Regulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite methylglyoxal.

Regulatory myeloid immune cells, such as myeloid-derived suppressor cells (MDSCs), populate inflamed or cancerous tissue and block immune cell effector functions. The lack of mechanistic insight into MDSC suppressive activity and a marker for their identification has hampered attempts to overcome T cell inhibition and unleash anti-cancer immunity. Here, we report that human MDSCs were characterized by strongly reduced metabolism and conferred this compromised metabolic state to CD8+ T cells, thereby paralyzing their effector functions. We identified accumulation of the dicarbonyl radical methylglyoxal, generated by semicarbazide-sensitive amine oxidase, to cause the metabolic phenotype of MDSCs and MDSC-mediated paralysis of CD8+ T cells. In a murine cancer model, neutralization of dicarbonyl activity overcame MDSC-mediated T cell suppression and, together with checkpoint inhibition, improved the efficacy of cancer immune therapy. Our results identify the dicarbonyl methylglyoxal as a marker metabolite for MDSCs that mediates T cell paralysis and can serve as a target to improve cancer immune therapy.

Bifunctional Molecules That Induce Both Targeted Degradation and Transcytosis of Extracellular Proteins in Brain Cells.

Targeted protein degradation (TPD) has emerged as an effective therapeutic strategy for a wide range of diseases; however, the blood-brain barrier (BBB) limits access of degraders into the central nervous system (CNS). Here, we present a new class of bifunctional small molecules, called TransMoDEs (Transcytosis-inducing molecular degraders of extracellular proteins), capable of both (1) removal of target protein via lysosomal proteolysis and (2) transcytosis of protein targets across brain endothelial cells. TransMoDEs are derived from Angiopep-2, a peptide motif previously employed as a covalent tag to facilitate receptor-mediated transcytosis across the BBB. We demonstrate that TransMoDEs containing either a biotin or chloroalkane ligand can trigger endocytosis of streptavidin or HaloTag protein, respectively. Interestingly, although low-density lipoprotein receptor-related protein 1 (LRP1) has been reported as the primary receptor for Angiopep-2, TransMoDE-mediated target uptake does not rely exclusively on this pathway. Furthermore, TransMoDE-mediated endocytosis of streptavidin in a bEnd.3 BBB model occurs in a clathrin-mediated mechanism and results in both lysosomal localization and transcytosis of the target protein. This study demonstrates that TransMoDEs can recruit, transcytose, and degrade proteins of interest in cells relevant to the CNS, supporting their further development for the removal of pathogenic neuroproteins.

Dyadic Investigation of Posttraumatic Stress Symptoms and Daily Sleep Health in Patients With Cancer and Their Caregivers.

OBJECTIVE: Cancer can be a traumatic experience affecting multidimensional aspects of sleep among patients and caregivers. This study examined the differential associations of cancer-related posttraumatic stress symptoms (PTSS) with various sleep markers in this population. METHODS: Patients newly diagnosed with colorectal cancer ( n = 138, mean age = 56.93 years, 31.88% female, 60.14% Hispanic, 6.53 months after diagnosis) and their sleep-partner caregivers ( n = 138, mean age = 55.32 years, 68.12% female, 57.97% Hispanic) completed questionnaires assessing the four PTSS clusters (intrusion, avoidance, alterations in arousal and reactivity, negative alterations in cognitions and mood). Participants also completed daily sleep diaries for 14 consecutive days, from which sleep onset latency (SOL), wake after sleep onset (WASO), and sleep duration were derived. RESULTS: Actor-partner interdependence model revealed that caregivers' greater alterations in arousal and reactivity were associated with their own longer SOL ( b = 15.59, p < .001) and their patients' longer sleep duration ( b = 0.61, p = .014), whereas patients' arousal and reactivity were associated with their caregivers' shorter SOL ( b = -8.47, p = .050). Patients' and caregivers' greater negative alterations in cognitions and mood were associated with patients' longer SOL ( b = 9.15, p = .014) and shorter sleep duration ( b = -0.41, p = .050), respectively. Caregivers' greater intrusion was related to their own shorter SOL ( b = -10.14, p = .004). CONCLUSIONS: The four PTSS clusters, particularly arousal and reactivity and negative cognitions and mood, have distinct associations with sleep markers individually and dyadically in patients and caregivers affected by cancer. Investigations of psychosocial and biobehavioral pathways underlying these relations are warranted. Tailored trauma treatments and sleep interventions may improve the well-being of this population.

