bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a novel sequence based real-time PCR assay for specific and sensitive detection of Burkholderia pseudomallei in clinical and environmental matrices
Authors: Yadav Pranjal Kumar , Singh Suchetna , Paul Moumita , Kumar Sanjay , Ponmariappan S. , Thavaselvam Duraipandian
Published: April 2024

Background

Melioidosis, caused by the category B biothreat agent Burkholderia pseudomallei, is a disease with a high mortality rate and requires an immediate culture-independent diagnosis for effective disease management. In this study, we developed a highly sensitive qPCR assay for specific detection of Burkholderia pseudomallei and melioidosis disease diagnosis based on a novel target sequence.

Methods

An extensive in-silico analysis was done to identify a novel and highly conserved sequence for developing a qPCR assay. The specificity of the developed assay was analyzed with 65 different bacterial cultures, and the analytical sensitivity of the assay was determined with the purified genomic DNA of B. pseudomallei. The applicability of the assay for B. pseudomallei detection in clinical and environmental matrices was evaluated by spiking B. pseudomallei cells in the blood, urine, soil, and water along with suitable internal controls.

Results

A novel 85-nucleotide-long sequence was identified using in-silico tools and employed for the development of the highly sensitive and specific quantitative real-time PCR assay S664. The assay S664 was found to be highly specific when evaluated with 65 different bacterial cultures related and non-related to B. pseudomallei. The assay was found to be highly sensitive, with a detection limit of 3 B. pseudomallei genome equivalent copies per qPCR reaction. The detection limit in clinical matrices was found to be 5 × 102 CFU/mL for both human blood and urine. In environmental matrices, the detection limit was found to be 5 × 101 CFU/mL of river water and 2 × 103 CFU/gm of paddy field soil.

Conclusions

The findings of the present study suggest that the developed assay S664 along with suitable internal controls has a huge diagnostic potential and can be successfully employed for specific, sensitive, and rapid molecular detection of B. pseudomallei in various clinical and environmental matrices.
Evaluation of the therapeutic efficacy of different doses of LT4 in pregnant women with high-normal TSH levels and TPOAb positivity in the first half of pregnancy
Authors: Tian Xin , Xu Yajuan , Ban Yanjie , Li Jingjing , Hu Lin , Liu Dong , Hu Lulu , Sun Zongzong , Zhang Miao , Zhang Chenchen , Wang Yixin , Lin Pengkun
Published: April 2024

Background

The objective was to investigate the efficacy of different doses of levothyroxine therapy among pregnant women exhibiting high-normal thyroid stimulating hormone levels and positive thyroid peroxidase antibodies throughout the first half of pregnancy.

Methods

Pregnant women exhibiting high-normal thyroid stimulating hormone levels and thyroid peroxidase antibodies positivity throughout the initial half of pregnancy were selected from January 2021 to September 2023. Based on the different doses of levothyroxine, the pregnant women were categorized into the nonintervention group (G0, 122 women), 25 µg levothyroxine intervention group (G25, 69 women), and 50 µg levothyroxine intervention group (G50, 58 women). Serum parameters, gastrointestinal symptoms, small intestinal bacterial overgrowth (SIBO), maternal and neonatal outcomes were compared after the intervention among the three groups.

Results

After the intervention, in the G25 and G50 groups, the thyroid stimulating hormone, triglyceride and low-density lipoprotein levels were notably less in contrast to those in the G0 group (P < 0.05). The rates of abdominal distension and SIBO in the G25 and G50 groups were notably lower in contrast to the G0 group (P = 0.043 and 0.040, respectively). The G50 group had a lower rate of spontaneous abortion and premature membrane rupture than the G0 group (P = 0.01 and 0.015, respectively). Before 11+ 2 weeks of gestation and at thyroid peroxidase antibodies levels ≥ 117 IU/mL, in contrast to the G0 group, the G50 group experienced a decreased rate of spontaneous abortion (P = 0.008). The G50 group had significantly higher newborn weight than the G0 group (P = 0.014), as well as a notably longer newborn length than the G0 and G25 groups (P = 0.005).

Conclusions

For pregnant women with high-normal thyroid stimulating hormone levels and thyroid peroxidase antibodies positive during the first half of pregnancy, supplementation with 50 µg levothyroxine was more effective in improving their blood lipid status and gastrointestinal symptoms, reducing the incidence of SIBO and premature rupture of membranes, and before 11+2 weeks, TPOAb ≥ 117 IU/mL proved more beneficial in mitigating the risk of spontaneous abortion.
VDR promotes pancreatic cancer progression in vivo by activating CCL20-mediated M2 polarization of tumor associated macrophage
Authors: Li Hengzhen , Ruan Yuli , Liu Chao , Fan Xiaona , Yao Yuanfei , Dai Yisheng , Song Yushuai , Jiang Dan , Sun Ning , Jiao Guangtao , Chen Zhuo , Fan Shiheng , Meng Fanfei , Yang Huike , Zhang Yanqiao , Li Zhiwei
Published: April 2024

Background

Activation of VDR pathway was a promising anti-tumor therapy strategy. However, numerous clinical studies have demonstrated the effect of activating VDR is limited, which indicates that VDR plays a complex role in vivos.

