Poor appetite, a major contributor to malnutrition, is highly prevalent among older adults and associated with adverse clinical outcomes. Nevertheless, there are currently no widely accepted or consistently effective pharmacological treatments targeting appetite that are routinely recommended alongside nutritional interventions. Medical cannabis has been proposed as a potential appetite stimulant in older adults with poor appetite through modulation of appetite-regulating hormones such as glucagon-like peptide-1 (GLP-1) and total ghrelin, but the evidence remains limited. To investigate the effects of Sativex® versus placebo on postprandial GLP-1 and total ghrelin concentrations following a single dose (8.1 mg Δ9-tetrahydrocannabinol (THC) and 7.5 mg cannabidiol (CBD)), and on subjective appetite following two separated doses, in older adults with poor appetite, and to investigate the associations between plasma concentrations of THC and its metabolites on these outcomes. This protocolized secondary analysis included 17 participants (≥65 years) with poor appetite from a double-blind, randomized, placebo-controlled crossover trial. Participants received Sativex® or placebo on two separate study days. GLP-1 and total ghrelin were measured following one dose of Sativex®/placebo and a standardized breakfast, and subjective appetite was assessed repeatedly using visual analog scales throughout the administration of two separate doses of Sativex®/placebo, the consumption of a standardized breakfast, and an ad libitum lunch meal. Effects/associations were analyzed using linear mixed-effects models. Compared with placebo, Sativex® produced an estimated 2.38 pmol/L (95% confidence intervals (CI): -0.71 to 5.46; Bonferroni-corrected p = 0.274) reduction in mean GLP-1 and time-dependent changes in mean total ghrelin (Bonferroni-corrected p = 0.054). Compared with placebo, Sativex® produced minimal changes in separate subjective appetite sensations (all Bonferroni-corrected p = 1.00) and a slightly lower combined appetite score (-5.2 mm; 95% CI: -24.4 to 4.0; Bonferroni-corrected p = 1.00). Increased plasma concentrations of THC and metabolites were associated with reduced estimates of mean GLP-1 concentrations and subjective appetite, as well as increased mean total ghrelin concentrations. However, no statistically significant differences were detected for any analyses, and estimates had wide CIs, warranting cautious interpretation. In conclusion, no statistically significant differences were detected between Sativex® and placebo in postprandial GLP-1, total ghrelin, or subjective appetite over time in older adults with poor appetite. Similarly, no statistically significant associations were observed between plasma concentrations of THC and its metabolites and GLP-1, total ghrelin, or subjective appetite. ClinicalTrials.gov ID: NCT05503147; EudraCT nr.: 2021-002318-15.
Background: Appetite regulation is governed by a complex neuroendocrine network that integrates peripheral peptide signals with hypothalamic and brainstem circuits to coordinate energy intake and maintain energy homeostasis. Disruption of these pathways contributes to obesity and other disorders characterised by dysregulated feeding behaviour. Objective: To map and synthesise the current evidence on the role of appetite-regulating peptide hormones and central neural pathways in appetite control, obesity pathophysiology, and emerging therapeutic approaches. Methods: A scoping review of the literature was conducted to identify and synthesise evidence relating to the physiological and pathological mechanisms of appetite regulation. The review examined the actions of key peptide hormones, including ghrelin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), leptin, and insulin, their interactions within the gut-brain axis, and their effects on central appetite-regulating circuits. Results: The evidence highlights the central role of the arcuate nucleus in integrating peripheral hormonal signals with neural pathways controlling feeding behaviour. Appetite regulation is mediated by the balance between orexigenic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons and anorexigenic pro-opiomelanocortin/cocaine- and amphetamine-regulated transcript (POMC/CART) neurons, with further modulation by the paraventricular, lateral, and ventromedial hypothalamic nuclei. The literature identifies hormone resistance, impaired satiety signalling, and altered neuroendocrine feedback as major contributors to obesity. Evidence on therapeutic interventions demonstrates the potential of GLP-1 receptor agonists, including liraglutide and semaglutide, and the dual incretin agonist tirzepatide, while also highlighting challenges related to treatment durability, adverse effects, and weight regain following discontinuation. Conclusions: Current evidence demonstrates that appetite regulation involves highly interconnected peripheral and central signalling pathways. The reviewed literature supports the development of multi-target and precision-based therapeutic strategies for obesity and identifies important areas for future research, including mechanisms of treatment resistance, long-term efficacy, and inter-individual variability in neuroendocrine responses.
