Individual Variation In Response Research Articles

Genetic determinants of IgG antibody response to COVID-19 vaccination

Human humoral immune responses to SARS-CoV-2 vaccines exhibit substantial inter-individual variability and have been linked to vaccine efficacy. To elucidate the underlying mechanism behind this variability, we conducted a genome-wide association study (GWAS) on the anti-spike IgG serostatus of UK Biobank participants who were previously uninfected by SARS-CoV-2 and had received either the first dose (n= 54,066) or the second dose (n= 46,232) of COVID-19 vaccines. Our analysis revealed significant genome-wide associations between the IgG antibody serostatus following the initial vaccine and human leukocyte antigen (HLA) class II alleles. Specifically, the HLA-DRB1∗13:02 allele (MAF= 4.0%, OR= 0.75, p= 2.34e-16) demonstrated the most statistically significant protective effect against IgG seronegativity. This protective effect was driven by an alteration from arginine (Arg) to glutamic acid (Glu) at position 71 on HLA-DRβ1 (p= 1.88e-25), leading to a change in the electrostatic potential of pocket 4 of the peptide binding groove. Notably, the impact of HLA alleles on IgG responses was cell type specific, and we observed a shared genetic predisposition between IgG status and susceptibility/severity of COVID-19. These results were replicated within independent cohorts where IgG serostatus was assayed by two different antibody serology tests. Our findings provide insights into the biological mechanism underlying individual variation in responses to COVID-19 vaccines and highlight the need to consider the influence of constitutive genetics when designing vaccination strategies for optimizing protection and control of infectious disease across diverse populations.

Core-Temperature Responses at the 3-km World Aquatics Open-Water Swimming Masters Championships in Doha 2024.

This study aimed to characterize core-temperature (Tc) responses of swimmers competing at the 2024 3-km World Aquatics Masters Open Water Swimming Championships. Within a cross-sectional observational study design, swimmers (n = 48 [23 male, 25 female]) ingested a telemetric Tc pill 4 hours before their race. Water temperatures were 20.9°C (male; mean wet-bulb-globe temperature 25.9°C) and 20.5°C (female; mean wet-bulb-globe temperature: 25.4°C). Linear mixed models determined differences between males and females for race-start, mean in-race, and peak Tc. Random coefficient models determined relationships between (1) sex, race time, body mass index (BMI), body-mass change or age, and Tc peak; (2) sex, race time, BMI, body-mass change or age, and Tc nadir; (3) sex, Tc peak, BMI, body-mass change or age, and race time, and (4) sex, Tc peak, BMI, body-mass change, or age and race ranking. The mean in-race Tc was 37.8°C (36.1-38.8°C); however, there were highly variable individual Tc responses (-3.1 to +2.7°C). One swimmer experienced mild hypothermia (Tc ≤ 35.0°C), and 5 exceeded 39.0°C, a risk factor for heat-related illness. There were no statistical differences between males and females for race-start, mean, and peak Tc (P ≥ .243). Higher peak Tc was associated with faster race time (P = .05), higher race rank (P = .027), and higher BMI (P = .001). Highly variable Tc responses (-3.1 to +2.7°C) were observed, demonstrating that organizers of mass-participation open-water swimming events should always be prepared for, and provide facilities to treat, swimmers experiencing cold-/heat-related health incidents during competition.

Islamic Mindfulness-Based Play Activities: Enhancing Child Mental Health in the Post-Pandemic Era

