Depression symptom outcomes and re-engagement among VA patients who discontinue care while symptomatic.

OBJECTIVE: Evaluate outcomes of Veterans who discontinued treatment with at least moderate ongoing depressive symptoms. METHOD: Veterans with elevated depression symptoms from 29 Department of Veterans Affairs facilities completed baseline surveys and follow-up assessments for one year. Analyses examined rates and predictors of treatment discontinuation, treatment re-engagement, and subsequent symptoms among patients who remained out of care. RESULTS: A total of 242 (17.8%; n = 1359) participants discontinued treatment while symptomatic, with Black participants, participants with less severe depression, and participants receiving only psychotherapy (versus combined psychotherapy and antidepressant medications) discontinuing at higher rates. Among all participants who discontinued treatment (n = 445), 45.8% re-engaged within the following six months with participants receiving combined treatment re-engaging at higher rates. Of participants who discontinued while symptomatic within the first 6 months of the study and did not return to care (n = 112), 68.8% remained symptomatic at 12 months. Lower baseline treatment expectancy and greater depression symptom severity were associated with remaining symptomatic while untreated. CONCLUSIONS: Black race, lower symptom severity, and treatment modality may help identify patients at higher risk for discontinuing care while symptomatic, whereas patients with lower treatment expectations may be at greater risk for remaining out of care despite continuing symptoms.

COGNITION: a prospective precision oncology trial for patients with early breast cancer at high risk following neoadjuvant chemotherapy.

BACKGROUND: COGNITION (Comprehensive assessment of clinical features, genomics and further molecular markers to identify patients with early breast cancer for enrolment on marker driven trials) is a diagnostic registry trial that employs genomic and transcriptomic profiling to identify biomarkers in patients with early breast cancer with a high risk for relapse after standard neoadjuvant chemotherapy (NACT) to guide genomics-driven targeted post-neoadjuvant therapy. PATIENTS AND METHODS: At National Center for Tumor Diseases Heidelberg patients were biopsied before starting NACT, and for patients with residual tumors after NACT additional biopsy material was collected. Whole-genome/exome and transcriptome sequencing were applied on tumor and corresponding blood samples. RESULTS: In the pilot phase 255 patients were enrolled, among which 213 were assessable: thereof 48.8% were identified to be at a high risk for relapse following NACT; 86.4% of 81 patients discussed in the molecular tumor board were eligible for a targeted therapy within the interventional multiarm phase II trial COGNITION-GUIDE (Genomics-guided targeted post neoadjuvant therapy in patients with early breast cancer) starting enrolment in Q4/2022. An in-depth longitudinal analysis at baseline and in residual tumor tissue of 16 patients revealed some cases with clonal evolution but largely stable genetic alterations, suggesting restricted selective pressure of broad-acting cytotoxic neoadjuvant chemotherapies. CONCLUSIONS: While most precision oncology initiatives focus on metastatic disease, the presented concept offers the opportunity to empower novel therapy options for patients with high-risk early breast cancer in the post-neoadjuvant setting within a biomarker-driven trial and provides the basis to test the value of precision oncology in a curative setting with the overarching goal to increase cure rates.

Long-distance dispersal suppresses introgression of local alleles during range expansions.

During range expansions, even low levels of interbreeding can lead to massive introgression of local alleles into an invader's genome. Nonetheless, this pattern is not always observed in human populations. For instance, European Americans in North America are barely introgressed by Amerindian genes in spite of known contact and admixture. With coalescent spatially explicit simulations, we examined the impact of long-distance dispersal (LDD) events on introgression of local alleles into the invading population using a set of different demographic scenarios applicable to a diverse range of natural populations and species. More specifically, we consider two distinct LDD models: one where LDD events originate in the range core and targets only the expansion front and a second one where LDD events can occur from any area to any other. We find that LDD generally prevents introgression, but that LDD events specifically targeting the expansion front are most efficient in suppressing introgression. This is likely due to the fact that LDD allows for the presence of a larger number of invader alleles at the wave front, where effective population size is thus increased and local introgressed alleles are rapidly outnumbered. We postulate that the documented settlement of pioneers directly on the wave front in North America has contributed to low levels of Amerindian admixture observed in European Americans and that this phenomenon may well explain the lack of introgression after a range expansion in natural populations without the need to evoke other mechanisms such as natural selection.

