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/Background - Depression and sleep disturbance are significant problems during chemotherapy. Study purposes were to identify subgroups of patients with distinct joint depression AND sleep disturbance profiles and evaluate for differences in demographic and clinical characteristics, severity of symptoms, and quality of life (QOL) outcomes among these subgroups.Oncology outpatients (n = 1331) completed measures of depression and sleep disturbance six times over two chemotherapy cycles. Latent profile analysis, that modeled the two symptoms together, was done to identify the distinct joint depression and sleep disturbance profiles.Five distinct profiles were identified (i.e., no depression or sleep disturbance (None, 21.4%); no depression and moderate sleep disturbance (32.3%); subsyndromal depression and very high sleep disturbance (20.4%); moderate depression and moderate sleep disturbance (17.7%); and high depression and very high sleep disturbance (8.2%)). Compared to the None class, the other four classes were more likely to be female; less likely to be employed; had a higher comorbidity burden; and had a lower functional status. Patients in the two very high sleep disturbance classes had problems with both sleep initiation and maintenance. These patients reported higher levels of depressive symptoms, trait and state anxiety, and fatigue as well as lower levels of energy, cognitive function, and poorer QOL.Over 45% of the patients had subsyndromal to high levels of depression AND moderate or very high levels of sleep disturbance. Characteristics associated with the higher risk profiles can be used to screen patients at increased risk for both symptoms.

To determine if islet autotransplantation (IAT) independently improves the quality of life (QoL) in patients after total pancreatectomy and islet autotransplantation (TP-IAT).TP-IAT is increasingly being used for intractable chronic pancreatitis. However, the impact of IAT on long-term islet function and QoL is unclear.TP-IAT patients at our center1 year after TP-IAT with ≥1 Short Form-36 QoL measure were included. Patients were classified as insulin-independent or insulin-dependent, and as having islet graft function or failure by C-peptide. The associations of insulin use and islet graft function with QoL measures were analyzed by using a linear mixed model, accounting for time since transplant and within-person correlation.Among 817 islet autograft recipients, 564 patients [median (interquartile range) age: 34 (20, 45) years, 71% female] and 2161 total QoL surveys were included. QoL data were available for5 years after TP-IAT for 42.7% and for10 years for 17.3%. Insulin-independent patients exhibited higher QoL in 7 of 8 subscale domains and for Physical Component Summary and Mental Component Summary scores ( P0.05 for all). Physical Component Summary was 2.91 (SE=0.57) higher in insulin-independent patients ( P0.001). No differences in QoL were observed between those with and without graft function, but islet graft failure was rare (15% of patients). However, glycosylated hemoglobin was much higher with islet graft failure.QoL is significantly improved when insulin independence is present, and glycosylated hemoglobin is lower with a functioning islet graft. These data support offering IAT, rather than just performing total pancreatectomy and treating with exogenous insulin.

BACKGROUND: Vaginal Lactobacillus is considered protective of some adverse reproductive health outcomes, including preterm birth. However, factors that increase or decrease the likelihood of harboring Lactobacillus in the vaginal microbiome remain largely unknown. In this study, we sought to identify risk and protective factors associated with vaginal Lactobacillus predominance within a cohort of pregnant African American women. MATERIALS AND METHODS: Vaginal microbiome samples were self-collected by African American women (N = 436) during their 8–14th week of pregnancy. Sociodemographic information and measures of health behaviors, including substance use, antibiotic exposure, sexual practices, frequency of vaginal intercourse, and the use of vaginal products, were collected through participant self-report. The V3–V4 region of the 16S rRNA gene was targeted for amplification and sequencing using Illumina HiSeq, with bacterial taxonomy assigned using the PECAN classifier. Univariate and a series of multivariate logistic regression models identified factors predictive of diverse vaginal microbiota or Lactobacillus predominance. RESULTS: Participants who used marijuana in the past 30 days (aOR 1.80, 95% CI 1.08–2.98) were more likely to have diverse non-Lactobacillus-predominant vaginal microbiota, as were women not living with their partners (aOR 1.90, 95% CI 1.20–3.01). Cohabitating or marijuana usage were not associated with type of Lactobacillus (non-iners Lactobacillus vs. Lactobacillus iners) predominance (aOR 1.11, 95% CI 0.52–2.38 and aOR 0.56, 95% CI 0.21–1.47, respectively). CONCLUSIONS: Living with a partner is conducive to vaginal Lactobacillus predominance. As such, cohabitation may be in important covariate to consider in vaginal microbiome studies.

This study evaluated stakeholders’ perspectives regarding participation in two hypothetical neuromodulation trials focused on individuals with Alzheimer's disease and related disorders (ADRDs). Stakeholders (i.e., individuals at risk for ADRDs [ n = 56], individuals with experience as a caregiver for someone with a cognitive disorder [ n = 60], and comparison respondents [ n = 124]) were recruited via MTurk. Primary outcomes were willingness to enroll (or enroll one's loved one), feeling lucky to have the opportunity to enroll, and feeling obligated to enroll in two protocols (transcranial magnetic stimulation, TMS; deep brain stimulation, DBS). Relative to the Comparison group, the At Risk group endorsed higher levels of “feeling lucky” regarding both research protocols, and higher willingness to participate in the TMS protocol. These findings provide tentative reassurance regarding the nature of decision making regarding neurotechnology-based research on ADRDs. Further work is needed to evaluate the full range of potential influences on research participation.

While anxiety is prevalent among women who undergo chemotherapy for breast or gynecologic cancer, research on its predictors has focused primarily on cross-sectional evaluations or on assessments of anxiety prior to and after receipt of chemotherapy. Few studies have evaluated for predictors of inter-individual variability in levels of anxiety during chemotherapy. This study evaluated for inter-individual differences in anxiety across two cycles of chemotherapy and identified demographic, clinical, symptom, and psychological adjustment (e.g., stress, coping) characteristics associated with initial levels and trajectories of anxiety.Patients with breast (n = 530) or gynecologic (n = 233) cancer completed the Spielberger State Anxiety Inventory six times over two cycles of chemotherapy. At enrollment, self-report measures were used to assess demographic, symptom, stress, and coping characteristics. Hierarchical linear modeling was used to evaluate for risk factors associated with initial levels and trajectories of state anxiety.At enrollment, demographic, clinical, symptom, and psychological adjustment characteristics associated with inter-individual differences of anxiety were: marital status, functional status, sleep disturbance, cognitive function, global stress, cancer-specific stress, resilience, sense of coherence, and the coping strategies of venting and self-blame. Employment status and morning fatigue were the only characteristics associated with inter-individual differences in the trajectories of anxiety. Denial was the only characteristic associated with both initial levels and the trajectories of anxiety.A variety of patient characteristics predicted initial levels of anxiety. Fewer characteristics predicted trajectories of anxiety. Identification of specific risk factors, such as avoidant coping, suggests the need for targeted interventions among higher-risk patients.

Patients undergoing chemotherapy for cancer often experience heightened anxiety. While receipt of chemotherapy occurs over multiple cycles, limited research has examined anxiety longitudinally. The purposes of this study, in a large sample of patients with breast, gynecological, gastrointestinal, or lung cancer, were to evaluate, over the course of two cycles of chemotherapy, for inter-individual differences in the trajectories of anxiety and identify associations between demographic, clinical, symptom, and psychological adjustment characteristics and initial levels and trajectories of anxiety.Patients with breast, gynecologic, lung, or gastrointestinal cancer (n = 1323) were assessed with the Spielberger State Anxiety Inventory (STAI-S) six times over two cycles of chemotherapy. At enrollment, patients completed self-report instruments assessing demographic, symptom, stress, and coping characteristics. We used hierarchical linear modeling to identify risk factors associated with initial levels and trajectories of state anxiety.Inter-individual differences in initial levels of anxiety were associated with functional status, sleep disturbance, morning fatigue, cognitive function, global and cancer-specific stress, resilience, and several coping characteristics (i.e., sense of coherence, acceptance, using emotional support, self-distraction, denial, venting, and self-blame). Demographic and clinical characteristics associated with interindividual differences in anxiety trajectories were age, employment status, and MAX-2 score.This study provides novel data on the course and predictors of anxiety during two cycles of chemotherapy among a large sample of patients with varied cancer types. Further research focused on risk factors for heightened levels of anxiety during chemotherapy may help point toward more effective interventions for this commonly experienced symptom.

