bluuebunny/crossref_metadata_2025 huggingface dataset:
Are pregnancy outcomes affected by the lack of legal status? A demographic study based on 850,288 live births in Switzerland
Authors: Montagnoli Caterina , Wanner Philippe
Published: August 2023

Background

In the context of increased global mobility, it is fundamental to understand migrants’ needs and how governments can ensure equal health opportunities for both regular and irregular migrants simply by applying low-cost primary health care measures. To identify health issues in which to intervene, this study analysed the impact of a mother’s lack of legal status, together with available biological and socioeconomic characteristics, on four indicators of adverse perinatal outcomes in Switzerland.

Methods

Based on the exhaustive records of the Swiss Federal Statistical Office (FSO) for its Vital Statistics (BEVNAT), different indicators of birth outcomes, including preterm birth (PTB), low and very low birth weight (LBW and VLBW), and small for gestational age (SGA), were analysed using logistic regressions on live births occurring from 2005 to 2018. These four adverse outcomes were defined as dependent variables. Statistical analysis was performed using the statistical package STATA, version 17.

Results

Selected pregnancy outcomes were conversely affected by an irregular legal status. Analysis run on the final sample showed that, compared to the neonates of mothers who are non-migrant legal residents in Switzerland, newborns of irregular migrants have higher risks of PTB (aOR 1.18 95% CI [1.05-1.32], p<0.01) and VLBW (aOR 1.43 [1.13-1.81], p < 0.01]). In contrast, we observed that in both irregular and regular migrant groups, the odds of SGA were lowered (aOR .76 [.68-.85] p<0.01) and aOR
.93 [.91-.94], p< 0.01, respectively). A similar effect was observed when controlling for any adverse outcome (any AOs) (aOR  .90 [.83-.99] p 0.022; and aOR .93 [.91-.94] p< 0.01, respectively).

Conclusions

Our results, together with those from the available literature, call for a more comprehensive assessment of all pregnancy outcomes as well as of the social determinants of health for which the analysis was adjusted. Given the complexity of the migration phenomenon, future studies should account for local structural restrictions in the organization of care, the extension of a person’s network as a means of health care accessibility, diverse backgrounds and cultures and the recent arrival status of migrants. This would allow researchers to understand the long-term impact of social determinants of health on the wellbeing of a mother and child and take them into account in the adoption of health policies.
Causal association between gut microbiota and intrahepatic cholestasis of pregnancy: mendelian randomization study
Authors: Li Chuang , Li Na , Liu Caixia , Yin Shaowei
Published: August 2023

Background

Previous observational cohort studies have shown that the composition of the gut microbiota is related to the risk of intrahepatic cholestasis of pregnancy (ICP), although it is unclear if the association is causative. This study used Mendelian randomization (MR) to systematically examine whether the gut microbiota was causally linked to ICP.

Methods

We obtained the genome-wide association study (GWAS) summary statistics of gut microbiota and ICP from published GWASs. Maximum likelihood (ML), MR-Egger regression, weighted median, inverse variance weighted (IVW), and weighted model were used to investigate the causal association between gut microbiota and ICP. We further conducted a series of sensitivity analyses to confirm the robustness of the primary results of the MR analyses. Reverse MR analysis was performed on the bacterial taxa that were reported to be causally linked to ICP risk in forwarding MR analysis to evaluate the possibility of reverse causation.

Results

MR analysis revealed that phylum Tenericutes (OR: 1.670, 95%CI: 1.073–2.598, P = 0.023), class Bacteroidia (OR: 1.644, 95%CI: 1.031–2.622, P = 0.037), class Mollicutes (OR: 1.670, 95%CI: 1.073–2.598, P = 0.023), and order Bacteroidales (OR: 1.644, 95%CI: 1.031–2.622, P = 0.037), and were positively associated with the risk of ICP. And we identified that the relative abundance of genus Dialister (OR: 0.562, 95%CI: 0.323–0.977, P = 0.041), genus Erysipelatoclostridium (OR: 0.695, 95%CI: 0.490–0.987, P = 0.042), genus Eubacterium (brachy group) (OR: 0.661, 95%CI: 0.497–0.880, P = 0.005), genus Eubacterium (hallii group) (OR: 0.664, 95%CI: 0.451–0.977, P = 0.037), genus Holdemania (OR: 0.590, 95%CI: 0.414–0.840, P = 0.003), genus Ruminococcus (torques group) (OR: 0.448, 95%CI: 0.235–0.854, P = 0.015), and genus Veillonella (OR: 0.513, 95%CI: 0.294–0.893, P = 0.018) were related to a lower risk of ICP. Additional sensitivity analyses confirmed the robustness of the association between specific gut microbiota composition and ICP. No evidence of reverse causality from ICP to identified bacterial taxa was found in the findings of the reverse MR analyses.

Conclusions

Under MR assumptions, our findings propose new evidence of the relationship between gut microbiota and ICP risk. Our results show that the gut microbiota may be useful target of intervention for ICP.
Construction and validation of an immune infiltration-related risk model for predicting prognosis and immunotherapy response in low grade glioma
Authors: Li Jinna , Guo Qing , Xing Rui
Published: August 2023

Background

Low grade glioma (LGG) is considered a heterogeneous tumor with highly variable survival and limited efficacy of immunotherapy. To identify high-risk subsets and apply immunotherapy effectively in LGG, the status and function of immune infiltration in the glioma microenvironment must be explored.

