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Pain is the most common complaint in primary care medicine, with approximately one-third of the world’s population currently experiencing some type of chronic pain . It’s not always a bad thing; pain serves an evolutionary purpose of warning us of unwellness. But when this signal persists, changes within the peripheral and central nervous systems perpetuate the process, leading to chronic pain (defined as experiencing pain for longer than 3–6 months) . Thus, chronic pain is not merely a symptom of an underlying condition; it is a disease in itself and must be treated as such.
OBJECTIVES/GOALS: Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related deaths by 2030. Though many other cancers have seen improvements in patient survival rates, patients diagnosed with PDAC have a 5-year survival rate of only ~9%. A major contributor to decreased survival is late-stage diagnosis of the disease. New methods of early detection are urgently needed. Extracellular vesicles (EVs) are secreted from cells of all tissue types into the circulation. EVs play important roles in a variety of diseases. They have shown to promote cancer progression and they are being studied as potential biomarkers for disease diagnosis. The purpose of this study was to perform qualitative and quantitative characterization of small-molecule profiles of EVs derived from various pancreatic cancer (PC) and normal pancreas cell lines, to provide proof-of-concept for evaluating the efficacy of leveraging EVs as potential biomarkers of PDAC. METHODS/STUDY POPULATION: EVs were isolated from the conditioned media of six PC and two normal pancreas cell lines using differential ultracentrifugation with filtration. EV enrichment was validated using quantitative ELISA, immunoblot and transmission electron microscopy. Targeted liquid chromatography coupled to mass spectrometry (LC-MS/MS) and untargeted (UPLC-QTOF-MS) metabolomics were used to analyze the biochemical composition of EVs. RESULTS/ANTICIPATED RESULTS: The biochemical profile of PC EVs was found to be significantly different from the profiles of normal cell EVs. Interestingly, amino acids were downregulated in PC EVs as compared to normal cell EVs. However, PC EVs were enriched in lactate and malate. PC EVs also had significant upregulation in other small molecules such as xanthosine, guanosine diphosphate and nicotinamide. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results indicate that the biochemical characterization of EVs using metabolomics has the potential to yield biomarkers which can delineate cancer cell-derived EVs from normal cell-derived EVs. Further work will test the clinical significance of these findings by similar analyses of plasma of PDAC patients. Furthermore, these profiles may be detectable before progression of the disease to late-stage PDAC, leading to the development of assays for earlier diagnosis in patients.
Exposure to traumatic events is common among individuals with substance use disorders (SUD). Self-medication hypothesis posits that substances are used to relieve distressing psychological symptoms. Moreover, few studies have assessed exposure to traumatic events and Posttraumatic stress disorder (PTSD) symptoms among samples suffering from addiction.
To explore SUD inpatients exposure to serious traumatic events both directly (the participant himself) and/or indirectly (the family).
(i) to investigate the prevalence of co-morbid PTSD in SUD clinical inpatients;
(ii) to identify the characteristics, severity and types of trauma experienced;
(iii) to compare SUD patients with and without co-morbid PTSD on psychiatric variables.
This study compared two groups:
(1) those without PTSD,
(2) those with PTSD.
SUD inpatients reported traumatic experiences (Trauma History Questionnaire), PTSD
symptoms (PTSD CheckList-Specific), addiction severity (Addiction Severity Index), and psychiatric symptoms (M.I.N.I.). Khi square or T tests were conducted to compare rates between non-PTSD group (SUD-only; n = 27) and PTSD group (SUD-PTSD; n = 17).
All participants (n = 44) reported having been exposed to one or more traumatic events and 17 (38.6%) met the criteria for probable current PTSD. Significant differences between the “PTSD” and “non-PTSD” groups were found on the crime cluster (p < .04), the composite score of Alcohol (p < .005), and psychiatric variables including depression (p < .001), psychotic syndromes (p < .02) and anxiety disorders (p < .0001).
This study highlights the prevalence of PTSD symptoms among SUD inpatients, and the importance of considering PTSD symptoms to improve quality of care for patients and their families.