Methods

We analyzed the TCGA database to examine the association between VDR expression and immune cell infiltration in pancreatic adenocarcinoma (PAAD). Western blot, ELISA, ChIP, and dual-luciferase reporter assays were performed to determine the mechanism of VDR regulating CCL20. Migration assay and immunofluorescence were used to investigate the role of CCL20 in M2 macrophage polarization and recruitment. We employed multiplexed immunohistochemical staining and mouse models to validate the correlation of VDR on macrophages infiltration in PAAD. Flow cytometry analysis of M2/M1 ratio in subcutaneous graft tumors.

Results

VDR is extensively expressed in PAAD, and patients with elevated VDR levels exhibited a significantly reduced overall survival. VDR expression in PAAD tissues was associated with increased M2 macrophages infiltration. PAAD cells overexpressing VDR promote macrophages polarization towards M2 phenotype and recruitment in vitro and vivo. Mechanistically, VDR binds to the CCL20 promoter and up-regulates its transcription. The effects of polarization and recruitment on macrophages can be rescued by blocking CCL20. Finally, the relationship between VDR and M2 macrophages infiltration was evaluated using clinical cohort and subcutaneous graft tumors. A positive correlation was demonstrated between VDR/CCL20/CD163 in PAAD tissues and mouse models.

Conclusion

High expression of VDR in PAAD promotes M2 macrophage polarization and recruitment through the secretion of CCL20, which activates tumor progression. This finding suggests that the combination of anti-macrophage therapy may improve the efficacy of VDR activation therapy in PAAD.
Surgeon-modified fenestrated endovascular grafts and thoracoscope-assisted fixation for treatment of thoraco-abdominal aortic aneurysms
Authors: Wang Hong , Wang Wei , Wang Weifan , Liu Debin
Published: April 2024

Background

Total endovascular technique with fenestrated endovascular graft might be hampered for the late dilatation of proximal landing zone, which may cause endografts migration. We describe a successful urgent hybrid procedure for extent III thoracoabdominal aortic aneurysm with aortic intramural hematoma.

Case Presentation

A 55-year-old female with thoracoabdominal aortic aneurysm was considered at high surgical risk and unfit for open repair due to multiple comorbidities. Therefore, a hybrid procedure of surgeon-modified fenestrated endovascular graft combined with thoracoscope-assisted Transaortic epicardial fixation of endograft was finally chosen and performed in the endovascular operating room. A 3-port technique was performed through a left video-assisted thoracoscopic approach. After the first tampering stent-graft was deployed, a double-needle suture was penetrated both the aortic wall and stent-graft to fixate it in the proximal descending aorta. Then the second endograft, which had been fenestrated on table, was introduced and oriented extracorporeally by rotating superior mesenteric artery and left renal artery fenestration radiopaque markers and deployed with perfect apposition between the fenestrations and target visceral artery. Each vessel was sequentially stented using Viabahn self-expandable stent to finish target vessel stenting. An Ankura cuff stent was deployed in the distal abdominal aortic artery.

Conclusion

Surgeon-modified fenestrated endovascular graft combined with thoracoscope-assisted fixation may be an innovative and viable alternative for selected high-risk patients with extent III thoracoabdominal aortic aneurysm. A longer follow-up is needed to ascertain the success of this approach.
RISEinFAMILY project: the integration of families at neonatal intensive care units (NICUs) to empower them as primary caregivers: study protocol for a stepped wedge cluster controlled trial
Authors: Alferink M. T. , Moreno-Sanz B. , Cabrera-Lafuente M. , Ergenekon E. , de Haan T. R. , van Kempen A. A. M. W. , Lakhwani J. , Rabe H. , Zaharie G. C. , Pellicer A. ,   on behalf of the RISEinFAMILY Consortium (European Union, MSCA-RISE-H2020)
Published: April 2024

Background

Family Integrated Care (FICare) has demonstrated positive outcomes for sick neonates and has alleviated the psychological burden faced by families. FICare involves structured training for professionals and caregivers along with the provision of resources to offer physical and psychological support to parents. However, FICare implementation has been primarily limited to developed countries. It remains crucial to assess the scalability of this model in overcoming social-cultural barriers and conduct a cost-effectiveness analysis. The RISEinFAMILY project aims to develop an adapted FICare model that can serve as the international standard for neonatal care, accommodating various cultural, architectural, and socio-economic contexts.

Methods

RISEinFAMILY is a pluri-cultural, stepped wedge cluster controlled trial conducted in Spain, Netherlands, the UK, Romania, Turkey, and Zambia. Eligible participants include infant-family dyads admitted to the Neonatal Intensive Care Unit (NICU) requiring specialised neonatal care for a minimum expected duration of 7 days, provided there are no comprehension barriers. Notably, this study will incorporate a value of implementation analysis on FICare, which can inform policy decisions regarding investment in implementation activities, even in situations with diverse data.

Discussion

This study aims to evaluate the scalability and adaptation of FICare across a broader range of geographical and sociocultural contexts and address its sustainability. Furthermore, it seeks to compare the RISEinFAMILY model with standard care, examining differences in short-term newborn outcomes, family mental health, and professional satisfaction.