Preliminary testing of "roadmap to parenthood" decision aid and planning tool for family building after cancer: Results of a single-arm pilot study.

OBJECTIVE: Many young adult female cancer survivors need to use reproductive medicine, surrogacy, or adoption to have a child. This study pilot tested Roadmap to Parenthood, a web-based, self-guided decision aid and planning tool for family building after cancer (disease agnostic). METHODS: A single-arm pilot study tested feasibility, acceptability, and obtained effect size estimates of the Roadmap tool. Participants, recruited via hospital-based and social media strategies, completed a baseline survey (T1), accessed the Roadmap tool (website), then completed surveys at one- and 3-months (T2 and T3, respectively). Feasibility and acceptability were evaluated with rates of eligibility, enrollment, and survey completion, and feedback. Pairwise t-tests and repeated measures ANOVA evaluated usage effects. Effect size estimates were calculated. RESULTS: Participants (N = 98) averaged 31 years old (SD = 5.61); 71% were nulliparous. Enrollment rate was 73%, T1-T2 completion rate was 80%, and 93% accessed the website. From T1-T2, participants reported improvements in decisional conflict (p < 0.001; Cohen's d = 0.85), unmet information needs (p < 0.001; Cohen's d = 0.70), self-efficacy (p = 0.003; Cohen's d = 0.40), and self-efficacy for managing negative emotions (p = 0.03; Cohen's d = 0.29); effects were sustained at T3. There was no change in reproductive distress (p = 0.22). By T3, 94% reported increased consideration of preparatory actions and 20%-61% completed such actions. CONCLUSIONS: The Roadmap intervention was feasible to conduct, acceptable to users, and led to improvements in key psychosocial outcomes. Future directions will test intervention efficacy in a randomized controlled trial with a larger sample and over a longer period. A web-based tool may help women make decisions about family building after cancer and prepare for potential challenges.

Tenapanor: A Phosphate Absorption Inhibitor for the Management of Hyperphosphatemia in Patients With Kidney Failure.

Because of increased risks of cardiovascular disease and death, patients with hyperphosphatemia receiving maintenance dialysis are advised to limit phosphorus consumption and are prescribed phosphate binders in an effort to better control serum phosphate concentrations. Because of large pill size, pill burden, and tolerability issues, phosphate binder adherence is relatively poor. On ingestion, phosphate is absorbed from the intestine via transcellular or paracellular transport. Data show that inhibiting sodium-hydrogen exchanger 3 modulates paracellular phosphate absorption (the predominant pathway in humans). Tenapanor is a first-in-class, minimally absorbed, phosphate absorption inhibitor that selectively inhibits sodium-hydrogen exchanger 3, with a mechanism distinct from, and complementary to, that of phosphate binders. In phase 3 and postregistrational studies, tenapanor conferred statistically significant and clinically meaningful reductions in serum phosphate in patients receiving maintenance dialysis with hyperphosphatemia. Here, we review the available preclinical and clinical data on the effects of tenapanor on controlling intestinal phosphate absorption.

Bifunctional small molecules that mediate the degradation of extracellular proteins.

Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy. Most TPD technologies use the ubiquitin-proteasome system, and are therefore limited to targeting intracellular proteins. To address this limitation, we developed a class of modular, bifunctional synthetic molecules called MoDE-As (molecular degraders of extracellular proteins through the asialoglycoprotein receptor (ASGPR)), which mediate the degradation of extracellular proteins. MoDE-A molecules mediate the formation of a ternary complex between a target protein and ASGPR on hepatocytes. The target protein is then endocytosed and degraded by lysosomal proteases. We demonstrated the modularity of the MoDE-A technology by synthesizing molecules that induce depletion of both antibody and proinflammatory cytokine proteins. These data show experimental evidence that nonproteinogenic, synthetic molecules can enable TPD of extracellular proteins in vitro and in vivo. We believe that TPD mediated by the MoDE-A technology will have widespread applications for disease treatment.

Changing cancer mindsets: A randomized controlled feasibility and efficacy trial.

OBJECTIVE: A cancer diagnosis and subsequent treatment can disrupt the full spectrum of physical, social, emotional, and functional quality of life. But existing psychological treatments are focused primarily on specific psychological symptoms as opposed to improving the overall patient experience. We studied the feasibility and efficacy of a novel digital intervention targeting patient mindsets-core assumptions about the nature and meaning of illness-designed to improve overall health-related quality of life (HRQoL) in newly diagnosed cancer patients undergoing treatment with curative intent. METHODS: Recently diagnosed (≤150 days) adult patients with non-metastatic cancers undergoing systemic treatment (N = 361) were recruited from across the United States to participate in this decentralized clinical trial. Patients were randomized 1:1 to receive the Cancer Mindset Intervention (CMI) or Treatment as Usual (TAU). Participants in the CMI group completed seven online modules over 10 weeks (2.5 h total) targeting mindsets about cancer and the body. The primary outcome was overall HRQoL, and secondary outcomes were coping behaviors and symptom distress. RESULTS: Patients in the CMI group reported significant (p < 0.001) improvements in adaptive mindsets about cancer and the body over time. Compared with the TAU condition, the CMI group reported significant improvements in overall HRQoL (B = 0.60; 95% CI 0.34-0.85; p < 0.001), increased engagement in adaptive coping behaviors (B = 0.03; 95% CI 0.02-0.04; p < 0.001), and reduced distress from physical symptoms (B = -0.29; 95% CI -0.44 to -0.14; p < 0.01). Effect sizes of these changes ranged from d = 0.42-d = 0.54. CONCLUSION: A brief mindset-focused digital intervention was effective at improving physical, social, emotional, and functional HRQoL, increasing adaptive coping behaviors, and reducing physical symptom distress in newly diagnosed cancer patients.

Pentosinane, a Post-Translational Modification of Human Proteins with Underappreciated Stability.

Pentosinane is a structurally complex nonenzymatic post-translational modification of proteins believed to be present in all living things. It falls into the category of advanced glycation end products (AGEs) and is structurally related to the other AGEs pentosidine and glucosepane. Although pentosidine and glucosepane have been widely studied for their role in wide-ranging conditions (e.g., diabetes mellitus, Alzheimer's disease, and human aging), relatively little is known about pentosinane. Interestingly, previous reports have suggested that pentosidine may derive from pentosinane. The (patho)physiological significance of pentosinane in humans is largely unexplored. As a first step to address this knowledge gap, we report herein the first total synthesis of pentosinane. Our synthesis is high yielding (1.7% over seven steps), concise, and enantioselective, and it leverages a strategy for synthesizing 2,5-diaminoimidazoles previously developed by our lab. Access to synthetic pentosinane has allowed us to perform additional studies showing that its oxidation to pentosidine is both pH and oxygen dependent and is substantially slower under physiological conditions than previously believed. Additionally, pentosinane rapidly decomposes under harshly acidic conditions typically employed for pentosidine isolation. Taken together, these results suggest that pentosinane is likely to be more abundant in vivo than previously appreciated. We believe these results represent a critical step toward illuminating the role(s) of pentosinane in human biology.

