bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermal and Chemical Evolution of an Archean Collision Zone: Insights from P–T–t History of Mafic Granulites from the Coorg Block, S. India
Authors: Basak Sampriti , Hasenstab Eric , Bhowmik Santanu Kumar , Gerdes Axel , Dasgupta Somnath , Münker Carsten , Kumar Gr. Ravindra , Chakraborty Sumit
Published: April 2023

Knowledge of pressure–temperature–time (P–T–t) evolution of Archean high-grade (deep crustal) metamorphic rocks is important for deciphering the nature of Archean tectonic processes. However, exposures of such rocks are limited in the present rock record. Here, we study a suite of high-grade, mafic rocks that are present along a crustal-scale shear zone (called the Mercara Shear Zone) between two Archean terrains of India, the Coorg block and the Dharwar Craton. Given that the Mercara Shear Zone is dated to be Mesoarchean, these shear zone rocks are well suited to elucidate Archean orogenic processes. Petrological investigation shows that these mafic rocks are characterized by a granulitic assemblage of orthopyroxene, clinopyroxene, plagioclase, quartz and amphibole ± garnet, and with accessory phases such as apatite, ilmenite, magnetite and rutile in some cases. We distinguish the investigated rocks into low-Mg and high-Mg varieties based on their whole-rock composition as well as their mode of occurrence in the field and mineral chemistry. This difference in the bulk composition led to different reaction histories—for example, the low-Mg mafic granulites underwent partial melting while high-Mg granulites were less fertile. Combining these observations with the results of geothermobarometry, phase equilibria modeling, geochronology (U–Pb in zircon and Lu–Hf in garnet ) and diffusion modeling, we have reconstructed a multi-stage P–T–t history for these rocks. The first phase (Stage 1) is represented by granulite-grade metamorphism at ~750–900°C and 8–13 kbar during ~3100 Ma (with uncertainties permitting a timing as recent as ~2700 Ma), after which they resided at T <500°C, likely at lower crustal levels (Stage 2). Subsequently, these rocks were reheated to a T of 700–750°C at 7–10 kbar at ~2400 Ma (Stage 3) and then again cooled down to ~500–600°C at 6–8 kbar (Stage 4). Application of diffusion chronometry shows that (1) the cooling rates of these granulites at high temperatures (>600°C) varied in the range of 25–50°C/Ma, and (2) the rocks resided for a long duration (~500 million years) at the Stage 2 metamorphic conditions, i.e. at T <500°C. We infer that such a protracted, high-T metamorphic history involving at least two heating pulses, and the relatively slow cooling rates on the order of 10’s °C/Ma are consistent with the operation of peel-back styled orogenesis (an embryonic form of plate tectonics) on an early hotter Earth (Mesoarchean to Paleoproterozoic). Moreover, the controls of bulk rock compositions on reaction histories provide a mechanism for intracrustal differentiation and generating Mg-rich, refractory material that may have eventually formed the lower continental crust over a protracted and pulsed thermal evolution spanning several hundred million years.
ENHANCED DISEASE SUSCEPTIBILITY 1 promotes hydrogen peroxide scavenging to enhance rice thermotolerance
Authors: Liao Min , Ma Zemin , Kang Yuanrong , Zhang Biaoming , Gao Xuanlin , Yu Feng , Yang Pingfang , Ke Yinggen
Published: April 2023

Heat stress is a major factor limiting the production and geographic distribution of rice (Oryza sativa), and breeding rice varieties with tolerance to heat stress is of immense importance. Although extensive studies have revealed that reactive oxygen species (ROS) play a critical role in rice acclimation to heat stress, the molecular basis of rice controlling ROS homeostasis remains largely unclear. In this study, we discovered a novel heat-stress-responsive strategy that orchestrates ROS homeostasis centering on an immune activator, rice ENHANCED DISEASE SUSCEPTIBILITY 1 (OsEDS1). OsEDS1, which confers heat stress tolerance, promotes hydrogen peroxide (H2O2) scavenging by stimulating catalase activity through the OsEDS1-catalase association. The loss-of-function mutation in OsEDS1 causes increased sensitivity to heat stress, whereas the overexpression of OsEDS1 enhances thermotolerance. Furthermore, overexpression lines greatly improved rice tolerance to heat stress during the reproductive stage, which was associated with substantially increased seed setting, grain weight, and plant yield. Rice CATALASE C (OsCATC), whose activity is promoted by OsEDS1, degrades H2O2 to activate rice heat stress tolerance. Our findings greatly expand our understanding of heat stress responses in rice. We reveal a molecular framework that promotes heat tolerance through ROS homeostasis regulation, suggesting a theoretical basis and providing genetic resources for breeding heat-tolerant rice varieties.
Evolution-strengthened knowledge graph enables predicting the targetability and druggability of genes
Authors: Quan Yuan , Xiong Zhan-Kun , Zhang Ke-Xin , Zhang Qing-Ye , Zhang Wen , Zhang Hong-Yu
Published: April 2023