Methods

Four independent glioma cohorts comprising 1,853 patients were enrolled for bioinformatics analysis. We used ConsensusClusterPlus to cluster patients into four different immune subtypes based on immune infiltration. The immune-infiltration signature (IIS) was constructed by LASSO regression analysis. Somatic mutation and copy number variation (CNV) analyses were performed to explore genomic and transcriptomic traits in the high- and low- risk groups. The correlation between response to programmed cell death 1 (PD-1) blockade and the IIS risk score was confirmed in an in vivo glioma model.

Results

Patients were clustered into four different immune subtypes based on immune infiltration, and the high immune infiltration subtype was associated with worse survival in LGG. The high immune infiltration subtype had stronger inflammatory response, immune response and immune cell chemotaxis. The IIS, consisting of EMP3, IQGAP2, METTL7B, SLC1A6 and TNFRSF11B, could predict LGG malignant progression, which was validated with internal clinical samples. M2 macrophage infiltration positively correlated with the IIS risk score. The high-risk group had significantly more somatic mutations and CNVs. The IIS risk score was related to immunomodulatory molecules and could predict immunotherapy clinical benefit. In vivo, immunotherapy-sensitive glioma model exhibited higher IIS risk score and more infiltration of immune cells, especially M2 macrophages. The IIS risk score was decreased in an immunotherapy-sensitive glioma model after anti-PD1 immunotherapy.

Conclusion

Different immune subtypes of LGG had unique immune cell infiltration characteristics, and the high immune infiltration subtype was associated with immunosuppressive signaling pathways. A novel IIS prognostic model based on immune infiltration status was constructed for immunophenotypic classification, risk stratification, prognostication and immunotherapy response prediction in LGG.
Large cameral coronary artery fistula in a 5 months old infant with unusual presentation and fatal outcome: -case report
Authors: Moges Tamirat , Ahmed Hayat , Gisila Azmeraw
Published: August 2023

Background

Congenital coronary fistulas (CAFs) are uncommon abnormalities communicating the coronary arteries with the cardiac chambers or portion of the systemic or pulmonary circulation. Over 90% of the cases drain into the right side of the heart with only 3% terminating in the left ventricle. Infants with a large CAFs may develop congestive heart failure.

Case presentation

A 5 months old female infant presented with labored breathing and worsening of bluish discoloration of the lips and extremities following a prolonged cry. She had a history of breastfeeding difficulty and noticeable bluish discoloration of the lips and extremities since birth. The infant was wasted and had a fast heart rate, bluish lips, and nail beds with clubbing of fingers and toes. A cardiac murmur was noted during her medical checkup. Chest x-ray showed cardiomegaly. Echocardiography and CT angiography showed large Cameral CAF involving the left main and left anterior descending artery draining into the left ventricle. The tricuspid valve was dysplastic, there was secundum ASD, and VSD with a right to left shunt. The patient developed episode of cyanotic spells after crying excessively following a CT angiographic procedure which culminated in respiratory arrest and her demise. She was managed as a case of hypoxic spells in the ICU before her death.

Conclusion

This report unveiled unfamiliar case of Cameral coronary artery fistula with left-to-left shunting, cyanosis, and dysplastic tricuspid valve.
Elevated leukotriene B4 and 8-isoprostane in exhaled breath condensate from preterm-born infants
Authors: Urs Rhea , Ni Chin Rubi , Hemy Naomi , Wilson Andrew C. , Pillow J. Jane , Hall Graham L. , Simpson Shannon J.
Published: August 2023

Background

Inflammation and oxidative stress play a key role in the development of bronchopulmonary dysplasia (BPD), possibly contributing to persistent respiratory morbidity after preterm birth. We aimed to assess if inflammatory markers were elevated in exhaled breath condensate (EBC) of infants born very prematurely (< 32 weeks gestation) at 12–16 corrected months of age, and if increased levels were associated with BPD diagnosis and respiratory morbidity.

Methods

EBC samples and respiratory questionnaires were collected from 15 term-born infants and 33 preterm-born infants, 12 with a neonatal BPD diagnosis. EBC samples were analysed for leukotriene B4 (inflammation) and 8-isoprostane (oxidative stress) concentrations using enzyme-linked immune-assays. Differences between groups were analysed by Kruskal-Wallis Test with post-hoc comparisons, independent samples t-test or Mann-Whitney U test depending on normality of the data.

Results

Leukotriene B4 and 8-isoprostane levels were elevated in exhaled breath condensate of preterm-born infants compared to those born at term (mean difference [95% CI]; 1.52 [0.45, 2.59], p = 0.02; 0.77 [0.52, 1.02], p < 0.001, respectively). Leukotriene B4 and 8-isoprostane levels were independent of BPD diagnosis and respiratory morbidity over the first year of life.

Conclusions

Infants born very prematurely exhibit elevated markers of airway neutrophilic inflammation and oxidative stress beyond the first year of life, regardless of a neonatal diagnosis of chronic lung disease or respiratory morbidity during infancy. These findings may have implications for future lung health.

Trial Registration

N/A.
Assessing the coverage and timeliness of coronavirus vaccination among people experiencing homelessness in Wales, UK: a population-level data-linkage study
Authors: Thomas Ian , Mackie Peter
Published: August 2023

Background

People experiencing homelessness have elevated morbidity, increasing their risk of COVID-19 related complications and mortality. Achieving high vaccination coverage in a timely manner among homeless populations was therefore important during the mass vaccination programme in Wales to limit adverse outcomes. However, no systematic monitoring of vaccinations among people experiencing homelessness in Wales has been undertaken.