This research focuses on developing Islamic mindfulness-based play activities to mitigate child mental health issues in the post-pandemic context. The study was conducted in Jakarta-Depok kindergartens using a modified Research and development (R&D) approach tailored for educational settings, as per Borg and Gall. The primary aim was to create and evaluate educational tools to foster Islamic mindfulness among young learners. The research involved identifying children's learning challenges post-pandemic and developing and refining educational games and teaching methods. Data collection encompassed observational studies, educator feedback, and direct interaction with children using the developed tools. The analysis evaluated these tools' usability, engagement level, and educational impact. The results highlighted the development of a physical model comprising a 14-chapter guidebook for tea. Still, it is a procedural model that condenses the original ten stages into seven. Essential components include yoga based on prayer movements, activities for enhancing food relationships, self-body awareness exercises, sensory training, gratitude journal writing, and positive affirmations based on Asmaul Husna. Evaluations by material and learning design experts and one-to-one teacher tests affirmed the model's quality. A field trial with 20 children showed enjoyment and preference for gratitude journal writing. Conclusively, the research effectively developed a model for Islamic mindfulness-based play activities, demonstrating the potential to enhance children's mental health post-pandemic. However, limitations such as geographic confinement and individual response variability suggest the need for broader application and further research to assess long-term impacts. This study contributes significantly to educational and psychological interventions, offering a culturally sensitive, holistic child development approach integrating mental health, spirituality, and education.

Cardiovascular benefits of moderate exercise: A comprehensive review of molecular and physiological mechanisms

This comprehensive review examines the cardiovascular benefits of moderate exercise, exploring the molecular and physiological mechanisms through which it reduces cardiovascular disease (CVD) risk. The study aimed to identify the specific ways in which moderate exercise improves cardiovascular health, focusing on key factors such as endothelial function, lipid metabolism, inflammation, and glucose homeostasis. A thorough review of existing literature was conducted to elucidate the mechanisms and impact of moderate exercise compared to other intensities. The findings highlight that moderate exercise optimizes cardiovascular health by enhancing nitric oxide production, reducing oxidative stress, and improving autonomic function, while also lowering blood pressure and cholesterol levels. Additionally, moderate exercise was shown to have anti-inflammatory effects, crucial for mitigating chronic conditions like atherosclerosis and diabetes-related cardiovascular complications. The review concludes that while high-intensity exercise offers rapid fitness improvements, moderate exercise is more accessible, safer, and sustainable for a broad population. Furthermore, it presents a promising non-pharmacological intervention for CVD prevention. Future research should explore individual variability in exercise responses, the role of skeletal muscle as a secretory organ, and the interaction between exercise and the gut microbiome. The study emphasizes the need for personalized exercise prescriptions and further investigation into the long-term benefits of exercise to optimize public health strategies. Keywords: Moderate Exercise, Cardiovascular Disease, Endothelial Function, Inflammation, Lipid Metabolism, Exercise Prescription.

Meta-Analysis of the Causality of Deformations in Marine Fish Larvae Culture

The development of deformities in farmed fish is largely the result of abiotic, biotic, and xenobiotic factors, information deficiencies in optimizing nutrition, and the genetic background to which the fish are exposed in their early life stages. In general, skeletal anomalies are considered to have significant adverse effects on animal welfare, biological performance of farmed fish, product quality, and production costs. In the data obtained by the meta-analysis method, the presence of negative effects on the formal structures of fish was found, regardless of the region, duration, stage, factor, stock density, and method used to detect deformation. In this regard, in the studies considered within the deformation region/type, 46% of deformities were found in the spine, 37% in the head, and 16% in the total skeleton. In turn, the results of the meta-analysis showed that the percentages of the apparent value were 35.82% in the spine, 33.12% in the skeleton, and 31.06% in the head. The deformation rate had an overall negative effect on the functional characteristics of the fish, regardless of the variables considered. In addition, all statistically significant individual response variables had a negative effect size. In the future, advanced statistical tools such as Bayesian meta-analysis, network meta-analysis, and meta-regression analysis can be used to explore more complex data structures. The rapid development of artificial intelligence techniques will increase the efficiency of data collection and the robustness of results for meta-analysis studies in aquaculture and other fields.

High-Quality Brain and Bone Marrow Nuclei Preparation for Single Nuclei Multiome Assays.

