bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upregulation of HMGB1 in tumor-associated macrophages induced by tumor cell-derived lactate further promotes colorectal cancer progression
Authors: Gao Xinyi , Zhou Shiqi , Qin Zhaofu , Li Dechuan , Zhu Yuping , Ma Dening 
Published: January 2023

Abstract
Background
Lactate accumulation leads to an acidic tumor microenvironment (TME), in turn promoting colorectal cancer (CRC) progression. Tumor-associated macrophages (TAMs) are the predominant cells in TME. This study aimed to reveal the regulation mechanism of CRC cell-derived lactate on TAMs and explore the mechanism underlying lactate accumulation-induced aggravation in CRC.

Methods
Cell growth and metastasis were evaluated by colony formation, Transwell, and wound healing assays. Western blot and RT-qPCR were applied to determine the protein and mRNA expression. Flow cytometry was used to analyze the polarization state and apoptotic rate of macrophages induced in THP-1 cells. The lactate in the cell supernatant was quantified using an ELISA kit. Immunofluorescence was performed to visualize the location of High Mobility Group Box 1 (HMGB1). H&E and Ki67 staining assays were used to assess tumorigenesis in nude mice bearing ectopic tumors.

Results
Cell growth and metastasis were promoted in the hypoxic CRC cells. The hypoxic cell supernatant stimulated the M2-type polarization of macrophages. The lactate level increased in hypoxic cancer cells. However, the inhibition of lactate using 3-hydroxy-butyrate (3-OBA) reversed the effects of hypoxia. Also, macrophages showed no promoting effect on cancer cell growth and migration in the presence of 3-OBA. HMGB1 was secreted into the extracellular space of lactate-induced macrophages, further enhancing the malignant behaviors of cancer cells. ERK, EMT, and Wnt signaling pathways were activated in cancer cells due to HMGB1 upregulation.

Conclusions
The lactate metabolized by cancer cells stimulated M2 polarization and HMGB1 secretion by macrophages, aggravating the carcinogenic behaviors of cancer cells.
Child maltreatment exposure and adolescent nonsuicidal self-injury: the mediating roles of difficulty in emotion regulation and depressive symptoms
Authors: Hu Changchun , Huang Jialing , Shang Yushan , Huang Tingting , Jiang Wenhao , Yuan Yonggui 
Published: January 2023

Abstract
Background
Although child maltreatment (CM) experiences are recognized risk factors for nonsuicidal self-injury (NSSI), the mechanisms underlying this relationship remain unclear. The purpose of this study was to examine whether difficulty in emotion regulation (DER) and depressive symptoms mediate the relationship between child maltreatment experiences and NSSI severity, adjusting for demographic variables.

Methods
The participants were 224 adolescent inpatients recruited from a hospital in China (mean age 15.30 years, SD = 1.83; 78.6% females). Study measures included the Clinician-Rated Severity of Nonsuicidal Self-Injury (CRSNSSI), Childhood Trauma Questionnaire (CTQ-SF), Difficulties in Emotion Regulation Scale (DERS), and Patient Health Questionnaire-9 (PHQ-9). The hypothesized chain mediation model was tested using the structural equation model.

Results
A total of 146 (65.18%) adolescents reported engaging in NSSI during the past 12 months, and 103 (45.98%) participants met the DSM-5 diagnostic criteria for NSSI. Emotional neglect (48.1%) and emotional abuse (46.1%) had the highest prevalence, followed by physical neglect (43.1%) and physical abuse (24.1%), whereas sexual abuse (12.5%) was the least prevalent form of CM. Separately, both DER and depressive symptoms significantly mediated the association between CM and NSSI, with DER being the strongest mediator, with an indirect effect of 49.40% (p = 0.014). At the same time, we also proved a potential chain-mediated pathway of DER and depression in the relationship between CM and NSSI.

