Controlled Rate Research Articles

Examining gender differentials in the association of low control work with cognitive performance in older workers.

BackgroundLimited workplace control, an important dimension of job strain, can reduce occupational opportunities for problem solving and learning. Women may have fewer professional resources to mitigate effects of low control, while conversely, gender-role norms may moderate the influence of occupational psychosocial risk factors. We therefore examined whether the links between control and cognitive function were similarly gendered.MethodsThis observational, longitudinal study included respondents of the Survey of Health, Ageing and Retirement in Europe who were aged 50–64 years at entry, employed and provided at least two measurements of control and cognition (n = 6697). Relationships between control and cognition, quantified with standardized scores from verbal fluency, immediate and delayed word recall tests, were explored using linear fixed-effect and random-effect models with gender interactions.ResultsConsistent trends of improved verbal fluency performance with high control were evident across analyses, equal to producing around three-quarters of a word more under high control conditions, with an effect size ∼0.1 SD units (fully adjusted models, range 0.077–0.104 SD), although associations with recall tests were inconsistent. We did not find evidence of clear gender differences in control–cognition relationships for any of the cognitive domains.ConclusionsThe cognitive health of older European workers may benefit from improved workplace control irrespective of gender. Possible sources of bias that could explain the lack of gender differences are discussed, particularly gender differences in labour force participation, response behaviour in job control ratings and implications of gender-role norms on the importance of occupational risk factors.

Preliminary Validation of an Abbreviated Acute Concussion Symptom Checklist Using Item Response Theory

Background: Symptom assessment is a critical component of concussion diagnosis and management, with item selection primarily driven by clinical judgment or expert consensus. We recently demonstrated that concussion symptoms assessed by the Sport Concussion Assessment Tool (SCAT) are essentially unidimensional, implying that overall symptom severity may be accurately estimated with relatively few questions. Briefer, evidence-based forms for symptom assessment would provide clinicians flexibility. Purpose: To develop and validate an abbreviated assessment of general concussion symptom severity using item response theory analyses. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: Broad clinical assessments (SCAT3, Immediate Post-concussion and Cognitive Testing, Balance Error Scoring System, and Brief Symptom Inventory–18 Global Severity Index) were completed by 265 injured athletes and 235 matched teammate controls at 24 to 48 hours and 8, 15, and 45 days after concussion. Symptom checklist short forms (3-14 items from the original 22) were selected using item response theory item information curves. Internal consistency reliability (Cronbach alpha), correlation with criterion measures assessed concurrently (ie, acute neurocognitive performance, balance, and emotional symptoms), predictive validity (correlations with symptom duration), and differences between concussed and control groups (Cohen d) were examined across forms. Sensitivity and false-positive rates of the forms were estimated and compared using reliable change indices derived from controls. Results: Across the 3- to 22-item forms, internal consistency was excellent (Cronbach alphas, 0.90-0.94). Clinical correlations were significant (P≤ .017) and to similar degrees for all short forms. Group difference confidence intervals overlapped across forms at 24- to 48-hour (Cohen d, 1.27-1.51) and 8-day follow-up (Cohen d, 0.31-0.44). Sensitivity remained similar across short forms, with a low false-positive rate in controls. Conclusion: Our findings suggest that even an ultrashort (3-item) inventory provides sufficiently reliable and valid estimates of overall concussion symptom severity 24 to 48 hours after injury. Future revisions of the SCAT could eliminate inefficient items, although replication in larger samples and extension to other postinjury time points are warranted.

Clinical characteristics and risk factors for mortality in hematologic patients affected by COVID-19.

