Prevalence of Familial Hypercholesterolemia Among the General Population and Patients With Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Contemporary studies suggest that familial hypercholesterolemia (FH) is more frequent than previously reported and increasingly recognized as affecting individuals of all ethnicities and across many regions of the world. Precise estimation of its global prevalence and prevalence across World Health Organization regions is needed to inform policies aiming at early detection and atherosclerotic cardiovascular disease (ASCVD) prevention. The present study aims to provide a comprehensive assessment and more reliable estimation of the prevalence of FH than hitherto possible in the general population (GP) and among patients with ASCVD. METHODS: We performed a systematic review and meta-analysis including studies reporting on the prevalence of heterozygous FH in the GP or among those with ASCVD. Studies reporting gene founder effects and focused on homozygous FH were excluded. The search was conducted through Medline, Embase, Cochrane, and Global Health, without time or language restrictions. A random-effects model was applied to estimate the overall pooled prevalence of FH in the general and ASCVD populations separately and by World Health Organization regions. RESULTS: From 3225 articles, 42 studies from the GP and 20 from populations with ASCVD were eligible, reporting on 7 297 363 individuals/24 636 cases of FH and 48 158 patients/2827 cases of FH, respectively. More than 60% of the studies were from Europe. Use of the Dutch Lipid Clinic Network criteria was the commonest diagnostic method. Within the GP, the overall pooled prevalence of FH was 1:311 (95% CI, 1:250-1:397; similar between children [1:364] and adults [1:303], P=0.60; across World Health Organization regions where data were available, P=0.29; and between population-based and electronic health records-based studies, P=0.82). Studies with ≤10 000 participants reported a higher prevalence (1:200-289) compared with larger cohorts (1:365-407; P<0.001). The pooled prevalence among those with ASCVD was 18-fold higher than in the GP (1:17 [95% CI, 1:12-1:24]), driven mainly by coronary artery disease (1:16; [95% CI, 1:12-1:23]). Between-study heterogeneity was large (I2>95%). Tests assessing bias were nonsignificant (P>0.3). CONCLUSIONS: With an overall prevalence of 1:311, FH is among the commonest genetic disorders in the GP, similarly present across different regions of the world, and is more frequent among those with ASCVD. The present results support the advocacy for the institution of public health policies, including screening programs, to identify FH early and to prevent its global burden.

Design and Fabrication of a Three-Dimensional In Vitro System for Modeling Vascular Stenosis.

Vascular stenosis, the abnormal narrowing of blood vessels, arises from defective developmental processes or atherosclerosis-related adult pathologies. Stenosis triggers a series of adaptive cellular responses that induces adverse remodeling, which can progress to partial or complete vessel occlusion with numerous fatal outcomes. Despite its severity, the cellular interactions and biophysical cues that regulate this pathological progression are poorly understood. Here, we report the design and fabrication of a three-dimensional (3D) in vitro system to model vascular stenosis so that specific cellular interactions and responses to hemodynamic stimuli can be investigated. Tubular cellularized constructs (cytotubes) were produced, using a collagen casting system, to generate a stenotic arterial model. Fabrication methods were developed to create cytotubes containing co-cultured vascular cells, where cell viability, distribution, morphology, and contraction were examined. Fibroblasts, bone marrow primary cells, smooth muscle cells (SMCs), and endothelial cells (ECs) remained viable during culture and developed location- and time-dependent morphologies. We found cytotube contraction to depend on cellular composition, where SMC-EC co-cultures adopted intermediate contractile phenotypes between SMC- and EC-only cytotubes. Our fabrication approach and the resulting artery model can serve as an in vitro 3D culture system to investigate vascular pathogenesis and promote the tissue engineering field.

"Parasite-induced aposematism" protects entomopathogenic nematode parasites against invertebrate enemies.