Single-cell analysis has become the approach of choice for unraveling the complexity of biological processes that require assessing the variability of individual cellular responses to treatment or infection with single-cell resolution. Many techniques for single-cell molecular profiling have been developed over the past 10 years, and several dedicated technologies have been commercialized. The 10X Genomics droplet-based single-cell profiling is a widespread technology that offers ready-to-use reagents for transcriptomic and multi-omic single-cell profiling. The technology includes workflows for single-cell and single-nuclei RNA sequencing (scRNA-Seq and snRNA-Seq, respectively), scATAC-Seq, single-cell immune profiling (BCR/TCR sequencing), and multiome. The latter combines transcriptional (scRNA-Seq) and epigenetic information (scATAC-Seq) coming from the same cell. The quality (viability, integrity, purity) of single-cell or single-nuclei suspensions isolated from tissues and analyzed by any of these approaches is critical for generating high-quality data. Therefore, the sample preparation protocols should be adapted to the particularities of each biological tissue and ensure the generation of high-quality cell and nuclei suspensions. This article describes two protocols for preparing brain and bone marrow samples for the downstream multiome 10X Genomics pipeline. The protocols are performed stepwise and cover tissue dissociation, cell sorting, nuclei isolation, and quality control of prepared nuclei suspension that is used as starting material for cell partitioning and barcoding, library preparation, and sequencing. These standardized protocols produce high-quality nuclei libraries and robust and reliable data.

Averaged versus individualized: pragmatic N-of-1 design as a method to investigate individual treatment response

Heterogeneous treatment effects represent a major issue for medicine as they undermine reliable inference and clinical decision-making. To overcome the issue, the current vision of precision and personalized medicine acknowledges the need to control individual variability in response to treatment. In this paper, we argue that gene-treatment-environment interactions (G × T × E) undermine inferences about individual treatment effects from the results of both genomics-based methodologies—such as genome-wide association studies (GWAS) and genome-wide interaction studies (GWIS)—and randomized controlled trials (RCTs). Then, we argue that N-of-1 trials can be a solution to overcome difficulties in handling individual variability in treatment response. Although this type of trial has been suggested as a promising strategy to assess individual treatment effects, it nonetheless has limitations that limit its use in everyday clinical practice. We analyze the existing variability within the designs of N-of-1 trials in terms of a continuum where each design prioritizes epistemic and pragmatic considerations. We then support wider use of the designs located at the pragmatic end of the explanatory-pragmatic continuum.

Role of Genetic Polymorphisms in the Development of Complications in Patients with Implanted Left Ventricular Assist Devices: HeartWare, HeartMate II, and HeartMate 3

Left ventricular assist device (LVAD) implantation is one of the mechanical circulatory support (MCS) treatments for advanced heart failure (HF) patients. MCS has emerged as a lifesaving therapy that improves patients’ quality of life. However, MCS remains limited by a paradoxical coagulopathy accompanied by thrombosis and bleeding. The mechanisms of MCS thrombosis are increasingly being defined, but MCS-related bleeding, which is related to shear-mediated alteration of platelet function, remains poorly understood. Complications might develop due to the high non-physiological shear stress in the device and as a consequence of individual variability in response to the antithrombotic therapy. Thromboelastography (TEG) and genotyping of gene polymorphisms that are involved in the coagulation cascade and in the metabolism of the antithrombotic therapy might be valuable sources of information for the reduction of complication development. The aim of the study was to identify genetic factors related to the development of device complications according to the implanted LVAD type. We compared the clinical and genetic data of HF patients (n = 98) with/without complications with three types of implanted devices: HeartWare HVAD (HW), HeartMate II (HMII), and HeartMate 3 (HM3). rs9923231 in VKORC1 (95%CI −6.28–0.22, p = 0.04) and rs5918 in ITGB3 genes (95%CI 0.003–4.36, p = 0.05) showed significant association with the TEG coagulation index parameter, which identified hyper- and hypo-coagulation states. The wild genotype of rs5918 in the ITGB3 gene prevailed in patients implanted with HM3 devices, which developed fewer complications than with HMII (p = 0.04). Individual genetic information could be useful in the management of patients with HF and the implantation of MCS to reduce the development of complications.

