bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimize data-driven multi-agent simulation for COVID-19 transmission
Authors: Jin Chao , Zhang Hao , Yin Ling , Zhang Yong , Feng Sheng-zhong
Published: July 2022

Background

Multi-Agent Simulation is an essential technique for exploring complex systems. In research of contagious diseases, it is widely exploited to analyze their spread mechanisms, especially for preventing COVID-19. Nowadays, transmission dynamics and interventions of COVID-19 have been elaborately established by this method, but its computation performance is seldomly concerned. As it usually suffers from inadequate CPU utilization and poor data locality, optimizing the performance is challenging and important for real-time analyzing its spreading.

Results

This paper explores approaches to optimize multi-agent simulation for COVID-19 disease. The focus of this work is on the algorithm and data structure designs for improving performance, as well as its parallelization strategies. We propose two successive methods to optimize the computation. We construct a case-focused iteration algorithm to improve data locality, and propose a fast data-mapping scheme called hierarchical hash table to accelerate hash operations. As a result, The case-focused method degrades $$\sim 90 \%$$

∼
90
%

cache references and achieves $$\times 4.3$$

×
4.3

speedup. Hierarchical hash table can further boost computation speed by 47%. And parallel implementation with 20 threads on CPU achieves $$\times 80$$

×
80

speedup consequently.

Conclusions

In this work, we propose optimizations for multi-agent simulation of COVID-19 transmission from aspects of algorithm and data structure. Benefit from improvement of locality and multi-thread implementation, our methods can significantly accelerate the simulation computation. It is promising in supporting real-time prevention of COVID-19 and other infectious diseases in the future.
MRI whole-lesion texture analysis on ADC maps for the prognostic assessment of ischemic stroke
Authors: Zhang Yuan , Zhuang Yuzhong , Ge Yaqiong , Wu Pu-Yeh , Zhao Jing , Wang Hao , Song Bin
Published: July 2022

Background

This study aims is to explore whether it is feasible to use magnetic resonance texture analysis (MRTA) in order to distinguish favorable from unfavorable function outcomes and determine the prognostic factors associated with favorable outcomes of stroke.

Methods

The retrospective study included 103 consecutive patients who confirmed unilateral anterior circulation subacute ischemic stroke by computed tomography angiography between January 2018 and September 2019. Patients were divided into favorable outcome (modified Rankin scale, mRS ≤ 2) and unfavorable outcome (mRS > 2) groups according to mRS scores at day 90. Two radiologists manually segmented the infarction lesions based on diffusion-weighted imaging and transferred the images to corresponding apparent diffusion coefficient (ADC) maps in order to extract texture features. The prediction models including clinical characteristics and texture features were built using multiple logistic regression. A univariate analysis was conducted to assess the performance of the mean ADC value of the infarction lesion. A Delong’s test was used to compare the predictive performance of models through the receiver operating characteristic curve.

Results

The mean ADC performance was moderate [AUC = 0.60, 95% confidence interval (CI) 0.49–0.71]. The texture feature model of the ADC map (tADC), contained seven texture features, and presented good prediction performance (AUC = 0.83, 95%CI 0.75–0.91). The energy obtained after wavelet transform, and the kurtosis and skewness obtained after Laplacian of Gaussian transformation were identified as independent prognostic factors for the favorable stroke outcomes. In addition, the combination of the tADC model and clinical characteristics (hypertension, diabetes mellitus, smoking, and atrial fibrillation) exhibited a subtly better performance (AUC = 0.86, 95%CI 0.79–0.93; P > 0.05, Delong’s).

Conclusion

The models based on MRTA on ADC maps are useful to evaluate the clinical function outcomes in patients with unilateral anterior circulation ischemic stroke. Energy obtained after wavelet transform, kurtosis obtained after Laplacian of Gaussian transform, and skewness obtained after Laplacian of Gaussian transform were identified as independent prognostic factors for favorable stroke outcomes.
A population-based validation study of the 8th edition UICC/AJCC TNM staging system for cutaneous melanoma
Authors: Hynes Matthew C. , Nguyen Paul , Groome Patti A. , Asai Yuka , Mavor Meaghan E. , Baetz Tara D. , Hanna Timothy P.
Published: July 2022

Background

The 8th edition UICC/AJCC TNM8 (Tumour, Nodes, Metastasis) melanoma staging system introduced several modifications from the 7th edition (TNM7), resulting in changes in survival and subgroup composition. We set out to address the limited validation of TNM8 (stages I-IV) in large population-based datasets.

Methods

This retrospective cohort-study included 6,414 patients from the population-based Ontario Cancer Registry diagnosed with cutaneous melanoma between January 1, 2007 and December 31, 2012. Kaplan–Meier curves estimated the melanoma-specific survival (MSS) and overall survival (OS). Cox proportional hazard models were used to estimate adjusted hazard ratios for MSS and OS across stage groups. The Schemper-Henderson measure was used to assess the variance explained in the Cox regression.

Results

In our sample, 21.3% of patients were reclassified with TNM8 from TNM7; reclassifications in stage II were uncommon, and 44.1% of patients in stage III were reclassified to a higher subgroup. Minimal changes in MSS curves were observed between editions, but the stage IIB curve decreased and the stage IIIC curve increased. For TNM8, Stage I (n = 4,556), II (n = 1,206), III (n = 598), and IV (n = 54) had an estimated 5-year MSS of 98.4%, 82.5%, 66.4%, and 14.4%, respectively. Within stage III, IIIA 5-year MSS was 91.7% while stage IIID was 23.5%. HRs indicated that TNM8 more evenly separates subgroups once adjusted for patient- and disease-characteristics. The variance in MSS explained by TNM7 and TNM8 is 18.9% and 19.7%, respectively.

