bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterizing the lack of diversity in musculoskeletal urgent care website content
Authors: Dlott Chloe C. , Metcalfe Tanner , Bahel Anchal , Jain Sanjana , Donnelley Claire A. , Kayani Jehanzeb , Wiznia Daniel H.
Published: March 2023

Background

Musculoskeletal urgent care centers (MUCCs) are becoming an alternative to emergency departments for non-emergent orthopedic injuries as they can provide direct access to orthopedic specialty care. However, they tend to be located in more affluent geographies and are less likely to accept Medicaid insurance than general urgent care centers. MUCCs utilize websites to drive patients to their centers, and the content may influence patients’ consumer behaviors and perceptions of the quality and accessibility of the MUCCs. Given that some MUCCs target insured patient populations, we evaluated the racial, gender, and body type diversity of website content for MUCCs.

Methods

Our group conducted an online search to create a list of MUCCs in the United States. For each MUCC, we analyzed the content featured prominently on the website (above the fold). For each website, we analyzed the race, gender, and body type of the featured model(s). MUCCs were classified according to their affiliation (i.e. academic versus private) and region (i.e. Northeast versus South). We performed chi-squared and univariate logistic regression to investigate trends in MUCC website content.

Results

We found that 14% (32/235) of website graphics featured individuals from multiple racial groups, 57% (135/235) of graphics featured women, and 2% (5/235) of graphics featured overweight or obese individuals. Multiracial presence in website graphics was associated with the presence of women on the websites and Medicaid acceptance.

Conclusion

MUCC website content has the potential to impact patients’ perceptions of medical providers and the medical care they receive. Most MUCC websites lack diversity based on race and body type. The lack of diversity in website content at MUCCs may introduce further disparities in access to orthopedic care.
Pregnancy-related sensory deficits might impair foraging in echolocating bats
Authors: Taub Mor , Mazar Omer , Yovel Yossi
Published: March 2023

Background

Reproduction entails substantial demands throughout its distinct stages. The mammalian gestation period imposes various energetic costs and movement deficits, but its effects on the sensory system are poorly understood. Bats rely heavily on active sensing, using echolocation to forage in complete darkness, or when lighting is uncertain. We examined the effects of pregnancy on bat echolocation.

Results

We show that pregnant Kuhl’s pipistrelles (Pipistrellus kuhlii) altered their echolocation and flight behavior. Specifically, pregnant bats emitted longer echolocation signals at an ~ 15% lower rate, while flying more slowly and at a lower altitude compared to post-lactating females. A sensorimotor foraging model suggests that these changes could lead to an ~ 15% reduction in hunting performance during pregnancy.

Conclusions

Sensory deficits related to pregnancy could impair foraging in echolocating bats. Our study demonstrates an additional cost of reproduction of possible relevance to other sensory modalities and organisms.
Association of diabetes mellitus and glycemic control with left ventricular function and deformation in patients after acute myocardial infarction: a 3 T cardiac magnetic resonance study
Authors: Gao Yue , Shi Rui , Li Yuan , Guo Ying-kun , Xu Hua-Yan , Shi Ke , Yang Zhi-gang
Published: March 2023

Background

Diabetes mellitus (DM) is considered a major risk factor for myocardial infarction (MI), and MI patients with DM have a poor prognosis. Accordingly, we aimed to investigate the additive effects of DM on LV deformation in patients after acute MI.

Materials and methods

One hundred thirteen MI patients without DM [MI (DM−)], 95 with DM [MI (DM+)] and 71 control subjects who underwent CMRscanning were included. LV function, infarct size and LV global peak strains in the radial, circumferential and longitudinal directions were measured. MI (DM+) patients were divided into two subgroups based on the HbA1c level (< 7.0% and ≥ 7.0%). The determinants of reduced LV global myocardial strain for all MI patients and MI (DM+) patients were assessed using multivariable linear regression analyses.

Results

Compared with control subjects, both MI (DM−) and MI (DM+) patients presented higher LV end-diastolic and end-systolic volume index and lower LV ejection fraction. LV global peak strains progressively declined from the control group to the MI(DM−) group to the MI(DM+) group (all p < 0.05). Subgroup analysis showed that LV global radial PS and longitudinal PS were worse in MI(MD+) patients with poor glycemic control than in those with good glycemic control (all p < 0.05). DM was an independent determinant of impaired LV global peak strain in radial, circumferential and longitudinal directions in patients after acute MI (β = − 0.166, 0.164 and 0.262, both p < 0.05). The HbA1c level was independently associated with a decreased LV global radial PS (β =  − 0.209, p = 0.025) and longitudinal PS (β = 0.221, p = 0.010) in MI (DM+) patients.

Conclusions

DM has an additive deleterious effect on LV function and deformation in patients after acute MI, and HbA1c was independently associated with impaired LV myocardial strain.
Prognostic implication of stress hyperglycemia in patients with acute coronary syndrome undergoing percutaneous coronary intervention
Authors: Wang Man , Su Wen , Cao Ning , Chen Hui , Li Hongwei
Published: March 2023

Background

It is now understood that stress hyperglycemia is associated with adverse outcomes in hospitalized patients. Herein, we aimed to investigate the association between stress hyperglycemia and mortality risk in acute coronary syndrome (ACS) patients who underwent percutaneous coronary intervention (PCI).