It is not clear whether patient's psycho-education enhances compliance to antipsychotic treatments and reduces the number of relapses. Here we investigated the impact of a new psycho-educational program (SOLEDUC®) on the one- and two-years rate of relapse (primary outcome measure) and a number of clinical assessments (secondary outcome measures). This was a multicentric French clinical trial (51 centers) of Phase IV, open, controlled, randomized, consisting in two parallel groups: the Soleduc group (N = 111) and the control group (N = 109). All subjects received a variable dose over the 2-year period of the same antipsychotic drug (amisulpride). Soleduc consisted of a 7-session program (1 h per session), presented three times (at baseline, 6-months and 12-months). Patients in the control group received a non-specific psychosocial training for an equivalent period of time. The models of Andersen-Gill (AG) and Prentice, Williams and Peterson (PWP) were used to analyze relapses. Patients in the Soleduc group attended 14.8 ± 6.1 sessions (mean ± SD), including 17 patients who never attended a session. Intent to treat analysis showed less patients relapsing in the Soleduc group as compared to the control group (21.6% versus 28.4% after 1 year and 84.4% versus 90.8% after 2 years), but the differences were not statistically significant. Relapse risk was significantly reduced for patients who followed at least 7 modules (p = 0.015 AG-test; p < 0.001 PWP-test). In conclusion, no significant differences in relapse rates were found between patients attending the Soleduc program and the control group. Attendance of at least 7 out of 21 program sessions was required to see a modest, but significant two-year relapse prevention in schizophrenia. Other well designed studies are required to evaluate the medical impact of patient's education programs.
The existence of bipolar disorder (BD) among teenagers is controversial. The study aims to review a number of studies regarding the diagnosis of BD in children and teenagers. The prevalence of BD-I is similar throughout many countries, apart from subsyndromal BD, with an estimated 1-3% of teenagers suffering from this illness. Both the presence of subsyndrome BD and full BD have a strong link with psychological difficulties and high risk for use of substances, issues related to legal utilization of services, and suicidality. Diagnosing BD in teenagers is difficult. Therefore, it requires a critical understanding of development stages, evaluation, and accurate recognition and diagnosis. If treatments are delayed, poor outcomes can result. Eight studies were conducted to evaluate the results, based on practices of increasing medical compliance and minimizing hospital readmission among youths with BD. Randomized trial of family-focused therapy was used to determine early interventions for symptomatic teenagers at risk for BD.
The Genomics Used to Improve DEpresssion Decisions (GUIDED) trial assessed outcomes associated with combinatorial pharmacogenomic (PGx) testing in patients with major depressive disorder (MDD). Analyses used the 17-item Hamilton Depression (HAM-D17) rating scale; however, studies demonstrate that the abbreviated, core depression symptom-focused, HAM-D6 rating scale may have greater sensitivity toward detecting differences between treatment and placebo. However, the sensitivity of HAM-D6 has not been tested for two active treatment arms. Here, we evaluated the sensitivity of the HAM-D6 scale, relative to the HAM-D17 scale, when assessing outcomes for actively treated patients in the GUIDED trial.
Outpatients (N=1,298) diagnosed with MDD and an inadequate treatment response to >1 psychotropic medication were randomized into treatment as usual (TAU) or combinatorial PGx-guided (guided-care) arms. Combinatorial PGx testing was performed on all patients, though test reports were only available to the guided-care arm. All patients and raters were blinded to study arm until after week 8. Medications on the combinatorial PGx test report were categorized based on the level of predicted gene-drug interactions: ‘use as directed’, ‘moderate gene-drug interactions’, or ‘significant gene-drug interactions.’ Patient outcomes were assessed by arm at week 8 using HAM-D6 and HAM-D17 rating scales, including symptom improvement (percent change in scale), response (≥50% decrease in scale), and remission (HAM-D6 ≤4 and HAM-D17 ≤7).
At week 8, the guided-care arm demonstrated statistically significant symptom improvement over TAU using HAM-D6 scale (Δ=4.4%, p=0.023), but not using the HAM-D17 scale (Δ=3.2%, p=0.069). The response rate increased significantly for guided-care compared with TAU using both HAM-D6 (Δ=7.0%, p=0.004) and HAM-D17 (Δ=6.3%, p=0.007). Remission rates were also significantly greater for guided-care versus TAU using both scales (HAM-D6 Δ=4.6%, p=0.031; HAM-D17 Δ=5.5%, p=0.005). Patients taking medication(s) predicted to have gene-drug interactions at baseline showed further increased benefit over TAU at week 8 using HAM-D6 for symptom improvement (Δ=7.3%, p=0.004) response (Δ=10.0%, p=0.001) and remission (Δ=7.9%, p=0.005). Comparatively, the magnitude of the differences in outcomes between arms at week 8 was lower using HAM-D17 (symptom improvement Δ=5.0%, p=0.029; response Δ=8.0%, p=0.008; remission Δ=7.5%, p=0.003).
Combinatorial PGx-guided care achieved significantly better patient outcomes compared with TAU when assessed using the HAM-D6 scale. These findings suggest that the HAM-D6 scale is better suited than is the HAM-D17 for evaluating change in randomized, controlled trials comparing active treatment arms.
