analgesic response to pain

Rotavirus and illness severity in children presenting with acute gastroenteritis at the primary care out-of-hours service

BACKGROUND: Rotavirus is a common cause of acute gastroenteritis in young children in the Netherlands, where rotavirus vaccination has not yet been implemented. OBJECTIVES: To evaluate a difference in illness severity course depending on the presence of rotavirus infection and assess the prevalence of viruses and the referral rate in children with acute gastroenteritis. METHODS: A prospective cohort of children aged 6 months to 6 years presenting with acute gastroenteritis to a primary care out-of-hours service from October 2016 to March 2018. Faeces were sampled and sent to a laboratory where viral pathogens were identified and quantified by real-time polymerase chain reaction. Severe course of acute gastroenteritis was defined as a Modified Vesikari Score of ≥11. In addition, we assessed referral rates. Chi-square tests were used to evaluate differences between groups. RESULTS: We included 75 children (34 boys) with a median age of 1.5 years (interquartile range, 0.9–2.0 years). The prevalence of rotavirus was 65.3% (95% confidence interval, 53.5–76.0) with a median cycle threshold of 16.0. Severe course of acute gastroenteritis was present in 31 of 71 children (4 were lost to follow-up). Those with rotavirus (20/47) did not have a severe course more often than those without (11/24): odds ratio, 0.88 (95% confidence interval, 0.33–2.36). Referral rates were comparable for rotavirus (15.2%) and non-rotavirus (14.3%). CONCLUSION: In out-of-hours primary care, rotavirus is common but not associated with increased severity and higher referral rates in children with acute gastroenteritis

Bis-Quaternary Ammonium Salts as Pain Modulating Agents

Provided are methods for using his-quaternary ammonium compounds to treat inflammatory pain, neuropathic pain and nociceptive pain

What is important to the GP in recognizing acute appendicitis in children:a delphi study

Background: For diagnostic research on appendicitis in registration data, insight is needed in the way GPs generate medical records. We aimed to reach a consensus on the features that GPs consider important in the consultation and medical records when evaluating a child with suspected appendicitis. Methods: We performed a three-round Delphi study among Dutch GPs selected by purposive sampling. An initial feature list was created based on a literature search and features in the relevant Dutch guideline. Finally, using a vignette describing a child who needed later reassessment, we asked participants to complete an online questionnaire about which consultation features should be addressed and recorded. Results: A literature review and Dutch guideline yielded 95 consultation features. All three rounds were completed by 22 GPs, with the final consensus list containing 26 symptoms, 29 physical assessments and signs, 2 additional tests, and 8 further actions (including safety-netting, i.e., informing the patient about when to contact the GP again). Of these, participants reached consensus that 37 should be actively addressed and that 20 need to be recorded if findings are negative. Conclusions: GPs agreed that negative findings do not need to be recorded for most features and that records should include the prognostic and safety-netting advice given. The results have implications in three main domains: for research, that negative findings are likely to be missing; for medicolegal purposes, that documentation cannot be expected to be complete; and for clinical practice, that safety-netting advice should be given and documented.</p

What is important to the GP in recognizing acute appendicitis in children:a delphi study

Background: For diagnostic research on appendicitis in registration data, insight is needed in the way GPs generate medical records. We aimed to reach a consensus on the features that GPs consider important in the consultation and medical records when evaluating a child with suspected appendicitis. Methods: We performed a three-round Delphi study among Dutch GPs selected by purposive sampling. An initial feature list was created based on a literature search and features in the relevant Dutch guideline. Finally, using a vignette describing a child who needed later reassessment, we asked participants to complete an online questionnaire about which consultation features should be addressed and recorded. Results: A literature review and Dutch guideline yielded 95 consultation features. All three rounds were completed by 22 GPs, with the final consensus list containing 26 symptoms, 29 physical assessments and signs, 2 additional tests, and 8 further actions (including safety-netting, i.e., informing the patient about when to contact the GP again). Of these, participants reached consensus that 37 should be actively addressed and that 20 need to be recorded if findings are negative. Conclusions: GPs agreed that negative findings do not need to be recorded for most features and that records should include the prognostic and safety-netting advice given. The results have implications in three main domains: for research, that negative findings are likely to be missing; for medicolegal purposes, that documentation cannot be expected to be complete; and for clinical practice, that safety-netting advice should be given and documented.</p

Course of uncomplicated acute gastroenteritis in children presenting to out-of-hours primary care

Background The aim of this article is to describe the courses of vomiting, diarrhea, fever, and clinical deterioration, in children with uncomplicated gastroenteritis at presentation. This study was performed as a 7-day prospective follow-up study in an out-of-hours primary care service. The course of vomiting, diarrhea, and fever was analyzed by generalized linear mixed modeling. Because young children ( 90%). Vomiting and fever decreased rapidly, but diarrhea decreased at a somewhat slower pace, especially among children aged 6-12 months. Children who deteriorated during follow-up had a higher frequency of vomiting at presentation and higher frequencies of vomiting and fever during follow-up. Conclusions The frequency of vomiting, not its duration, appears to be the more important predictor of deterioration. When advising parents, it is important to explain the typical symptom duration and to focus on alarm symptoms. Clinicians should be vigilant for children with higher vomiting frequencies at presentation and during follow-up because these children are more likely to deteriorate

Appendicitis in children with acute abdominal pain in primary care:a retrospective cohort study

BACKGROUND: General practitioners (GPs) face a diagnostic challenge when assessing acute abdominal pain in children. However, no information is available on the current diagnostic process or the diagnostic accuracy of history and physical examination in primary care settings. OBJECTIVE: To describe the diagnostic process for acute abdominal pain among children in primary care, focusing on appendicitis, and to assess the diagnostic accuracy of individual clinical features. METHODS: A retrospective cohort study in Dutch primary care, using the Integrated Primary Care Information database. Children aged 4-18 years were included if they had no history of appendicitis and presented with acute abdominal pain during 2010-2016. We evaluated GP management and the diagnostic accuracy of clinical features for appendicitis. Pre- and post-test probabilities were calculated for each clinical feature and compared with the probability of appendicitis after GP assessment. RESULTS: Out of 5691 children, 944 (16.6%) were referred and 291 (5.1%) had appendicitis, of whom 55 (18.9%) were initially misdiagnosed. The pre-test probability (i.e. of appendicitis in evaluated children) varied from 3% (rigidity) to 28% (migratory pain). Concerning post-test probabilities, positive values for rebound pain (32.1%) and guarding (35.8%) and the negative value for right lower quadrant tenderness (0.6%) were superior to overall GP assessment (29.6% and 1.1%, respectively). CONCLUSIONS: GP assessment will miss almost one-fifth of children with appendicitis at their first presentation, and about two-third of GP referrals will be negative. The presence of specific signs can increase or decrease the likelihood of appendicitis, emphasising the importance of a physical examination