Background: Plant and animal proteins have been shown to affect postprandial glycaemic, insulin, and appetite responses to carbohydrate meals. Here we compared lamb protein and soy protein effects on glycaemic response, insulin secretion and appetite, examining whether the protein source modified the relative glycaemic effects of different carbohydrate foods, and whether lamb and soy protein differed in their effects. Methods: Healthy participants (n = 15) were randomised to consume meals containing potato, pasta, or rice, either alone or combined with equal amounts of lamb or soy protein, and with lamb fat content equalised across meals. Blood glucose and insulin responses were measured over the postprandial period, and subjective appetite was assessed. Results: Both lamb and soy protein reduced postprandial glycaemic responses and increased insulin responses compared with the carbohydrate staples consumed alone. Soy protein induced a slightly lower glycaemic response than lamb protein (132 ± 18 vs. 144 ± 13; 103 ± 16 vs. 123 ± 19; 112 ± 12 vs. 130 ± 17 mmol/L.min, potato, pasta and rice, respectively), although differences were small and not consistently significant. Adding protein also reduced the differences in glycaemic responses between the carbohydrate staples, particularly diminishing the higher response to potato. Both protein sources suppressed appetite to a similar extent relative to the carbohydrate-only meals. Conclusions: Adding protein to mixed meals had a dominant effect on postprandial glycaemic, insulin, and appetite responses, whereas the specific protein source (lamb versus soy) had a minor influence. These findings indicate that, under the conditions of this study, both animal and plant proteins were effective in moderating postprandial glycaemia and enhancing satiety.
The oral frailty index-8 (OFI-8) is a measure of oral frailty to identify impaired oral function. However, its validity and associations with health outcomes remain unclear. We aim to evaluate its construct validity and associations with appetite, muscle health, falls, functional outcomes, and quality of life (QoL). Cross-sectional analysis of 300 community-dwelling older adults (mean age 67.4 ± 7.10 years; 68.7% female). Exploratory factor analysis (EFA) assessed OFI-8's factor structure. Participants were classified as oral non-frail (ONF), pre-frail (OPF), or frail (OF) based on total scores. Associations with outcomes were assessed using logistic regression, adjusted for relevant covariates. Outcomes included appetite (SNAQ), muscle health (DEXA muscle mass, handgrip strength, SARC-F), falls risk (STEADI), function (IADL), life-space mobility (LSA), mood (GDS), and QoL (EQ-5D-5L). EFA revealed OFI-8's 3-factor structure: swallowing and oral conditions, dental care, and dietary and social habits. Prevalence of ONF, OPF, and OF was 62%, 16%, and 22%, respectively. Compared to ONF, OF showed worse appetite, handgrip strength, SARC-F scores, falls risk, IADL function, and mood (all p < 0.05). In adjusted models, OF was associated with poor appetite (OR = 1.97, 95% CI: 1.07-3.65), increased falls risk (OR = 2.64, 95% CI: 1.21-5.74), and low mood (OR = 5.51, 95% CI: 2.07-14.69). OPF was not associated with any outcomes. No differences were observed across groups in muscle mass, LSA, or QoL. Our findings provide preliminary support for OFI-8's validity as a multi-dimensional tool to identify community-dwelling older persons with oral frailty, which is associated with adverse outcomes. Further research is needed to refine cut-offs and evaluate longitudinal predictive validity.