Incompatible living donor kidney transplant recipients (ILDKTr) have pre-existing donor-specific antibody (DSA) that, despite desensitization, may persist or reappear with resulting consequences, including delayed graft function (DGF) and acute rejection (AR). To quantify the risk of DGF and AR in ILDKT and downstream effects, we compared 1406 ILDKTr to 17 542 compatible LDKT recipients (CLDKTr) using a 25-center cohort with novel SRTR linkage. We characterized DSA strength as positive Luminex, negative flow crossmatch (PLNF); positive flow, negative cytotoxic crossmatch (PFNC); or positive cytotoxic crossmatch (PCC). DGF occurred in 3.1% of CLDKT, 3.5% of PLNF, 5.7% of PFNC, and 7.6% of PCC recipients, which translated to higher DGF for PCC recipients (aOR = 1.03 1.682.72 ). However, the impact of DGF on mortality and DCGF risk was no higher for ILDKT than CLDKT (p interaction > .1). AR developed in 8.4% of CLDKT, 18.2% of PLNF, 21.3% of PFNC, and 21.7% of PCC recipients, which translated to higher AR (aOR PLNF = 1.45 2.093.02 ; PFNC = 1.67 2.403.46 ; PCC = 1.48 2.243.37 ). Although the impact of AR on mortality was no higher for ILDKT than CLDKT (p interaction = .1), its impact on DCGF risk was less consequential for ILDKT (aHR = 1.34 1.621.95 ) than CLDKT (aHR = 1.96 2.292.67 ) (p interaction = .004). Providers should consider these risks during preoperative counseling, and strategies to mitigate them should be considered.

OBJECTIVE To assess the real-world efficacy, tolerability, and safety of ubrogepant in a tertiary headache center. BACKGROUND The efficacy and safety of ubrogepant for the acute treatment of migraine were established in phase 3 randomized controlled trials. However, there is no real-world data of patient experience with ubrogepant in a population in which the majority of patients have chronic migraine, multiple prior unsuccessful treatments, complex medical comorbidities, and concurrent use of other migraine-specific medications. METHOD This was a post-market cohort study conducted at Mayo Clinic Arizona. All patients prescribed ubrogepant were tracked and contacted 1-3 months after the prescription to answer a list of standardized questions. Demographic information and additional headache history were obtained from chart review. RESULTS We obtained eligible questionnaire responses from 106 patients. Chronic migraine accounted for 92/106 (86.8%) of the population. Complete headache freedom (from mild/moderate/severe to no pain) and headache relief (from moderate/severe to mild/no pain or mild to no pain) for ≥75% of all treated attacks at 2 hours after taking ubrogepant were achieved in 20/105 (19.0%) and 50/105 (47.6%) patients, respectively. A total of 33/106 (31.1%) patients reported being "very satisfied" with ubrogepant. Adverse events were reported in 42/106 (39.6%) patients, including fatigue in 29/106 (27.4%), dry mouth in 8/106 (7.5%), nausea/vomiting in 7/106 (6.6%), constipation in 5/106 (4.7%), dizziness in 3/106 (2.8%), and other adverse events in 7/106 (6.6%). Predictive factors for being a "good responder" to ubrogepant, defined as headache relief for ≥75% of all treated attacks at 2 hours after taking ubrogepant, included migraine with aura, episodic migraine

Cytoglobin is important in the progression of oral squamous cell carcinoma but the molecular and cellular basis remain to be elucidated. In the current study, we develop a new cell model to study the function of cytoglobin in oral squamous carcinoma and response to cisplatin. Transcriptomic profiling showed cytoglobin mediated changes in expression of genes related to stress response, redox metabolism, mitochondrial function, cell adhesion, and fatty acid metabolism. Cellular and biochemical studies show that cytoglobin expression results in changes to phenotype associated with cancer progression including: increased cellular proliferation, motility and cell cycle progression. Cytoglobin also protects cells from cisplatin-induced apoptosis and oxidative stress with levels of the antioxidant glutathione increased and total and mitochondrial reactive oxygen species levels reduced. The mechanism of cisplatin resistance involved inhibition of caspase 9 activation and cytoglobin protected mitochondria from oxidative stress-induced fission. To understand the mechanism behind these phenotypic changes we employed lipidomic analysis and demonstrate that levels of the redox sensitive and apoptosis regulating cardiolipin are significantly up-regulated in cells expressing cytoglobin. In conclusion, our data shows that cytoglobin expression results in important phenotypic changes that could be exploited by cancer cells in vivo to facilitate disease progression.

Background: Obesity and insulin resistance are associated with an impaired sensitivity to anabolic stimuli such as dietary protein (anabolic resistance). Omega-3 polyunsaturated fatty acids (n-3 PUFA) may be protective against the deleterious effects of saturated fatty acids (SFA) on insulin resistance. However, the contribution of excess fat consumption to anabolic and insulin resistance and the interaction between SFA and n-3 PUFA is not well studied. Aim: The primary aim of this study was to investigate the effects of an oral fat pre-load, with or without the partial substitution of SFA with fish oil (FO)-derived n-3 PUFA, on indices of insulin and anabolic sensitivity in response to subsequent dietary protein and carbohydrate (dextrose) co-ingestion. Methods: Eight middle-aged males with overweight or obesity (52.8 ± 2.0 yr, BMI 31.8 ± 1.4 kg·m−2) ingested either an SFA, or isoenergetic SFA and FO emulsion (FO), or water/control (Con), 4 h prior to a bolus of milk protein and dextrose. Results: Lipid ingestion (in particular FO) impaired the early postprandial uptake of branched chain amino acids (BCAA) into the skeletal muscle in response to protein and dextrose, and attenuated the peak glycaemic response, but was not accompanied by differences in whole body (Matsuda Index: Con: 4.66 ± 0.89, SFA: 5.10 ± 0.94 and FO: 4.07 ± 0.59) or peripheral (forearm glucose netAUC: Con: 521.7 ± 101.7; SFA: 470.2 ± 125.5 and FO: 495.3 ± 101.6 μmol·min−1·100 g lean mass·min [t = 240–420 min]) insulin sensitivity between visits. Postprandial whole body fat oxidation was affected by visit (P = 0.024) with elevated rates in SFA and FO, relative to Con (1.85 ± 0.55; 2.19 ± 0.21 and 0.65 ± 0.35 kJ·h−1·kg−1 lean body mass, respectively), however muscle uptake of free fatty acids (FFA) was unaffected. Conclusion: Oral lipid preloads, consisting of SFA and FO, impair the early postprandial BCAA uptake into skeletal muscle, which occurs independent of changes in insulin sensitivity. Clinical trial registry number: ClinicalTrials.gov Identifier NCT03146286.

The medical needs of the transgender population are increasingly recognized within the US health care system. Hormone therapy and gender-affirming surgery present distinct anatomic, hormonal, infectious, and psychosocial issues among transgender kidney transplant donors and recipients. We present the first reported experience with kidney transplantation and donation in transgender patients. A single-center case series (January 2014-December 2018) comprising 4 transgender kidney transplant recipients and 2 transgender living donors was constructed and analyzed. Experts in transplant surgery, transplant psychiatry, transplant infectious disease, pharmacy, and endocrinology were consulted to discuss aspects of care for these patients. Four transgender patients identified as male-to-female and 2 as female-to-male. Three of 6 had gender-affirming surgeries prior to transplant surgery, 1 of whom had further procedures posttransplant. Additionally, 4 patients were on hormone therapy. All 6 had psychiatric comorbidities. The 4 grafts have done well, with an average serum creatinine of 1.45 mg/dL at 2 years (range 1.01-1.85 mg/dL). However, patients encountered various postoperative complications, 1 of which was attributable to modified anatomy. Thus, transgender kidney transplant patients can present novel challenges in regard to surgical considerations as well as pre- and posttransplant care. Dedicated expertise is needed to optimize outcomes for this population.

Objectives To evaluate the relationship between gender and coping strategies in patients with cancer undergoing chemotherapy in outpatient settings. Sample & setting Women (N = 277) and men (N = 293) were recruited from two comprehensive cancer centers, one Veterans Affairs hospital, and four community-based oncology programs. Methods & variables Coping data were obtained from patients with gastrointestinal (n = 412) or lung (n = 158) cancer through the Brief COPE scale. Results In terms of engagement coping strategies, women reported higher scores for positive reframing, religion, and using instrumental support. Men reported higher scores for humor. In terms of disengagement coping strategies, women reported higher scores for denial, venting, and self-distraction. Men reported higher scores for substance use. Implications for nursing Gender-based stereotypes of emotional expectations may affect how patients express themselves and the ways in which support is offered. Clinicians should be aware of their own preconceived notions about sex and gender and reflect on how these may influence the psychosocial care they provide.