Methods

This cohort study comprised 5190 ACS patients who underwent PCI from the Cardiovascular Center Beijing Friendship Hospital Database Bank (CBDBANK) from January 2013 to January 2021. Stress hyperglycemia was defined by the glucose/glycated albumin (GA) ratio, calculated as admission fasting plasma glucose divided by GA. The patients were divided into four groups according to glucose/GA ratio quartiles (Q1-Q4). Cox proportional hazards regression and restricted cubic spline were used to evaluate the association between glucose/GA ratio and all-cause and cardiovascular mortality.

Results

During a median follow-up of 4.0 years, the number of all-cause deaths was 313 (6.0%) and cardiovascular-associated deaths was 177 (3.4%). After adjustment for potential confounders, the risk of all-cause mortality increased in the lowest (HR, 1.43; 95% CI, 1.01–2.03) and highest (HR, 1.51; 95% CI, 1.03–2.21) glucose/GA ratio quartiles compared to Q2. The restricted cubic splines showed that the association between glucose/GA ratio and all-cause mortality was U-shaped after full adjustment (Pnonlinear = 0.008). Similar results were observed for cardiovascular mortality. In subgroup analyses according to diabetes status, the U-shaped relationship was only significant in patients with diabetes mellitus.

Conclusion

In ACS patients undergoing PCI, low and high glucose/GA ratio values were associated with an increased all-cause and cardiovascular mortality, especially in those with diabetes mellitus.
NEDD8 promotes radioresistance via triggering autophagy formation and serves as a novel prognostic marker in oral squamous cell carcinoma
Authors: Yuan Tsu-Zong , Lin Hui-Yu , Kuei Chia-Hao , Lin Che-Hsuan , Lee Hsun-Hua , Lee Hsin-Lun , Lu Hsiao-Wei , Su Chia-Yi , Chiu Hui-Wen , Lin Yuan-Feng
Published: March 2023

Background

Radiotherapy is the first-line regimen for treating oral squamous cell carcinoma (OSCC) in current clinics. However, the development of therapeutic resistance impacts the anticancer efficacy of irradiation in a subpopulation of OSCC patients. As a result, discovering a valuable biomarker to predict radiotherapeutic effectiveness and uncovering the molecular mechanism for radioresistance are clinical issues in OSCC.

Methods

Three OSCC cohorts from The Cancer Genome Atlas (TCGA), GSE42743 dataset and Taipei Medical University Biobank were enrolled to examine the transcriptional levels and prognostic significance of neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8). Gene set enrichment analysis (GSEA) was utilized to predict the critical pathways underlying radioresistance in OSCC. The colony-forming assay was used to estimate the consequences of irradiation sensitivity after the inhibition or activation of the NEDD8-autophagy axis in OSCC cells.

Results

NEDD8 upregulation was extensively found in primary tumors compared to normal adjacent tissues and potentially served as a predictive marker for the therapeutic effectiveness of irradiation in OSCC patients. NEDD8 knockdown enhanced radiosensitivity but NEDD8 overexpression reduced it in OSCC cell lines. The inclusion of MLN4924, a pharmaceutical inhibitor for NEDD8-activating enzyme, dose-dependently restored the cellular sensitivity to irradiation treatment in irradiation-insensitive OSCC cells. Computational simulation by GSEA software and cell-based analyses revealed that NEDD8 upregulation suppresses Akt/mTOR activity to initiate autophagy formation and ultimately confers radioresistance to OSCC cells.

Conclusion

These findings not only identify NEDD8 as a valuable biomarker to predict the efficacy of irradiation but also offer a novel strategy to overcome radioresistance via targeting NEDD8-mediated protein neddylation in OSCC.
Gaps in research and capacity development for malaria surveillance and response in the Asia–Pacific: meeting report
Authors: Sirimatayanant Massaya , Hein Phone Si , Anderson Laura Fay , Montoya Lucía Fernández , Potter Rebecca , Nghipumbwa Mwalenga , Ranaweera Prasad , Ngor Pengby , Phetsouvanh Rattanaxay , Maude Richard J.
Published: March 2023

Background

This report is based on the 2021 annual meeting of the Asia–Pacific Malaria Elimination Network Surveillance and Response Working Group held online on November 1–3, 2021. In light of the 2030 regional malaria elimination goal, there is an urgency for Asia–Pacific countries to accelerate progress towards national elimination and prevent re-establishment. The Asia Pacific Malaria Elimination Network (APMEN) Surveillance Response Working Group (SRWG) supports elimination goals of national malaria control programmes (NMCPs) by expanding the knowledge base, guiding the region-specific operational research agenda and addressing evidence gaps to improve surveillance and response activities.

Methods

An online annual meeting was hosted from 1 to 3 November 2021, to reflect on research needed to support malaria elimination in the region, challenges with malaria data quality and integration, current surveillance-related technical tools, and training needs of NMCPs to support surveillance and response activities. Facilitator-led breakout groups were held during meeting sessions to encourage discussion and share experience. A list of identified research priorities was voted on by attendees and non-attending NMCP APMEN contacts.

Findings

127 participants from 13 country partners and 44 partner institutions attended the meeting, identifying strategies to address malaria transmission amongst mobile and migrant populations as the top research priority, followed by cost effective surveillance strategies in low resource settings, and integration of malaria surveillance into broader health systems. Key challenges, solutions and best practices for improving data quality and integrating epidemiology and entomology data were identified, including technical solutions to improve surveillance activities, guiding priority themes for hosting informative webinars, training workshops and technical support initiatives. Inter-regional partnerships and SRWG-led training plans were developed in consultation with members to be launched from 2022 onwards.