Conclusion

TNM8 performed well in our sample, with more even separation of stage subgroups and a modest improvement in predictive ability compared to TNM7.
Efficacy and safety of pomalidomide and low-dose dexamethasone in Chinese patients with relapsed or refractory multiple myeloma: a multicenter, prospective, single-arm, phase 2 trial
Authors: Fu Wei-Jun , Wang Ya-Fei , Zhao Hong-Guo , Niu Ting , Fang Bai-Jun , Liao Ai-Jun , Bai Hai , Lu Jin
Published: July 2022

Background

Pomalidomide in combination with dexamethasone has demonstrated positive results in patients with relapsed or refractory multiple myeloma (RRMM), but no data are available in China. We conducted a multicenter, single-arm trial to examine the efficacy and safety of bioequivalent generic pomalidomide plus low-dose dexamethasone in Chinese RRMM patients.

Methods

Adult (≥ 18 years of age) RRMM patients who progressed after at least two previous treatments, including bortezomib and lenalidomide, were eligible. Pomalidomide was given orally at 4 mg/day on days 1 to 21 of a 28-day cycle. Dexamethasone was given at 40 mg/day (either orally or intravenously; 20 mg/day at 75 years or older) on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression or intolerable adverse events (AEs). The primary end point was objective response rate (ORR).

Results

Seventy-four patients were enrolled between February 2017 and February 2019. All patients had progressed within 60 days of their last therapy. 74.3% of the patients were resistant to lenalidomide, 31.1% had renal insufficiency and 33.8% had high-risk cytogenetic RRMM. The median follow-up duration was 33.0 months (range 31.1–34.8 months). The ORR was 37.8% in the overall analysis, 32.7% in lenalidomide-refractory patients, 36.0% in patients with high-risk cytogenetics and 34.8% in RRMM patients with renal impairment. The median progression-free survival was 5.7 months (95% CI 3.7–8.8 months). The median overall survival was 24.3 months (95% CI 14.4–41.1 months). The most common grade 3 and 4 treatment-emergent adverse events (TEAEs) were neutropenia (63.5%), leukopenia (37.8%), thrombocytopenia (28.4%), and anemia (31.1%). Pulmonary infection (27.0%) was the most frequent grade 3 and 4 nonhematologic TEAE. No previously unreported AEs were observed. No venous thromboembolism was reported.

Conclusions

Pomalidomide in combination with low-dose dexamethasone is effective and safe in Chinese RRMM patients.

Trial registration

The study is registered at Chinese Clinical Trial Registry (ChiCTR) (ChiCTR-OIC-17013234, first registered on 03/11/2017).
Prognostic significance of 4R lymph node dissection in patients with right primary non-small cell lung cancer
Authors: Zhou Di , Yue Dongsheng , Zhang Zhenfa , Tian Pengfei , Feng Yingnan , Liu Zuo , Zhang Bin , Wang Meng , Zhao Xiaoliang , Wang Changli
Published: July 2022

Background

To investigate the prognostic significance of station 4R lymph node (LN) dissection in patients who underwent operations for right primary non-small cell lung cancer (NSCLC).

Methods

We performed a retrospective study involving patients with right primary NSCLC who received lobotomy or pneumonectomy with mediastinal LN dissection between January 2011 and December 2017. Propensity score matching was performed. Disease-free survival (DFS) and overall survival (OS) were compared between patients with and without station 4R dissection.

Results

Our study included 2070 patients, with 207 patients having no station 4R dissection (S4RD− group) and 1863 patients having station 4R dissection (S4RD+ group). The 4R LN metastasis rate was 13.4% (142/1748), higher than that for other mediastinal LN metastases. Compared with the S4RD− group, the S4RD+ group had higher 5-year DFS (48.1% vs. 39.1%, P = 0.009) and OS (54.4% vs. 42.8%, P = 0.025). Station 4R dissection was an independent risk factor for DFS (odds ratio, OR, 1.28, 95% confidence interval, CI, 1.08–1.64, P = 0.007) and OS (OR 1.31, 95% CI 1.04–1.63, P = 0.018). Patients with adjuvant chemotherapy had a better prognosis after station 4R dissection than those without adjuvant chemotherapy (57.4% vs. 52.3%, P = 0.006). The 5-year OS in the station 4R metastasis group was lower than that in the station 4R non-metastasis group (26.9% vs. 44.3%, P = 0.006) among N2 patients. The 5-year OS of the single-station 4R metastasis group was lower than that of the single-station 7 metastasis group (15.7% vs. 51.6%, P = 0.002).

Conclusions

Station 4R metastasis was the highest among all the mediastinal station metastases in right primary NSCLC patients. Station 4R dissection can improve the prognosis and should be recommended as a routine procedure for these patients.
Proteomics-based investigation of cerebrovascular molecular mechanisms in cerebral amyloid angiopathy by the FFPE-LMD-PCT-SWATH method
Authors: Handa Takumi , Sasaki Hayate , Takao Masaki , Tano Mitsutoshi , Uchida Yasuo
Published: July 2022

Background

Cerebral amyloid angiopathy (CAA) occurs in 80% of patients with Alzheimer’s disease (AD) and is mainly caused by the abnormal deposition of Aβ in the walls of cerebral blood vessels. Cerebrovascular molecular mechanisms in CAA were investigated by using comprehensive and accurate quantitative proteomics.

