bluuebunny/crossref_metadata_2025 huggingface dataset:
Research on heavy ion irradiation effects on SOI SRAM
Authors: Li Ke , Hao Jianhong , Zhao Qiang , Fan Jieqing , Gong Yanfei , Hou Tianhao , Fang Jie , Zhang Fang , Dong Zhiwei
Published: October 2023

SRAM based on SOI devices has been widely used in aerospace storage devices due to its good electrical characteristics and radiation resistance. However, with the development of semiconductor technology, the feature size of devices continues to shrink, and the irradiation effects of high-energy ions have become increasingly serious. Single event effect has become the biggest threat to the failure of the spacecraft. A mixed-simulation method was used to research the heavy ion irradiation effects on SOI SRAM. SRAM consists of two coupled inverters. Firstly, the voltage changes of the inverter and SRAM output nodes under heavy ion irradiation were compared and analyzed, then the influence of the device itself and heavy ion parameters on the single particle flipping effect of the SRAM is investigated, and finally the necessary conditions for the flipping of the stored information in the SRAM are discussed and derived. The results show that heavy ion incidence does not permanently change the final state of the inverter; devices in the off state in the SRAM will undergo information flipping only when they are irradiated by heavy ions, and the threshold voltage of the N-type MOSFET is lower than that of the P-type MOSFET; an increase in the penetration depth will accelerate the flipping speed of the SRAM, but when the LET is high, the influence of the penetration depth on the flipping speed decreases; the change of the stored information in the SRAM is the result of the combined effect of pulse width and pulse height.
A fast and accurate method for SARS-CoV-2 genomic tracing
Authors: Ma Wentai , Shi Leisheng , Li Mingkun
Published: October 2023

To contain infectious diseases, it is crucial to determine the origin and transmission routes of the pathogen, as well as how the virus evolves. With the development of genome sequencing technology, genome epidemiology has emerged as a powerful approach for investigating the source and transmission of pathogens. In this study, we first presented the rationale for genomic tracing of SARS-CoV-2 and the challenges we currently face. Identifying the most genetically similar reference sequence to the query sequence is a critical step in genome tracing, typically achieved using either a phylogenetic tree or a sequence similarity search. However, these methods become inefficient or computationally prohibitive when dealing with tens of millions of sequences in the reference database, as we encountered during the COVID-19 pandemic. To address this challenge, we developed a novel genomic tracing algorithm capable of processing 6 million SARS-CoV-2 sequences in less than a minute. Instead of constructing a giant phylogenetic tree, we devised a weighted scoring system based on mutation characteristics to quantify sequences similarity. The developed method demonstrated superior performance compared to previous methods. Additionally, an online platform was developed to facilitate genomic tracing and visualization of the spatiotemporal distribution of sequences. The method will be a valuable addition to standard epidemiological investigations, enabling more efficient genomic tracing. Furthermore, the computational framework can be easily adapted to other pathogens, paving the way for routine genomic tracing of infectious diseases.
A Meta-analysis of Randomised Controlled Trials Comparing Combination Therapy as Second-line Treatment With Monotherapy in Advanced Non-small Cell Lung Cancer With Epidermal Growth Factor Receptor Mutation
Authors: Zhao Kai-xiang , Zhang Yan-fang , Zheng Lei , Pan Ya-fei , He Ze-huang
Published: October 2023

Background:

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors are standard therapy for patients with non-small cell lung cancer (NSCLC) with EGFR mutation; however, resistance is common. Combinatorial strategies have been explored to improve survival. This meta-analysis assesses the efficacy and safety of combination therapy versus monotherapy in patients with advanced NSCLC who failed first-line EGFR-tyrosine kinase inhibitor treatment.

Methods:

We searched randomized controlled trials from PubMed, Web of Science, Google Scholar, Cochrane Library, and ClinicalTrial.gov. The efficacy and toxicity of combination treatment groups were assessed in terms of progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and adverse events (AEs).

Results:

This meta-analysis included 6 randomized controlled trials covering 785 participants. The results showed that the combined regimen arm had no significant improvement of PFS (log hazard ratio = −0.228, 95% CI: −0.543 to 0.087,P= 0.157), ORR (odds ratio = 1.147 [95% CI: 0.577, 2.281],P= 0.695), DCR (odds ratio = 1.578 [95% CI: 0.428, 5.821],P= 0.493), and AEs, including fatigue and diarrhea (odds ratio = 0.833 [95% CI: 0.297, 2.333],P= 0.728 for fatigue and odds ratio = 2.268 [95% CI: 0.544, 9.448],P= 0.261 for diarrhea).

Conclusions:

Combination therapy may not provide a significant improvement in PFS, ORR, DCR, and incidence of AEs compared with monotherapy in patients with advanced NSCLC with EGFR mutations. Further research is needed to investigate the optimal sequencing of combination therapy in patients with NSCLC with different molecular targets to determine the most effective treatment strategy that can improve outcomes and quality of life for these patients.
Perioperative anaesthetic management and short-term outcome of neonatal repair of oesophageal atresia with or without tracheo-oesophageal fistula in Europe
Authors: van den Berg Johanneke , Johansen Mathias , Disma Nicola , Engelhardt Thomas , Hansen Tom Giedsing , Veyckemans Francis , Zielinska Marzena , de Graaff Jurgen C.
Published: October 2023

BACKGROUND

Oesophageal atresia with or without a tracheo-oesophageal fistula is a congenital abnormality that usually requires surgical repair within the first days of life.