Patients with cancer are considered highly vulnerable to the recent coronavirus disease 2019 (COVID-19) pandemic. However, there are still few data on COVID-19 occurring in hematologic patients. One hundred two patients with COVID-19 symptoms and a nasopharyngeal swab positive for severe acute respiratory syndrome coronavirus 2 seen at 2 hematologic departments located in Lombardy, Italy, during March 2020 were studied. Risk factors for acquiring COVID-19 were analyzed by comparisons of patients with COVID-19 and the standard hematologic population managed at the same institutions in 2019. Thirty-day survival was compared with the survival of matched uninfected control patients with similar hematologic disorders and nonhematologic patients affected by COVID-19. Male sex was significantly more prevalent in patients with COVID-19. The infection occurred across all different types of hematologic disease; however, the risk of acquiring a COVID-19 infection was lower for patients with chronic myeloproliferative neoplasms, including chronic myeloid leukemia, and higher for patients with immune-mediated anemia on immunosuppressive-related treatments. The 30-day mortality rate was 39.2%, which was higher than the rates for nonhematologic patients with COVID-19 (23.5%; P=.02) and uninfected hematologic controls (3%; P<.001). The severity of the respiratory syndrome at presentation and active hematologic treatment were independently associated with a worse prognosis. Neither diagnosis nor disease status affected the prognosis. The worst prognosis was demonstrated among patients on active hematologic treatment and those with more severe respiratory syndrome at COVID-19 presentation. During the COVID-19 pandemic, patients should be advised to seek medical attention at the earliest signs of dyspnea and/or respiratory infection. Physicians should perform a risk-benefit analysis to determine the impact of temporarily deferring nonlifesaving treatments versus the risk of adverse outcomes associated with COVID-19. Coronavirus disease 2019 (COVID-19) infection occurs across all different types of hematologic disease; however, the risk of acquiring it is lower for patients with chronic myeloproliferative neoplasms, including chronic myeloid leukemia, and higher for patients with immune-mediated anemia on immunosuppressive treatment. The 30-day mortality rate is 39.2%, which is far higher than the rates for both uninfected hematologic controls (3%; P<.001) and nonhematologic patients with COVID-19 (23.5%; P=.02) despite matching for age, sex, comorbidities, and severity of disease. Variables independently associated with a worse prognosis are the severity of the respiratory syndrome at presentation and any type of active hematologic treatment. Neither diagnosis nor disease status influence the prognosis.

The epidemiology of hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease defined clinically by multiple, painful inflammatory lesions occurring predominantly in flexural sites. Onset is typically soon after puberty; however, it remains unknown whether the menopause induces remission. In North American and European patients with HS the female-to-male ratio is approximately 3:1 but the ratio is 1:2 in South Korean patients. It may be that some elements of HS epidemiology cannot be generalized across all populations. Elements of HS epidemiology in the USA and Europe are well established, including strong associations with obesity and smoking, which may increase disease severity. There are associations between HS and other cardiovascular disease (CVD) risk factors, including type 2 diabetes and metabolic syndrome. People with HS have double the risk of death from CVD compared with those without HS and 1·5 times the risk compared with patients with psoriasis. Depression and anxiety are associated with HS and completed suicide rates in those with HS are more than double the rates in controls. Associations exist between HS and other chronic inflammatory conditions, particularly inflammatory bowel disease and inflammatory arthritis. Case-control studies demonstrate associations with pilonidal sinus, polycystic ovary syndrome, Down syndrome, obstructive sleep apnoea and pyoderma gangrenosum. Population-based studies using routinely collected healthcare data from the USA estimate a prevalence of 0·1%, suggesting HS is relatively uncommon. European studies include undiagnosed patients and typically estimate prevalence of 1% or more, suggesting a common condition. Resolving the controversy surrounding a greater than 10-fold difference in HS prevalence estimates remains a high priority.

Feeling in Control: The Role of Cardiac Timing in the Sense of Agency

The sense of agency describes the experience of controlling one’s body to cause desired effects in the world. We explored whether this is influenced by interoceptive processes. Specifically, we investigated whether the sense of agency changes depending on where, in the cardiac cycle (systole or diastole), the action was executed and where the outcome of the action occurred. In two experiments, participants completed decision-making task to win/lose money. Explicit (ratings of control) and implicit (temporal judgement) measures of agency were differentially affected by cardiovascular state. Implicit agency scores were affected by the cardiac phase at the point of action execution. Explicit ratings of control were affected by the type of (free vs. instructed) and by outcome valence (win vs. lose). The time of the action was uniformly distributed across the cardiac cycle. These results show interoceptive impact on agency, but that cardiac cycle may affect explicit and implicit agency differently.