Ageing compromises skeletal muscle mass and function through poorly defined molecular aetiology. Here we have used untargeted metabolomics using UHPLC-MS to profile muscle tissue from young (n=10, 25±4y), middle aged (n=18, 50±4y) and older (n=18, 70±3y) men and women (50:50). Random Forest was used to prioritise metabolite features most informative in stratifying older age, with potential biological context examined using the prize-collecting Steiner forest algorithm embedded in the PIUMet software, to identify metabolic pathways likely perturbed in ageing. This approach was able to filter a large dataset of several thousand metabolites down to subnetworks of age important metabolites. Identified networks included the common age-associated metabolites such as androgens, (poly)amines/amino acids and lipid metabolites, in addition to some potentially novel ageing related markers such as dihydrothymine and imidazolone-5-proprionic acid. The present study reveals that this approach is a potentially useful tool to identify processes underlying human tissue ageing, and could therefore be utilised in future studies to investigate the links between age predictive metabolites and common biomarkers linked to health and disease across age.

Objective When total pancreatectomy with islet autotransplantation (TPIAT) is performed for chronic pancreatitis, the pancreas and most of the duodenum are removed, with Roux-en-Y reconstruction of the gastrointestinal tract. Enteroendocrine cells in the intestines and pancreas secrete hormones coordinating digestion and motility, but anatomic reconstruction alters transit of nutrients to these cells. We hypothesized that TPIAT leads to changes in enteroendocrine hormones. Methods Glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and pancreatic polypeptide (PP) were measured from mixed-meal tolerance tests of 34 clinical trial participants before and 18 months after TPIAT. Area under the curve of GLP-1 and PYY-stimulated responses were calculated by trapezoidal method, and the PP response was measured as the stimulated max minus baseline (ΔPP). Results Area under the curve of GLP-1 and PYY increased significantly after TPIAT (GLP-1 average +553.1 pg/mL per minute, P = 0.004; PYY average +4647.9 pg/mL per minute, P = 0.02). ΔPP trended toward lower after TPIAT (average, -52.2 pg/mL, P = 0.06). Conclusions In this novel study of enteroendocrine hormones in TPIAT patients, stimulated levels of GLP-1 and PYY were significantly higher after versus before TPIAT. ΔPP was lower after TPIAT, but not significantly. These hormone changes have potential clinical implications that warrant further research.

BACKGROUND Desensitization protocols for HLA-incompatible living donor kidney transplantation (ILDKT) vary across centers. The impact of these, as well as other practice variations, on ILDKT outcomes remains unknown. METHODS We sought to quantify center-level variation in mortality and graft loss following ILDKT using a 25-center cohort of 1358 ILDKT recipients with linkage to Scientific Registry of Transplant Recipients for accurate outcome ascertainment. We used multilevel Cox regression with shared frailty to determine the variation in post-ILDKT outcomes attributable to between-center differences and to identify any center-level characteristics associated with improved post-ILDKT outcomes. RESULTS After adjusting for patient-level characteristics, only 6 centers (24%) had lower mortality and 1 (4%) had higher mortality than average. Similarly, only 5 centers (20%) had higher graft loss and 2 had lower graft loss than average. Only 4.7% of the differences in mortality (P < 0.01) and 4.4% of the differences in graft loss (P < 0.01) were attributable to between-center variation. These translated to a median hazard ratio of 1.36 for mortality and 1.34 of graft loss for similar candidates at different centers. Post-ILDKT outcomes were not associated with the following center-level characteristics: ILDKT volume and transplanting a higher proportion of highly sensitized, prior transplant, preemptive, or minority candidates. CONCLUSIONS Unlike most aspects of transplantation in which center-level variation and volume impact outcomes, we did not find substantial evidence for this in ILDKT. Our findings support the continued practice of ILDKT across these diverse centers.

Background: Advancements in next-generation sequencing have allowed for a more complete understanding of the vaginal microbiome and its role in health and disease. The role of race/ethnicity in the...

Context Cancer and its treatment are inherently stressful and stress impacts important patient outcomes. Patients vary considerably in their response to stress. Understanding this variability requires a patient-centered multidimensional approach. Objectives The objectives of this study were to identify and characterize patient subgroups with distinct multidimensional stress profiles (stress appraisal, exposure, and adaptation) during cancer treatment. Methods Among 957 patients undergoing chemotherapy for breast, gastrointestinal, gynecological, or lung cancer, latent profile analysis was performed to identify patient subgroups using concurrent evaluations of global (Perceived Stress Scale) and cancer-specific (Impact of Events Scale–Revised) stress, lifetime stress exposure (Life Stressor Checklist–Revised), and resilience (Connor-Davidson Resilience Scale-10). Results Three latent classes were identified: “Normative” (54.3%; intermediate global stress and resilience, lower cancer-related stress, lowest life stress); “Stressed” (39.9%; highest global and cancer-specific stress scores, lowest resilience, most life stress); and “Resilient” (5.7%; lowest global stress, cancer-specific stress comparable to Normative class, highest resilience, intermediate life stress). Characteristics that distinguished the Stressed from the Normative class included the following: younger age, female gender, lower socioeconomic status, unmarried/partnered, living alone, poorer functional status, and higher comorbidity burden. Compared to Stressed patients, Resilient patients were more likely to be partnered, to not live alone, and had a higher functional status. No demographic or clinical characteristics differentiated Normative from Resilient patients. Exposure to specific life stressors differed significantly among the classes. Conclusion A subset of patients warrants intensive psychosocial intervention to reduce stress and improve adaptation to cancer. Intervention efforts may be informed by further study of Resilient patients.

Public trust in research depends on implementation of research protections. Genetic and psychiatric research may elicit "exceptionalism," the belief that these types of research deserve special protections. Genetic information has been viewed as different from other health information. Psychiatric research has been scrutinized based on concerns about the impact of psychiatric illness on individuals' abilities to make decisions. This study compared four stakeholder groups' attitudes toward research safeguards. Psychiatric genetic researchers and institutional review board chairs received structured surveys. Individuals with mental illness and family members participated in semistructured interviews. Paired sample t-tests were used to compare mean ratings of importance of safeguard procedures for genetic versus nongenetic research on physical versus mental illnesses. All groups provided higher ratings for the importance of safeguards for genetic research and for mental illness. Individuals with mental illness and family members rated the importance of safeguards more highly than researchers and chairs did. Results of generalized linear models showed significant effects of gender and ethnicity.

Involving patients and consumers in research design helps ensure relevance for those affected by the problem being investigated and can optimize recruitment to clinical trials. This is particularly important when conducting research involving pregnant women. We investigated women’s motivations to participate in a hypothetical randomized control trial (RCT) of a third-trimester screening test for intrapartum fetal compromise (IFC) and adverse perinatal outcomes. Women attending for routine antenatal care at a tertiary center were invited to complete a short, anonymized patient acceptability survey. The survey was developed with the assistance of the Perinatal Society of Australia and New Zealand’s Consumer Advisory Panel and consisted of Likert scales and open-ended questions. It was designed to ascertain women’s responses to research issues, particularly the acceptability of being randomized to a non-revealed arm of a screening test RCT. 100 pregnant women took part; 40% indicated that they would agree/strongly agree to participate in a hypothetical RCT regardless of whether they were given the result of a screening test and 31% were unsure. Randomization to either an intervention or control group was acceptable to 47%, 30% were unsure and 23% were not willing to be randomized. Reasons to participate included the desire to contribute to research and to improve pregnancy care. Participation in an RCT of a screening test for IFC involving non-disclosure of the test result was acceptable to a large minority of pregnant women. This finding supports the feasibility of conducting a large-scale study of this design.