OBJECTIVE

Description of the perioperative anaesthetic management and outcomes of neonates undergoing surgery for oesophageal atresia with or without a tracheo-oesophageal fistula, included in the ‘neonate and children audit of anaesthesia practice in Europe’ (NECTARINE) database.

DESIGN

Sub-analyses of prospective observational NECTARINE study.

SETTING

European multicentre study.

PATIENTS

Neonates who underwent surgery for oesophageal atresia with or without a tracheo-oesophageal fistula in the NECTARINE cohort were selected.

MAIN OUTCOME MEASURES

Incidence rates with 95% confidence intervals were calculated for peri-operative clinical events which required a predetermined intervention, postoperative complications, and mortality.

RESULTS

One hundred and three neonates undergoing a first surgical intervention for oesophageal atresia with or without a tracheo-oesophageal fistula repair were identified. Their median gestational age was 38 weeks with a median birth weight of 2840 [interquartile range 2150 to 3150] grams. Invasive monitoring was used in 66% of the procedures. The incidence of perioperative clinical events was 69% (95% confidence interval 59 to 77%), of 30-day postoperative complications 47% (95% confidence interval 38 to 57%) and the 30- and 90 days mortality rates were 2.1% and 2.6%, respectively.

CONCLUSION

Oesophageal atresia with or without a tracheo-oesophageal fistula repair in neonates is associated with a high number of perioperative interventions in response to clinical events, a high incidence of postoperative complications, and a substantial mortality rate.
Pre-emptive TIPS in high-risk acute variceal bleeding. An updated and revised individual patient data meta-analysis
Authors: Nicoară-Farcău Oana , Han Guohong , Rudler Marika , Angrisani Debora , Monescillo Alberto , Torres Ferran , Casanovas Georgina , Bosch Jaime , Lv Yong , Dunne Philip D.J. , Hayes Peter C. , Thabut Dominique , Fan Daiming , Hernández-Gea Virginia , García-Pagán Juan C. ,   on behalf of the pre-emptive TIPS individual data metanalysis, International Variceal Bleeding Study and Baveno Cooperation Study groups
Published: October 2023

Background and Aims:

A previous individual patient data meta-analysis (IPD-MA) showed that compared with drugs+endoscopy, the placement of transjugular portosystemic shunt within 72 hours of admission (pre-emptive transjugular intrahepatic portosystemic shunt: p-TIPS) increases the survival of high-risk patients (Child-Pugh B+ active bleeding and Child-Pugh C<14 points) with cirrhosis and acute variceal bleeding. However, the previous IPD-MA was not a two-stage meta-analysis, did not consider the potential risk of selection bias of observational studies, and did not include the most recent randomized clinical trial. We performed an updated and revised IPD-MA to reassess the efficacy of p-TIPS, addressing all previous issues.

Approach and Results:

We included all studies from the previous IPD-MA and searched for other possible eligible publications until September 2022. We performed a two-stage IPD-MA of data from 8 studies (4 randomized clinical trials and 4 observational). In addition, we performed a sensitivity analysis excluding those patients dying up to the first 72 hours after admission in the Drugs+Endoscopy arms of the 4 observational studies. The primary end point was the effects of p-TIPS versus Drugs+Endoscopy on 1-year survival.

We identified 1389 patients (342 p-TIPS and 1047 Drugs+Endoscopy). The two-stage IPD-MA showed that p-TIPS significantly reduced the mortality in the overall population (HR=0·43, 95% CI: 0.32–0.60, p<0.001. This effect was observed in both subgroups of patients with Child-Pugh. The sensitivity analysis confirmed the survival benefit of p-TIPS.

Conclusions:

The updated two-stage IPD-MA confirms the significant survival advantage of p-TIPS in high-risk patients with cirrhosis and acute variceal bleeding. As a result, we recommend p-TIPS as the preferred first-choice treatment for these patients.
Quantitative lymphoscintigraphy of the lower limbs for the diagnosis of phlebolymphoedema
Authors: McMeekin Helena J. , Peters A. Michael , Burniston Maria T. , Vadrucci Manuela
Published: October 2023

Introduction

Phlebolymphoedema is caused by the interaction of the venous and lymphatic systems in a state of chronic venous insufficiency in which increased microvascular filtration causes an increased rate of lymph production. Lymphatic drainage rate increases in response, but this is unsustainable and can cause lymphatic failure and oedema. We hypothesise that in phlebolymphoedema we could measure unusually high lymphatic drainage while the lymph system is still fully functional.

Method

Patients referred for lymphoscintigraphic investigation of swollen legs between April 2021 and December 2022 were reviewed. Quantitative lymphoscintigraphy was performed following the technique of Keramida et al. (2017) and ilio-inguinal nodal uptake (IIQ%) was calculated. The presence of scintigraphic features of increased lymph production was noted for each limb.

Results

A total of 39 patients were reviewed (78 limbs, 29F, 10M). Seven limbs were identified with supranormal lymphatic function (IIQ > 30%) plus three borderline. Of these 10 limbs, all had at least two scintigraphic features of increased lymph production.