Methods

Retrospective cohort analysis was conducted using de-identified administrative data. Study cohort members were adults (≥ 18 years old) living in Wales on the 2 December 2020 and who had recently experienced homelessness, defined as experiencing homelessness between 1 July 2020 and 2 December 2020. The outcome of interest was first coronavirus vaccine dose. Follow-up started on 2 December 2020, and ended if the participant died, had a break in address history > 30 days, reached the end of follow up (30 November 2021), or had the outcome of interest. Median-time-to-vaccination was used as a crude measure of ‘timeliness’ of vaccine uptake. To account for competing risk of death prior to vaccination, vaccine coverage was described using cumulative incidence at 350-days, and at 50-day increments over follow-up (2 December 2020 to 17 November 2021). As a benchmark, all time-to-event measures were generated for the adult population in Wales with similar baseline individual and residential characteristics as the study cohort.

Results

1,595 people with recent experiences of homelessness were identified and included in analysis. The study cohort were disproportionately male (68.8%) and concentrated in the most deprived areas in Wales. Median time-to-vaccination for the study cohort was 196 days (95% CI.: 184–209 days), compared to 141 days (95% CI.: 141–141 days) among the matched adult population in Wales. Cumulative incidence of vaccination after 350-days of follow-up was 60.4% (95% CI.: 57.8–62.8%) among the study cohort, compared to 81.4% (95% CI.: 81.3–81.5%) among the matched adult population. Visual analysis of cumulative incidence over time suggests that vaccine inequality, i.e., difference between study cohort and matched adult population, peaked after 200-days of follow-up, and declined slightly until last follow-up at 350-days.

Conclusions

Despite being prioritised for vaccination, people experiencing homelessness in Wales appear to have been under-engaged, leading to lower vaccination coverage and greater time unvaccinated, potentially increasing their risk of COVID-19 complications and mortality.
RETRACTED ARTICLE: The effects of intermittent bolus paravertebral block on analgesia and recovery in open hepatectomy: a randomized, double-blinded, controlled study
Authors: Wang Jin , Cui Xulei , Zhang Yuelun , Sang Xinting , Shen Le
Published: August 2023

Background

We aimed to investigate the effects of intermittent bolus paravertebral block on analgesia and recovery in open hepatectomy.

Methods

Eighty 18–70 years old, American Society of Anesthesiologists level I-III patients scheduled for hepatectomy with a J-shaped subcostal incision were enrolled and randomized to receive either intermittent bolus paravertebral ropivacaine (0.5% loading, 0.2% infusion) or 0.9% saline infusion at 1:1 ratio (25 ml loading before surgery, 0.125 ml/kg/h bolus for postoperative 48 h). The primary outcome was set as postoperative 48 h cumulative intravenous morphine consumption recorded by a patient-controlled analgesic pump.

Results

Thirty-eight patients in each group completed the study. The cumulative morphine consumptions were lower in the paravertebral block than control group at postoperative 24 (difference -10.5 mg, 95%CI -16 mg to -6 mg, P < 0.001) and 48 (difference -12 mg, 95%CI -19.5 mg to -5 mg, P = 0.001) hours. The pain numerical rating scales at rest were lower in the paravertebral block than control group at postoperative 4 h (difference -2, 95%CI -3 to -1, P < 0.001). The active pain numerical rating scales were lower in the paravertebral block than control group at postoperative 12 h (difference -1, 95%CI -2 to 0, P = 0.005). Three months postoperatively, the paravertebral block group had lower rates of hypoesthesia (OR 0.28, 95%CI 0.11 to 0.75, P = 0.009) and numbness (OR 0.26, 95%CI 0.07 to 0.88, P = 0.024) than the control group.

Conclusions

Intermittent bolus paravertebral block provided an opioid-sparing effect and enhanced recovery both in hospital and after discharge in patients undergoing hepatectomy.

Trial registration

clinicaltrials.gov (NCT04304274), date: 11/03/2020.
An unusual case of linear IgA disease affecting only the oral gingiva: a case report
Authors: He Jianing , Shen Jun , Guo Wei
Published: August 2023

Background

We present a case report on desquamative gingivitis diagnosed as linear IgA disease (LAD), which is a rare autoimmune bullous disease exclusively affecting the oral gingiva. The oral mucosa can be impacted by various autoimmune bullous diseases, and our report focuses on this particular manifestation of LAD.

Case presentation

This patient presented with atypical symptoms, as frequent blister formation on the gingiva was the primary clinical manifestation. A combination of systemic and local treatment was administered to the patient. Following the treatment, there was a significant improvement observed in both the erythema and the bullous lesions on the gingiva.

Conclusions

A more suitable local treatment strategy should be formulated for patients presenting with oral topical lesions, which clinicians can employ effectively.
Vitamin D and vitamin D receptor polymorphism in Asian adolescents with primary dysmenorrhea
Authors: Donayeva Ainur , Amanzholkyzy Ainur , Nurgaliyeva Roza , Gubasheva Gulnara , Saparbayev Samat , Ayaganov Dinmukhamed , Kaldybayeva Aiman , Abdelazim Ibrahim A. , Farghali Mohamed M.
Published: August 2023

Background

The expression of vitamin D receptor in the normal endometrium and ovaries supports the role of vitamin D in local immunity and inflammatory cytokines regulation.

Objective

This study aimed to detect the relation between serum 25(OH)D and primary dysmenorrhea in Asian Adolescents.

Methods

Two hundred and five (205) adolescents complaining of primary dysmenorrhea (study group) were compared in this prospective study to matched controls (210 controls) after informed consent following the Helsinki Declaration.