Methods

Concerning the molecular mechanisms specific to CAA, formalin-fixed paraffin-embedded (FFPE) sections were prepared from patients having AD neuropathologic change (ADNC) with severe cortical Aβ vascular deposition (ADNC +/CAA +), and from patients having ADNC without vascular deposition of Aβ (ADNC +/CAA −; so called, AD). Cerebral cortical vessels were isolated from FFPE sections using laser microdissection (LMD), processed by pressure cycling technology (PCT), and applied to SWATH (sequential window acquisition of all theoretical fragment ion spectra) proteomics.

Results

The protein expression levels of 17 proteins in ADNC +/CAA +/H donors (ADNC +/CAA + donors with highly abundant Aβ in capillaries) were significantly different from those in ADNC +/CAA − and ADNC −/CAA − donors. Furthermore, we identified 56 proteins showing more than a 1.5-fold difference in average expression levels between ADNC +/CAA + and ADNC −/CAA − donors, and were significantly correlated with the levels of Aβ or Collagen alpha-2(VI) chain (COL6A2) (CAA markers) in 11 donors (6 ADNC +/CAA + and 5 ADNC −/CAA −). Over 70% of the 56 proteins showed ADNC +/CAA + specific changes in protein expression. The comparative analysis with brain parenchyma showed that more than 90% of the 56 proteins were vascular-specific pathological changes. A literature-based pathway analysis showed that 42 proteins are associated with fibrosis, oxidative stress and apoptosis. This included the increased expression of Heat shock protein HSP 90-alpha, CD44 antigen and Carbonic anhydrase 1 which are inhibited by potential drugs against CAA.

Conclusions

The combination of LMD-based isolation of vessels from FFPE sections, PCT-assisted sample processing and SWATH analysis (FFPE-LMD-PCT-SWATH method) revealed for the first time the changes in the expression of many proteins that are involved in fibrosis, ROS production and cell death in ADNC +/CAA +  (CAA patients) vessels. The findings reported herein would be useful for developing a better understanding of the pathology of CAA and for promoting the discovery and development of drugs and biomarkers for CAA.
Single-isocenter multiple-target stereotactic radiosurgery for multiple brain metastases: dosimetric evaluation of two automated treatment planning systems
Authors: Raza Giorgio Hamid , Capone Luca , Tini Paolo , Giraffa Martina , Gentile Piercarlo , Minniti Giuseppe
Published: July 2022

Purpose

Automated treatment planning systems are available for linear accelerator (linac)-based single-isocenter multi-target (SIMT) stereotactic radiosurgery (SRS) of brain metastases. In this study, we compared plan quality between Brainlab Elements Multiple Brain Metastases (Elements MBM) software which utilizes dynamic conformal arc therapy (DCAT) and Varian HyperArc (HA) software using a volumetric modulated arc therapy (VMAT) technique.

Patients and methods

Between July 2018 and April 2021, 36 consecutive patients ≥ 18 years old with 367 metastases who received SIMT SRS at UPMC Hillman Cancer San Pietro Hospital, Rome, were retrospectively evaluated. SRS plans were created using the commercial software Elements MBM SRS (Version 1.5 and 2.0). Median cumulative gross tumor volume (GTV) and planning tumor volume (PTV) were 1.33 cm3 and 3.42 cm3, respectively. All patients were replanned using HA automated software. Extracted dosimetric parameters included mean dose (Dmean) to the healthy brain, volumes of the healthy brain receiving more than 5, 8,10, and 12 Gy (V5Gy, V8Gy, V10Gy and V12Gy), and doses to hippocampi.

Results

Both techniques resulted in high-quality treatment plans, although Element MBM DCAT plans performed significantly better than HA VMAT plans, especially in cases of more than 10 lesions). Median V12Gy was 13.6 (range, 1.87–45.9) cm3 for DCAT plans and 18.5 (2.2–62,3) cm3 for VMAT plans (p < 0.0001), respectively. Similarly, V10Gy, V8Gy, V5Gy (p < 0.0001) and median dose to the normal brain (p = 0.0001) were favorable for DCAT plans.

Conclusions

Both Elements MBM and HA systems were able to generate high-quality plans in patients with up to 25 brain metastases. DCAT plans performed better in terms of normal brain sparing, especially in patients with more than ten lesions and limited total tumor volume.
Does Anti-Müllerian hormone vary during a menstrual cycle? A systematic review and meta-analysis
Authors: Khodavirdilou Rasa , Pournaghi Marjaneh , Rastgar Rezaei Yeganeh , Hajizadeh Khadijeh , Khodavirdilou Lida , Javid Farzin , Hamdi Kobra , Shahnazi Mahnaz , Nouri Mohammad , Fattahi Amir , Beckmann Matthias W. , Dittrich Ralf
Published: July 2022

Objective

Numerous studies have indicated that the level of the Anti-Müllerian hormone (AMH), one of the main markers for the ovarian reserve, does not fluctuate throughout a menstrual cycle, while some studies have rejected this finding. The purpose of this systematic and meta-analysis study is to consensus on all contradictory studies that have measured AMH levels throughout the menstrual cycle and to investigate the exact extent of AMH variation in a cycle.

Methods

The protocol for this meta-analysis was registered at PROSPERO before data extraction. Relevant studies were identified by systematic search in PubMed, ScienceDirect, Embase, Cochrane Library, and Google Scholar with no limitation on publication date. Longitudinal studies which have evaluated AMH levels in the follicular and luteal phases of an unstimulated (natural) menstrual cycle in healthy women without endocrinology or ovarian disorders were included. We used the JBI Critical Appraisal Checklist for assessing the quality of studies found eligible for meta-analysis.