Conclusion

Quantitative lymphoscintigraphy, although developed for diagnosing abnormally low lymphatic function, may also have utility at the upper end of the spectrum for identifying chronic venous insufficiency. An IIQ% upper normal limit of 30% could be used to diagnose venous insufficiency as the cause for limb swelling. This is of note for patients of large body habitus in whom venous ultrasound is difficult.
Epidemiology, causes, and morbidities of stroke in the young
Authors: Janas Anna M. , Barry Megan , Lee Sarah
Published: October 2023

Purpose of review

The purpose is to describe the latest research on epidemiology, causes, and morbidities of stroke in neonates and children.

Recent findings

The global incidence of childhood stroke is approximately 2 per 100 000 person-years, which is significantly lower compared to neonates (20–40 per 100 000 live births) and adults (80–90 per 100 000 person-years). Placental abnormalities are a risk factor for perinatal stroke, although cause is usually multifactorial. In children, nonatherosclerotic arteriopathies and arteriovenous malformations are major causes of ischemic and hemorrhagic strokes, respectively. The perinatal period confers a high risk of stroke and can lead to long-term disability, including motor delay, cognitive or speech impairment, and epilepsy. Recent studies suggest that at least 50% of survivors of perinatal stroke have abnormal neurodevelopmental scores in long-term follow up. Childhood stroke is associated with significant morbidity, including epilepsy, motor impairments, and behavioral disability. Recent studies have also identified an association between pediatric stroke and behavioral disorders, such as attention deficit hyperactivity disorder and autism.

Perinatal and childhood strokes are important causes of neurological morbidity. Given the low incidence of childhood stroke, prospective research studies on epidemiology, causes, and outcomes remain limited, highlighting the need for continued multisite collaborations.
Current Situation and Problems in Diagnosis of Early Chronic Pancreatitis
Authors: Ito Koichi , Takasaki Yusuke , Fujisawa Toshio , Ishii Shigeto , Tomishima Ko , Takahashi Sho , Ikoma Ippei , Jimbo Yasuhisa , Ota Hiroto , Kabemura Daishi , Ikemura Muneo , Ushio Mako , Fukuma Taito , Suzuki Akinori , Isayama Hiroyuki
Published: October 2023

Objectives

The Japan Pancreas Society introduced the concept of early chronic pancreatitis (ECP) in 2009, but its epidemiology remains unclear. This study investigated challenges in ECP diagnosis.

Methods

Early chronic pancreatitis was diagnosed in 4 cohorts between April 2019 and November 2021 using the Clinical Diagnostic Criteria for Chronic Pancreatitis 2019. These cohorts included patients with abdominal/back pain, abnormal pancreatic enzyme levels, ECP suspected due to other reasons, and those who underwent endoscopic ultrasonography for other diseases.

Results

A total of 2502 cases were analyzed and 150 (40 alcoholic and 110 nonalcoholic) cases with ECP findings on endoscopic ultrasonography were included. Early chronic pancreatitis was confirmed in 14 cases (9%), including 9 (22.5%) alcoholic and 5 (4.5%) nonalcoholic cases. Early chronic pancreatitis was confirmed in 15%, 0%, 2.2%, and 0.13% cases in the 4 cohorts, respectively. Early chronic pancreatitis was confirmed in 10 (48%) of the 21 (14%) cases with pancreatic pain.

Conclusions

Early chronic pancreatitis diagnostic rate was low, particularly in nonalcoholic cases, but was slightly higher in cases with pancreatic pain. The diagnostic rate was highest in the abdominal/back pain group. Further studies are required to establish appropriate diagnostic criteria for ECP.
Psychometric evaluation of the heart failure somatic perception scale in Iranian heart failure patients: a cross-sectional study
Authors: Ghorbani Vajargah Pooyan , Jafaraghaee Fateme , Maroufizadeh Saman , Karkhah Samad , Osuji Joseph , Karami Samaneh , Mirrazeghi Seyedeh Fatemeh , Javadi-Pashaki Nazila
Published: October 2023

Background:

This study aimed to evaluate the psychometric evaluation of heart failure somatic perception scale (HFSPS) in Iranian heart failure patients.

Materials and methods:

A total of 220 heart failure (HF) patients were enroled in the study. Data gathering was conducted via consecutive sampling from August 2022 to April 2023. Face validity, content validity, construct validity, and internal consistency were used to evaluate the validity and reliability of the Persian version of the HFSPS. Construct validity was done through confirmatory factor analysis and convergent validity. Convergent validity between HFSPS and symptom status questionnaire-heart failure was measured using Pearson’s correlation coefficient. Cronbach’s alpha and Macdonald’s omega coefficient were used to evaluate the reliability of instruments.

Results:

A total of 220 HF patients participated in this study. Their mean age was 66.46 (SD=11.40). Among the participants, 70% were men. The results of the confirmatory factor analysis evaluation showed the goodness of fit indices of the final HFSPS model after modification was within an acceptable range (χ2=306.18 P<0.001, Minimum Discrepancy Function Divided by Degrees of Freedom=2.47, Comparative of Fit Index=0.91, Tucker-Lewis index=0.90, Adjusted goodness of fit index=0.81, Parsimonious norm fit index=0.70, root mean square error of approximation=0.082). Convergent validity between HFSPS and symptom status questionnaire-heart failure indicated a positive and significant correlation. Cronbach’s alpha coefficient in the HFSPS was 0.868, and McDonald’s omega coefficient in the HFSPS was 0.832.

