bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing Patient Reported Outcomes among Anti-TNF Experienced Patients with Ulcerative Colitis Initiating Vedolizumab versus Tofacitinib
Authors: Kappelman Michael D , Long Millie D , Zhang Xian , Lin Feng-Chang , Weisbein Laura , Chen Wenli , Burris Jessica , Dorand Jennifer E , Parlett Lauren E , Fehlmann Tara , Brensinger Colleen M , Haynes Kevin , Nair V Vinit , Kaul Alan F , Dobes Angela , Lewis JD James D ,   the SPARC IBD Investigators
Published: May 2023

Background

Primary and secondary non-response to Anti-Tumor Necrosis Factor (TNF) therapy is common in patients with ulcerative colitis (UC), yet limited research has compared the effectiveness of subsequent biological therapy.

Objective

We sought to compare the effectiveness of vedolizumab and tofacitinib in anti-TNF experienced patients with UC, focusing on patient-prioritized patient reported outcomes (PROs).

Methods

We conducted a prospective cohort study nested within the Crohn’s & Colitis Foundation’s IBD Partners and SPARC IBD initiatives. We identified anti-TNF experienced patients with UC initiating vedolizumab or ustekinumab and analyzed PROs reported approximately 6 months later (minimum 4 months, maximum 10 months). Co-primary outcomes were Patient Reported Outcome Measurement Information System (PROMIS) domains of Fatigue and Pain Interference. Secondary outcomes included PRO-2, treatment persistence, and need for colectomy.

Results

We compared 72 vedolizumab initiators and 33 tofacitinib initiators. At follow-up, Pain Interference (P=0.04), but not Fatigue (P=0.53,) was lower among tofacitinib initiators. A trend towards higher Social Role Satisfaction was not significant. The remainder of secondary outcomes (PRO2, treatment persistence, colectomy) did not differ between treatment groups.

Conclusion

Among anti-TNF experienced patients with UC, Pain Interference 4-10 months after treatment initiation was lower among tofacitinib users as compared to vedolizumab users. Many, but not all, secondary endpoints and subanalyses also favored favored tofacitinib. Future studies with larger sample sizes are needed to further evaluate these findings.
Sex on mission: care, control and coloniality in peacekeeping and humanitarian operations
Authors: Westendorf Jasmine-Kim
Published: May 2023

This article critically reflects on twenty years of efforts to prevent and punish sexual exploitation by peacekeepers and humanitarian actors through the UN's zero-tolerance policy (‘the Bulletin’). I trace the assumptions and motivations that underpin the Bulletin's framing of (un)acceptable sex and investigate the operational and normative implications of its strong discouragement of sexual relationships with beneficiaries. I argue that, by construing the power differential between local communities and UN/NGO personnel as inherent, singular and totalizing, the Bulletin first reinforces conservative gender norms by framing women as perpetually and uniquely vulnerable and reinscribing gendered power imbalances. Second, it denies women agency in an era of Women, Peace and Security, laying the foundation for a detrimental separation between local people and international personnel. Third, it restructures paternalism in ways that entrench power imbalances between local communities and the organizations mandated to ‘protect’ them, reproducing colonial patterns of dealing with sex and sexuality. This analysis lays bare the tensions between care and control in how the international community responds to sexual misconduct by UN/NGO personnel and demonstrates the ramifications of these tensions for the practice and effectiveness of peace and humanitarian operations.
Quantitative Rigidity of Differential Inclusions in Two Dimensions
Authors: Lamy Xavier , Lorent Andrew , Peng Guanying
Published: May 2023

For any compact connected one-dimensional submanifold $K\subset \mathbb R^{2\times 2}$ without boundary that has no rank-one connection and is elliptic, we prove the quantitative rigidity estimate $$\begin{align*} \inf_{M\in K}\int_{B_{1/2}}| Du -M |^2\, \textrm{d}x \leq C \int_{B_1} \operatorname{dist}^2(Du, K)\, \textrm{d}x, \qquad\forall u\in H^1(B_1;\mathbb R^2). \end{align*}$$This is an optimal generalization, for compact connected submanifolds of $\mathbb R^{2\times 2}$ without boundary, of the celebrated quantitative rigidity estimate of Friesecke, James, and Müller for the approximate differential inclusion into $SO(n)$. The proof relies on the special properties of elliptic subsets $K\subset{{\mathbb{R}}}^{2\times 2}$ with respect to conformal–anticonformal decomposition, which provide a quasilinear elliptic partial differential equation satisfied by solutions of the exact differential inclusion $Du\in K$. We also give an example showing that no analogous result can hold true in $\mathbb R^{n\times n}$ for $n\geq 3$.
Accelerated Evolution Analysis UncoversPKNOX2as a Key Transcription Factor in the Mammalian Cochlea
Authors: Trigila Anabella P , Castagna Valeria C , Berasain Lara , Montini Dante , Rubinstein Marcelo , Gomez-Casati Maria Eugenia , Franchini Lucía F
Published: May 2023