Morning Chronotype Decreases the Risk of Chemotherapy-Induced Peripheral Neuropathy in Women With Breast Cancer.

BACKGROUND: The purpose of this longitudinal prospective cohort study was to investigate the role of chronotype in the incidence of chemotherapy-induced peripheral neuropathy (CIPN) among women with breast cancer. METHODS: We recruited women with breast cancer awaiting adjuvant chemotherapy, including four cycles of docetaxel. Participants reported peripheral neuropathy symptoms of numbness/tingling at the baseline, and at 4weeks after completion of chemotherapy. Candidate psychiatric factors associated with CIPN were assessed at the baseline, using the Composite Scale of Morningness, the Pittsburgh Sleep Quality Index, and the Hospital Anxiety and Depression Scale. To examine the association between chronotype and CIPN, we built logistic regression models, adjusting for demographic, clinical, and other psychiatric variables. RESULTS: Among 48 participants, 29 participants developed CIPN. The morning chronotype was inversely associated with CIPN (odds ratio, 0.06; confidence interval, 0.01-0.74; P = 0.028) after adjusting for age, BMI, education, type of operation, alcohol use, smoking, sleep quality, depression, and anxiety. CONCLUSION: Our results suggest that the morning chronotype is a protective factor against the development of CIPN in patients with breast cancer who were treated with docetaxel. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01887925.

Age-related changes in the physical properties, cross-linking, and glycation of collagen from mouse tail tendon.

Collagen is a structural protein whose internal cross-linking critically determines the properties and functions of connective tissue. Knowing how the cross-linking of collagen changes with age is key to understanding why the mechanical properties of tissues change over a lifetime. The current scientific consensus is that collagen cross-linking increases with age and that this increase leads to tendon stiffening. Here, we show that this view should be reconsidered. Using MS-based analyses, we demonstrated that during aging of healthy C57BL/6 mice, the overall levels of collagen cross-linking in tail tendon decreased with age. However, the levels of lysine glycation in collagen, which is not considered a cross-link, increased dramatically with age. We found that in 16-week-old diabetic db/db mice, glycation reaches levels similar to those observed in 98-week-old C57BL/6 mice, while the other cross-links typical of tendon collagen either decreased or remained the same as those observed in 20-week-old WT mice. These results, combined with findings from mechanical testing of tendons from these mice, indicate that overall collagen cross-linking in mouse tendon decreases with age. Our findings also reveal that lysine glycation appears to be an important factor that contributes to tendon stiffening with age and in diabetes.

Sirtuin 2 Regulates Protein LactoylLys Modifications.

Post-translational modifications (PTMs) play roles in both physiological and pathophysiological processes through the regulation of enzyme structure and function. We recently identified a novel PTM, lactoylLys, derived through a nonenzymatic mechanism from the glycolytic by-product, lactoylglutathione. Under physiologic scenarios, glyoxalase 2 prevents the accumulation of lactoylglutathione and thus lactoylLys modifications. What dictates the site-specificity and abundance of lactoylLys PTMs, however, remains unknown. Here, we report sirtuin 2 as a lactoylLys eraser. Using chemical biology and CRISPR-Cas9, we show that SIRT2 controls the abundance of this PTM both globally and on chromatin. These results address a major gap in our understanding of how nonenzymatic PTMs are regulated and controlled.

The risk of medically uncontrolled secondary hyperparathyroidism depends on parathyroid hormone levels at haemodialysis initiation.

