Chemotherapy-induced gut microbiome disruption, inflammation, and cognitive decline in female patients with breast cancer.

Chemotherapy is notorious for causing behavioral side effects (e.g., cognitive decline). Notably, the gut microbiome has recently been reported to communicate with the brain to affect behavior, including cognition. Thus, the aim of this clinical longitudinal observational study was to determine whether chemotherapy-induced disruption of the gut microbial community structure relates to cognitive decline and circulating inflammatory signals. Fecal samples, blood, and cognitive measures were collected from 77 patients with breast cancer before, during, and after chemotherapy. Chemotherapy altered the gut microbiome community structure and increased circulating TNF-α. Both the chemotherapy-induced changes in microbial relative abundance and decreased microbial diversity were related to elevated circulating pro-inflammatory cytokines TNF-α and IL-6. Participants reported subjective cognitive decline during chemotherapy, which was not related to changes in the gut microbiome or inflammatory markers. In contrast, a decrease in overall objective cognition was related to a decrease in microbial diversity, independent of circulating cytokines. Stratification of subjects, via a reliable change index based on 4 objective cognitive tests, identified objective cognitive decline in 35% of the subjects. Based on a differential microbial abundance analysis, those characterized by cognitive decline had unique taxonomic shifts (Faecalibacterium, Bacteroides, Fusicatenibacter, Erysipelotrichaceae UCG-003, and Subdoligranulum) over chemotherapy treatment compared to those without cognitive decline. Taken together, gut microbiome change was associated with cognitive decline during chemotherapy, independent of chemotherapy-induced inflammation. These results suggest that microbiome-related strategies may be useful for predicting and preventing behavioral side effects of chemotherapy.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in-silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. We also describe preliminary results obtained for 23 systems involving eight protein targets of the proteome of SARS CoV-2. THe MD performed is temperature replica-exchange enhanced sampling, making use of the massively parallel supercomputing on the SUMMIT supercomputer at Oak Ridge National Laboratory, with which more than 1ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to ten configurations of each of the 23 SARS CoV-2 systems using AutoDock Vina. We also demonstrate that using Autodock-GPU on SUMMIT, it is possible to perform exhaustive docking of one billion compounds in under 24 hours. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and AI methods to cluster MD trajectories and rescore docking poses.

The inverse electron-demand Diels-Alder reaction as a new methodology for the synthesis of 225Ac-labelled radioimmunoconjugates.

The inverse electron-demand Diels-Alder reaction between tetrazine (Tz) and trans-cyclooctene (TCO) facilitates the efficient radiosynthesis of 225Ac-labelled radioimmunoconjugates in a two-step method, outperforming conventional approaches based on isothiocyanate couplings.

Physician burnout, work engagement and the quality of patient care.

BACKGROUND: Research suggests that burnout in physicians is associated with poorer patient care, but evidence is inconclusive. More recently, the concept of work engagement has emerged (i.e. the beneficial counterpart of burnout) and has been associated with better care. Evidence remains markedly sparse however. AIMS: To examine the associations of burnout and work engagement with physicians' self-perceived quality of care. METHODS: We drew on cross-sectional data from physicians in Germany. We used a six-item version of the Maslach Burnout Inventory measuring exhaustion and depersonalization. We employed the nine-item Utrecht Work Engagement Scale to assess work engagement and its subcomponents: vigour, dedication and absorption. We measured physicians' own perceptions of their quality of care by a six-item instrument covering practices and attitudes. We used continuous and categorized dependent and independent variables in linear and logistic regression analyses. RESULTS: There were 416 participants. In multivariable linear regression analyses, increasing burnout total scores were associated with poorer perceived quality of care [unstandardized regression coefficient (b) = 0.45, 95% confidence interval (CI) 0.37, 0.54]. This association was stronger for depersonalization (b = 0.37, 95% CI 0.29, 0.44) than for exhaustion (b = 0.26, 95% CI 0.18, 0.33). Increasing work engagement was associated with higher perceived quality care (b for the total score = -0.20, 95% CI -0.28, -0.11). This was confirmed for each subcomponent with stronger associations for vigour (b = -0.21, 95% CI -0.29, -0.13) and dedication (b = -0.16, 95% CI -0.24, -0.09) than for absorption (b = -0.12, 95% CI -0.20, -0.04). Logistic regression analyses yielded comparable results. CONCLUSIONS: Physician burnout was associated with self-perceived poorer patient care, while work engagement related to self-reported better care. Studies are needed to corroborate these findings, particularly for work engagement.