Conclusion

The 2021 SRWG annual meeting provided an opportunity for regional stakeholders, both NMCPs and APMEN partner institutions, to highlight remaining challenges and barriers and identify research priorities pertaining to surveillance and response in the region, and advocate for strengthening capacity through training and supportive partnerships.
Neoehrlichia mikurensis in Danish immunocompromised patients: a retrospective cohort study
Authors: Gynthersen Rosa Maja Møhring , Hansen Mette Frimodt , Ocias Lukas Frans , Kjaer Andreas , Petersen Randi Føns , Ostrowski Sisse Rye , Harritshøj Lene , Jacobsen Søren , Overgaard Ulrik , Krogfelt Karen Angeliki , Lebech Anne-Mette , Mens Helene
Published: March 2023

Background

The tick-borne bacterium, Neoehrlichia mikurensis (N. mikurensis) can cause severe febrile illness and thromboembolic complications in immunocompromised individuals. We investigated the presence of N. mikurensis DNA in retrospectively collected plasma from a well-characterized cohort of Danish immunocompromised patients.

Methods

Plasma samples from 239 patients with immune dysfunction related to hematological or rheumatological disease or due to immunosuppressive therapy, were retrieved from a transdisciplinary biobank (PERSIMUNE) at Rigshospitalet, Copenhagen, Denmark. Serving as immunocompetent controls, plasma samples from 192 blood donors were included. All samples were collected between 2015 and 2019. Real-time PCR targeting the groEL gene was used to detect N. mikurensis DNA. Sequencing was used for confirmation. Borrelia burgdorferi sensu lato IgG antibodies were detected by ELISA as a proxy of tick exposure. Prevalence was compared using Fisher’s exact test.

Results

Neoehrlichia mikurensis DNA was detected in 3/239 (1.3%, 95% confidence interval (CI): 0.3 – 3.6%) patients, all of whom primarily had a hematological disease. Follow-up samples of these patients were negative. N. mikurensis DNA was not detected in any of the blood donor samples. IgG antibodies against B. burgdorferi s.l. were detected with similar prevalence in immunocompromised patients and blood donors, i.e., 18/239 (7.5%, 95% CI: 4.8–11.5%) and 11/192 (5.7%, 95%: CI 3.2–10.0%).

Conclusion

In this study, patients with N. mikurensis were not identified by clinical indication and N. mikurensis may therefore be underdiagnosed in Danish patients. Further investigations are needed to explore the clinical significance and implications of this infection.
Analyses of familial chylomicronemia syndrome in Pereira, Colombia 2010–2020: a cross-sectional study
Authors: Rodriguez Franklin Hanna , Estrada Jorge Mario , Quintero Henry Mauricio Arenas , Nogueira Juan Patricio , Porras-Hurtado Gloria Liliana
Published: March 2023

Background and aim

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive metabolic disorder caused by mutations in genes involved in chylomicron metabolism. On the other hand, multifactorial chylomicronemia syndrome (MCS) is a polygenic disorder and the most frequent cause of chylomicronemia, which results from the presence of multiple genetic variants related to chylomicron metabolism, in addition to secondary factors. Indeed, the genetic determinants that predispose to MCS are the presence of a heterozygous rare variant or an accumulation of several SNPs (oligo/polygenic). However, their clinical, paraclinical, and molecular features are not well established in our country. The objective of this study was to describe the development and results of a screening program for severe hypertriglyceridemia in Colombia.

Methods

A cross-sectional study was performed. All patients aged >18 years with triglyceride levels ≥500 mg/dL from 2010 to 2020 were included. The program was developed in three stages: 1. Review of electronic records and identification of suspected cases based on laboratory findings (triglyceride levels ≥500 mg/dL); 2. Identification of suspected cases based on laboratory findings that also allowed us to exclude secondary factors; 3. Patients with FCS scores <8 were excluded. The remaining patients underwent molecular analysis.

Results

In total, we categorized 2415 patients as suspected clinical cases with a mean age of 53 years, of which 68% corresponded to male patients. The mean triglyceride levels were 705.37 mg/dL (standard deviation [SD] 335.9 mg/dL). After applying the FCS score, 2.4% (n = 18) of patients met the probable case definition and underwent a molecular test. Additionally, 7 patients had unique variants in the APOA5 gene (c.694 T > C; p. Ser232Pro) or in the GPIHBP1 gene (c.523G > C; p. Gly175Arg), for an apparent prevalence of familial chylomicronemia in the consulting population of 0.41 per 1.000 patients with severe HTG measurement. No previously reported pathogenic variants were detected.

Conclusion

This study describes a screening program for the detection of severe hypertriglyceridemia. Although we identified seven patients as carriers of a variant in the APOA5 gene, we diagnosed only one patient with FCS. We believe that more programs of these characteristics should be developed in our region, given the importance of early detection of this metabolic disorder.
Rheolytic thrombectomy using an AngioJet ZelanteDVT catheter or a Solent Omni catheter for patients with proximal vein thrombosis
Authors: Gong Maofeng , Fu Guanqi , Liu Zhengli , Zhou Yangyi , Kong Jie , Zhao Boxiang , Lou Wensheng , Gu Jianping , He Xu
Published: March 2023

Purpose

The present study aimed to investigate the preliminary safety and efficacy of rheolytic thrombectomy (RT) using an AngioJet Zelante DVT catheter or a Solent Omni catheter for acute proximal deep vein thrombosis (DVT).