Background Solid organ transplant recipients (SOTRs) are at increased risk for adverse outcomes with COVID-19. Early data shows a lower SARS-CoV-2 spike antibody immune response among SOTRs leading to patient concerns about vaccine efficacy. Public health messaging has largely left out immunocompromised individuals leading to a higher risk of vaccine misinformation. The American Society of Transplantation recommends COVID-19 vaccination for all SOTRs, however, patient concerns and beliefs about vaccination are largely unknown. Methods We conducted a transplant-center-based, pragmatic pilot trial to encourage COVID-19 vaccination among 103 unvaccinated SOTRs. We assessed vaccine concerns, barriers to vaccination, answered questions about efficacy, side effects, and clinical recommendations. Results A total of 24% (n = 25) of SOTRs reported that they will schedule COVID-19 vaccination after the study call, 46% reported that they will consider vaccination in the future, and 30% said they will not consider vaccination. Older age and White race were associated with lower willingness to schedule the vaccine, whereas Black race and longer time from transplant were associated with higher willingness. Common vaccine concerns included lack of long-term data, inconsistent messaging from providers, scheduling inconvenience, and insufficient resources. Follow-up approximately one month after the initial outreach found 52% (n = 13) of liver transplant recipients (LTRs) and 10% (n = 3) of kidney transplant recipients (KTRs) subsequently received COVID-19 vaccines for a vaccination rate of 29% among respondents. Conclusion Transplant center-based vaccine outreach efforts can decrease misinformation and increase vaccination uptake;however, vaccine-related mistrust remains high. This article is protected by copyright. All rights reserved

Multimedia Psychotherapy is a new form of brief psychotherapy based on narrative medicine and ethnopsychoanalytic theories, developed to help patients affected by prolonged grief disorder (ICD-11). It consists of eight sessions, during which an 'audio-video memory object' is produced by using pictures, video clips, and music chosen by the bereaved patient. The audio-video montage is focused on remembering the deceased relative and help the patient to move on. Considering initial positive results, we ran a first controlled pilot study comparing experimental and control group.We enrolled a sample of bereaved patients who were referred for prolonged grief disorder (ICD-11) by their general practitioners or psychiatrists. Patients were randomly assigned to the experimental group (n=18) or to the control group (n=18). Patients in the experimental group received psycho-pharmacological therapy and multimedia psychotherapy, while patients in the control group received psycho-pharmacological therapy and psycho-oncological support. All patients were assessed with Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and Prolonged Grief-13 (PG-13) prior to beginning treatment (pre-treatment), and with PG-13 after six months from the end of the treatment (post-treatment).Patients in the experimental group (i.e., Multimedia Psychotherapy treatment) after six months performed better than patients in the control group in Criteria B, D, and E of PG-13 (i.e.: Separation Distress, Cognitive, Emotional, and Behavioral Symptoms, Functional Impairment).We will discuss our results, issues related to the screening of patients (due to possible contraindications of Multimedia Psychotherapy), and methodological limitations. Finally, we will discuss new future applications in other clinical situations.These findings suggest that multimedia psychotherapy may hold promise for the treatment of prolonged grief disorder (ICD-11).

To evaluate for inter-individual differences in financial distress and identify demographic, clinical, and symptom characteristics associated with higher levels of financial distress.Patients (n = 387) were enrolled prior to breast cancer surgery and followed for 12 months. Financial distress was measured using a 0 (no problem) to 10 (severe problem) numeric rating scale. Hierarchical linear modeling was used to evaluate for inter-individual differences in trajectories of financial distress and characteristics associated with financial distress at enrollment and over 12 months.Patients' mean age was 55.0 (± 11.7) years and the majority underwent breast conservation surgery (80.6%). Mean financial distress score prior to surgery was 3.3 (± 3.4; range 0 to 10). Unconditional model for financial distress demonstrated no significant changes over time (-0.006/month). Younger age, lower income, receipt of an axillary lymph node dissection and adjuvant chemotherapy, and lower attentional function were associated with higher preoperative levels of financial distress.Risk factors identified in this study can be used to inform clinicians regarding the need to initiate financial discussions and social work referrals for some patients. Additional clinical or system level interventions should be considered for vulnerable groups with these risk factors.

The use of dried blood spot (DBS) and dried urine spot (DUS) samples represents an attractive opportunity for researchers in biomedical metabolomics to collect whole blood and urine samples in the absence of a processing laboratory and so to allow collection in remote areas or in longitudinal studies away from the clinic. The 12-month stability of the thousands of metabolites present in these biofluids and the applicability of DBS and DUS samples for untargeted metabolomics applications has not previously been investigated in detail and compared to blood and urine samples. Here, the 12-month stability of DBS and DUS at different storage temperatures (-20, +4, and +21 °C) have been compared to plasma and urine biofluids stored at the same storage temperatures and time. Samples were analyzed applying complementary HILIC and C18 reversed-phase UHPLC-MS untargeted metabolomic assays. Results show that metabolites demonstrate increased stability in DBS and DUS compared to whole blood and urine at all storage temperatures and times. DBS and DUS stored at +21 °C are stable for up to 4 weeks but are not stable over a 1 year period. DBS and DUS showed good stability when stored at -20 °C for 1 year. We recommend that DBS and DUS samples are collected and transported within 28 days at room temperature and are stored for longer periods of time at -20 or -80 °C. The metabolomes of DUS samples and urine were very similar but the metabolome of DBS included additional metabolites not detected in plasma and therefore proposed to be released from cells in whole blood.

Liver transplantation is an effective intervention for end-stage liver disease, fulminant hepatic failure, and early hepatocellular carcinoma. Yet, there is marked patient-to-patient variation in liver transplantation outcomes. This calls for novel diagnostics to enable rational deployment of donor livers. Metabolomics is a postgenomic high-throughput systems biology approach to diagnostic innovation in clinical medicine. We report here an original systematic review of the metabolomic studies that have identified putative biomarkers in the context of liver transplantation. Eighteen studies met the inclusion criteria that involved sampling of blood (

INTRODUCTION: Complement activation is essential for select physiologic processes during pregnancy, however excess activation has been associated with an increased risk for preterm birth (PTB). African American (AA) women experience disproportionately higher rates of inflammation-associated PTB as compared to other groups of women, thus the purpose of this study was to explore the relationship between complement activation and perinatal outcomes among AA women. METHODS: A plasma sample was collected between 8–14 weeks gestation from a cohort of healthy AA women (N=144) enrolled in a larger preterm birth cohort study. Chart review was conducted to collect information on clinical factors (cervical length, health behaviors, gestational age at delivery). Multiple regression was used to explore the relationships between complement marker (C3a/Bb) concentrations and the outcomes of interest after adjusting for baseline characteristics. RESULTS: C3a/Bb concentrations were not significant predictors of the gestational age at delivery, cervical length, or behavioral risk factors for PTB in this sample. CONCLUSIONS: Complement markers may not influence pregnancy outcomes among AA women in the same way as in predominantly white populations, however more studies are needed to define complement dysregulation and the relationship with outcomes among AA women.

Background Decrements in attentional function-perceived effectiveness in everyday functioning related to cognitive dysfunction-are frequently reported by cancer patients during treatment. However, patients vary widely in their experiences of changes in attentional function. Objective The aim of this study was to understand differences in attentional function among cancer patients during chemotherapy. Methods Patients (n = 1329) undergoing chemotherapy were assessed at 6 time points during 2 rounds of chemotherapy. Latent profile analysis was used to identify subgroups of patients based on patterns in changes on the Attentional Function Index. Differences among the subgroups in demographic and clinical characteristics, psychological symptoms, and stress were evaluated. Results Three latent classes (ie, high, moderate, and low attentional function) were identified. Patients in the low and moderate classes were younger, more likely to be female, and less likely to be employed compared with those in the high class. Patients in the low class had higher levels of depressive and anxiety symptoms, cancer-related distress, and perceived stress compared with those in the moderate class, who, in turn, reported higher levels of these symptoms compared with those in the high class. Conclusions Different experiences of changes in self-perceived attentional function are associated with psychological symptoms in cancer patients. Implications for practice Relationships between changes in attentional function and psychological symptoms and stress suggest that clinicians should attend to the potential that patients' cognitive and psychological experiences may be closely linked and may need to be addressed as related phenomena. Clinical trials are needed that evaluate treatments for both attentional and psychological symptoms.