Conclusion:

Overall, the Persian version of the HFSPS was determined to be a reliable and valid scale among Iranians with HF.
An enormous benign primary retroperitoneal mucinous cystadenoma: a case report and literature review of a seldom seen abdominal pathology
Authors: Al Laham Omar , Adi Amir , Alaitouni Aliaa , Sharaf Aldeen Rahaf , Alshiekh Ali , Hamed Hamoud
Published: October 2023

Introduction and importance:

Retroperitoneal neoplasia comprise less than 2% of all tumours. benign primary retroperitoneal mucinous cystadenoma (PRMC) is an extremely rare tumour. Their clinical course is overall silent unless the patient presents with a vague abdominal or pelvic pain, abdominal distention, or a palpable mass. Their aetiology remains theorized and since 1989, only 46 cases (excluding ours) worldwide were documented in the literature. The majority of cases were discovered in females but the overall tumour incidence rate is still undetermined due to its rarity. Well-timed recognition of this pathology permits the necessary curative surgical intervention to take place.

Case presentation:

We hereby illustrate the rare case of a 23-year-old female who presented to the surgical clinic complaining solely of an unexplained gradual increase of the abdominal contour. Their presurgical radiological analysis yielded an intraabdominal large-sized well-demarcated retroperitoneal mass.

Clinical discussion:

Thorough resection of the mass was accomplished via open surgery. The subsequent microscopic analysis of excised tumour yielded the diagnosis of primary retroperitoneal mucinous cystadenoma of benign nature.

Conclusion:

Primary retroperitoneal mucinous cystadenoma is a seldom seen tumour. The scarcity of its occurrence is further highlighted by the published data. Based on their conclusive review of the available published English-based literature, ours is the 47th documented case of a benign PRMC and it is the first documented case from our country; Syria. The impact of these findings warrants raising awareness on the subject and considering PRMC as a differential diagnosis when presented with a similar case in the clinical practice.
Citrobacter freundii-associated osteomyelitis and thromboembolic events following Moderna COVID-19 vaccination: a rare case report from Nepal
Authors: Adhikari Subodh , KC Sony , Dev Santosh , Bhandari Sujata , Parajuli Prakriti , Poudel Man B. , Adhikari Yagya R. , Poudel Binod
Published: October 2023

Introduction:

Vaccination against coronavirus disease 2019 (COVID-19) is essential for controlling the ongoing cases of this disease. Citrobacter infections of the bones and joints are extremely uncommon. Thromboembolism and deep vein thrombosis (DVT) are very rare complications.

Case presentation:

The authors present a rare case of osteomyelitis, septic arthritis, deep venous thrombosis, and pulmonary embolism in a 15-year-old previously healthy boy occurring shortly after receiving the second dose of the Moderna COVID-19 vaccine. He experienced pain, swelling in the right leg, shortness of breath, and fever, followed by chest pain and leg edema. Treatment included anticoagulation, ketorolac for pain management, antipyretics, and intravenous antibiotics (Tazobactam/Piperacillin, Linezolid, Clindamycin) for osteomyelitis.

Discussion:

The risk of COVID-19 vaccine-related thrombotic events is minimal. Thrombotic events reported among mRNA is very rare.Citrobacter freundiibone and joint infections are very rare, accounting for a small percentage of cases. Some documented cases include cefotaxime-resistant strains causing necrotizing fascitis and osteomyelitis, including postarthroplasty infections. Due to the diverse range of susceptibility patterns and the widespread occurrence of drug resistance, personalized treatment based on culture and sensitivity testing is recommended. However, in rare cases, severe complications like DVT and joint infections associated with Citrobacter infection may occur and should be reported to the vaccine adverse events reporting system.

Conclusion:

Administering the COVID-19 vaccine to enhance natural antibodies is crucial, despite the low risk of infection, thromboembolism, and DVT. Healthcare providers should stay vigilant about adverse effects postvaccination and promptly report those cases.
Computed tomographic assessment of risk of anterior skull base injury of adult patients in tertiary care centre: a cross-sectional study
Authors: Katwal Shailendra , Kumar Ravi Ranjan , Ansari Mukhtar Alam , Suwal Sundar , Ghimire Prasoon
Published: October 2023

Background and objectives:

Functional endoscopic sinus surgery (FESS) carries the risk of anterior skull base injury. Understanding computed tomography of the paranasal sinuses (CT PNS) and anatomical variations is crucial before surgery. Several classifications, including Kero’s, Gera’s, and Thailand-Malaysia-Singapore (TMS), assess the risk of skull base injury. The objective was to determine the risk of anterior skull base injury using CT PNS in adult patients.

Methods:

A study of 188 patients with head and paranasal sinus pathologies used CT scans to measure olfactory fossa depth, the angle between lamina papyracea and horizontal plane, and the distance from the orbital rim to the cribriform plate. Variations were classified using Kero’s, Gera’s, and TMS classifications.

Results:

The study involved 188 individuals aged 18–85, with OF depths ranging from 0.1 to 0.52 cm. Kero’s Class I was observed in 82.44% and 81.38% of individuals, while distances from orbital floor to cribriform plate and ethmoidal roof ranged from 1.37 to 2.93 cm. TMS Type I was observed in all individuals, and the angle between lateral lamella of the cribriform plate and cribriform plate ranged from 34° to 85°. Gera’s Class II was observed in 77.12% and 84.57% of individuals.