Enhanced susceptibility of obese mice to glycidamide-induced sperm chromatin damage without increased oxidative stress.

Diet-induced obesity is known to impair male reproduction and may aggravate the male reproductive toxicity of the food contaminant acrylamide. Exposure of male mice to acrylamide induces paternally mediated pre- and post-implantation losses because of spermatozoal toxicity and these effects are potentiated in mice fed a high-fat diet. Glycidamide - an acrylamide metabolite - is the primary mediator of reproductive effects in males. The mechanisms causing the interaction between diet and acrylamide are not clear. However, diet-induced obesity is associated with oxidative stress in male reproductive tissues which might contribute to increased germ cell susceptibility. In this study, we investigated whether a moderate diet-induced obesity regimen could interfere with glycidamide-induced spermatozoal toxicity and increase oxidative stress. For this purpose, sperm chromatin integrity, oxidised DNA and protein levels, transcript levels of oxidative stress responsive genes and glycidamide-induced DNA and haemoglobin adducts were analysed in samples from male mice exposed to a high-fat diet for 6 weeks in combination with a single glycidamide exposure 7 days prior to sacrifice. We found that glycidamide-induced sperm DNA fragmentation was markedly higher in obese than in lean mice. However, the levels of oxidised DNA and/or protein in blood, liver and testicular tissue was lower in obese than in lean mice. Accompanying the reduced level of oxidised macromolecules, the transcript levels of several oxidative stress-related genes were altered in the liver and testis from obese mice suggesting induction of an antioxidant response in these animals. The haemoglobin-glycidamide adduct levels were higher in obese than in lean animals, whereas obesity did not seem to increase the level of glycidamide-induced DNA adducts. These findings show that a moderate diet-induced obesity regimen may potentiate glycidamide-induced sperm cells toxicity and suggest that the increase in glycidamide-induced sperm toxicity observed in obese mice does not depend on overt oxidative stress.

New Results from the Search for Low-Mass Weakly Interacting Massive Particles with the CDMS Low Ionization Threshold Experiment.

The CDMS low ionization threshold experiment (CDMSlite) uses cryogenic germanium detectors operated at a relatively high bias voltage to amplify the phonon signal in the search for weakly interacting massive particles (WIMPs). Results are presented from the second CDMSlite run with an exposure of 70 kg day, which reached an energy threshold for electron recoils as low as 56 eV. A fiducialization cut reduces backgrounds below those previously reported by CDMSlite. New parameter space for the WIMP-nucleon spin-independent cross section is excluded for WIMP masses between 1.6 and 5.5 GeV/c^{2}.

Riesgo de infección del sitio quirúrgico, según tiempo operatorio en cirugía maxilofacial mayor limpia contaminada: estudio observacional analítico / Risk of surgical site infection according to operating time in major clean-contaminated maxillofacial surgery. Observational analytical study

Introducción: La infección del sitio quirúrgico (ISQ) sigue generando gran morbimortalidad, a pesar de los avances en control de infecciones y técnicas quirúrgicas. Objetivos Determinar si en cirugía maxilofacial mayor limpia contaminada el aumento del tiempo operatorio incrementa la proporción de infección del sitio quirúrgico. Materiales y método Estudio observacional analítico en pacientes ASA I intervenidos en cirugía maxilofacial mayor limpia contaminada entre los años 1997 y 2010 en el Hospital Clínico San Borja Arriarán (Santiago, Chile). Las variables medidas fueron género, edad, tiempo operatorio e ISQ. Se realizó un análisis estadístico mediante prueba de Chi cuadrado, test de la t de Student y regresión logística simple, con un IC del 95 por ciento y el paquete estadístico SPSS. Resultados De un total de 522 pacientes presentaron ISQ 36 (6,9 por ciento). Al comparar los 2 grupos, con ISQ y sin ISQ, no hubo diferencias significativas según género (p = 0,319) y edad (p = 0,238), pero sí según tiempo operatorio (p = 0,046). Se obtuvo un OR = 1,003 (IC 95 por ciento = 1,000-1,006) entre el tiempo operatorio y la infección del sitio quirúrgico. Conclusión Se encontraron diferencias significativas en la proporción de ISQ al aumentar el tiempo operatorio. Sin embargo, esta asociación no es clínicamente significativa.