Results

A total of 11 studies involving 733 women with regular menstrual cycles were included. The results showed that the AMH level in the follicular phase was significantly higher than in the luteal phase (95% Cl = 0.11 [0.01 to 0.21]; p < 0.05) and it varies about 11.5% from the luteal phase. The analysis of studies which had also examined the ovulatory phase (n = 380) showed that the serum levels of AMH in the ovulatory phase (about 2.02 ng/ml) did not significantly vary compared to follicular (95% Cl = 0.11 [-0.10 to 0.33]; p = 0.30) and luteal (95% Cl = 0.06 [-0.08 to 0.20]; p = 0.43) phases.

Conclusions

According to the results of this study, AMH levels differ between follicular and luteal phases which might be due to ovarian response to the gonadotropins. It seems the phase of AMH measurement needs to be considered for interpretation of the serum AMH test.
Successful endovascular treatment with a stent graft for chronic deep vein thrombosis with multiple arteriovenous fistulas: a case report
Authors: Kato Tamon , Fuke Megumi , Nagai Fumio , Nomi Hidetomo , Kanzaki Yusuke , Yui Hisanori , Maruyama Shusaku , Nagae Ayumu , Sakai Takahiro , Saigusa Tatsuya , Ebisawa Soichiro , Okada Ayako , Motoki Hirohiko , Kuwahara Koichiro
Published: July 2022

Background

Deep vein thrombosis with arteriovenous fistulas is rare, with few therapeutic options available for chronic-phase deep vein thrombosis. Moreover, the effectiveness of endovascular treatment for chronic-phase deep vein thrombosis with arteriovenous fistulas has not been established. We describe herein a case of successful endovascular treatment for chronic deep vein thrombosis with multiple arteriovenous fistulas.

Case presentation

We describe the case of a 72-year-old Asian woman who had begun experiencing left leg swelling and intermittent claudication 2 years prior. Enhanced computed tomography revealed left common iliac vein occlusion with vein-to-vein collateral formation and several arteriovenous fistulas. Angiography and ultrasound showed the arteriovenous fistulas to run from the common and internal iliac arteries to the external iliac and superficial femoral veins. We opted against surgical repair for the arteriovenous fistulas due to their complex nature and complicated morphology. Since her condition was progressive, endovascular treatment with a stent graft was performed for the deep vein thrombosis, after which her symptoms gradually improved. Four months following the procedure, enhanced computed tomography confirmed remarkable reduction of the vein-to-vein collaterals and arteriovenous fistulas.

Conclusions

In the present case, enhanced computed tomography with a stent graft was effective in improving symptoms. This strategy may therefore be a treatment option for intractable chronic deep vein thrombosis with arteriovenous fistulas.
Medications for preventing hypertensive disorders in high-risk pregnant women: a systematic review and network meta-analysis
Authors: Liabsuetrakul Tippawan , Yamamoto Yoshiko , Kongkamol Chanon , Ota Erika , Mori Rintaro , Noma Hisashi
Published: July 2022

Objectives

To determine the relative effectiveness of medications for preventing hypertensive disorders in high-risk pregnant women and to provide a ranking of medications using network meta-analysis.

Methods

All randomized controlled trials comparing the most commonly used medications to prevent hypertensive disorders in high-risk pregnant women that are nulliparity and pregnant women having family history of preeclampsia, history of pregnancy-induced hypertension in previous pregnancy, obstetric risks, or underlying medical diseases. We received the search results from the Cochrane Pregnancy and Childbirth’s Specialised Register of Controlled Trials, searched on 31st July 2020. At least two review authors independently selected the included studies and extracted the data and the methodological quality. The comparative risk ratios (RR) and 95% confidence intervals (CI) were analyzed using pairwise and network meta-analyses, and treatment rankings were estimated by the surface under the cumulative ranking curve for preventing preeclampsia (PE), gestational hypertension (GHT), and superimposed preeclampsia (SPE). Safety of the medications is also important for decision-making along with effectiveness which will be reported in a separate review.

Results

This network meta-analysis included 83 randomized studies, involving 93,864 women across global regions. Three medications, either alone or in combination, probably prevented PE in high-risk pregnant women when compared with a placebo or no treatment from network analysis: antiplatelet agents with calcium (RR0.19, 95%CI0.04 to 0.86; 1 study; low-quality evidence), calcium (RR0.61, 95%CI0.47 to 0.80; 13 studies; moderate-quality evidence), antiplatelet agents (RR0.69, 95%CI0.57 to 0.82; 31 studies; moderate-quality evidence), and antioxidants (RR0.77, 95%CI0.63 to 0.93; 25 studies; moderate-quality evidence). Calcium probably prevented PE (RR0.63, 95%CI0.46 to 0.86; 11 studies; moderate-quality evidence) and GHT (RR0.89, 95%CI0.84 to 0.95; 8 studies; high-quality evidence) in nulliparous/primigravida women. Few included studies for the outcome of superimposed preeclampsia were found.

Conclusion

Antiplatelet agents, calcium, and their combinations were most effective medications for preventing hypertensive disorders in high-risk pregnant women when compared with a placebo or no treatment. Any high-risk characteristics for women are important in deciding the best medications. The qualities of evidence were mostly rated to be moderate.

