The current state of apolipoprotein E in dyslipidemia.

PURPOSE OF REVIEW: Apolipoprotein E (apoE) plays a pivotal role in lipid metabolism in the peripheral circulation and in the brain. This has been recognized for decades; however, the importance of the full spectrum of variation in the APOE gene has been less investigated. This review focusses on current progresses in this field with main focus on apoE in dyslipidemia and vascular disease. RECENT FINDINGS: Whereas ε4 is the risk increasing allele for Alzheimer disease, ε2 is associated with increased risk for age-related macular degeneration. Rare functional ε2-like variants in APOE have previously been reported to have protective associations for Alzheimer disease but recent findings suggest a simultaneous high risk of age-related macular degeneration, in line with observations for the ε2 allele. SUMMARY: ApoE plays an important and well established role in dyslipidemia, vascular disease, and dementia. Recent evidence from large general population studies now also suggests that apoE is involved in age-related macular degeneration. ApoE-targeted therapeutics are being developed for multiple purposes; this heralds a promising change in the approach to disease processes involving apoE. The different risk profile for dementia and age-related macular degeneration should, however, be kept in mind when developing drugs targeting mechanisms resembling these variants.

Women's and maternity care providers' perceptions of pain management during childbirth in hospitals in Southern Tanzania.

BACKGROUND: The majority of women experience pain during childbirth. Offering and supporting women to use different methods for coping with pain is an essential competency for maternity care providers globally. Research suggests a gap between what women desire for pain management and what is available and provided in many low-and middle-income settings. The study aimed to understand how pain management is perceived by those involved: women experiencing childbirth and maternity care providers. METHODS: Individual semi-structured interviews with women (n = 23), maternity care providers (n = 17) and focus group discussions (n = 4) with both providers and women were conducted in two hospitals in Southern Tanzania in 2021. Transcribed interviews were analysed using reflexive thematic analysis. Coding and analysis were supported by the software MAXQDA. RESULTS: Three main themes were generated from the data. The first, 'pain management is multifaceted', describes how some providers and women perceived pain management as entailing various methods to manage pain. Providers perceived themselves as having a role in utilization of pain management to varying degree. The second theme 'pain management is primarily a woman's task' highlights a perception of pain management as unnecessary, which appeared to link with some providers' perceptions of pain as natural and necessary for successful childbirth. Few women explicitly shared this perception. The third theme 'practice of pain management can be improved' illustrates how women and maternity care providers perceived current practices of pain management as suboptimal. According to providers, this is primarily due to contextual factors such as shortage of staff and poor ward infrastructure. CONCLUSION: Women's and maternity care providers' perceptions ranged from perceiving pain management as involving a combination of physiological, psychological and social aspects to perceive it as related with limited to no pain relief and/or support. While some women and providers had similar perceptions about pain management, other women also reported a dissonance between what they experienced and what they would have preferred. Efforts should be made to increase women's access to respectful pain management in Tanzania.

The days we never forget: Flashbulb memories across the life span in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by autobiographical memory deficits, with the ability to retrieve episodic-rich memories being particularly affected. Here, we investigated the influence of AD on a specific subtype of episodic memories known as flashbulb memories (i.e., the ability to remember the personal circumstances for the reception of important news events). We examined the frequency, characteristics, and the temporal distribution of flashbulb memories across the life span. To this aim, 28 older adults diagnosed with AD and a matched sample of 29 healthy older controls were probed for flashbulb memories for two historical events from each decade of their lives. They also estimated the subjective degree of reexperiencing for the memories reported. AD participants showed impaired access to flashbulb memories, the frequency of reported memories being lower than for healthy older adults. However, qualitative aspects of AD participants' flashbulb memories were quite similar to those of the controls, as no group differences were obtained with respect to the canonical categories or degree of reexperience. AD participants' flashbulb memories clustered during the early years of their life, consistent with a reminiscence bump, whereas healthy controls also reported memories dated to later lifetime periods. Our results suggest that probing for personal memories of important public events may serve as a powerful cue for detailed episodic memories in AD.

Remembering a life: an examination of open-ended life stories and the reminiscence bump in patients with Alzheimer's disease.