Education vs Clinician Feedback on Antibiotic Prescriptions for Acute Respiratory Infections in Telemedicine: a Randomized Controlled Trial

Antibiotics prescribed for acute respiratory tract infections in the telemedicine setting are often unwarranted. We hypothesized that education plus individualized feedback, compared with education alone, would significantly reduce antibiotic prescription rates for upper respiratory infections, bronchitis, sinusitis, and pharyngitis in a telemedicine setting. Two-arm, parallel-group randomized controlled trial conducted at a telemedicine practice from January 1, 2018, to November 30, 2018. Clinicians employed at the practice on or after January 1, 2017 (n = 45). The control group received education (treatment guideline presentation and online course) in April 2018. The intervention group received education plus individualized feedback via an online dashboard with monthly rates of personal and practice-wide antibiotic prescription rates starting May 2018. Antibiotic prescription for any visit with at least one target condition: upper respiratory tract infection, bronchitis, sinusitis, and pharyngitis. Baseline antibiotic prescription rates in control and intervention groups across conditions were as follows: upper respiratory infection (URI): 626/3410 (18.4%), 413/2752 (15.0%), bronchitis: 689/1471 (46.8%), 742/1162 (64.0%), sinusitis: 5154/6131 (84.1%), 4250/4876 (87.2%), pharyngitis: 2308/2838 (81.3%), 1593/2126 (74.9%). Antibiotic prescriptions for all conditions decreased in the post-intervention period compared with those in the pre-intervention period, for both control and intervention groups. Reduction of antibiotic prescriptions for URI and bronchitis was greater for the group receiving education plus individualized feedback compared with that for the group receiving education alone (interaction term ratio 0.60, 95% CI 0.47 to 0.77 for URI; and interaction term ratio 0.42, 95% CI 0.32 to 0.55 for bronchitis), but not sinusitis and pharyngitis. Education plus individualized feedback in a telemedicine practice significantly decreased antibiotic prescription rates for upper respiratory tract infections and bronchitis, compared with education alone. Future studies should focus on tailoring antibiotic stewardship programs based on underlying conditions, and the maintenance of early reductions in antibiotic prescription.

Parametric removal rate survey study and numerical modeling for deterministic optics manufacturing.

Surface errors directly affect the performance of optical systems in terms of contrast and resolution. Surface figure errors at different surface scales are deterministically removed using controlled material removal rate (MRR) during a precision optics fabrication process. We systematically sectioned the wide range of MRR space with systematic parameters and experimentally evaluated and mapped the MRR values using a flexible membrane-polishing tool. We performed numerical analysis with a tool influence function model using a distributed MRR-based Preston's constant evaluation approach. The analysis procedure was applied to a series of experimental data along with the tool influence function models to evaluate removal rates. In order to provide referenceable survey data without entangled information, we designed the experiments using Taguchi's L27 orthogonal array involving five control parameters and statistically analyzed a large number of programmatic experiments. The analysis of variance showed that the most significant parameters for achieving a higher MRR are the spot size and active diameter.

Development of prepubertal goat oocytes after their in vitro maturation and chemical activation.

Experiments were conducted to study in vitro maturation of prepubertal goat oocytes and their developmental potential after chemical activation. In Experiment 1, cumulus-oocytes complexes collected from the ovaries of prepubertal goats slaughtered at a local abattoir were matured in vitro in TCM-199-based medium supplemented with 10 µg/ml luteinizing hormone (LH) (treatment 1) or 10 µg/ml LH + 0.1 mM l-cysteine (treatment 2). In Experiment 2, mature oocytes were activated with either 5 µM ionomycin or 7% ethanol. After 18 h, some oocytes were randomly fixed and stained to evaluate their chromatin status, while others were cultured in embryo culture medium to study their further development. In Experiment 3, oocytes activated with 5 µM ionomycin were cultured for 7 days in one of the four different culture media [Charles Rosenkrans medium (CR-1), TCM-199, potassium simplex optimization medium (KSOM) and synthetic oviductal fluid (SOF)] to study their developmental potential. The maturation rate in control, treatment 1, and treatment 2 media did not differ from each other (P > 0.05). However, the lowest degeneration of oocytes was observed in treatment 3 (P < 0.05) when compared with the other two groups. The proportion of activated oocytes was higher, while non-activated oocytes were lower in ionomycin group when compared with the group activated with ethanol (P < 0.05). The proportions of oocytes cleaved were 65.7, 56.8, 61.0 and 54.4% in CR-1, TCM-199, KSOM and SOF medium, respectively, with no significant difference. However, further development of cleaved oocytes was better in KSOM followed by SOF.