Identifying promising targets is a critical step in modern drug discovery, with causative genes of diseases that are an important source of successful targets. Previous studies have found that the pathogeneses of various diseases are closely related to the evolutionary events of organisms. Accordingly, evolutionary knowledge can facilitate the prediction of causative genes and further accelerate target identification. With the development of modern biotechnology, massive biomedical data have been accumulated, and knowledge graphs (KGs) have emerged as a powerful approach for integrating and utilizing vast amounts of data. In this study, we constructed an evolution-strengthened knowledge graph (ESKG) and validated applications of ESKG in the identification of causative genes. More importantly, we developed an ESKG-based machine learning model named GraphEvo, which can effectively predict the targetability and the druggability of genes. We further investigated the explainability of the ESKG in druggability prediction by dissecting the evolutionary hallmarks of successful targets. Our study highlights the importance of evolutionary knowledge in biomedical research and demonstrates the potential power of ESKG in promising target identification. The data set of ESKG and the code of GraphEvo can be downloaded from https://github.com/Zhankun-Xiong/GraphEvo.
Inequalities in smoking among pregnant women in North West London
Authors: Pinho-Gomes Ana-Catarina , Mullins Edward
Published: April 2023

Background

London has the lowest smoking prevalence among pregnant women in England. However, it was unclear whether the low overall prevalence masked inequalities. This study investigated the prevalence of smoking among pregnant women in North West London stratified by ethnicity and deprivation.

Methods

Data regarding smoking status, ethnicity and deprivation were extracted from electronic health records collected by maternity services at Imperial Healthcare NHS Trust between January 2020 and August 2022.

Results

A total of 25 231 women were included in this study. At the time of booking of antenatal care (mean of 12 weeks), 4% of women were current smokers, 17% were ex-smokers and 78% never smokers. There were marked differences in the smoking prevalence between ethnic groups. Women of Mixed—White and Black Caribbean ethnicity and White Irish women had the highest prevalence of smoking (12 and 9%, respectively). There was an over 4-fold increase in the prevalence of smoking between the most and the least deprived groups (5.6 versus 1.3%).

Conclusions

Even in a population with an overall low prevalence of smoking in pregnancy, women experiencing deprivation and from certain ethnic backgrounds have a high smoking prevalence and hence are the most likely to benefit from smoking cessation interventions.
Role of activated p21-activated kinase 2 in methylmercury-induced embryotoxic effects on mouse blastocysts
Authors: Lee Cheng-Kai , Wang Fu-Ting , Huang Chien-Hsun , Chan Wen-Hsiung
Published: April 2023

Methylmercury (MeHg), a biotransformation product derived from mercury or inorganic mercury compounds in waterways, is a potent toxin that exerts hazardous effects on human health via environmental contamination. Previous studies have reported MeHg-induced impairment of nerve development in embryogenesis and placental development. However, the potential deleterious effects and regulatory mechanisms of action of MeHg on pre- and post-implantation embryo development are yet to be established. Experiments from the current study clearly demonstrate that MeHg exerts toxic effects on early embryonic development processes, including the zygote to blastocyst stage. Induction of apoptosis and decrease in embryo cell number were clearly detected in MeHg-treated blastocysts. Additionally, intracellular reactive oxygen species (ROS) generation and activation of caspase-3 and p21-activated protein kinase 2 (PAK2) were observed in MeHg-treated blastocysts. Importantly, prevention of ROS generation by pre-treatment with Trolox, a potent antioxidant, significantly attenuated MeHg-triggered caspase-3 and PAK2 activation as well as apoptosis. Notably, the downregulation of PAK2 via transfection of specifically targeted siRNA (siPAK2) led to marked attenuation of PAK2 activity and apoptosis and the deleterious effects of MeHg on embryonic development in blastocysts. Our findings strongly suggest that ROS serve as an important upstream regulator to trigger the activation of caspase-3, which further cleaves and activates PAK2 in MeHg-treated blastocysts. Activated PAK2 promotes apoptotic processes that, in turn, cause sequent impairment of embryonic and fetal development.
Tumor Microenvironment CD8 T and Treg Cells–related Genes Signature Distinguishes Distinct Prognosis and Targeted Therapies Response in Endometrial Cancer
Authors: Liu Xiaodie , Feng Dingqing , Wang Wenhui , Liang Jing , Yu Huan , Ling Bin
Published: April 2023