Material and methods

We conducted a retrospective review of 40 patients who were treated with an AngioJet RT between January 2019 and January 2021, and then the patients were divided into the ZelanteDVT group (n = 17) and the Solent group (n = 23). Data on demographics, clinical characteristics, technical success, clinical success, complications, and early follow-up were analysed.

Results

No significant differences regarding demographics were detected (all p > .05). The technical success rates were both 100%. The ZelanteDVT group had a shorter duration of RT and a higher primary RT success than the Solent group (all p < .05), and the percentage of adjunctive catheter-directed thrombolysis (CDT) was 29.4% in the ZelanteDVT group, which was significantly lower than the 73.9% in the Solent group (p = .010). The clinical success rates for the ZelanteDVT group and Solent group were 100% (17/17) and 95.7% (22/23), respectively, and these values were high in the two groups (p > .05). Apart from transient macroscopic haemoglobinuria occurring in all the patients during the first 24 hours post-RT, none of the patients in either group suffered other procedure-related adverse events or major complications. Minor complications included bleeding events in 21.7% (5/23) of the patients in the Solent group and one (5.9%) patient in the ZelanteDVT group (p > .05). At 6 months, the frequency of PTS was 5.9% (1/17) in the ZelanteDVT group and 17.4% (4/23) in the Solent group (p > .05).

Conclusion

Both catheters are safe and effective in managing patients with proximal DVT, thus leading to improved clinical outcomes with few complications. The ZelanteDVT catheter was more effective than the Solent catheter in thrombectomy, thus allowing for faster extraction of the DVT with a shorter run time and lower proportions of patients with adjunctive CDT.
Evidence for continuing professional development standards for regulated health practitioners in Australia: a systematic review
Authors: Main Penelope Ann Elizabeth , Anderson Sarah
Published: March 2023

Background

Health practitioner regulators throughout the world use continuing professional development (CPD) standards to ensure that registrants maintain, improve and broaden their knowledge, expertise and competence. As the CPD standard for most regulated health professions in Australia are currently under review, it is timely that an appraisal of the evidence be undertaken.

Methods

A systematic review was conducted using major databases (including MEDLINE, EMBASE, PsycInfo, and CINAHL), search engines and grey literature for evidence published between 2015 and April 2022. Publications included in the review were assessed against the relevant CASP checklist for quantitative studies and the McMaster University checklist for qualitative studies.

Results

The search yielded 87 abstracts of which 37 full-text articles met the inclusion criteria. The evidence showed that mandatory CPD requirements are a strong motivational factor for their completion and improves practitioners’ knowledge and behaviour. CPD that is more interactive is most effective and e-learning is as effective as face-to-face CPD. There is no direct evidence to suggest the optimal quantity of CPD, although there was some evidence that complex or infrequently used skills deteriorate between 4 months to a year after training, depending on the task.

Conclusions

CPD is most effective when it is interactive, uses a variety of methods and is delivered in a sequence involving multiple exposures over a period of time that is focused on outcomes considered important by practitioners. Although there is no optimal quantity of CPD, there is evidence that complex skills may require more frequent CPD.
Women as a driver to address gaps in the global surgical workforce
Authors: Busa Isabella , Nagraj Shobhana
Published: March 2023

Five billion people around the world lack access to safe and affordable surgical, anaesthetic, and obstetric care. There is a link between countries in which women are underrepresented in the surgical workforce and those struggling to meet their surgical need. In this commentary article, the underrepresentation of women in low- and middle-income country’s (LMIC) surgical workforce is discussed. It is argued that the issue is self-reinforcing. On one hand, active change requires a sufficient number of female surgeons to initiate it. On the other, women can only start to penetrate the surgical workforce once they are safe, healthy, and motivated enough to do so, in turn depending on the presence of female surgeons to advocate for their female patients and empower future generations of young girls and women.
Constructing a novel mitochondrial-related gene signature for evaluating the tumor immune microenvironment and predicting survival in stomach adenocarcinoma
Authors: Chang Jingjia , Wu Hao , Wu Jin , Liu Ming , Zhang Wentao , Hu Yanfen , Zhang Xintong , Xu Jing , Li Li , Yu Pengfei , Zhu Jianjun
Published: March 2023

Background

The incidence and mortality of gastric cancer ranks fifth and fourth worldwide among all malignancies, respectively. Accumulating evidences have revealed the close relationship between mitochondrial dysfunction and the initiation and progression of stomach cancer. However, rare prognostic models for mitochondrial-related gene risk have been built up in stomach cancer.

Methods

In current study, the expression and prognostic value of mitochondrial-related genes in stomach adenocarcinoma (STAD) patients were systematically analyzed to establish a mitochondrial-related risk model based on available TCGA and GEO databases. The tumor microenvironment (TME), immune cell infiltration, tumor mutation burden, and drug sensitivity of gastric adenocarcinoma patients were also investigated using R language, GraphPad Prism 8 and online databases.