Trial registration

ClinicalTrials.gov NCT06087666. Registered on 17 October 2023. Protocol version: 19 December 2022; version 2.2.
Australasian Malignant PLeural Effusion (AMPLE)-4 trial: study protocol for a multi-centre randomised trial of topical antibiotics prophylaxis for infections of indwelling pleural catheters
Authors: Lau Estee P. M. , Ing Matthew , Vekaria Sona , Tan Ai Ling , Charlesworth Chloe , Fysh Edward , Shrestha Ranjan , Yap Elaine L. C. , Smith Nicola A. , Kwan Benjamin C. H. , Saghaie Tajalli , Roy Bapti , Goddard John , Muruganandan Sanjeevan , Badiei Arash , Nguyen Phan , Hamid Mohamed Faisal Abdul , George Vineeth , Fitzgerald Deirdre , Maskell Nick , Feller-Kopman David , Murray Kevin , Chakera Aron , Lee Y C Gary
Published: April 2024

Background

Malignant pleural effusion (MPE) is a debilitating condition as it commonly causes disabling breathlessness and impairs quality of life (QoL). Indwelling pleural catheter (IPC) offers an effective alternative for the management of MPE. However, IPC-related infections remain a significant concern and there are currently no long-term strategies for their prevention. The Australasian Malignant PLeural Effusion (AMPLE)-4 trial is a multicentre randomised trial that evaluates the use of topical mupirocin prophylaxis (vs no mupirocin) to reduce catheter-related infections in patients with MPE treated with an IPC.

Methods

A pragmatic, multi-centre, open-labelled, randomised trial. Eligible patients with MPE and an IPC will be randomised 1:1 to either regular topical mupirocin prophylaxis or no mupirocin (standard care). For the interventional arm, topical mupirocin will be applied around the IPC exit-site after each drainage, at least twice weekly. Weekly follow-up via phone calls or in person will be conducted for up to 6 months. The primary outcome is the percentage of patients who develop an IPC-related (pleural, skin, or tract) infection between the time of catheter insertion and end of follow-up period. Secondary outcomes include analyses of infection (types and episodes), hospitalisation days, health economics, adverse events, and survival. Subject to interim analyses, the trial will recruit up to 418 participants.

Discussion

Results from this trial will determine the efficacy of mupirocin prophylaxis in patients who require IPC for MPE. It will provide data on infection rates, microbiology, and potentially infection pathways associated with IPC-related infections.

Ethics and dissemination

Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee has approved the study (RGS0000005920). Results will be published in peer-reviewed journals and presented at scientific conferences.

Trial registration

Australia New Zealand Clinical Trial Registry ACTRN12623000253606. Registered on 9 March 2023.
Safety and efficacy of ketorolac in improving the prognosis of acute type A aortic dissection patients: a protocol of a randomized, double-blinded, and placebo-controlled study
Authors: Lv Zhikang , Pan Tuo , Zhang Haitao , Wang Yapeng , Matniyaz Yusanjian , Tang Yuxian , Lu Lichong , Wang Dongjin
Published: April 2024

Background

Acute type A aortic dissection (aTAAD) is a critical and life-threatening condition. Previous research has demonstrated that the use of ketorolac not only reduces the progression, incidence, and severity of aortic aneurysms in animal models, but also decreases postoperative mortality and complications in patients undergoing open abdominal aortic aneurysm replacement. However, there is a lack of studies investigating the efficacy of ketorolac in treating aTAAD in humans. Therefore, we conducted a study to evaluate the safety and efficacy of ketorolac in patients with aTAAD. Our hypothesis was that ketorolac treatment for aTAAD patients would meet safety indicators and effectively improve patient prognosis.

Methods/design

This study is a single-center, randomized, double-blinded, and placebo-controlled study. A total of 120 patients with aTAAD will be recruited and will be randomized into the ketorolac group and placebo group with a ratio of 1:1. Ketorolac tromethamine 60 mg per 2 ml will be intramuscularly injected within 2 h before surgery, followed by intramuscular injections of 30 mg per 1 ml BID. on the first and second postoperative days in the Ketorolac group, while 0.9% saline will be administered at the same dose, dosage form, and time in the placebo group. This study aims to evaluate the safety and efficacy of ketorolac in improving the prognosis of aTAAD. The primary endpoint is the composite endpoint event concerning drug-related adverse events. Secondary endpoints include drug-related adverse events, laboratory examination of blood, diagnostic imaging tests, clinical biomarkers, etc.

Discussion

This study has been approved by the Medical Ethics Committee of Affiliated Nanjing Drum Tower Hospital, Nanjing University Medical College (approval number: 2023–197-02). This study is designed to evaluate the safety and efficacy of ketorolac in patients with aTAAD. All participating patients will sign an informed consent form, and the trial results will be published in international peer-reviewed journals.

Trial registration

The Chinese Clinical Trial Registry (http://www.chictr.org.cn) ChiCTR2300074394. Registered on 4 October 2023.
Advances in the study of the interaction between schistosome infections and the host's intestinal microorganisms
Authors: Hong Ao , Umar Abdulrahim , Chen Hao , Yu Zheng , Huang Jing
Published: April 2024

Schistosomiasis, also called bilharziasis, is a neglected tropical disease induced by schistosomes that infects hundreds of millions of people worldwide. In the life cycle of schistosomiasis, eggs are regarded as the main pathogenic factor, causing granuloma formation in the tissues and organs of hosts, which can cause severe gastrointestinal and liver granulomatous immune responses and irreversible fibrosis. Increasing evidence suggests that the gut microbiome influences the progression of schistosomiasis and plays a central role in liver disease via the gut–liver axis. When used as pharmaceutical supplements or adjunctive therapy, probiotics have shown promising results in preventing, mitigating, and even treating schistosomiasis. This review elucidates the potential mechanisms of this three-way parasite–host–microbiome interaction by summarizing schistosome-mediated intestinal flora disorders, local immune changes, and host metabolic changes, and elaborates the important role of the gut microbiome in liver disease after schistosome infection through the gut–liver axis. Understanding the mechanisms behind this interaction may aid in the discovery of probiotics as novel therapeutic targets and sustainable control strategies for schistosomiasis.