Although most endometrial cancer (EC) patients have a favorable prognosis, the overall survival (OS) of metastatic and recurrent EC could hardly be improved by the current chemoradiotherapy. We aimed to reveal the tumor microenvironment immune infiltration characteristics to elucidate the underlying mechanism of EC progression and guide clinical decisions. In the Cancer Genome Atlas (TCGA) cohort, Kaplan-Meier survival curves confirmed Tregs and CD8 T cells were prognosis-protective factors in OS of EC (P<0.05). Weighted gene coexpression network analysis identified 2 gene modules closely correlated with Tregs and CD8 T-cell infiltration. We randomly split the TCGA EC cohort into the training and testing cohorts at a ratio of 7:3. An immune-related prognosis risk index (IRPRI), including NR3C1, E2F1, OTOG, TTK, PPP1R16B, and FOXP3, was established by univariate, Least Absolute Shrinkage and Selection Operator, and multivariate Cox regression with area under the curve >0.67. Distinct clinical, immune, and mutation characteristics existed between IRPRI groups by multiomics analysis. Cell proliferation and DNA damage repair-related pathways were activated, and immune-related pathways were inactivated in the IRPRI-high group. Furthermore, patients in the IRPRI-high group had lower tumor mutation burden, programmed death-ligand 1 expression, and Tumor Immune Dysfunction and Exclusion scores, indicating a poor response to immune checkpoint inhibitors therapy (P<0.05), which was also validated in the TCGA testing cohort and independent cohorts, GSE78200, GSE115821, and GSE168204. Also, the higher mutation frequencies of BRCA1, BRCA2, and genes enrolled in homologous recombination repair in the IRPRI-low group predicted a good response to PARP inhibitors. Finally, a nomogram integrating the IRPRI group and prognosis significant clinicopathological factors for EC OS prediction was developed and validated with good discrimination and calibration.
Landiolol: An Ultra-Short-Acting β-Blocker
Authors: Rao Shiavax J. , Kanwal Arjun , Kanwal Amreen , Danilov Alexandrina , Frishman William H.
Published: April 2023

Landiolol is an ultra-short-acting, highly cardio-selective, β-blocker, that is currently approved for clinical use in Japan and the European Union, for the treatment of tachyarrhythmias. Landiolol is highly cardio-selective with high β1 selectivity and receptor affinity, resulting in a more potent chronotropic effect and less potent hypotensive effect compared with other β-blockers such as esmolol and propranolol. Based on the recent randomized controlled trials, low-dose landiolol may have a beneficial role in the prevention and management of postoperative atrial fibrillation following noncardiac and cardiac surgeries, including on-pump and off-pump coronary artery bypass grafting and valve surgery. Additionally, landiolol may have potential utility for myocardial salvage and prevention of postpercutaneous coronary intervention myocardial infarction. Furthermore, the use of landiolol may also have a therapeutic effect for rate control of sepsis-related tachyarrhythmias. Positive results of recent randomized controlled trials should continue to inspire clinicians to conduct further, larger studies, to find new potential clinical applications for this novel drug.
Descriptive Analysis of Documentation Time for the National Developmental-Behavioral Pediatric Physician Workforce Using a Commercial Electronic Health Record System
Authors: Patel Rohan , Yang Yumei , Lin Feng-Chang , Shumaker Amanda , Nash Patricia , Newmeyer Amy , Baum Rebecca , Hoffman Jeffrey
Published: April 2023

Objective:

The national developmental-behavioral pediatric (DBP) workforce struggles to meet current service demands because of several factors. Lengthy and inefficient documentation processes are likely to contribute to service demand challenges, but DBP documentation patterns have not been sufficiently studied. Identifying clinical practice patterns may inform strategies to address documentation burden in DBP practice.

Methods:

Nearly 500 DBP physicians in the United States use a single commercial electronic health record (EHR) system (EpicCare Ambulatory, Epic Systems Corporation, Verona WI). We evaluated descriptive statistics using the US Epic DBP provider data set. We then compared DBP documentation metrics against those of pediatric primary care and selected pediatric subspecialty providers who provide similar types of care. One-way analyses of variance (ANOVAs) were conducted to determine whether outcomes differed among provider specialties.

Results:

We identified 4 groups for analysis from November 2019 through February 2020: DBP (n = 483), primary care (n = 76,423), pediatric psychiatry (n = 783), and child neurology (n = 8589). Post hoc pairwise comparisons revealed statistically significant differences between multiple outcome-specialty combinations. Time in notes per appointment and progress note length demonstrated the strongest evidence of an increased burden on DBP providers compared with other similar provider groups.

Conclusion:

DBP providers spend a significant amount of time documenting progress notes both during and outside of normal clinic hours. This preliminary analysis highlights the utility of using EHR user activity data to quantitatively measure documentation burden.
Pharmacogenetics of tenofovir renal toxicity in HIV-positive Southern Africans
Authors: Mateza Somila , Bradford Yuki , Maartens Gary , Sokhela Simiso , Chandiwana Nomathemba C. , Venter Willem D.F. , Post Frank A. , Ritchie Marylyn D. , Haas David W. , Sinxadi Phumla
Published: April 2023

Objective

Renal toxicity is more common with tenofovir disoproxil fumarate (TDF) than with tenofovir alafenamide fumarate (TAF). We investigated whether polymorphisms in genes relevant to tenofovir disposition affect renal toxicity among HIV-positive Southern Africans.