Recent changes in policies guiding allocation of transplant kidneys are predicted to increase sharing between distant geographic regions. The potential exists for an increase in cold ischemia time (CIT) with resulting increases in delayed graft function (DGF) and transplant-related costs (TRC). We sought to explore the impact of CIT on metrics that may influence TRC.Between 2006 and 2014, 81 945 adult solitary deceased donor kidney transplants were performed in the United States; 477 (0.6%) at our institution. Regression models were constructed to describe the relationship between CIT on DGF and length of stay (LOS). Using hospital accounting data, we created regression models to evaluate the effect of DGF on LOS and TRC.In multivariable models, longer CIT was associated with an increased rate of DGF (odds ratio [OR], 1.41; 95% confidence interval [CI], 1.38-1.44) and increased LOS (OR, 1.04; 95% CI, 1.02-1.05). Recipients at our institution who developed DGF had longer LOS (OR, 1.71; 95% CI, 1.50-1.95), suggesting that the effect is partially mediated by DGF. After adjusting for LOS, neither CIT nor DGF were independently associated with increased TRC. However, an increased LOS resulted in an increase in TRC by US $3422 (95% CI, US $3180 to US $3664) per additional day, indicating that the effect of CIT on TRC is partially mediated through LOS.The prolongation of CIT is associated with an increase in DGF rates and LOS, resulting in increased TRC. This study raises the need to balance increased access of traditionally underserved populations to kidney transplant with the inadvertent increase in TRC.

Purpose In a sample of oncology patients, identify subgroups of patients with distinct depressive symptom profiles and evaluate for differences in demographic and clinical characteristics, levels of stress and resilience, and the severity of common co-occurring symptoms. Methods Patients (n=1327) had a diagnosis of breast, gastrointestinal, gynecological, or lung cancer; had received chemotherapy within the preceding four weeks; and were scheduled to receive at least two additional cycles of chemotherapy. Demographic and clinical characteristics, stress, resilience, and co-occurring symptoms were evaluated at enrollment. Depressive symptoms were evaluated using the Center for Epidemiological Studies-Depression (CES-D) scale a total of six times over two cycles of chemotherapy. Latent profile analysis (LPA) was used to identify subgroups of patients (i.e., latent classes) with distinct depressive symptom profiles using the six CES-D scores. Results Based on the findings from the LPA, 47.3% of the patients were classified as “None”; 33.6% as “Subsyndromal”; 13.8% as “Moderate”; and 5.3% as “High”. Compared to None class, patients in the Subsyndromal, Moderate, and High classes had a lower functional status, a higher comorbidity burden, and a self-reported diagnosis of depression or back pain. Those patients with higher levels of depressive symptoms reported higher levels of stress, lower levels of resilience, and increased severity of co-occurring symptoms. Conclusions Inter-individual variability in depressive symptoms was associated with demographic and clinical characteristics, multiple types of stress and levels of resilience, as well as with the increased severity of multiple co-occurring symptoms. The risk factors associated with worse depressive symptom profiles can assist clinicians to identify high risk patients and initiate more timely supportive care interventions.

There is hope that psychiatric genetics inquiry will provide important insights into the origins and treatment of mental illness given the burden of these conditions. We sought to examine perspectives of psychiatric genetic investigators regarding the potential benefits of genetic research in general and the potential benefits of genetic research for the diagnosis and treatment of mental illnesses specifically. We compared investigator attitudes with those of chairs of Institutional Review Boards (IRBs) entrusted with evaluating the benefits and risks of human research studies. Two groups directly engaged with the conduct and oversight of psychiatric genetic research were examined (psychiatric investigators, n = 203; IRB Chairs, n = 183). Participants rated 15 survey items regarding current and future benefits of general genetic research, possible benefits of psychiatric genetic research, and the importance to society of genetic vs. non-genetic research examining causes and treatments of illnesses. Investigators and IRB Chairs strongly endorsed the future benefits of general genetic research for society and for the health of individuals; compared to IRB Chairs, investigators were more positive about these benefits. Even after adjusting for demographic variables, psychiatric genetic investigators were significantly more optimistic about genetic research compared with IRB Chairs. Both groups were moderately optimistic about the possible benefits of genetic research related to mental illness. Greater optimism was seen regarding new or personalized medications for mental illnesses, as well as genetic predictive testing of mental illnesses. Greater precision and circumspection about the potential benefits of psychiatric genetic research are needed.

Background An elevated body mass index (>30 kg/m2) has been a relative contraindication for living kidney donation; however, such donors have become more common. Given the association between obesity and development of diabetes, hypertension, and end-stage renal disease, there is concern about the long-term health of obese donors. Methods Donor and recipient demographics, intraoperative parameters, complications, and short- and long-term outcomes were compared between contemporaneous donors—obese donors (body mass index ≥30 kg/m2) versus nonobese donors (body mass index Results Between the years 1975 and 2014, we performed 3,752 donor nephrectomies; 656 (17.5%) were obese donors. On univariate analysis, obese donors were more likely to be older (P 30 days) readmissions. Estimated glomerular filtration rate and rates of end-stage renal disease were not significantly different between donor groups >20 years after donation (P = .71). However, long-term development of diabetes mellitus (adjusted hazard ratio (HR) 3.14; P Conclusion Obese donors develop diabetes mellitus and hypertension more frequently and earlier than nonobese donors after donation, raising concerns about increased rates of end-stage renal disease.

BACKGROUND Chorioamnionitis is associated with preterm delivery and morbidities; its role in lung disease is controversial. The aim of this study is to assess the effect of chorioamnionitis on metabolite and lipid profiles of epithelial lining fluid in preterm newborns with respiratory distress syndrome (RDS). METHODS The study involved 30 newborns with RDS, born from mothers with or without histological chorioamnionitis (HCA): HCA+, N = 10; HCA-, N = 20. Patients had a gestational age ≤30 weeks; the groups were matched for age and birth weights. Tracheal aspirates were collected within 24 h after birth and analyzed using liquid chromatography/mass spectrometry-based untargeted lipidomics. RESULTS According to Mann-Whitney U tests, 570 metabolite features had statistically significantly higher or lower concentrations (p

High plasma triacylglyceride levels are known to be associated with increased risk of atherosclerotic cardiovascular disease. Apolipoprotein C-III (apoC-III) is a key regulator of plasma triacylglyceride levels and is associated with hypertriglyceridemia via a number of pathways. There is consistent evidence for an association of cardiovascular events with blood apoC-III level, with support from human genetic studies of APOC3 variants. As such, apoC-III has been recognised as a potential therapeutic target for patients with severe hypertriglyceridaemia with one of the most promising apoC-III-targeting drugs, volanesorsen, having recently progressed through Phase III trials.To exploit a rare loss of function variant in APOC3 (rs138326449) to characterise the potential long-term treatment effects of apoC-III targeting interventions on the metabolome.In a recall-by-genotype study, 115 plasma samples were analysed by UHPLC-MS to acquire non-targeted metabolomics data. The study included samples from 57 adolescents and 33 adults. Overall, 12 985 metabolic features were tested for an association with APOC3 genotype.161 uniquely annotated metabolites were found to be associated with rs138326449(APOC3). The highest proportion of associated metabolites belonged to the acyl-acyl glycerophospholipid and triacylglyceride metabolite classes. In addition to the anticipated (on-target) reduction of metabolites in the triacylglyceride and related classes, carriers of the rare variant exhibited previously unreported increases in levels of a number of metabolites from the acyl-alkyl glycerophospholipid class.Overall, our results suggest that therapies targeting apoC-III may potentially achieve a broad shift in lipid profile that favours better metabolic health.

Although considerable research has examined factors that influence social-cognitive processes related to aggression, few studies have examined the factors that influence adolescents' appraisal of the effectiveness of responses, particularly nonviolent alternatives to aggression. This study addressed that gap by examining patterns of adolescents' perceived effectiveness of nonviolent and aggressive responses to hypothetical problem situations and their relations with aggression, victimization, and individual and contextual risk factors. The participants were a predominantly African American (90%) sample of 1469 students (55% female; mean age = 12.7 years; age range = 11-16) from three middle schools who completed measures of perceived effectiveness, self-efficacy, aggression and victimization, and contextual factors. Ratings of adolescents' physical, relational, and verbal aggression and victimization, nonviolent and prosocial behavior were also obtained from their teachers. Latent class analysis identified four subgroups of adolescents including distinguishes effective, mixed support, everything works, and nothing works. Subgroups differed on measures of aggression, victimization, prosocial and nonviolent behavior, self-efficacy for nonviolence, witnessing community violence, and parents' and peers' support for nonviolence and aggression. The findings underscore the importance of designing violence prevention programs to target the unique needs of subgroups of adolescents.