Graphical Abstract
Effectiveness of immunoglobulin replacement therapy in preventing infections in patients with chronic obstructive pulmonary disease: a systematic review
Authors: Kim Justin J. Y. , Dennett Liz , Ospina Maria B. , Hicks Anne , Vliagoftis Harissios , Adatia Adil
Published: April 2024

Purpose

Immunoglobulin replacement therapy is a standard treatment for patients with antibody production deficiencies, which is of interest in patients with chronic obstructive pulmonary disease (COPD). This systematic review, registered with PROSPERO (CRD42021281118), assessed the current literature regarding immunoglobulin replacement therapy on COPD clinical outcomes in patients with low immunoglobulin G (IgG) serum concentrations.

Methods

Literature searches conducted from inception to August 23, 2021, in databases including MEDLINE, EMBASE, and CINAHL. Population (sex, age, comorbidities), baseline clinical characteristics (pulmonary function testing results, IgG levels), and outcome (hospitalizations, emergency department visits) were extracted after title/abstract and full text screening. The Cochrane risk of bias assessment form was used for risk of bias assessment of randomized controlled trials and the National Heart, Lung, and Blood Institute (NHLBI) assessment was used for pre and post studies.

Results

A total of 1381 studies were identified in the preliminary search, and 874 records were screened after duplicates were removed. Screening 77 full texts yielded four studies that were included in the review.

Conclusion

It is unclear whether immune globulin replacement therapy reduces acute exacerbation frequency and severity in COPD. Current evidence suggests that it is worth considering, but better developed protocols for administration of immune globulin supplementation is required for future randomized controlled trials.
Allogeneic bone marrow mesenchymal stem cell-derived exosomes alleviate human hypoxic AKI-on-a-Chip within a tight treatment window
Authors: Çam Sefa Burak , Çiftci Eda , Gürbüz Nazlıhan , Altun Bülent , Korkusuz Petek
Published: April 2024

Background

Acute hypoxic proximal tubule (PT) injury and subsequent maladaptive repair present high mortality and increased risk of acute kidney injury (AKI) - chronic kidney disease (CKD) transition. Human bone marrow mesenchymal stem cell-derived exosomes (hBMMSC-Exos) as potential cell therapeutics can be translated into clinics if drawbacks on safety and efficacy are clarified. Here, we determined the real-time effective dose and treatment window of allogeneic hBMMSC-Exos, evaluated their performance on the structural and functional integrity of 3D microfluidic acute hypoxic PT injury platform.

Methods

hBMMSC-Exos were isolated and characterized. Real-time impedance-based cell proliferation analysis (RTCA) determined the effective dose and treatment window for acute hypoxic PT injury. A 2-lane 3D gravity-driven microfluidic platform was set to mimic PT in vitro. ZO-1, acetylated α-tubulin immunolabelling, and permeability index assessed structural; cell proliferation by WST-1 measured functional integrity of PT.

Results

hBMMSC-Exos induced PT proliferation with ED50 of 172,582 µg/ml at the 26th hour. Hypoxia significantly decreased ZO-1, increased permeability index, and decreased cell proliferation rate on 24–48 h in the microfluidic platform. hBMMSC-Exos reinforced polarity by a 1.72-fold increase in ZO-1, restored permeability by 20/45-fold against 20/155 kDa dextran and increased epithelial proliferation 3-fold compared to control.

Conclusions

The real-time potency assay and 3D gravity-driven microfluidic acute hypoxic PT injury platform precisely demonstrated the therapeutic performance window of allogeneic hBMMSC-Exos on ischemic AKI based on structural and functional cellular data. The novel standardized, non-invasive two-step system validates the cell-based personalized theragnostic tool in a real-time physiological microenvironment prior to safe and efficient clinical usage in nephrology.
Automatic classification of spread‐F types in ionogram images using support vector machine and convolutional neural network
Authors: Benchawattananon Phongsachot , Siritaratiwat Apirat , Supnithi Pornchai , Nishioka Michi , Perwitasari Septi , Suthisopapan Puripong , Kruesubthaworn Anan
Published: April 2024

An ionogram image serves as a valuable data for examining the ionospheric bottom side characteristics and variabilities. Spread-F is indicated or identified by plasma irregularity in the ionospheric region. Diffused echo in the ionogram images particularly pose challenges for efficient interpretation required in further applications. An automatic classification of spread-F is presented in this study. Ionogram images are automatically classified using preprocessing techniques to improve the classification performance. In this study, the classification is designed by two machine learning algorithms, including support vector machine (SVM) and convolutional neural network (CNN). The CNN model with preprocessing technique outperforms the SVM alternative based on 4,692 labelled ionogram images from the FMCW-type ionosonde at Chumphon station, Thailand. The model successfully classified clear, frequency spread-F (FSF), range spread-F (RSF), strong spread-F (SSF), and unidentified class with an accuracy of 98.0%, 85.1%, 90.7%, 66.7%, and 99.2%, respectively. The proposed automatic classification models achieved to classify classes of ionogram images. In addition, the image filtering and data preprocessing are useful with ionogram images for improving the model classification performance.