Highlighting the impacts of ciguatera poisoning on fishers and fish consumers in Hawaiʻi to inform future management strategies

Ciguatera poisoning (CP) occurs as a result of consuming seafood that has bioaccumulated toxins produced by dinoflagellates (primarily Gambierdiscus) in tropical, coastal ecosystems. The impacts of CP can be long-lasting for affected individuals and communities, especially in places like the Hawaiian Islands, where fish provide sustenance and have important financial and cultural value. This study used anonymous online surveys (n = 106) and targeted interviews (n = 20) to address data gaps on the prevalence, distribution, and impacts of CP among fishers and fish consumers in Hawaiʻi. Survey results indicated that few individuals (22%) reported their CP cases to the Department of Health, despite the fact that most impacted respondents (67%) experienced symptoms lasting more than a week and some (10%) were affected for more than a year. Certain locations (e.g., north shore of Kauaʻi) and species (e.g., uku - Aprion virescens and knifejaw - Oplegnathus punctatus) emerged as being highly problematic, though they have received little research, monitoring, or management attention historically. Interview data revealed common interests and themes among affected individuals, including a desire for more data on the environmental drivers, factors affecting individual CP response variability, and increased education and awareness, particularly for vulnerable populations. This study offers essential information for managers crafting policy and outreach materials to mitigate the risk of CP in Hawaiʻi and provides baseline information that can be used to inform future studies in Hawaiʻi and throughout the region.

Vocal Cues to Assess Arousal State of Bottlenose Dolphins (Tursiops spp.) Involved in Public Presentations

Emotions in animals may be expressed by arousal and understanding this often relies upon the monitoring of their behaviour. Under human care, animals’ arousal states may be linked to husbandry decisions, whereby animals may display arousal responses to scheduled events such as feeding and human interaction. Here, we investigate vocal correlates of arousal associated with public presentations of bottlenose dolphins (Tursiops spp.) in human care by comparing vocal production rates and characteristics between high and low arousal contexts. Elevated arousal during the day compared with overnight was characterised by increased signature and non-signature whistle production. High intensity broadband crack vocalisations were produced less than whistles during the day and did not correlate with increased arousal around presentation times. Three of ten dolphins increased signature whistle production before and/or after presentation sessions, indicating elevated arousal and variation in individual responses. Many individuals elevated minimum frequency and suppressed maximum frequency of signature whistles in a way that correlated with higher arousal contexts, indicating that these may therefore be good indicators of changes in arousal state. Overall, our study demonstrates that passive acoustic monitoring can provide a useful indication of arousal linked to husbandry decisions, and that individual variation in vocal responses, likely linked to personality, is important to consider.

Bailout inclisiran-based triple lipid-lowering therapy reduces plaque lipid content in stable coronary artery disease patients

Abstract Background Low-density lipoprotein cholesterol (LDL-C) has a causal role in atherosclerotic cardiovascular disease. Genetic studies and variability in individual response to lipid-lowering therapies suggest combining hypolipidaemic medications with different mechanisms of action. Purpose The aim of this study was to evaluate the effect of triple inclisiran-based hypolipidaemic therapy in patients not reaching LDL-C target on maximum statin/ezetimibe treatment. Methods This prospective study enrolled 37 stable coronary artery disease patients admitted for elective percutaneous coronary intervention after 4-6 weeks on maximum tolerated statin and/or ezetimibe therapy during run-in period. Afterwards, patients with LDL-C level >1.8 mmol/l at the time of inclusion were assigned to receive add-on inclisiran (triple therapy group). In all participants near-infrared spectroscopy (NIRS) was performed at baseline and after 15 months for atherosclerotic plaque evaluation in the segment of interest, defined as 20-50% lesion in the proximal or middle third of a coronary artery. Statistical analysis was carried out with SPSS Statistics software. Results Average LDL-C level among screened patients was 2.81 (±1.17) mmol/l. In 19 patients LDL-C level remained >1.8 mmol/l on maximally tolerated statin and/or ezetimibe treatment, and after 15 months of triple therapy mean LDL-C reached 1.81 (±1.02) mmol/l with a significant LDL-C percentage change of 35.59% (95%CI -47.31 to -9.18, P=0.006) in this group. 17 patients continued statin/ezetimibe as mono or dual treatment and at 15-month follow-up mean LDL-C level comprised 1.67 (±0.61) mmol/l among these participants. According to NIRS data, maximum lipid-core burden index within 4 mm (maxLCBI4 mm) was significantly reduced by 28.85 (95%CI -189.39 to 17.64, P=0.041) in triple therapy group and by 114.72 in mono or dual therapy group (-194.76 to 23.01, P=0.004), with no statistically significant difference established between both groups (P=0.494). Conclusions Triple therapy demonstrated significant atherosclerotic plaque lipid content reduction along with LDL-C level lowering in patients with insufficient effectiveness of statin/ezetimibe treatment.