Depression, daily stressors and inflammatory responses to high-fat meals: when stress overrides healthier food choices.

Depression, stress and diet can all alter inflammation. This double-blind, randomized crossover study addressed the impact of daily stressors and a history of major depressive disorder (MDD) on inflammatory responses to high-fat meals. During two separate 9.5 h admissions, 58 healthy women (38 breast cancer survivors and 20 demographically similar controls), mean age 53.1 years, received either a high saturated fat meal or a high oleic sunflower oil meal. The Daily Inventory of Stressful Events assessed prior day stressors and the Structured Clinical Interview for DSM-IV evaluated MDD. As expected, for a woman with no prior day stressors, C-reactive protein (CRP), serum amyloid A (SAA), intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) were higher following the saturated fat meal than the high oleic sunflower oil meal after controlling for pre-meal measures, age, trunk fat and physical activity. But if a woman had prior day stressors, these meal-related differences disappeared-because the stressors heightened CRP, SAA, sICAM-1 and sVCAM-1 responses to the sunflower oil meal, making it look more like the responses to the saturated fat meal. In addition, women with an MDD history had higher post-meal blood pressure responses than those without a similar history. These data show how recent stressors and an MDD history can reverberate through metabolic alterations, promoting inflammatory and atherogenic responses.

Intervention to reduce heat stress and improve efficiency among sugarcane workers in El Salvador: Phase 1.

BACKGROUND: Chronic heat stress and dehydration from strenuous work in hot environments is considered an essential component of the epidemic of chronic kidney disease in Central America. OBJECTIVE: (1) To assess feasibility of providing an intervention modelled on OSHA's Water.Rest.Shade programme (WRS) during sugarcane cutting and (2) to prevent heat stress and dehydration without decreasing productivity. METHODS: Midway through the 6-month harvest, the intervention introduced WRS practices. A 60-person cutting group was provided water supplied in individual backpacks, mobile shaded rest areas and scheduled rest periods. Ergonomically improved machetes and efficiency strategies were also implemented. Health data (anthropometric, blood, urine, questionnaires) were collected preharvest, preintervention, mid-intervention and at the end of harvest. A subsample participated in focus group discussions. Daily wet bulb globe temperatures (WBGT) were recorded. The employer provided individual production records. RESULTS: Over the harvest WBGT was >26°C from 9:00 onwards reaching average maximum of 29.3±1.7°C, around 13:00. Postintervention self-reported water consumption increased 25%. Symptoms associated with heat stress and with dehydration decreased. Individual daily production increased from 5.1 to a high of 7.3 tons/person/day postintervention. This increase was greater than in other cutting groups at the company. Focus groups reported a positive perception of components of the WRS, and the new machete and cutting programmes. CONCLUSIONS: A WRS intervention is feasible in sugarcane fields, and appears to markedly reduce the impact of the heat stress conditions for the workforce. With proper attention to work practices, production can be maintained with less impact on worker health.

[Multiple, 'false positive' diagnoses in patients with severe mental illness; interference-effect between different diagnostic models]. / Multipele, 'fout-positieve' diagnosen bij patiënten met ernstige psychiatrische aandoeningen; effect van interferentie tussen verschillende diagnostische modellen.

BACKGROUND: On the basis of clinical experience the author of the essay asserts that the medical files of patients with severe mental illness quite often show multiple psychiatric dsm diagnoses. Overdiagnosing in the form of multiple, false positive dsm diagnoses confuses patients (who then, for instance, ask: 'Do I have autism or schizophrenia?'), facilitating incorrect treatment indications and possibly leading to stigmatisation. The fact that dimensional diagnostic models have emerged and now co-exist with the dsm cagetorical diagnostic model, can be seen as a risk factor for multiple, false positive dsm diagnoses. AIM: To obtain insight into the mechanisms that support the hypothesis that dimensional diagnosis increases the risk of multiple, false positive dsm diagnoses. METHOD: On the basis of a clinical scientific analysis of the principles and application of dsm categorical and dimensional diagnosis, the author addresses factors that support the hypothesis that dimensional diagnosis increases the risk of multiple, false positive dsm diagnoses. RESULTS: The application of the principles of dimensional diagnosis to the dsm categorical diagnostic model increases the risk of multiple, false positive dsm diagnoses. CONCLUSION: To prevent multiple, false positive dsm diagnoses, it is of crucial importance that the principles of dimensional diagnosis are not applied to the dsm categorical diagnostic model.