Introduction: Despite advances in infection control and surgical techniques, surgical site infection (SSI) continues to be a cause of high morbidity and mortality. Objectives To determine if operating time increases the proportion of surgical site infections in clean-contaminated maxillofacial surgery. Materials and method This was an observational analytical study, including ASA I patients undergoing clean-contaminated maxillofacial surgery between 1997 and 2010 at the Clinical Hospital San Borja Arriarán (Santiago, Chile). The outcome variable was surgical site infection. Predictor variables were gender, age, operating time and SSI. Statistical analysis was performed using chi-squared test, Student t test, and simple logistic regression. Results A total of 522 patients met the inclusion criteria. The infection rate was 6.9 percent. Statistically significant differences were only observed in the operation time (P = .046) with an Odds ratio of 1.003 (95 percent CI = 1.000-1.006). Conclusion Significant differences in the proportion of SSI were found when operation time increased. However, this association is not clinically significant.

Data2Dynamics: a modeling environment tailored to parameter estimation in dynamical systems.

UNLABELLED: Modeling of dynamical systems using ordinary differential equations is a popular approach in the field of systems biology. Two of the most critical steps in this approach are to construct dynamical models of biochemical reaction networks for large datasets and complex experimental conditions and to perform efficient and reliable parameter estimation for model fitting. We present a modeling environment for MATLAB that pioneers these challenges. The numerically expensive parts of the calculations such as the solving of the differential equations and of the associated sensitivity system are parallelized and automatically compiled into efficient C code. A variety of parameter estimation algorithms as well as frequentist and Bayesian methods for uncertainty analysis have been implemented and used on a range of applications that lead to publications. AVAILABILITY AND IMPLEMENTATION: The Data2Dynamics modeling environment is MATLAB based, open source and freely available at http://www.data2dynamics.org. CONTACT: andreas.raue@fdm.uni-freiburg.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

First direct limits on lightly ionizing particles with electric charge less than e/6.

While the standard model of particle physics does not include free particles with fractional charge, experimental searches have not ruled out their existence. We report results from the Cryogenic Dark Matter Search (CDMS II) experiment that give the first direct-detection limits for cosmogenically produced relativistic particles with electric charge lower than e/6. A search for tracks in the six stacked detectors of each of two of the CDMS II towers finds no candidates, thereby excluding new parameter space for particles with electric charges between e/6 and e/200.

Search for low-mass weakly interacting massive particles with SuperCDMS.

We report a first search for weakly interacting massive particles (WIMPs) using the background rejection capabilities of SuperCDMS. An exposure of 577 kg days was analyzed for WIMPs with mass <30 GeV/c(2), with the signal region blinded. Eleven events were observed after unblinding. We set an upper limit on the spin-independent WIMP-nucleon cross section of 1.2×10(-42) cm(2) at 8 GeV/c(2). This result is in tension with WIMP interpretations of recent experiments and probes new parameter space for WIMP-nucleon scattering for WIMP masses <6 GeV/c(2).

Search for low-mass weakly interacting massive particles using voltage-assisted calorimetric ionization detection in the SuperCDMS experiment.

SuperCDMS is an experiment designed to directly detect weakly interacting massive particles (WIMPs), a favored candidate for dark matter ubiquitous in the Universe. In this Letter, we present WIMP-search results using a calorimetric technique we call CDMSlite, which relies on voltage-assisted Luke-Neganov amplification of the ionization energy deposited by particle interactions. The data were collected with a single 0.6 kg germanium detector running for ten live days at the Soudan Underground Laboratory. A low energy threshold of 170 eVee (electron equivalent) was obtained, which allows us to constrain new WIMP-nucleon spin-independent parameter space for WIMP masses below 6 GeV/c2.