Pengaruh Edukasi Terintegrasi Terhadap Gangguan Mineral Dan Tulang Pada Penyakit Ginjal Kronik Di Rumah Sakit Dr. Soedjono Magelang

This study aims to evaluate the positive influence of Integrated Education on body mineral balance and bone health in sufferers of Chronic Kidney Disease (CKD). An experimental research design with a control group was used. The research subjects involved sufferers of stage 3-4 CKD, who were divided into an intervention group (receiving Integrated Education) and a control group (no intervention). Research parameters include levels of calcium, phosphorus, parathormone, bone mineral density, as well as patient knowledge and behavior. Findings: Increased Knowledge: The intervention group experienced a significant increase in knowledge related to CKD management compared to the control group, Positive Behavioral Changes: Patients who took part in the integrated education program showed more positive behavioral changes, including medication adherence, a healthy diet, and a healthy lifestyle, Improvement in Mineral and Bone Disorder Parameters: The intervention group showed significant improvement in calcium, phosphorus and parathormone levels. Bone mineral density also increased significantly. Clinical Implications: The results of the study suggest that Integrated Education can be an effective approach in improving CKD management, with a positive impact on the body's mineral balance and bone health. Conclusion: Integrated education has a significant influence on knowledge, behavior and mineral and bone balance parameters in CKD sufferers. Implementation of this program can improve CKD management and prevent complications related to mineral and bone disorders. Recommendation: Further research could explore the long-term effects of Integrated Education, consider variations in individual responses, and involve a wider sample group.

Cognition mediates response to anthropogenic noise in wild Western Australian magpies (Gmynorhina tibicen dorsalis).

Anthropogenic noise is a pollutant of growing concern, with wide-ranging effects on taxa across ecosystems. Until recently, studies investigating the effects of anthropogenic noise on animals focused primarily on population-level consequences, rather than individual-level impacts. Individual variation in response to anthropogenic noise may result from extrinsic or intrinsic factors. One such intrinsic factor, cognitive performance, varies between individuals and is hypothesised to aid behavioural response to novel stressors. Here, we combine cognitive testing, behavioural focals and playback experiments to investigate how anthropogenic noise affects the behaviour and anti-predator response of Western Australian magpies (Gymnorhina tibicen dorsalis), and to determine whether this response is linked to cognitive performance. We found a significant population-level effect of anthropogenic noise on the foraging effort, foraging efficiency, vigilance, vocalisation rate and anti-predator response of magpies, with birds decreasing their foraging, vocalisation behaviours and anti-predator response, and increasing vigilance when loud anthropogenic noise was present. We also found that individuals varied in their response to playbacks depending on their cognitive performance, with individuals that performed better in an associative learning task maintaining their anti-predator response when an alarm call was played in anthropogenic noise. Our results add to the growing body of literature documenting the adverse effects of anthropogenic noise on wildlife and provide the first evidence for an association between individual cognitive performance and behavioural responses to anthropogenic noise.