After thorough evaluation, including a thorough history and pelvic ultrasound examination, blood samples were collected from the studied adolescents to measure serum 25(OH)D and for vitamin D receptor TaqI (rs731236) genotyping.

The studied adolescents’ data were analyzed using the Pearson’s correlation to detect the relation between serum 25(OH)D and primary dysmenorrhea (primary outcome). The secondary outcome measures the odds of primary dysmenorrhea in Asian adolescents with vitamin D receptor TaqI (rs731236) polymorphism.

Results

The serum 25(OH)D was significantly lower in the studied-dysmenorrhea group compared to controls (16.17 ± 7.36 versus 17.65 ± 6.36 ng/ml, respectively), (P = 0.01). The correlation analysis showed a significant negative correlation between the serum 25(OH)D and visual analogue scale of dysmenorrhea (r = -0.9003, P < 0.0001).

The studied-dysmenorrhea cases with vitamin D receptor T/t and t/t genotypes had significantly lower serum 25(OH)D (16.7 ± 8.05 and 14.4 ± 4.1 ng/ml, respectively) compared to controls (18.97 ± 6.7 and 21.4 ± 2.45 ng/ml, respectively), (P = 0.02 and 0.004, respectively).

The VDR T/t and t/t polymorphisms significantly increase the odds of primary dysmenorrhea (OR 1367.2, P < 0.0001 and OR 106.2, P = 0.001, respectively).

Conclusion

The serum 25(OH)D was significantly lower in the studied-dysmenorrhea group compared to controls. The studied-dysmenorrhea cases with VDR T/t and t/t TaqI genotypes had significantly lower serum 25(OH)D compared to controls. The VDR T/t and t/t polymorphisms significantly increase the odds of primary dysmenorrhea.
Development and validation of predictive models for unplanned hospitalization in the Basque Country: analyzing the variability of non-deterministic algorithms
Authors: Olza Alexander , Millán Eduardo , Rodríguez-Álvarez María Xosé
Published: August 2023

Background

The progressive ageing in developed countries entails an increase in multimorbidity. Population-wide predictive models for adverse health outcomes are crucial to address these growing healthcare needs. The main objective of this study is to develop and validate a population-based prognostic model to predict the probability of unplanned hospitalization in the Basque Country, through comparing the performance of a logistic regression model and three families of machine learning models.

Methods

Using age, sex, diagnoses and drug prescriptions previously transformed by the Johns Hopkins Adjusted Clinical Groups (ACG) System, we predict the probability of unplanned hospitalization in the Basque Country (2.2 million inhabitants) using several techniques. When dealing with non-deterministic algorithms, comparing a single model per technique is not enough to choose the best approach. Thus, we conduct 40 experiments per family of models - Random Forest, Gradient Boosting Decision Trees and Multilayer Perceptrons - and compare them to Logistic Regression. Models’ performance are compared both population-wide and for the 20,000 patients with the highest predicted probabilities, as a hypothetical high-risk group to intervene on.

Results

The best-performing technique is Multilayer Perceptron, followed by Gradient Boosting Decision Trees, Logistic Regression and Random Forest. Multilayer Perceptrons also have the lowest variability, around an order of magnitude less than Random Forests. Median area under the ROC curve, average precision and positive predictive value range from 0.789 to 0.802, 0.237 to 0.257 and 0.485 to 0.511, respectively. For Brier Score the median values are 0.048 for all techniques. There is some overlap between the algorithms. For instance, Gradient Boosting Decision Trees perform better than Logistic Regression more than 75% of the time, but not always.

Conclusions

All models have good global performance. The only family that is consistently superior to Logistic Regression is Multilayer Perceptron, showing a very reliable performance with the lowest variability.
Natural killer cell-derived exosomes for cancer immunotherapy: innovative therapeutics art
Authors: Hatami Zahra , Hashemi Zahra Sadat , Eftekhary Mohamad , Amiri Ala , Karpisheh Vahid , Nasrollahi Kaveh , Jafari Reza
Published: August 2023

Chimeric antigen receptor natural killer cells (CAR-NK) promote off-the-shelf cellular therapy for solid tumors and malignancy.However,, the development of CAR-NK is due to their immune surveillance uncertainty and cytotoxicity challenge was restricted. Natural killer cell-derived exosome (NK-Exo) combine crucial targeted cellular therapies of NK cell therapies with unique non-toxic Exo as a self-origin shuttle against cancer immunotherapy. This review study covers cytokines, adoptive (autologous and allogenic) NK immunotherapy, stimulatory and regulatory functions, and cell-free derivatives from NK cells. The future path of NK-Exo cytotoxicity and anti-tumor activity with considering non-caspase-independent/dependent apoptosis and Fas/FasL pathway in cancer immunotherapy. Finally, the significance and implication of NK-Exo therapeutics through combination therapy and the development of emerging approaches for the purification and delivery NK-Exo to severe immune and tumor cells and tissues were discussed in detail.
Genomic variants exclusively identified in children with birth defects and concurrent malignant tumors predispose to cancer development
Authors: Liu Yichuan , Qu Hui-Qi , Chang Xiao , Mentch Frank D , Qiu Haijun , Wang Xiang , Saeidian Amir Hossein , Watson Deborah , Glessner Joseph , Hakonarson Hakon
Published: August 2023

