Familial hypercholesterolemia and elevated lipoprotein(a): double heritable risk and new therapeutic opportunities.

There is compelling evidence that the elevated plasma lipoprotein(a) [Lp(a)] levels increase the risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. Like low-density lipoprotein (LDL) particles, Lp(a) particles contain cholesterol and promote atherosclerosis. In addition, Lp(a) particles contain strongly proinflammatory oxidized phospholipids and a unique apoprotein, apo(a), which promotes the growth of an arterial thrombus. At least one in 250 individuals worldwide suffer from the heterozygous form of familial hypercholesterolemia (HeFH), a condition in which LDL-cholesterol (LDL-C) is significantly elevated since birth. FH-causing mutations in the LDL receptor gene demonstrate a clear gene-dosage effect on Lp(a) plasma concentrations and elevated Lp(a) levels are present in 30-50% of patients with HeFH. The cumulative burden of two genetically determined pro-atherogenic lipoproteins, LDL and Lp(a), is a potent driver of ASCVD in HeFH patients. Statins are the cornerstone of treatment of HeFH, but they do not lower the plasma concentrations of Lp(a). Emerging therapies effectively lower Lp(a) by as much as 90% using RNA-based approaches that target the transcriptional product of the LPA gene. We are now approaching the dawn of an era, in which permanent and significant lowering of the high cholesterol burden of HeFH patients can be achieved. If outcome trials of novel Lp(a)-lowering therapies prove to be safe and cost-effective, they will provide additional risk reduction needed to effectively treat HeFH and potentially lower the CVD risk in these high-risk patients even more than currently achieved with LDL-C lowering alone.

Factors influencing GPs' perception of specialised palliative homecare (SPHC) importance - results of a cross-sectional study.

BACKGROUND: General Practitioners (GPs) are the main providers of primary palliative care (PPC). At the same time they are the main initiators of specialised palliative homecare (SPHC). In Germany, little is known about factors which influence GPs in their involvement of SPHC. Aim of our study is to identify factors that drive GPs to give value to and involve SPHC. METHODS: A cross-sectional survey was performed. In 2018, questionnaires were mailed to 6000 randomly selected GPs from eight German federal states, focusing on the extent of GPs' palliative care activities and their involvement of SPHC. RESULTS: With a response rate of 19.4% and exclusion of GPs working in SPHC-teams, n = 1026 questionnaires were appropriate for analysis. GPs valued SPHC support as the most "important/very important" for both "technical/invasive treatment measures" (95%) and availability outside practice opening hours (92%). The most relevant factor influencing perceived SPHC-importance was GPs' self-reported extent of engagement in palliative care (ß = - 0.283; CI 95% = - 0.384;-0.182), followed by the perceived quality of utilised SPHC (ß = 0.119; CI 95% = 0.048;0.190), involvement in treatment of palliative patients after SPHC initiation (ß = 0.088; CI 95% = 0.042;0.134), and conviction that palliative care should be a central part of GPs' work (ß = - 0.062; CI 95% = - 0.116;-0.008). Perceived SPHC-importance is also associated with SPHC-referrals (ß =0.138; p < 0.001). The lower the engagement of GPs in palliative care, the more they involve SPHC and vice versa. CONCLUSIONS: GPs with low reported activity in palliative care are more likely to initialise SPHC for palliative care activities they do not deliver themselves for various reasons, which might mean that the involvement of SPHC is substitutive instead of complementary to primary palliative care. This finding and its interpretation should be given more attention in the future policy framework for (specialised) palliative homecare. TRIAL REGISTRATION: German Clinical Trials Register DRKS00014726 , 14.05.2018.

Mining the Gap: Assessing Leadership Needs to Improve 21st Century Plant Pathology.

Scientists and plant pathologists are trained in scientific knowledge and critical thinking as part of their career preparation process. However, the extensive training in science-related skills may come at a cost to "soft skills," the competencies needed for interpersonal skills, communication, management, and leadership. A survey of the American Phytopathological Society indicated that the vast majority of its members (91%) were in leadership and management roles. Despite this, a minority of survey participants felt that their scientific training had prepared them to lead (30%) or manage others (36%). Plant pathologists had received the most training in topics that were tied to science. Less common were critical topics such as resilience, entrepreneurship, visioning, and persuasion, and participants were likely to choose skills considered necessary for management, as opposed to leadership. While scientific training is the primary purpose of graduate training, the lack of leadership training and professional development represents a critical deficiency at a time when science is increasingly moving toward larger collaborative projects. Soft skills training options are available, but utilization of these resources needs to be encouraged. An increased emphasis on augmenting leadership and management skills is critical to prepare scientists for a competitive, dynamic, and increasingly collaborative science landscape.

