bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of garlic supplementation on components of metabolic syndrome: a systematic review, meta-analysis, and meta-regression of randomized controlled trials
Authors: Fu Zhenyue , Lv Jiayu , Gao Xiya , Zheng Haoran , Shi Shuqing , Xu Xia , Zhang Bingxuan , Wu Huaqin , Song Qingqiao
Published: July 2023

Background

Garlic (Allium sativum), the underground bulb of the Allium genus, has been consumed on Earth for thousands of years. Many clinical trials of garlic supplementation on components of metabolic syndrome (MetS) have emerged in recent years, but there is no consensus on the effect. This meta-analysis aimed at systematically evaluating the effect of garlic supplementation on components of MetS.

Methods

In this meta-analysis, we searched Pubmed, Embase, Cochrane, Medline, Web of Science databases, and clinical trials online sites from inception to November 1, 2022, with language restrictions to English. We engaged participants > 18 years and eligible for the clinical diagnosis of MetS or those with metabolic disorders and garlic was the only intervention. Outcomes included waist circumference, and body mass index, triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, blood pressure, and fasting blood glucose. Meta-regression and subgroup analyses were conducted based on six covariates (total sample size, the mean age, the mean dose, the duration of intervention, the oral form of garlic, and the dietary intervention).

Results

Results from 19 RCTs were included engaging 999 participants. Compared to placebo, garlic significantly reduced TG [SMD (95%CI) = -0.66 (-1.23, -0.09)], TC [SMD (95%CI) = -0.43 (-0.86, -0.01)], LDL [SMD (95%CI) = -0.44(-0.88, -0.01)], DBP [SMD (95%CI) = -1.33 (-2.14, -0.53)], BMI [SMD (95%CI) = -1.10(-1.90, -0.20)], and WC [SMD (95%CI) = -0.78(-1.09, -0.47)]. Meta-regression showed age and sample size are potential effect modifiers.

Conclusion

According to the results of meta-analysis, the modulatory effect of garlic on some MetS components is evident. More high-quality, large-scale RCTs are needed to confirm iat based on the high heterogeneity and potential publication bias of the current data.

Trial registration

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=373228, ID: CRD42022373228.
Myco-synthesized copper oxide nanoparticles using harnessing metabolites of endophytic fungal strain Aspergillus terreus: an insight into antibacterial, anti-Candida, biocompatibility, anticancer, and antioxidant activities
Authors: Nassar Abdel-Rahman A. , Atta Hossam M. , Abdel-Rahman Mohamed Ali , El Naghy Wageih S. , Fouda Amr
Published: July 2023

Background

The overuse of antibiotics leads to the emergence of antibiotic-resistant microbes which causes high mortality worldwide. Therefore, the synthesis of new active compounds has multifunctional activities are the main challenge. Nanotechnology provides a solution for this issue.

Method

The endophytic fungal strain Aspergillus terreus BR.1 was isolated from the healthy root of Allium sativum and identified using internal transcribed spacer (ITS) sequence analysis. The copper oxide nanoparticles (CuO-NPs) were synthesized by harnessing the metabolites of the endophytic fungal strain. The UV-Visble spectroscopy, Fourier-transform infrared spectroscopy (FT-IR), Transmission electron micrscopy (TEM), Energy dispersive X-ray (EDX), X-ray diffraction (XRD), Dynamic light scattering (DLS), and zeta potential (ζ) were used for the characterization of synthesized CuO-NPs. The activity against different pathogenic bacteria and Candida species were investigated by agar well-diffusion method. The biocombatibility and anticancer activity were assessed by MTT assay method. The scavenging of DPPH was used to investigate the antioxidant activity of synthesized CuO-NPs.

Results

Data showed the successful formation of crystalline nature and spherical shape CuO-NPs with sizes in the ranges of 15–55 nm. The EDX reveals that the as-formed sample contains ions of C, O, Cl, and Cu with weight percentages of 18.7, 23.82, 11.31, and 46.17%, respectively. The DLS and ζ-potential showed high homogeneity and high stability of synthesized CuO-NPs with a polydispersity index (PDI) of 0.362 and ζ-value of − 26.6 mV. The synthesized CuO-NPs exhibited promising antibacterial and anti-Candida activity (concentration-dependent) with minimum inhibitory concentration (MIC) values in the ranges of 25–50 µg mL–1. Moreover, the fungal mediated-CuO-NPs targeted cancer cells of MCF7 and PC3 at low IC50 concentrations of 159.2 ± 4.5 and 116.2 ± 3.6 µg mL–1, respectively as compared to normal cells (Vero and Wi38 with IC50 value of 220.6 ± 3.7 and 229.5 ± 2.1 µg mL–1, respectively). The biosynthesized CuO-NPs showed antioxidant activity as detected by the DPPH method with scavenging percentages of 80.5 ± 1.2% at a concentration of 1000 µg mL–1 and decreased to 20.4 ± 4.2% at 1.9 µg mL–1 as compared to ascorbic acid (control) with scavenging activity of 97.3 ± 0.2 and 37.5 ± 1.3% at the same concentrations, respectively.