The genetic bases underlying the evolution of morphological and functional innovations of the mammalian inner ear are poorly understood. Gene regulatory regions are thought to play an important role in the evolution of form and function. To uncover crucial hearing genes whose regulatory machinery evolved specifically in mammalian lineages, we mapped accelerated noncoding elements (ANCEs) in inner ear transcription factor (TF) genes and found that PKNOX2 harbors the largest number of ANCEs within its transcriptional unit. Using reporter gene expression assays in transgenic zebrafish, we determined that four PKNOX2-ANCEs drive differential expression patterns when compared with ortholog sequences from close outgroup species. Because the functional role of PKNOX2 in cochlear hair cells has not been previously investigated, we decided to study Pknox2 null mice generated by CRISPR/Cas9 technology. We found that Pknox2−/− mice exhibit reduced distortion product otoacoustic emissions (DPOAEs) and auditory brainstem response (ABR) thresholds at high frequencies together with an increase in peak 1 amplitude, consistent with a higher number of inner hair cells (IHCs)-auditory nerve synapsis observed at the cochlear basal region. A comparative cochlear transcriptomic analysis of Pknox2−/− and Pknox2+/+ mice revealed that key auditory genes are under Pknox2 control. Hence, we report that PKNOX2 plays a critical role in cochlear sensitivity at higher frequencies and that its transcriptional regulation underwent lineage-specific evolution in mammals. Our results provide novel insights about the contribution of PKNOX2 to normal auditory function and to the evolution of high-frequency hearing in mammals.
Design of synthetic promoters for cyanobacteria with generative deep-learning model
Authors: Seo Euijin , Choi Yun-Nam , Shin Ye Rim , Kim Donghyuk , Lee Jeong Wook
Published: May 2023

Deep generative models, which can approximate complex data distribution from large datasets, are widely used in biological dataset analysis. In particular, they can identify and unravel hidden traits encoded within a complicated nucleotide sequence, allowing us to design genetic parts with accuracy. Here, we provide a deep-learning based generic framework to design and evaluate synthetic promoters for cyanobacteria using generative models, which was in turn validated with cell-free transcription assay. We developed a deep generative model and a predictive model using a variational autoencoder and convolutional neural network, respectively. Using native promoter sequences of the model unicellular cyanobacterium Synechocystis sp. PCC 6803 as a training dataset, we generated 10 000 synthetic promoter sequences and predicted their strengths. By position weight matrix and k-mer analyses, we confirmed that our model captured a valid feature of cyanobacteria promoters from the dataset. Furthermore, critical subregion identification analysis consistently revealed the importance of the -10 box sequence motif in cyanobacteria promoters. Moreover, we validated that the generated promoter sequence can efficiently drive transcription via cell-free transcription assay. This approach, combining in silico and in vitro studies, will provide a foundation for the rapid design and validation of synthetic promoters, especially for non-model organisms.
Leptomeningeal disease in histone-mutant gliomas
Authors: Diaz Maria , Rana Satshil , Silva Correia Carlos Eduardo , Reiner Anne S , Lin Andrew L , Miller Alexandra M , Graham Maya S , Chudsky Sofia , Bale Tejus A , Rosenblum Marc , Karajannis Matthias A , Pentsova Elena
Published: May 2023

Background

The 2016 WHO classification described a subtype of midline gliomas harboring histone 3 (H3) K27M alterations, and the 2021 edition added a new subtype of hemispheric diffuse gliomas with H3 G34R/V mutations. The incidence and clinical behavior of leptomeningeal disease (LMD) in these patients is not well defined.

Methods

Retrospective study of patients with H3-altered gliomas diagnosed from 01/2012 to 08/2021; histone mutations were identified through next-generation sequencing (NGS) of tumor biopsy and/or cerebrospinal fluid (CSF).

Results

We identified 42 patients harboring H3 mutations (K27M mutations in 33 patients, G34R/V in 8, and both in one). Median age was 21 (4–70); 27 were male. LMD was diagnosed in 21/42 (50%) patients, corresponding to a 3-year cumulative incidence of 44.7% (95% confidence interval (CI): 26.1%–63.4%) for the K27-mutant group and a 1-year cumulative incidence of 37.5% in the G34-mutant group (95% CI: 0.01%–74.4%; no events after 1 year). Median time from tumor diagnosis to LMD was 12.9 months for H3-K27 patients and 5.6 months for H3-G34 patients. H3 mutation was detected in CSF in all patients with LMD who had NGS (8 H3-K27-mutant patients). In the H3-K27-mutant group, modeled risk of death was increased in patients who developed LMD (hazard ratio: 7.37, 95% CI: 2.98–18.23, P < .0001).

Conclusions

In our cohort, 50% of patients developed LMD. Although further studies are needed, CSF ctDNA characterization may aid in identifying molecular tumor profiles in glioma patients with LMD, and neuroaxis imaging and CSF NGS should be considered for early LMD detection.
Allelic variation in transcription factor PtoWRKY68 contributes to drought tolerance in Populus
Authors: Fang Yuanyuan , Wang Dan , Xiao Liang , Quan Mingyang , Qi Weina , Song Fangyuan , Zhou Jiaxuan , Liu Xin , Qin Shitong , Du Qingzhang , Liu Qing , El-Kassaby Yousry A , Zhang Deqiang
Published: May 2023