Evidence for two genetically distinct pathways to co-occurring internalizing and externalizing problems in adolescence characterized by negative affectivity or behavioral inhibition.

Unique pathways to adolescents' co-occurring internalizing/externalizing problems, a severe and common form of psychopathology, remain poorly delineated; this paucity of knowledge impedes the development of personalized interventions. We examined established measures of genetic risk and early childhood temperamental dimensions to clarify potentially distinct pathways to adolescents' co-occurring internalizing/externalizing problems. Participants were drawn from a longitudinal randomized controlled trial of a family-based intervention. The study employed multiple informants and methods, including observer ratings of toddlers' negative affectivity and behavioral inhibition, and primary caregiver ratings of toddlers' inhibitory control; internalizing and aggression polygenic risk scores (PRS) based on prior meta-genome-wide association studies (GWAS); and parents' and teachers' reports of adolescents' internalizing and externalizing problems. Higher levels of the aggression PRS indirectly predicted primary caregiver- and teacher-reported co-occurring problems relative to all other groups through greater early childhood negative affectivity. Lower levels of the aggression PRS and higher levels of the internalizing PRS indirectly predicted co-occurring problems relative to the externalizing "only" and low problem groups (primary caregivers only) through greater early childhood behavioral inhibition. Findings suggest two different genetic pathways to co-occurring problems that could lead to distinct prevention and intervention efforts. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

A microvolume shear cell for combined rheology and x-ray scattering experiments.

An experimental setup is presented for x-ray scattering studies of soft matter under shear flow that employs a low-background coaxial capillary cell coupled to a high-resolution commercial rheometer. The rotor of the Searle type cell is attached to the rheometer shaft, which allows the application of either steady or oscillatory shear of controlled stress or rate on the sample confined in the annular space between the stator and the rotor. The shearing device facilitates ultrasmall-angle x-ray scattering and ultrasmall-angle x-ray photon correlation spectroscopy measurements with relatively low scattering backgrounds. This enables the elucidation of weak structural features otherwise submerged in the background and probes the underlying dynamics. The performance of the setup is demonstrated by means of a variety of colloidal systems subjected to different rheological protocols. Examples include shear deformation of a short-range attractive colloidal gel, dynamics of dilute colloids in shear flow, distortion of the structure factor of a dense repulsive colloidal suspension, shear induced ordering of colloidal crystals, and alignment of multilamellar microtubes formed by a surfactant-polysaccharide mixture. Finally, the new possibilities offered by this setup for investigating soft matter subjected to shear flow by x-ray scattering are discussed.

Oral Bisphosphonate use Reduces Cardiovascular Events in a Cohort of Danish Patients Referred for Bone Mineral Density.

The cardiovascular (CV) safety of oral bisphosphonates (oBPs) is uncertain. Determine the risk of CV events in oBP users referred for bone mineral density (BMD) testing compared with matched controls. Cohort study. Danish national prescription registry enriched with local hospital data from Odense. Individuals aged ≥45 years referred for BMD testing. oBP. Hospitalization for any CV event. Secondary study outcomes were specific CV events. Negative (inguinal hernia surgery and ingrown toenail) and positive (fragility fracture) control outcomes assessed systemic bias. Cox proportional hazards models were fitted to estimate hazard ratio (HR) and 95% confidence intervals. There were 2565 oBP users (82.6% women) and 4568 (82.3% women) propensity score-matched controls. Alendronate accounted for 96% of oBP prescription. A total of 406 (15.8%) CV events occurred in oBP users (rate = 73.48 [66.67-80.98]); rate = events divided by person-time; and 837 (18.3%) events in controls (rate = 104.73 [97.87-112.07]) with an adjusted HR of 0.68 (95% CI 0.60-0.77). Additional adjustment for BMD did not attenuate estimates (HR 0.67; 95% CI 0.58-0.78]. Similar results were seen for secondary outcomes where risk reductions were seen regarding atrial fibrillation, stroke, heart failure, and aneurysms. Positive and negative control outcome analyses identified minimal residual confounding. Oral BP users experienced a 33% reduced risk of CV events. This observational real-world study adds to a growing body of evidence for cardioprotection by oBP that warrants testing in a randomized setting.