Methods

Genetic sub-study of adults randomized to initiate TAF or TDF together with dolutegravir and emtricitabine was conducted. Outcomes were changes from week 4 to 48 in the estimated glomerular filtration rate (eGFR) and from baseline to week 48 in urine retinol-binding protein and urine β2-microglobulin adjusted for urinary creatinine (uRBP/Cr and uB2M/Cr). Primary analyses prioritized 14 polymorphisms previously reported to be associated with tenofovir disposition or renal outcomes, and all polymorphisms in 14 selected genes. We also explored genome-wide associations.

Results

336 participants were enrolled. Among 14 polymorphisms of primary interest, the lowest P values for change in eGFR, uRBP/Cr, and uB2M/Cr were ABCC4 rs899494 (P = 0.022), ABCC10 rs2125739 (P = 0.07), and ABCC4 rs1059751 (P = 0.0088); and in genes of interest, the lowest P values were ABCC4 rs4148481 (P = 0.0013), rs691857 (P = 0.00039), and PKD2 rs72659631 (P = 0.0011). However, none of these polymorphisms withstood correction for multiple testing. Genome-wide, the lowest P values were COL27A1 rs1687402 (P = 3.4 × 10−9), CDH4 rs66494466 (P = 5.6 × 10−8), and ITGA4 rs3770126 (P = 6.1 × 10−7).

Conclusion

Two ABCC4 polymorphisms, rs899494 and rs1059751, were nominally associated with change in eGFR and uB2M/Cr, respectively, albeit in the opposite direction of previous reports. COL27A1 polymorphism was genome-wide significantly associated with change in eGFR.
Comparing outcomes of ovarian cystectomy by vaginal natural orifice transluminal endoscopic surgery versus laparoendoscopic single-site surgery: A retrospective cohort study
Authors: Chang Chi-Han , Ding Dah-Ching
Published: April 2023

Background:

We aimed to compare the outcomes of ovarian cystectomy (OC) performed by vaginal natural orifice transluminal endoscopic surgery (vNOTES) vs transumbilical laparoendoscopic single-site surgery (LESS).

Methods:

We retrospectively analyzed the data of patients in our hospital who underwent OC either by vNOTES or LESS between January 2015 and September 2021. Demographic data were collected. The primary outcome was the conversion rate. The secondary outcomes were the duration of surgery, length of hospital stay, estimated blood loss, maximum body temperature within 48 hours after operation, and duration of maximum body temperature (hours), among others. Statistical analysis was done using the SPSS software.

Results:

Exactly 284 patients were screened. The vNOTES and LESS groups consisted of 21 and 47 patients, respectively. There was no significant difference in the conversion rates between the two groups (0 vs 8.5% in vNOTES and LESS, respectively; p = 0.303). Compared with the vNOTES group, the LESS group had a larger cyst diameter (6.00 ± 2.32 vs 4.69 ± 1.29 cm; p = 0.004), more endometriotic cysts (42.6% vs 9.5%; p < 0.001), and more pelvic adhesions requiring adhesiolysis (57.4% vs 19.0%; p = 0.003). At baseline, there were no other differences between the groups. The secondary outcomes included a shorter duration of surgery (70.14 ± 27.30 vs 99.57 ± 36.26 minutes; p = 0.001) and lower estimated blood loss (64.29 ± 39.19 vs 163.43 ± 251.20 mL; p = 0.011) in the vNOTES group. Regression analysis showed the diameter of the ovarian cyst correlated with surgical time. The complication was comparable between the two groups.

Conclusion:

Above all, the advantages of vNOTES include an absence of visible scars, shorter surgical duration, and less blood loss when compared with LESS. Further large-scale prospective trials should confirm the results of our study.
Simultaneous Cochlear Implantation and Salvage Translabyrinthine Resection of Vestibular Schwannoma after Radiotherapy
Authors: Choi Jonathan S. , Fritz Christian G. , Babu Kavan C. , Fan Caleb J. , Babu Seilesh C.
Published: April 2023

Objective

To report on the novel use of simultaneous cochlear implantation (CI) during salvage translabyrinthine resection of vestibular schwannoma (VS) after failed stereotactic radiosurgery (SRS).

Patient

A 52-year-old woman presented with a medium-sized right VS. She experienced continued tumor growth despite previous SRS, resulting in medial extension beyond the internal auditory canal into the cerebellopontine angle. Associated symptoms included asymmetrical right moderate to severe sensorineural hearing loss, poor word recognition, tinnitus, and dizziness.

Intervention

Simultaneous CI with translabyrinthine VS resection.