Drought stress limits woody species productivity and influences tree distribution. However, dissecting the molecular mechanisms that underpin drought responses in forest trees can be challenging due to trait complexity. Here, using a panel of 300 Chinese white poplar (Populus tomentosa) accessions collected from different geographical climatic regions in China, we performed a genome-wide association study (GWAS) on seven drought-related traits and identified PtoWRKY68 as a candidate gene involved in the response to drought stress. A 12-bp insertion and/or deletion and three nonsynonymous variants in the PtoWRKY68 coding sequence categorized natural populations of P. tomentosa into two haplotype groups, PtoWRKY68hap1 and PtoWRKY68hap2. The allelic variation in these two PtoWRKY68 haplotypes conferred differential transcriptional regulatory activities and binding to the promoters of downstream abscisic acid (ABA) efflux and signaling genes. Overexpression of PtoWRKY68hap1 and PtoWRKY68hap2 in Arabidopsis (Arabidopsis thaliana) ameliorated the drought tolerance of two transgenic lines and increased ABA content by 42.7% and 14.3% compared to wild-type plants, respectively. Notably, PtoWRKY68hap1 (associated with drought tolerance) is ubiquitous in accessions in water-deficient environments, whereas the drought-sensitive allele PtoWRKY68hap2 is widely distributed in well-watered regions, consistent with the trends in local precipitation, suggesting that these alleles correspond to geographical adaptation in Populus. Moreover, quantitative trait loci analysis and an electrophoretic mobility shift assay showed that SHORT VEGETATIVE PHASE (PtoSVP.3) positively regulates the expression of PtoWRKY68 under drought stress. We propose a drought tolerance regulatory module in which PtoWRKY68 modulates ABA signaling and accumulation, providing insight into the genetic basis of drought tolerance in trees. Our findings will facilitate molecular breeding to improve the drought tolerance of forest trees.
Use of sexual stimuli in research and clinical settings: expert opinion and recommendations
Authors: Katz Maddie A , Penniston Trinda L , Barry Caitlin , Micanovic Nina , Seto Michael C , Chivers Meredith L
Published: May 2023

Background

Sexual stimuli, such as sexual videos, images, and narratives describing sexual interactions, are one of many tools used by clinicians and researchers to elicit or augment sexual response. Given the wide variability within sexual stimuli and their effects on sexual response, we provide guidance on when and how to use sexual stimuli, selecting sexual stimuli, and standardizing the use and reporting of sexual stimuli in research and clinical practice.

Aim

This expert opinion review article discusses standard operating procedures when using sexual stimuli in clinical and research applications, addressing 3 broad areas: settings in which sexual stimuli are used, characteristics and contexts of the stimuli, and practical and ethical considerations when using the stimuli.

Methods

This article is based on an expert opinion review of the sexual psychophysiology literature.

Results

First, we discuss the settings in which sexual stimuli are typically used and evaluate the ecological validity of each setting. Second, we review the types of sexual stimuli used in sexual response research, including physical characteristics, depicted sexual activity, and context, and the impacts of these characteristics on sexual response. Last, we discuss the practical and ethical considerations that come with the choice and use of sexual stimuli in clinical and research settings. We address potential limitations of certain sexual stimuli, including practical and ethical considerations such as participant vs experimenter choice, diversity and representation, and proper sourcing of sexual stimuli for use in clinical and research applications. Discussions on the future applications of sexual stimuli, such as the use of virtual reality, and ethical considerations in terms of user-generated Internet sexual stimuli are also explored.

Conclusion

We provide an expert opinion review of the literature regarding use of sexual stimuli for clinical and research applications and offer best use practices and recommendations.
Erectile dysfunction in ankylosing spondylitis: a systematic review and meta-analysis
Authors: Zhang Yuyang , Wu Xu , Zhang Wei , Liu Guodong , Feng Xingliang , Jiang Hui , Zhang Xiansheng
Published: May 2023

Background

The prevalence of erectile dysfunction (ED) in ankylosing spondylitis (AS) patients was reported rarely and with small sample.

Aim

The study sought to explore the prevalence of ED in men with AS and to determine whether AS is a risk factor for ED.

Methods

A systematic search was conducted in the China National Knowledge Infrastructure, Wanfang, VIP Database, CBM, PubMed, Web of Science, and Cochrane Library. The search was restricted to the articles published up to October 2022. Assessment tools adapted for prevalence studies were used to evaluate the quality of cross-sectional studies, and the quality of case-control studies was assessed by Newcastle–Ottawa scale. The relative risk (RR) and the standard mean difference (SMD) were used to evaluate the association between AS and ED. The subgroup analyses were conducted to identify the resources of heterogeneity. The sensitivity analysis was performed to assess the stability of the pooled estimates. Data were analyzed and graphed using STATA 16.0.

Outcomes

The pooled prevalence of ED in AS patients was calculated and the RR and the SMD were used to evaluate the association between AS and ED.

Results

A total of 393 AS patients, enrolled in the 8 included studies, were assessed for the prevalence of ED. The pooled ED prevalence estimate was 44% (95% confidence interval [CI], 25% to 63%, P < .001) with the statistical heterogeneity (I2 = 95.1%, P < .001). After pooling the data for RR, the results showed that men with AS were at a significantly higher risk for ED when compared with the general population without AS (RR, 2.04; 95% CI, 1.28 to 3.25, P = .003; heterogeneity: I2 = 72.6%, P = .003). The pooled results of 5 studies, which provided the International Index of Erectile Function (IIEF) score, demonstrated that patients with AS had significantly lower values in the IIEF erectile function domain as compared with the healthy control subjects (SMD, −0.60; 95% CI, −0.80 to −0.41; P < .001; heterogeneity: I2 = 34.4%, P = .192). Additionally, the other domain of the IIEF also showed lower values when compared with the general population without AS (P < .05).

Clinical Implications

The present meta-analysis provides evidence of the management of ED in men with AS.