There is a continual need for invasive plant science to develop approaches for cost-effectively benefiting native over nonnative species in dynamic management and biophysical contexts, including within predominantly nonnative plant landscapes containing only small patches of native plants. Our objective was to test the effectiveness of a minimal-input strategy for enlarging native species patches within a nonnative plant matrix. In Pecos National Historical Park, New Mexico, USA, we identified 40 native perennial grass patches within a matrix of the nonnative annual forb kochia [Bassia scoparia (L.) A.J. Scott]. We mechanically cut B. scoparia in a 2-m-wide ring surrounding the perimeters of half the native grass patches (with the other half as uncut controls) and measured change in native grass patch size (relative to pretreatment) for 3 yr. Native grass patches around which B. scoparia was cut grew quickly the first posttreatment year and by the third year had increased in size four times more than control patches. Treated native grass patches expanded by an average of 25 m2, from 4 m2 in October 2015 before treatment to 29 m2 in October 2018. The experiment occurred during a dry period, conditions that should favor B. scoparia and contraction of the native grasses, suggesting that the observed increase in native grasses occurred despite suboptimal climatic conditions. Strategically treating around native patches to enlarge them over time showed promise as a minimal-input technique for increasing the proportion of the landscape dominated by native plants.
Gilead et al.'s approach to human cognition places abstraction and prediction at the heart of “mental travel” under a “representational diversity” perspective that embraces foundational concepts in cognitive science. But, it gives insufficient credit to the possibility that the process of abstraction produces a gradient, and underestimates the importance of a highly influential domain in predictive cognition: language, and related, the emergence of experientially based structure through time.
Self-reported activity restriction is an established correlate of depression in dementia caregivers (dCGs). It is plausible that the daily distribution of objectively measured activity is also altered in dCGs with depression symptoms; if so, such activity characteristics could provide a passively measurable marker of depression or specific times to target preventive interventions. We therefore investigated how levels of activity throughout the day differed in dCGs with and without depression symptoms, then tested whether any such differences predicted changes in symptoms 6 months later.
Design, setting, participants, and measurements:
We examined 56 dCGs (mean age = 71, standard deviation (SD) = 6.7; 68% female) and used clustering to identify subgroups which had distinct depression symptom levels, leveraging baseline Center for Epidemiologic Studies of Depression Scale–Revised Edition and Patient Health Questionnaire-9 (PHQ-9) measures, as well as a PHQ-9 score from 6 months later. Using wrist activity (mean recording length = 12.9 days, minimum = 6 days), we calculated average hourly activity levels and then assessed when activity levels relate to depression symptoms and changes in symptoms 6 months later.
Clustering identified subgroups characterized by: (1) no/minimal symptoms (36%) and (2) depression symptoms (64%). After multiple comparison correction, the group of dCGs with depression symptoms was less active from 8 to 10 AM (Cohen’s d ≤ −0.9). These morning activity levels predicted the degree of symptom change on the PHQ-9 6 months later (per SD unit β = −0.8, 95% confidence interval: −1.6, −0.1, p = 0.03) independent of self-reported activity restriction and other key factors.
These novel findings suggest that morning activity may protect dCGs from depression symptoms. Future studies should test whether helping dCGs get active in the morning influences the other features of depression in this population (i.e. insomnia, intrusive thoughts, and perceived activity restriction).
Recent advances in nucleic acid extraction and sequencing have changed and expanded our understanding of the diversity of life in the terrestrial and marine subsurface. This chapter highlights recent developments in sequencing genetic material from the deep biosphere (spurred in part by the Census of Deep Life) and new bioinformatics approaches to present a synthesis of our current understanding of the biogeography of life in the deep biosphere. Building from this data framework, this chapter also explores emerging trends in understanding the ecology and evolution of subsurface life.
Motivated by the need for accurate determination of wall shear stress from profile measurements in turbulent boundary layer flows, the total shear stress balance is analysed and reformulated using several well-established semi-empirical relations. The analysis highlights the significant effect that small pressure gradients can have on parameters deduced from data even in nominally zero pressure gradient boundary layers. Using the comprehensive shear stress balance together with the log-law equation, it is shown that friction velocity, roughness length and zero-plane displacement can be determined with only velocity and turbulent shear stress profile measurements at a single streamwise location for nominally zero pressure gradient turbulent boundary layers. Application of the proposed analysis to turbulent smooth- and rough-wall experimental data shows that the friction velocity is determined with accuracy comparable to force balances (approximately 1 %–4 %). Additionally, application to boundary layer data from previous studies provides clear evidence that the often cited discrepancy between directly measured friction velocities (e.g. using force balances) and those derived from traditional total shear stress methods is likely due to the small favourable pressure gradient imposed by a fixed cross-section facility. The proposed comprehensive shear stress analysis can account for these small pressure gradients and allows more accurate boundary layer wall shear stress or friction velocity determination using commonly available mean velocity and shear stress profile data from a single streamwise location.