Autobiographical memory impairments are prominent in Alzheimer's disease (AD). Yet, life narratives of AD patients are scarcely examined. Here, twenty-one older adults diagnosed with probably AD and 22 age-matched healthy controls told their life story, and dated the events mentioned in these narratives. AD patients provided significantly fewer life story memories overall, but the proportion of memories with reference to specific events did not differ between groups. Patients included fewer negative events in their life story, while the emotional tone of narratives was similar across groups. Impairments were found on most structural aspects, with patients' narratives being less coherent and ending somewhere in the past, while no differences were seen for life story beginnings. Both groups showed a peak in remembered events dated to young adulthood, consistent with a reminiscence bump. However, in contrast to controls, patients displayed a steep drop in life story memories after the age of 30. For both groups, a high proportion of memories within the bump period were of life script events, consistent with the idea that the life script helps to structure the recall of personal life story memories, thus suggesting that AD patients still benefit from the retrieval support of this semantic structure.

Deficient semantic knowledge of the life course-Examining the cultural life script in Alzheimer's disease.

Cultural life scripts are culturally transmitted semantic knowledge of the expected order and timing of major transitional events in a prototypical life course. This cognitive schema has been shown to serve as an important mnemonic template that guides retrieval from autobiographical memory, especially for positive and important life events. Autobiographical memory deficits are one of the earliest and most prominent symptoms in Alzheimer's disease (AD). However, no studies have examined cultural life scripts in patients with AD, despite semantic memory impairments being reported even in the early stages of the disease. The aim of the present work was to assess life-script knowledge in older adults diagnosed with AD, particularly in terms of knowledge for the content of life-script events and the timing and temporal order of these events. Twenty-one older adults diagnosed with AD and 22 healthy age-matched controls completed the standard life-script task (Berntsen & Rubin, 2004, Memory & Cognition, 32[3], 427-442). We found that while AD patients produced significantly fewer life-script events, the content of the generated events were quite consistent with those of the controls and the cultural norms. AD patients were particular impaired with regard to the normative timing and order of life-script events, suggesting that these components of the cultural life script are more vulnerable to cognitive decline. The findings are discussed in relation to impaired script knowledge and semantic memory deficits in AD.

Complement C3 and allergic asthma: a cohort study of the general population.

Complement C3 plays a role in asthma development and severity. We tested the hypothesis that high plasma complement C3 concentration is associated with high risks of asthma hospitalisation and exacerbation.We prospectively assessed the risk of asthma hospitalisation in 101 029 individuals from the Copenhagen General Population Study with baseline measurements of plasma complement C3, and genotyped for rs1065489, rs429608 and rs448260 determining levels of complement C3. Risk of asthma exacerbation was further assessed in 2248 individuals with allergic asthma.The multivariable adjusted hazard ratio of asthma hospitalisation was 1.23 (95% CI 1.04-1.45) for individuals in the highest tertile (>1.19 g·L-1) of plasma complement C3 compared with those in the lowest tertile (<1.03 g·L-1). The C3 rs448260 genotype was associated with risk of asthma hospitalisation with an observed hazard ratio of 1.17 (95% CI 1.06-1.28) for the CC genotype compared with the AA genotype. High plasma complement C3 was associated with high levels of blood eosinophils and IgE (p for trends ≤6×10-9), but only the SKIV2L rs429608 genotype was positively associated with blood eosinophil count (p=3×10-4) and IgE level (p=3×10-4). In allergic asthma, the multivariable adjusted incidence rate ratio for risk of exacerbation was 1.69 (95% CI 1.06-2.72) for individuals in the highest plasma complement C3 tertile (>1.24 g·L-1) versus the lowest (<1.06 g·L-1).In conclusion, a high concentration of plasma complement C3 was associated with a high risk of asthma hospitalisation in the general population and with a high risk of asthma exacerbation in individuals with allergic asthma. Our findings support a causal role of the complement system in asthma severity.

Impact of cardiovascular risk factors and genetics on 10-year absolute risk of dementia: risk charts for targeted prevention.