Force and Rate Metrics Provide Return-to-Sport Criterion after ACL Reconstruction.

Peak vertical ground reaction force and linear loading rate can be valuable metrics for return-to-sport assessment because they represent limb loading dynamics; yet, there is no defined cutoff criterion to differentiate between healthy and altered limb loading. Studies have shown that healthy individuals exhibit strong first-order relationships between gait variables whereas individuals with pathological conditions did not. Thus, this study sought to explore and exploit this first-order relationship to define a region of healthy limb dynamics, which individuals with pathological conditions would reside outside of, to rapidly assess individuals with altered limb loading dynamics for return to sport. We hypothesized that there would be a strong first-order linear relationship between vertical ground reaction force peak force and linear loading rate in healthy controls' limbs, which could be exploited to identify abnormal limb loading dynamics in post-anterior cruciate ligament reconstruction (ACLR) individuals. Thirty-one post-ACLR individuals and 31 healthy controls performed a running protocol. A first-order regression analysis modeled the relationship between peak vertical ground reaction forces and linear vertical ground reaction force loading rate in the healthy control limbs to define a region of healthy dynamics to evaluate post-ACLR reconstructed limb dynamics. A first-order regression model aided in the determination of cutoff criteria to define a region of healthy limb dynamics. Ninety percent of the post-ACLR reconstructed limbs exhibited abnormal limb dynamics based on their location outside of the region of healthy dynamics. This approach successfully delineated between healthy and abnormal limb loadings dynamics in controls and post-ACLR individuals. The findings demonstrate how force and loading rate-dependent metrics can help develop criteria for individualized post-ACLR return-to-sport assessment.

Assessment of the structural conditions in steel pipeline under various operational conditions – A machine learning approach

Oil and water transport pipeline systems are susceptible to damage due to harsh environmental conditions and operational factors. Hence, ongoing maintenance and inspection are required. The development of continuous and reliable monitoring will ensure the safe usage of these structures and assist in the extension of their life spans. In this study, the monitoring and assessment of pipelines are performed using a network of Fiber Bragg Grating (FBG) sensors mounted in the longitudinal and circumferential directions pipelines. The sensitivity of these measurements to assess pipe pressure and flow variations, and leakage detection and localization were evaluated. Water, at a controlled pressure and flow rate, was pumped into the designed 6-m pipe testbed. Leakage was simulated by opening one of the four designated valves installed on the pipe. Support Vector Machine (SVM) algorithms were implemented, using the collected data, to assist in the prediction of the structural condition of the pipe under various operational conditions. Pressure variations inside the pipe highly impacted the amplitude of the measured strain, increasing it significantly up to 20%. A flow rate increase of 5 GPM had the inverse effect, resulting in a 5% decrease in the amplitude of the measured strain. A change of leakage hole size greatly influenced the measured signal, resulting in a 55% change in amplitude between a 2-cm2 and a 5-cm2 hole. To determine the leakage location, only the temporal aspects of the signal were affected, resulting in slight shifts in sensor response times. The developed SVM classifiers reached accuracies of 88% for flow rate classification, greater than 95% for pressure classification, and 100% for leakage size classification. The accuracy of leakage localization did not exceed 72%. These results are promising for the monitoring of the structural conditions related to leakage detection and localization, based on the patterns observed.

Comparison of brain atrophy in patients with multiple sclerosis treated with first- versus second-generation disease modifying therapy without clinical relapse.

The silent progression of patients with multiple sclerosis (MS) has been reported. The aim of this study was to investigate the association between brain atrophy rates and disease-modifying drugs (DMDs) in patients with MS during their relapse-free period. Patients with relapsing-remitting MS were classified into two groups on the basis of clinical records, i.e. a first-generation DMD group treated with interferon-beta-1a, interferon-beta-1b or glatiramer acetate and a second-generation DMD group treated with dimethyl fumarate, fingolimod or natalizumab. Brain volume was calculated with SPM12. A total of 45 patients with relapsing-remitting MS were enrolled in the first-generation (n=22) or second-generation (n=23) DMD group. The annualized relapse rate was lower in the first-generation than in the second-generation DMD group (median 0.26 vs. 0.59; P<0.001). The annualized atrophy rate of the normalized brain volume was not different between the first- and second-generation DMD groups after analysis of covariance (median 0.13% vs. 0.59%; P=0.17). The median annualized atrophy rate of normalized brain volume in the first-generation DMD group was similar to the previously reported annual brain atrophy rate of healthy controls, which may suggest that treatment with a first-generation DMD need not be changed when patients with MS are clinically inactive.