Graphical Abstract
Braille glove design toward interdisciplinary approach for visually impaired people: developing independent sensing design with MXene and embroidery
Authors: Kim Miha , Shin Hwansoo , Jekal Mee
Published: April 2024

This study developed a wearable device designed to aid visually impaired people (VIP) who are unfamiliar with Braille and/or struggle to learn and use Braille employing the design thinking process. VIP often face challenges in learning and using Braille, and even with existing equipment, including smart technologies, they frequently experience aesthetic and emotional discomfort beyond usability and accessibility. The interdisciplinary research team conducted mixed-method research following the double diamond module of the design thinking process. Initially, qualitative interviews to analyze VIP’s Braille utilization were conducted to derive design factors. Subsequently, identified design factors were applied to conduct experiments with appropriate embroidery methods and connection structures using MXene-coated yarn. The strategies effectively enhanced pressure sensing performance by two times and realized highly localized and independent sensing to enable Braille recognition. Finally, a specific design for the wearable Braille recognition glove was proposed that incorporated these findings. The proposed wearable glove, equipped with a high-performance Braille recognition sensor, is designed to enhance the psychological and aesthetic satisfaction of VIP. The glove’s universal design and accompanying technical support allow VIP to maintain their existing Braille reading methods while enjoying enhanced performance and avoiding social stigmas.
CA19-9 producing locally advanced papillary thyroid carcinoma: a case report
Authors: Morikawa Hiroki , Oba Takaaki , Kitazawa Ayaka , Iji Ryoko , Kiyosawa Nami , Amitani Masatsugu , Shimizu Tadafumi , Kanai Toshiharu , Uehara Takeshi , Ito Ken-ichi
Published: April 2024

Background

CA19-9 is a tumor marker for gastrointestinal and biliary-pancreatic adenocarcinomas; however, its association with thyroid cancer is unknown. Here, we report a case of CA19-9 producing locally advanced papillary thyroid carcinoma (PTC).

Case presentation

A 66-year-old woman who was identified with a thyroid tumor after a close examination of an elevated serum CA19-9 level, which was detected at health screening, was referred to our hospital. Ultrasonography revealed a 34 × 31 mm hypoechoic lesion in the lower pole of the left thyroid lobe. Computed tomography revealed a solid thyroid tumor with tracheal invasion without any distant metastases. Bronchoscopy revealed tumor exposure into the tracheal lumen on the left side of the trachea. Fine-needle aspiration cytology led to a diagnosis of papillary thyroid carcinoma (PTC). The patient underwent a total thyroidectomy, tracheal sleeve resection with end-to-end anastomosis, and lymph node dissection in the left cervical and superior mediastinal regions (D3c) with a reversed T-shaped upper sternotomy down to the third intercostal level. Histopathological analysis confirmed the diagnosis of PTC with tracheal invasion and no lymph node metastases (pT4a Ex2 N0). Immunohistochemical staining showed the expression of CA19-9 in cancer cells. Postoperatively, the serum CA19-9 level of the patient decreased to within the normal range.

Conclusions

Some PTCs produce CA19-9, although less frequently. When elevated serum CA19-9 levels are observed, PTC should be included in the differential diagnosis for further investigation.
Ambiguous citizenship policies: Examining implementation gaps across levels of legislation in Jordan
Authors: Frost Lillian
Published: April 2024

Despite the prevalence of ambiguous citizenship policies that say one thing in law and another in implementing regulations, few studies have focused on systematically studying this type of implementation gap, particularly in contexts beyond North America and Europe. This largely has remained the case despite research on discursive policy gaps, which occur between a policy’s stated objectives and its laws, efficacy gaps, which describe when a policy’s outcomes fail to meet its goals, and compliance gaps, which reflect disparities between a state’s commitments to international law and its corresponding domestic policies. How can we advance conceptualizations of law-regulation implementation gaps? This paper proposes one approach by focusing on the content of domestic laws, on the one hand, and the content of related implementing regulations, on the other. When law-regulation discrepancies occur, they illustrate the agency of senior officials in writing this intentional ambiguity into different levels of legislation, challenging assumptions about institutional weakness and lower-level bureaucratic discretion as chief drivers of implementation gaps. The paper illustrates this concept by analyzing discrepancies between Jordan’s nationality and passports laws and their related implementing regulations, particularly regarding Gaza refugees’ access to passports, investors’ access to nationality, and Palestinian-Jordanians’ subjection to nationality withdrawals. These diverse cases of intentional ambiguity demonstrate that such gaps can serve to partially exclude or include a group and can occur with noncitizen and citizen as well as more or less vulnerable groups.
Association of serum sodium minus chloride level at initiation of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and hyperkalemia in patients with CKD: a case control study
Authors: Mae Haruki , Fujimaru Takuya , Shimoyama Koutarou , Kadota Nozomi , Konishi Kasumi , Itou Yugo , Nagahama Masahiko , Taki Fumika , Nakayama Masaaki
Published: April 2024

Background

Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) exert a renoprotective effect on patients with chronic kidney disease (CKD). Despite their benefit, one of their side effects is hyperkalemia, and it is one of the most common reasons for discontinuation of these drugs. Hyperchloremic metabolic acidosis is a known risk factor for hyperkalemia in patients with CKD. However, whether it is a risk factor for hyperkalemia after initiating ACE-I or ARB remains unclear.