Systematic review registration

PROSPEROCRD42018096276
Maps are plans: re-evaluating territorial hermeneutics through Manuel de Solà-Morales’ project of description
Authors: Salgueiro Barrio Roi
Published: July 2022

During the late 1970s, Catalan architect Manuel de Solà-Morales focuses his research on understanding territory as an architectural construct. Influenced by post-war French urban geography and, especially, by the Italian debates about thecittà-territorioand Henri Lefebvre’s notion of total urbanization, Solà-Morales seeks to define methods of territorial analysis and description with the purpose of understanding how architecture can contribute to articulate an urbanized territory. The crucial piece of this intellectual quest is the research ‘La forma d’un país’ (‘The Shape of a Country’), an atlas in which the production of maps is simultaneously understood as an act of territorial description and territorial design. In Solà-Morales’ terminology: maps are already ‘plans’; their conception needs to move from the ‘literal’ to the ‘literary’. The goal of this article is to interrogate this cartographic project, by asking what its value is both within Solà-Morales broader theorization of territorial production, and for a contemporary understanding of the relations between architecture and territory.
Weighted Zernike defocus coefficient of treatment zone is a meaningful indicator for myopia control efficacy of Ortho-K lenses
Authors: Fan Yuzhuo , Li Yan , Wang Kai , Qu Jia , Zhao Mingwei
Published: July 2022

Background

The goal of this study was to reproduce a three-dimensional representation of corneal defocus characteristics after orthokeratology (Ortho-K) treatment via an indicator defined as the weighted Zernike defocus coefficient of the treatment zone (Cweighted defocus). This could be used to predict the effectiveness of Ortho-K treatment quantitatively in a timely manner after the one-month visit.

Methods

Seventy myopic children with axial length (AL) elongation after Ortho-K treatment (group A) and 63 myopic children with AL shortening after Ortho-K treatment (group B) were included in this one-year retrospective study. The proposed indicator was calculated by a customized MATLAB program. Multivariate binomial logistic regression and multivariate linear regression analyses were used to explore the association between AL change and the Cweighted defocus, age, sex, and other ocular biometric parameters.

Results

The 12-month AL change, age, pupil diameter, and vertical decentration of the Ortho-K lens were significantly different between the two groups. Multivariate logistic regression analysis showed that a larger Cweighted defocus (≥ 0.35 D/mm2) (OR: 0.224; 95% CI: 0.078–0.646; P = 0.006) was correlated with the emergence of AL shortening after orthokeratology treatment. A multivariate linear regression model showed that a greater Cweighted defocus was associated with slower 12-month AL elongation (β =  − 0.51, P = 0.001).

Conclusions

The Cweighted defocus is an effective predictive indicator of myopia control, and a larger Cweighted defocus may lead to slower elongation of AL. This meaningful indicator may help in the evaluation and adjustment of Ortho-K lens parameters in a timely manner and minimize the cost of clinical trial and error.
Ustekinumab during pregnancy and lactation: drug levels in maternal serum, cord blood, breast milk, and infant serum
Authors: Saito Jumpei , Kaneko Kayoko , Kawasaki Hiroyo , Hayakawa Takeshi , Yakuwa Naho , Suzuki Tomo , Sago Haruhiko , Yamatani Akimasa , Murashima Atsuko
Published: July 2022

Background

Patients with ulcerative colitis (UC) may be concerned about medication safety during preconception, pregnancy, and lactation, and they should be closely followed up to ensure that UC activity is controlled during the perinatal period. Reported information on the safety of ustekinumab during pregnancy and lactation is limited. In this case report, we examined the safety of ustekinumab in a fetus and breastfed infant with reference to drug concentrations in maternal serum, cord blood, breast milk, and infant serum.

Case presentation

A 36-year-old female who developed hematochezia and was diagnosed with ulcerative colitis at age 24 was pregnant with her first child. During pregnancy she was treated with subcutaneous bimonthly ustekinumab, at a dose of 90 mg, until 29 weeks of gestation. Her ulcerative colitis symptoms remained in remission. At 38 weeks of gestation she underwent cesarean section and delivered a healthy female infant weighing 3043 g and with no congenital malformations. The infant received routine vaccinations with no adverse events. Ustekinumab treatment was resumed at 7 weeks postpartum.

The ustekinumab concentration in maternal serum at 12 days after injection (30.7 weeks of gestation) was 7968.5 ng/mL, and it decreased to 106.1 ng/mL at 114 days after the last dose. In cord blood, the ustekinumab concentration was 1131.2 ng/mL at 65 days after the last dose; this was 2.5 times higher than that in the maternal serum, which was consistent with a previous report. Ustekinumab was detected in infant serum collected at 71 days after the last maternal dose (299.0 ng/mL), with rapid elimination from the infant’s body. In breast milk, the maximum ustekinumab concentrations were 13.6 ng/mL at 9 days after the last maternal dose, respectively. The ratio of the calculated areas under the time-concentration curves of ustekinumab in breast milk and maternal serum was 0.0008 (257.1/327632.7), which was comparable with a previous human study.

Conclusion

The placental transfer and breast milk secretion of ustekinumab in our case were comparable with previous reports. Use of ustekinumab during pregnancy and lactation was feasible in this case. Further research is needed to clarify the safety of ustekinumab during pregnancy and lactation.
Single transcription factor efficiently leads human induced pluripotent stem cells to functional microglia
Authors: Sonn Iki , Honda-Ozaki Fumiko , Yoshimatsu Sho , Morimoto Satoru , Watanabe Hirotaka , Okano Hideyuki
Published: July 2022

Background

Microglia are innate immune cells that are the only residential macrophages in the central nervous system. They play vital physiological roles in the adult brain and during development. Microglia are particularly in the spotlight because many genetic risk factors recently identified for neurodegenerative diseases are largely expressed in microglia. Rare polymorphisms in these risk alleles lead to abnormal activity of microglia under traumatic or disease conditions.