Effects of new PLM scoring rules on PLM rate in relation to sleep and resting wake for RLS and healthy controls.

This study evaluates the differences in periodic leg movement (PLM) rates for Restless Legs Syndrome (RLS) and healthy controls when using the updated PLM scoring criteria developed by IRLSSG in 2016 versus the prior PLM scoring criteria developed by IRLSSG in 2006. Four major problems with the prior standards had been objectively identified, i.e. minimum inter-movement interval should be 10 not 5s, non-PLM leg movements should end any preceding PLM sequence, a leg movement (LM) can be any length > 0.5s, and a PLM should be a persisting movement not a couple or a series of closely spaced, very brief events. Each of these led to including, erroneously, various random leg movements as PLM. Correcting these problems was expected to increase specificity, reducing the number of PLM detected, particularly in situations producing relatively more random leg movements, e.g. wake vs. sleep and controls without PLMD vs. RLS patients. This study evaluated the putative benefits of the updated, 2016-scoring criteria. The LMs from 42 RLS patients and 30 age- and gender-matched controls were scored for PLMS and PLMW from standard all-night PSG recordings using both 2006 and 2016 WASM criteria. The results confirmed that that the 2016 compared to the 2006 criteria generally decreased the PLM rates with particularly large decreases for the conditions with more random non-PLM events, e.g. wake times and normal healthy controls. This supported the view that the new criteria succeeded in increasing the specificity of PLM detection. Moreover, the changes in PLM rates were generally small for the conditions with relatively few random LM, e.g. RLS and sleep. Thus the bulk of existing PLMS research does not require reconsideration of results, with possible exception of special situations with relatively more random leg movements than periodic leg movements, e.g. wake, healthy normals and children.

Lethal and Sublethal Effects of Methyl Benzoate on the Predatory Bug Nesidiocoris tenuis

Benzoates (naturally occurring plant toxins) produce pesticidal effects on various pest insects and mites, but their effects on non-target insects are poorly understood. In this study, we evaluate the lethal and sublethal toxicity of methyl benzoate (MB) to adults of the generalist predatory bug Nesidiocoris tenuis (Reuter) (Hemiptera: Miridae). To assess lethal effects, N. tenuis was exposed to plant surfaces treated with 0.25%, 0.5% and 1% MB, as well as negative and positive controls (water and the neonicotinoid acetamiprid, respectively). Exposure to 1% MB resulted in the highest corrected mortality of 17.8% and 13.3% under laboratory and greenhouse conditions, respectively. Thus, 1% MB can be classified as harmless to N. tenuis according to the International Organization for Biological Control rating scheme. At the sublethal level, MB exposure did not significantly affect the consumption of eggs of the whitefly Bemisia tabaci by N. tenuis relative to negative control feeding rates. In contrast, acetamiprid at the manufacturer’s recommended concentration reduced N. tenuis feeding activity by 45.4%. Furthermore, in a Y-tube olfactometer assay, there were no significant differences between the olfactory responses of N. tenuis to MB concentrations and the negative control (water). This study therefore suggests that MB could be used safely for pest control in combination with N. tenuis.

Accumulation rate of advanced glycation end products in recent onset psychosis: A longitudinal study

Schizophrenia is associated with excessive oxidative stress. Production of advanced glycation end products (AGEs) in the skin is strongly associated with oxidative stress. Increased skin AGE-levels have been demonstrated at cross-sectional level in recent onset psychosis and chronic schizophrenia, indicating increased cardiovascular risk. We aimed to investigate factors underlying AGE-accumulation and accumulation rate of AGEs in recent onset psychosis. From December 2016 through May 2017, 66 patients and 160 (highly educated) healthy controls from a previous case-control study of AGE-levels were assessed for a follow-up measurement 12–24 months after baseline. Possible determinants of AGE-accumulation were analyzed. AGE-accumulation rates in patients and controls were compared adjusted for relevant confounders. In healthy controls, a significant association of AGE-accumulation with ethnicity and tobacco exposure was found. An indication of a markedly higher AGE-accumulation rate was found in patients suffering from recent onset psychosis compared to healthy controls, independent of ethnicity and tobacco smoking, but not independent of cannabis use (more prevalent in patients than controls), although results were not significant.