Methods

In a previous study, serum sodium minus chloride level ([Na+) − (Cl−]) was identified as useful for diagnosing metabolic acidosis. To estimate the baseline acid–base status, we determined for the cutoff value of [Na+] − [Cl−] that correlates with [HCO3−] below 24 mEq/L in patients with CKD. We then investigated whether this cutoff value was associated with hyperkalemia (serum potassium level ≥ 5.0 mEq/L) after initiating ACE-I or ARB in patients with CKD.

Results

In the investigation of the cutoff value of [Na+] − [Cl−], 612 patients were examined, and [Na+] − [Cl−] showed a good correlation with [HCO3−] (r = 0.67, p < 0.001). Based on receiver operating curve analysis, we derived a cut-off value of [Na+] − [Cl−] below 33.5 mEq/L. Using this cut off value, the sensitivity and specificity of [Na+] − [Cl−] for metabolic acidosis were 75.2% and 75.0%, respectively. To explore whether metabolic acidosis is associated with hyperkalemia after initiating ACE-I or ARB, we examined 1143 patients with CKD. Among this cohort, 403 (35.3%) patients had [Na+] − [Cl−] < 33.5 mEq/L at baseline, and the incidence of hyperkalemia was significantly higher in univariate analysis (9.2% versus 4.2%, p = 0.03). However, in multivariate analysis, [Na+] − [Cl−] < 33.5 mEq/L was not associated with hyperkalemia (odds ratio 1.13; 95% confidence interval 0.65–1.95).

Conclusions

Hyperchloremic metabolic acidosis was not associated with hyperkalemia after initiation of ACE-I or ARB in patients with CKD.
Hyperpolarized [1-13C]-pyruvate MRS evaluates immune potential and predicts response to radiotherapy in cervical cancer
Authors: Lin Gigin , Hsieh Ching-Yi , Lai Ying-Chieh , Wang Chun-Chieh , Lin Yenpo , Lu Kuan-Ying , Chai Wen-Yen , Chen Albert P. , Yen Tzu-Chen , Ng Shu-Hang , Lai Chyong-Huey
Published: April 2024

Background

Monitoring pyruvate metabolism in the spleen is important for assessing immune activity and achieving successful radiotherapy for cervical cancer due to the significance of the abscopal effect. We aimed to explore the feasibility of utilizing hyperpolarized (HP) [1-13C]-pyruvate magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to evaluate pyruvate metabolism in the human spleen, with the aim of identifying potential candidates for radiotherapy in cervical cancer.

Methods

This prospective study recruited six female patients with cervical cancer (median age 55 years; range 39–60) evaluated using HP [1-13C]-pyruvate MRI/MRS at baseline and 2 weeks after radiotherapy. Proton (1H) diffusion-weighted MRI was performed in parallel to estimate splenic cellularity. The primary outcome was defined as tumor response to radiotherapy. The Student t-test was used for comparing 13C data between the groups.

Results

The splenic HP [1-13C]-lactate-to-total carbon (tC) ratio was 5.6-fold lower in the responders than in the non-responders at baseline (p = 0.009). The splenic [1-13C]-lactate-to-tC ratio revealed a 1.7-fold increase (p = 0.415) and the splenic [1-13C]-alanine-to-tC ratio revealed a 1.8-fold increase after radiotherapy (p = 0.482). The blood leukocyte differential count revealed an increased proportion of neutrophils two weeks following treatment, indicating enhanced immune activity (p = 0.013). The splenic apparent diffusion coefficient values between the groups were not significantly different.

Conclusions

This exploratory study revealed the feasibility of HP [1-13C]-pyruvate MRS of the spleen for evaluating baseline immune potential, which was associated with clinical outcomes of cervical cancer after radiotherapy.

Trial registration

ClinicalTrials.gov NCT04951921, registered 7 July 2021.

Relevance statement

This prospective study revealed the feasibility of using HP 13C MRI/MRS for assessing pyruvate metabolism of the spleen to evaluate the patients’ immune potential that is associated with radiotherapeutic clinical outcomes in cervical cancer.

Key points

• Effective radiotherapy induces abscopal effect via altering immune metabolism.

• Hyperpolarized 13C MRS evaluates patients’ immune potential non-invasively.

• Pyruvate-to-lactate conversion in the spleen is elevated following radiotherapy.

Graphical Abstract
Evaluation of the EMulate Therapeutics Voyager’s ultra-low radiofrequency energy in murine model of glioblastoma
Authors: Mukthavaram Rajesh , Jiang Pengfei , Pastorino Sandra , Nomura Natsuko , Lin Feng , Kesari Santosh
Published: April 2024

Background

Glioblastoma (GBM) presents as an aggressive brain cancer, notorious for its recurrence and resistance to conventional treatments. This study aimed to assess the efficacy of the EMulate Therapeutics Voyager®, a non-invasive, non-thermal, non-ionizing, battery-operated, portable experimental medical device, in treating GBM. Using ultra-low radiofrequency energy (ulRFE) to modulate intracellular activity, previous preliminary results in patients have been encouraging. Now, with a focus on murine models, our investigation seeks to elucidate the device's mechanistic impacts, further optimizing its therapeutic potential and understanding its limitations.