AIMS: Dementia is a major global challenge for health and social care in aging populations. A third of all dementia may be preventable due to cardiovascular risk factors. Intensive multi-domain intervention trials targeting primarily cardiovascular risk factors show improved cognitive function in people at risk. Such interventions will, however, be expensive to implement in all individuals at risk and will represent unrealistic economic tasks for most societies. Therefore, a risk score identifying high-risk individuals is warranted. METHODS AND RESULTS: In 61 664 individuals from two prospective cohorts of the Danish general population, we generated 10-year absolute risk scores for all-cause dementia from cardiovascular risk factors and genetics. In both sexes, 10-year absolute risk of all-cause dementia increased with increasing age, number of apolipoprotein E (APOE) ɛ4 alleles, number of genome-wide association studies (GWAS) risk alleles, and cardiovascular risk factors. The highest 10-year absolute risks of all-cause dementia seen in smoking women with diabetes, low education, APOE ɛ44 genotype, and 22-31 GWAS risk alleles were 6%, 23%, 48%, and 66% in those aged 50-59, 60-69, 70-79, and 80-100, respectively. Corresponding values for men were 5%, 19%, 42%, and 60%, respectively. CONCLUSION: Ten-year absolute risk of all-cause dementia increased with age, APOE ɛ4 alleles, GWAS risk alleles, diabetes, low education, and smoking in both women and men. Ten-year absolute risk charts for dementia will facilitate identification of high-risk individuals, those who likely will benefit the most from an early intervention against cardiovascular risk factors.

Unexpected, isolated activated partial thromboplastin time prolongation: A practical mini-review.

A common inquiry in coagulation laboratories is how to interpret an unexpected, isolated prolonged activated partial thromboplastin time (APTT). In this context, isolated means together with a normal prothrombin time (PT) and/or normal international normalized ratio (INR). This finding may lead to contact with laboratory doctors for further advice on a diagnostic strategy. Occasionally, the need for a diagnostic algorithm can be subacute, where surgery has to be postponed until an explanation for the isolated, prolonged APTT has been established. Activated partial thromboplastin time as a coagulation test was developed to monitor patients with hemophilia. Different APTT reagents display considerable differences in their sensitivity to deficiencies of coagulation factors. An isolated, prolonged APTT is seen in (a) individuals/patients with lupus anticoagulants, (b) patients in treatment with anticoagulants, mainly heparin, and (c) patients with deficiencies of specific coagulation factors. In this tutorial review, we summarize what may cause an isolated prolonged APTT and we present a simple diagnostic algorithm to differentiate between lupus anticoagulants (common) and factor deficiencies (rare). The identification of an isolated prolonged APTT as well as the underlying cause can be of the utmost importance in ensuring the correct therapeutic follow-up.

Observational and genetic studies of short telomeres and Alzheimer's disease in 67,000 and 152,000 individuals: a Mendelian randomization study.

Short telomeres might lead to increased risk of Alzheimer's disease, but observational analyses have been inconclusive and potentially confounded by the strong association of both telomere length and risk of Alzheimer's disease with age and adverse lifestyle. To circumvent this, analyses including single nucleotide polymorphisms associated with telomere length used in an instrumental variable analysis produces risk estimates likely free of distortions from reverse causation and of most confounding. We tested the hypothesis that short telomeres are associated with increased risk of Alzheimer's disease, observationally and causal, genetically. Telomere length was measured in 66,567 individuals, and genotyped for rs2487999 in OBFC1, rs7726159 in TERT, and rs1317082 in TERC causing lifelong telomere shortening in 98,146 individuals from two Copenhagen studies. Genetic data on 54,162 individuals from the International Genomics of Alzheimer's Project were also included. Observationally, multifactorially adjusted hazard ratio for Alzheimer's disease was 1.02 (95% CI 1.00-1.03) per 200 base pair shorter telomeres. Telomere length was 335 base pairs shorter in individuals with 6 versus 0-1 alleles (p = 5 × 10-105). Genetically, odds ratio for Alzheimer's disease was 1.08 (1.01-1.16) per 200 base pairs shorter telomeres. Similar results were found in strata of age and comorbidities. In comparative analyses, genetically predicted shorter telomeres were associated with increased risk of myocardial infarction, and with decreased risks of lung cancer and melanoma as previously reported. Short telomeres were associated observationally and causal, genetically with increased risk of Alzheimer's disease. Telomere biology is therefore a potential pathway involved in the development of Alzheimer's disease.

Plasma levels of apolipoprotein E, APOE genotype, and all-cause and cause-specific mortality in 105 949 individuals from a white general population cohort.