Resistance training (RT) is widely prescribed for health, yet its effects on energy compensation and appetite regulation remain poorly defined, particularly across sexes. This study examined the effects of chronic RT on energy intake and appetite-regulating hormones in rats. Animals (n = 40) were assigned to female control, female RT, male control, or male RT and completed a 12-week ladder-based RT protocol. Energy intake was assessed longitudinally, and hormonal responses were measured during a resistance training exercise test (RTET). RT reduced total energy intake (p = 0.022) without altering energy intake relative to body weight. Males exhibited reduced body weight and energy intake, whereas females did not, despite greater relative training volume. Postexercise energy intake was elevated in RT groups (p = 0.029), indicating delayed compensatory feeding. Acyl-ghrelin increased following RTET (p < 0.001) and was higher in RT and females (p < 0.001). Leptin, insulin, GLP-1, and PYY were unchanged. These findings demonstrate sexually dimorphic energy compensation during RT, associated with ghrelin secretion rather than tonic appetite hormones. RT appears to shift compensation toward episodic, ghrelin-mediated pathways, with females exhibiting greater sensitivity. This identifies an endocrine framework for RT-induced energy compensation and emphasizes the need for sex-specific approaches to exercise prescription and energy balance regulation.
Non-caloric sweeteners are increasingly used as alternatives to sugar to reduce energy intake, yet their metabolic effects remain controversial. This study aimed to evaluate the effects of sucrose, saccharin, and steviol glycosides on glucose regulation and cardiometabolic risk markers in healthy adults. In a randomized, double-blind, crossover trial, 39 healthy, normal-weight adults consumed beverages containing sucrose (66 g/day), saccharin (220 mg/day), or steviol glycosides (220 mg/day) for 14 days, with washout periods between interventions. Metabolic outcomes were assessed at baseline and after each intervention under fasting conditions and during a 2 h postprandial test. Primary outcomes were glucose and insulin responses; secondary outcomes included gut hormones, lipids, inflammatory markers, and subjective appetite. Compared with baseline, fasting glucose increased after sucrose and saccharin, and fasting insulin increased after stevia (p < 0.01). All interventions increased postprandial insulin responses and reduced indices of insulin sensitivity (p < 0.05). Fasting PYY and GLP-2 increased following all treatments (p < 0.001), without differences between sweeteners. Triglycerides were higher after sucrose than saccharin (p < 0.05), while no differences were seen for cholesterol, apolipoproteins, or CRP. Appetite ratings were unchanged, with a trend (p = 0.053) towards a reduced desire to eat after stevia in the late postprandial phase. Short-term intake of sucrose and non-caloric sweeteners resulted in broadly similar metabolic responses, with no significant differences in glucose regulation. However, triglyceride concentrations were higher following sucrose than saccharin, whereas no consistent differences were observed across the remaining outcomes. Observed deviations from baseline should be interpreted with caution. Further long-term studies in diverse populations are warranted.
Phasic dopamine signalling updates the value of stimuli and actions. Most empirical support for this critical process involves manipulation of extrinsic stimuli (e.g., reward magnitude, reward omission). Yet interoceptive signals clearly influence motivated behaviour. Sodium depletion generates a sodium appetite where the value of sodium increases. How the value of sodium is updated during ingestion and as animals satiate their need remains unknown. Here, we administered sodium chloride solutions via intraoral delivery and measured appetitive behaviour and dopamine release in sodium replete and deplete rats. Two different concentrations of sodium chloride were used to modulate the rate of repletion for sodium deplete rats. Appetitive behaviour was evoked by infusions only when rats were deplete, and this behavioural motif faded away during the session only when high concentration infusions were delivered. Phasic dopamine release in the nucleus accumbens had a similar pattern. We identified transition points for both behaviour and dopamine in the subgroup of rats that reached satiation and found that transitions were sharp, with dopamine decreasing just before behaviour. Moreover, transitions occurred only after enough sodium was infused to replace that typically lost upon depletion. These findings demonstrate that mesolimbic dopamine dynamically updates the value of taste stimuli based on interoceptive signals that relay satiation.