Methods

The device employs a silicone over molded coil to deliver oscillating magnetic fields, which are believed to interact with and disrupt cellular targets. These fields are derived from the magnetic fluctuations of solvated molecules. Xenograft and syngeneic murine models were chosen for the study. Mice were injected with U-87 MG or GL261 glioma cells in their flanks and were subsequently treated with one of two ulRFE cognates: A1A, inspired by paclitaxel, or A2, based on murine siRNA targeting CTLA4 + PD1. A separate group of untreated mice was maintained as controls.

Results

Mice that underwent treatments with either A1A or A2 exhibited significantly reduced tumor sizes when compared to the untreated cohort.

Conclusion

The EMulate Therapeutics Voyager® demonstrates promising potential in inhibiting glioma cells in vivo through its unique ulRFE technology and should be further studied in terms of biological effects in vitro and in vivo.
Assessing the effect of childbearing on blood DNA methylation through comparison of parous and nulliparous females
Authors: Chen Su , Johs Miranda , Karmaus Wilfried , Holloway John W. , Kheirkhah Rahimabad Parnian , Goodrich Jaclyn M. , Peterson Karen E. , Dolinoy Dana C. , Arshad S. Hasan , Ewart Susan
Published: April 2024

Background

Pregnancy and childbirth have been connected to modified risk of a wide variety of conditions in later life, including neurodegenerative disorders and cancers. The presence, extent, and direction of the effect that childbearing status has on decreasing or increasing the risk of these conditions differs depending on the disease. The mechanisms by which pregnancy and childbirth modify the risk of diseases are still unknown. DNA methylation (DNAm) alterations that occur during pregnancy and persist after childbirth may help us understand this phenomenon.

Results

Blood DNAm was available from 89 women (28 parous; 61 nulliparous) at ages 18 and 26 years in the Isle of Wight birth cohort; no significant differences in the population characteristics were present between the analyzed population and the full cohort. We performed an epigenome-wide association study on 389,355 CpGs and identified 184 CpGs to be significantly differentially methylated between parous and nulliparous women after adjusting for confounders and multiple testing. Of these CpGs, 105 had regression coefficients in the same direction in an independent Mexico City based ELEMENT cohort, of which 13 were significant (replication P < 0.05). These 13 CpGs were associated with 16 unique genes. DNAm levels tracked with gene expression in 3 of the replicated genes, one of which (TM2D3) was differentially expressed in parous vs nulliparous women. Gene disease association analysis identified a network of parous-associated diseases.

Conclusions

Our results suggest that pregnancy and childbirth lead to DNAm changes in parous women and these changes persist at least 6 months and up to 8 years postpartum. Parous-related CpG sites may play a role in how childbearing status modifies risk of later life diseases in women. Further studies are needed to explore the linkage and mechanism.
Culturally adapted Turkish version of an internet-based mindfulness intervention for university students: a randomized controlled feasibility trial
Authors: Balci Sumeyye , Küchler Ann-Marie , Ebert David Daniel , Baumeister Harald
Published: April 2024

Background

Studying at university is a stressful time for many, which might result in the development of mental health problems. In the first wave of Covid-19, university students in Turkey reported suffering from an elevated level of stress compared to their peers in other countries. Mindfulness-based interventions could provide the means of successfully decreasing the stress level of university students. Moreover, offering interventions via the Internet could be a scalable option to prevent and treat mental health problems, while offering time/place flexibility, anonymity, and cost-effectiveness.

Method

In a randomized controlled trial of parallel design, the feasibility of a culturally adapted internet- and mobile-based intervention (IMI) (StudiCareM-TR) to promote mindfulness among Turkish-speaking university students was tested. Participants (N = 58) of a public university in Istanbul were randomized into an intervention (IG) vs. waitlist control group (WL). Measurements took place at baseline (t0) and 10 weeks post-randomization (t1). Intervention adherence, acceptance, and potential negative effects were feasibility outcomes. Levels of mindfulness, perceived stress, depression, anxiety, and wellbeing were analyzed in linear regression models to assess the potential efficacy of StudiCareM-TR. All analyses were conducted with the intention-to-treat sample, adjusting for baseline values.

Results

Based on participants’ feedback, StudiCareM-TR was perceived as acceptable, resulted in few negative effects (n = 7), and yielded improvements in mindfulness (β = 0.70) and presenteeism (β = − 0.61) compared to WL. Secondary outcomes of depression, anxiety, stress, and wellbeing did not show significant improvements. Assessment dropout was 31% (IG: 50%: WL: 89%), and intervention dropout was 45%.

Conclusions

StudiCareM-TR is feasible and acceptable to use among university students in Turkey and has the potential to improve their mindfulness levels. The intervention should be further developed with a focus on engagement-facilitating features in order to reduce intervention dropouts.