Conclusion

The fungal mediated-CuO-NPs exhibited promising activity and can be integrated into various biomedical and theraputic applications.
Catastrophic out-of-pocket payments for dental treatment: regional evidence from Spain
Authors: López-López Samuel , del Pozo-Rubio Raúl , Ortega-Ortega Marta , Escribano-Sotos Francisco
Published: July 2023

Background

To estimate the incidence and concentration of catastrophic out-of-pocket payments for healthcare and dental treatment, by region in Spain (calculated as the proportion of households needing to exceed a given threshold of their income to make these payments) in 2008, 2011 and 2015.

Methods

The data analysed were obtained from the Spanish Family Budget Survey reports for the years in question. The study method was that proposed by Wagstaff and van Doorslaer (2003), contrasting payments for dental treatment versus household income and considering thresholds of 10%, 20%, 30% and 40%, thus obtaining incidence rates. In addition, relevant sociodemographic variables were obtained for each household included in the study.

Results

With some regional heterogeneity, on average 4.75% of Spanish households spend more than 10% of their income on dental treatment, and 1.23% spend more than 40%. Thus, 38.67% of catastrophic out-of-pocket payments for dental services in Spain corresponds to payments at the 10% threshold. This value rises to 55.98% for a threshold of 40%.

Conclusions

An important proportion of catastrophic out-of-pocket payments for health care in Spain corresponds to dental treatment, a service that has very limited availability under the Spanish NHS. This finding highlights the need to formulate policies aimed at enhancing dental cover, in order to reduce inequalities in health care and, consequently, enhance the population’s quality of life and health status.
Self-reported delays in care-seeking in West Africa during the first wave of the COVID-19 pandemic
Authors: Conboy Natalie E. , Nickow Andre , Awoonor-Williams John Koku , Hirschhorn Lisa R.
Published: July 2023

Background

The COVID-19 pandemic caused delays in care-seeking due to fears of infection and decreased healthcare access globally. These delays have been linked in some countries to COVID-19 perceptions, decreased income, and food insecurity, but little is known about patient-level factors for decreased care-seeking specifically at the beginning of COVID-19 in West Africa. Understanding these factors is important to identify those at highest risk and address healthcare-related barriers.

Methods

This study used self-reported data from telephone surveys in a population-based sample in Burkina Faso (n = 1352), Ghana (n = 1621), and Sierra Leone (n = 1301) in May–June 2020. Questions assessed delays in care-seeking, sociodemographic variables, COVID-19 beliefs, and food insecurity. Bivariate analyses using chi-square and multivariate analyses using logistic regression were used to explore associations between factors and delays in care-seeking by country. Independent variables were chosen based on prior research suggesting that financial insecurity, older age, female sex, rural location, and COVID-related concerns are associated with delays.

Results

Between March-June 2020, 9.9%, 10.6%, and 5.7% of participants in Burkina Faso, Ghana, and Sierra Leone, respectively, delayed care-seeking. Food insecurity was prevalent (21.8–46.1%) and in bivariate analyses was associated with delays in care-seeking in Burkina Faso and Ghana. Concern about risk of household contraction of COVID-19 was common (18.1–36.0%) and in Ghana and Sierra Leone was associated with delays in care-seeking in both bivariate and multivariate analyses. In bivariate analyses, females showed more delays in Burkina Faso, while age above 30 and urban location were associated with delays in Ghana. In multivariate analyses, food insecurity was associated with increased delayed care-seeking in Burkina Faso.

Conclusions

Multiple factors were associated with delays in care-seeking early in the COVID-19 pandemic, with food insecurity and concerns about infection showing significant associations in multiple countries. These findings highlight the need to invest in clinic accessibility, community education, and financial assistance to address barriers in healthcare. While many delays have subsided since the initial phase of the COVID-19 pandemic, understanding factors associated with early disruptions of care-seeking at the patient and household level will inform strategies for maintaining healthcare access during future pandemics in West Africa.
Long-term changes of Th17 and regulatory T cells in peripheral blood of dogs with spinal cord injury after intervertebral disc herniation
Authors: Wesolowski M. , Can P. , Warzecha K. , Freise F. , Carlson R. , Neßler J. , Tipold A.
Published: July 2023

Background

Intervertebral disc herniation (IVDH) is one of the most common causes of spinal cord injury (SCI) in dogs. As a result of acute SCI, a complex inflammatory response occurs in the spinal cord. Th17 cells (Th17) produce pro-inflammatory cytokines, while regulatory T cells (Treg) have opposite effects producing anti-inflammatory cytokines. Therefore, the aim of this study was to determine whether Th17- and Treg cells are involved in the pathogenesis of SCI or whether cellular changes occur due to coexisting inflammatory diseases. We hypothesized that chronic alterations in the Th17/Treg ratio are associated with a worse outcome after SCI.

Methods

Twenty-six paretic or plegic dogs with IVDH with and without coexisting inflammatory disease were investigated in the acute stage of the disease and after recovery of SCI. In addition, a healthy control group was included (n = 14). Quantification of Th17 and Treg cells, from peripheral blood samples, was performed by multicolor flow cytometry and IL17 was measured using an enzyme-linked immunosorbent assay (ELISA).

Results

After recovery significantly higher levels of Th17 (p = 0.0265) and Treg cells (p = 0.00025) were detected compared to acute IVDH but Th17/Treg ratio did not differ significantly. Recovered dogs and the control group did not differ significantly from each other. No association between an imbalance in the ratio and neurologic severity or underlying inflammatory diseases was found.