Main outcome measure

CI-aided pure-tone averages.

Results

After 4 months of device use, CI-aided speech audiometry revealed hearing thresholds in the normal range, with a four-tone pure-tone, average of 16.3 dB. Speech perception with consonant-nucleus-consonant testing in the CI-only condition was 46%, representing a 12% improvement compared with preoperatively. Tinnitus and dizziness burden were subjectively reduced.

Conclusions

Despite challenges inherent to second procedures after radiotherapy failure, successful CI outcomes can be achieved. The current study demonstrates the feasibility of simultaneous CI during salvage VS resection after SRS. A larger study should be undertaken to further substantiate these preliminary findings.
Efficacy of Intratympanic OTO-104 for the Treatment of Ménière's Disease: The Outcome of Three Randomized, Double-Blind, Placebo-Controlled Studies
Authors: Phillips John , Mikulec Anthony A. , Robinson James M. , Skarinsky David , Anderson Jeffery J.
Published: April 2023

Objective

To determine the efficacy of intratympanic OTO-104 for the treatment of Ménière's disease.

Study Designs

Three randomized, double-blind, placebo-controlled, multicenter studies of OTO-104 in patients with Ménière's disease.

Setting

The United States and throughout Europe.

Patients

Individuals with Ménière's disease aged 18 to 85 years.

Interventions

All three studies were conducted according to a similar protocol, whereby after a 1-month lead-in period, eligible patients received a single intratympanic injection of either 12 mg OTO-104 (otic formulation of dexamethasone in thermosensitive poloxamer) or placebo (1:1) and were observed for 3 months.

Main Outcome Measures

The primary efficacy endpoint was measured by the number of definitive vertigo days (DVDs) at month 3. Secondary objective was OTO-104 safety and tolerability including adverse events, audiometry, tympanometry, and otoscopic examinations.

Results

Although OTO-104 demonstrated numerically greater reductions in DVD compared with placebo across all three studies, statistical significance versus placebo (primary efficacy endpoint) was only achieved in one study, the AVERTS-2 study (n = 174, p = 0.029). Secondary vertigo efficacy endpoints were statistically significant at month 3 in that study including vertigo severity, the effect of vertigo on daily activity (days at home sick or bedridden), and vertigo frequency. In the AVERTS-1 study, which did not meet the primary endpoint, a subgroup analysis of the 115 patients (69.7% of study population) who did not previously receive intratympanic steroid injections demonstrated that OTO-104 patients had significantly lower mean DVD at month 3 than patients receiving placebo (1.9 for OTO-104 versus 3.0 for placebo; p = 0.045). Importantly, a significant placebo response was observed across studies in Ménière's disease patients. OTO-104 and the intratympanic injection procedure were well tolerated.

Conclusions

In all three high-quality, randomized, double-blind, placebo-controlled, multicenter studies, a single intratympanic injection of 12 mg OTO-104 demonstrated numerically greater reductions in vertigo versus placebo in patients with Ménière's disease, but statistical separation from placebo was demonstrated in only one of the studies. OTO-104 was safe and well tolerated.

(Otonomy, Inc. funded; NCT02717442, NCT02612337, NCT03664674).
RNF26 Promotes Pancreatic Cancer Proliferation by Enhancing RBM38 Degradation
Authors: Lu Xiangyu , Zhang Yu , Wu Yilei , Lu Tao , Yang Hongji , Yang Wenhao , Pang Beichuan , Yang Chong
Published: April 2023

Objectives

RING finger protein 26 (RNF26) plays an essential role in determining malignant tumor growth, whereas the role of which in pancreatic cancer (PC) has not been reported. This study aimed to investigate the role of RNF26 in PC cells.

Methods

The Gene Expression Profiling Interactive Analysis was applied to study the role of RNF26 in malignant tumors. The in vitro or in vivo cell proliferation assays were used to investigate the role of RNF26 on the PC. The protein-protein interaction network analysis was used to search the binding partner of RNF26. The Western blot was used to reveal whether RNF26 promoted RNA binding motif protein-38 (RBM38) degradation in PC cells.

Results

The Gene Expression Profiling Interactive Analysis tool showed that RNF26 was overexpressed in PC. Repressing RNF26 expression decreased PC cells growth, but overexpression of RNF26 increased PC proliferation. Furthermore, we demonstrated RNF26 degraded RBM38 to promote PC cell proliferation.

Conclusions

RNF26 was abnormally increased in PC, and upregulated RNF26 was correlated with a poor prognosis. RNF26 enhanced PC proliferation by inducing RBM38 degradation. We identified a novel RNF26-RBM28 axis involved in the progression of PC.
Associations Between Iron Homeostasis and Pancreatic Enzymes After an Attack of Pancreatitis
Authors: Kimita Wandia , Ko Juyeon , Li Xinye , Bharmal Sakina H. , Petrov Maxim S.
Published: April 2023

Objectives

Dysregulation of iron homeostasis and exocrine pancreatic dysfunction are linked but remain undefined in individuals with a history of pancreatitis. The objective is to investigate the relationship between iron homeostasis and pancreatic enzymes in individuals after a pancreatitis attack.