To summarize symptom network characteristics in patients with solid tumors undergoing chemotherapy and synthesize evidence on core symptoms, bridge symptoms, and temporal associations. We systematically searched eight databases through October 2025 to identify studies that applied symptom network analysis to adults with solid tumors receiving chemotherapy. Eligible studies assessed symptoms using cross-sectional, longitudinal, or interventional designs. Two reviewers independently screened articles and extracted data on study characteristics, symptom assessment, and network outcomes. Methodological quality was assessed using the National Institutes of Health Study Quality Assessment Tool. Twenty-seven studies involving 13,452 participants were included, yielding 79 symptom networks. Fatigue was the most frequently identified core symptom (10/20, 50%), whereas sadness, lack of appetite, and nausea each occurred in 10% of studies, with variation across cancer types, treatment phases, and latent classes. Bridge symptoms included disturbed sleep, lack of appetite, and dry mouth (2/7, 28.6%). Studies evaluating temporal associations found that symptoms such as sadness, dyspnea, somnolence, and dry mouth predicted subsequent changes in appetite, distress, nausea, and other outcomes. Strength metrics showed acceptable stability (correlation stability coefficients: 0.28-0.83). Fatigue was frequently identified as a central symptom across studies, largely reflecting evidence from breast cancer studies. Core symptoms varied across cancer types, treatment phases, and latent classes, suggesting heterogeneity. These findings highlight the importance of considering relationships among symptoms in clinical care. Focusing on key symptoms such as fatigue, while tailoring management strategies to cancer-specific symptom patterns, may support more effective symptom management.
This prospective study compared postoperative patient experience between the superciliary approach (supra-eyebrow incision) and the trans-scalp lateral supraorbital approach (scalp incision) for unruptured anterior circulation aneurysms. Patients (n=111) undergoing a superciliary or trans-scalp lateral supraorbital approach completed a six-item daily Visual Analogue Scale (VAS) symptom questionnaire (wound-related pain, generalized headache, depressed mood, fatigue, decreased appetite, and nausea) and underwent neurological examinations for 5 days postoperatively. Surgical outcomes, including clip placement adequacy and complications, did not differ between groups. On postoperative day (POD) 5, the superciliary group reported significantly less wound-related pain (3.34 vs. 4.70, p=0.003), headache (3.54 vs. 5.16, p=0.001), depressed mood (2.33 vs. 3.44, p=0.018), fatigue (3.11 vs. 4.46, p=0.009), and decreased appetite (3.61 vs. 5.00, p= 0.007) than the trans-scalp group. Stepwise regression identified the trans-scalp approach as a dominant predictor of wound-related pain, headache, depressed mood, and fatigue. Significant mood depression (VAS ≥5) occurred in 10 patients (16.4%) in the superciliary group versus 17 (34.0%) in the trans-scalp group on POD 5, and depressed mood correlated significantly with fatigue, decreased appetite, nausea, and headache. The superciliary approach was associated with less postoperative pain and discomfort than the trans-scalp lateral supraorbital approach in the early period after successful aneurysm clipping. The trans-scalp approach was a dominant determinant of wound-related pain, headache, depressed mood, and fatigue, and depressed mood correlated with other postoperative symptoms in both groups.
The safety, tolerability, pharmacokinetics, and efficacy of TERN-601, a once-daily, oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist, were studied in Phase 1 and 2 clinical studies. The Phase 1 (28-day) and Phase 2 (12-week), randomized, double-blind, placebo-controlled, multiple-ascending-dose studies evaluated the safety, tolerability, pharmacokinetics, and efficacy (change in weight, appetite, and gastric emptying) of TERN-601 for adults with obesity or overweight. In the Phase 1 study, TERN-601 produced dose-dependent weight loss over 28 days, with statistically significant reductions versus placebo at all doses. Treatment was associated with GLP-1-consistent pharmacodynamic effects, including reduced appetite and delayed gastric emptying. In the Phase 2 study, TERN-601 doses ≥ 500 mg resulted in significantly greater mean percentage weight loss at Week 12 versus placebo. Gastrointestinal treatment-emergent adverse events were consistent with the GLP-1 receptor agonist class and dose-related. Three participants in the Phase 2 study experienced transaminase elevations consistent with potential drug-induced liver injury. TERN-601 demonstrated modest, dose-dependent weight loss with a gastrointestinal tolerability profile consistent with GLP-1 receptor agonists. However, liver safety findings observed in the Phase 2 study led to clinical development discontinuation. These data contribute to the overall understanding of oral small-molecule GLP-1 receptor agonists in obesity. ClinicalTrials.gov identifier: NCT06854952.