AIMS: To determine whether plasma apoE levels and APOE genotype are associated with all-cause and cause-specific mortality. METHODS AND RESULTS: Using a prospective cohort design with 105 949 white individuals from the general population, we tested the association between plasma apoE at study enrolment and death during follow-up, and whether this was independent of APOE genotype. We confirmed the well-known association between APOE genotypes and mortality. For all-cause, cardiovascular, and cancer mortality, high levels of apoE were associated with increased risk, while for dementia-associated mortality low levels were associated with increased risk. For the highest vs. the fifth septile of plasma apoE, hazard ratios (HRs) were 1.20 (95% confidence interval 1.12-1.28) for all-cause mortality, 1.28 (1.13-1.44) for cardiovascular mortality, and 1.18 (1.05-1.32) for cancer mortality. Conversely, for the lowest vs. the fifth septile the HR was 1.44 (1.01-2.05) for dementia-associated mortality. Results were similar in analyses restricted to APOE ɛ33 carriers. Examining genetically determined plasma apoE, a 1 mg/dL increase conferred risk ratios of 0.97 (0.92-1.03) for cardiovascular mortality and 1.01 (0.95-1.06) for cancer mortality, while a 1 mg/dL decrease conferred a risk ratio of 1.70 (1.36-2.12) for dementia-associated mortality. CONCLUSION: High plasma levels of apoE were associated with increased all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low levels were causally associated with increased dementia-associated mortality.

APOE and dementia - resequencing and genotyping in 105,597 individuals.

INTRODUCTION: The mechanism behind the strong association between the ɛ2/ɛ3/ɛ4 apolipoprotein E gene (APOE) polymorphism and Alzheimer's disease is not well-characterized. Because low plasma levels of apoE associate with risk of dementia, genetic variants altering apoE levels in general may also associate with dementia. METHODS: The APOE gene was sequenced in 10,369 individuals, and nine amino acid-changing variants with frequencies ≥2/10,000 were further genotyped in 95,228 individuals. Plasma apoE levels were measured directly. RESULTS: Risk of all dementia and Alzheimer's disease (AD) increased with decreasing genetically determined apoE levels (P = 5 × 10-4 and P = 1 × 10-4 after APOE ɛ2/ɛ3/ɛ4 adjustment). Hazard ratios (95% confidence intervals) for all dementia and AD were 2.76 (1.39 to 5.47) and 4.92 (2.36 to 10.29) for the group with the genetically lowest apoE versus ɛ33. DISCUSSION: We found that genetically low apoE levels increase and genetically high levels decrease risk, beyond ɛ2/ɛ3/ɛ4. This underscores that dementia risk more likely relates to variants affecting levels of apoE.

Blood-brain barrier transcytosis genes, risk of dementia and stroke: a prospective cohort study of 74,754 individuals.

To test whether genetic variants in PICALM, BIN1, CD2AP, and RIN3-suggested to be involved in blood-brain barrier amyloid-ß transcytosis pathways-associate with Alzheimer's disease, all dementia, suggested vascular dementia, and stroke, and whether such associations are independent of the strong ε4 APOE risk allele. In a prospective cohort study of 74,754 individuals from the general population we genotyped PICALM (rs10792832), BIN1 (rs6733839), CD2AP (rs10948363), and RIN3 (rs10498633), and generated a weighted and a simple allele score. Multifactorially adjusted hazard ratios for the fourth quartile versus the first quartile of the weighted allele score were 1.42 (95% confidence interval 1.22-1.64) for Alzheimer's disease, and 1.33 (1.19-1.48) for all dementia. For suggested vascular dementia and stroke the corresponding estimates were 1.71 (1.18-2.49) and 1.12 (1.04-1.22), respectively. Hazard ratios were similar after APOE adjustment. Genetic variants in PICALM, BIN1, CD2AP, and RIN3 are associated with increased risk of Alzheimer's disease, all dementia, and suggested vascular dementia independent of the strong APOE ε4 allele. These findings may suggest that clathrin-mediated endocytosis in clearance of amyloid-ß across the blood-brain barrier is important for the integrity of both brain tissue and cerebral vessels.

Five weeks of immersive reminiscence therapy improves autobiographical memory in Alzheimer's disease.