FRI083 Identifying Determinants Of Change In Physical Activity In Women With Obesity And Infertility Following The Obesity-Fertility Program

Abstract Disclosure: M. Gélinas: None. M. Belan: None. F. Jean-Denis: None. M. Pesant: None. M. Langlois: None. B. Carranza-Mamane: None. J. Baillargeon: Grant Recipient; Self; Ferring Pharmaceuticals. INTRODUCTION: Obesity is common among women of childbearing age and a risk factor for infertility. The Obesity-Fertility (OF) lifestyle program is an intervention that supports healthy lifestyle habits in women with infertility during the preconception period. Such support, that includes practice of physical activity (PA), is recommended for the management of obesity, and could improve fertility in individuals with obesity. However, there is a large variability in individual response in low-intensity lifestyle interventions. It is therefore important to determine whether there is a typical profile of women with obesity and infertility who benefit more from such program. OBJECTIVE: To determine the baseline characteristics associated with a change in sedentary time in hours per week (ST), the intensity level in leisure PA in METs, and the distance in meters walked during the 6-minute walk test (6MWT) after 6 months of participation in the OF lifestyle program. The 6MWT is associated to the functional capacity in populations with obesity. METHODS: Data from 85 participants enrolled in a randomized controlled trial and who had a research visit after 6 ± 1 months of follow-up were analyzed using univariate and multiple linear regressions (intervention, IG = 42; control, CG = 43). Participants in the CG received standard fertility care, while those in the IG received the OF program alone, which combines individual meetings with a kinesiologist and a nutritionist, and group sessions. Participants were assessed at baseline and after 6 months for outcomes, other lifestyle, anthropometry, weight loss readiness tool, quality of life, and the socio-economical status. RESULTS: After 6 months, women of the IG significantly improved their PA (+0.87 METs, p <0.001), ST (-6.74 hours/week, p <0001), and 6MWT (+23.8 m, p <0.001). The only independent baseline determinants of these changes were a lower baseline level of PA for an increase in PA (p=0.032); a higher baseline ST for a decrease in ST (p=0.002); and a lower baseline distance at the 6MWT for an increase in 6MWT distance (p<0.001). Regarding the CG, the 6-month changes in these outcomes were not significant (PA: +0.21, p=0.34; ST: -0.13, p=0.95; 6MWT: +7.3, p=0.26). The determinants of such changes were the same than in the IG, except for the baseline BMI ≥40 kg/m², which was an additional independent determinant of increase in ST, and baseline 6MWT was not associated with change in 6MWT. CONCLUSION: Less active women with lower functional capacity at baseline appear to benefit more from the OF lifestyle program. Based on the literature, psychosocial factors (motivation, self-efficacy, social support, etc.) were expected to be associated with changes in PA outcomes, but it is likely that our sample did not provide enough power to identify these relationships, or the tools we used were not enough sensitive for assess these characteristics. Presentation: Friday, June 16, 2023

SAT666 Feasibility, Acceptability And Preliminary Efficacy Of Continuous Glucose Monitoring In Adolescents With Obesity