Strengths and Limitations

This is the first meta-analysis to provide the prevalence of ED in AS patients and to demonstrate that AS is a risk factor for ED. However, the results after pooling the included studies showed significant heterogeneity.

Conclusion

Our meta-analysis demonstrated the high prevalence of ED in men with AS and that AS is a potential risk factor for ED.
0001 Effect of Time-Restricted Eating on Actigraphy-Derived Sleep Parameters
Authors: Duan Daisy , Pham Luu , Jun Jonathan , Turkson-Ocran Ruth-Alma , Pilla Scott , Clark Jeanne , Maruthur Nisa
Published: May 2023

Introduction

Time-restricted eating (TRE) is an emerging dietary intervention for weight loss. Sleep can be influenced by timing of food intake. Nevertheless, the impact of TRE on sleep patterns remains under-explored. The Time-Restricted Intake of Meals (TRIM) study was a parallel-arm, controlled feeding trial in 41 adults with obesity and prediabetes or untreated diabetes, randomized to TRE (8am-6pm) or usual eating pattern (UEP; 8am-12am) for 12 weeks, where the primary outcome was weight change. We hypothesized that TRE would cause changes in sleep/wake patterns.

Methods

This was a post-hoc analysis of TRIM using wrist actigraphy data obtained at baseline and week-12. We applied an objective process to determine sleep parameters after sleep estimation (Cole-Kripke) from actigraphy data. We analyzed 6 days/nights of recordings for each participant at each timepoint. Outcomes were sleep duration defined by mean total sleep time per 24-hour period (TST), sleep timing measured by mid-sleep time, sleep onset/offset, and sleep continuity. We used paired t-tests or Wilcoxon signed rank tests to compare data between baseline and week-12 within intervention arms and Mann-Whitney U tests or Wilcoxon signed rank tests to compare changes between intervention arms.

Results

38 participants (20 UEP; 18 TRE) with adequate actigraphy data (mean age 60 years, 92% female, and 92% Black) were analyzed. Baseline TST (mean□SD) was 394□90 minutes and 386□81 minutes for UEP and TRE, respectively. Week-12 TST was 397□92 minutes and 444□95 minutes for UEP and TRE, respectively. Compared to UEP, TRE increased TST by 55 minutes (p=0.03). TRE shifted mid-sleep time to 44 minutes earlier, from 3:24am to 2:40am (p=0.01), while UEP maintained the same mid-sleep time at 3:15am. Sleep onset shifted from a median of 12:22am to 11:52pm in TRE (p=0.03) while it remained stable in UEP (p=0.97). There were no differences in sleep offset and sleep continuity within and between intervention arms.

Conclusion

Sleep behaviors were different by treatment arm with increased total sleep time and earlier sleep onset in TRE participants. TRE may have ancillary consequences on sleep, which could have clinical implications for sleep regulation.

Support (if any)

AHA SFRN 17SFRN33590069 K23DK133690
0004 Using Apple Watch to predict circadian phase in night shift workers
Authors: Cheng Philip , Walch Olivia , Hannay Kevin , Roth Thomas , Drake Christopher
Published: May 2023

Introduction

A critical obstacle for circadian medicine is the lack of feasibility in measuring circadian phase in the clinic. Existing tools such as assessment of dim light melatonin onset (DLMO) are too resource intensive, especially in populations with extreme circadian disruption such as night shift workers. Recent studies have demonstrated the validity and feasibility of estimating circadian phase via mathematical modeling data collected with wearable technology. However, these studies have mostly relied on research grade devices (e.g., actigraphs) that have limited scalability. In this work, we validate the use of a consumer wearable (the Apple Watch) to predict DLMO in a population of night shift workers.

Methods

A sample of 21 fixed-night shift workers wore an Apple Watch for two weeks before completing DLMO in the lab. DLMO was assessed via hourly salivary melatonin samples collected in dim light (< 10 lux) for a period of 24 hours. Activity data was used as input into the Hannay model of the circadian clock to produce a predicted DLMO, which was then compared to in-lab DLMO.

Results

Model predictions of DLMO showed high correlation with in-lab DLMO, with a Lin’s concordance correlation coefficient (CCC) of 0.81, with a mean absolute error (MAE) of 2.10. This was comparable to the previously published validation using research grade actigraphy (CCC = 0.70; MAE = 2.88).

Conclusion

This study is the first to provide evidence suggesting that estimates of circadian phase using the Apple Watch have comparable validity with research grade actigraphy. These results have significant implications for the scalability of circadian medicine, particularly as consumer-based wearable technology is already commonplace. Apple Watches are also the most common consumer-based wearable device. Future research should extend findings to other wearable devices, especially devices at a lower price-point to increase accessibility.

Support (if any)

Support for this study was provided from the American Academy of Sleep Medicine Foundation (245-SR-21) awarded to Dr. Philip Cheng.
0006 Circadian Misalignment Increases the Impact of Visceral Adiposity on Metabolic Syndrome Burden in Adolescents
Authors: Morales-Ghinaglia Natasha , He Fan , Liao Jason , Calhoun Susan , Vgontzas Alexandros , Bixler Edward , Liao Duanping , Fernandez-Mendoza Julio
Published: May 2023

Introduction

Although insufficient sleep is a known risk factor for metabolic syndrome (MetS), the circadian timing of sleep is also involved in cardiac and metabolic regulation. As a result, circadian misalignment of the sleep-wake cycle, which is highly prevalent in adolescents, may independently impact the burden of MetS in youth.