Introduction Acute myocardial ischaemia and the transition from reversible to irreversible myocardial injury are associated with abnormal metabolic patterns. Advances in metabolomics have extended our capabilities to define these metabolic perturbations on a metabolome-wide scale. Objectives This study was designed to identify cardiac metabolic changes in serum during the first 5 min following early myocardial ischaemia in humans, applying an untargeted metabolomics approach. Methods Peripheral venous samples were collected from 46 patients in a discovery study (DS) and a validation study (VS) (25 for DS, 21 for VS). Coronary sinus venous samples were collected from 7 patients (4 for DS, 3 for VS). Acute myocardial ischaemia was induced by transient coronary occlusion during percutaneous coronary intervention (PCI). Plasma samples were collected at baseline (prior to PCI) and at 1 and 5 min post-coronary occlusion. Samples were analyzed by Ultra Performance Liquid Chromatography-Mass Spectrometry in an untargeted metabolomics approach. Results The study observed changes in the circulating levels of metabolites at 1 and 5 min following transient coronary ischaemia. Both DS and VS identified 54 and 55 metabolites as significant (P Conclusion Using an untargeted metabolomics approach, the study identified important cardiac metabolic changes in peripheral and coronary sinus plasma, in a human model of controlled acute myocardial ischaemia. Distinct classes of metabolites were shown to be involved in the rapid cardiac response to ischemia and provide insights into diagnostic and interventional targets.

IntroductionMyocardial protection against ischaemic-reperfusion injury is a key determinant of heart function and outcome following cardiac surgery in children. However, with current strategies, myocardial injury occurs routinely following aortic cross-clamping, as demonstrated by the ubiquitous rise in circulating troponin. Remote ischaemic preconditioning, the application of brief, non-lethal cycles of ischaemia and reperfusion to a distant organ or tissue, is a simple, low-risk and readily available technique which may improve myocardial protection. The Bilateral Remote Ischaemic Conditioning in Children (BRICC) trial will assess whether remote ischaemic preconditioning, applied to both lower limbs immediately prior to surgery, reduces myocardial injury in cyanotic and acyanotic young children.Methods and analysisThe BRICC trial is a two-centre, double-blind, randomised controlled trial recruiting up to 120 young children (age 3 months to 3 years) undergoing primary repair of tetralogy of Fallot or surgical closure of an isolated ventricular septal defect. Participants will be randomised in a 1:1 ratio to either bilateral remote ischaemic preconditioning (3×5 min cycles) or sham immediately prior to surgery, with follow-up until discharge from hospital or 30 days, whichever is sooner. The primary outcome is reduction in area under the time-concentration curve for high-sensitivity (hs) troponin-T release in the first 24 hours after aortic cross-clamp release. Secondary outcome measures include peak hs-troponin-T, vasoactive inotrope score, arterial lactate and central venous oxygen saturations in the first 12 hours, and lengths of stay in the paediatric intensive care unit and the hospital.Ethics and disseminationThe trial was approved by the West Midlands-Solihull National Health Service Research Ethics Committee (16/WM/0309) on 5 August 2016. Findings will be disseminated to the academic community through peer-reviewed publications and presentation at national and international meetings. Parents will be informed of the results through a newsletter in conjunction with a local charity.Trial registration numberNCT12923441.

Introduction: The metabolomics quality assurance and quality control consortium (mQACC) evolved from the recognized need for a community-wide consensus on improving and systematizing quality assurance (QA) and quality control (QC) practices for untargeted metabolomics. Objectives: In this work, we sought to identify and share the common and divergent QA and QC practices amongst mQACC members and collaborators who use liquid chromatography-mass spectrometry (LC–MS) in untargeted metabolomics. Methods: All authors voluntarily participated in this collaborative research project by providing the details of and insights into the QA and QC practices used in their laboratories. This sharing was enabled via a six-page questionnaire composed of over 120 questions and comment fields which was developed as part of this work and has proved the basis for ongoing mQACC outreach. Results: For QA, many laboratories reported documenting maintenance, calibration and tuning (82%); having established data storage and archival processes (71%); depositing data in public repositories (55%); having standard operating procedures (SOPs) in place for all laboratory processes (68%) and training staff on laboratory processes (55%). For QC, universal practices included using system suitability procedures (100%) and using a robust system of identification (Metabolomics Standards Initiative level 1 identification standards) for at least some of the detected compounds. Most laboratories used QC samples (>86%); used internal standards (91%); used a designated analytical acquisition template with randomized experimental samples (91%); and manually reviewed peak integration following data acquisition (86%). A minority of laboratories included technical replicates of experimental samples in their workflows (36%). Conclusions: Although the 23 contributors were researchers with diverse and international backgrounds from academia, industry and government, they are not necessarily representative of the worldwide pool of practitioners due to the recruitment method for participants and its voluntary nature. However, both questionnaire and the findings presented here have already informed and led other data gathering efforts by mQACC at conferences and other outreach activities and will continue to evolve in order to guide discussions for recommendations of best practices within the community and to establish internationally agreed upon reporting standards. We very much welcome further feedback from readers of this article. Fil: Evans, Anne M.. No especifíca; Fil: ODonovan, Claire. European Bioinformatics Institute; Reino Unido Fil: Playdon, Mary. University of Utah; Estados Unidos Fil: Beecher, Chris. No especifíca; Fil: Beger, Richard D.. National Center For Toxicological Research; Estados Unidos Fil: Bowden, John A.. University of Florida; Estados Unidos Fil: Broadhurst, David. Edith Cowan University; Australia Fil: Clish, Clary B.. Broad Institute; Estados Unidos Fil: Dasari, Surendra. Mayo Clinic; Estados Unidos Fil: Dunn, Warwick B.. University Of Birmingham; Reino Unido Fil: Griffin, Julian L.. University of Cambridge; Estados Unidos. Imperial College London; Reino Unido Fil: Hartung, Thomas. University Johns Hopkins; Estados Unidos Fil: Hsu, Ping Ching. University of Arkansas for Medical Sciences; Estados Unidos Fil: Huan, Tao. University of British Columbia; Canadá Fil: Jans, Judith. University of Utrecht; Países Bajos Fil: Jones, Christina M.. National Institute Of Standards And Technology; Estados Unidos Fil: Kachman, Maureen. Michigan State University; Estados Unidos Fil: Kleensang, Andre. University Johns Hopkins; Estados Unidos Fil: Lewis, Matthew R.. Imperial College London; Reino Unido Fil: Monge, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina Fil: Mosley, Jonathan D.. Environmental Protection Agency; Estados Unidos Fil: Taylor, Eric. University of Iowa; Estados Unidos Fil: Tayyari, Fariba. University of Iowa; Estados Unidos Fil: Theodoridis, Georgios. Aristotle University; Grecia Fil: Torta, Federico. No especifíca; Fil: Ubhi, Baljit K.. No especifíca; Fil: Vuckovic, Dajana. Concordia University; Canadá

Identify subgroups of gastrointestinal (GI) cancer patients with distinct multiple co-occurring symptom profiles and evaluate for differences among these subgroups in demographic and clinical characteristics and quality of life (QOL) outcomes.Patients with GI cancers (n = 399) completed the Memorial Symptom Assessment Scale (MSAS) that was used to assess for multiple co-occurring symptoms. Latent class analysis (LCA) was used to identify subgroups of patients with distinct symptom profiles using symptom occurrence ratings. Differences in demographic and clinical characteristics and QOL outcomes among the subgroups were evaluated using parametric and nonparametric tests.All Low (36.6%), Moderate (49.4%), and All High (14.0%) classes were identified. Compared to the All Low class, patients in the other two classes were significantly younger and were more likely to report depression and back pain. Compared to the other two classes, patients in the All High class had fewer years of education and a higher number of comorbidities. Significant differences were found among the three classes for comorbidity burden and total number of MSAS symptoms (i.e., All LowModerateAll High), as well as for performance status (i.e., All LowModerateAll High). A higher symptom burden was associated with poorer QOL outcomes.The first study to identify subgroups of patients with GI cancers based on distinct symptom profiles. LCA allowed for the identification of risk factors associated with a higher symptom burden. Clinicians can use this information to identify high-risk patients and develop personalized symptom management interventions.