[Medicalization of social problems using the example of patients with pain]. / Medikalisierung sozialer Probleme am Beispiel von Schmerzpatienten.

The number of invalidity pensions for mental and psychosomatic disorders has dramatically increased in the last decade. Given the experience in sociomedical assessment of people with chronical pain diseases, we developed the impression that primarily social problems-especially long-term unemployment-play an important role in the processes of chronification of pain diseases. We evaluated 100 expert opinions from 2002-2007 according to quantitative and qualitative critieria. We found that at the time of applying for retirement nearly the whole sample was long-term unemployed and that the especially these people suffered from diseases characterized by pain at the beginning of their patient career and they all had received a large range of diagnostic and therapeutic interventions. Only during the course of their disease-usually after the rejection of their application for pension by expert medical opinions-did they receive the diagnosis in the field of psychiatry and psychosomatics. In a next step they were assessed by experts in the field of psychiatry and psychosomatics. In this article, the important social factors that influence this development are discussed.

[Cognitive rehabilitation in early stage Alzheimer's disease]. / Kognitive Rehabilitation bei Alzheimer-Krankheit im Frühstadium.

BACKGROUND: Dementia impairs the coping with routine daily tasks and social relationships due to an increasing degeneration of cognitive abilities. An appropriate treatment must adequately consider the effects of declined cognitive abilities on patients and their environment. Therefore, in recent times, integrative procedures for cognitive rehabilitation (CR) have become increasingly important for the therapy of patients with mild cognitive impairment (MCI) and mild dementia (MD). CR approaches provide compensatory possibilities for clearly defined routine challenges and the individual needs of those affected. MATERIAL AND METHODS: This overview article in the form of a selective review elaborates factors for the effectiveness of CR on the basis of the currently available literature: 1) individuality - consideration of personal needs and targets, 2) compensation - mediation of skills and strategies to compensate for cognitive impairments, 3) interaction - inclusion of relatives and environmental conditions and 4) integration - integration of various therapeutic disciplines and methods. RESULTS AND DISCUSSION: On the basis of this assessment with regards to the content, a critical analysis of the methods of short and long-term therapeutic effects on MCD and MD was carried out. Although the resulting factors were of high long-term relevance for the improvement of depression and quality of life, effects on cognition were more pronounced for MCI than for MD, which emphasizes the importance of beginning therapy as early as possible. The results show that future studies on effectiveness must employ endpoints relevant for routine daily life, and that the possibility of an implementation of therapeutic concepts in a healthcare system should be considered as an essential criterion.

Differences between thermal and laser-induced diffusion.

A combination of femtosecond laser excitation with a low-temperature scanning tunneling microscope is used to study long-range interaction during diffusion of CO on Cu(111). Both thermal and laser-driven diffusion show an oscillatory energy dependence on the distance to neighboring molecules. Surprisingly, the phase is inverted; i.e., at distances at which thermal diffusion is most difficult, it is easiest for laser-driven diffusion and vice versa. We explain this unexpected behavior by a transient stabilization of the negative ion during diffusion as corroborated by ab initio calculations.

Fetomaternal hemorrhage (FMH), an update: review of literature and an illustrative case.

BACKGROUND: Blood trafficking from fetus to mother and vice versa is a well-known physiological event that occurs at any stage in pregnancy. If the fetus looses high blood quantities to the maternal blood stream it becomes symptomatic. These symptoms can vary from cardiovascular distress to fetal death. MATERIALS AND METHODS: We give a review of current literature on Fetomaternal hemorrhage (FMH). CONCLUSION: This article highlights the importance of physician's awareness on detecting this rare but life threatening entity with both severe consequences for mother and neonate. The traditional measurement of FMH and the co-usage of alpha-fetoprotein are debated. To conclude we describe and discuss an illustrative case of FMH. This article gives an applicatory overview of symptoms, diagnostics and treatment of FMH to facilitate physicians to detect this disease precociously.

[Specialised out-patient palliative care (SAPV) in Bavaria: efficiency, structural and process-related effects and rural care]. / Zur Praxis von SAPV in Bayern: Wirksamkeit, Struktur-/prozesseffekte und ländliche Versorgung.