Conclusion
Child maltreatment seems to play a role in the aetiology of NSSI. DER and depressive symptoms both have a mediating role in the relationship between CM and NSSI. Importantly, DER seems to be a mediator with a stronger indirect effect compared to depressive symptoms.
Pre-hospital analgesia in pediatric trauma and critically ill patients: An analysis of a German air rescue service
Authors: Eimer Christine , Reifferscheid Florian , Jung Philipp , Rudolph Marcus , Terboven Tom , Hoffmann Florian , Lorenzen Ulf , Köser Andrea , Seewald Stephan 
Published: January 2023

AbstractBackgroundPain management in the pre-hospital setting remains a particular challenge for paramedics and emergency physicians, especially in children. This study evaluates the pre-hospital use and effect of analgesics in children with trauma or pain due to other reasons.MethodsThis study is a retrospective analysis of the database of a German air rescue service and was conducted over a period of 9 years (2012–2020) to assess pain in general and whether patients with trauma pain due to other reasons received treatment with analgesics. We included all patients in the registry under the age of 16 years. Patients with a Glasgow Coma Scale of 3 at hospital admission and incomplete records were excluded. The intensity of pain was determined by the emergency physician on scene at arrival and hospital admission in a ten-point rating scale (0 = no pain). Effective pain reduction was analyzed.ResultsOut of 227,458 cases, a total of 22,025 emergency cases involved pediatric patients aged 0–16 years. 20,405 cases were included in the study. 12,000 (58.8%) children had suffered a trauma, 8108 (39.7%) had pain due to other reasons and 297 (1.5%) had both. In total, 4,608 (38.4%) of the children with trauma were assessed having a numerical rating scale (NRS) > 4 at EMS arrival. These patients received mainly ketamine (34.5%) and the opioids fentanyl (38.7%) and piritramide (19.1%). The value on the NRS was significantly lower at admission to hospital (mean 1.9) compared with the EMS arrival (mean 6.9). In 4.9% the NRS at hospital admission was still > 4. 282 patients within the non-trauma group had a pre-hospital NRS of > 4. The pain therapy consisted of opioids (35.8%) and ketamine (2.8%). 28.4% patients in the non-trauma group received no pain medication. In 16.0% the NRS at hospital admission was still > 4.ConclusionsGerman emergency physicians achieved a sufficient pain therapy in pediatric patients with a NRS > 4 after trauma. In case of non-trauma, the pain management by the emergency physicians is restrained and less successful. The most common analgesic medications administered were ketamine and fentanyl, followed by piritramide.Trial registration: The study has been retrospectively registered at DRKS (DRKS00026222).
The prognostic value and immune correlation of IL18 expression and promoter methylation in renal cell carcinoma
Authors: Wang Xiaonan , Zhu Wancui , Long Qian , Chen Enni , Sun Haohui , Li Xiaodi , Xu Hailin , Li Weizhao , Dong Pei , He Liru , Chen Miao , Deng Wuguo 
Published: January 2023

Abstract
Background
Renal cell carcinoma (RCC) is not sensitive to immunotherapy and has poor prognosis. DNA methylation regulates gene expression, and its abnormal changes are related to many human diseases. Recently, DNA methylation has been found to participate in immune infiltration in various cancers. However, its pattern in RCC remains poorly understood.

Results
We found that IL18 was significantly over-expressed in RCC tumor tissues compared to normal adjacent tissues The IL18 promoter region was hypomethylated, which was strongly correlated with elevated IL18 mRNA expression, and predicted advanced clinicopathological characteristics and shorter overall survival. Furthermore, we found that IL18 promoter methylation was significantly related to the down-regulation of immune checkpoint molecules and increase of CD8 + T cell infiltration in RCC tumor tissues.

Conclusions
We have identified the important role of IL18 promoter methylation and expression, which are associated with clinicopathological characteristics, overall survival, immune cell infiltration and expression of immune checkpoint molecules in RCC. We present the rationale for IL18 promoter methylation as a molecular biomarker for predicting the response of RCC to immune checkpoint inhibitors.
A phase 1 clinical trial of the repurposable acetyllysine mimetic, n-methyl-2-pyrrolidone (NMP), in relapsed or refractory multiple myeloma
Authors: Jake Shortt  , Galettis Peter , Cheah Chan Y. , Davis Joanne , Ludford-Menting Mandy , Link Emma K. , Martin Jennifer H. , Koldej Rachel , Ritchie David 
Published: January 2023

Abstract
Background
N-methyl-2-pyrrolidone (NMP) is an epigenetically active chemical fragment and organic solvent with numerous applications including use as a drug-delivery vehicle. Previously considered biologically inert, NMP demonstrates immunomodulatory and anti-myeloma properties that are partly explained by acetyllysine mimetic properties and non-specific bromodomain inhibition. We therefore evaluated orally administered NMP in a phase 1 dose-escalation trial to establish its maximum tolerated dose (MTD) in patients with relapsed/refractory multiple myeloma (RR–MM). Secondary endpoints were safety, pharmacokinetics (PK), overall response rate and immunological biomarkers of activity.

