Bellotti ES et al. · Jul 1, 2026
Background Accurate range verification is crucial in hadrontherapy to fully exploit the ballistic advantages of charged particles and prevent damage to healthy tissues. Among the proposed approaches, prompt gamma imaging (PGI) has emerged as an effective technique for real-time monitoring, but its performance is limited by the intense neutron background generated during irradiation, especially with carbon-ions. Purpose This work presents a Monte Carlo study performed with the FLUKA code to investigate prompt gamma and neutron emission in proton and carbon-ion therapy. A prototype detection system based on a knife-edge collimator coupled to a pixelated LYSO scintillator was simulated to evaluate its capability for range verification. The aim is to quantify how neutron fields and neutron induced signals bias or degrade range related quantities, and how these effects differ between proton and carbon-ion beams. Methods The analysis includes the characterization of prompt gamma energy spectra and spatial profiles, the assessment of neutron fields within a treatment room, and the decomposition of the detector signal into primary gammas, secondary gammas, and neutrons. Results Results show that prompt gamma profiles correlate well with the Bragg peak position, particularly within the 3-7 MeV energy window, while carbon ions exhibit higher prompt gamma yields but also significantly stronger neutron backgrounds compared to protons. Detector simulations highlight the impact of neutron capture on lutetium, producing distinct peaks that must be accounted for in the detector signal analysis. The fall-off retrieval precision (FRP) analysis indicates that the distal fall-off of prompt gamma profiles can be used to estimate the Bragg peak position, while secondary radiation components introduce additional fluctuations that affect the achievable precision, particularly for carbon-ion beams. Conclusions The study provides a detailed characterization of prompt gamma and neutron contributions in proton and carbon-ion therapy and highlights the main physical factors affecting PGI-based range monitoring, particularly in the presence of neutron-induced backgrounds. These results provide useful insights for the design and optimization of prompt gamma detection systems in clinical applications.
Medicine
Bartsch DK et al. · Jul 1, 2026
Introduction VIPoma is an extremely rare functioning pancreatic neuroendocrine tumor. Therefore, data regarding treatment and outcome are very limited. Aim (s): This multicenter study aimed to analyze clinical characteristics, real-world management, and outcomes of patients with VIPoma. Methods Patients with VIPoma treated in a 20-year period at 14 referral centers for neuroendocrine tumors (NET) were collected in the ENETS Database. Clinical characteristics, therapeutic interventions, and outcomes were analyzed retrospectively. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results Of 70 patients, 59 (54% male) with a median age of 55 years were included. Forty-six (78%) patients were diagnosed due to the classical watery diarrhea-hypokalemia-achlorhydria (WDHA) syndrome, and 40 (68%) presented with distant metastases at diagnosis. Fifty-two (88%) had serum VIP levels >2 times the upper normal limit and the median Ki-67 index was 5% (range 1%-40%). Surgery of the primary VIPoma was performed in 32 (54%), with curative intent in 22 (37%). In patients with stage I-III disease (n = 19), long-term cure was achieved in only 26% (5/19), with a median DFS of 81 (95%-CI: 1-215) months and 10-year OS of 78% (95%-CI: 61%-100%). In stage IV patients (n = 53, 40 at diagnosis, 13 disease progression), the sequence and type of 354 treatment lines varied, while SSA (n = 77, 22%), loco-regional liver-directed therapy (n = 72, 20%), and chemotherapy (n = 69, 19%) were most often applied. Median OS for patients with stage IV at diagnosis was 142 (95%-CI: 87-not available (NA)) months with 10-year survival of 50% (95%-CI: 35%-73%). Conclusion Patients with VIPoma treated at NET centers have relatively favorable survival, even with distant metastases at diagnosis, although long-term cure rates remain low.