Early-life environmental and nutritional exposures are considered to contribute to the differences in cardiovascular disease (CVD) burden. Among sub-Saharan African populations, the association between markers of early-life exposures such as leg length and sitting height and CVD risk is yet to be investigated. This study assessed the association between leg length, sitting height, and estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk among Ghanaian-born populations in Europe and Ghana. We constructed sex-specific quintiles for sitting height and leg length for 3250 participants aged 40–70 years (mean age 52 years; men 39.6%; women 60.4%) in the cross-sectional multicenter Research on Diabetes and Obesity among African Migrants study. Ten-year risk of ASCVD was estimated using the Pooled Cohort Equations; risk ≥7.5% was defined as “elevated” CVD risk. Prevalence ratios (PR) were estimated to determine the associations between sitting height, leg length, and estimated 10-year ASCVD risk. For both men and women, mean sitting height and leg length were highest in Europe and lowest in rural Ghana. Sitting height was inversely associated with 10-year ASCVD risk among all women (PR for 1 standard deviation increase of sitting height: 0.75; 95% confidence interval: 0.67, 0.85). Among men, an inverse association between sitting height and 10-year ASCVD risk was significant on adjustment for study site, adult, and parental education but attenuated when further adjusted for height. No association was found between leg length and estimated 10-year ASCVD risk. Early-life and childhood exposures that influence sitting height could be the important determinants of ASCVD risk in this adult population.
Some studies found that providing micronutrient powder (MNP) causes adverse health outcomes, but modifying factors are unknown. We aimed to investigate whether Fe status and inherited Hb disorders (IHbD) modify the impact of MNP on growth and diarrhoea among young Lao children. In a double-blind controlled trial, 1704 children of age 6–23 months were randomised to daily MNP (with 6 mg Fe plus fourteen micronutrients) or placebo for about 36 weeks. IHbD, and baseline and final Hb, Fe status and anthropometrics were assessed. Caregivers provided weekly morbidity reports. At enrolment, 55·6 % were anaemic; only 39·3 % had no sign of clinically significant IHbD. MNP had no overall impact on growth and longitudinal diarrhoea prevalence. Baseline Hb modified the effect of MNP on length-for-age (LAZ) (P for interaction = 0·082). Among children who were initially non-anaemic, the final mean LAZ in the MNP group was slightly lower (–1·93 (95 % CI –1·88, –1·97)) v. placebo (–1·88 (95 % CI –1·83, –1·92)), and the opposite occurred among initially anaemic children (final mean LAZ –1·90 (95 % CI –1·86, –1·94) in MNP v. –1·92 (95 % CI –1·88, –1·96) in placebo). IHbD modified the effect on diarrhoea prevalence (P = 0·095). Among children with IHbD, the MNP group had higher diarrhoea prevalence (1·37 (95 % CI 1·17, 1·59) v. 1·21 (95 % CI 1·04, 1·41)), while it was lower among children without IHbD who received MNP (1·15 (95 % CI 0·95, 1·39) v. 1·37 (95 % CI 1·13, 1·64)). In conclusion, there was a small adverse effect of MNP on growth among non-anaemic children and on diarrhoea prevalence among children with IHbD.
Obesity is considered a risk factor for surgical site infection (SSI). We quantified impact of body mass index (BMI) on the risk of SSI for a variety of surgical procedures.
We included 2012–2017 data from the Dutch national surveillance network PREZIES on a selection of frequently performed surgical procedures across different specialties. Patients were stratified into 5 categories: underweight (BMI, <18.5 kg/m2), normal weight (BMI, 18.5–25), overweight (BMI, 25–30), obese (BMI, 30–40) and morbidly obese (BMI, ≥40). Multilevel log binomial regression analyses were performed to assess the effect of BMI category on the risk of superficial, deep (including organ-space) and total SSI.
Of the 387,919 included patients (ranging from 2,616 for laparoscopic appendectomy to 119,834 for total hip prosthesis), 3,676 (1%) were underweight, 116,778 (30%) had normal weight, 154,339 (40%) were overweight, 104,288 (27%) had obesity, and 8,838 (2%) were morbidly obese. A trend of increasing risk of SSI when BMI increased from normal to morbidly obese was observed for almost all surgery types. The increase was most profound in surgeries with clean wounds, with relative risks for morbidly obese patients ranging up to 7.8 (95% CI, 6.0–10.2) for deep SSI in total hip prosthesis. In chest and abdominal surgeries, the impact was larger for superficial SSI than for deep SSI.
The results of our research provide evidence for the need of preventive programs targeting SSI in overweight and obese patients, as well as for the prevention of obesity in the general population.