Methods

This was a cross-sectional study of adults with a history of pancreatitis. Markers of iron metabolism (hepcidin and ferritin) and pancreatic enzymes (pancreatic amylase, pancreatic lipase, and chymotrypsin) were measured in venous blood. Habitual dietary iron intake data (total, heme, and nonheme iron) were collected. Multivariable linear regression analyses were performed while considering covariates.

Results

One hundred and one participants were studied at a median of 18 months after their last pancreatitis attack. Hepcidin was significantly associated with pancreatic amylase (β coefficient, −6.68; 95% confidence interval, −12.88 to −0.48; P = 0.035) and heme iron intake (β coefficient, 0.34; 95% confidence interval, 0.08 to 0.60; P = 0.012) in the adjusted model. Hepcidin was not significantly associated with pancreatic lipase or chymotrypsin. Ferritin was not significantly associated with pancreatic enzymes and dietary iron intake.

Conclusions

An iron homeostasis–exocrine pancreas crosstalk exists in individuals after an attack of pancreatitis. The role of iron homeostasis in pancreatitis warrants high-quality purposely-designed studies.
Glucagon-Like Peptide 1–Based Therapies and Risk of Pancreatic Cancer in Patients With Diabetes and Obesity
Authors: Krishnan Arunkumar , Hadi Yousaf , Hutson William R. , Thakkar Shyam , Singh Shailendra
Published: April 2023

Objectives

There have been conflicting reports concerning an increased risk of pancreatic cancer (PC) in new users of glucagon-like peptide-1 agonists (GLP-1As). We aimed to explore whether the use of GLP-1A is associated with an increased risk of PC.

Methods

A multicenter, retrospective cohort study was conducted using TriNetX. Adult patients with diabetes and/or overweight and obesity who were newly treated with GLP-1A or metformin for the first time between 2006 and 2021 were matched 1:1 using propensity score matching. The risk of PC was estimated using a Cox proportional hazards model.

Results

A total of 492,760 patients were identified in the GLP-1A and 918,711 patients in the metformin group. After propensity score matching, both cohorts (370,490 each) were well matched. During follow-up, 351 patients in the GLP-1A and 956 on metformin developed PC after an exposure lag of 1 year. Glucagon-like peptide-1 agonists was associated with a significantly lower risk of PC (hazard ratio, 0.47; 95% confidence interval, 0.42–0.52).

Conclusions

The use of GLP-1A in patients with obesity/diabetes is associated with a lower risk of PC compared with a similar cohort of patients using metformin. Our study findings reassure clinicians and patients with apprehensions about any possible association between GLP-1A and PC.
Role of Somatostatin Receptor 2 in Nonfunctional Pancreatic Neuroendocrine Tumors
Authors: Hu Hai-Feng , Hu Yu-Heng , Xu Xiao-Wu , Ye Zeng , Lou Xin , Zhang Wu-Hu , Chen Xue-Min , Zhang Yue , Yu Xian-Jun , Gao He-Li , Xu Jun-Yan , Ji Shun-Rong
Published: April 2023

Objectives

Somatostatin receptors are commonly expressed in most pancreatic neuroendocrine tumors (pNETs), a rare type of pancreatic tumors with high heterogeneity. However, the role of somatostatin receptor 2 (SSTR2) has seldom been investigated separately in pNET. This retrospective study aims to evaluate the role of SSTR2 in the clinicopathological features and genomic background of nonfunctional and well-differentiated pNET.

Methods

A total of 223 cases of nonfunctional well-differentiated pNET were included, and the correlation between SSTR2 status and clinicopathological outcome was evaluated. In addition, we performed whole exome sequencing in SSTR2-positive and SSTR2-negative pNETs and identified that the 2 lesions harbored different mutational landscapes.

Results

Negative SSTR2 immunochemistry staining was significantly related to an earlier onset of disease, larger tumor size, advanced stage of American Joint Committee on Cancer, and tumor metastasis in lymph nodes and liver. Under pathological assessment, positive peripheral aggression, vascular invasion, and perineural invasion were markedly increased in SSTR2-negative cases. Moreover, SSTR2-negative patients exhibited significantly worse progression-free survival than SSTR2-positive patients (hazard ratio, 0.23; 95% confidence interval, 0.10–0.53; P = 0.001).