Metabolomic Profiles Associated with Mortality of Children with Complicated Severe Malnutrition: A Nested Case-Control Study

Abstract Objectives Children hospitalized with complicated severe malnutrition (CSM) have unacceptably high mortality rates despite receiving standard nutritional and medical treatment. The underlying pathology of the poor prognosis is not well understood. Growing evidence indicates presence of metabolic dysfunction in CSM. Yet, it is unclear whether and how metabolic dysfunction contributes the poor prognosis. This study aimed to identify metabolic signatures and pathways associated with CSM mortality. Methods A case-control study was performed on CSM patients enrolled to a multicenter (one Malawi and two Kenya hospitals) randomized control trial (NCT02246296). A total of 90 death cases and 90 discharged controls that were propensity score matched by age, HIV and mid-upper arm circumferences were included in the study. Targeted metabolomics was performed on their serum samples collected at admission and on day 3 of hospitalization. In particular, 206 metabolites, including amino acids, acylcarnitines, lipids and organic acids were quantified by LC-MS/MS. Results Discriminant analysis (PLS-DA) showed that metabolomic signatures at admission could differentiate cases from controls, with a cross-validated classification error rate of 21.8%. An increase of homovanillic, isobutyric and propionic acids, and decrease of lipids lysoPC a C18:2, lysoPC a C20:4, PC ae C42:2, SM C26:0, and SM C26:1 were the top 8 significant features characterizing the admission metabolomes of cases. Notably, cases with higher levels of isobutyrate, a microbial fermentation product, had significantly shorter survival time, implying a role of gut integrity in mortality. Pathway analysis revealed that metabolites of the tricarboxylic acid (TCA) cycle pathway differentiated cases from controls. Analysis of day 3 samples showed metabolic differences in response to treatment, especially in the recovery rate of lipids, between cases and controls. Conclusions CSM non-survivors have metabolomes distinct from survivors indicating perturbations in mitochondrial function and nutrition utilization. Perturbed metabolites identified shed light on biological mechanisms of mortality and may serve as targets of nutritional or therapeutic interventions to improve CSM survival. Funding Sources Bill and Melinda Gates Foundation, Thrasher Research Fund, and RESTRACOMP Graduate Scholarship.

Mitochondrial Oxidative Phosphorylation Function and Mitophagy in Ischaemic/Reperfused Hearts from Control and High-Fat Diet Rats: Effects of Long-Term Melatonin Treatment.

Oxidative stress causes mitochondrial dysfunction in myocardial ischaemia/reperfusion (I/R) as well as in obesity. Mitochondrial depolarization triggers mitophagy to degrade damaged mitochondria, a process important for quality control. The aims of this study were to evaluate (i) the effect of I/R on mitochondrial oxidative phosphorylation and its temporal relationship with mitophagy in hearts from obese rats and their age-matched controls, and (ii) the role of oxidative stress in these processes using melatonin, a free radical scavenger. Male Wistar rats were divided into 4 groups: control (normal diet ± melatonin) and high-fat sucrose diet (HFSD ± melatonin). Rats received melatonin orally (10mg/kg/day). After 16weeks, hearts were removed and subjected to 40-min stabilization, and 25-min global ischaemia/10-min reperfusion for preparation of mitochondria. Mitochondrial oxidative phosphorylation was measured polarographically. Western blotting was used for evaluation of PINK1, Parkin, p62/SQSTM1 (p62) and TOM 70. Infarct size was measured using tetrazolium staining. Ischaemia and reperfusion respectively reduced and increased mitochondrial QO2 (state 3) and the ox-phos rate in both control and HFSD mitochondria, showing no major changes between the groups, while melatonin pretreatment had little effect. p62 as indicator of mitophagic flux showed up- and downregulation of mitophagy by ischaemia and reperfusion respectively, with melatonin having no significant effect. Melatonin treatment caused a significant reduction in infarct size in hearts from both control and diet groups. The results suggest that I/R (i) affects mitochondria from control and HFSD hearts similarly and (ii) melatonin-induced cardioprotection is not associated with reversal of mitochondrial dysfunction or changes in the PINK1/Parkin pathway.