Medicine
Khodarahmi M et al. · Jul 1, 2026
Introduction Diminished ovarian reserve (DOR) represents a significant contributor to female infertility and adverse reproductive outcomes. Although diet may play a role, the specific impact of phytochemical-rich dietary patterns remains underexplored. So, we aimed to investigate the association between adherence to a dietary phytochemical index (DPI) and the likelihood of DOR among women attending fertility clinics. Methods This case-control study enrolled 370 women, comprising 120 individuals diagnosed with DOR and 250 age- and body mass index (BMI)-matched controls with normal ovarian reserve. A validated semi-quantitative food frequency questionnaire (FFQ) was applied to assess dietary intakes and, accordingly, DPI was calculated as the proportion of total energy intake obtained from phytochemical-abundant foods. Antral follicle count (AFC) and serum anti-Müllerian hormone (AMH) measurements were utilized as indicators of ovarian reserve. The association between DPI and the odds of DOR was investigated using multivariable logistic regression models. Results Our findings showed that higher DPI was associated with a reduced odds of DOR (Q4 vs. Q1 OR: 0.79; 95% CI: 0.55-0.93; p-trend = 0.010). After adjustment for physical activity and energy intake, the association remained significant (OR: 0.80; 95% CI: 0.54-0.95; p-trend = 0.033). In the fully adjusted model, which included additional adjustments for fat mass and body mass index, women in the highest DPI quartile had 27% lower odds of DOR compared to those in the lowest quartile (OR: 0.73; 95% CI: 0.42-0.97; p-trend = 0.02). Besides, in the control group, AFC differed significantly across DPI quartiles (p Conclusion Our findings suggest that a phytochemical-rich diet may help reduce the odds of DOR, highlighting the role of diet in reproductive health. However, further prospective studies and mechanistic research are warranted to confirm these results and clarify underlying pathways.
Medicine
Nakao M et al. · Jul 1, 2026
Objectives Etizolam is a short-acting thienodiazepine widely prescribed for anxiety and insomnia despite increasing concerns regarding dependence and guideline recommendations limiting long-term benzodiazepine use. This study examined long-term prescribing trends of etizolam compared with benzodiazepine and non-benzodiazepine hypnotics. Methods We conducted a retrospective database study including 16,886,524 prescriptions issued between April 2001 and March 2022 at a tertiary university hospital in Japan. Seventeen hypnotic agents were identified (10 benzodiazepines and 7 non-benzodiazepines). Multivariable logistic regression was used to identify factors associated with prescribing hypnotic etizolam versus non-benzodiazepine hypnotics. Results Among 124,179 etizolam prescriptions, 83,927 (67.6%) were issued for hypnotic use. Although the absolute number of prescriptions declined over time, the proportion prescribed for hypnotic use remained stable. The ratio of hypnotic etizolam prescriptions to non-benzodiazepine hypnotics was higher in internal medicine than in psychiatry. In multivariable analysis, prescribing hypnotic etizolam was independently associated with internal medicine (adjusted OR 1.57), female sex, outpatient status, younger age, and earlier calendar year. Conclusions Despite declining overall use, etizolam continues to be prescribed as a hypnotic, particularly in non-psychiatric settings. These findings highlight the persistence of specialty-specific prescribing patterns and underscore the importance of targeted educational and policy interventions to promote safer hypnotic prescribing practices.
Psychology
Nigatu EW. · Jul 1, 2026
Background Adaptive traits, along with productive and reproductive performance, are essential for assessing the suitability and long-term sustainability of indigenous cattle in specific production environments. Objective This study evaluated the adaptive, productive and reproductive performance of Boran dairy cattle in the lowland agro-ecology of the Kaffa Zone, south-western Ethiopia. Methods The study was conducted at a commercial farm in Gojeb, and sixty (60) multiparous Boran dairy cows were selected based on health status, parity, and lactation stage, following an adaptation period before data collection. This study covered the early, mid and late lactation stages over a 25-week monitoring period. Daily milk yield was recorded twice daily, and reproductive parameters, including age at first calving (AFC), calving interval (CI), number of services per conception (NSPC), days open (DO) and gestation length (GL), were obtained from farm records. Adaptive performance was assessed using rectal temperature (RT) and respiration rate (RR) in relation to the meteorological variables. Blood samples were collected from 30 cows (10 per lactation stage) for haematological (HC, RBC, WBC and PCV) and biochemical (TP, GLU, URE, TGL, TC, AST and ALT) analyses. Data were analysed using SPSS version 20, and descriptive statistics were summarized as mean ± SD. Results The current study revealed that the mean daily milk yield was 2.43 ± 0.62, 2.12 ± 0.58 and 1.72 ± 0.45 L/day for early, mid and late lactation, respectively. Parity 1 and 2 cows produced 1.71 ± 0.46 L and 2.47 ± 0.52 L, respectively, with an overall mean of 2.09 ± 0.62 L/day. Parity and lactation stage significantly (p Conclusion The productive and reproductive performances of Boran cows were within the expected ranges for indigenous breeds, suggesting that crossbreeding could enhance productivity. Further studies should consider age, season and comparisons with other locally adapted breeds.