Children with birth defects (BD) express distinct clinical features that often have various medical consequences, one of which is predisposition to the development of cancers. Identification of the underlying genetic mechanisms related to the development of cancer in BD patients would allow for preventive measures. We performed a whole genome sequencing (WGS) study on blood-derived DNA samples from 1566 individuals without chromosomal anomalies, including 454 BD probands with at least one type of malignant tumors, 767 cancer-free BD probands, and 345 healthy individuals. Exclusive recurrent variants were identified in BD-cancer and BD-only patients and mapped to their corresponding genomic regions. We observed statistically significant overlaps for protein-coding/ncRNA with exclusive variants in exons, introns, ncRNAs, and 3’UTR regions. Exclusive exonic variants, especially synonymous variants, tend to occur in prior exons locus in BD-cancer children. Intronic variants close to splicing site (< 500 bp from exon) have little overlaps in BD-cancer and BD-only patients. Exonic variants in non-coding RNA (ncRNA) tend to occur in different ncRNAs exons regardless of the overlaps. Notably, genes with 5’ UTR variants are almost mutually exclusive between the two phenotypes. In conclusion, we conducted the first genomic study to explore the impact of recurrent variants exclusive to the two distinguished clinical phenotypes under study, BD with or without cancer, demonstrating enrichment of selective protein-coding/ncRNAs differentially expressed between these two phenotypes, suggesting that selective genetic factors may underlie the molecular processes of pediatric cancer development in BD children.
Epithelial cell adhesion molecule (EpCAM) regulates HGFR signaling to promote colon cancer progression and metastasis
Authors: Lee Chi-Chiu , Yu Chia-Jui , Panda Sushree Shankar , Chen Kai-Chi , Liang Kang-Hao , Huang Wan-Chen , Wang Yu-Shiuan , Ho Pei-Chin , Wu Han-Chung
Published: August 2023

Background

Epithelial cell adhesion molecule (EpCAM) is known to highly expression and promotes cancer progression in many cancer types, including colorectal cancer. While metastasis is one of the main causes of cancer treatment failure, the involvement of EpCAM signaling in metastatic processes is unclear. We propose the potential crosstalk of EpCAM signaling with the HGFR signaling in order to govern metastatic activity in colorectal cancer.

Methods

Immunoprecipitation (IP), enzyme-linked immunosorbent assay (ELISA), and fluorescence resonance energy transfer (FRET) was conducted to explore the extracellular domain of EpCAM (EpEX) and HGFR interaction. Western blotting was taken to determine the expression of proteins in colorectal cancer (CRC) cell lines. The functions of EpEX in CRC were investigated by proliferation, migration, and invasion analysis. The combined therapy was validated via a tail vein injection method for the metastasis and orthotopic colon cancer models.

Results

This study demonstrates that the EpEX binds to HGFR and induces downstream signaling in colon cancer cells. Moreover, EpEX and HGF cooperatively mediate HGFR signaling. Furthermore, EpEX enhances the epithelial-to-mesenchymal transition and metastatic potential of colon cancer cells by activating ERK and FAK-AKT signaling pathways, and it further stabilizes active β-catenin and Snail proteins by decreasing GSK3β activity. Finally, we show that the combined treatment of an anti-EpCAM neutralizing antibody (EpAb2-6) and an HGFR inhibitor (crizotinib) significantly inhibits tumor progression and prolongs survival in metastatic and orthotopic animal models of colon cancer.

Conclusion

Our findings illuminate the molecular mechanisms underlying EpCAM signaling promotion of colon cancer metastasis, further suggesting that the combination of EpAb2-6 and crizotinib may be an effective strategy for treating cancer patients with high EpCAM expression.
The role of triple therapy and therapy sequence in treatment of BRAF-mutant metastatic melanoma. Response to overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study
Authors: Dummer Reinhard , Welti Michèle , Ramelyte Egle
Published: August 2023

Novel therapies have achieved unprecedented benefit in survival of advanced melanoma patients. While immunotherapy (ICI) can be administered independent of mutational status, BRAF and MEK kinase inhibitors represent another effective treatment option for patients with BRAF mutant melanoma. Given the benefits these therapies demonstrate, the natural instinct was to combine. Three studies have investigated the benefit of combination of ICI using anti-PD-1 or anti-PD-L1 antibody and targeted therapy (TT) with BRAF and MEK inhibitors over TT and placebo. Among these studies, statistically significantly superior duration of response was observed, however overall and progression-free survival were only numerically superior, if at all. One triple combination was approved for BRAF mutant metastatic melanoma; however, the expected synergistic effect of triple therapy could not be universally confirmed and the observed benefits with triple seem to depend on statistical considerations rather than a biological reason. As patients with BRAF mutant melanoma have both ICI and TT as their first-line treatment options, the question whether the sequence matters was addressed. Two prospective trials compared first-line ICI, followed by TT at progression, or vice-versa, with additional “sandwich” approach (8 weeks of TT followed by ICI until progression, then TT again) in the Secombit study. The benefit of first-line ICI was demonstrated in both studies with Secombit study showing the “sandwich” approach to have similar effect. Current data advices for immunotherapy based regiments in patients with BRAF mutant melanoma or, possibly, sandwich approach. Whether triple therapy is superior to ICI monotherapy still needs to be addressed considering not only efficacy, but also safety.
Lysosomal acidification dysfunction in microglia: an emerging pathogenic mechanism of neuroinflammation and neurodegeneration
Authors: Quick Joseph D. , Silva Cristian , Wong Jia Hui , Lim Kah Leong , Reynolds Richard , Barron Anna M. , Zeng Jialiu , Lo Chih Hung
Published: August 2023