Results

We established a mitochondrial-related risk prognostic model including NOX4, ALDH3A2, FKBP10 and MAOA and validated its predictive power. This risk model indicated that the immune cell infiltration in high-risk group was significantly different from that in the low-risk group. Besides, the risk score was closely related to TME signature genes and immune checkpoint molecules, suggesting that the immunosuppressive tumor microenvironment might lead to poor prognosis in high-risk groups. Moreover, TIDE analysis demonstrated that combined analysis of risk score and immune score, or stromal score, or microsatellite status could more effectively predict the benefit of immunotherapy in STAD patients with different stratifications. Finally, rapamycin, PD-0325901 and dasatinib were found to be more effective for patients in the high-risk group, whereas AZD7762, CEP-701 and methotrexate were predicted to be more effective for patients in the low-risk group.

Conclusions

Our results suggest that the mitochondrial-related risk model could be a reliable prognostic biomarker for personalized treatment of STAD patients.
Identification of FCN1 as a novel macrophage infiltration-associated biomarker for diagnosis of pediatric inflammatory bowel diseases
Authors: Chen Xixi , Gao Yuanqi , Xie Jinfang , Hua Huiying , Pan Chun , Huang Jiebin , Jing Mengxia , Chen Xuehua , Xu Chundi , Gao Yujing , Li Pu
Published: March 2023

Background

The incidence of pediatric inflammatory bowel disease (PIBD) has been steadily increasing globally. Delayed diagnosis of PIBD increases the risk of complications and contributes to growth retardation. To improve long-term outcomes, there is a pressing need to identify novel markers for early diagnosis of PIBD.

Methods

The candidate biomarkers for PIBD were identified from the GSE117993 dataset by two machine learning algorithms, namely LASSO and mSVM-RFE, and externally validated in the GSE126124 dataset and our PIBD cohort. The role of ficolin-1 (FCN1) in PIBD and its association with macrophage infiltration was investigated using the CIBERSORT method and enrichment analysis of the single-cell dataset GSE121380, and further validated using immunoblotting, qRT-PCR, and immunostaining in colon biopsies from PIBD patients, a juvenile murine DSS-induced colitis model, and THP-1-derived macrophages.

Results

FCN1 showed great diagnostic performance for PIBD in an independent clinical cohort with the AUC of 0.986. FCN1 expression was upregulated in both colorectal biopsies and blood samples from PIBD patients. Functionally, FCN1 was associated with immune-related processes in the colonic mucosa of PIBD patients, and correlated with increased proinflammatory M1 macrophage infiltration. Furthermore, single-cell transcriptome analysis and immunostaining revealed that FCN1 was almost exclusively expressed in macrophages infiltrating the colonic mucosa of PIBD patients, and these FCN1+macrophages were related to hyper-inflammation. Notably, proinflammatory M1 macrophages derived from THP-1 expressed high levels of FCN1 and IL-1β, and FCN1 overexpression in THP-1-derived macrophages strongly promoted LPS-induced activation of the proinflammatory cytokine IL-1β via the NLRP3-caspase-1 axis.

Conclusions

FCN1 is a novel and promising diagnostic biomarker for PIBD. FCN1+macrophages enriched in the colonic mucosa of PIBD exhibit proinflammatory phenotypes, and FCN1 promotes IL-1β maturation in macrophages via the NLRP3-caspase-1 axis.
Tumor-targeted superantigens produce curative tumor immunity with induction of memory and demonstrated antigen spreading
Authors: Azulay Meir , Shahar Michal , Shany Eitan , Elbaz Eti , Lifshits Sveta , Törngren Marie , Friedmann Adam , Kramer Robert , Hedlund Gunnar
Published: March 2023

Background

Despite remarkable progress, the immunotherapies currently used in the clinic, such as immune checkpoint blockade (ICB) therapy, still have limited efficacy against many types of solid tumors. One major barrier to effective treatment is the lack of a durable long-term response. Tumor-targeted superantigen (TTS) therapy may overcome this barrier to enhance therapeutic efficacy. TTS proteins, such as the clinical-stage molecule naptumomab estafenatox (NAP), increase tumor recognition and killing by both coating tumor cells with bacterial-derived superantigens (SAgs) and selectively expanding T-cell lineages that can recognize them. The present study investigated the efficacy and mechanism of action of repeated TTS (C215Fab-SEA) treatments leading to a long-term antitumor immune response as monotherapy or in combination with PD-1/PD-L1 inhibitors in murine tumor models.

Methods

We used syngeneic murine tumor models expressing the human EpCAM target (C215 antigen) to assess the efficacy and mechanism of action of repeated treatment with TTS C215Fab-SEA alone or with anti-PD-1/PD-L1 monoclonal antibodies. Tumor draining lymph nodes (TDLNs) and tumor tissues were processed and analyzed by immunophenotyping and immunohistochemistry. Isolated RNA from tumors was used to analyze gene expression and the TCR repertoire. Tumor rechallenge and T-cell transfer studies were conducted to test the long-term antitumor memory response.

Results

TTS therapy inhibited tumor growth and achieved complete tumor rejection, leading to a T-cell-dependent long-term memory response against the tumor. The antitumor effect was derived from inflammatory responses converting the immunosuppressive TME into a proinflammatory state with an increase in T-cell infiltration, activation and high T-cell diversity. The combination of TTS with ICB therapy was significantly more effective than the monotherapies and resulted in higher tumor-free rates.