Macrophage capping protein CapG is a putative oncogene involved in migration and invasiveness in ovarian carcinoma.

The actin binding protein CapG modulates cell motility by interacting with the cytoskeleton. CapG is associated with tumor progression in different nongynecologic tumor entities and overexpression in breast cancer cell lines correlates with a more invasive phenotype in vitro. Here, we report a significant CapG overexpression in 18/47 (38%) of ovarian carcinomas (OC) analyzed by qRealTime-PCR analyses. Functional analyses in OC cell lines through siRNA mediated CapG knockdown and CapG overexpression showed CapG-dependent cell migration and invasiveness. A single nucleotide polymorphism rs6886 inside the CapG gene was identified, affecting a CapG phosphorylation site and thus potentially modifying CapG function. The minor allele frequency (MAF) of SNP rs6886 (c.1004A/G) was higher and the homozygous (A/A, His335) genotype was significantly more prevalent in patients with fallopian tube carcinomas (50%) as in controls (10%). With OC being one of the most lethal cancer diseases, the detection of novel biomarkers such as CapG could reveal new diagnostic and therapeutic targets. Moreover, in-depth analyses of SNP rs6886 related to FTC and OC will contribute to a better understanding of carcinogenesis and progression of OC.

PPARγ activation inhibits cerebral arteriogenesis in the hypoperfused rat brain.

AIMS: PPARγ stimulation improves cardiovascular (CV) risk factors, but without improving overall clinical outcomes. PPARγ agonists interfere with endothelial cell (EC), monocyte and smooth muscle cell (SMC) activation, function and proliferation, physiological processes critical for arterial collateral growth (arteriogenesis). We therefore assessed the effect of PPARγ stimulation on cerebral adaptive and therapeutic collateral growth. METHODS: In a rat model of adaptive cerebral arteriogenesis (3-VO), collateral growth and function were assessed (i) in controls, (ii) after PPARγ stimulation (pioglitazone 2.8 mg kg(-1); 10 mg kg(-1) compared with metformin 62.2 mg kg(-1) or sitagliptin 6.34 mg kg(-1)) for 21 days or (iii) after adding pioglitazone to G-CSF (40 µg kg(-1) every other day) to induce therapeutic arteriogenesis for 1 week. Pioglitazone effects on endothelial and SMC morphology and proliferation, monocyte activation and migration were studied. RESULTS: PPARγ stimulation decreased cerebrovascular collateral growth and recovery of hemodynamic reserve capacity (CVRC controls: 12 ± 7%; pio low: -2 ± 9%; pio high: 1 ± 7%; metformin: 9 ± 13%; sitagliptin: 11 ± 12%), counteracted G-CSF-induced therapeutic arteriogenesis and interfered with EC activation, SMC proliferation, monocyte activation and migration. CONCLUSION: Pharmacologic PPARγ stimulation inhibits pro-arteriogenic EC activation, monocyte function, SMC proliferation and thus adaptive as well as G-CSF-induced cerebral arteriogenesis. Further studies should evaluate whether this effect may underlie the CV risk associated with thiazolidinedione use in patients.

[Gastrointestinal bleeding in the elderly]. / Gastrointestinale Blutungen im fortgeschrittenen Lebensalter.

Peptic ulcer disease is a common cause of gastrointestinal bleeding, independent of the patient's age. With advancing age, an increase of lower gastrointestinal bleeding (diverticula, angiodysplasia) has been observed. The administration of non-steroidal anti-inflammatory drugs and aspirin is an important risk factor for upper and lower gastrointestinal bleeding, thus in patients aged 65 years and more a concomitant therapy with proton pump inhibitors is recommended in order to prevent ulcer bleeding. Even in very old individuals endoscopy should be used for the diagnosis of gastrointestinal bleeding, providing the opportunity for definite endoscopic bleeding therapy. In elderly patients with comorbidities and recurrent bleeding after endoscopic therapy or continuous blood loss, surgery or transarterial embolisation should be considered in good time.