Results
Thirteen patients received NMP at starting doses between 50 and 400 mg daily. Intra-patient dose escalation occurred in five patients, with one attaining the ceiling protocolised dose of 1 g daily. Median number of monthly cycles commenced was three (range 1–20). Grade 3–4 adverse events (AEs) were reported in seven (54%; 95% CI 25–81%) patients. Most common AEs (> 30% of patients) of any grade were nausea and musculoskeletal pain. The only dose limiting toxicity (DLT) was diarrhoea in a patient receiving 200 mg NMP (overall DLT rate 8%; 95% CI 0–36%). Hence, the MTD was not defined. Median progression-free and overall survival were 57 (range 29–539) days and 33 (95% CI 9.7– > 44) months, respectively. The best response of stable disease (SD) was achieved in nine patients (69%; 95% CI 39–91%). PK analysis demonstrated proportional dose–concentrations up to 400 mg daily, with a more linear relationship above 500 mg. Maximum plasma concentrations (Cmax) of 16.7 mg/L at the 800 mg dose were below those predicted to inhibit BET-bromodomains. Peripheral blood immune-profiling demonstrated maintenance of natural killer (NK) cells, and a gene expression signature suggestive of enhanced T, B and NK cell functions; a subject with prolonged exposure manifested sustained recovery of B and NK cells at 12 months.

Conclusions
NMP demonstrated potential disease stabilising and immunomodulatory activity at sub-BET inhibitory plasma concentrations and was well tolerated in RR–MM; an MTD was not determined up to a maximum dose of 1 g daily. Further dose-finding studies are required to optimise NMP dosing strategies for therapeutic intervention.
An assessment of out of pocket payments in public sector health facilities under the free maternal healthcare policy in Ghana
Authors: Kumbeni Maxwell Tii , Afaya Agani , Apanga Paschal Awingura 
Published: January 2023

Abstract
Background
The free maternal healthcare policy was introduced in Ghana in 2008 under the national health insurance scheme as a social intervention to improve access to maternal health services. This study investigated the prevalence of out of pocket (OOP) payment among pregnant women with valid national health insurance who sought skilled delivery services at public sector health facilities in Ghana. The study also assessed the health system factors associated with OOP payment.

Methods
We used data from the Ghana Maternal Health Survey (GMHS), which was conducted in 2017. The study comprised 7681 women who delivered at a public sector health facility and had valid national health insurance at the time of delivery. We used multivariable logistic regression analysis to assess factors associated with OOP payment, whiles accounting for clustering, stratification, and sampling weights.

Results
The prevalence of OOP payment for skilled delivery services was 19.0%. After adjustment at multivariable level, hospital delivery services (adjusted Odds Ratio [aOR] = 1.23, 95% Confidence Interval [CI] = 1.00, 1.52), caesarean section (aOR = 1.73, 95% CI = 1.36, 2.20), and receiving intravenous infusion during delivery (aOR = 1.31, 95% CI = 1.08, 1.60) were associated with higher odds of OOP payment. Women who were discharged home 2 to 7 days after delivery had 19% lower odds of OOP payment compared to those who were discharged within 24 hours after delivery.

Conclusion
This study provides evidence of high prevalence of OOP payment among women who had skilled delivery services in public sector health facilities although such women had valid national health insurance. Government may need to institute measures to reduce OOP payment in public sector facilities especially at the hospitals and for women undergoing caesarean sections.
13C analysis of cow tail hair and farm slurry can be used to implicitly distinguish between different dairy production systems
Authors: Sieve Friederike , Isselstein Johannes , Kayser Manfred 
Published: January 2023

Abstract
Background
Public interest in the way food is produced on the farm and processed along the food-production chain is increasing. The analysis of isotopic signatures (13C) in cow tail hair provides a method to reconstruct the dietary proportion of maize in cow diets. Based on this, we further investigated whether there is a relationship between isotopic signatures in cow tail hair or farm slurry and the proportion of maize of the total utilized agricultural area per farm [%]. We did an on-farm survey on 17 dairy farms in coastal Northwest Germany and collected cow tail hair from dairy cows and slurry samples on each farm. The farms differed in their feeding regime (C3 vs. C4 plants), their site conditions (sandy soil = ‘Geestland’; organic soil = ‘Peatland’; clayey soil = ‘Marshland’), and in the area cultivated with maize as a proportion of the total utilized agricultural area per farm.