Conclusion

This study demonstrated that altered Th17 and Treg levels in peripheral blood are altered in the acute stage of IVDH, preexisting inflammatory diseases seem not to influence these cell populations. Th17 and Treg cells could be considered when evaluating new treatment strategies for SCI.
Nanotechnology-based ocular drug delivery systems: recent advances and future prospects
Authors: Li Shiding , Chen Liangbo , Fu Yao
Published: July 2023

Ocular drug delivery has constantly challenged ophthalmologists and drug delivery scientists due to various anatomical and physiological barriers. Static and dynamic ocular barriers prevent the entry of exogenous substances and impede therapeutic agents' active absorption. This review elaborates on the anatomy of the eye and the associated constraints. Followed by an illustration of some common ocular diseases, including glaucoma and their current clinical therapies, emphasizing the significance of drug therapy in treating ocular diseases. Subsequently, advances in ocular drug delivery modalities, especially nanotechnology-based ocular drug delivery systems, are recommended, and some typical research is highlighted. Based on the related research, systematic and comprehensive characterizations of the nanocarriers are summarized, hoping to assist with future research. Besides, we summarize the nanotechnology-based ophthalmic drugs currently on the market or still in clinical trials and the recent patents of nanocarriers. Finally, inspired by current trends and therapeutic concepts, we provide an insight into the challenges faced by novel ocular drug delivery systems and further put forward directions for future research. We hope this review can provide inspiration and motivation for better design and development of novel ophthalmic formulations.

Graphical abstract
Mesenchymal stem cells, as glioma exosomal immunosuppressive signal multipliers, enhance MDSCs immunosuppressive activity through the miR-21/SP1/DNMT1 positive feedback loop
Authors: Qiu Wei , Guo Qindong , Guo Xiaofan , Wang Chaochao , Li Boyan , Qi Yanhua , Wang Shaobo , Zhao Rongrong , Han Xiao , Du Hao , Zhao Shulin , Pan Ziwen , Fan Yang , Wang Qingtong , Gao Zijie , Li Gang , Xue Hao
Published: July 2023

Background

The immunosuppressive microenvironment in glioma induces immunotherapy resistance and is associated with poor prognosis. Glioma-associated mesenchymal stem cells (GA-MSCs) play an important role in the formation of the immunosuppressive microenvironment, but the mechanism is still not clear.

Results

We found that GA-MSCs promoted the expression of CD73, an ectonucleotidase that drives immunosuppressive microenvironment maintenance by generating adenosine, on myeloid-derived suppressor cells (MDSCs) through immunosuppressive exosomal miR-21 signaling. This process was similar to the immunosuppressive signaling mediated by glioma exosomal miR-21 but more intense. Further study showed that the miR-21/SP1/DNMT1 positive feedback loop in MSCs triggered by glioma exosomal CD44 upregulated MSC exosomal miR-21 expression, amplifying the glioma exosomal immunosuppressive signal. Modified dendritic cell-derived exosomes (Dex) carrying miR-21 inhibitors could target GA-MSCs and reduce CD73 expression on MDSCs, synergizing with anti-PD-1 monoclonal antibody (mAb).

Conclusions

Overall, this work reveals the critical role of MSCs in the glioma microenvironment as signal multipliers to enhance immunosuppressive signaling of glioma exosomes, and disrupting the positive feedback loop in MSCs with modified Dex could improve PD-1 blockade therapy.

Graphical abstract
Colorectal adenocarcinoma in Uganda: are right-sided and left-sided colon cancers two distinct disease entities?
Authors: Wismayer Richard , Kiwanuka Julius , Wabinga Henry , Odida Michael
Published: July 2023

Introduction

In Western countries, right-sided colon cancers (RSCC) present at an older age and advanced stage. Researchers believe that there is a difference between left-sided colon cancer (LSCC) and RSCC. In Uganda, however, it is unknown whether differences exist in the pathological profile between RSCC and LSCC. The aim of this study was to determine the differences in clinicopathological characteristics between RSCC and LSCC in Ugandan patients.

Methodology

A cross-sectional study was conducted in which colorectal adenocarcinoma formalin-fixed paraffin-embedded tissue (FFPE) blocks were obtained from 2008 to 2021. Colorectal specimens were obtained from prospectively recruited patients. In the retrospective study arm, FFPE blocks and data were obtained from the archives of pathology laboratory repositories. Parameters studied included age, sex, location of the tumour, grade, stage, lymphovascular (LVI) status, and histopathological subtype between LSCC and RSCC.

Results

Patients with RSCC were not older than those with LSCC (mean age, 56.3 years vs 53.5 years; p = 0.170). There was no difference in the stage between RSCC and LSCC. Poorly differentiated tumours were more commonly found in RSCC than in LSCC (18.7% vs 10.1%; p = 0.038). Moderately and poorly differentiated colonic tumours were more common with RSCC (89.3%) than with LSCC (75.1%) (p = 0.007). Younger patients had more poorly differentiated tumours than older patients (19.6% versus 8.6%; p = 0.002). LVI was more common with RSCC than with LSCC (96.8% vs 85.3%; p = 0.014). Mucinous adenocarcinoma (MAC) was more common with RSCC (15.8%) compared with LSCC (8.5%) (p = 0.056) although statistical significance was borderline.