BACKGROUND: Optimal parathyroid hormone (PTH) control during non-dialysis chronic kidney disease (ND-CKD) might decrease the subsequent risk of parathyroid hyperplasia and uncontrolled secondary hyperparathyroidism (SHPT) on dialysis. However, the evidence for recommending PTH targets and therapeutic strategies is weak for ND-CKD. We evaluated the patient characteristics, treatment patterns and PTH control over the first year of haemodialysis (HD) by PTH prior to HD initiation. METHODS: We studied 5683 incident HD patients from 21 countries in Dialysis Outcomes and Practice Patterns Study Phases 4-6 (2009-18). We stratified by PTH measured immediately prior to HD initiation and reported the monthly prescription prevalence of active vitamin D and calcimimetics over the first year of HD and risk of PTH >600 pg/mL after 9-12 months on HD. RESULTS: The 16% of patients with PTH >600 pg/mL prior to HD initiation were more likely to be prescribed active vitamin D and calcimimetics during the first year of HD. The prevalence of PTH >600 pg/mL 9-12 months after start of HD was greater for patients who initiated HD with PTH >600 (29%) versus 150-300 (7%) pg/mL (adjusted risk difference: 19%; 95% confidence interval : 15%, 23%). The patients with sustained PTH >600 pg/mL after 9-12 months on HD were younger, more likely to be black, and had higher serum phosphorus and estimated glomerular filtration rates at HD initiation. CONCLUSIONS: Increased PTH before HD start predicted a higher PTH level 9-12 months later, despite greater use of active vitamin D and calcimimetics. More targeted PTH control during ND-CKD may influence outcomes during HD, raising the need for PTH target guidelines in these patients.

Impact of assessment frequency of patient-reported outcomes: an observational study using an eHealth platform in cancer patients.

BACKGROUND AND AIM: The evaluation of patient-reported outcomes (PRO) in cancer has proven relevant positive clinical impact on patients' communication with healthcare professionals, decision-making for management, well-being, and overall survival. However, the optimal frequency of PRO assessment has yet to be defined. Based on the assumption that more frequent sampling would enhance accuracy, we aimed at identifying the optimal sampling frequency that does not miss clinically relevant insight. METHODS: We used pilot data from 31 advanced cancer patients who completed once daily the 19-item MD Anderson Symptom Inventory at home. The resulting dataset allowed us to compare different PRO assessment frequencies to daily sampling, i.e., alternate days (q2d), every third day (q3d), or once a week (q1w). We evaluated the sampling frequencies for two main outcomes: average symptom intensity and identification of severe symptoms. RESULTS: The majority of the differences between corresponding averages of daily data and those for q2d, q3d, and q1w datasets were close to 0, yet the extremes exceeded 5. Clinically meaningful differences, i.e., > 1, were observed in 0.76% of patient items for q2d, in 2.72% for q3d, and in 11.93% for q1w. Moreover, median values of missed instances of a severe symptom (i.e., > 6) were 14.6% for q2d, 27.8% for q3d, and 55.6% for q1w. CONCLUSIONS: Our analysis suggests that in patients receiving chemotherapy for advanced cancer, increasing the density of PRO collection enhances the accuracy of PRO assessment to a clinically meaningful extent. This is valid for both computations of averages symptom burden and for the recognition of episodes of severe symptom intensity.

Association between Anterior Cingulate Neurochemical Concentration and Individual Differences in Hypnotizability.

Hypnosis is the oldest form of Western psychotherapy and a powerful evidence-based treatment for numerous disorders. Hypnotizability is variable between individuals; however, it is a stable trait throughout adulthood, suggesting that neurophysiological factors may underlie hypnotic responsiveness. One brain region of particular interest in functional neuroimaging studies of hypnotizability is the anterior cingulate cortex (ACC). Here, we examined the relationships between the neurochemicals, GABA, and glutamate, in the ACC and hypnotizability in healthy individuals. Participants underwent a magnetic resonance imaging (MRI) session, whereby T1-weighted anatomical and MEGA-PRESS spectroscopy scans were acquired. Voxel placement over the ACC was guided by a quantitative meta-analysis of functional neuroimaging studies of hypnosis. Hypnotizability was assessed using the Hypnotic Induction Profile (HIP), and self-report questionnaires to assess absorption (TAS), dissociation (DES), and negative affect were completed. ACC GABA concentration was positively associated with HIP scores such that the higher the GABA concentration, the more hypnotizable an individual. An exploratory analysis of questionnaire subscales revealed a negative relationship between glutamate and the absorption and imaginative involvement subscale of the DES. These results provide a putative neurobiological basis for individual differences in hypnotizability and can inform our understanding of treatment response to this growing psychotherapeutic tool.