Methods

In the present study, to investigate the multifaceted functions of human microglia, we established a novel robust protocol to generate microglia from human induced pluripotent stem cells (hiPSCs) using a combination of cytokines and small chemicals essential for microglia ontogeny. Moreover, we highly enhanced the microglial differentiation efficiency by forcing the expression of PU.1, a crucial transcription factor for microglial development, during posterior mesoderm differentiation.

Results

By our novel method, we demonstrated the generation of a greater number of hiPSC-derived microglia (hiMGLs, approximately 120-folds) than the prior methods (at most 40-folds). Over 90% of the hiMGLs expressed microglia-specific markers, such as CX3CR1 and IBA-1. Whole-transcriptome analysis revealed that these hiMGLs are similar to human primary microglia but differ from monocytes/macrophages. Furthermore, the specific physiological functions of microglia were confirmed through indices of lipopolysaccharide responsiveness, phagocytotic ability, and inflammasome formation. By co-culturing these hiMGLs with mouse primary neurons, we demonstrated that hiMGLs can regulate the activity and maturation of neurons.

Conclusions

In this study, our new simple, rapid, and highly efficient method for generating microglia from hiPSCs will prove useful for future investigations on microglia in both physiological and disease conditions, as well as for drug discovery.
Electrocardiographic features in SCN5A mutation-positive patients with Brugada and early repolarization syndromes: a systematic review and meta-analysis
Authors: Radford Danny , Chou Oscar Hou In , Bazoukis George , Letsas Konstantinos , Liu Tong , Tse Gary , Lee Sharen
Published: July 2022

Background

Early repolarization syndrome (ERS) and Brugada syndrome (BrS) are both J-wave syndromes. Both can involve mutations in the SCN5A gene but may exhibit distinct electrocardiographic (ECG) differences. The aim of this systematic review and meta-analysis is to investigate possible differences in ECG markers between SCN5A-positive patients with ERS and BrS.

Methods

PubMed and Embase were searched from their inception to 20 October 2021 for human studies containing the search terms “SCN5A” and “variant” and “early repolarization” or “Brugada”, with no language restrictions. Continuous variables were expressed as mean±standard deviation. PR interval, QRS duration, QTc and heart rate from the included studies were pooled to calculate a mean for each variable amongst BrS and ERS patients. A two-tailed Student’s t test was then performed to for comparisons.

Results

A total of 328 studies were identified. After full-text screening, 12 studies met our inclusion criteria and were included in this present study. One hundred and four ERS patients (mean age 30.86±14.45) and 2000 BrS patients (mean age 36.17±11.39) were studied. Our meta-analysis found that ERS patients had shorter QRS duration (90.40±9.97 vs. 114.79±20.10, P = 0.0001) and shorter corrected QT intervals (QTc) with borderline significance (393.63±40.04 vs. 416.82±37.43, P = 0.052). By contrast, no significant differences in baseline heart rate (65.15±18.78 vs. 76.06±18.78, P = 0.068) or PR intervals (197.40±34.69 vs. 191.88±35.08, P = 0.621) were observed between ERS and BrS patients.

Conclusion

BrS patients with positive SCN5A mutations exhibited prolonged QRS, indicating conduction abnormalities, whereas ERS patients with positive SCN5A mutations showed normal QRS. By contrast, whilst QTc intervals were longer in BrS than in ERS SCN5A positive patients, they were within normal limits. Further studies are needed to examine the implications of these findings for arrhythmic risk stratification.
UAV-based magnetometry — Practical considerations, performance measures, and application to magnetic anomaly detection
Authors: Noriega Gerardo
Published: July 2022

Interest in ubiquitous low-cost unmanned aerial vehicles (UAVs) for use in aeromagnetic surveying has grown dramatically over the past decade. While their appeal is alluring, caution is called for as high-quality airborne magnetometry requires diligent system design and performance qualification. This paper discusses considerations and trade-offs in UAV-based magnetometry, standard measures to qualify performance, and application to magnetic anomaly detection (MAD). The apparent simplicity of towed-bird installations needs careful consideration. Logistical complexities, stability, and safety issues aside, critical compensation for time-varying swing effects is seldom, if at all, standard practice. While well-compensated fixed-mount sensor installations are preferable, they require careful attention to a number of unique aspects including the complex magnetic signatures of typical UAVs. The paper introduces a novel anomaly detection method that is based on the entropy of the total-field magnetometer signal, gated by an analogous measure obtained from a vector magnetometer. Two field studies using a fixed-mount single-magnetometer configuration on a helicopter UAV empirically demonstrate the application of the performance measures and the performance of the MAD method. Notably, the latter clearly illustrates the importance of sound aeromagnetic compensation and enhances the output of an earlier entropy-based detection method.
Clove Oil Endorsed Transdermal Flux of Dronedarone Hydrochloride Loaded Bilosomal Nanogel: Factorial Design, In vitro Evaluation and Ex vivo Permeation
Authors: Teaima Mahmoud H. , Alsofany Jihad Mahmoud , El-Nabarawi Mohamed A.
Published: July 2022

The goal of this study was to develop a bilosomal gel formulation to enhance transdermal permeability of dronedarone hyrdrochloride (DRN) which suffers from poor oral absorption and limited bioavailability. To overcome this obstacle, bilosomes were successfully prepared using 23full-factorial design. Span®40, cholesterol, sodium deoxycholate (bile salt), clove oil (permeability enhancer), and either Tween® 60 or Tween® 80 (edge activator) were used in bilosome preparation by ethanol injection method. In this design, independent variables were X1, edge activator type; X2, edge activator amount (mg); and X3, permeability enhancer concentration (% w/v). Optimal formula (B2) of the highest desirability of (0.776) demonstrated minimum vesicle size (VS) of 312.4 ± 24.42 nm, maximum absolute value of zeta potential (ZP) − 36.17 ± 2.57 mV, maximum entrapment efficiency (EE %) of 80.95 ± 3.01%, maximum deformability Index (DI) of 8.24 ± 1.26 g and maximum drug flux after 12 h (J12) of 21.23 ± 1.54 µg/cm2h upon ex vivo permeation study. After 12 h, 70.29 ± 6.46% of DRN was released from B2. TEM identification of B2 showed spherical shaped nanosized vesicles which were physically stable for 3 months at different temperatures. B2 was incorporated into carboxymethylcellulose gel base for easiness of dermal application. B2 gel demonstrated good physical properties, non-Newtonian psuedoplastic flow, and enhanced release (57.0 ± 8.68% of DRN compared to only 13.3 ± 1.2% released from drug suspension after 12 h) and enhanced skin permeation.