Aposematism is a well-known strategy in which prey defend themselves from predation by pairing defenses such as toxins, with warning signals that are often visually conspicuous color patterns. Here, we examine the possibility that aposematism can be induced in a host by colonies of infectious parasites in order to protect the parasites from the consequences of attacks on the host. Earlier studies show that avian predators are reluctant to feed on carcasses of host prey that are infected with the entomopathogenic nematode, Heterorhabditis bacteriophora. As the age of infection increases, the parasites kill and preserve the host and subsequently cause its color to change, becoming bright pink then red. Nematode colonies in dead hosts may also be vulnerable, however, to nocturnally active foragers that do not use vision in prey detection. Here, then we test a novel hypothesis that the nematode parasites also produce a warning odor, which functions to repel nocturnally active predators (in this case, the beetle Pterostichus madidus). We show that beetles decrease their feeding on infected insect prey as the age of infection increases and that olfactory cues associated with the infections are effective mechanisms for deterring beetle predation, even at very early stages of infection. We propose that "parasite-induced aposematism" from the nematodes serves to replace the antipredator defenses of the recently killed host. Because sessile carcasses are exposed to a greater range of predators than the live hosts, several alternative defense mechanisms are required to protect the colony, hence aposematic signals are likely diverse in such "parasite-induced aposematism."

Spatial organization of AMPAR subtypes in ON RGCs.

Retinal ganglion cells (RGCs) receive glutamatergic input from bipolar cells through NMDA- and AMPA-type glutamate receptors. Both GluA2-containing, Ca(2+)-impermeable AMPA receptors (CI-AMPARs) and GluA2-lacking, Ca(2+)-permeable AMPA receptors (CP-AMPARs) contribute to light-evoked responses in ON RGCs; however, specific roles for each subtype are not well understood. Here, we present evidence that light intensity determines the subtype of AMPAR that is activated during the synaptic response in ON RGCs. Using current voltage analysis of the EPSC we show that light intensities near RGC threshold, intensities that travel through the well described primary rod pathway, evoke synaptic currents that are preferentially mediated by CP-AMPARs. Synaptic responses evoked by spontaneous release of transmitter from bipolar cell terminals also preferentially activate CP-AMPARs. Conversely, higher light intensities, most likely carried by secondary rod pathways, activate CI-AMPARs. The same pattern of CP-AMPAR and CI-AMPAR activation was observed in mice containing only functional rods, suggesting that the recruitment of CI-AMPARs at higher light intensity does not require cone stimulation. When glutamate spillover was induced by blocking transporters with TBOA, both the near threshold and spontaneous EPSCs contained a significant CI-AMPAR component. We propose that CI-AMPARs are activated by "spillover" of synaptic glutamate only during bright illumination, or when glutamate uptake is blocked. Glutamate may spill over to more distant sites at the same synapse, or perhaps as far as neighboring synapses. Together, our data suggest that the spatial organization of AMPARs at ON RGCs synapses allows for selective, intensity-dependent activation of AMPARs with distinct subunit composition.

Light-induced plasticity of synaptic AMPA receptor composition in retinal ganglion cells.

Light-evoked responses of all three major classes of retinal ganglion cells (RGCs) are mediated by NMDA receptors (NMDARs) and AMPA receptors (AMPARs). Although synaptic activity at RGC synapses is highly dynamic, synaptic plasticity has not been observed in adult RGCs. Here, using patch-clamp recordings in dark-adapted mouse retina, we report a retina-specific form of AMPAR plasticity. Both chemical and light activation of NMDARs caused the selective endocytosis of GluA2-containing, Ca(2+)-impermeable AMPARs on RGCs and replacement with GluA2-lacking, Ca(2+)-permeable AMPARs. The plasticity was expressed in ON but not OFF RGCs and was restricted solely to the ON responses in ON-OFF RGCs. Finally, the plasticity resulted in a shift in the light responsiveness of ON RGCs. Thus, physiologically relevant light stimuli can induce a change in synaptic receptor composition of ON RGCs, providing a mechanism by which the sensitivity of RGC responses may be modified under scotopic conditions.

"...they should be offering it": a qualitative study to investigate young peoples' attitudes towards chlamydia screening in GP surgeries.