Hypnotic predictors of agency: Responsiveness to specific suggestions in hypnosis is associated with involuntariness in fibromyalgia.

Hypnosis is associated with alterations in the sense of agency which can play a role in its utilization as a nonpharmacological option for pain management. The goal of the current study was to examine the relationships between responsiveness to suggestions in hypnosis and alterations of the sense of agency among patients with fibromyalgia. Ninety-eight participants with fibromyalgia underwent two hypnotizability assessments followed by the Sense of Agency Rating Scale. Clinical pain measures were also collected. Involuntariness was predicted by responsiveness to control, ideomotor, and dissociation suggestions. Effortlessness was predicted by responsiveness to control and ideomotor suggestions, and age. Hypnotizability was associated with main clinical pain outcomes, but agency alterations were not. Results suggest a shared mechanism between responsiveness to specific suggestions and the sense of agency in hypnosis. We discuss theoretical and clinical implications for pain management and the need for further research.

Methylglyoxal-derived posttranslational arginine modifications are abundant histone marks.

Histone posttranslational modifications (PTMs) regulate chromatin dynamics, DNA accessibility, and transcription to expand the genetic code. Many of these PTMs are produced through cellular metabolism to offer both feedback and feedforward regulation. Herein we describe the existence of Lys and Arg modifications on histones by a glycolytic by-product, methylglyoxal (MGO). Our data demonstrate that adduction of histones by MGO is an abundant modification, present at the same order of magnitude as Arg methylation. These modifications were detected on all four core histones at critical residues involved in both nucleosome stability and reader domain binding. In addition, MGO treatment of cells lacking the major detoxifying enzyme, glyoxalase 1, results in marked disruption of H2B acetylation and ubiquitylation without affecting H2A, H3, and H4 modifications. Using RNA sequencing, we show that MGO is capable of altering gene transcription, most notably in cells lacking GLO1. Finally, we show that the deglycase DJ-1 protects histones from adduction by MGO. Collectively, our findings demonstrate the existence of a previously undetected histone modification derived from glycolysis, which may have far-reaching implications for the control of gene expression and protein transcription linked to metabolism.

Outcomes After Surgical Fixation of Posterior Sternoclavicular Physeal Fractures and Dislocations in Children.

BACKGROUND: Acute sternoclavicular fractures and dislocations (SCFDs) are a rare but important injury in pediatric patients. SCFDs are either true dislocations, or more commonly, physeal fractures in children. The reduction is advised given the proximity to surrounding vascular structures, and some authors advocate for routine fixation given rates of redisplacement after closed reduction. The purpose of the current study was to provide validated long-term functional outcome data following open reduction and surgical fixation of pediatric SCFDs, as well as provide injury and demographic information. METHODS: This is a retrospective observational study with a subset of patients reporting functional outcomes. Patients under the age of 18 that had surgically managed acute posterior SCFD from 1990 to 2018 were included. A retrospective chart review was performed to obtain demographic, clinical, and surgical details. Patients with a minimum of 6-month follow-up were contacted to assess outcomes. Functional outcomes of interest included QuickDash, Visual Analog Scale pain rating, Single Assessment Numeric Evaluation of shoulder function, and PROMIS Upper Extremity questionnaire. Statistical analysis included descriptive statistics. RESULTS: A total of 37 patients that sustained an acute posterior SCFD during the study period were included. The average age at the time of injury was 15.2±2.1 years and 89% were male. Patient-reported outcomes were obtained for 14 patients with a mean follow-up of 4.5 years. The mean QuickDash score was 5.1/100 with 0 being normal, and the mean Visual Analog Scale pain rating was 0.7/10. The mean Single Assessment Numeric Evaluation score was 96% with 100% being completely normal. The mean PROMIS score was 55 with 50 being the mean of the relevant reference population. Approximately 29% (4/14 patients) stated that their injury negatively affected their ability to participate in sports. CONCLUSIONS: There is a paucity of literature on functional outcomes after surgical management of pediatric acute posterior SCFD. Functional outcomes after surgery were satisfactory in this cohort with most patients being able to perform major activities of daily living. Additional future studies with larger cohorts and comparative groups are needed to better understand outcomes in this population. LEVEL OF EVIDENCE: Level IV.