Conclusions

Somatostatin receptor 2–negative nonfunctional pNET might represent a subtype of pNET with poor outcomes and evolve from a different genomic background.
Factors Predicting the Development of Necrosis in Patients Presenting With Edematous Acute Pancreatitis
Authors: Acehan Fatih , Comoglu Mustafa , Kayserili Fatih Mehmet , Hayat Büşra , Ates Ihsan
Published: April 2023

Objectives

There is no marker that can accurately predict the development of pancreatic necrosis in edematous acute pancreatitis (AP). This study aimed to investigate the factors associated with necrosis development in cases of edematous AP and to create an easy-to-use scoring system.

Methods

We retrospectively reviewed patients diagnosed with edematous AP between 2010 and 2021. Among the patients, those who were found to have developed necrosis during follow-up were categorized as the necrotizing group, whereas the others constituted the edematous group.

Results

With multivariate analysis, white blood cell, hematocrit, lactate dehydrogenase, and C-reactive protein levels at the 48th hour were revealed to be independent risk factors for necrosis. Using these 4 independent predictors, the Necrosis Development Score 48 (NDS-48) was derived. While the cutoff value was 2.5, the sensitivity and specificity of the NDS-48 for necrosis were 92.5% and 85.9%, respectively. The area under the curve value of the NDS-48 for necrosis was 0.949 (95% confidence interval, 0.920–0.977).

Conclusions

White blood cell, hematocrit, lactate dehydrogenase, and C-reactive protein levels at the 48th hour are independent predictors of necrosis development. The NDS-48, a new scoring system created with these 4 predictors, satisfactorily predicted the development of necrosis.
Peri-Intubation Adverse Events in the Critically Ill Child After Hematopoietic Cell Transplant
Authors: Lenz Kyle B. , Nishisaki Akira , Lindell Robert B. , Yehya Nadir , Laverriere Elizabeth K. , Bruins Benjamin B. , Napolitano Natalie , Traynor Danielle M. , Rowan Courtney M. , Fitzgerald Julie C.
Published: April 2023

Objectives:

Mechanically ventilated children post-hematopoietic cell transplant (HCT) have increased morbidity and mortality compared with other mechanically ventilated critically ill children. Tracheal intubation-associated adverse events (TIAEs) and peri-intubation hypoxemia universally portend worse outcomes. We investigated whether adverse peri-intubation associated events occur at increased frequency in patients with HCT compared with non-HCT oncologic or other PICU patients and therefore might contribute to increased mortality.

Design:

Retrospective cohort between 2014 and 2019.

Setting:

Single-center academic noncardiac PICU.

Patients:

Critically ill children who underwent tracheal intubation (TI).

Interventions:

None.

Measurements and Main Results:

Data from the local airway management quality improvement databases and Virtual Pediatric Systems were merged. These data were supplemented with a retrospective chart review for HCT-related data, including HCT indication, transplant-related comorbidity status, and patient condition at the time of TI procedure. The primary outcome was defined as the composite of hemodynamic TIAE (hypo/hypertension, arrhythmia, cardiac arrest) and/or peri-intubation hypoxemia (oxygen saturation < 80%) events. One thousand nine hundred thirty-one encounters underwent TI, of which 92 (4.8%) were post-HCT, while 319 (16.5%) had history of malignancy without HCT, and 1,520 (78.7%) had neither HCT nor malignancy. Children post-HCT were older more often had respiratory failure as an indication for intubation, use of catecholamine infusions peri-intubation, and use of noninvasive ventilation prior to intubation. Hemodynamic TIAE or peri-intubation hypoxemia were not different across three groups (HCT 16%, non-HCT with malignancy 10%, other 15). After adjusting for age, difficult airway feature, provider type, device, apneic oxygenation use, and indication for intubation, we did not identify an association between HCT status and the adverse TI outcome (odds ratio, 1.32 for HCT status vs other; 95% CI, 0.72–2.41; p = 0.37).

Conclusions:

In this single-center study, we did not identify an association between HCT status and hemodynamic TIAE or peri-intubation hypoxemia during TI.
Low Diagnostic Utility of Frequent Serial Tracheal Aspirate Cultures in the PICU*
Authors: Feldman Evin , Shah Shivang S. , Ahn Danielle
Published: April 2023

OBJECTIVES:

To determine the diagnostic outcomes of serial tracheal aspirate cultures (TACs) in the PICU.

DESIGN:

A retrospective chart review of TAC utilization was performed. Items recorded for each TAC included the time and date of culture acquisition, result, changes in microbial resistance patterns, antimicrobial therapy, and patient clinical course.

SETTING:

A single urban tertiary care children’s hospital in the United States.

SUBJECTS:

Patients admitted to the PICU from January 1, to October 31, 2021, for whom a TAC was performed.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

One hundred fifty unique subjects had 582 TACs performed during the study period, of which 145 (24.9%) were serially repeated within 72 hours. Of these serial TACs, 82 (56.6%) had no growth, 41 (28.3%) grew the same organism as the prior culture, with most (36/41) displaying no major change in antimicrobial susceptibilities, 11 (7.6%) grew a new organism previously grown during the admission, and 11 (7.6%) grew a new organism not previously grown during the admission. Overall, only 26 of these serial TACs (17.9%) provided new diagnostic information, whereas only five (3.4%) led to a change in management.