Background and Objectives: Effective palliative care relies on accurate identification and management of symptoms, especially in patients referred for palliative radiotherapy (PRT). This study aimed to identify symptom clusters (SCs)-defined as ≥2 interrelated symptoms-in patients evaluated at a multidisciplinary Radiotherapy and Palliative Care (RaP) outpatient clinic, using the Edmonton Symptom Assessment System (ESAS). Materials and Methods: We retrospectively analyzed data from patients referred to the RaP clinic between February 2017 and April 2020. Demographic and clinical characteristics, including ESAS scores at first visit, were collected. SCs were identified with principal component analysis (PCA) and unsupervised k-means clustering (KMC), determining the number of SCs based on the maximum gap statistic and interpretability. Associations with ECOG performance status (PS), primary tumor and metastases site, and PRT administration were analyzed. Exploratory survival analyses were performed. Results: Among 215 patients (median age = 71 years; 53% male), the mean total ESAS score was 24.03 (SD = 15.28). PCA identified four SCs: SCPCA1 (tiredness, drowsiness, dyspnea, malaise), SCPCA2 (depression, anxiety), SCPCA3 (nausea, loss of appetite) and SCPCA4 (pain). KMC revealed three SCs: SCKMC1 (pain, tiredness, drowsiness, malaise), SCKMC2 (nausea, loss of appetite, dyspnea), and SCKMC3 (depression, anxiety). Worse ECOG PS correlated with physical SCs (p < 0.05). Psychological SCs were associated with lower likelihood of receiving PRT (ORPCA2 = 0.26, CI: 0.07-0.80, ORkmc3 = 0.19, CI: 0.02-0.85, p < 0.05), but when associated with pain/systemic clusters correlated with greater PRT use. A trend toward shorter survival was seen in SCKMC2. Conclusions: SC analysis could improve personalized symptom management and clinical decision-making in the PRT setting.
Eating experience is shaped not only by oral sensory input, but also by hedonic evaluation, interoceptive state, and cue-driven motivation. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for obesity treatment, offer a clinically relevant model for examining how these processes interact during appetite regulation. Some patients receiving GLP-1RAs report that food tastes different, is less enjoyable, or becomes less tempting, yet these experiences are often grouped together as "taste changes." This review argues that such reports should be interpreted through a sensory-liking-wanting framework rather than as evidence of a uniform gustatory disorder. We synthesise evidence from peripheral taste signalling, brainstem interoceptive integration, and central food reward pathways. Current evidence does not support a consistent primary impairment of basic gustatory function during GLP-1RA treatment. Instead, altered eating experience appears more consistent with state-dependent food revaluation and reduced reward-driven motivation. However, these responses are heterogeneous and may include limited response, persistent appetite, weight regain, or atypical behavioural phenotypes in some individuals. This framework may help clarify how incretin-based therapies influence food preference, dietary intake, nutritional behaviour, and treatment adherence.