Conclusions

Clinicopathological features of RSCCs tend to be different from those of LSCCs. RSCCs tend to be associated with MAC, a higher grade and LVI status compared to LSCC. LSCC and RSCC present predominantly with an advanced stage; therefore, national screening programmes for the early detection of CRC are necessary to reduce mortality in our Ugandan population.
Socioeconomic position as a predictor of youth's movement trajectory profiles between ages 10 and 14 years
Authors: Wilhite Katrina , del Pozo Cruz Borja , Noetel Michael , Lonsdale Chris , Ridgers Nicola D. , Maher Carol , Bradshaw Emma , Sanders Taren
Published: July 2023

Background

Combinations of movement behaviors (i.e., physical activity, sedentary behavior, sleep) are associated with health and developmental outcomes in youth. Youth vary in how they accumulate these behaviors, both in volume and specific domains (e.g., sedentary time spent on recreational screen activities vs homework). The aim of this study was to examine how youth’s combined general and domain-specific movement trajectories differ by socioeconomic position.

Methods

We conducted a longitudinal, group-based multi-trajectory analysis to identify general and domain-specific movement trajectory profiles for 2457 youth from age 10 to 14 years from the Longitudinal Study of Australian Children from 2014–2018. We used multinomial logistic regression to test if socioeconomic position predicted profile membership.

Results

We identified three general movement trajectory profiles for both sexes, four domain-specific profiles for males, and five for females. For general movement trajectories, females from lower socioeconomic positions were more likely to be a combination of less active and more sedentary than females from higher socioeconomic positions. Males across socioeconomic positions spend similar amounts of time in physical activity, sedentary time, and sleep. For domain-specific movement trajectories, youth from lower socioeconomic positions were likely to spend a combination of less time in education-based sedentary behavior and more time in recreational screen activities than their higher socioeconomic position peers.

Conclusion

Our results indicate that socioeconomic position predicted in which domains youth accumulate their movements. Future observational research and interventions targeting different socioeconomic groups should therefore consider domain-specific movement trajectories.
SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes
Authors: Chang Yanmin , Wang Cailin , Zhu Jiahui , Zheng Siyi , Sun Shangqi , Wu Yanqing , Jiang Xingjun , Li Lulu , Ma Rong , Li Gang
Published: July 2023

Background

Diabetes is associated with an increased risk of cognitive decline and dementia. These diseases are linked with mitochondrial dysfunction, most likely as a consequence of excessive formation of mitochondria-associated membranes (MAMs). Sirtuin3 (SIRT3), a key mitochondrial NAD+-dependent deacetylase, is critical responsible for mitochondrial functional homeostasis and is highly associated with neuropathology. However, the role of SIRT3 in regulating MAM coupling remains unknown.

Methods

Streptozotocin-injected diabetic mice and high glucose-treated SH-SY5Y cells were established as the animal and cellular models, respectively. SIRT3 expression was up-regulated in vivo using an adeno-associated virus in mouse hippocampus and in vitro using a recombinant lentivirus vector. Cognitive function was evaluated using behavioural tests. Hippocampus injury was assessed using Golgi and Nissl staining. Apoptosis was analysed using western blotting and TUNEL assay. Mitochondrial function was detected using flow cytometry and confocal fluorescence microscopy. The mechanisms were investigated using co-immunoprecipitation of VDAC1–GRP75–IP3R complex, fluorescence imaging of ER and mitochondrial co-localisation and transmission electron microscopy of structural analysis of MAMs.

Results

Our results demonstrated that SIRT3 expression was significantly reduced in high glucose-treated SH-SY5Y cells and hippocampal tissues from diabetic mice. Further, up-regulating SIRT3 alleviated hippocampus injuries and cognitive impairment in diabetic mice and mitigated mitochondrial Ca2+ overload-induced mitochondrial dysfunction and apoptosis. Mechanistically, MAM formation was enhanced under high glucose conditions, which was reversed by genetic up-regulation of SIRT3 via reduced interaction of the VDAC1–GRP75–IP3R complex in vitro and in vivo. Furthermore, we investigated the therapeutic effects of pharmacological activation of SIRT3 in diabetic mice via honokiol treatment, which exhibited similar effects to our genetic interventions.

Conclusions

In summary, our findings suggest that SIRT3 ameliorates cognitive impairment in diabetic mice by limiting aberrant MAM formation. Furthermore, targeting the activation of SIRT3 by honokiol provides a promising therapeutic candidate for diabetes-associated cognitive dysfunction. Overall, our study suggests a novel role of SIRT3 in regulating MAM coupling and indicates that SIRT3-targeted therapies are promising for diabetic dementia patients.
Chimeric antigen receptor T cells targeting cell surface GRP78 efficiently kill glioblastoma and cancer stem cells
Authors: Wang Shijie , Wei Wenwen , Yuan Yuncang , Sun Bin , Yang Dong , Liu Nan , Zhao Xudong
Published: July 2023

Background

Glioblastoma (GBM) is recognized as among the most aggressive forms of brain tumor. Patients typically present with a five-year survival rate of less than 6% with traditional surgery and chemoradiotherapy, which calls for novel immunotherapies like chimeric antigen receptor T (CAR-T) cells therapy. In response to endoplasmic reticulum (ER) stress in multiple tumor cells including GBM, the glucose-regulated protein 78 (GRP78) expression increases and the protein is partially translocated to the cell surface, while it is restricted to the cytoplasm and the nucleus in normal cells.