Synthetic Rhamnose Glycopolymer Cell-Surface Receptor for Endogenous Antibody Recruitment.

Synthetic materials capable of engineering the immune system are of great relevance in the fight against cancer to replace or complement the current monoclonal antibody and cell therapy-based immunotherapeutics. Here, we report on antibody recruiting glycopolymers (ARGPs). ARGPs consist of polymeric copies of a rhamnose motif, which can bind endogenous antirhamnose antibodies present in human serum. As a proof-of-concept, we have designed ARGPs with a lipophilic end group that efficiently inserts into cell-surface membranes. We validate the specificity of rhamnose to attract antibodies from human serum to the target cell surface and demonstrate that ARGPs outperform an analogous small-molecule compound containing only one single rhamnose motif. The ARGP concept opens new avenues for the design of potent immunotherapeutics that mark target cells for destruction by the immune system through antibody-mediated effector functions.

Morning chronotype is a protective factor against chemotherapy-induced hot flashes in premenopausal women with breast cancer.

PURPOSE: Adjuvant chemotherapy in patients with breast cancer often causes hot flashes, impairing quality of life. However, the chronobiological or psychiatric factors associated with the development of chemotherapy-induced hot flashes (CIHFs) remain undetermined. The purpose of this study was to investigate whether chronotype was associated with the incidence of CIHFs. METHODS: A total of 119 premenopausal women with non-metastatic breast cancer awaiting adjuvant chemotherapy after surgery without hot flashes were included. The presence of CIHF was defined as having moderate to severe hot flashes, as measured by the subscale of hot flashes in the Menopause Rating Scale, at 4 weeks after the completion of chemotherapy. Chronotype (Morning/Intermediate/Evening) was assessed with the Composite Scale of Morningness before adjuvant chemotherapy. To examine the association between chronotype and CIHF, we built logistic regression models, adjusting for age, body mass index, sleep quality, and radiation therapy. RESULTS: CIHF occurred in 50.4% of participants. Morning type was inversely associated with CIHF (reference: Intermediate type, odds ratio [OR], 0.37; 95% confidence interval [CI], 0.16-0.94; p = 0.040) in the univariate model, and the association remained significant (OR, 0.37; CI, 0.13-0.96; p = 0.045) after adjusting for age, body mass index, sleep quality, and radiation therapy. CONCLUSIONS: Morning chronotype is a protective factor against the development of CIHF in patients with breast cancer. Chronotypes should be assessed and considered in the prediction and management of CIHF.

Wrangling with p-values versus effect sizes to improve medical decision-making: A tutorial.

The most pervasive and damaging myth in clinical research is that the smaller the p-value, the stronger the hypothesis. In reality, the p-value primarily reflects the quality of research design decisions. The most common proposal to avoid misleading conclusions from clinical research requires the appropriate use of effect sizes, but which effect size, used when and how, is an open question. A solution is proposed for perhaps the most common problem in clinical research, the comparison between two populations, for example, comparison of two treatments in a randomized clinical trial or comparison of high risk versus low risk individuals in an epidemiological study: the success rate difference or equivalently the number needed to treat/take (NNT).