We previously demonstrated that reducing the caloric load of a model drink from 30 g (10 %) sucrose to 21 g (7 %), while maintaining sweetness level with the taste modifier hesperetin, lowered postprandial glucose fluctuations and energy intake at an ad libitum breakfast. However, the contribution of the reduction of the caloric load compared to the addition of hesperetin remained unclear. We hypothesized that independent of participants' sex, the reduction of carbohydrate content is decisive for the glycemic and appetite and sweet craving responses. In a single-blinded, randomized crossover study with 39 healthy adults (21 female), we compared a 10 % sucrose solution, an equi-sweet 7 % sucrose solution containing hesperetin, and a less sweet 7 % sucrose solution with respect to postprandial glucose and incretin responses, as well as energy intake, taking sex-specific differences into account. Females showed lower glucose peaks after both sucrose-reduced drinks (without hesperetin: Δ 59 ± 17 %, p < 0.01; with hesperetin: Δ 50 ± 17 %, p < 0.05), whereas male responses were similar independent of the carbohydrate content. The equi-sweet treatments similarly increased GLP-1 in females (Δ 100 ± 36 %, p < 0.05), but not in males. In contrast, GIP levels rose in men only (Δ 177 ± 65 %, p < 0.05) following the equi-sweet treatments. Despite lower appetite and sweet craving ratings after the sugar-reduced treatments across sexes, subsequent energy intake at an ad libitum breakfast was not significantly different between treatments. These results indicate sex-specific metabolic responses and suggest that lowering sucrose content while maintaining sweetness preserves satiety signaling, without affecting subsequent energy intake at an ad libitum breakfast in both male and female individuals.
Despite evidence suggesting that Mycobacterium tuberculosis induces tryptophan depletion, microbiota dysbiosis and ultimately immune dysfunction, no data exist on serum levels of tryptophan and microbiota-metabolite (indole proprionic acid, IPA) in Nigerian TB patients. This study determined anthropo-nutritional status [Body Mass Index(BMI), Mid-Upper Arm Circumference(MUAC), Waist Circumference(WC), Hip Circumference(HC)], and Simplified Nutritional Appetite Questionnaire(SNAQ) scores, serum albumin, tryptophan and IPA in Nigerian PTB patients using questionnaire and ELISA as appropriate. Higher prevalence of DS-TB(92%) than MDR-TB(19%) or control(4%) showed appetite loss with a clinically meaningful risk of 5% weight loss within six months. The BMI, MUAC, WC, HC and SNAQ scores were significantly reduced in DS-TB patients or MDR-TB patients compared with control. The MUAC, WC, HC and SNAQ scores were significantly reduced in DS-TB patients compared with MDR-TB patients. The serum levels of albumin were not significantly reduced while the levels of IPA were not significantly increased in DS-TB patients or MDR-TB patients compared with control. The serum levels of tryptophan were significantly increased in DS-TB patients or MDR-TB patients compared with control. Our findings revealed a need for tryptophan-based management for PTB patients and that PTB is an infectious, metabolic and nutritional disease.
As survival after gastric and esophageal cancer continues to improve, sustained work participation has become an important survivorship outcome. We aimed to evaluate return-to-work (RTW) rates 18 months after curative-intent surgery for gastric and esophageal cancers and to identify clinical and socioeconomic factors associated with delayed or failed RTW. This multicenter, longitudinal, prospective cohort study evaluated working-age Japanese patients undergoing curative-intent surgery for gastric or esophageal cancer. Working status was assessed preoperatively and at 6, 12, and 18 months postoperatively. The primary outcome was working status at 18 months. Secondary outcomes included time to first RTW, and factors associated with non-working and delayed RTW. Exploratory analyses evaluated 6-month patient-reported outcomes (QLQ-C30) and postoperative weight loss. Among 158 eligible patients, 124 (78.5%) were working at 18 months. Older age (≥ 65 years) and pathological stage≥ III were associated with non-working at 18 months, whereas sedentary work and self-employment were associated with a lower risk of non-working. Postoperative appetite loss, financial difficulties (QLQ-C30), and ≥ 10% body weight loss at 6 months were associated with non-working status. Median time to first RTW was 30 and 70 days for gastric and esophageal cancers, respectively. Esophageal cancer and advanced stage were consistently associated with delayed RTW, with weaker evidence for associations with female sex and preoperative retirement. Approximately 80% of patients were working at 18 months after surgery. Postoperative nutritional impairment and symptom burden were associated with long-term work participation and may help identify patients at risk of not working after surgery.