Methods

In this study, to target the cell surface GRP78 (csGRP78), CAR-T cells based on its binding peptide were generated. In vitro two GBM cell lines and glioma stem cells (GSCs) were used to confirm the localization of csGRP78 and the cytotoxicity of the CAR-T cells. In vivo a GBM xenograft model was used to assess the killing activity and the safety of the CAR-T cells.

Results

We confirmed the localization of csGRP78 at the cell surface of two GBM cell lines (U-251MG and U-87MG) and in GSCs. Co-culture experiments revealed that the CAR-T cells could specifically kill the GBM tumor cells and GSCs with specific IFN-γ release. Furthermore, in the tumor xenograft model, the CAR-T cells could decrease the number of GSCs and significantly suppress tumor cell growth. Importantly, we found no obvious off-target effects or T cell infiltration in major organs following systemic administration of these cells.

Conclusions

The csGRP78 targeted CAR-T cells efficiently kill GBM tumor cells and GSCs both in vitro and in vivo, and ultimately suppress the xenograft tumors growth without obvious tissue injuries. Therefore, our study demonstrates that csGRP78 represents a valuable target and the csGRP78-targeted CAR-T cells strategy is an effective immunotherapy against GBM.
Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis
Authors: Chang Haoxiao , Ma Jia , Feng Kai , Feng Ning , Wang Xinxin , Sun Jiali , Guo Tianshu , Wei Yuzhen , Xu Yun , Wang Huabing , Yin Linlin , Zhang Xinghu
Published: July 2023

Background

Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the central nervous system (CNS). Matrix metalloproteinase-9 (MMP9) and cluster of differentiation (CD44) were measured to evaluate blood‒brain barrier (BBB) permeability in anti-NMDAR encephalitis. The roles of microglial activation and BBB disruption in anti-NMDAR encephalitis are not well known.

Findings

In this work, we detected increased expression levels of CSF sTREM2, CSF and serum CD44, and serum MMP9 in anti-NMDAR encephalitis patients compared with controls. CSF sTREM2 levels were positively related to both CSF CD44 levels (r = 0.702, p < 0.0001) and serum MMP9 levels (r = 0.428, p = 0.021). In addition, CSF sTREM2 levels were related to clinical parameters (modified Rankin Scale scores, r = 0.422, p = 0.023, and Glasgow Coma Scale scores, r = − 0.401, p = 0.031).

Conclusion

Increased sTREM2 levels in CSF as well as increased CD44 and MMP9 in serum and CSF reflected activation of microglia and disruption of the BBB in anti-NMDAR encephalitis, expanding the understanding of neuroinflammation in this disease. The factors mentioned above may have potential as novel targets for intervention or novel diagnostic biomarkers.
Iron induces B cell pyroptosis through Tom20–Bax–caspase–gasdermin E signaling to promote inflammation post-spinal cord injury
Authors: Wu Chengjie , Wang Lining , Chen Sixian , Shi Lei , Liu Mengmin , Tu Pengcheng , Sun Jie , Zhao Ruihua , Zhang Yafeng , Wang Jianwei , Pan Yalan , Ma Yong , Guo Yang
Published: July 2023

Background

Immune inflammatory responses play an important role in spinal cord injury (SCI); however, the beneficial and detrimental effects remain controversial. Many studies have described the role of neutrophils, macrophages, and T lymphocytes in immune inflammatory responses after SCI, although little is known about the role of B lymphocytes, and immunosuppression can easily occur after SCI.

Methods

A mouse model of SCI was established, and HE staining and Nissl staining were performed to observe the pathological changes. The size and morphology of the spleen were examined, and the effects of SCI on spleen function and B cell levels were detected by flow cytometry and ELISA. To explore the specific mechanism of immunosuppression after SCI, B cells from the spleens of SCI model mice were isolated using magnetic beads and analyzed by 4D label-free quantitative proteomics. The level of inflammatory cytokines and iron ions were measured, and the expression of proteins related to the Tom20 pathway was quantified by western blotting. To clarify the relationship between iron ions and B cell pyroptosis after SCI, we used FeSO4 and CCCP, which induce oxidative stress to stimulate SCI, to interfere with B cell processes. siRNA transfection to knock down Tom20 (Tom20-KD) in B cells and human B lymphocytoma cell was used to verify the key role of Tom20. To further explore the effect of iron ions on SCI, we used deferoxamine (DFO) and iron dextran (ID) to interfere with SCI processes in mice. The level of iron ions in splenic B cells and the expression of proteins related to the Tom20–Bax–caspase–gasdermin E (GSDME) pathway were analyzed.

Results

SCI could damage spleen function and lead to a decrease in B cell levels; SCI upregulated the expression of Tom20 protein in the mitochondria of B cells; SCI could regulate the concentration of iron ions and activate the Tom20–Bax–caspase–GSDME pathway to induce B cell pyroptosis. Iron ions aggravated CCCP-induced B cell pyroptosis and human B lymphocytoma pyroptosis by activating the Tom20–Bax–caspase–GSDME pathway. DFO could reduce inflammation and promote repair after SCI by inhibiting Tom20–Bax–caspase–GSDME-induced B cell pyroptosis.