Trial registration ID

DRKS00024557.
Effects of base frequency, duty cycle, and waveform repetition on transient electromagnetic responses: Insights from models of a deep-buried conductor
Authors: Li Jianhui , Wang Yao
Published: April 2024

In transient electromagnetic (TEM) methods, the recorded data for the magnetic field and its time derivative are influenced by the waveforms of the transmitting current. These waveforms are characterized by parameters such as the durations of the turn-on, steady, and turn-off stages as well as the base frequency, duty cycle, and waveform repetition. The full-waveform effects encompass all counteracting effects observed in TEM responses that arise from using a waveform other than a step-off or step-on waveform. To address these complexities, a 3D forward-modeling solver is developed for TEM methods, capable of calculating TEM responses while considering realistic waveforms with considerations for base frequency, duty cycle, and waveform repetition. The effects of these parameters on the magnetic field and its time derivative are investigated through numerical experiments using models involving deep-buried horizontal and vertical conductors. The results indicate that as the waveform period increases, there is a significant improvement in the detection and discrimination capability of the magnetic field for perfect conductors with a conductivity of 1000 S/m or higher in the models presented in this study. However, the improvement in the time derivative of the magnetic field is minimal. Interestingly, the improvement in the magnetic field and its time derivative does not indicate a consistent trend as the conductor conductivity increases. In addition, a novel equivalence phenomenon is uncovered in the magnetic field and its time derivative data. The results also suggest that as the number of waveform repetitions increases or the duty cycle decreases, the discrepancies between the recorded TEM responses at the two off-time stages within a single period gradually diminish. However, the influence of the full waveform on the TEM responses becomes more pronounced with an increasing number of waveform repetitions or a decrease in the duty cycle, especially in terms of the magnetic field.
Cystatin C Is a Predictor for Long-Term, All-Cause, and Cardiovascular Mortality in US Adults With Metabolic Syndrome
Authors: Song Xiaoying , Xiong Lijiao , Guo Tianting , Chen Xue , Zhang Pinjun , Zhang Xiaoan , Liang Zhen
Published: April 2024

Objective

This study examined the relationship between cystatin C (CysC) levels and all-cause, cardiovascular disease (CVD), and cancer mortality in US metabolic syndrome (MetS) patients.

Methods

The 1999-2002 National Health and Nutrition Examination Survey (NHANES) prospective cohort research included 1980 MetS participants. To assess CysC levels and all-cause, CVD, and cancer mortality, fitted curves, Kaplan-Meier survival curves, Cox regression analysis, and receiver operating characteristic curves were performed.

Results

During a mean follow-up of 15.3 ± 5.4 years, a total of 819 deaths occurred. The fitted and Kaplan-Meier survival curves revealed that greater CysC levels were linked to higher all-cause, CVD, and cancer mortality rates (P < .05). After adjusting for variables, CysC level was associated with all-cause, CVD, and cancer mortality at 1.63 (1.42-1.88), 1.53 (1.19-1.95), and 1.53 (1 ∼ 2.32), respectively (P < .05). Tertile models showed consistent results: high CysC Tertile participants showed higher risk of all-cause mortality (HR 1.87; 1.43-2.45), CVD mortality (HR 1.97, 1.15 ∼ 3.38), and cancer mortality (HR 1.72, 1.01 ∼ 2.91) compared to those in the lowest tertile (P < .05). Subgroup studies by sex and other characteristics confirmed the findings. CysC demonstrated the higher predictive efficacy across mortality outcomes, followed by eGFR, outperforming urea nitrogen, creatinine, uric acid, and C-reactive protein. CysC alone exhibited substantial predictive value for all-cause (AUC 0.773; P < .05) and CVD mortality (AUC 0.726; P < .05). Combining CysC with age enhanced predictive value for all-cause mortality to 0.861 and CVD mortality to 0.771 (P < .05).

Conclusion

MetS patients with elevated CysC levels have a higher risk of all-cause, CVD, and cancer death. CysC may predict MetS all-cause and CVD mortality.
Efficiency of a Neurosurgical Operating Room According to Nursing Characteristics in a University Hospital: From Operating Times to a Cost-Benefit Analysis
Authors: Bartoli Andrea , Pinget Christophe
Published: April 2024

BACKGROUND AND OBJECTIVES:

The primary objective of this study was to evaluate the influence of operating room nurse (ORN) characteristics on the duration of elective neurosurgical procedures in adults. In addition, we conducted a cost-benefit analysis of various strategies for organizing the workflow of ORNs.

METHODS:

We collected and analyzed operating times for adult elective neurosurgical procedures, categorizing them by surgeon, procedure complexity (dichotomized as technologically complex and simple), and ORN characteristics (dichotomized as ORN dedicated to neurosurgery [dORN] and ORN not dedicated to neurosurgery [ndORN]). The monetary valuation of operating times is based on the unitary cost per minute of the operating room, including opportunity costs of ORN, as well as their training costs and salaries. Cost-benefit analysis adopted the hospital perspective.

RESULTS:

Analysis of operating times reveals an approximately 20-minute difference for complex procedures when performed with ndORN. However, there is no significant difference in operating times for simple procedures, whether they are conducted by dORN or ndORN. The additional annual cost incurred by complex procedures performed with ndORN is estimated at CHF 68 144.4 for the Geneva University Hospitals.

CONCLUSION:

Complex neurosurgical procedures exhibit shorter durations when performed by dORNs. We explore several hypotheses to explain this difference. By adapting available human resources and optimizing workflow organization, hospitals can potentially achieve a net benefit.