Graphical abstract
GLP-1 Receptor Blockade Reduces Stimulated Insulin Secretion in Fasted Subjects With Low Circulating GLP-1
Authors: Gray Sarah M , Hoselton Andrew L , Krishna Radha , Slentz Cris A , D’Alessio David A
Published: July 2022

Context

Glucagon-like peptide 1 (GLP-1), an insulinotropic peptide released into the circulation from intestinal enteroendocrine cells, is considered a hormonal mediator of insulin secretion. However, the physiological actions of circulating GLP-1 have been questioned because of the short half-life of the active peptide. Moreover, there is mounting evidence for localized, intra-islet mediation of GLP-1 receptor (GLP-1r) signaling including a role for islet dipeptidyl-peptidase 4 (DPP4).

Objective

To determine whether GLP-1r signaling contributes to insulin secretion in the absence of enteral stimulation and increased plasma levels, and whether this is affected by DPP4.

Methods

Single-site study conducted at an academic medical center of 20 nondiabetic subjects and 13 subjects with type 2 diabetes. This was a crossover study in which subjects received either a DPP4 inhibitor (DPP4i; sitagliptin) or placebo on 2 separate days. On each day they received a bolus of intravenous (IV) arginine during sequential 60-minute infusions of the GLP-1r blocker exendin[9-39] (Ex-9) and saline. The main outcome measures were arginine-stimulated secretion of C-Peptide (C-PArg) and insulin (InsArg).

Results

Plasma GLP-1 remained at fasting levels throughout the experiments and IV arginine stimulated both α- and β-cell secretion in all subjects. Ex-9 infusion reduced C-PArg in both the diabetic and nondiabetic groups by ~14% (P < .03 for both groups). Sitagliptin lowered baseline glycemia but did not affect the primary measures of insulin secretion. However, a significant interaction between sitagliptin and Ex-9 suggested more GLP-1r activation with DPP4i treatment in subjects with diabetes.

Conclusion

GLP-1r activation contributes to β-cell secretion in diabetic and nondiabetic people during α-cell activation, but in the absence of increased circulating GLP-1. These results are compatible with regulation of β-cells by paracrine signals from α-cells. This process may be affected by DPP4 inhibition.
Distinctions in PCOS Induced by Letrozole Vs Dehydroepiandrosterone With High-fat Diet in Mouse Model
Authors: Poojary Pooja Suresh , Nayak Guruprasad , Panchanan Gangotri , Rao Arpitha , Kundapur Sanjna Das , Kalthur Sneha Guruprasad , Mutalik Srinivas , Adiga Satish Kumar , Zhao Yulian , Bakkum-Gamez Jamie , Chang Alice Y , DeStephano Christopher , Sherman Mark , Kannan Nagarajan , Kalthur Guruprasad
Published: July 2022

Polycystic ovarian syndrome (PCOS) is a complex health condition associated with metabolic disturbances and infertility. Recent data suggest that the prevalence of PCOS is increasing among women globally, although the etiology of these trends is undefined. Consequently, preclinical models that better reflect the biology of PCOS are urgently needed to facilitate research that can lead to the discovery of prevention strategies or improved management. The existing animal models have several limitations as they do not reflect all the PCOS features metabolically and/or phenotypically. Therefore, there is no clear consensus on the use of appropriate animal model and selection of the most appropriate PCOS-inducing agent. To that end, we have established a Swiss albino mouse model of PCOS based on 3 weeks of daily treatment with letrozole (50 μg/day; intraperitoneal) and dehydroepiandrosterone (DHEA, 6 mg/100 g body weight; subcutaneous) in 5-week-old female mice fed on normal or high-fat diet (HFD). Mice were regularly assessed for body weight, blood glucose, and estrous cycle. Three weeks after drug administration, mice were sacrificed and assessed for blood-based metabolic parameters as well as ovarian function. Our results indicate that DHEA combined with HFD produces changes mimicking those of clinical PCOS, including elevated serum testosterone and luteinizing hormone, dyslipidemia, poor ovarian microenvironment, and development of multiple ovarian cysts, recapitulating cardinal features of PCOS. In comparison, normal diet and/or letrozole produced fewer features of PCOS. The data from the experimental models presented here can improve our understanding of PCOS, a growing concern in women’s health.
Nuclear localization of histamine receptor 2 in primary human lymphatic endothelial cells
Authors: Pal Sarit , Gashev Anatoliy , Roy Debarshi
Published: July 2022

Histamine exerts its physiological functions through its four receptor subtypes. In this work, we report the subcellular localization of histamine receptor 2 (H2R), a G protein-coupled receptor (GPCR), which is expressed in a wide variety of cell and tissue types. A growing number of GPCRs have been shown to be localized in the nucleus and contribute toward transcriptional regulation. In this study, for the first time, we demonstrate the nuclear localization of H2R in lymphatic endothelial cells. In the presence of its ligand, we show significant upregulation of H2R nuclear translocation kinetics. Using fluorescently tagged histamine, we explored H2R-histamine binding interaction, which exhibits a critical role in this translocation event. Altogether, our results highlight the previously unrecognized nuclear localization pattern of H2R. At the same time, H2R as a GPCR imparts many unresolved questions, such as the functional relevance of this localization, and whether H2R can contribute directly to transcriptional regulation and can affect lymphatic specific gene expression. H2R blockers are commonly used medications that recently have shown significant side effects. Therefore, it is imperative to understand the precise molecular mechanism of H2R biology. In this aspect, our present data shed new light on the unexplored H2R signaling mechanisms.