Abstract Disclosure: S. Chimatapu: None. S. Mittelman: None. M. Habib: None. L. Wisk: None. A. Klomhaus: None. A.P. Vidmar: None. Background: Childhood obesity is a global health concern that presents as a multifaceted challenge requiring comprehensive interventions targeting nutritional, physical activity and behavioral domains. Despite this, treatment outcomes have been modest due to challenges in adherence and individual variability in response. Wearable technologies, such as Continuous Glucose Monitors(CGMs), offer a unique solution to promote consistent weight control in youth. These devices provide real-time biofeedback, allowing youth to make timely and informed decisions about their lifestyle choices. To date, no trial has explored the feasibility and efficacy of CGM use as a standalone intervention for adolescents with obesity. Hypothesis: We hypothesize that this study will demonstrate feasibility, acceptability and preliminary efficacy of CGMs in facilitating weight management among adolescents with obesity. Furthermore, we postulate that the unblinded CGM use will lead to greater changes in diet and physical activity compared to blinded use; emphasizing the use of biofeedback as a motivator for behavior change in this population. Methods: Adolescents with obesity have been recruited into a six-week cross-over trial. All participants wear the CGM daily for six weeks. For three weeks subjects will wear the CGM in a blinded manner, and for the other three weeks they will have access to the real-time CGM data, with blocks assigned in a random, cross-over manner. Outcomes will include recruitment and retention rate, adherence, CGM metrics, sleep, dietary intake, physical activity, eating behaviors and change in weight compared between study arms. Results: We have so far recruited 16 of a goal of 30 adolescents (15.3± 2.4 years old, 68% female, 75% Hispanic). Baseline A1c was 5.6 ± 0.3%. Four participants completed the study; one was lost to follow up, and 11 are currently enrolled in the study. Data logs from weekly telephone calls revealed high continuous engagement throughout the six weeks of the study. Our qualitative analysis of participant feedback suggest that they engaged with their real-time device data during the unblinded window. Device itself was deemed comfortable to wear, fit properly, without adverse effects or negative impacts on daily functioning. One participant reported 2 lbs. weight loss in 2 weeks after wearing the CGM by modifying their behaviors based on the glucose readings. Conclusions: Our preliminary findings suggest that CGM use in youth with obesity is a feasible, acceptable and well-tolerated tool. CGMs also have the potential to bring forth sustainable changes in youth behavior and could be a powerful intervention to enhance lifestyle changes in pediatric weight management programs. Further analyses will be pursued to help understand effect of continuous glucose monitoring on glycemic variability, body composition and self-reported health behaviors in youth with obesity. Presentation: Saturday, June 17, 2023

The effects of sleep restriction during abstinence on oxycodone seeking: Sex-dependent moderating effects of behavioral and hypothalamic-pituitary-adrenal axis-related phenotypes

During opioid use and abstinence, sleep disturbances are common and are thought to exacerbate drug craving. In this study, we tested the hypothesis that sleep restriction during abstinence from oxycodone self-administration would increase drug seeking during extinction and footshock reinstatement tests. We also performed behavioral phenotyping to determine if individual variation in responses to stressors and/or pain are associated with oxycodone seeking during abstinence, as stress, pain and sleep disturbance are often co-occurring phenomena. Sleep restriction during abstinence did not have selective effects on oxycodone seeking for either sex in extinction and footshock reinstatement tests. Some phenotypes were associated with drug seeking; these associations differed by sex and type of drug seeking assessment. In female rats, pain-related phenotypes were related to high levels of drug seeking during the initial extinction session. In male rats, lower anxiety-like behavior in the open field was associated with greater drug seeking, although this effect was lost when correcting for oxycodone intake. Adrenal sensitivity prior to oxycodone exposure was positively associated with footshock reinstatement in females. This work identifies sex-dependent relationships between HPA axis function and opioid seeking, indicating that HPA axis function could be a therapeutic target for the treatment of opioid use disorder, with tailored approaches based on sex. Sleep disturbance during abstinence did not appear to be a major contributing factor to opioid seeking.

Poor response to methylphenidate is associated with a smaller dorsal attentive network in adult Attention-Deficit/Hyperactivity Disorder (ADHD)

Stimulants, such as methylphenidate (MPH), are effective in treating attention-deficit/hyperactivity disorder (ADHD), but there is individual variability in response, especially in adults. To improve outcomes, we need to understand the factors associated with adult treatment response. This longitudinal study investigated whether pre-treatment anatomy of the fronto-striatal and fronto-parietal attentional networks was associated with MPH treatment response. 60 adults with ADHD underwent diffusion brain imaging before starting MPH treatment, and response was measured at two months. We tested the association between brain anatomy and treatment response by using regression-based approaches; and compared the identified anatomical characteristics with those of 20 matched neurotypical controls in secondary analyses. Finally, we explored whether combining anatomical with clinical and neuropsychological data through machine learning provided a more comprehensive profile of factors associated with treatment response. At a group level, a smaller left dorsal superior longitudinal fasciculus (SLF I), a tract responsible for the voluntary control of attention, was associated with a significantly lower probability of being responders to two-month MPH-treatment. The association between the volume of the left SLF I and treatment response was driven by improvement on both inattentive and hyperactive/impulsive symptoms. Only non-responders significantly differed from controls in this tract metric. Finally, our machine learning approach identified clinico-neuropsychological factors associated with treatment response, such as higher cognitive performance and symptom severity at baseline. These novel findings add to our understanding of the pathophysiological mechanisms underlying response to MPH, pointing to the dorsal attentive network as playing a key role.