Microglia are the resident innate immune cells in the brain with a major role in orchestrating immune responses. They also provide a frontline of host defense in the central nervous system (CNS) through their active phagocytic capability. Being a professional phagocyte, microglia participate in phagocytic and autophagic clearance of cellular waste and debris as well as toxic protein aggregates, which relies on optimal lysosomal acidification and function. Defective microglial lysosomal acidification leads to impaired phagocytic and autophagic functions which result in the perpetuation of neuroinflammation and progression of neurodegeneration. Reacidification of impaired lysosomes in microglia has been shown to reverse neurodegenerative pathology in Alzheimer’s disease. In this review, we summarize key factors and mechanisms contributing to lysosomal acidification impairment and the associated phagocytic and autophagic dysfunction in microglia, and how these defects contribute to neuroinflammation and neurodegeneration. We further discuss techniques to monitor lysosomal pH and therapeutic agents that can reacidify impaired lysosomes in microglia under disease conditions. Finally, we propose future directions to investigate the role of microglial lysosomal acidification in lysosome–mitochondria crosstalk and in neuron–glia interaction for more comprehensive understanding of its broader CNS physiological and pathological implications.
Prevalence of suicidal thoughts and attempts in the transgender population of the world: a systematic review and meta-analysis
Authors: Kohnepoushi Parisa , Nikouei Maziar , Cheraghi Mojtaba , Hasanabadi Parsa , Rahmani Hamza , Moradi Maryam , Moradi Ghobad , Moradpour Farhad , Moradi Yousef
Published: August 2023

Background

The aim of this meta-analysis was to determine global pooled prevalence of suicide thoughts and attempts in transgender population.

Methods

For doing comprehensive search strategy related to objectives in the presence meta-analysis, all international databases like PubMed (Medline), Scopus, Embase, Web of Sciences, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature (CINHAL) were searched from January 1990 to December 2022. The quality of the final selected studies was evaluated according to Newcastle–Ottawa Quality Assessment Scale for cross-sectional studies. The subgroup analysis was done based on type of transgender (female to male, male to female) and prevalence (point, period, and lifetime), country, and criteria of diagnosis. All analysis was done in STATA version 17.

Results

From the total number of 65 selected studies, 71 prevalence of suicidal thoughts, including point, period, and lifetime prevalence were extracted and combined. After combining these values, the prevalence of suicidal thoughts in the transgender population in the world was 39% in the past month (pooled point prevalence: 39%; 95% CI 35–43%), 45% in the past year (pooled period prevalence: 45%; % 95 CI 35–54%) and 50% during lifetime (pooled lifetime prevalence: 50%; % 95 CI 42–57%). Also, the prevalence of suicide attempt in the transgender population of the world was 16% in the past month (pooled point prevalence: 16%; 95% CI 13–19%), 11% in the past year (pooled period prevalence: 11%; % 95 CI 5–19%) and 29% during lifetime (pooled lifetime prevalence: 29%; % 95 CI 25–34%).

Conclusion

The present meta-analysis results showed the prevalence of suicidal thoughts and attempts in the transgender community was high, and more importantly, about 50% of transgenders who had suicidal thoughts, committed suicide.
Radiotherapy refusal in breast cancer with breast-conserving surgery
Authors: Liu Jiameng , Zhu Zhanlin , Hua Zhipeng , Lin Weijie , Weng Yiyin , Lin Juli , Mao Hehui , Lin Lifen , Chen Xuming , Guo Jujiang
Published: August 2023

Background

Although radiotherapy after breast-conserving surgery has been the standard treatment for breast cancer, some people still refuse to undergo radiotherapy. The aim of this study is to identify risk factors for refusal of radiotherapy after breast-conserving surgery.

Methods

To investigate the trend of refusing radiotherapy after breast-conserving surgery in patients with breast cancer using the Surveillance, Epidemiology, and End Results database. The patients were divided into radiotherapy group and radiotherapy refusal group. Survival results were compared using a multivariate Cox risk model adjusted for clinicopathological variables. Multivariate logistic regression was used to analyze the influencing factors of patients refusing radiotherapy after breast-conserving surgery and a nomogram model was established.

Results

The study included 87,100 women who underwent breast-conserving surgery for breast cancer between 2010 and 2015. There were 84,948 patients (97.5%) in the radiotherapy group and 2152 patients (2.5%) in the radiotherapy refusal group. The proportion of patients who refused radiotherapy after breast-conserving surgery increased from 2.1% in 2010 to 3.1% in 2015. The Kaplan–Meier survival curve showed that radiotherapy can improve overall survival (p < 0.001) and breast cancer specific survival (p < 0.001) in the patients with breast-conserving surgery. The results of multivariate logistic regression showed that age, income, marital status, race, grade, stage, subtype and chemotherapy were independent factors associated with the refusal of radiotherapy.

Conclusions

Postoperative radiotherapy can improve the benefits of breast-conserving surgery. Patients with old age, low income, divorce, white race, advanced stage, and no chemotherapy were more likely to refuse radiotherapy.
Laminar airflow ventilation systems in orthopaedic operating room do not prevent surgical site infections: a systematic review and meta-analysis
Authors: Ouyang Xueqian , Wang Qiaolin , Li Xiaohua , Zhang Ting , Rastogi Sanjay
Published: August 2023

Background

Laminar airflow (LAF) technologies minimize infectious microorganisms to enhance air quality and surgical site infections (SSIs). LAF lowers SSIs in some clinical studies but not others. This study analyzes laminar airflow ventilation's capacity to reduce orthopaedic surgery-related SSIs.