Conclusion:

CT PNS provides important anatomical information for assessing the risk of skull base injury during FESS. Kero’s, Gera’s, and TMS classifications can be utilized to evaluate this risk. The study findings provide insights into the variations in olfactory fossa depth, distance measurements, and angle, which can aid in preoperative planning and reducing complications during FESS in Nepalese populations.
Perceptions of Military Experience Among Veterans Reporting Lifetime Warzone Moral Injury
Authors: Borges Lauren M. , Holliman Brooke Dorsey , Farnsworth Jacob K. , Barnes Sean M.
Published: October 2023

Exposures to potentially morally injurious events (PMIEs) and possible moral injury are risk factors for a range of difficulties impacting individual functioning. Although exposure to PMIEs is a somewhat common product of war, qualitative methods to understand Veterans' experiences of moral injury and Veterans Affairs treatment are limited. To better characterize Veterans' experiences, 14 male warzone Veterans who reported moral injury post–warzone deployment and completed posttraumatic stress disorder treatment in the past year were asked to describe their military service as part of a qualitative study. Through thematic analysis, we found two moral injury-consistent themes and four subthemes. The first theme was “military experiences were associated with morally questioning one's self” with subthemes of “moral shift” and “depersonalization.” The second theme was “military experiences were associated with morally questioning others” with subthemes of “disillusionment” and “resignation.” Based on these findings, we conclude with a discussion of treatment implications for moral injury.
A Literature Review Examining Virtual Reality Exposure Therapy for Individuals Diagnosed With Social Anxiety Disorder
Authors: Arif Rimsha , Ashraf Sahar , Bhatt Kesha , Shah Kaushal
Published: October 2023

Social anxiety disorder (SAD) is a specific subtype of anxiety disorder where individuals experience uncomfortable social situations that induce anxious feelings including nervousness and panic. Computer technology has been applied in interventions for many mental health disorders. We aim to understand and explore the use of virtual reality exposure therapy (VRET) to treat adults with SAD. We conducted a literature search using relevant mesh keywords in PubMed and PsycINFO. Six studies met inclusion criteria in our final qualitative synthesis review. Results showed a significant reduction in SAD symptom severity based on primary measures in all studies, suggesting that VRET is an effective option in treating SAD. Studies have shown the success of VRET in formats such as a single-user implementation, one-session treatment, and self-training intervention. In conclusion, VRET is effective in reducing SAD symptoms. The limitations of most studies included a small sample size and weak ecological validity. Future research can examine VRET with a more extensive clinical sample and broader social behaviors.
Clinical Efficacy of 2-Needle Joint Lavage for Osteoarthritis-Related Knee Pain and Predictors of Response Based on Knee MRI Osteoarthritis Knee Score: A Medical Records Review Study
Authors: Li Shiyao , Jiang Xiaohan , Wang Junnan , Chen Yang , Shi Rongchao , Ding Feier , Chu Lingyan , Sun Tao
Published: October 2023

Background

Knee osteoarthritis (OA) is notoriously difficult to treat. Pain is the key symptom for patients to seek medical attention. This study aimed to evaluate the therapeutic efficacy of joint lavage (JL) for OA-related knee pain and to explore the knee pathological changes detected by magnetic resonance imaging that may affect the prognosis of patients who received JL.

Methods

Eighty-two hospitalized patients who were diagnosed with knee OA and received JL in our department were finally enrolled in this study. The patients' clinical data including Numeric Rating Scale (NRS), Western Ontario and McMaster Osteoarthritis Index pain subscale, analgesic medication usage, adverse events, and magnetic resonance imaging data of the affected knee joint scored by the MRI Osteoarthritis Knee Score were recorded and analyzed.

Results

The NRS scores significantly decreased after JL and remained steady until 6 months (p < 0.001). The Western Ontario and McMaster Osteoarthritis Index pain scores and the percentage of patients who needed analgesic medication significantly decreased at 6 months compared with baseline (p < 0.001). At 6 months after JL, 51 of the 82 patients experienced ≥50% improvement in their NRS scores (effective). Multivariate binary logistic regression analysis revealed that duration of pain (odds ratio [OR], 1.022; 95% confidence interval [CI], 1.003–1.042; p = 0.024), bone marrow lesion score (OR, 1.221; 95% CI, 1.028–1.450; p = 0.023), and cartilage loss score (OR, 1.272; 95% CI, 1.021–1.585; p = 0.032) significantly influenced the therapeutic efficacy of JL.

Conclusions

JL treatment can significantly alleviate the OA-related knee pain in at least 6 months. JL tends to provide limited benefit for patients with long duration of pain, serious bone marrow lesions, and severe cartilage loss.
Innovative Research Methods
Authors: Green Ellen P. , Dong Yue , Shah Nilay D.
Published: October 2023

Summary Statement

Health care policies have the potential to improve patient outcomes, access to care, and reduce health disparities. However, new policy is often tested in the field, where unintended consequences are paid for by patients. In this perspective, we argue that health care simulations, which can elucidate the potential for policy to hinder clinicians' ability to provide high-quality care, are a complement to large-scale policy evaluations in the field.
Differential Vessel features according to the Pathophysiologic Type of Intracranial Atherosclerosis
Authors: Kim Hyung Jun , Cho Hwan-Ho , Park Hyunjin , Choi Jong-Un , Song Ha-Na , Lee Ji-Eun , Baek In-Young , Chung Jong-Won , Bang Oh Young , Kim Gyeong-Moon , Seo Woo-Keun
Published: October 2023

BACKGROUND

Previous studies have assessed the relationship between vessel tortuosity and atherosclerosis in long vessel segments. We evaluated the relationship between tortuosity and parent artery atherosclerotic disease (PAD) in short vessel segments, and the differences between the PAD and branch atheromatous disease (BAD).