Conclusions

These new results indicate that TTSs not only can turn a “cold” tumor into a “hot” tumor but also can enable epitope spreading and memory response, which makes TTSs ideal candidates for combination with ICB agents and other anticancer agents.
Helicobacter pylori outer membrane vesicles induce astrocyte reactivity through nuclear factor-κappa B activation and cause neuronal damage in vivo in a murine model
Authors: Palacios Esteban , Lobos-González Lorena , Guerrero Simón , Kogan Marcelo J. , Shao Baohai , Heinecke Jay W. , Quest Andrew F. G. , Leyton Lisette , Valenzuela-Valderrama Manuel
Published: March 2023

Background

Helicobacter pylori (Hp) infects the stomach of 50% of the world’s population. Importantly, chronic infection by this bacterium correlates with the appearance of several extra-gastric pathologies, including neurodegenerative diseases. In such conditions, brain astrocytes become reactive and neurotoxic. However, it is still unclear whether this highly prevalent bacterium or the nanosized outer membrane vesicles (OMVs) they produce, can reach the brain, thus affecting neurons/astrocytes. Here, we evaluated the effects of Hp OMVs on astrocytes and neurons in vivo and in vitro.

Methods

Purified OMVs were characterized by mass spectrometry (MS/MS). Labeled OMVs were administered orally or injected into the mouse tail vein to study OMV-brain distribution. By immunofluorescence of tissue samples, we evaluated: GFAP (astrocytes), βIII tubulin (neurons), and urease (OMVs). The in vitro effect of OMVs in astrocytes was assessed by monitoring NF-κB activation, expression of reactivity markers, cytokines in astrocyte-conditioned medium (ACM), and neuronal cell viability.

Results

Urease and GroEL were prominent proteins in OMVs. Urease (OMVs) was present in the mouse brain and its detection coincided with astrocyte reactivity and neuronal damage. In vitro, OMVs induced astrocyte reactivity by increasing the intermediate filament proteins GFAP and vimentin, the plasma membrane αVβ3 integrin, and the hemichannel connexin 43. OMVs also produced neurotoxic factors and promoted the release of IFNγ in a manner dependent on the activation of the transcription factor NF-κB. Surface antigens on reactive astrocytes, as well as secreted factors in response to OMVs, were shown to inhibit neurite outgrowth and damage neurons.

Conclusions

OMVs administered orally or injected into the mouse bloodstream reach the brain, altering astrocyte function and promoting neuronal damage in vivo. The effects of OMVs on astrocytes were confirmed in vitro and shown to be NF-κB-dependent. These findings suggest that Hp could trigger systemic effects by releasing nanosized vesicles that cross epithelial barriers and access the CNS, thus altering brain cells.
Decrease in naturally occurring antibodies against epitopes of Alzheimer’s disease (AD) risk gene products is associated with cognitive decline in AD
Authors: Gu Dongmei , Wang Luchun , Zhang Nan , Wang Huali , Yu Xin
Published: March 2023

Background

Naturally occurring antibodies (NAbs) are germline-encoded immunoglobulins that can bind to and clear out self-neo-epitopes as well as apoptotic and necrotic cells. However, NAbs pathological relevance in Alzheimer’s disease (AD) is not well-understood.

Methods

Twenty-eight candidate proteins encoded by AD-associated genes were selected for this study based on a number of selection criteria, including preferential expression in the brain and B-lymphocyte cells. The levels of NAbs in plasma were analyzed according to their epitopes in age- and gender-matched cognitively normal subjects (CN, n = 56), subjects with mild cognitive impairment (MCI, n = 16) and subjects with AD (n = 56). We aimed to study the levels of their NAbs in plasma and their associations with cognitive decline in individuals with AD.

Results

Of the 28 antigens tested, 17 showed decreased NAbs in individuals with AD; in particular, NAb-TREM2 had an area under the ROC curve of 0.806, with the highest sensitivity (0.370) at 95% specificity among all 28 tests. Further protein–protein interaction networks and functional enrichment analysis suggested that target genes were enriched in AD-related pathological processes classified under “Alzheimer’s disease”, “neurodegenerative disease” and “amyloidosis”. The “Alzheimer’s disease” and “neurodegenerative disease” clusters, which converged on the initial “recognition” step of microglial phagocytosis, showed the best diagnostic performance for AD.

Conclusions

This study suggests a decline in the function of the adaptive immune system in AD, and the levels of circulating NAbs are likely to serve as biomarkers for surveilling the progression of AD.
Reproductive health service utilization and associated factors among secondary school students in Harari regional state, eastern Ethiopia, 2022: a multicenter study
Authors: Sertsu Addisu , Eyeberu Addis , Bete Tilahun , Yadeta Elias , Lami Magarsa , Balcha Tegenu , Berhanu Bekelu , Alemu Ayichew , Meseret Fentahun , Mohammed Hanan , Alemu Addisu , Husen Ahmed Mohammed , Ahemed Fila , Birhanu Abdi , Gemechu Kabtamu , Debella Adera , Getachew Tamirat , Nigussie Kabtamu , Nigussie Shambel , Negash Abraham
Published: March 2023

Introduction

Reproductive health encompasses all conditions relating to the reproductive system and goes beyond simply being free from disease or infirmity. Several socioeconomic and socio-cultural factors affect reproductive health service utilization.

Objectives

To assess reproductive health service utilization and its associated factors among government secondary school students in Harari regional state, Eastern Ethiopia 2022.