Intermediary quantitative traits--an alternative in the identification of disease genes in asthma?

Intermediary quantitative traits are a possible alternative for the identification of disease genes. This may be particularly relevant when diagnostic criteria are not very well defined as described for asthma. We analyzed serum samples from 944 individuals of 218 asthma families for 17 cytokines (eotaxin, GM-CSF, IFNγ, IL1B, IL1RA, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12(p40), IL-13, IL-17, IL-23, IL-33, TSLP and TNF-α) and determined the heritability. Linked chromosomal regions were identified by a genome-wide analysis using 334 autosomal microsatellite marker and association tested by further 550 SNP marker at genes implicated earlier with immune response. Heritability varied with TNF-α and IL-8 levels having the highest and TSLP having the lowest heritability. Linkage was significantly increased only for IL-12(p40) at D17S949. There were multiple significant single-nucleotide polymorphisms (SNP) associations (P<0.05) as found in the transmission disequilibrium test, whereas only a few replicated in parents or children only. These include SNPs in IL1RN that were associated with IL-33 and TSLP levels, and a SNP in NR3C2 that was associated with eotaxin, IL-13 and IFN-γ levels. Circulating level of serum cytokines exhibits genetic associations with asthma traits that are otherwise not detected using clinical diagnosis or when the clinical details are ambiguous.

Silicon detector dark matter results from the final exposure of CDMS II.

We report results of a search for weakly interacting massive particles (WIMPS) with the silicon detectors of the CDMS II experiment. This blind analysis of 140.2 kg day of data taken between July 2007 and September 2008 revealed three WIMP-candidate events with a surface-event background estimate of 0.41(-0.08)(+0.20)(stat)(-0.24)(+0.28)(syst). Other known backgrounds from neutrons and 206Pb are limited to <0.13 and <0.08 events at the 90% confidence level, respectively. The exposure of this analysis is equivalent to 23.4 kg day for a recoil energy range of 7-100 keV for a WIMP of mass 10 GeV/c2. The probability that the known backgrounds would produce three or more events in the signal region is 5.4%. A profile likelihood ratio test of the three events that includes the measured recoil energies gives a 0.19% probability for the known-background-only hypothesis when tested against the alternative WIMP+background hypothesis. The highest likelihood occurs for a WIMP mass of 8.6 GeV/c2 and WIMP-nucleon cross section of 1.9×10(-41) cm2.

Irradiation-induced morphea: x-rays as triggers of autoimmunity.

We report on 3 females with breast cancer who developed morphea at the site of post-surgery radiotherapy. One was suffering from other autoimmune skin diseases before the diagnosis and treatment of breast cancer. Postirradiation morphea is a potential complication after radiotherapy, particularly radiotherapy for cancer. This troublesome skin disease can occur months to years after treatment, and is associated with remarkable morbidity and pain, and also cosmetic aspects. Therefore, it is crucial to be aware of this condition, and to try to identify patients who might be at an increased risk of developing morphea.

Gold(I) and mercury(II)-isoelectronic ions with strongly different chemistry: ab initio QMCF molecular dynamics simulations of their hydration structure.

The hydration structure of the isoelectronic Au(I) and Hg(II) ions was determined by means of ab initio quantum mechanical charge field molecular dynamics (QMCF MD) simulations. The two hydrates proved as very labile but entirely different in their structural features. While Hg(II) forms two distinct hydration shells, Au(I) is characterized by an additional extended first shell (meso-shell) which has a considerable influence on all data extracted from the simulation trajectory, namely, radial and angular distribution functions, coordination number distribution, and dynamical data such as mean ligand residence times (MRT) and vibrational frequencies. The short MRT values of the first shell ligands, amounting to a few picoseconds, lead to the simultaneous presence of a number of hydrate complexes with differing geometries, which explains the difficulties in assigning structural data to spectroscopic measurements. The results presented here demonstrate that isoelectronic transition metal ions can show strongly different chemical properties, which cannot be explained on the basis of their different charge alone. The importance of including the second hydration shell and thus the intershell hydrogen bonds in the quantum mechanical treatment of the simulation is clearly proven.