Results
We found a positive relationship between δ13C values in both cow tail hair and slurry and the annual dietary proportion of maize (R2 = 0.67; and R2 = 0.63). Furthermore, we confirmed that there was a relationship between δ13C values in cow tail hair and area of maize as a proportion of the total utilized agricultural area per farm (R2 = 0.69).

Conclusion
Our findings suggest a general applicability of using isotopic signatures (13C) along a wide gradient of site conditions and productions systems in practice.
Life expectancy and healthy life expectancy of patients with advanced schistosomiasis in Hunan Province, China
Authors: Jiang Honglin , Zhou Jie , Xia Meng , Li Guangping , Di Jie , Mao Feng , Yu Liangqing , Cai Yu , Wang Zhengzhong , Xiong Ying , Tong Yixin , Yin Jiangfan , Chen Yue , Jiang Qingwu , Zhou Yibiao 
Published: January 2023

Abstract
Background
Few studies have investigated the change in life expectancy (LE) and the healthy lifespan among patients with advanced schistosomiasis. This study was to evaluate the LE and healthy life expectancy (HLE) for patients and assess the mechanism responsible for the LE inequality.

Methods
We utilized data from a dynamic advanced schistosomiasis cohort (10,362 patients) for the period from January 2008 to December 2019 in Hunan Province, China, to calculate the LEs of patients, and made a comparison with that of general population (19,642 schistosomiasis-free individuals) in the schistosomiasis endemic areas. LEs were estimated from 15 years of age by constructing period life tables. Arriaga’s decomposition method was applied to quantify the influence of the age structure on the difference in LE. HLE for advanced schistosomiasis patients was calculated by using Sullivan method with age-specific disability weight. The LE and HLE were calculated for both males and females to perform further analyses on gender gap.

Results
The estimated LE for advanced schistosomiasis patients aged 15–19 was 49.51 years (48.86 years for males and 51.07 years for females), which was 20.14 years lower compared with general population (69.65 years), and the LE gap between patients and general population decreased with age. The largest age-specific mortality contribution to the gap (32.06%) occurred at age 80–84 years. Women had a lower LE and HLE than men at age ≥ 60 years (both gender gaps in LE and HLE < 0). For advanced schistosomiasis patients, the gender gap in LE was largely attributed to the difference in mortality among those under the age of 55; the age-specific mortality in women exerted positive influence on the gap at age 25–64 and 75–79 years, with the contribution rate ranging from 0.59% to 57.02%, and made the negative contribution at other age groups.

Conclusions
The LE of advanced schistosomiasis patients was still much lower compared with general population. Strengthened prevention strategies and targeted treatments are needed to reduce morbidity and mortality due to advanced schistosomiasis, especially for younger population and elderly female patients.
Use of a “tablet pole” for the administration of ivermectin for strongyloidiasis in a field study in Ecuador
Authors: Buonfrate Dora , Anselmi Mariella , Prandi Rosanna , Marquez Monica , Mazzi Cristina , Montresor Antonio 
Published: January 2023

Abstract
Background
Establishment of efficient control programs for strongyloidiasis, the infection by Strongyloides stercoralis, is among the World Health Organization (WHO) targets for 2030. Ivermectin is a drug of choice for strongyloidiasis, but its weight-based administration can be unfeasible in remote areas. We evaluated a WHO tablet pole for administration of ivermectin in school-age children living in remote villages in Ecuador.

Methods
Children were enrolled in 16 villages in Esmeraldas Province of Ecuador, between July 2021 and June 2022. The pole identified four height intervals corresponding to ivermectin doses going from one to four tablets. For each child, we calculated the dose (µg/kg) administered with both weight-based and pole-based administration. Results were classified as follows: optimal dose, acceptable, overdose, underdose. Agreement between the two methods for estimating the number of tablets was assessed with Cohen’s kappa coefficient. Estimations were reported with 95% confidence intervals (CIs).