METHODS

Computerized analysis of the images provided quantitative vessel features at every 0.2841 mm interval point of the vessel’s centerline. The vessel features that reflect vessel tortuosity include curvature and torsion. To analyze the local features of the vessels, the middle cerebral artery (MCA) was divided into three segments.

RESULTS

A total of 59 and 77 patients with PAD and BAD of the MCA were included. Stenotic segments were isolated in 33 patients with PAD and were mostly located in the distal segment; stenotic segments were also isolated in 24 patients with BAD and were mostly located in the middle segment (P=0.074). The curvature of the stenotic segment of PAD was significantly increased compared to the non-stenotic segments of the ipsilateral (0.29 ± 0.08 for the stenotic segment vs. 0.26 ± 0.07 for the non-stenotic segment,P=0.048), and increased but not significant compared to the stenotic segment of BAD (0.29 ± 0.08 for PAD vs. 0.26 ± 0.05 for BAD,P=0.083). In the multivariable regression analysis, curvature (odds ratio, 2.136; 95% confidence interval, 1.251–3.645;P=0.005) was associated with PAD.

CONCLUSIONS

Our findings suggested that increased tortuosity is associated with the development of PAD and that PAD and BAD have different vessel features and plaque locations and thereby, different pathophysiological mechanisms.
Integration of metabolic flux with hepatic glucagon signaling and gene expression profiles in the conscious dog
Authors: Coate Katie C. , Ramnanan Christopher J. , Smith Marta , Winnick Jason J. , Kraft Guillaume , Irimia-Dominguez Jose , Farmer Ben , Donahue E. Patrick , Roach Peter J. , Cherrington Alan D. , Edgerton Dale S.
Published: October 2023

Glucagon rapidly and profoundly simulates hepatic glucose production (HGP), but for reasons which are unclear, this effect normally wanes after a few hours, despite sustained plasma glucagon levels. This study characterized the time course and relevance (to metabolic flux) of glucagon-mediated molecular events in the livers of conscious dogs. Glucagon was either infused into the hepato-portal vein at a 6-fold basal rate in the presence of somatostatin and basal insulin, or it was maintained at a basal level in control studies. In one control group glucose remained at basal while in the other glucose was infused to match the hyperglycemia that occurred in the hyperglucagonemic group. Elevated glucagon caused a rapid (30 min) but only partially sustained increase in hepatic cAMP over 4h, a continued elevation in G6P, and activation and deactivation of glycogen phosphorylase and synthase activities, respectively. Net hepatic glycogenolysis and HGP increased rapidly, peaking at 30 min, then returned to baseline over the next three hours (although glucagon’s stimulatory effect on HGP was sustained relative to the hyperglycemic control group). Hepatic gluconeogenic flux did not increase due to lack of glucagon effect on substrate supply to the liver. Global gene expression profiling highlighted glucagon-regulated activation of genes involved in cellular respiration, metabolic processes, and signaling, and downregulation of genes involved in extracellular matrix assembly and development.
A portable and wind resistant drift fence array for arid environments
Authors: Camper Benjamin T. , Laughlin Zachary T. , Kanes Andrew S. , Manuel Riley T. , Bewick Sharon A.
Published: October 2023

Abstract

Drift fences are passive trapping systems for both small vertebrates and large invertebrates. Most drift fence designs are semi-permanent or otherwise difficult to transport after initial installation. While these designs are effective for replicate trapping through time, most designs lack portability. Here, we propose a novel drift fence design that uses PVC pipes and fiberglass mesh screen. The combination of hollow PVC pipes and mesh screen creates a lightweight system that facilitates rapid deployment and redeployment across locations. Since the PVC pipes can be filled with topsoil from the site of trap installation, enhanced portability does not come at the cost of fence stability or wind resistance. We provide results on trap performance in a New Mexico flatland desert and discuss the efficacy and cost of our proposed drift fence design.
Metabolic imaging across scales reveals distinct prostate cancer phenotypes
Authors: Sushentsev Nikita , Hamm Gregory , Flint Lucy , Birtles Daniel , Zakirov Aleksandr , Richings Jack , Ling Stephanie , Tan Jennifer Y. , McLean Mary A. , Ayyappan Vinay , Menih Ines Horvat , Brodie Cara , Miller Jodi L. , Mills Ian G. , Gnanapragasam Vincent J. , Warren Anne Y. , Barry Simon T. , Goodwin Richard J.A. , Barrett Tristan , Gallagher Ferdia A.
Published: October 2023

Hyperpolarised magnetic resonance imaging (HP-13C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we have used a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1-13C]lactate labelling between benign and malignant prostate, as well as tumours containing cribriform and non-cribriform Gleason pattern 4 disease. The elevated hyperpolarised [1-13C]lactate signal in prostate cancer compared to the benign prostate is primarily driven by increased tumour epithelial cell density and vascularity, rather than differences in epithelial lactate concentration between tumour and normal. We also demonstrate that tumours of the cribriform subtype may lack [1-13C]lactate labelling, which is explained by their lower epithelial lactate dehydrogenase expression, higher mitochondrial pyruvate carrier density, and increased lipid abundance compared to lactate-rich non-cribriform lesions. These findings highlight the potential of combining spatial metabolic imaging tools across scales to identify novel metabolic phenotypes in prostate cancer.
Discovery of Ancestry-specific Variants Associated with Clopidogrel Response among Caribbean Hispanics
Authors: Yang Guang , González Pablo , Moneró Mariangeli , Carrasquillo Kelvin , Renta Jessicca Y. , Hernandez-Suarez Dagmar F. , Botton Mariana R. , Melin Kyle , Scott Stuart A. , Ruaño Gualberto , Roche-Lima Abiel , Alarcon Cristina , Ritchie Marylyn D. , Perera Minoli A. , Duconge Jorge
Published: October 2023