Conclusions

Iron overload activates the Tom20–Bax–caspase–GSDME pathway after SCI, induces B cell pyroptosis, promotes inflammation, and aggravates the changes caused by SCI. This may represent a novel mechanism through which the immune inflammatory response is induced after SCI and may provide a new key target for the treatment of SCI.
Contextual factors influencing the roles of patent medicine vendors in the provision of injectable contraception services in Nigeria
Authors: Adebayo Ayodeji Matthew , Oluwasanu Mojisola Morenike , Okunade Faizah Tosin , Ajayi Olayinka Olufunke , Akindele Akinwumi Oyewole , Ajuwon Ademola Johnson
Published: July 2023

Background

Patent medicine vendors (PMVs) play vital roles in the delivery of family planning services in Nigeria and other developing countries. There is a growing recognition of the need to integrate them into the formal health care system as a strategy to increase the contraceptive prevalence rate and achieve universal health coverage. Though promising, the success of this proposition is largely dependent on a critical analysis of the factors which influence their operations. This study was designed to identify the contextual factors influencing the provision of injectable contraceptive services by PMVs and the broader effects of their activities on the health system to inform similar interventions in Nigeria.

Methods

This was a qualitative study guided by the UK Medical Research Council’s Framework for Complex Interventions. Twenty-seven in-depth interviews were conducted among officials of the association of PMVs, health workers, government regulatory officers and programme implementers who participated in a phased 3-year (2015–2018) intervention designed to enhance the capacity of PMVs to deliver injectable contraceptive services. The data were transcribed and analyzed thematically using NVIVO software.

Results

The contextual factors which had implications on the roles of PMVs were socio-cultural and religious, the failing Nigerian health system coupled with government regulatory policies. Other factors were interprofessional tensions and rivalry between the PMVs and some categories of health care workers and increasing donors’ interest in exploring the potentials of PMVs for expanded healthcare service provision. According to the respondents, the PMVs bridged the Nigerian health system service delivery gaps serving as the first point of contact for injectable contraceptive services and this increased contraceptive uptake in the study sites. A negative effect of their operation is the tendency to exceed their service provision limits, which has spurred a planned tiered PMV accreditation system.

Conclusions

This study has highlighted the contextual factors which define the roles and scope of practice of PMVs involved in injectable contraceptive service provision. Strategies and interventions aimed at expanding the healthcare delivery roles of PMVs must be encompassing to address the broader contextual factors which underpin their capacities and functions.
Assessment of emerging pretraining strategies in interpretable multimodal deep learning for cancer prognostication
Authors: Azher Zarif L. , Suvarna Anish , Chen Ji-Qing , Zhang Ze , Christensen Brock C. , Salas Lucas A. , Vaickus Louis J. , Levy Joshua J.
Published: July 2023

Background

Deep learning models can infer cancer patient prognosis from molecular and anatomic pathology information. Recent studies that leveraged information from complementary multimodal data improved prognostication, further illustrating the potential utility of such methods. However, current approaches: 1) do not comprehensively leverage biological and histomorphological relationships and 2) make use of emerging strategies to “pretrain” models (i.e., train models on a slightly orthogonal dataset/modeling objective) which may aid prognostication by reducing the amount of information required for achieving optimal performance. In addition, model interpretation is crucial for facilitating the clinical adoption of deep learning methods by fostering practitioner understanding and trust in the technology.

Methods

Here, we develop an interpretable multimodal modeling framework that combines DNA methylation, gene expression, and histopathology (i.e., tissue slides) data, and we compare performance of crossmodal pretraining, contrastive learning, and transfer learning versus the standard procedure.

Results

Our models outperform the existing state-of-the-art method (average 11.54% C-index increase), and baseline clinically driven models (average 11.7% C-index increase). Model interpretations elucidate consideration of biologically meaningful factors in making prognosis predictions.

Discussion

Our results demonstrate that the selection of pretraining strategies is crucial for obtaining highly accurate prognostication models, even more so than devising an innovative model architecture, and further emphasize the all-important role of the tumor microenvironment on disease progression.
Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial
Authors: Schubert Maria-Luisa , Schmitt Anita , Hückelhoven-Krauss Angela , Neuber Brigitte , Kunz Alexander , Waldhoff Philip , Vonficht Dominik , Yousefian Schayan , Jopp-Saile Lea , Wang Lei , Korell Felix , Keib Anna , Michels Birgit , Haas Dominik , Sauer Tim , Derigs Patrick , Kulozik Andreas , Kunz Joachim , Pavel Petra , Laier Sascha , Wuchter Patrick , Schmier Johann , Bug Gesine , Lang Fabian , Gökbuget Nicola , Casper Jochen , Görner Martin , Finke Jürgen , Neubauer Andreas , Ringhoffer Mark , Wolleschak Denise , Brüggemann Monika , Haas Simon , Ho Anthony D. , Müller-Tidow Carsten , Dreger Peter , Schmitt Michael
Published: July 2023

Background

Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL).

Methods

Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 106and 50 × 106CARTs/m2. Leukapheresis, manufacturing and administration of CARTs were performed in-house.