Results
Total of 778 children (47.3% female) were enrolled, with median age of 9.59 years (interquartile range: 7.42‒11.22). Optimal dose was achieved for a higher proportion of children when assessed with weight (37.9%) than with pole (25.7%). Underdose and overdose were more frequent with the pole (8.3% and 19.2% children, respectively) than with the weight-based (3.7% and 6.0%, respectively) administration. Agreement between weight-based and pole-based administration was moderate: 0.56 (95% CI 0.51, 0.61). The two methods indicated the same number of tablets in 71.6% (95% CI 0.684, 0.748) cases.

Conclusions
In our setting, the tablet pole could be a valid alternative. The tool needs further evaluation in different populations.

Graphical Abstract
Spatio-temporal trends of malaria incidence from 2011 to 2017 and environmental predictors of malaria transmission in Myanmar
Authors: Zhao Yan , Aung Pyae Linn , Ruan Shishao , Win Kyawt Mon , Wu Zifang , Soe Than Naing , Soe Myat Thu , Cao Yaming , Sattabongkot Jetsumon , Kyaw Myat Phone , Cui Liwang , Menezes Lynette , Parker Daniel M. 
Published: January 2023

Abstract
Background
Myanmar bears the heaviest malaria burden in the Greater Mekong Subregion (GMS). This study assessed the spatio-temporal dynamics and environmental predictors of Plasmodium falciparum and Plasmodium vivax malaria in Myanmar.

Methods
Monthly reports of malaria cases at primary health centers during 2011–2017 were analyzed to describe malaria distribution across Myanmar at the township and state/region levels by spatial autocorrelation (Moran index) and spatio-temporal clustering. Negative binomial generalized additive models identified environmental predictors for falciparum and vivax malaria, respectively.

Results
From 2011 to 2017, there was an apparent reduction in malaria incidence in Myanmar. Malaria incidence peaked in June each year. There were significant spatial autocorrelation and clustering with extreme spatial heterogeneity in malaria cases and test positivity across the nation (P < 0.05). Areas with higher malaria incidence were concentrated along international borders. Primary clusters of P. falciparum persisted in western townships, while clusters of P. vivax shifted geographically over the study period. The primary cluster was detected from January 2011 to December 2013 and covered two states (Sagaing and Kachin). Annual malaria incidence was highest in townships with a mean elevation of 500‒600 m and a high variance in elevation (states with both high and low elevation). There was an apparent linear relationship between the mean normalized difference vegetative index and annual P. falciparum incidence (P < 0.05).

Conclusion
The decreasing trends reflect the significant achievement of malaria control efforts in Myanmar. Prioritizing the allocation of resources to high-risk areas identified in this study can achieve effective disease control.

Graphical Abstract
A scoping review of community-based post-opioid overdose intervention programs: implications of program structure and outcomes
Authors: Bailey Amelia , Harrington Calla , Evans Elizabeth A. 
Published: January 2023

Abstract
Background
An emergent intervention to address the opioid epidemic is the use of multidisciplinary outreach teams which connect an individual in the community to healthcare resources after the experience of an opioid overdose. While these interventions are receiving federal funding, less is known empirically to inform future interventions. Understanding the process and outcomes of these interventions is advisable due to the novel partnerships of public health and law enforcement agencies who sometimes hold divergent goals. The objective of the present review was to describe program structure and evaluated outcomes of community-based post-overdose interventions.

Results
A search of PubMed, PsycInfo, and Web of Science yielded 5 peer-reviewed articles that detail the implementation and outcomes of interventions delivered in the United States published from 2001 to July 2021. Most interventions used a multidisciplinary outreach team and referenced first responder data to contact individuals who recently experienced an overdose at their residence. Services offered often included referral to substance use treatment, recovery coaches, and social services. Method of outreach, evaluation measures, and outcomes varied. From the available literature, facilitators of program engagement included communication, information sharing, and leadership buy-in among multidisciplinary partners.

Conclusions
Future studies could benefit from exploration of service provision in rural areas, for family affected by overdose, and for minoritized populations. Community-based post-overdose interventions utilizing a law enforcement partnership are emergent with promising yet limited examples in empirical literature.