[Old, sick, unemployed, without a chance? Results of a randomised controlled trial of the effects of a combined health and employment promotion program for the older long-term unemployed (AmigA-M)]. / Alt, krank, arbeitslos, chancenlos? Ergebnisse einer randomisierten Kontrollstudie zur Wirksamkeit einer kombinierten Gesundheits- und Arbeitsförderung bei älteren Langzeitarbeitslosen (AmigA-M).

Illness can be the cause and consequence of unemployment. These relationships are well documented but only few data on the effectiveness of interventions are available. The study examines the effectiveness of a combined health and employment promotion intervention (AmigA - currently projected in several sites in Germany) for the older long-term unemployed with the main goals of an improvement of health and integrability as well as sustainable reintegration into the labour market. The evaluation design is a randomised controlled trial with a multi-method approach. A total of 71 participants could be included in the evaluation. Initial results confirm earlier findings on health and unemployment and show a psychologically and physically highly burdened sample. The intervention tended to improve depression, self-efficacy and quality of life. No effects were found for physical health, integrability and sustainable reintegration. It is discussed whether a longer duration and a higher intensity of the intervention might produce better results. The necessity of help and interventions for this highly burdened group of persons is evident but further studies are necessary to decide if the evaluated intervention is adequate to reach the goals of health and employment promotion as a standard measure.

Laparoscopic repair of a large interstitially incarcerated inguinal hernia.

A 68 year old female presented for elective repair of an abdominal wall hernia. Preoperative CT imaging revealed a right inguinal hernia defect with hernia contents coursing cephalad between the external and internal abdominal oblique muscles. This was consistent with an interstitial inguinal hernia, a rare entity outside of post- traumatic hernias. At operation the hernia contents were reduced laparoscopically. The hernia was then repaired by transitioning to the totally extraperitoneal (TEP) approach using a 15cm X 15cm piece of polyester mesh. The patient had an uneventful recovery. Interstitial hernias are rare, difficult to diagnose and potentially dangerous if left untreated. There is no consensus on the ideal repair of these unique hernias. This represents a minimally invasive repair of an unusual hernia, with a novel approach to diagnose and manage the hernia and its redundant sac.

Tube width fluctuations in F-actin solutions.

We determine the statistics of the local tube width in F-actin solutions, beyond the usually reported mean value. Our experimental observations are explained by a segment fluid theory based on the binary collision approximation. In this systematic generalization of the standard mean-field approach, effective polymer segments interact via a potential representing the topological constraints. The analytically predicted universal tube width distribution with a stretched tail is in good agreement with the data.

Psychotic reactivity in borderline personality disorder.

OBJECTIVE: To investigate the stress relatedness and paranoia specificity of psychosis in borderline personality disorder (BPD). METHOD: Fifty-six borderline patients, 38 patients with cluster C personality disorder, 81 patients with psychotic disorder and 49 healthy controls were studied with the experience sampling method (a structured diary technique) to assess: i) appraised subjective stress and ii) intensity of psychotic experiences. RESULTS: All patient groups experienced significantly more increases in psychotic experiences in relation to daily life stress than healthy controls, borderline patients displaying the strongest reactivity. Borderline patients, moreover, reported significantly more hallucinatory reactivity than healthy controls and subjects with cluster C personality disorder. Paranoid reactivity to daily life stress did not differ between the patient groups. CONCLUSION: These results are the first to ecologically validate stress-related psychosis in BPD. However, psychotic reactivity was not limited to expression of paranoia but involved a broader range of psychotic experiences including hallucinations.

Dynamic structure factor of a stiff polymer in a glassy solution.