Methods

A school-based cross-sectional study design was conducted among 1275 secondary school students in six randomly selected secondary schools in Harari Regional state, in eastern Ethiopia. The study participants were chosen using a simple random sampling method. Data was gathered using self-administered questionnaires, entered into Epi Data version 3.1, and exported to SPSS version 25 for cleaning and analysis. Descriptive statistics, bivariable, and multivariable logistic regression analyses were carried out to compute the frequency of each independent variable and the magnitude of the outcome variables, then to identify factors associated with the outcome variable, respectively. To declare a significant association, an adjusted odd ratio (AOR) with a 95% confidence interval and a p-value of 0.05 were used.

Results

Our finding indicated that 25.3% (95% CI:22.9, 27.7) of the secondary school students utilized reproductive health services. Being in grade 11–12 (AOR = 1.67, 95% CI: 1.18, 2.38), having a history of sexually transmitted infection (AOR = 6.11, 95% CI: 2.20, 16.99), presence of a health facility nearby (AOR = 1.49, 95% CI: 1.12, 1.99), discuss voluntary counseling and testing with family (AOR = 2.73, 95% CI: 1.90, 3.94), and discussing about contraceptive with friends (AOR = 1.22, 95% CI: 0.91, 1.65) were the elements that had a strong correlation with reproductive health service utilization.

Conclusion

In this study, only one-fourth of secondary school students utilized RH service during the past year. The student's educational level, having a history of STI, the presence of a health facility nearby, and discussing RH service with family/friends were the factors significantly associated with reproductive service utilization among secondary school students.
Nab-paclitaxel and gemcitabine plus camrelizumab and radiotherapy versus nab-paclitaxel and gemcitabine alone for locally advanced pancreatic adenocarcinoma: a prospective cohort study
Authors: Chen Shuling , Li Jiaxin , Dong Aoran , Liu Zelong , Zhu Meiyan , Jin Meng , Wei Guangyan , Wu Shuang , Wang Yan , Chen Yong , Peng Zhenwei
Published: March 2023

Treatment options specifically for patients with locally advanced pancreatic adenocarcinoma (LAPC) are scare and chemotherapy alone delivers limited efficacy. Immunotherapy and radiotherapy are potential effective treatments for LAPC, and both of them may synergize with chemotherapy. Therefore, in this prospective cohort study, we compared the efficacy and safety of nab-paclitaxel plus gemcitabine combined with anti-programmed cell death (PD-1) immunotherapy and radiotherapy (hereafter, combination treatment) versus nab-paclitaxel plus gemcitabine (chemotherapy alone) in the treatment of LAPC. In the combination group, participants received conventional fractionated radiotherapy with doses ranging from 54 to 63 Gy in 28 fractions, intravenous camrelizumab 200 mg once every 3 weeks, and intravenous nab-paclitaxel plus gemcitabine on day 1 and 8 of a 21-day cycle for eight cycles until disease progression, death or unacceptable toxicity. In the chemotherapy group, participants received intravenous nab-paclitaxel plus gemcitabine on day 1 and 8 of a 21-day cycle for eight cycles. From April, 2020 to December, 2021, 96 participants with LAPC were prospectively enrolled with 32 received combination treatment and 64 received chemotherapy alone at a single center. The combination treatment yielded significantly longer median overall-survival (22.3 months vs. 18.6 months, P = 0.031) and progression-free survival (12.0 months vs. 10.5 months, P = 0.043) than chemotherapy alone did. And the incidence of severe adverse events was not significantly different between the combination group and chemotherapy group (P = 0.856). In conclusion, nab-paclitaxel plus gemcitabine combined with anti-PD-1 immunotherapy and radiotherapy was effective and safe for LAPC patients, and it warrants further investigation in larger randomized trials.
Validation of a modified South African triage scale in a high-resource setting: a retrospective cohort study
Authors: Markussen Dagfinn Lunde , Brevik Heidi Synnøve , Bjørneklett Rune Oskar , Engan Mette
Published: March 2023

Background

Triage systems are widely used in emergency departments, but are not always validated. The South African Triage Scale (SATS) has mainly been studied in resource-limited settings. The aim of this study was to determine the validity of a modified version of the SATS for the general population of patients admitted to an ED at a tertiary hospital in a high-income country. The secondary objective was to study the triage performance according to age and patient categories.

Methods

We conducted a retrospective cohort study of patients presenting to the Emergency Department of Haukeland University Hospital in Norway during a four-year period. We used short-term mortality, ICU admission, and the need for immediate surgery and other interventions as the primary endpoints.

Results

A total of 162,034 emergency department visits were included in the analysis. The negative predictive value of a low triage level to exclude severe illness was 99.1% (95% confidence interval: 99.0–99.2%). The level of overtriage, defined as the proportion of patients assigned to a high triage level who were not admitted to the hospital, was 4.1% (3.9–4.2%). Receiver operating characteristic (ROC) curves showed an area under the ROC for the detection of severe illness of 0.874 (95% confidence interval: 0.870–0.879) for all patients and 0.856 (0.837–0.875), 0.884 (0.878–0.890) and 0.869 (0.862–0.876) for children, adults and elderly individuals respectively.