Methods

We analyzed data from 277 population-based randomly-selected adolescents from the Penn State Child Cohort (median 16 years; 47% female; 21% racial/ethnic minority) who had at least 5 nights of at-home actigraphy (ACT), an in-lab 9-h polysomnography (PSG) and an in-lab dual-energy X-ray absorptiometry (DEXA) scan. Two ACT-measured metrics of circadian misalignment were examined as effect modifiers: sleep midpoint (SM), the intra-individual mean midpoint of the sleep period, and sleep regularity (SR), the intra-individual standard deviation of sleep midpoint. DEXA-measured visceral adipose tissue (VAT) was the primary predictor. A continuous MetS score (i.e., sum of the age and sex adjusted z-scores of waist circumference, blood pressure, HOMA-IR, triglycerides, and HDL cholesterol) was the primary outcome. Linear regression models tested SM and SR as effect modifiers of the association of VAT with MetS, while accounting for sex, race/ethnicity, age, ACT-sleep duration, ACT-sleep variability, and PSG-apnea/hypopnea index.

Results

A significant interaction was found between VAT and SR on MetS (p-interaction=0.05), while not between VAT and SM (p-interaction=0.15). Among adolescents with high sleep irregularity (≥ 45 minutes; n=164), each standard deviation increase in VAT was associated with 2.4 (0.2) standard deviations increase in MetS (p< 0.01), while this association was weaker among adolescents with low sleep irregularity [< 45 minutes; n=113; β=1.7 (0.3), p< 0.01].

Conclusion

An irregular circadian timing of sleep may further increase the impact of visceral adiposity on MetS burden in adolescents. Sleep irregularity, independent of sleep apnea and insufficient sleep, may contribute to the development of cardiometabolic sequelae associated with central obesity.

Support (if any)

National Institutes of Health (R01HL136587, UL1TR000127) and American Heart Association (23PRE1011962)
0013 Rebels Without a (Sleep Timing) Cause: Circadian Misalignment Does Not Predict Risky Behavior in Adolescents
Authors: Kamhout Sarah , Pilling Mason , Johnson Lauren , Wright Isabella , Duraccio Kara
Published: May 2023

Introduction

Previous studies have shown that sleep impairments may contribute to a variety of problems in adolescents, including behavioral dysregulation. As current research explores the specific mechanisms behind sleep’s influence on risk-taking behaviors, circadian misalignment may be particularly important to consider. Previous studies suggest that adolescents experiencing greater circadian misalignment are more likely to use illicit substances and to be involved in motor vehicle accidents. However, most studies on sleep and adolescent risk-taking only use self-report measures of sleep or focus on sleep duration. This study used gold-standard physiological methods to further examine the relationship between risk-taking behaviors and circadian misalignment in adolescents.

Methods

Fifty healthy adolescents (ages 14-18, 58% female; 94% white) came to the lab for a six-hour appointment in a dim-light room (lux < 5). Every 30 minutes, participants provided saliva samples to measure salivary dim-light melatonin onset (DLMO). Circadian misalignment was defined as the timing of melatonin onset subtracted from average bedtimes noted in participant sleep diaries completed on the previous 10 nights; higher estimates reflect lower circadian misalignment. During each DLMO appointment, participants also completed the Youth Risk Behavior Survey (YRBS) to evaluate levels of risk-taking behaviors

Results

We conducted multiple regression analyses to examine circadian misalignment as a predictor of risky car behavior, risky substance abuse, violence, suicide, and sexual behaviors. We hypothesized that circadian misalignment would be associated with higher levels of all risky behaviors. However, we found no significant relationship between circadian misalignment and risky car (p=.712), substance use (p=.693), violence (p=.317), suicide (p=.259), or sexual behaviors (p=.427).

Conclusion

While our results did not support our hypothesis that circadian misalignment is positively associated with risk-taking behaviors in youth, our use of gold-standard methods to assess circadian misalignment adds robustness to existing literature and raises questions over what aspects of sleep are most associated with previously identified increases in risk-taking behaviors. Future studies can utilize this methodology to further clarify the relationship between risky behaviors and circadian misalignment.

Support (if any)
0014 Sleep Desert = More Dessert? Circadian Misalignment Predicts Greater Sugar Consumption in Adolescents
Authors: Lee Lindsey , Wright Isabella , Kamhout Sarah , Duraccio Kara
Published: May 2023

Introduction

As adolescent sleep duration and quality is declining, obesity rates are also increasing. Previous studies suggest a connection between sleep behaviors and obesity, with sleep’s relationship with dietary intake emerging as a primary mechanism. Circadian misalignment may be particularly important to consider in this context due to its previously observed effects on reward processing and snack selection. This study examined the relationship between circadian misalignment and dietary intake among adolescents.

Methods

Fifty healthy adolescents (14-18, 58% female, 94% white) participated in an 11-day procedure. On day one, participants’ height, weight, and Body Mass Index (BMI) were measured. For the next ten days, participants maintained a sleep diary and completed three 24-hour dietary recalls on randomized days. On the eleventh day, participants came to the lab for a six-hour appointment in a dim-light room (lux < 5). Every 30 minutes, participants provided saliva samples to measure dim-light melatonin onset (DLMO). To measure circadian misalignment, the timing of melatonin onset was subtracted from average bedtime noted in the sleep diaries; lower values suggest greater misalignment.