Methods

The PRISMA-compliant keywords were utilized to conduct a search for pertinent articles in various databases including PubMed, MEDLINE, CENTRAL, Web of Sciences, and the Cochrane databases. Observational studies, including retrospective, prospective, and cohort designs, satisfy the PICOS criteria for research methodology. The assessment of quality was conducted utilizing the Robvis software, while the meta-analysis was performed using the RevMan application. The study’s results were assessed based on effect sizes of odds ratio (OR) and risk ratio (RR).

Results

From 2000 to 2022, 10 randomized controlled clinical trials with 10,06,587 orthopaedic surgery patients met the inclusion criteria. The primary outcomes were: (1) Risk of SSI, (2) Bacterial count in sampled air and (3) Reduction in SSIs. The overall pooled OR of all included studies was 1.70 (95% CI 1.10–2.64), and the overall pooled RR was 1.27 (95% CI 1.02–1.59) with p < 0.05. LAF is ineffective at preventing SSIs in orthopaedic procedures due to its high-risk ratio and odds ratio.

Conclusions

The present meta-analysis has determined that the implementation of LAF systems does not result in a significant reduction in the incidence of surgical site infections (SSIs), bacterial count in the air, or SSIs occurrence in orthopaedic operating rooms. Consequently, the installation of said equipment in operating rooms has been found to be both expensive and inefficient.
Fibula allograft with cannulated screw fixation versus ordinary cannulated screw fixation for femoral neck fractures: a 10-year retrospective comparative study
Authors: Wei Yangwenxiang , Lin Tianye , Liu Yuhao , Chen Zhenqiu , Zhou Chi
Published: August 2023

Background

For femoral neck fractures in young and middle-aged patients, both fibula allograft with cannulated screw fixation and ordinary cannulated screw fixation are clinically effective treatments. However, for unstable femoral neck fractures, ordinary cannulated screw fixation is characterized by a high risk of postoperative complications and a high rate of mechanical failure after internal fixation. For this study, we systematically compared the long-term efficacy and postoperative complications of these two procedures.

Methods

A total of 156 subjects diagnosed as femoral neck fractures participated in our study. Subjects in the combination group underwent fibula allograft with cannulated screw fixation (n = 76), and those in the control group were treated with ordinary cannulated screw fixation (n = 80). Baseline characteristics, perioperative outcomes, Harris hip score (HHS) and EuroQoL five-dimension questionnaire (EQ-5D); and the incidence of postoperative and bone healing complications in the two groups were recorded and compared.

Results

The average follow-up time was more than 10 years. Intra-operative blood loss significantly increased in the combination group compared with the control group (P < 0.05). There were significantly improved performances in healing time, the time course of recovery of full-weight-bearing stepping, HHS and EQ-5D scores in the combination group compared with the control group (P < 0.05). Besides, the incidence rates of femoral head necrosis, nonunion, femoral neck shortening and total hip replacement were significantly lower in the combination group than those in the control group (P < 0.05).

Conclusion

Fibula allograft with cannulated screw fixation shows a better long-term therapeutic effect than ordinary cannulated screw fixation for femoral neck fractures in young and middle-aged patients. Patients receiving the combination strategy have faster and high-quality functional recovery after femoral neck fractures and a lower incidence rate of postoperative complications.
Predictors of osteoporotic fracture in postmenopausal women: a meta-analysis
Authors: Long Guanghua , Liu Chong , Liang Tuo , Zhang Zide , Qin Zhaojie , Zhan Xinli
Published: August 2023

Osteoporosis affects more than 200 million women worldwide, with postmenopausal women being particularly susceptible to this condition and its severe sequelae disproportionately, such as osteoporotic fractures. To date, the current focus has been more on symptomatic treatment, rather than preventive measures. To address this, we performed a meta-analysis aiming to identify potential predictors of osteoporotic fractures in postmenopausal women, with the ultimate goal of identifying high-risk patients and exploring potential therapeutic approaches. We searched Embase, MEDLINE and Cochrane with search terms (postmenopausal AND fracture) AND (“risk factor” OR “predictive factor”) in May 2022 for cohort and case–control studies on the predictors of osteoporotic fracture in postmenopausal women. Ten studies with 1,287,021 postmenopausal women were found eligible for analyses, in which the sample size ranged from 311 to 1,272,115. The surveyed date spanned from 1993 to 2021. Our results suggested that age, BMI, senior high school and above, parity ≥ 3, history of hypertension, history of diabetes mellitus, history of alcohol intake, age at menarche ≥ 15, age at menopause < 40, age at menopause > 50, estrogen use and vitamin D supplements were significantly associated with osteoporotic fracture in postmenopausal women. Our findings facilitate the early prediction of osteoporotic fracture in postmenopausal women and may contribute to potential therapeutic approaches. By focusing on preventive strategies and identifying high-risk individuals, we can work toward reducing the burden of osteoporosis-related fractures in this vulnerable population.
TSPAN18 facilitates bone metastasis of prostate cancer by protecting STIM1 from TRIM32-mediated ubiquitination
Authors: Zhou Qianghua , Chen Xu , Yao Kai , Zhang Yangjie , He Haixia , Huang Hao , Chen Hao , Peng Shengmeng , Huang Ming , Cheng Liang , Zhang Qiang , Xie Ruihui , Li Kaiwen , Lin Tianxin , Huang Hai
Published: August 2023

Background

Bone metastasis is a principal cause of mortality in patients with prostate cancer (PCa). Increasing evidence indicates that high expression of stromal interaction molecule 1 (STIM1)-mediated store-operated calcium entry (SOCE) significantly activates the calcium (Ca2+) signaling pathway and is involved in multiple steps of bone metastasis in PCa. However, the regulatory mechanism and target therapy of STIM1 is poorly defined.