We examined the effects of a new Immersive Reminiscence Therapy (IRT) programme on cognitive function, including autobiographical memory, in a sample Alzheimer's disease (AD) patients. A total of 43 AD patients with mild to moderate disease severity were randomly assigned to either an intervention group (n = 22, MMMSE = 20.77), or a control group (n = 21, MMMSE = 19.24). The intervention group received one weekly group-based session of IRT for five weeks in an authentic 1950s style museum environment, matching the time of the participants' youth. IRT included semi-structured conversations about the past. The control group received standard care. We assessed performance on cognitive function and autobiographical memory at baseline and post-intervention. Five weeks of IRT enhanced subsequent autobiographical memory performance, when participants were cued by concrete objects dated to their youth. Object-cued memories reported post intervention included a significantly higher degree of episodic details and higher word counts. The intervention showed no effect on the Autobiographical Memory Interview or word-cued recall. Global cognitive function and semantic autobiographical memory performance increased across time for both groups. Our findings demonstrate that immersion into a setting, rich on concrete cues dated to the participants' youth can improve autobiographical remembering.

Genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population: cohort studies and meta-analyses of 362,338 individuals.

BACKGROUND: Clusterin, also known as apolipoprotein J (apoJ), is one of the most abundantly expressed apolipoproteins in the brain after apolipoprotein E (apoE). Like the ε4 allele of the apolipoprotein E gene (APOE), the clusterin gene (CLU) is a risk locus for Alzheimer's disease, and may play additional roles in atherosclerosis pathogenesis. We tested whether genetic variation in CLU was associated with either Alzheimer's disease or atherosclerosis-related diseases. METHODS: We studied individual data on 103,987 participants from the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS). We genotyped a common CLU variant (rs9331896) and two common APOE variants (rs7412 and rs429358), defining the ε2, ε3, and ε4, alleles in CGPS and CCHS. All individuals in the CGPS and CCHS cohorts were followed from study inclusion to occurrence of event, death, emigration, or until 10 November 2014, whichever came first. Summary consortia data on 258,351 individuals from the International Genomics of Alzheimer's Project (IGAP) and the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus the Coronary Artery Disease (C4D) Genetics and 1000-Genomes-based genome-wide association studies (CARDIoGRAMplusC4D) were used in meta-analyses. RESULTS: In CGPS and CCHS, multifactorially adjusted hazard ratios for Alzheimer's disease, all dementia, vascular dementia, ischemic cerebrovascular disease, and ischemic heart disease were 1.18 (1.07-1.30), 1.09 (1.02-1.17), 0.96 (0.80-1.17), 1.02 (0.97-1.07), and 0.97 (0.93-1.01) per T allele, respectively. Multifactorially adjusted hazard ratios for Alzheimer's disease and all dementia were 2.72 (2.45-3.01) and 2.21 (2.05-2.38) for the APOE ɛ4 allele. There was no interaction between rs9331896 in CLU and rs429358 (defining the ɛ4 allele) in APOE in predicting Alzheimer's disease or all dementia (P = 0.39 and P = 0.21). In a meta-analysis including consortium data, the overall fixed- and random-effects odds ratios for Alzheimer's disease per T allele were 1.16 (1.13-1.18) (I 2 = 0.0%; P for heterogeneity = 0.89). CONCLUSIONS: A common variant in CLU was associated with a high risk of Alzheimer's disease and all dementia in the general population but not with vascular dementia or ischemic vascular disease. Important novel aspects compared to previous studies are the incorporation of individual risk factor data, the exact causative ε4 allele, and several subtypes of dementia and atherosclerosis-related endpoints.

Complement C3 and Risk of Diabetic Microvascular Disease: A Cohort Study of 95202 Individuals from the General Population.