Empirical indications show that specialised out-patient palliative care (SAPV), introduced in Germany in 2007, allows critically ill and dying patients to pass away within their own home even under complex symptoms. SAPV avoids emergency and hospital interferences, and the patient's wish to stay at home until the very end can be respected in most cases. The performance of SAPV is not solely focused on medical and patient-care aspects. It includes consulting and coordination work and also psycho-social support both of patients and family members. Within this framework, different active factors could be identified that are essential for high-quality care. Furthermore, the results show that the general ambulant care commodities on site determine the need, the extent and even the efficiency of SAPV. At the same time, SAPV changes also the respective care environment: it changes the roles of previous care providers and offers new resources, though not all existing resources (e. g., hospice services) are taken into account.

[Memorandum 'Development of health services research in Bavaria from the perspective of the Bavarian State Working Group 'Health Services Research (LAGeV)': status quo - potential - strategies']. / Memorandum "Weiterentwicklung der Gesundheitsversorgungsforschung in Bayern aus Sicht der Landesarbeitsgemeinschaft Gesundheitsversorgungsforschung: Status quo - Entwicklungspotenziale - Strategien".

The aim of the memorandum on the development of health services research (HSR) in Bavaria is to operationalise the global objectives of the State Working Group "Health Services Research" (LAGeV) and to collectively define future topics, specific implementation steps, methods as well as ways of working for the future course of the LAGeV. The LAGeV is an expert committee that integrates and links the competencies of different actors from science, politics and health care regarding HSR and facilitates their cooperation. The memorandum is based on an explorative survey among the LAGeV members, which identified the status quo of health services research in Bavaria, potential for development, important constraints, promoting factors, specific recommendations as well as future topics for the further development of HSR in Bavaria. From the perspective of the LAGeV members, the 12 most important future topics are: 1) Interface and networking research, 2) Innovative health care concepts, 3) Health care for multimorbid patients, 4)Health care for chronically ill patients, 5) Evaluation of innovations, processes and technologies, 6) Patient orientation and user focus, 7) Social and regional inequalities in health care, 8) Health care for mentally ill patients, 9) Indicators of health care quality, 10) Regional needs planning, 11) Practical effectiveness of HSR and 12) Scientific use of routine data. Potential for development of HSR in Bavaria lies a) in the promotion of networking and sustainable structures, b) the establishment of an HSR information platform that bundles information and results in regard to current topics and aims to facilitate cooperation as well as c) in the initiation of measures and projects. The latter ought to pinpoint health care challenges and make recommendations regarding the improvement of health care and its quality. The cooperation and networking structures that were established with the LAGeV should be continuously expanded and be used to work on priority topics in order to achieve the global objectives of the LAGeV.

800-fs, 330-µJ pulses from a 100-W regenerative Yb:YAG thin-disk amplifier at 300 kHz and THz generation in LiNbO3.

Yb:YAG thin-disk lasers offer extraordinary output power, but systems delivering femtosecond pulses at a repetition rate of hundreds of kilohertz are scarce, even though this regime is ideal for ultrafast electron diffraction, coincidence imaging, attosecond science, and terahertz (THz) spectroscopy. Here we describe a regenerative Yb:YAG amplifier based on thin-disk technology, producing 800-fs pulses at a repetition rate adjustable between 50 and 400 kHz. The key design elements are a short regenerative cavity and fast-switching Pockels cell. The average output power is 130 W before the compressor and 100 W after compression, which at 300 kHz corresponds to pulse energies of 430 and 330 µJ, respectively. This is sufficient for a wide range of nonlinear conversions and broadening/compression schemes. As a first application, we use optical rectification in LiNbO3 to produce 30-nJ single-cycle THz pulses with 6 W pump power. The electric field exceeds 10 kV/cm at a central frequency of 0.3 THz, suitable for driving structural dynamics or controlling electron beams.

Screening metagenomic data for viruses using the e-probe diagnostic nucleic acid assay.

Next generation sequencing (NGS) is not used commonly in diagnostics, in part due to the large amount of time and computational power needed to identify the taxonomic origin of each sequence in a NGS data set. By using the unassembled NGS data sets as the target for searches, pathogen-specific sequences, termed e-probes, could be used as queries to enable detection of specific viruses or organisms in plant sample metagenomes. This method, designated e-probe diagnostic nucleic acid assay, first tested with mock sequence databases, was tested with NGS data sets generated from plants infected with a DNA (Bean golden yellow mosaic virus, BGYMV) or an RNA (Plum pox virus, PPV) virus. In addition, the ability to detect and differentiate among strains of a single virus species, PPV, was examined by using probe sets that were specific to strains. The use of probe sets for multiple viruses determined that one sample was dually infected with BGYMV and Bean golden mosaic virus.