Conclusion

We found that the modified SATS had a good sensitivity to identify short-term mortality, ICU admission, and the need for rapid surgery and other interventions. The sensitivity was higher in adults than in children and higher in medical patients than in surgical patients. The over- and undertriage rates were acceptable.
The use of pediatric short-stay observation in Italy
Authors: Pinto Luciano , Bianchini Sonia , Barbieri Maria Antonietta , Cherchi Gabriella , Miceli Andrea , Mirauda Maria Pia , Russotto Valeria Spica , Raffaldi Irene , Zangardi Tiziana , Perri Domenico , Agostiniani Rino , Rugolotto Simone , Cardinale Fabio , Zampogna Stefania , Staiano Annamaria
Published: March 2023

Background

In Italy, the State Regions Conference on 1st August 2019 approved the Guidelines for Short-Stay Observation (SSO). At the beginning of 2022, the main Scientific Societies of the pediatric hospital emergency-urgency area launched a national survey to identify the extent to which these national guidelines had been adopted in the emergency rooms and pediatric wards of the Italian Regions.

Methods

A survey has been widespread, among Pediatric Wards and Pediatric Emergency Departments (EDs), using both a paper questionnaire and a link to a database on Google Drive, for those who preferred to fill it directly online. Those who did not spontaneously answer, where directly contacted, via email and/or through a phone call and invited to participate. The data collected have been: age of managed children, presence of triage, presence of Sub-intensive Care Unit and Intensive Care Unit and special questions about Pediatric SSO, availability of training courses for workers, number of ED access in the last 4 years.

Results

This survey is still ongoing, without a definite deadline, so we presented the preliminary data.

Currently, 8/20 Regions have not yet adopted the Guidelines. Till 02 January 2023, data from 253 hospitals were collected. There are currently 180/253 active Pediatric SSO (71.03% of the Hospitals). There are not active SSO in 33.27% of first level ED, in 19.35% of second level ED and in 33.66% of General Hospitals with Pediatric Wards. Active SSO are located mainly (75.97%) within Pediatric Wards. At the moment, the survey has been completed in 16 Regions: in the 8 Regions which are using guidelines, pediatric SSOs are active in all the second level ED (compared to 60.87% of the other 8 regions), in the 91.66% of first level ED (compared to the 33.3%), and in the 97.1% of General Hospitals (compared to 33.3%), with a statistically significance (p < 0.0001).

The territorial analysis of these 16 regions highlighted geographical differences in the percentage of SSOs active: 35.22% are active in hospitals in Southern Italy, 88.64% in Central Italy and 91.67% in those of the North.

Conclusions

The delay in adopting specific guidelines negatively influences activation of pediatric SSOs in hospital system and prevents the adjustment of welfare level to new needs. To facilitate the activation of SSOs in hospitals, it is also necessary to guarantee adequate economic recognition. It is essential to implement public interventions to overcome the current inequalities in the interest of children and their families: the current delay seriously penalizes emergency pediatric hospital care, especially in the southern Italian Regions.
A structured diagnostic algorithm for patients with ARDS
Authors: Bos Lieuwe Durk Jacobus , de Grooth Harm Jan , Tuinman Pieter Roel
Published: March 2023

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2023. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2023. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901.
Effect of total cholesterol and statin therapy on mortality in ARDS patients: a secondary analysis of the SAILS and HARP-2 trials
Authors: Pienkos Shaun M. , Moore Andrew R. , Guan Jiazhen , Levitt Joseph E. , Matthay Michael A. , Baron Rebecca M. , Conlon John , McAuley Daniel F. , O’Kane Cecilia M. , Rogers Angela J.
Published: March 2023

Background

Two acute respiratory distress syndrome (ARDS) trials showed no benefit for statin therapy, though secondary analyses suggest inflammatory subphenotypes may have a differential response to simvastatin. Statin medications decrease cholesterol levels, and low cholesterol has been associated with increased mortality in critical illness. We hypothesized that patients with ARDS and sepsis with low cholesterol could be harmed by statins.

Methods

Secondary analysis of patients with ARDS and sepsis from two multicenter trials. We measured total cholesterol from frozen plasma samples obtained at enrollment in Statins for Acutely Injured Lungs from Sepsis (SAILS) and Simvastatin in the Acute Respiratory Distress Syndrome (HARP-2) trials, which randomized subjects with ARDS to rosuvastatin versus placebo and simvastatin versus placebo, respectively, for up to 28 days. We compared the lowest cholesterol quartile (< 69 mg/dL in SAILS, < 44 mg/dL in HARP-2) versus all other quartiles for association with 60-day mortality and medication effect. Fisher’s exact test, logistic regression, and Cox Proportional Hazards were used to assess mortality.

Results

There were 678 subjects with cholesterol measured in SAILS and 509 subjects in HARP-2, of whom 384 had sepsis. Median cholesterol at enrollment was 97 mg/dL in both SAILS and HARP-2. Low cholesterol was associated with higher APACHE III and shock prevalence in SAILS, and higher Sequential Organ Failure Assessment score and vasopressor use in HARP-2. Importantly, the effect of statins differed in these trials. In SAILS, patients with low cholesterol who received rosuvastatin were more likely to die (odds ratio (OR) 2.23, 95% confidence interval (95% CI) 1.06–4.77, p = 0.02; interaction p = 0.02). In contrast, in HARP-2, low cholesterol patients had lower mortality if randomized to simvastatin, though this did not reach statistical significance in the smaller cohort (OR 0.44, 95% CI 0.17–1.07, p = 0.06; interaction p = 0.22).

Conclusions

Cholesterol levels are low in two cohorts with sepsis-related ARDS, and those in the lowest cholesterol quartile are sicker. Despite the very low levels of cholesterol, simvastatin therapy seems safe and may reduce mortality in this group, though rosuvastatin was associated with harm.

Graphical abstract