BACKGROUND: Whether the complement system is involved in the development of diabetic microvascular disease is unknown. We tested the hypothesis that high concentrations of complement C3 are associated with increased risk of diabetic retinopathy, nephropathy, and neuropathy in individuals from the general population. METHODS: We studied 95202 individuals from the general population with baseline measurements of complement C3, genotyped for rs1065489, rs429608, and rs448260 determining concentrations of complement C3, and enrolled in the Copenhagen General Population Study from 2003 through 2013, following them until April 10, 2013. Rs1065489, rs429608, and rs448260 were identified with genome-wide association scans in 3752 individuals from the Copenhagen City Heart Study. RESULTS: The cumulative incidence was increased from the lowest tertile to the highest tertile of complement C3 for diabetic retinopathy (log-rank trend, P = 1 × 10-20), nephropathy (P = 7 × 10-15), and neuropathy (P = 5 × 10-10). Multifactorially adjusted hazard ratios for a 1 SD higher concentration of complement C3 were 1.87 (95% CI, 1.61-2.18) for diabetic retinopathy, 1.90 (1.62-2.23) for diabetic nephropathy, and 1.56 (1.29-1.89) for diabetic neuropathy. The multifactorially adjusted hazard ratio for individuals with the highest vs lowest tertile of complement C3 was 3.29 (1.78-6.07) for retinopathy, 2.71 (1.42-5.16) for nephropathy, and 2.40 (1.26-4.54) for neuropathy. CONCLUSIONS: High baseline concentrations of complement C3 were associated with increased risk of diabetic retinopathy, nephropathy, and neuropathy in individuals from the general population. These epidemiological findings were substantiated by a Mendelian randomization approach, potentially indicating causality.

Absolute 10-year risk of dementia by age, sex and APOE genotype: a population-based cohort study.

BACKGROUND: Dementia is a major cause of disability, and risk-factor reduction may have the potential to delay or prevent the disease. Our aim was to determine the absolute 10-year risk of dementia, by age, sex and apolipoprotein E (APOE) genotype. METHODS: We obtained data from the Copenhagen General Population Study (from 2003 to 2014) and the Copenhagen City Heart Study (from 1991 to 1994 and 2001 to 2003). Participants underwent a questionnaire, physical examination and blood sampling at baseline. Diagnoses of dementia and cerebrovascular disease were obtained from the Danish National Patient Registry up to Nov. 10, 2014. RESULTS: Among 104 537 individuals, the absolute 10-year risk of Alzheimer disease in 3017 women and men who were carriers of the APOE ɛ44 genotype was, respectively, 7% and 6% at age 60-69 years, 16% and 12% at age 70-79 years, and 24% and 19% at age 80 years and older. Corresponding values for all dementia were 10% and 8%, 22% and 19%, and 38% and 33%, respectively. Adjusted hazard ratios (HRs) for all dementia increased by genotype, from genotype ɛ22 to ɛ32 to ɛ33 to ɛ42 to ɛ43 to ɛ44 (p for trend < 0.001). Compared with ɛ33 carriers, ɛ44 carriers were more likely to develop Alzheimer disease (adjusted HR 8.74, 95% confidence interval [CI] 7.08-10.79), vascular dementia (adjusted HR 2.87, 95% CI 1.54-5.33), unspecified dementia (adjusted HR 4.68, 95% CI 3.74-5.85) and all dementia (adjusted HR 5.77, 95% CI 4.89-6.81). INTERPRETATION: Age, sex and APOE genotype robustly identify high-risk groups for Alzheimer disease and all dementia. These groups can potentially be targeted for preventive interventions.

Plasma apolipoprotein E levels and risk of dementia: A Mendelian randomization study of 106,562 individuals.

INTRODUCTION: In recent prospective studies, low plasma levels of apolipoprotein E (apoE) are associated with high risk of dementia. Whether this reflects a causal association remains to be established. METHODS: Using a Mendelian randomization approach, we studied 106,562 and 75,260 individuals from the general population in observational and genetic analyses, respectively. RESULTS: In observational analyses risk of Alzheimer's disease and all dementia increased stepwise as a function of stepwise lower apoE levels (P for trend, 2 × 10-17 and 9 × 10-21). APOE-weighted allele scores were associated with stepwise decreases in apoE (P for trend, <1 × 10-300). In instrumental variable analysis, the causal risk ratios for a 1 mg/dL genetically determined lower apoE were 1.41 (1.27-1.57) for Alzheimer's disease and 1.33 (1.25-1.43) for all dementia (F-statistics = 3821). DISCUSSION: Genetic and hence lifelong low apoE is associated with high risk of dementia in the general population. The concordance between observational and genetic estimates suggests a potential causal relationship.

An updated Alzheimer hypothesis: Complement C3 and risk of Alzheimer's disease-A cohort study of 95,442 individuals.