[Clinical manifestation of extravasation caused by infusion and its therapeutic management]. / Klinische Manifestationen infusionsbedingter Extravasate und ihr therapeutisches Management.

INTRODUCTION: Extravasal application of chemo-therapeutic agents may cause necrosis of surrounding tissue. Often tendons, nerves and muscles are destroyed. In some cases a surgical excision with an additional coverage is indicated. PATIENTS AND METHODS: In the last ten years we have treated 44  patients with necrosis after extravasation. The defects were mostly localised at the hand or distal forearm, but the cubital fossa and the thorax were affected, too. Excision of the infiltrated tissue was performed and the defect covered with local or free flaps, split skin graft or primary closure. RESULTS: In nearly all cases a stable coverage was achieved. An amputation of the hand was never necessary. Patients with immunosuppression or comorbidity sometimes had wound-healing difficulties that in some cases necessitated further operations. Serious complications were in one case a flap necrosis and another patient died 2  days after the operation because of his nephrotic syndrome. CONCLUSION: Chemotherapy extravasation is an important oncological complication that may cause permanent functional disability of the anatomic region. A variety of free and local flaps with tolerable donor site morbidity can be used for -coverage. We prefer a two-step procedure with radical resection of the area and conditioning of the wound with vacuum therapy or temporary wound coverage and in the next step the definitive wound closure. Conservative treatment is -often followed by a high rate of complications. Early radical debridement and coverage with an adequate flap offers a cure with good functional results.

The effect of measurement error on the positive predictive value of PSW methods for SLD identification: How buffer zones dispel the illusion of inaccuracy.

Patterns of Strengths and Weaknesses (PSW) methods are widely used for identifying specific learning disabilities (SLDs). Several researchers, however, have reported that the diagnostic accuracy of PSW methods is unacceptably low when strict thresholds were used to identify students with SLDs. We believe these findings give a misleading impression of the magnitude of the diagnostic errors that are likely to arise in PSW assessments. In a simulation study of 10 million cases using a simplified PSW method for demonstration, most of what have been called diagnostic errors were cases in which observed scores and true scores fell on opposite sides of a strict threshold but were still within a buffer zone the size of a typical measurement error. Because small score differences do not result in meaningfully different case conceptualizations, the use of buffer zones reveals that previous estimates of the diagnostic accuracy of PSW methods are misleadingly low. We also demonstrate that diagnostic decisions become increasingly reliable when observed scores are comfortably distant from diagnostic thresholds. For practitioners, we present a flowchart and practical guidelines to improve the accuracy and stability of SLD identification decisions.

Development of Primers and Probes for Genus and Species Specific Detection of 'Candidatus Liberibacter Species' by Real-Time PCR.

Huanglongbing (HLB), also known as citrus greening, is currently the most devastating disease impacting citrus production. The disease is associated with three different 'Candidatus Liberibacter species', 'Ca. Liberibacter asiaticus', 'Ca. Liberibacter americanus', and 'Ca. Liberibacter africanus', which induce similar and overlapping symptoms. When HLB-symptomatic trees are tested, one of the Candidatus Liberibacters is normally detected by conventional or real-time PCR (qPCR). The most widely used assays use primers and probes based on the 16S ribosomal RNA (rRNA) gene. The 16S rRNA-based assays to detect the three species are species-specific and must be performed sequentially. We describe a single assay that detected all species of 'Ca. Liberibacter' at the genus level, providing increased convenience. Recent molecular analyses of 'Ca. Liberibacter species' and other bacteria suggest that the rpoB gene (encoding the ß-subunit of RNA polymerase) provides an alternative target for bacterial identification. We report here the design of a single pair of degenerate primers and a hybridization probe corresponding to the rpoB region and their application for the detection of all three citrus 'Ca. Liberibacter species', enabling detection of 'Ca. Liberibacter' at the genus level. In addition, species-specific primers and probes based on the rplJ/rplK genes were designed and used for detection at the species level in a multiplexed format. Both the genus- and species-specific assays were validated in both SYBR Green I and TaqMan formats, and with both plant and insect extracts that contained the pathogen. These one-step qPCR diagnostic methods are useful for the detection of all species of Liberibacter infecting citrus. In addition, the degenerate genus-specific primers and probe successfully detected 'Ca. Liberibacter solanacearum', a psyllid-transmitted pathogen associated with disease in tomato, carrot, and potato.