Background

High on-treatment platelet reactivity (HTPR) with clopidogrel is predictive of ischemic events in adults with coronary artery disease. Despite strong data suggesting HTPR varies with ethnicity, including clinical and genetic variables, no genome-wide association study (GWAS) of clopidogrel response has been performed among Caribbean Hispanics. This study aimed to identify genetic predictors of HTPR in a cohort of Caribbean Hispanic cardiovascular patients from Puerto Rico.

Methods

Local Ancestry inference (LAI) and traditional GWASs were performed on a cohort of 511 clopidogrel-treated patients, stratified based on their P2Y12 reaction units (PRU) into responders and non-responders (HTPR).

Results

The LAI GWAS identified variants within theCYP2C19region associated with HTPR, predominantly driven by individuals of European ancestry and absent in those with native ancestry. Incorporating local ancestry adjustment notably enhanced our ability to detect associations. While no loci reached traditional GWAS significance, three variants showed suggestive significance at chromosomes 3, 14 and 22 (OSBPL10rs1376606,DERL3rs5030613, andRGS6rs9323567). In addition, a variant in theUNC5Cgene on chromosome 4 was associated with an increased risk of HTPR. These findings were not identified in other cohorts, highlighting the unique genetic landscape of Caribbean Hispanics.

Conclusion

This is the first GWAS of clopidogrel response in Hispanics, confirming the relevance of theCYP2C19cluster, particularly among those with European ancestry, and also identifying novel markers in a diverse patient population. Further studies are warranted to replicate our findings in other diverse cohorts and meta-analyses.
Cortical parenchyma wall width (CPW) regulates root metabolic cost and maize performance under suboptimal water availability
Authors: Sidhu Jagdeep Singh , Lopez-Valdivia Ivan , Strock Christopher F. , Schneider Hannah M. , Lynch Jonathan P.
Published: October 2023

We describe how increased root cortical parenchyma wall width (CPW) can improve tolerance to drought stress in maize by reducing the metabolic costs of soil exploration. Significant variation (1.0 to 5.0 µm) for CPW was observed within maize germplasm. The functional-structural modelRootSlicepredicts that increasing CPW from 2 to 4 µm is associated withca.15% reduction in root cortical cytoplasmic volume, respiration rate, and nitrogen content. Analysis of genotypes with contrasting CPW grown with and without water stress in the field confirms that increased CPW is correlated with ca. 32 to 42% decrease in root respiration. Under water stress in the field, increased CPW is correlated with 125% increased stomatal conductance, 325% increased leaf CO2assimilation rate, 73 to 78% increased shoot biomass, and 92 to 108% increased grain yield. CPW was correlated with leaf mesophyll midrib parenchyma wall width, indicating pleiotropy. GWAS analysis identified candidate genes underlying CPW.OpenSimRootmodeling predicts that a reduction in root respiration due to increased CPW would also benefit maize growth under suboptimal nitrogen, which requires empirical testing. We propose CPW as a new phene that has utility under edaphic stress meriting further investigation.

Significance Statement

Suboptimal water availability is a primary constraint for global crop production that is intensifying due to climate change. The metabolic cost of soil exploration is a critical factor in plant performance under suboptimal water availability. This study highlights how increased root cortical parenchyma wall width (CPW) reduces root metabolic cost and improves crop adaptation to water deficit. Modeling results also indicate that increased CPW would be beneficial under suboptimal nitrogen availability. Therefore, CPW is a promising target for breeding crops with improved water and nitrogen use efficiency.
Mutation-specific CAR T cells as precision therapy for IGLV3-21R110expressing high-risk chronic lymphocytic leukemia
Authors: Märkl Florian , Schultheiß Christoph , Ali Murtaza , Chen Shih-Shih , Egli Lukas , Mietz Juliane , Chijioke Obinna , Paschold Lisa , Spajic Sebastijan , Holtermann Anne , Dörr Janina , Stock Sophia , Piseddu Ignazio , Anz David , Minden Marcus Dühren-von , Zhang Tianjiao , Nerreter Thomas , Hudecek Michael , Chiorazzi Nicholas , Kobold Sebastian , Binder Mascha
Published: October 2023

The concept of precision cell therapy targeting tumor-specific mutations is appealing but requires surface-exposed neoepitopes, which is a rarity in cancer. B cell receptors (BCR) of mature lymphoid malignancies are exceptional in that they harbor tumor-specific-stereotyped sequences in the form of point mutations that drive self-engagement of the BCR and autologous signaling. Here, we used a BCR light chain neoepitope defined by a characteristic point mutation (IGLV3-21R110) for selective targeting of a poor-risk subset of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR) T cells. We developed murine and humanized CAR constructs expressed in T cells from healthy donors and CLL patients that eradicated IGLV3-21R110expressing cell lines and primary CLL cells, but not polyclonal healthy B cells. In vivo experiments confirmed epitope-selective cytolysis in xenograft models using engrafted IGLV3-21R110expressing cell lines or primary CLL cells. We further demonstrate in two humanized mouse models lack of cytotoxicity towards human B cells. These data provide the basis for novel avenues of resistance-preventive and biomarker-guided cellular targeting of functionally relevant lymphoma driver mutations sparing normal B cells.
MpmiR319 promotes gemma/gemma cup formation in the Liverwort Marchantia polymorpha
Authors: Futagami Kazutaka , Tsuzuki Masayuki , Watanabe Yuichiro
Published: October 2023