Results

For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response.

Conclusion

In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL.

Trial registrationThis trial was registered atwww.clinicaltrials.govas NCT03676504.
Novel target and treatment agents for natural killer/T-cell lymphoma
Authors: Tian Xiao-Peng , Cao Yi , Cai Jun , Zhang Yu-Chen , Zou Qi-Hua , Wang Jin-Ni , Fang Yu , Wang Jia-Hui , Guo Song-Bin , Cai Qing-Qing
Published: July 2023

The rapidly increasing use of high-throughput screening had produced a plethora of expanding knowledge on the molecular basis of natural killer/T-cell lymphoma (NKTCL), which in turn has revolutionized the treatment. Specifically, the use of asparaginase-containing regimens has led to substantial improvement in survival outcomes in NKTCL patients. Novel treatment strategies that are currently under development include cell-surface-targeted antibodies, immune checkpoint inhibitors, Epstein-Barr virus targeted cytotoxic T lymphocyte, immunomodulatory agents, chimeric antigen receptor T cells, signaling pathway inhibitors and epigenetic targeted agents. In almost all cases, initial clinical studies of newly developed treatment are conducted in patients relapsed, and refractory NKTCL due to very limited treatment options. This review summarizes the results of these novel treatments for NKTCL and discusses their potential for likely use in NKTCL in a wider setting in the future.
Chronic respiratory disorders due to aberrant innominate artery: a case series and critical review of the literature
Authors: Corcione Adele , Borrelli Melissa , Radice Leonardo , Sacco Oliviero , Torre Michele , Santoro Francesco , Palma Gaetano , Acampora Eleonora , Cillo Francesca , Salvati Pietro , Florio Angelo , Santamaria Francesca
Published: July 2023

Background

Tracheal compression (TC) due to vascular anomalies is an uncommon, but potentially serious cause of chronic respiratory disease in childhood. Vascular slings are congenital malformations resulting from abnormal development of the great vessels; in this group of disorders the most prevalent entity is the aberrant innominate artery (AIA). Here we provide a report on diagnosis and treatment of AIA in nine children with unexplained chronic respiratory symptoms. We describe the cases, perform a literature review, and provide a discussion on the diagnostic workup and treatment that can help manage AIA.

Methods

Clinical history, diagnostic procedures and treatment before and after the AIA diagnosis were retrospectively reviewed in nine children (5 boys and 4 girls), who were referred for recurrent-to-chronic respiratory manifestations over 10 years (2012–2022). We performed a comprehensive report on the ongoing clinical course and treatment as well as an electronic literature search on the topic.

Results

Diagnoses at referral, before AIA was identified, were chronic dry barking cough associated with recurrent pneumonia (n = 8, 89%), lobar/segmental atelectasis (n = 3, 33%), atopic/non atopic asthma (n = 3, 33%); pneumomediastinum with subcutaneous emphysema complicated the clinical course in one case. When referred to our Unit, all patients had been previously treated with repeated antibiotic courses (n = 9, 100%), alone (n = 6, 67%) or combined with prolonged antiasthma medications (n = 3, 33%) and/or daily chest physiotherapy (n = 2, 22%), but reported only partial clinical benefit. Median ages at symptom onset and at AIA diagnosis were 1.5 [0.08–13] and 6 [4–14] years, respectively, with a relevant delay in the definitive diagnosis (4.5 years). Tracheal stenosis at computed tomography (CT) was ≥ 51% in 4/9 cases and ≤ 50% in the remaining 5 subjects. Airway endoscopy was performed in 4 cases with CT evidence of tracheal stenosis ≥ 51% and confirmed CT findings. In these 4 cases, the decision of surgery was made based on endoscopy and CT findings combined with persistence of clinical symptoms despite medical treatment. The remaining 5 children were managed conservatively.

Conclusions

TC caused by AIA may be responsible for unexplained chronic respiratory disease in childhood. Early diagnosis of AIA can decrease the use of expensive investigations or unsuccessful treatments, reduce disease morbidity, and accelerate the path toward a proper treatment.
Pragmatic clinic-based investigation of echocardiogram parameters in asymptomatic patients with type 2 diabetes in routine clinical practice and its association with suggestive coronary artery disease: a pilot study
Authors: Palma Catia Cristina Silva Sousa Vergara , Lopes Pablo Moura , de Souza Bomfim Alfredo , Gomes Marilia Brito
Published: July 2023

Background

Patients with diabetes mellitus (DM) have cardiovascular diseases (CVD) as a major cause of mortality and morbidity. The primary purpose of this study was to assess the echocardiographic parameters that showed alterations in patients with type 2 diabetes mellitus(T2DM) with suggestive coronary artery disease (CAD) determined by electrocardiography and the secondary was to assess the relationship of these alterations with established cardiovascular risk factors.

Methods

This cross-sectional, observational pilot study included 152 consecutive patients with T2DM who attended a tertiary DM outpatient care center. All patients underwent clinical examination and history, anthropometric measurements, demographic survey, determination of the Framingham global risk score, laboratory evaluation, basal electrocardiogram, echocardiogram, and measurement of carotid intima-media thickness (CIMT).