It's the destination and it's the journey: using multilevel modeling to assess patterns of change in psychotherapy.

BACKGROUND: The pairing of analysis of variance (ANOVA)-based analyses with designs lacking multiple measurement of client change may lead to conclusions that are inconsistent with theoretical expectations about how change will occur. Multilevel modeling (MLM), when used with multiple assessments of client outcomes, provides a flexible set of tools to analyze trajectories of client change. PURPOSE: The authors present an overview of MLM and growth curve analysis as applied to psychotherapy outcome. Results from a simulated data set illustrate how MLM-specifically, growth curve analysis-can be used to test hypotheses from randomized clinical trials. RESULTS: Growth curve analyses were applied to simulated data from an experimental design (treatment versus control group) with multiple assessments of client distress and a client individual difference variable. Results of growth curve analyses confirmed what was found with a pretreatment/posttreatment repeated-measures ANOVA but provided additional information not available from the ANOVA framework. CONCLUSIONS: Given its flexibility, MLM is the recommended method to assess patterns of change in studies of psychotherapy outcome.

A Psychometric Network Analysis of CHC Intelligence Measures: Implications for Research, Theory, and Interpretation of Broad CHC Scores "Beyond g".

For over a century, the structure of intelligence has been dominated by factor analytic methods that presume tests are indicators of latent entities (e.g., general intelligence or g). Recently, psychometric network methods and theories (e.g., process overlap theory; dynamic mutualism) have provided alternatives to g-centric factor models. However, few studies have investigated contemporary cognitive measures using network methods. We apply a Gaussian graphical network model to the age 9-19 standardization sample of the Woodcock-Johnson Tests of Cognitive Ability-Fourth Edition. Results support the primary broad abilities from the Cattell-Horn-Carroll (CHC) theory and suggest that the working memory-attentional control complex may be central to understanding a CHC network model of intelligence. Supplementary multidimensional scaling analyses indicate the existence of possible higher-order dimensions (PPIK; triadic theory; System I-II cognitive processing) as well as separate learning and retrieval aspects of long-term memory. Overall, the network approach offers a viable alternative to factor models with a g-centric bias (i.e., bifactor models) that have led to erroneous conclusions regarding the utility of broad CHC scores in test interpretation beyond the full-scale IQ, g.

How low can you go? Minimum energy pathways for O2 dissociation on Pt(111).

Many DFT studies of O(2) dissociation on Pt(111) give conflicting information on preferred paths and final states. Here we report large p(4 × 4) unit cell minimum energy pathway evaluations and compare O(2) adsorption and dissociated states on Pt(111). Calculations reveal how the pathways for O(2) dissociation starting from top-fcc-bridge, top-hcp-bridge, and top-bridge-top sites are interconnected. They also provide a direct reaction pathway for the dissociation of an O(2) molecule from a top-fcc-bridge into an hcp and an fcc site, which is consistent with low temperature scanning tunneling microscope experiments. Such a pathway is shown to be considerably perturbed by the presence of co-adsorbed oxygen atoms. We quantify the coverage dependence through the construction of a Brønsted-Evans-Polanyi relationship relating the O(2) dissociation activation energies to the binding energies of the dissociated O atoms. We also show that all pathways starting from a top-fcc-bridge site give the smallest barriers for O(2) dissociation.

Potential energy surfaces for oxygen adsorption, dissociation, and diffusion at the Pt(321) surface.

We report a first-principles, periodic supercell analysis of oxygen adsorption, diffusion, and dissociation at the kinked Pt(321) surface. Binding energies and binding site preferences of isolated oxygen atoms and molecules have been determined, and we show that both atomic and molecular oxygen prefer binding in bridge sites involving coordinatively unsaturated kink Pt atoms. Binding energies of atomic and molecular oxygen in different sites correlate well with the average metallic Pt coordination number of Pt atoms forming each site, although differences exist between adsorbates in symmetrically similar sites due to the inherent chirality of the surface. Atomic O in the strongest binding bridge sites experiences relatively small energy barriers for diffusion to neighboring sites compared to O on Pt(111). However, due to the structure of the surface, O diffusion is only rapid between different sites around the kink Pt atom, whereas the effective long-range tracer diffusion, as determined from a simple course-grain model, is shown to be anisotropic and slower than on the Pt(111) surface. Four dissociation pathways for O(2) at low coverage are also reported and found to be in agreement with experimental observations of facile dissociation, even at low temperature.