[Chronic venous insufficiency in postthrombotic syndrome and varicose veins]. / Chronische venöse Insuffizienz bei postthrombotischem Syndrom und Varikose.

Venous disorders have a high prevalence and require approximately 1% of health budgets of industrialized countries. The postthrombotic syndrome (PTS) is defined by subjective symptoms and morphologic trophical skin changes following deep venous thrombosis. Prevention of venous thromboembolism in risk situations, easy availability of diagnostic tools (D-dimers, colour-coded duplex sonography) and early detection of deep venous thrombosis, as well as immediate therapeutic anticoagulation along with leg compression during the acute phase and over a two year period of time significantly reduce the incidence of PTS. Chronic venous insufficiency (CVI) includes trophical skin and soft tissue pathologies of the lower leg due to venous hypertension in the distal venous system of the lower extremity. Roughly, two main causes can be distinguished. (A) Deep venous insufficiency (A1 in postthrombotic syndrome; A2 in primary deep venous insufficiency) and (B) superficial venous reflux, usually varicose veins. Compression therapy, surgical ablation of superficial venous reflux, and tangential ablation with split skin graft (shave treatment) of refractory venous ulcers are the mainstays in the treatment of CVI.

Detecting loci under selection in a hierarchically structured population.

Patterns of genetic diversity between populations are often used to detect loci under selection in genome scans. Indeed, loci involved in local adaptations should show high F(ST) values, whereas loci under balancing selection should rather show low F(ST) values. Most tests of selection based on F(ST) use a null distribution generated under a simple island model of population differentiation. Although this model has been shown to be robust, many species have a more complex genetic structure, with some populations sharing a recent ancestry or due to the presence of barriers to gene flow between different parts of a species range. In this paper, we propose the use of a hierarchical island model, in which demes exchange more migrants within groups than between groups, to generate the joint distribution of genetic diversity within and between populations. We show that tests not accounting for a hierarchical structure, when it exists, do generate a large excess of false positive loci, whereas the hierarchical island model is robust to uncertainties about the exact number of groups and demes per group in the system. Our approach also explicitly takes into account the mutational process, and does not just rely on allele frequencies, which is important for short tandem repeat (STR) data. An application to human and stickleback STR data sets reveals a much lower number of significant loci than previously obtained under a non-hierarchical model. The elimination of false positive loci from genome scans should allow us to better determine on which specific class of genes selection is operating.

SysBioMed report: advancing systems biology for medical applications.