Environmental Science
Allen J et al. · Jul 1, 2026
Issues Alcohol use disorder (AUD) shows sex-related differences in prevalence, harm and treatment response. Despite growing interest in sex differences, evidence synthesis evaluating pharmacotherapy effectiveness by sex remains limited. Approach Web of Science, PubMed, Scopus, PsycINFO and Cochrane were searched twice. Eligible records included RCTs or non-randomised studies of adults with AUD receiving pharmacological interventions (licensed or off-label), and reporting or providing outcomes (binary relapse or continuous alcohol consumption change) by sex. Multi-level random-effects models calculated risk ratios (RR) and standardised mean differences (SMD), with sex as a moderator. Key findings Twenty-eight studies (25,041 participants, 25% female) were included. No outcomes were rated low risk of bias; non-RCTs were moderate-to-high quality. Overall treatment effects vs. control were small for abstinence (RR = 0.96, 95% CI [0.52, 1.74]; 4 studies; I 2 = 95%) and modest for consumption reduction (SMD = 0.23, 95% CI [0.01, 0.45]; 13 studies; I 2 = 89%); sex did not meaningfully moderate these outcomes (ratio of RR = 1.04, 95% CI [0.87, 1.25]; ΔSMD = 0.05, 95% CI [-0.09, 0.18]). Power was low (median 13.7%), requiring ~6358 participants per group to detect the observed sex difference. Narrative synthesis suggested possible sex differences for naltrexone and baclofen, while highlighting the influence of drug (e.g., tolerability), participant (e.g., drinking motives) and design factors (e.g., recruitment setting) on treatment response. Implications AUD pharmacotherapies provide modest benefits, with sex differences remaining unclear. Future trials should be adequately powered, report sex-specific outcomes and consider adherence, tolerability and psychosocial moderators. Conclusion Evidence for sex-specific efficacy remains inconclusive. Patterns for naltrexone and baclofen warrant exploration in large, rigorously designed, sex-stratified trials.
Medicine
He W et al. · Jul 1, 2026
Underage drinking has become a global public health concern. One of the major causes of underage drinking is stress. The orexin system has been reported to be involved in both alcohol addiction and stress. However, few studies have examined this system, especially among adolescents. Therefore, we constructed protein-protein interaction (PPI) networks to confirm that orexin receptors are connected to stress- and alcohol dependence-related genes, providing a theoretical basis for our experimental approach. Animal experiments employed the conditioned place preference (CPP), the foot-shock stress model and the enzyme-linked immunosorbent assay (ELISA), to elucidate the role of the orexin system in the stress-induced alcohol addiction-related behaviour among adolescent mice. Our results revealed that there were interactions among orexin system, chronic/acute stress and alcohol dependence related proteins. Otherwise, chronic stress can increase the animals' vulnerability to alcohol addition-related behaviour. Additionally, acute foot-shock can promote alcohol-seeking behaviour reinstatement and facilitate orexin concentrations in brain regions that have been shown to be associated with reward and addiction. Moreover, the inhibition of orexin receptors can attenuate the formation and reinstatement of alcohol addiction-like behaviour among adolescent mice. Collectively, our findings indicate that orexin system may be a pivotal target for preventing stress-induced alcohol addiction and reinstatement among the adolescents.