Results

We conducted multiple regression analyses to examine circadian misalignment as a predictor of average kcal, protein, fat, and sugar consumption. We hypothesized that circadian misalignment would be a positive predictor of greater kcal, fat, and sugar intake but a negative predictor of less protein intake. However, circadian phase did not significantly predict average kcal (F(1, 42) = 1.37, p = .25, R2 = .03, β = -.18, b = -102.86), fat F(1,42) =.001, p=.97, R2=.00, β=-.01, b=-.17), or protein (F(1,42) =.59, p=.45, R2=.01, β=-.12, b=-2.75) consumption. Circadian misalignment did significantly predict average sugar intake, with greater misalignment predicting less sugar intake F(1,42) =4.27, p=.04, R 2 =.09, β=-.30, b=-13.77.

Conclusion

Although adolescents’ circadian misalignment does not predict kcal, protein, or fat consumption, it does predict sugar consumption. Adolescents whose sleep is not aligned with their intrinsic circadian rhythm may be at greater risk for consuming more sugar, which may ultimately increase obesity risk. These findings add to the literature on the potential relationship between sleep and obesity as moderated by dietary intake.

Support (if any)
0015 A circadian-informed lighting intervention markedly accelerates circadian adjustment to a night shift-work schedule
Authors: Guyett Alisha , Lovato Nicole , Manners Jack , Stuart Nicole , Lechat Bastien , Lack Leon , Kemps Eva , Banks Siobhan , Dorrian Jill , Vakulin Andrew , Adams Robert , Eckert Danny , Catcheside Peter , Scott Hannah
Published: May 2023

Introduction

Night shift-work results in misalignment between circadian timing and the sleep/wake schedule, negatively impacting sleep and performance. In encapsulated environments (e.g., submarines), the lack of strong daily solar lighting cues may impair circadian entrainment to the night shift-work schedule. This study designed and tested a circadian-informed lighting strategy to promote faster circadian phase delays to adjust to night shift-work compared to standard lighting.

Methods

Nineteen healthy sleepers (12 males/7 females, mean±SD aged 28.7±10.4 years) underwent two separate 8-day experimental conditions (circadian-informed lighting versus standard lighting). After a baseline sleep from 22:00 – 07:00 (day 1) and salivary dim light melatonin onset assessment ([DLMO], day 2), participants undertook simulated night shift-work (00:00 - 08:00) and slept during the day (10:00 - 19:00) for days 3-7 followed by a post-DLMO assessment on day 8. Ingestible capsules collected core body temperature (CBT) continuously throughout days 2-8, and cosine curve fitting was applied to estimate the timing of each daily temperature minima. The standard lighting condition mimicked current lighting on submarines (largely dim, blue-depleted light), while the circadian-informed lighting administered bright, blue-enriched and dim, blue-depleted lighting at times estimated to facilitate rapid circadian delay. The magnitude of daily CBT minima changes and the delay in pre- vs. post-DLMO were compared across conditions.

Results

There were significant day-by-condition interactions on CBT minima timing and DLMO timing (both p< 0.001). After 4 days of simulated night-shift work there was a mean [95%CI] 4.5 [3.4 to 5.7] hour greater delay in CBT minima and a 4.6 [3.6 to 5.6] hour greater delay in DLMO timing compared to standard lighting, equating to 3.6 and 2.4-fold faster delays in DLMO and CBT minima timing shifts, respectively.

Conclusion

Circadian-informed lighting substantially accelerates circadian re-adjustment to night shift-work. Lighting interventions could usefully improve sleep, performance, and safety in shift-workers.

Support (if any)

This research is supported by the Commonwealth of Australia as represented by the Defence Science and Technology Group of the Department of Defence through the Research Network for Undersea Decision Superiority (research agreement number: 9334), with additional financial support from Flinders University and lighting provision support from REDARC.
0017 Obstructive sleep apnea is associated with altered circadian rhythms in systolic blood pressure at rest and during exercise
Authors: Thosar Saurabh , Bowles Nicole , Butler Matthew , McHill Andrew , Emens Jonathan , Shea Steven
Published: May 2023

Introduction

Obstructive sleep apnea (OSA) is associated with an increased risk for major adverse cardiovascular events (MACE), such as sudden cardiac death. MACE is more frequent in the morning in the general population but more frequent in the middle of the night in people with OSA. Whether these differences are associated with changes in circadian rhythms of blood pressure regulation is unknown. We tested if circadian rhythms in systolic blood pressure (SBP) during rested wakefulness and in response to a standardized mild exercise are disturbed in people with OSA compared to healthy controls (HC).

Methods

We studied 39 participants (HC [n=25, age 52.8±7.8 {mean±SD} years], (OSA [n=14, 50.6±6.6 years]) during ten identical recurring 5-h 20-min behavioral cycles in dim light and in an environment free of time cues. SBP was measured in the supine position during rested wakefulness followed by while seated at rest and during mild-intensity (heart rate at 50% heart rate reserve using the Karvonen formula) exercise on a static cycle ergometer. Circadian phases were determined relative to the dim-light melatonin onset. We performed mixed-model cosinor analyses to test whether the groups differed in their SBP rhythms during rested wakefulness and in their BP responses to exercise.