Methods

Liquid chromatography-mass spectrometry analysis was performed to identify tetraspanin 18 (TSPAN18) as a binding protein of STIM1. Co-IP assay was carried out to explore the mechanism by which TSPAN18 inhibits STIM1 degradation. The biological function of TSPAN18 in bone metastasis of PCa was further investigated in vitro and in vivo models.

Result

We identified that STIM1 directly interacted with TSPAN18, and TSPAN18 competitively inhibited E3 ligase tripartite motif containing 32 (TRIM32)-mediated STIM1 ubiquitination and degradation, leading to increasing STIM1 protein stability. Furthermore, TSPAN18 significantly stimulated Ca2+ influx in an STIM1-dependent manner, and then markedly accelerated PCa cells migration and invasion in vitro and bone metastasis in vivo. Clinically, overexpression of TSPAN18 was positively associated with STIM1 protein expression, bone metastasis and poor prognosis in PCa.

Conclusion

Taken together, this work discovers a novel STIM1 regulative mechanism that TSPAN18 protects STIM1 from TRIM32-mediated ubiquitination, and enhances bone metastasis of PCa by activating the STIM1-Ca2+ signaling axis, suggesting that TSPAN18 may be an attractive therapeutic target for blocking bone metastasis in PCa.
Sex-related differences in adult patients with status epilepticus: a seven-year two-center observation
Authors: Baumann Sira M. , De Stefano Pia , Kliem Paulina S. C. , Grzonka Pascale , Gebhard Caroline E. , Sarbu Oana E. , De Marchis Gian Marco , Hunziker Sabina , Rüegg Stephan , Kleinschmidt Andreas , Pugin Jérôme , Quintard Hervé , Marsch Stephan , Seeck Margitta , Sutter Raoul
Published: August 2023

Background

Conflicting findings exist regarding the influence of sex on the development, treatment, course, and outcome of status epilepticus (SE). Our study aimed to investigate sex-related disparities in adult SE patients, focusing on treatment, disease course, and outcome at two Swiss academic medical centers.

Methods

In this retrospective study, patients treated for SE at two Swiss academic care centers from Basel and Geneva from 2015 to 2021 were included. Primary outcomes were return to premorbid neurologic function, death during hospital stay and at 30 days. Secondary outcomes included characteristics of treatment and disease course. Associations with primary and secondary outcomes were assessed using multivariable logistic regression. Analysis using propensity score matching was performed to account for the imbalances regarding age between men and women.

Results

Among 762 SE patients, 45.9% were women. No sex-related differences were found between men and women, except for older age and lower frequency of intracranial hemorrhages in women. Compared to men, women had a higher median age (70 vs. 66, p = 0.003), had focal nonconvulsive SE without coma more (34.9% vs. 25.5%; p = 0.005) and SE with motor symptoms less often (52.3% vs. 63.6%, p = 0.002). With longer SE duration (1 day vs. 0.5 days, p = 0.011) and a similar proportion of refractory SE compared to men (36.9% vs. 36.4%, p = 0.898), women were anesthetized and mechanically ventilated less often (30.6% vs. 42%, p = 0.001). Age was associated with all primary outcomes in the unmatched multivariable analyses, but not female sex. In contrast, propensity score-matched multivariable analyses revealed decreased odds for return to premorbid neurologic function for women independent of potential confounders. At hospital discharge, women were sent home less (29.7% vs. 43.7%, p < 0.001) and to nursing homes more often (17.1% vs. 10.0%, p = 0.004).

Conclusions

This study identified sex-related disparities in the clinical features, treatment modalities, and outcome of adult patients with SE with women being at a disadvantage, implying that sex-based factors must be considered when formulating strategies for managing SE and forecasting outcomes.
Early endovascular intervention for unfavorable remodeling of the thoracic aorta after open surgery for acute DeBakey type I aortic dissection: study protocol for a multicenter, randomized, controlled trial
Authors: Liu Yu , Li Ling , Xiao Zhenghua , Peng Liqing , Yang Peng , Lu Chen , Zhang Yu , Wang Haiyue , Hu Jia
Published: August 2023

Background

Total arch replacement with frozen elephant trunk has been developed with promising results for DeBakey type I aortic dissection. However, several problems, such as continuous perfusion of distal false lumen and unfavorable remodeling of distal aorta postoperatively, can seriously affect the long-term outcome. This trial aims to assess the effects of early minimally invasive endovascular repair on distal aortic remodeling and long-term clinical outcomes in patients with dominant false lumen and residual tears in the descending thoracic aorta after total arch replacement and frozen elephant trunk procedure.

Methods

This is a protocol for a two-arm, parallel, multicenter, randomized controlled trial. A total of 154 eligible patients will be recruited from four hospitals in China and randomized on a 1:1 basis either to the experiment group (endovascular repair in addition to routine antihypertensive therapy) or the control group (routine antihypertensive therapy without early surgical treatment). The primary outcome will be the five-year all-cause mortality. The secondary outcomes will include re-intervention, ischemic symptoms, organ dysfunction, and stent-related adverse events.

Discussion

If early minimally invasive endovascular repair could safely and effectively promote distal aortic remodeling and bring favorable long-term outcomes for patients with dominant false lumen and residual tears in the descending thoracic aorta after total arch replacement and frozen elephant trunk technique, it would improve the treatment strategy for DeBakey type I aortic dissection.

Trial registration

Chinese Clinical Trial Registry, CHiCTR2000030050. Registered on 11 March 2020.