Neuroscience
Bhuiyan MSA et al. · Jul 1, 2026
Background Inclusion body hepatitis (IBH), caused by fowl adenoviruses (FAdVs), is an emerging disease of commercial broilers associated with significant economic losses. In Malaysia, molecular epidemiological data on circulating FAdV serotypes have largely been restricted to Peninsular regions, with limited information available from East Malaysia (Sabah), despite its rapidly expanding poultry industry and distinct production systems. This regional knowledge gap limits comprehensive understanding of FAdV transmission dynamics at the national level. Objectives This study aimed to detect FAdV infection in broiler flocks with IBH-compatible lesions in Sabah, Malaysia, and to characterize circulating serotypes and their phylogenetic relationships. Methods Thirty pooled tissue samples (liver and gizzard) and 60 serum samples were collected from three broiler farms (YAN, KON, and NIS). FAdV detection was performed using polymerase chain reaction (PCR) targeting the hexon gene. Serological responses were assessed using enzyme-linked immunosorbent assay (ELISA). Positive PCR products were sequenced, and phylogenetic analysis was conducted to determine serotype distribution and genetic relatedness. Results FAdV DNA was detected in 33.3% (10/30; 95% CI: 17.3-52.8) of pooled tissue samples, with detection rates of 70% (95% CI: 44.4-97.5), 20% (95% CI: 2.5-55.6) and 10% (95% CI: 0.3-44.5) in the YAN, KON and NIS farms, respectively. Although descriptive differences were observed among farms, these variations were not statistically significant (p > 0.05). All positive samples yielded the expected 897 bp hexon gene amplicon. ELISA revealed high seropositivity in unvaccinated flocks, with the highest mean antibody titre observed in the YAN farm (24,716.5 ± 4516.1). Molecular characterization identified FAdV-8b (species E) and FAdV-11 (species D), indicating co-circulation. Phylogenetic analysis showed close relatedness to strains from Korea, Belgium, China and Australia. Conclusions The co-circulation of FAdV-8b and FAdV-11 in Sabah broiler farms underscores the need for continuous molecular surveillance, enhanced biosecurity and breeder-level vaccination strategies using locally circulating FAdV strains to control IBH in Malaysia.
Biochemistry, Genetics and Molecular Biology
Chen C et al. · Jul 1, 2026
Cardiomyocyte senescence drives cardiovascular disease, underscoring the need to define its molecular mechanisms. The role of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel in this process remains unclear, particularly regarding its expression and function. Atrial tissues were collected from patients with sinus rhythm or atrial fibrillation (AF) of varying durations. CFTR was downregulated in AF patients and negatively correlated with p16, p21, and p53. Myocardial aging models were established using D-galactose (D-gal) in both mice and neonatal mouse cardiomyocytes (CMs). In both animal and cellular models, D-gal increased SA-β-gal positivity and senescence markers while decreasing CFTR. Overexpressing CFTR reduced D-gal-induced elevations in p16, p21, p53, and malondialdehyde (MDA), and restored superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities. Mechanistically, CFTR alleviates mitochondrial oxidative stress damage by enhancing plasma membrane Ca 2+ ATPase (PMCA) activity to reduce cytoplasmic Ca 2+ levels. Furthermore, we identified USP45 as a direct binding partner of CFTR, which deubiquitinates CFTR by specifically targeting K48-linked chains and the K688 residue. CFTR knockdown exacerbated D-gal-induced senescence and mitochondrial oxidative stress, which was rescued by USP45 overexpression. In conclusion, this study reveals a novel mechanism in which USP45-mediated deubiquitination of CFTR mitigates cardiomyocyte senescence and mitochondrial oxidative stress, offering a targeted intervention against age-related cardiovascular diseases.
Neuroscience
Wang S et al. · Jul 1, 2026
Oxidative stress drives tumor microenvironment (TME) remodeling by inducing metabolic reprogramming and cellular senescence. Glutamine, a key substrate supporting oxidative stress defense, has been implicated in TME remodeling and metastasis, yet its specific role in initiating tumor invasion remains unclear. Here, oxidative stress induced the generation of senescent macrophages in the TME, and clinical samples showed that their accumulation positively correlates with malignancy. We established cisplatin- and radiation-induced senescent macrophage models that exhibited distinct senescence-associated secretory phenotypes (SASP) and enhanced squamous cell carcinoma (SCC) migration and invasion. Integrated metabolomic and transcriptomic analyses revealed the glutamine-glutamate pathway as a central metabolic hub, with glutaminase 2 upregulated to drive glutaminolysis and strongly associated with IL-1β expression. Mechanistically, IL-1β secreted by senescent macrophages promoted tumor invasion by downregulating IL-1R2 and activating NF-κB signaling in SCC cells. Targeting the glutamine metabolism-regulated IL-1β/IL-1R2 axis effectively suppressed SCC invasion. These findings uncover a novel metabolic mechanism linking glutamine metabolism to SASP regulation and suggest a therapeutic strategy to limit SCC invasion.
Biochemistry, Genetics and Molecular Biology