BACKGROUND: Despite the known health and healthcare costs of untreated chlamydia infection and the efforts of the National Chlamydia Screening Programme (NCSP) to control chlamydia through early detection and treatment of asymptomatic infection, the rates of screening are well below the 2010-2011 target rate of 35%. General Practitioner (GP) surgeries are a key venue within the NCSP however; previous studies indicate that GP surgery staff are concerned that they may offend their patients by offering a screen. This study aimed to identify the attitudes to, and preferences for, chlamydia screening in 15-24 year old men and women attending GP surgeries (the target group). METHODS: We undertook 36 interviews in six surgeries of differing screening rates. Our participants were 15-24 year olds attending a consultation with a staff member. Data were analysed thematically. RESULTS: GP surgeries are acceptable to young people as a venue for opportunistic chlamydia screening and furthermore they think it is the duty of GP surgery staff to offer it. They felt strongly that it is important for surgery staff to have a non-judgmental attitude and they did not want to be singled out as 'needing' a chlamydia screen. Furthermore, our sample reported a strong preference for being offered a screen by staff and providing the sample immediately at the surgery rather than taking home a testing kit. The positive attitude and subjective norms demonstrated by interviewees suggest that young peoples' behaviour would be to accept a screen if it was offered to them. CONCLUSION: Young people attending GP surgeries have a positive attitude towards chlamydia screening and given the right environment are likely to take up the offer in this setting. The right environment involves normalising screening by offering a chlamydia screen to all 15-24 year olds at every interaction with staff, offering screening with a non-judgmental attitude and minimising barriers to screening such as embarrassment. The GP surgery is the ideal place to screen young people for chlamydia as it is not a threatening place for them and our study has shown that they think it is the normal place to go to discuss health matters.

Using family paradigms to improve evidence-based practice.

PURPOSE: Evidence-based practice (EBP) describes clinical decision making using research, clinical experience, and client values. For family-centered practices, the client's family is integral to this process. This article proposes that using family paradigms, a family science framework, may help elicit and understand client/family values within family-centered EBP. METHOD: This article describes the family paradigms framework: 4 classic paradigms of "closed," "random," "open," and "synchronous." Its applicability to family-centered EBP is proposed using augmentative and alternative communication examples. RESULTS: A family-centered approach to EBP requires families to be an integral part of clinical decision making, but some families may need assistance in enumerating their views and values. Family paradigms (which consider how a family uses its resources of time, space, energy, and material in the pursuit of its goals of control, affect, meaning, and content) may be a way to elicit family values and preferences relevant to clinical decisions. CONCLUSIONS: Family and client values can be incorporated throughout the EBP steps. Considering family paradigms may increase awareness and understanding of how families' views of their goals and resources affect clinical decisions. Further research is needed into both the processes and effectiveness of using family paradigms to conduct family-centered EBP.

Antibiotic prescribing for chronic skin wounds in primary care.

The aim of this study was to describe and quantify systemic antibiotic prescribing for patients with chronic skin wounds presenting at the primary care, nonspecialist setting. Data for 1 year were extracted from a general practice morbidity database comprising approximately 185,000 patients attending family medical practitioners in Wales. Patients with chronic wounds (PCW) were identified using Read Codes and compared with nonwound patients who were randomly selected after matching for age-band, sex, and general practice. PCW received a significantly greater number of antibiotic courses than nonwound patients (p<0.001). This increased level of prescribing was evident for flucloxacillin, co-amoxiclav, cefaclor, cefalexin, erythromycin, trimethoprim, metronidazole, and ciprofloxacin (p<0.01 for all). While PCW also had a significantly higher prevalence of diabetes (16.5% compared with 6.6%, p<0.001), and attended at general practice significantly more frequently than nonwound patients (median (interquartile range) of 25 (17-40) visits per year compared with 12 (4-20), p<0.001), importantly, exclusion of diabetic patients and analysis of the proportion of visits on which patients received antibiotics did not affect the significance of the difference in antibiotic consumption. These data show a strong association between occurrence of chronic wounds and prescribing of antibiotics in primary health care, and wide variation in the type and duration of antibiotic therapy for chronic wounds. Further work is now indicated to rationalize this prescribing and determine the role that this exposure to antibiotics plays in the prevalence of antibiotic resistance in this at-risk elderly population.

Use and recovery of a homogeneous catalyst with carbon dioxide as a solubility switch.

A method for fluorous biphasic catalysis is described,in which the fluorous liquid is replaced by fluorinated silica, the fluorous catalyst is induced to dissolve in the organic solvent by the presence of CO2, and the recovery of the catalyst after the reaction is achieved by release of the CO2 pressure.