Cancer neuroscience has emerged as a field that explores the bidirectional interactions between tumors and the nervous system. From this perspective, we review the pharmacological and neurobiological effects of kinase inhibitors, which are widely used as anticancer therapeutics. Certain kinase inhibitors not only exert potent antitumor activity but also modulate neural function as a consequence of kinase inhibition. Representative examples include small molecules and therapeutic antibodies targeting the tropomyosin receptor kinase (Trk), rearranged during transfection (RET), vascular endothelial growth factor/ vascular endothelial growth factor receptor (VEGF/VEGFR), epidermal growth factor receptor (EGFR), and anaplastic lymphoma kinase (ALK) signaling pathways. These agents influence the nervous system through molecular mechanisms, examples of which include TrkA-mediated pain perception and growth differentiation factor 15/RET signaling-dependent appetite regulation. Elucidating these mechanistic intersections between oncogenic and neural signaling can broaden our understanding of tumor-nerve crosstalk.
To assess the real-world associations of five glucagon-like peptide-1 receptor agonists (GLP-1RAs) with weight loss in a diverse US population of adults with obesity, with and without type 2 diabetes, and whether the relative ordering of weight loss observed in trials is mirrored in routine practice. We conducted a retrospective, new-user, active-comparator cohort study using the National Institutes of Health All of Us Research Program. We included 14,046 adults with obesity (body mass index [BMI] ≥30 kg/m2) initiating exenatide, liraglutide, dulaglutide, semaglutide, or tirzepatide. Groups were compared after multivariable adjustment for baseline confounders. Participants were followed from the index date until the outcome, death, or loss to follow-up; percent weight and BMI change was assessed at 12 months (±45 days). Cox proportional hazards models estimated the relative likelihood over time of achieving weight-loss thresholds (≥5%, ≥10%, ≥15%) and ≥1 BMI-category reduction; linear regression assessed the magnitude of weight change, with liraglutide as reference. Tirzepatide showed the highest likelihood of ≥15% weight loss (adjusted hazard ratio [aHR] 5.57; 95% CI, 3.66-8.49) and the greatest mean weight loss at 12 months (-13.0%), followed by semaglutide (aHR 1.77; 95% CI, 1.56-2.01; -5.9%); both were significantly greater than the older agents in adjusted analyses. Exenatide, dulaglutide, and liraglutide showed comparable, modest weight loss (approximately -4.0%). This ordering was consistent regardless of type 2 diabetes status, although weight loss was greater without diabetes for semaglutide but similar for tirzepatide. In this large, diverse real-world cohort, tirzepatide and semaglutide were associated with significantly greater weight loss than older agents. These findings are consistent with the relative ordering reported in trials, though the observational design cannot confirm it. Residual confounding cannot be excluded, and the small tirzepatide sample (n=386) and limited follow-up warrant cautious interpretation. Obesity is a long-term condition, and many people need more than lifestyle changes to manage it. Newer medicines called GLP-1 receptor agonists can reduce appetite and have worked well in clinical trials. But trials enroll selected volunteers who may differ from people in everyday care. We compared how five of these medicines work for weight loss in a large, diverse, real-world group. We studied health records from 14,046 adults with obesity in the National Institutes of Health All of Us Research Program. We compared how much weight patients lost in one year after starting exenatide, liraglutide, dulaglutide, semaglutide, or tirzepatide. On average, tirzepatide users lost about 13.0% and semaglutide users about 5.9%, while patients taking the three older medicines lost around 4%. Tirzepatide users were also the most likely to achieve large weight loss of 15% or more. These findings suggest the two newest medicines, tirzepatide and semaglutide, are linked to greater weight loss than older options, even in everyday care. Greater weight loss is generally linked to better health, so these differences could matter for patients, though our study cannot prove the drugs caused them. Because we used everyday medical records rather than a clinical trial, the results show links rather than proof of cause and effect. Tirzepatide is new, so few patients had taken it; larger studies are needed to confirm these early findings.