We provide a comprehensive overview of the current theoretical understanding of the dynamic structure factor of stiff polymers in semidilute solution based on the wormlike chain (WLC) model. We extend previous work by computing exact numerical coefficients and an expression for the dynamic mean square displacement (MSD) of a free polymer and compare various common approximations for the hydrodynamic interactions, which need to be treated accurately if one wants to extract quantitative estimates for model parameters from experimental data. A recent controversy about the initial slope of the dynamic structure factor is thereby resolved. To account for the interactions of the polymer with a surrounding (sticky) polymer solution, we analyze an extension of the WLC model, the glassy wormlike chain (GWLC), which predicts near power law and logarithmic long-time tails in the dynamic structure factor.

A momentary assessment study of the reputed emotional phenotype associated with borderline personality disorder.

BACKGROUND: Stress is postulated to play an essential role in the expression of core borderline symptoms. However, the phenomenology of stress reactivity in borderline personality disorder remains unclear. The current study investigated the phenomenology of stress sensitivity in borderline personality disorder in the flow of daily life and compared this with stress sensitivity in patients suffering from psychotic disorders, a group so far known to report the largest reactivity to stress. METHOD: A total of 44 borderline patients, 42 patients with psychotic disorder and 49 healthy controls were studied with the Experience Sampling Method (a structured diary technique assessing current context and mood in daily life) to assess: (1) appraised subjective stress related to daily events and activities; and (2) emotional reactivity conceptualized as changes in positive and negative affect. RESULTS: Multilevel regression analysis revealed that subjects with borderline personality disorder experienced significantly more emotional reactivity to daily life stress compared with both patients with psychosis and healthy controls, as evidenced by a larger increase in negative affect and a larger decrease in positive affect following stress. CONCLUSION: These results are the first to ecologically validate the incorporation of stress reactive symptoms in the diagnosis of borderline personality disorder. Borderline patients continually react stronger than patients with psychosis and healthy controls to small disturbances that continually happen in the natural flow of everyday life. Altered emotional stress reactivity may define borderline personality disorder.

Dynorphin-containing axons directly innervate noradrenergic neurons in the rat nucleus locus coeruleus.

Stress causes increased dynorphin (DYN) expression in limbic brain regions and antagonism of kappa-opioid receptors may offer therapeutic potential for the treatment of depression. A potential site of DYN action relevant to stress and related neuropsychiatric disorders is the locus coeruleus (LC), the primary source of forebrain norepinephrine. Therefore, using immunofluorescence and immunoelectron microscopic analyses, we characterized the cellular substrates for interactions between DYN and tyrosine hydroxylase (TH), a catecholamine synthesizing enzyme in single sections through the rat LC. Light microscopic analysis of DYN immunoreactivity indicated that DYN fibers are distributed within the core and pericoerulear subregions of the LC. Using electron microscopy, immunoperoxidase labeling for DYN was primarily found in axon terminals, although in some cases was diffusely localized to somatodendritic processes. When DYN-containing axons formed synaptic contacts, they typically (89%) exhibited an asymmetric morphology. Almost a third (28%) of the postsynaptic targets of DYN-containing axons contained immunogold labeling for TH. These findings reveal some diversity as to the localization of DYN in the LC within axons that contact both TH and non-TH containing dendrites. However, the present data provide the first ultrastructural evidence that DYN-containing axon terminals directly innervate catecholaminergic LC dendrites. Moreover, DYN axon terminals targeting catecholaminergic LC dendrites via asymmetric synapses are consistent with localization within excitatory type afferents to the LC. Therefore, direct modulation of catacholaminergic LC neurons maybe an important site of action for DYN relevant to stress and stress-related disorders.

Long-term caregiving: what happens when it ends?

Data from a longitudinal study were used to examine what happens to caregivers in the years after their cognitively impaired spouse dies. Comparisons of 42 current caregivers, 49 former caregivers, and 52 noncaregivers over a 4-year period showed that former caregivers did not improve on several measures of psychological well-being. Although former caregivers experienced decreases in stress and negative affect, their scores on depression, loneliness, and positive affect did not rebound to levels comparable to noncaregivers and, in fact, remained similar to those of current caregivers up to 3 years after caregiving had ceased. The most consistent predictors of postcaregiving outcomes were social support and intrusive-avoidant thinking about caregiving. The data suggest that some consequences of long-term caregiving may be long-term as well. The needs of former spousal caregivers warrant greater attention both in research and in practice.