The following report selects and summarises some of the conclusions and recommendations generated throughout a series of workshops and discussions that have lead to the publication of the Science Policy Briefing (SPB) Nr. 35, published by the European Science Foundation. (Large parts of the present text are directly based on the ESF SPB. Detailed recommendations with regard to specific application areas are not given here but can be found in the SPB. Issues related to mathematical modelling, including training and the need for an infrastructure supporting modelling are discussed in greater detail in the present text.)The numerous reports and publications about the advances within the rapidly growing field of systems biology have led to a plethora of alternative definitions for key concepts. Here, with 'mathematical modelling' the authors refer to the modelling and simulation of subcellular, cellular and macro-scale phenomena, using primarily methods from dynamical systems theory. The aim of such models is encoding and testing hypotheses about mechanisms underlying the functioning of cells. Typical examples are models for molecular networks, where the behaviour of cells is expressed in terms of quantitative changes in the levels of transcripts and gene products. Bioinformatics provides essential complementary tools, including procedures for pattern recognition, machine learning, statistical modelling (testing for differences, searching for associations and correlations) and secondary data extracted from databases.Dynamical systems theory is the natural language to investigate complex biological systems demonstrating nonlinear spatio-temporal behaviour. However, the generation of experimental data suitable to parameterise, calibrate and validate such models is often time consuming and expensive or not even possible with the technology available today. In our report, we use the term 'computational model' when mathematical models are complemented with information generated from bioinformatics resources. Hence, 'the model' is, in reality, an integrated collection of data and models from various (possibly heterogeneous) sources. The present report focuses on a selection of topics, which were identified as appropriate case studies for medical systems biology, and adopts a particular perspective which the authors consider important. We strongly believe that mathematical modelling represents a natural language with which to integrate data at various levels and, in doing so, to provide insight into complex diseases: 1. Modelling necessitates the statement of explicit hypotheses, a process which often enhances comprehension of the biological system and can uncover critical points where understanding is lacking. 2. Simulations can reveal hidden patterns and/or counter-intuitive mechanisms in complex systems. 3. Theoretical thinking and mathematical modelling constitute powerful tools to integrate and make sense of the biological and clinical information being generated and, more importantly, to generate new hypotheses that can then be tested in the laboratory.Medical Systems Biology projects carried out recently across Europe have revealed a need for action: 4. While the need for mathematical modelling and interdisciplinary collaborations is becoming widely recognised in the biological sciences, with substantial implications for the training and research funding mechanisms within this area, the medical sciences have yet to follow this lead. 5. To achieve major breakthroughs in Medical Systems Biology, existing academic funding schemes for large-scale projects need to be reconsidered. 6. The hesitant stance of the pharmaceutical industry towards major investment in systems biology research has to be addressed. 7. Leading medical journals should be encouraged to promote mathematical modelling.

Large allele frequency differences between human continental groups are more likely to have occurred by drift during range expansions than by selection.

Several studies have found strikingly different allele frequencies between continents. This has been mainly interpreted as being due to local adaptation. However, demographic factors can generate similar patterns. Namely, allelic surfing during a population range expansion may increase the frequency of alleles in newly colonised areas. In this study, we examined 772 STRs, 210 diallelic indels, and 2834 SNPs typed in 53 human populations worldwide under the HGDP-CEPH Diversity Panel to determine to which extent allele frequency differs among four regions (Africa, Eurasia, East Asia, and America). We find that large allele frequency differences between continents are surprisingly common, and that Africa and America show the largest number of loci with extreme frequency differences. Moreover, more STR alleles have increased rather than decreased in frequency outside Africa, as expected under allelic surfing. Finally, there is no relationship between the extent of allele frequency differences and proximity to genes, as would be expected under selection. We therefore conclude that most of the observed large allele frequency differences between continents result from demography rather than from positive selection.

An epistemology of patient safety research: a framework for study design and interpretation. Part 1. Conceptualising and developing interventions.

This is the first of a four-part series of articles examining the epistemology of patient safety research. Parts 2 and 3 will describe different study designs and methods of measuring outcomes in the evaluation of patient safety interventions, before Part 4 suggests that "one size does not fit all". Part 1 sets the scene by defining patient safety research as a challenging form of service delivery and organisational research that has to deal (although not exclusively) with some very rare events. It then considers two inter-related ideas: a causal chain that can be used to identify where in an organisation's structure and/or processes an intervention may impact; and the need for preimplementation evaluation of proposed interventions. Finally, the paper outlines the authors' pragmatist ontological stance to patient safety research, which sets the philosophical basis for the remaining three articles.

An epistemology of patient safety research: a framework for study design and interpretation. Part 3. End points and measurement.

This article builds on the previous two articles in this series, which focused on an evaluation framework and study designs for patient safety research. The current article focuses on what to measure as evidence of safety and how these measurements can be undertaken. It considers four different end points, highlighting their methodological advantages and disadvantages: patient outcomes, fidelity, intervening variables and clinical error. The choice of end point depends on the nature of the intervention being evaluated and the patient safety problem it has been designed to address. This paper also discusses the different methods of measuring error, reviewing best practice and paying particular attention to case note review. Two key issues with any method of data collection are ensuring construct validity and reliability. Since no end point or method of data collection is infallible, the present authors advocate the use of multiple end points and methods where feasible.