Hematological and solid cancers catabolize the semiessential amino acid arginine to drive cell proliferation. However, the resulting low arginine microenvironment also impairs chimeric antigen receptor T cells (CAR-T) cell proliferation, limiting their efficacy in clinical trials against hematological and solid malignancies. T cells are susceptible to the low arginine microenvironment because of the low expression of the arginine resynthesis enzymes argininosuccinate synthase (ASS) and ornithine transcarbamylase (OTC). We demonstrate that T cells can be reengineered to express functional ASS or OTC enzymes, in concert with different chimeric antigen receptors. Enzyme modifications increase CAR-T cell proliferation, with no loss of CAR cytotoxicity or increased exhaustion. In vivo, enzyme-modified CAR-T cells lead to enhanced clearance of leukemia or solid tumor burden, providing the first metabolic modification to enhance CAR-T cell therapies.

Clinical metabolic phenotyping employs metabolomics and lipidomics to detect and measure hundreds to thousands of metabolites and lipids within human samples. This approach aims to identify metabolite and lipid changes between phenotypes (e.g. disease status) that aid understanding of biochemical mechanisms driving the phenotype. Sample preparation is a critical step in clinical metabolic phenotyping: it must be reproducible and give a high extraction yield of metabolites and lipids, and in high-throughput studies it needs to be rapid. Here, we assessed the extraction of polar metabolites from human urine and polar metabolites and lipids from human plasma for analysis by ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) metabolomics and lipidomics. We evaluated several monophasic (urine and plasma) and biphasic (plasma) extractions, and we also tested alterations to (a) solvent–biofluid incubation time and temperature during monophasic extraction, and (b) phase partitioning time during biphasic extraction. Extracts were analysed by three UHPLC-MS assays: (i) hydrophilic interaction chromatography (HILIC) for urine and plasma, (ii) C18 aqueous reversed phase for urine, and (iii) C18 reversed phase for plasma lipids, and the yield and reproducibility of each method was assessed. We measured UHPLC-MS injection reproducibility as well as sample preparation reproducibility to assess sample solvent composition compatibility with UHPLC-MS and to pinpoint the origin of variance within the methods. For HILIC UHPLC-MS plasma and urine analysis, monophasic 50 : 50 methanol : acetonitrile had the most detected putatively-identified polar metabolites with high method reproducibility. This method had the highest lipid yield for plasma extracts analysed by the HILIC method. If lipid removal from the plasma polar HILIC extract is required, then the biphasic methanol/chloroform/water method is recommended. For C18 (aqueous) UHPLC-MS urine analysis, 50 : 50 methanol : water had high reproducibility and yield. For C18 UHPLC-MS plasma lipidomics, monophasic 100% isopropanol had the highest detection response of all annotated lipid classes with high reproducibility. Increasing monophasic incubation time and temperature had little benefit on metabolite and lipid yield and reproducibility for all methods.

We read with great interest and appreciation the careful consideration and analysis by Ambagtsheer et al. of the most critical ethical objections to Global Kidney Exchange (GKE). Ambagtsheer et al. conclude that implementation of GKE is a means to increase access to transplantation ethically and effectively.1,2 These conclusions by their European Society of Transplantation (ESOT) committee on Ethical, Legal and Psychological Aspects of Transplantation (ELPAT) represent a step forward toward a greater understanding and an open, honest debate about GKE.

Characterisation of animal models of diabetic cardiomyopathy may help unravel new molecular targets for therapy. Long-living individuals are protected from the adverse influence of diabetes on the heart, and the transfer of a longevity-associated variant (LAV) of the human BPIFB4 gene protects cardiac function in the db/db mouse model. This study aimed to determine the effect of LAV-BPIFB4 therapy on the metabolic phenotype (ultra-high-performance liquid chromatography-mass spectrometry, UHPLC-MS) and cardiac transcriptome (next-generation RNAseq) in db/db mice. UHPLC-MS showed that 493 cardiac metabolites were differentially modulated in diabetic compared with non-diabetic mice, mainly related to lipid metabolism. Moreover, only 3 out of 63 metabolites influenced by LAV-BPIFB4 therapy in diabetic hearts showed a reversion from the diabetic towards the non-diabetic phenotype. RNAseq showed 60 genes were differentially expressed in hearts of diabetic and non-diabetic mice. The contrast between LAV-BPIFB4- and vehicle-treated diabetic hearts revealed eight genes differentially expressed, mainly associated with mitochondrial and metabolic function. Bioinformatic analysis indicated that LAV-BPIFB4 re-programmed the heart transcriptome and metabolome rather than reverting it to a non-diabetic phenotype. Beside illustrating global metabolic and expressional changes in diabetic heart, our findings pinpoint subtle changes in mitochondrial-related proteins and lipid metabolism that could contribute to LAV-BPIFB4-induced cardio-protection in a murine model of type-2 diabetes.

IntroductionPregnancy is characterised by a high rate of metabolic shifts from early to late phases of gestation in order to meet the raised physiological and metabolic needs. This change in levels of metabolites is influenced by gestational weight gain (GWG), which is an important characteristic of healthy pregnancy. Inadequate/excessive GWG has short-term and long-term implications on maternal and child health. Exploration of gestational metabolism is required for understanding the quantitative changes in metabolite levels during the course of pregnancy. Therefore, our aim is to study trimester-specific variation in levels of metabolites in relation to GWG and its influence on fetal growth and newborn anthropometric traits at birth.Methods and analysisA prospective longitudinal study is planned (start date: February 2018; end date: March 2023) on pregnant women that are being recruited in the first trimester and followed in subsequent trimesters and at the time of delivery (total 3 follow-ups). The study is being conducted in a hospital located in Bikaner district (66% rural population), Rajasthan, India. The estimated sample size is of 1000 mother-offspring pairs. Information on gynaecological and obstetric history, socioeconomic position, diet, physical activity, tobacco and alcohol consumption, depression, anthropometric measurements and blood samples is being collected for metabolic assays in each trimester using standardised methods. Mixed effects regression models will be used to assess the role of gestational weight in influencing metabolite levels in each trimester. The association of maternal levels of metabolites with fetal growth, offspring’s weight and body composition at birth will be investigated using regression modelling.Ethics and disseminationThe study has been approved by the ethics committees of the Department of Anthropology, University of Delhi and Sardar Patel Medical College, Rajasthan. We are taking written informed consent after discussing the various aspects of the study with the participants in the local language.

Whole-organ pancreas and islet transplantations are performed in a highly selected group of patients with diabetes mellitus, primarily those with type 1 diabetes mellitus, complicated by recurrent severe hypoglycaemia or renal failure requiring kidney transplantation. Clinical accessibility to pancreases or islets, and patient characteristics and therapeutic goals, may dictate choice of procedure. Pancreas transplantation is most often performed simultaneous with a kidney transplant, but patients with particularly labile type 1 diabetes may be considered for a pancreas transplant alone. While highly successful at restoring insulin independence, pancreas transplants carry the significant risks of major surgery and immunosuppression. Islet transplantation is a relatively minor procedure, usually performed for labile type 1 diabetes with severe hypoglycaemia. It is highly successful at resolving hypoglycaemia, but more than one pancreas donor may be required for insulin independence. Both pancreas and islet transplantation are limited in applicability by a paucity of deceased donors. Pigs provide one promising replenishable source of islets. Porcine islets can successfully reverse diabetes mellitus in non-human primates under the appropriate immunosuppressive conditions, with promise for eventually translating this success to a larger population of patients with diabetes mellitus in the future. Graphical abstract.

PurposeA breast cancer diagnosis has a substantial economic impact. Study aims were to evaluate for inter-individual differences in cancer's level of interference with employment and identify phenotypic and symptom characteristics associated with higher levels of interference.MethodsPatients (n= 387) were enrolled prior to breast cancer surgery and followed for 12months. Interference with employment was measured using a 0 (no problem) to 10 (severe problem) numeric rating scale. Hierarchical linear modeling (HLM) was used to evaluate for inter-individual differences in trajectories of employment interference and characteristics associated with employment interference at enrollment and over 12months.ResultsPatients' mean age was 55.0 (±11.7) years and the majority underwent breast conservation surgery (80.6%). Mean employment interference score was 3.2 (±3.7). Unconditional model for employment interference demonstrated a decreasing linear trend (-.076/month). Younger age, lower income, higher pain intensity, and having an axillary lymph node dissection were associated with higher pre-surgical interference scores. Having a sentinel lymph node biopsy was associated with ongoing employment interference scores. Higher sleep disturbance scores were associated with both initial and ongoing employment interference scores. Receipt of chemotherapy, use of complementary or alternative therapies, and re-excision or mastectomy following surgery were significant time varying covariates.ConclusionThis study is the first to use HLM to describe inter-individual differences in the trajectories of cancer's interference with employment and associated factors prior to and for 12months following breast cancer surgery. Patients with the identified risk factors warrant ongoing assessments of employment interference and appropriate referrals.