Results

Melatonin levels or phases relative to clock time were not different between groups (p=0.17), suggesting similar timing of central circadian clock outputs. There was an overall rhythm (p< 0.001) and a trend to group x circadian phase interaction for resting SBP (p=0.10). A separate group analysis showed a significant circadian rhythm in SBP in HC (p< 0.001) with a peak in the evening but no evident circadian rhythm in people with OSA (p=0.17). There was no circadian phase x exercise reactivity interaction between groups, but overall, exercise reactivity of SBP was significantly higher in people with OSA (+4mmHg, p=0.001).

Conclusion

OSA is characterized by a blunted circadian rhythm in resting blood pressure and an exaggerated blood pressure reactivity to exercise. Mechanisms for these rhythm changes should be investigated further.

Support (if any)

Support: NIH F32HL163232, R01HL125893, R01HL163232, R35HL155681, R01HL156948, ULTR00128, Oregon Institute of Occupational Health Sciences.
0019 Assessing Genetic Variation for Effects of Lithium on Circadian Clock Period and Mortality in Fruit Flies
Authors: Fryou Noah , Li Mingjia , Possidente Bernard
Published: May 2023

Introduction

Lithium is the treatment of choice for bipolar disorder, but the mechanism for its therapeutic effect remains unknown, and it has a low threshold for toxic side-effects. Bipolar disorder is cyclical disorder with periodic onsets of illness including depressive and manic episode that vary in cycle length among patients. One of lithium’s well-documented effects- a lengthened circadian clock period- is intriguing since a circadian system abnormality is a potential explanation for the cyclical nature of bipolar disorder. Fruit flies are an efficient model organism for genetic analysis of circadian clock mechanisms, but few Drosophila studies have documented circadian effects of lithium, and none have examined genetic variation.

Methods

We used a random sample of 13 inbred strains from the Drosophila Genetic Resource Panel and three wild-type strains to examine genetic variation for the response of circadian clock period to 20mM LiCl, and its toxicity. Adults were assayed for circadian locomotor activity in constant dark using Drosophila Activity Monitors. Circadian clock period was estimated using chi-squared periodogram.

Results

Among 13 inbred strains examined there is no significant effect of lithium or genetic variation for effects of lithium on circadian period, and only one inbred strain significantly lengthened circadian clock period in response to lithium. There was a significant sex difference in the response to lithium for circadian period, with an increase female and a slight decrease in males, and significant strain variation for sex-differences in circadian response to lithium. There are significant strain differences in mortality in response to lithium. All three wild-type strains significantly increased circadian period in response to lithium and varied in sensitivity to its toxicity.

Conclusion

Results to date suggest that the set of approximately 200 DGRP strains will be useful for investigating genetic variation for lithium toxicity and sex-differences for effects of lithium on circadian clock period. Circadian period in wild-type strains is more responsive to the period-lengthening effects of lithium, suggesting that genetic heterozygosity may play a role in the effects of lithium on circadian clock period.

Support (if any)

Skidmore College Biology Department and Summer Collaborative Research Program.
0021 Bimodality prevalence in a sample of undergraduate students in Sao Paulo city
Authors: Vallim Julia , Tsuji Heloisa , Lima Gabriela , Xylaras Beatriz , Louzada Fernando , Tufik Sergio , D'Almeida Vânia
Published: May 2023

Introduction

The concept of bimodality comprises a fourth circadian phenotype, the bimodal, whose identification is made by a re-scoring of the Morningness-Eveningness Questionnaire and was first described by Martynhak and colleagues in 2010. Bimodal subjects are originally classified as “intermediate” because they answer the questions sometimes as a morning person and, some others, as an evening one. The present work aimed to describe the prevalence of the bimodal chronotype in a sample of undergraduate students in Sao Paulo city.

Methods

A web-based cross-sectional study conducted between September 2018 and March 2021, with a convenience sampling method, composed by 615 undergraduate students (82% females, mean age: 23.4±6.5 years) from two higher education institutions at Sao Paulo city.

Results

Forty-four students (7%) had positive bimodality indexes and bimodal individuals comprised 19 students (74% female; 26% male), 3% of the total sample.

Conclusion

We met our initial goal and found a bimodality prevalence of 3%. The description of bimodality prevalence in a sample of college students is interesting because they may be a maladaptive population from a sleep and rhythmicity point of view, which may be interesting for the design of academic public policies more consistent with the circadian preferences of students.

Support (if any)

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Associação Fundo de Incentivo à Pesquisa (AFIP).
0023 Circadian fragmentation and stability distinguish employment status
Authors: Glickenstein David , Karamchandani Avinash , Korbut Camille , Bang Michelle , Aucoin Alexa , Callovini Leah , Lin Kevin , Haynes Patricia
Published: May 2023

Introduction

This analysis used data from the Assessing Daily Activity Patterns Through Occupational Transitions (ADAPT) study to compare differences in employment status on activity variability, as an indicator of circadian fragmentation and stability. Circadian fragmentation refers to frequency of alterations between rest and activity relative to the daily rhythm and stability refers to day-to-day similarity. High fragmentation and low stability have been linked to a number of negative health outcomes including depression, obesity, and heightened mortality risk.

Methods

The sample consisted of 155 participants that included 702 total cases (n = 434 employed, n = 268 unemployed) assessed over 18 months. Participants were required to have involuntarily lost their jobs in the last 90 days. Employment status was determined for all participants at each visit based on demographic surveys. Daily activity patterns were assessed via actigraphy (Actiwatch-Spectrum) at 30 second epochs for 14 days. The nonparametric measures of intradaily variability (IV) and interdaily stability (IS) were used as measures of circadian fragmentation and stability. Several subsampling intervals were considered for IV, ranging from 5 minutes to 4 hours.