Placebo effects in osteoarthritis: implications for treatment and drug development.

Osteoarthritis (OA) is the most common form of arthritis worldwide, affecting ~500 million people, yet there are no effective treatments to halt its progression. Without any structure-modifying agents, management of OA focuses on ameliorating pain and improving function. Treatment approaches typically have modest efficacy, and many patients have contraindications to recommended pharmacological treatments. Drug development for OA is hindered by the gradual and progressive nature of the disease and the targeting of established disease in clinical trials. Additionally, new medications for OA cannot receive regulatory approval without demonstrating improvements in both structure (pathological features of OA) and symptoms (reduced pain and/or improved function). In clinical trials, people with OA show high 'placebo responses', which hamper the ability to identify new effective treatments. Placebo responses refer to the individual variability in response to placebos given in the context of clinical trials and other settings. Placebo effects refer specifically to short-lasting improvements in symptoms that occur because of physiological changes. To mitigate the effects of the placebo phenomenon, we must first understand what it is, how it manifests, how to identify placebo responders in OA trials and how these insights can be used to improve clinical trials in OA. Leveraging placebo responses andeffects in clinical practice might provide additional avenues to augment symptom management of OA.

Behavior of Mothers after Infant Loss in Bonnet Macaques (Macaca radiata)

Mother–offspring bonds in primates often last for life and shape the behavior of both mother and offspring. Therefore, the death of an infant may trigger an emotional response from its mother akin to human grief, which is characterized by active distress and passive depression. Our goal was to investigate whether the behavior of female bonnet macaques (Macaca radiata) changed after the loss of their infants. In the Thenmala area, southern India, between 2020 and 2022, we observed 18 mothers in two groups who lost, in total, 19 infants and three juveniles aged < 18 months. We compared affiliative, aggressive, and stress-related behavior of females before and after the death of their infants. We also examined individual variation in responses to infant loss. After the death of their infants, females withdrew socially, stayed on the periphery of the group, and had fewer companions. Bereaved females were less involved in grooming and hugging and initiated aggressive behavior more frequently than before they lost their infants. Moreover, females who lost infants showed frequent stress-related behaviors, such as self-scratching and yawning compared with when their infants were alive. Our results suggest that female bonnet macaques react to deaths of their infants in a manner that is consistent with the interpretation of grief in humans and other primates.

Diet composition and energy intake in humans.

Absolute energy from fats and carbohydrates and the proportion of carbohydrates in the food supply have increased over 50 years. Dietary energy density (ED) is primarily decreased by the water and increased by the fat content of foods. Protein, carbohydrates and fat exert different effects on satiety or energy intake (EI) in the order protein > carbohydrates > fat. When the ED of different foods is equalized the differences between fat and carbohydrates are modest. Covertly increasing dietary ED with fat, carbohydrate or mixed macronutrients elevates EI, producing weight gain and vice versa. In more naturalistic situations where learning cues are intact, there appears to be greater compensation for the different ED of foods. There is considerable individual variability in response. Macronutrient-specific negative feedback models of EI regulation have limited capacity to explain how availability of cheap, highly palatable, readily assimilated, energy-dense foods lead to obesity in modern environments. Neuropsychological constructs including food reward (liking, wanting and learning), reactive and reflective decision making, in the context of asymmetric energy balance regulation, give more comprehensive explanations of how environmental superabundance of foods containing mixtures of readily assimilated fats and carbohydrates and caloric beverages elevate EI through combined hedonic, affective, cognitive and physiological mechanisms. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.