After microRNAs (miRNAs) were initially detected as approximately 21-nt sequences in plants, miRNA-mediated regulation of target gene expression was characterized in many cases. The sequences of miR159/319 family miRNAs are highly conserved and their development-related roles have been comprehensively characterized in dicot and monocot plants. However, their effects in basal land plants remain relatively unknown. We used a CRISPR/Cas9 system to edit genome sequences at MpMIR319a and/or MpMIR319b loci. Mutant mir319b lines developed relatively few gemma cups, while mutant mir319a lines produced relatively few gemmae in each gemma cup. Earlier 5′-RACE or degradome analyses suggested that MpmiR319 targets MpRKD and MpR2R3-MYB21 transcripts and suppresses expression. To determine whether these candidate genes influence the mir319a/mir319b phenotype we constructed miR319-resistant MpRKD (mMpRKD) and MpR2R3-MYB21 (mMpR2R3-MYB21) by decreasing the complementarity to miR319. We also introduced the genes into wild-type liverwort and screened for phenotypic changes. We observed that mMpRKD resulted in gemma/gemma cup-less liverwort mutants, but mMpR2R3-MYB21 did not. No major adverse effects were detected during male and female reproductive development induced by far-red illumination. These results indicate that miR319 influences gemma formation mainly by repressing MpRKD expression rather than MpR2R3-MYB21 expression.
Ribotin: Automated assembly and phasing of rDNA morphs
Authors: Rautiainen Mikko
Published: October 2023

The ribosomal DNA (rDNA) arrays are highly repetitive and homogenous regions which exist in all life. Due to their repetitiveness, current assembly methods do not fully assemble the rDNA arrays in humans and many other eukaryotes, and so variation within the rDNA arrays cannot be effectively studied. Here we present the tool ribotin to assemble full length rDNA copies, ormorphs. Ribotin uses a combination of highly accurate long reads and extremely long nanopore reads to resolve the variation between rDNA morphs. We show that ribotin successfully recovers the most abundant morphs in human and nonhuman genomes. We also find that genome wide consensus sequences of the rDNA arrays frequently produce a mosaic sequence that does not exist in the genome. Ribotin is available onhttps://github.com/maickrau/ribotinand as a package on bioconda.
Atomistic simulations of RNA duplex thermal denaturation: sequence- and forcefield-dependence
Authors: Dabin Aimeric , Stirnemann Guillaume
Published: October 2023

Double-stranded RNA is the end-product of template-based replication, and is also the functional state of some biological RNAs. Similarly to proteins and DNA, they can be denatured by temperature, with important physiological and technological implications. Here, we use anin silicostrategy to probe the thermal denaturation of RNA duplexes. Following previous results that were obtained on a few different duplexes, and which nuanced the canonical 2-state picture of nucleic acid denaturation, we here specifically address three different aspects that improve our description of the temperature-induced dsRNA separation. First, we investigate the effect of the spatial distribution of weak and strong base-pairs among the duplex sequence. We show that the deviations from the two-state dehybridization mechanism are more pronounced when a strong core is flanked with weak extremities, while duplexes with a weak core but strong extremities exhibit a two-state behavior, which can be explained by the key role played by base fraying. This was later verified by generating artificial hairpin or circular states containing one or two locked duplex extremities, which results in an important reinforcement of the entire HB structure of the duplex and higher melting temperatures. Finally, we demonstrate that our results are little sensitive to the employed combination of RNA and water forcefields. The trends in thermal stability among the different sequences as well as the observed unfolding mechanisms (and the deviations from a two-state scenario) remain the same regardless of the employed atomistic models. However, our study points to possible limitations of recent reparametrizations of the Amber RNA forcefield, which sometimes results in duplexes that readily denature under ambient conditions, in contradiction with available experimental results.
Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response
Authors: Lior Chen , Barki Debra , Iacobuzio-Donahue Christine A , Kelsen David , Scherz-Shouval Ruth
Published: October 2023

The tumor microenvironment (TME) is a challenging environment where cells must cope with stressful conditions such as fluctuating pH levels, hypoxia, and free radicals. In response, stress pathways are activated, which can both promote and inhibit tumorigenesis. In this study, we set out to characterize the stress response landscape across four carcinomas: breast, pancreas, ovary, and prostate tumors, focusing on five pathways: Heat shock response, oxidative stress response, unfolded protein response, hypoxia stress response, and DNA damage response. Using a combination of experimental and computational methods, we create an atlas of the stress response landscape across various types of carcinomas. We find that stress responses are heterogeneously activated in the TME, and highly activated near cancer cells. Focusing on the non-immune stroma we find, across tumor types, that NRF2 and the oxidative stress response are distinctly activated in immune-regulatory cancer-associated fibroblasts and in a unique subset of cancer associated pericytes. Our study thus provides an interactome of stress responses in cancer, offering new ways to intersect survival pathways within the tumor, and advance cancer therapy.