Digital medicine is a medical treatment that combines technology with drug delivery. The promises of this combination are continuous and remote monitoring, better disease management, self-tracking, self-management of diseases, and improved treatment adherence. These devices pose ethical challenges for patients, providers, and the social practice of medicine. For patients, having both informed consent and a user agreement raises questions of understanding for autonomy and informed consent, therapeutic misconception, external influences on decision making, confidentiality and privacy, and device dependability. For providers, digital medicine changes the relationship where trust can be verified, clinicians can be monitored, expectations must be managed, and new liability risks may be assumed. Other ethical questions include direct third-party monitoring of health treatment, affordability, and planning for adverse events in the case of device malfunction. This article seeks to lay out the ethical landscape for the implementation of such devices in patient care.

Purpose: To test the hypothesis that patients treated with radiotherapy for choroidal melanoma enjoy better quality of life (QoL) than patients who have undergone enucleation. Methods: In this nonrandomized study, patients with choroidal melanoma treated at the Royal Liverpool University Hospital, Liverpool, UK, were invited to complete QoL questionnaires approximately 6 months postoperatively and then on each anniversary of their primary treatment. These instruments consisted of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-OPT30 questionnaire, Hospital Anxiety & Depression Scale, and the Functional Assessment of Cancer Treatment questionnaire. Patient-reported outcomes were correlated with demographics, ocular treatment, social factors, presenting tumor and ocular status, self-reported general health, marital status, and employment status. Results: The 1596 patients were treated with radiotherapy (72.3%) or enucleation (27.7%). Enucleation was associated with male sex (χ2, P = .004), older age (t test, P < .001), larger tumor diameter (t test, P < .001), monosomy 3 (χ2, P < .001), depression (linear regression, 95% confidence interval [CI], .17 to 1.01), and reduced physical and functional well-being (linear regression, 95% CI, −1.14 to −0.12 and −1.96 to −0.47), respectively. Poor QoL was attributed to the ocular disease by 21% and 20% of enucleated and irradiated patients, respectively (χ2, P = .938). Conclusions: Patient-reported outcomes and QoL were worse in patients who had undergone primary enucleation for choroidal melanoma. These outcomes may partly have been caused by factors predisposing to enucleation rather than enucleation itself, because enucleated patients tended to be older, with more advanced disease at presentation, and a worse prognosis for survival. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Objective Specific personality traits are associated with differential use of various coping strategies. Few studies have examined the relationship between personality and coping in oncology patients undergoing chemotherapy. We, therefore, examined the relationship between previously identified personality profiles (ie, Distressed [14.3% of total sample], Normative [53.8%], Resilient [31.9%]) and measures of coping and adjustment. Methods Patients (n = 1248) undergoing chemotherapy for breast, gastrointestinal, gynecological, or lung cancer completed measures of personality (NEO-Five Factor Inventory), coping (Brief COPE), and psychological adjustment to cancer (Mental Adjustment to Cancer [MAC] scale). Differences in coping and adjustment among the three personality profiles were evaluated using analysis of variance. Results On the Brief COPE, the Distressed class endorsed lower use of Active Coping, Positive Reframing, Acceptance, Emotional Support (ie, "engagement" coping); and greater use of Denial, Venting, Behavioral Disengagement, Self-Blame (ie, "disengagement" coping) compared to the Normative and Resilient classes. On the MAC scale, the Distressed class scored higher on Anxious Preoccupation, Helplessness/Hopelessness, Fatalism, and Avoidance, and lower on Fighting Spirit, compared to the other two classes. Conclusions In this sample of oncology patients receiving chemotherapy, patients in the Distressed personality class showed a reduced repertoire of adaptive coping strategies, while those in the Resilient class reported greater use of adaptive or engagement coping strategies. Further work should examine the potential mediating or moderating role of coping and adjustment in the relationships between personality and patient outcomes. Interventions to enhance beneficial and reduce harmful coping strategies in cancer patients should be evaluated.

Psychiatric researchers grapple with concerns that individuals with mental illness may be less likely to appreciate risks of research participation, particularly compared to people not suffering from mental illness. Therefore, empirical studies that directly compare the perspectives of such individuals are needed. In addition, it is important to evaluate perspectives regarding varied types of research protocols, particularly as innovative psychiatric research protocols emerge. In this pilot study, respondents with a mood disorder (n = 25) as well as respondents without a mood disorder (n = 55) were recruited using Amazon's Mechanical Turk (MTurk) platform. These respondents were surveyed regarding four psychiatric research projects (i.e., experimental medication [pill form]; non-invasive magnetic brain stimulation; experimental medication [intravenous infusion]; and implantation of a device in the brain). Regardless of health status, respondents rated the four research protocols as somewhat to highly risky. The brain-device implant protocol was seen as the most risky, while the magnetic brain stimulation project was viewed as “somewhat risky”. Respondents, on average and regardless of health status, rated their willingness at or below “somewhat willing.” Respondents were least willing to participate in the brain-device implant protocol, whereas they were “somewhat willing” to participate in the magnetic brain stimulation protocol. Trust in medical research was negatively associated with perceived risk of research protocols. Perceived risk was negatively associated with willingness to participate, even when adjusting for potential confounders, suggesting that attunement to risk crosses diagnostic, gender, and ethnic categories, and is more salient to research decision-making than trust in medical research and dispositional optimism. The findings of this study may offer reassurance about the underlying decision-making processes of individuals considering participation in innovative neuroscience studies.

The bifunctional alkylating agents epichlorohydrin (ECH) and diepoxybutane (DEB) have been linked to increased cancer risks in industrial workers. These compounds react with DNA and proteins, leading to genotoxic effects. We used the comet assay to monitor formation of cross-links in HL-60 cells treated with ECH, DEB, and the structurally related anti-cancer drug mechlorethamine (HN2). We report a time- and dose-dependent cytotoxicity that correlated with cross-linking activity, following the order HN2 > DEB > ECH. The rate of cross-link repair also varied with drug, with ECH-induced lesions the fastest to repair. High drug doses led to the formation of saturating amounts of HN2 cross-links that were repaired inefficiently. DEB and ECH produced fewer overall cross-links, but some were also resistant to repair. These persistent cross-links may activate cell-cycle arrest to allow repair of damage, with prolonged arrest triggering apoptosis. Quantitative reverse transcription polymerase chain reaction experiments revealed that treatment of HL-60 cells with DEB and ECH results in up-regulation of several genes involved in the intrinsic (mitochondrial) apoptosis pathway, including BAX, BAK1, CASP-9, APAF-1, and BCL-2. These findings contribute to our understanding of the principles underlying the carcinogenic potentials of these xenobiotics.

Background Although thousands of different chemicals have been identified in cigarette smoke, the characterization of their urinary metabolites still requires significant research. The aim of this work was to perform an untargeted metabolomic approach to a pilot cross-sectional study conducted on subjects with different smoking habits and to compare the results with those of the targeted measurement of mercapturic acids. Methods Urine samples from 67 adults, including 38 non-smokers, 7 electronic cigarette users, and 22 traditional tobacco smokers were collected. Samples were analysed by liquid chromatography/time-of flight mass spectrometry. Data were processed using the R-packages IPO and XCMS to perform feature detection, retention time correction and alignment. One-way ANOVA test was used to identify different features among groups. Quantitative determination of 17 mercapturic acids was available from a previous study. Results One hundred and seventeen features, out of 3613, were different among groups. They corresponded to 91 potential metabolites, 5 of which were identified vs authentic standards, 43 were putatively annotated and 13 were attributed to chemical classes. Among identified compounds there were the mercapturic acids of acrolein, 1,3-butadiene, and crotonaldehyde; among putatively annotated compounds there were the glucuronide conjugated of 3-hydroxycotinine and the sulfate conjugate of methoxyphenol; with the lowest degree of confidence several sulfate conjugates of small molecules were annotated. Considering mercapturic acids, the coherence between the targeted and untargeted approach was found for a limited number of chemicals, typically the most abundant. Conclusions Differences in the urinary levels of several compounds were associated to the different smoking habits, suggesting that the proposed approach is useful for the investigation of the metabolite patterns related to the exposure to toxicants. However, limitations were highlighted, in particular regarding the identification of low concentration compounds.