This article has an associated First Person interview with the first author of the paper.
Symbiosis of disciplines: how can developmental biologists join conservationists in sustaining and restoring earth's biodiversity?
Authors: Gilbert Scott F. , Hadfield Michael G.
Published: July 2022

What can developmental biology contribute toward mitigating the consequences of anthropogenic assaults on the environment and climate change? In this Spotlight article, we advocate a developmental biology that takes seriously Lynn Margulis' claim that ‘the environment is part of the body’. We believe this to be a pre-condition for developmental biology playing important roles in conservation and environmental restoration. We need to forge a developmental biology of the holobiont – the multi-genomic physiologically integrated organism that is also a functional biome. To this end, we highlight how developmental biology needs to explore more deeply the interactions between developing organisms, and their chemical, physical and biotic environments.
Redox-dependent AMPK inactivation disrupts metabolic adaptation to glucose starvation in xCT-overexpressing cancer cells
Authors: Lee Younghwan , Itahana Yoko , Ong Choon Chen , Itahana Koji
Published: July 2022

Accelerated aerobic glycolysis is a distinctive metabolic property of cancer cells that confers dependency on glucose for survival. However, the therapeutic strategies targeting this vulnerability are still inefficient and have unacceptable side effects in clinical trials. Therefore, developing biomarkers to predict therapeutic efficacy would be essential to improve the selective targeting of cancer cells. Here, we found that cell lines that are sensitive to glucose deprivation have high expression of cystine/glutamate antiporter xCT (also known as SLC7A11). We found that cystine uptake and glutamate export through xCT contributed to rapid NADPH depletion under glucose deprivation. This collapse of the redox system oxidized and inactivated AMP-activated protein kinase (AMPK), a major regulator of metabolic adaptation, resulting in a metabolic catastrophe and cell death. Although this phenomenon was prevented by pharmacological or genetic inhibition of xCT, overexpression of xCT sensitized resistant cancer cells to glucose deprivation. Taken together, these findings suggest a novel crosstalk between AMPK and xCT that links metabolism and signal transduction, and reveal a metabolic vulnerability to glucose deprivation in cancer cells expressing high levels of xCT.
Chief Resident Election of Emergency Department (CREED) – An innovative approach to fair and bias-free chief resident selection in a residency program
Authors: Waheed Shahan , Ali Noman
Published: July 2022

Emergency medicine has transitioned from developing to a developed specialty in Pakistan. It is gaining recognition in the national and international arena. Residency in emergency medicine is a tough pathway in which a resident learns and is assessed at multiple levels. The attributes that are needed for an empathetic emergency medicine physician are multifaceted. Chief resident selection has been an important step in postgraduate residency. The selection process was traditionally based on seniority and academic achievements with no consideration for soft skills. In the current write-up, we are proposing an evidence-base sequential chief resident selection process called Chief Resident Election of Emergency Department (CREED). The program was developed keeping in consideration the traditional method of election and interviews with the incorporation of reflexive, leadership, communication, and collaboration skills.

doi: https://doi.org/10.12669/pjms.38.6.6099

How to cite this:Waheed S, Ali N. Chief Resident Election of Emergency Department (CREED) – An innovative approach to fair and bias-free chief resident selection in a residency program. Pak J Med Sci. 2022;38(6):---------.  doi: https://doi.org/10.12669/pjms.38.6.6099

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The relationship of age, sex and prothrombin time related to the severity and mortality of COVID-19 patients with diabetes mellitus: a systematic review and meta analysis
Authors: Mirza Audrey Fabianisa , Halim Ceria , Sari Mutiara Indah
Published: July 2022

Background: SARS-CoV-2 first appeared in Wuhan, China, in December 2019. Looking at the prevalence data in the world and in Indonesia, the highest mortality rate due to COVID-19 involves age, gender and comorbidities such as diabetes mellitus. Severity of the condition also refers to coagulation abnormalities, such as abnormal prothrombin time values.

Methods: This systematic review study and meta-analysis used online literature sourced from PubMed, Science Direct, EBSCO, Cochrane and Google Scholar. The literature used here is literature that has data on age, sex and prothrombin time of COVID-19 patients with diabetes mellitus whose quality is assessed by the NOS (Newcastle-Ottawa Scale) criteria and processing data using Review Manager 5.4.

Results: Out of 8711 literatures that were traced from various search sources, there were 46 literatures that were included in this study. The results of the analysis on age showed the Standardized Mean Difference (SMD) value of 0.45 and P <0.0001 (95% CI: 0.23–0.68), the gender analysis showed an Odds Ratio (OR) value of 3.28 and P = 0.01 (95% CI: 1.26–8.52) and the prothrombin time analysis showed SMD values of 0.41 and P = 0.07 (95%CI = -0.03–0.85).

Conclusion: A person who is infected with COVID-19 and has comorbid diabetes mellitus has a high risk of disease severity and mortality if he is older and male.