INTRODUCTION: We tested the hypothesis that low plasma complement C3 is observationally and genetically associated with high risk of Alzheimer's disease (AD). METHODS: We studied 95,442 individuals enrolled in the Copenhagen General Population Study. In genetic analyses, we further included 8367 individuals from the Copenhagen City Heart Study. In the two studies, 1189 and 35 developed AD during median 8 years follow-up. RESULTS: The multifactorially adjusted hazard ratio for risk of AD for a one standard deviation lower levels of complement C3 was 1.11 (95% confidence interval: 1.04-1.19) in all individuals and 1.66 (1.33-2.07) in APOE ε44 carriers. In Mendelian randomization, the corresponding genetic estimates were 1.66 (1.05-2.63) overall and 1.99 (0.52-7.65) in APOE ε44 carriers. DISCUSSION: Low baseline levels of complement C3 were associated with high risk of AD. The risk was amplified in APOE ε44 highly susceptible individuals, and these findings were substantiated by a Mendelian randomization approach, potentially implying causality. Based on these findings, we present and thoroughly discuss an updated Alzheimer hypothesis incorporating low complement C3 levels.

Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection.

BACKGROUND.: Treatment with latency reversing agents (LRAs) enhances human immunodeficiency virus type 1 (HIV-1) transcription in vivo but leads to only modest reductions in the size of the reservoir, possibly due to insufficient immune-mediated elimination of infected cells. We hypothesized that a single drug molecule-a novel Toll-like receptor 9 (TLR9) agonist, MGN1703-could function as an enhancer of innate immunity and an LRA in vivo. METHODS.: We conducted a single-arm, open-label study in which 15 virologically suppressed HIV-1-infected individuals on antiretroviral therapy received 60 mg MGN1703 subcutaneously twice weekly for 4 weeks. We characterized plasmacytoid dendritic cell, natural killer (NK), and T-cell activation using flow cytometry on baseline and after 4 weeks of treatment. HIV-1 transcription was quantified by measuring plasma HIV-1 RNA during MGN1703 administration. RESULTS.: In accordance with the cell type-specific expression of TLR9, MGN1703 treatment led to pronounced activation of plasmacytoid dendritic cells and substantial increases in plasma interferon-α2 levels (P < .0001). Consistently, transcription of interferon-stimulated genes (eg, OAS1, ISG15, Mx1; each P < .0001) were upregulated in CD4+ T cells as demonstrated by RNA sequencing. Further, proportions of activated cytotoxic NK cells and CD8+ T cells increased significantly during MGN1703 dosing, suggesting an enhancement of cellular immune responses. In 6 of 15 participants, plasma HIV-1 RNA increased from <20 copies/mL to >1500 copies/mL (range, 21-1571 copies/mL) during treatment. CONCLUSIONS.: TLR9 agonist treatment in HIV infection has a dual potential by increasing HIV-1 transcription and enhancing cytotoxic NK cell activation, both of which are key outcomes in HIV-1 eradication therapy. CLINICAL TRIALS REGISTRATION.: NCT02443935.

Poor relation between biomechanical and clinical studies for the proximal femoral locking compression plate.

Background and purpose - The proximal femur locking compression plate (PF-LCP) is a new concept in the treatment of hip fractures. When releasing new implants onto the market, biomechanical studies are conducted to evaluate performance of the implant. We investigated the relation between biomechanical and clinical studies on PF-LCP. Methods - A systematic literature search of relevant biomechanical and clinical studies was conducted in PubMed on December 1, 2015. 7 biomechanical studies and 15 clinical studies were included. Results - Even though the biomechanical studies showed equivalent or higher failure loads for femoral neck fracture, the clinical results were far worse, with a 37% complication rate. There were no biomechanical studies on pertrochanteric fractures. Biomechanical studies on subtrochanteric fractures showed that PF-LCP had a lower failure load than with proximal femoral nail, but higher than with angled blade plate. 4 clinical studies had complication rates less than 8% and 9 studies had complication rates between 15% and 53%. Interpretation - There was no clear relation between biomechanical and clinical studies. Biomechanical studies are generally inherently different from clinical studies, as they examine the best possible theoretical use of the implant without considering the long-term outcome in a clinical setting. Properly designed clinical studies are mandatory when introducing new implants, and they cannot be replaced by biomechanical studies.