Effects and mechanism of pyrroloquinoline quinine on mitochondrial function and cell survival of rat bone marrow mesenchymal stem cells under oxidative stress

Objective: To observe the effects of pyrroloquinoline quinine (PQQ) on the mitochondrial function and cell survival of rat bone marrow mesenchymal stem cells (BMSCs) under oxidative stress, and to explore its mechanism. Methods: BMSCs of rats were cultured in vitro with Dulbecco's minimum essential medium/F12 medium containing fetal bovine serum in the volume fraction of 10% (hereinafter referred to as normal medium). The rat BMSCs of third to fifth passages in logarithmic growth phase were selected for the following experiments. (1) The cells were divided into normal control group, normal control+ PQQ group, hydrogen peroxide (H(2)O(2)) alone group, and H(2)O(2)+ PQQ group. The cells in normal control group were cultured in normal medium for 24 hours; the cells in normal control+ PQQ group were cultured in normal medium containing 100 μmol/L PQQ for 24 hours; the cells in H(2)O(2) alone group were cultured in normal medium containing 200 μmol/L H(2)O(2) for 24 hours; the cells in H(2)O(2)+ PQQ group were pre-incubated with normal medium containing 100 μmol/L PQQ for 2 hours, and then with H(2)O(2) added to the concentration of 200 μmol/L and cultured for 24 hours. The cell morphology of each group was observed under the inverted phase contrast microscope, and the cell survival rate was detected by cell count kit 8 method. (2) Five batches of cells were collected, and the cells of each batch were divided into normal control group, H(2)O(2) alone group, and H(2)O(2)+ PQQ group. The cells in each group received the same treatment as that in the corresponding group of experiment (1). After 24 hours of culture, one batch of cells was collected for apoptosis detection by flow cytometry, and the apoptosis rate was calculated. One batch of cells was subjected to mitochondrial membrane potential assay and JC-1 fluorescent staining observation using the JC-1 mitochondrial membrane potential detection kit and the inverted phase contrast fluorescence microscope, respectively. One batch of cells was collected for mitochondrial morphology observation under the transmission electron microscope. One batch of cells was subjected to catalase (CAT) and superoxide dismutase (SOD) activity assay by CAT activity assay kit and SOD activity assay kit, respectively. One batch of cells was subjected to Western blotting for determination of protein level of Epac1, adenine monophosphate activated protein kinase (AMPK), phosphorylated AMPK, cysteinyl aspartate-specific proteinase 3 (caspase-3), and cleaved caspase-3, and the phosphorylation level of AMPK and cleaved caspase-3/caspase-3 ratio were calculated. Six replicates were measured in each group for each index except for morphological observation. Data were statistically analyzed with one-way analysis of variance and independent sample equal variance t test. Results: (1) After 24 hours of culture, compared with those in normal control group (the cell survival rate was set to 100.0%), there was an increase in cell vacuole and a decrease in cell number in H(2)O(2) alone group, and the cell survival rate was significantly reduced to (74.3±2.9)% (t=6.39, P 0.05). (2) After 24 hours of culture, compared with (13.6±1.0)% in normal control group, the apoptosis rate of cells in H(2)O(2) alone group was significantly increased to (37.1±2.0)% (t=10.57, P 0.05). (6) After 24 hours of culture, compared with those in normal control group, the protein expression of Epac1 of cells in H(2)O(2) alone group was significantly decreased (t=4.67, P<0.01), while the AMPK phosphorylation level and the cleaved caspase-3/caspase-3 ratio were significantly increased (t=7.88, 3.62, P<0.01). Compared with those in H(2)O(2) alone group, the protein expression of Epac1 and the AMPK phosphorylation level of cells in H(2)O(2)+ PQQ group were both significantly increased (t=4.34, 16.37, P<0.01), while the cleaved caspase-3/caspase-3 ratio was significantly declined (t=3.17, P<0.05). Conclusions: Pretreatment with PQQ can improve the mitochondrial function, reduce cell apoptosis rate, and enhance cell survival rate of rat BMSCs under oxidative stress, which may be related to the up-regulation of Epac1 protein expression, activation of AMPK signaling pathway, and down-regulation of cleaved caspase-3 protein level.