Results

From the overall sample, 134 (88.1%) patients underwent an electrocardiogram. They were divided into two groups: patients with electrocardiograms suggestive of CAD (n = 11 [8.2%]) and those with normal or non-ischemic alterations on electrocardiogram (n = 123 [91.79%]). In the hierarchical multivariable logistic model examining all selected independent factors that entered into the model, sex, high triglycerides levels, and presence of diabetic retinopathy were associated with CAD in the final model. No echocardiographic parameters were significant in multivariate analysis. The level of serum triglycerides (threshold) related to an increased risk of CAD was ≥ 184.5 mg/dl (AUC = 0.70, 95% IC [0.51–0.890]; p = 0.026.

Conclusion

Our pilot study demonstrated that no echocardiogram parameters could predict or determine CAD. The combination of CIMT and Framingham risk score is ideal to determine risk factors in asymptomatic patients with T2DM. Patients with diabetic retinopathy and hypertriglyceridemia need further investigation for CAD. Further prospective studies with larger sample sizes are needed to confirm our results.
Correcting calculation and data errors reveals that the original conclusions were incorrect in “The best drug supplement for obesity treatment: a systematic review and network meta-analysis”
Authors: Yu Xiaoxin , Capers Patrice L. , Zoh Roger S. , Allison David B.
Published: July 2023

The goal of this study was to reproduce and evaluate the reliability of the network meta-analysis performed in the article “The best drug supplement for obesity treatment: A systematic review and network meta-analysis” by Salari et al. In recent years, it has become more common to employ network meta-analysis to assess the relative efficacy of treatments often used in clinical practice. To duplicate Salari et al.‘s research, we pulled data directly from the original trials and used Cohen’s D to determine the effect size for each treatment. We reanalyzed the data since we discovered significant differences between the data we retrieved and the data given by Salari et al. We present new effect size estimates for each therapy and conclude that the prior findings were somewhat erroneous. Our findings highlight the importance of ensuring the accuracy of network meta-analyses to determine the quality and strength of existing evidence.
Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome in the intensive care unit: a case report
Authors: Belicard Félicie , Belhomme Nicolas , Bouzy Simon , Saillard Clémence , Nedelec Fabienne , Mear Jean-Baptiste , Ardois Samuel , Pastoret Cedric , Reizine Florian , Camus Christophe , Painvin Benoit
Published: July 2023

Background

Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome is a newly discovered inflammatory disease affecting male subjects, for which few data exist in the literature. Here, we describe the case of a patient with known Sweet’s syndrome admitted to the intensive care unit and for whom a vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome was diagnosed, allowing for appropriate treatment and the patient’s discharge and recovery.

Case presentation

A 70-year-old male White patient was hospitalized in the intensive care unit following an intrahospital cardiac arrest. History started a year before with repeated deep vein thrombosis and episodes of skin eruption compatible with Sweet’s syndrome. After a course of oral steroids, fever and inflammatory syndrome relapsed with onset of polychondritis, episcleritis along with neurological symptoms and pulmonary infiltrates. Intrahospital hypoxic cardiac arrest happened during patient’s new investigations, and he was admitted in a critical state. During the intensive care unit stay, he presented with livedoid skin lesions on both feet. Vasculitis was not proven; however, cryoglobulinemia screening came back positive. Onset of pancytopenia was explored with a myelogram aspirate. It showed signs of dysmyelopoiesis and vacuoles in erythroid and myeloid precursors. Of note, new deep vein thrombosis developed, despite being treated with heparin leading to the diagnosis of heparin-induced thrombocytopenia. The course of symptoms were overlapping multiple entities, and so a multidisciplinary team discussion was implemented. Screening for UBA1-mutation in the blood came back positive, confirming the vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome. Corticosteroids and anti-IL1 infusion were started with satisfactory results supporting patient’s discharge from intensive care unit to the internal medicine ward.

Conclusions

Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome should be suspected in male patients presenting with inflammatory symptoms, such as fever, skin eruption, chondritis, venous thromboembolism, and vacuoles in bone marrow precursors. Patients with undiagnosed vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome may present with organ failure requiring hospitalization in intensive care unit, where screening for UBA1 mutation should be performed when medical history is evocative. Multidisciplinary team involvement is highly recommended for patient management, notably to start appropriate immunosuppressive treatments.
A novel robust iterated CKF for GNSS/SINS integrated navigation applications
Authors: Wang Junwei , Chen Xiyuan , Shi Chunfeng
Published: July 2023

In challenging circumstances, the estimation performance of integrated navigation parameters for tightly coupled GNSS/SINS is impacted by outlier measurements. An effective solution that employs a novel iterative sigma-point structure with a modified robustness optimization approach for enhancing the error compensation effectiveness and robustness of filters utilized in GNSS challenge conditions is proposed in this paper. The proposed method modifies the CKF scheme by incorporating nonlinear regression and numerous iteration processes for ameliorating error compensation. Subsequently, a loss function and penalty mechanism are implemented to enhance the filter's robustness to outlier measurements. Furthermore, to fully incorporate valid information of the innovation and speed up the operation of the proposed method, the outlier measurement detection criteria are established to bypass the penalty mechanism against measurement weights in the absence of outliers in GNSS measurements. Field experiments demonstrate that the proposed method outperforms traditional methods in mitigating navigation errors, particularly when multipath errors and non-line-of-sight (NLOS) reception are increased.