Results

Unemployment was associated with higher IV (for 1 hour subsampling intervals, t=5.23, p < .001) and lower IS than employment (t=2.38, p <.05). The same is true with changes in the subsampling interval for IV, with highest significance at 45 minutes to 1.5 hours. Significant findings remained even for 5 minute (t=2.15, p < .05) and 4 hour (t = 4.07, p<.001) intervals.

Conclusion

In a sample of adults with variable employment status, employment was associated with less circadian fragmentation and more stability than unemployment. These findings suggest that circadian fragmentation and instability may be two mechanisms by which job loss increases negative health risk. Future planned studies examining prospective changes in circadian fragmentation/stability during employment transitions will help answer this question.

Support (if any)

NIH #1R01HL117995-01A1, NSF DMS 1937229, NSF CCF 1740858
0024 Decreased circadian period associated with enhanced autophagy in cereblon knockout mice
Authors: Kim Jinhong , Park Chul-Seung , Kim Tae
Published: May 2023

Introduction

The circadian rhythm plays a critical role in many biological processes. Recently, autophagy was suggested as a regulating factor of circadian rhythm by reducing protein trafficking. Cereblon (CRBN) is a component of the E3 ubiquitin ligase complex for ubiquitination and degradation of the target proteins. Interestingly, cereblon ubiquitinates beclin 1, a potent autophagy inducer. Accordingly, the changes in cereblon are likely to affect the circadian rhythm. However, how cereblon can regulate circadian rhythm is not understood yet. Therefore, we hypothesized that cereblon might be an important regulator of the circadian rhythm and sought to investigate the relationship.

Methods

We obtained 3-month-old CRBN gene knockout (KO) and wild-type (WT) mice (n=4 and 8, respectively). The mice were housed in the wheel-based activity recording system under 12:12 light-dark (LD) condition for 1 week and constant darkness (DD) condition for the subsequent 2 weeks. Activity data were analyzed by ClockLab Analysis 6 (Actimetrics, USA). Autophagy-related proteins, including beclin1, microtubule-associated protein light chain-3 (LC3), and p63, were measured by the ELISA and western blot.

Results

We found that CRBN KO mice showed decreased circadian period during constant darkness (23.7 vs 23.4 hours, p< 0.05). The latency from the light-off time to initiating activities in the dark period was shorter in CRBN KO mice and WT mice. Protein analysis assay revealed that beclin1, LC3, and p62 increased in CRBN KO mice, indicating increased autophagy.

Conclusion

Our results demonstrated that CRBN knockout mice showed shorter circadian periods and reduced autophagy-related molecules. We interpret that the lack of cereblon resulted in reduced degradation of beclin1 that triggers autophagy. As per Beesley et al (2020), autophagy-induced decrease in cytoplasmic congestion facilitates the protein trafficking for the crucial components of the molecular circadian clock. The shorter circadian period in CRBN KO mice was primarily due to the enhanced autophagy, although its implication in general health is unclear. Taken together, we suggest that CRBN is associated with circadian rhythm via controlling autophagy. Further investigations to understand how circadian amplitude was increased and the activity latency during the dark period was shortened are needed.

Support (if any)
0028 Systematic Review: Time of day differences in complete blood count values
Authors: Busza Anna , Sharma Vani , Ferguson Kendall , Fawcett Andrea , Knoll Justin , Zee Phyllis , Fishbein Anna
Published: May 2023

Introduction

The complete blood count (CBC) is the most commonly ordered blood test with a large range of reference values that do not consider time of day for interpretation. Clinicians are largely unfamiliar with the influence of time of day on CBC values. Our objective was to systematically review this topic to report on peak and trough timing of CBC values.

Methods

A systematic search of PubMed, Ovid, Scopus, CINAHL, Cochrane, Embase, and Web of Science was performed for studies evaluating any part of the CBC over 24 hours. The studies were screened for eligibility based on predetermined criteria including: measurement of a part of the CBC with at least 3 time points in 24 hours. In total, 164 full-text articles were screened and 32 were included in the final analysis. The aggregated data was analyzed with the Cosinor package of R statistical environment and Stata SE to create cosinor graphs and Forest plots for each component of the CBC, respectively.

Results

Of the 32 articles, a metalysis was performed on the following CBC subsets: leukocytes, erythrocytes, hemoglobin, hematocrit, platelets, neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Lymphocytes exhibited a statistically significant diurnal rhythm (p=0.014, n=10 articles) with a peak of 2280.10 cells/uL at 23:17 (CI: 1731.80, 2828.40) and trough of 1661.49 cells/uL at 08:53 (CI: 1242.64, 2080.33). Erythrocytes, hemoglobin, and hematocrit peaked in the morning; while platelets, neutrophils, monocytes, and basophils peaked in the late afternoon and early evening; and lymphocytes and eosinophils peaked late at night. High heterogeneity in the results across studies was noted, likely attributable to the difference in circadian factors controlled. Limitations include the small sample size for each component of the CBC, the limited samples included in the meta analysis, and the significant heterogeneity affecting the results.

Conclusion

There are significant time of day changes in CBC values that might be important to consider as we move towards precision medicine. Given the limited number of studies with small sample sizes, future work should evaluate large data sources to inform time-dependent interpretation of the CBC.

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