Dog ownership provides physical and psychological benefits; however, inappropriate handling may lead to behavioural problems, particularly owner-directed aggression, which can compromise human wellbeing. This study investigated factors associated with owner-directed aggression and evaluated the effectiveness of interventions in Thailand. A randomised, single-blind clinical trial was conducted in 80 dogs exhibiting moderate to severe owner-directed aggression (including a history of biting). Aggression was assessed using owner questionnaires and veterinary interviews. Dogs were allocated to four groups: feeding toy (TOY), fluoxetine (DRUG), combination therapy (DRUG + TOY) and control. All groups received behavioural modification guidance. Aggression scores were measured before and after four weeks using a standardised scale. Multivariable analysis indicated that human-dog interactions and management practices were significantly associated with aggression scores, whereas owner and dog demographic factors were not. Baseline aggression did not differ among groups (p ≥ 0.05). Following treatment, all groups showed significant improvement (p < 0.05), with the DRUG and DRUG + TOY groups demonstrating greater reductions than the TOY and control groups. No significant differences were observed between DRUG and DRUG + TOY or between TOY and control. Mild side effects of fluoxetine, primarily drowsiness and reduced appetite, were observed during the first week and were less frequent in the combination group. Overall, fluoxetine (0.5-1 mg/kg) was more effective in reducing owner-directed aggression than environmental enrichment and owner education alone. However, enrichment and education play a crucial role in improving dog welfare and in sustainably reducing or preventing aggression and may enhance treatment outcomes when used alongside pharmacological intervention.
Franz Kafka has often been posthumously diagnosed with anorexia nervosa, but recent research impels a re-evaluation of his disordered eating. This study presents a qualitative analysis of Kafka's diaries, correspondence, medical reports and fiction, focusing on appetite, diet, somatic symptoms, and cognitions concerning food and fasting. Diagnostic indicators are matched against DSM-5 criteria for anorexia nervosa and avoidant/restrictive food intake disorder. Kafka's clinical profile, which is characterised by diminished appetite, anorexia, selective intake, obsessive mastication, low body weight and undernourishment needing repeated sanatorium admissions, suggests a presentation more consistent with avoidant/restrictive food intake disorder. These disturbances are reflected in his fiction, in which food operates as a symbolic register of alienation, ontological anxiety and existential resistance, most notably in The Metamorphosis and A Hunger Artist. Integration of medical and literary perspectives demonstrates the clinical value of phenomenological evidence in capturing lived experience of eating disorders, enriching diagnostic insight by foregrounding cognitive, psychosocial and cultural contexts.
Obesity, diabetes, and hypertension are major global health burdens influenced not only by lifestyle factors but also by genetic predisposition, sleep quality, chrononutrition, and circadian rhythms. This review examined how these factors interact in metabolic and cardiovascular diseases, with emphasis on sex-specific differences. A narrative review was conducted using PubMed, Scopus, and Web of Science databases for studies published between 2006 and 2026. A total of 112 studies were synthesized, including randomized trials, observational studies, systematic reviews, meta-analyses, Mendelian randomization, and mechanistic investigations. Evidence indicates that genetic susceptibility and circadian disruption contribute significantly to obesity, diabetes, and hypertension. Sleep deprivation, obstructive sleep apnea, and circadian misalignment were consistently associated with insulin resistance, appetite dysregulation, elevated blood pressure, and increased cardiometabolic risk, particularly among shift workers. Hormonal and metabolic pathways involving leptin, ghrelin, cortisol, and melatonin appear to mediate these effects. Important sex differences were observed, with women showing greater vulnerability to sleep-related appetite disturbances and men presenting a higher prevalence of visceral adiposity, sleep apnea, and hypertension. Chrononutrition strategies, including time-restricted eating and Mediterranean dietary patterns, showed beneficial effects on sleep quality, glycemic control, inflammation, and metabolic health. Emerging evidence also suggests bidirectional interactions between gut microbiota rhythmicity and circadian regulation. Genetic predisposition, sleep disturbances, and circadian disruption interact to influence metabolic and cardiovascular disease risk. Integrative approaches combining chrononutrition, sleep hygiene, circadian alignment, and personalized nutritional strategies may improve the prevention and management of cardiometabolic diseases.