CONCLUSIONS:

Frequent serial TAC sampling in the PICU is common and infrequently yields new data that impact clinical decision-making. Considering worsening antimicrobial resistance and the role of diagnostic stewardship in mitigating it, these findings further support a 72-hour reassessment period before performing a repeat TAC in critically ill children.
Medico-Legal Evaluation of Keloid Formation Following Prominent Ear Correction: Malpractice or Complication?
Authors: Demir Canser Yilmaz , Hekimoglu Yavuz , Asirdizer Mahmut
Published: April 2023

  

Prominent ear is an anatomic auricular deformity seen in 5% of the population.

Keloid formation may occur following prominent ear correction operations.

Such undesirable results can lead to a claim of medical malpractice.

It is necessary to determine whether the undesired outcome is a complication or malpractice.

The physician’s compliance with the standards of care and patient rights is decisive in this distinction.
Influence of Residual Quadrupolar Interaction on Quantitative Sodium Brain Magnetic Resonance Imaging of Patients With Multiple Sclerosis
Authors: Wilferth Tobias , Mennecke Angelika , Huhn Konstantin , Uder Michael , Doerfler Arnd , Schmidt Manuel , Nagel Armin M.
Published: April 2023

Objectives

The purpose of this work was to evaluate the influence of residual quadrupolar interaction on the determination of human brain apparent tissue sodium concentrations (aTSCs) using quantitative sodium magnetic resonance imaging (23Na MRI) in healthy controls (HCs) and patients with multiple sclerosis (MS). Especially, it was investigated if the more detailed examination of residual quadrupolar interaction effects enables further analysis of the observed 23Na MRI signal increase in MS patients.

Materials and Methods

23Na MRI with a 7 T MR system was performed on 21 HC and 50 MS patients covering all MS subtypes (25 patients with relapsing-remitting MS, 14 patients with secondary progressive MS, and 11 patients with primary progressive MS) using 2 different 23Na pulse sequences for quantification: a commonly used standard sequence (aTSCStd) as well as a sequence with shorter excitation pulse length and lower flip angle for minimizing signal loss resulting from residual quadrupolar interactions (aTSCSP). Apparent tissue sodium concentration was determined using the same postprocessing pipeline including correction of the receive profile of the radiofrequency coil, partial volume correction, and relaxation correction. Spin dynamic simulations of spin-3/2 nuclei were performed to aid in the understanding of the measurement results and to get deeper insight in the underlying mechanisms.

Results

In normal-appearing white matter (NAWM) of HC and all MS subtypes, the aTSCSP values were approximately 20% higher than the aTSCStd values (P < 0.001). In addition, the ratio aTSCSP/aTSCStd was significantly higher in NAWM than in normal-appearing gray matter (NAGM) for all subject cohorts (P < 0.002). In NAWM, aTSCStd values were significantly higher in primary progressive MS compared with HC (P = 0.01) as well as relapsing-remitting MS (P = 0.03). However, in contrast, no significant differences between the subject cohorts were found for aTSCSP. Spin simulations assuming the occurrence of residual quadrupolar interaction in NAWM were in good accordance with the measurement results, in particular, the ratio aTSCSP/aTSCStd in NAWM and NAGM.

Conclusions

Our results showed that residual quadrupolar interactions in white matter regions of the human brain have an influence on aTSC quantification and therefore must be considered, especially in pathologies with expected microstructural changes such as loss of myelin in MS. Furthermore, the more detailed examination of residual quadrupolar interactions may lead to a better understanding of the pathologies themselves.
High Effectiveness of Midazolam and Lidocaine in the Treatment of Acute Neonatal Seizures
Authors: Castro Conde José Ramón , González Campo Candelaria , González Barrios Desiré , Reyes Millán Beatriz , Díaz González Candelaria Leticia , Jiménez Sosa Alejandro
Published: April 2023

Purpose:

To assess the clinical effectiveness of treating acute seizures with midazolam and lidocaine infusion.

Methods:

This single-center historical cohort study included 39 term neonates with electrographic seizures who underwent treatment with midazolam (1st line) and lidocaine (2nd line). Therapeutic response was measured using continuous video-EEG monitoring. The EEG measurements included total seizure burden (minutes), maximum ictal fraction (minutes/hour), and EEG-background (normal/slightly abnormal vs. abnormal). Treatment response was considered good (seizure control with midazolam infusion), intermediate (need to add lidocaine to the control), or no response. Using clinical assessments supplemented by BSID-III and/or ASQ-3 at 2 to 9 years old age, neurodevelopment was classified as normal, borderline, or abnormal.

Results:

A good therapeutic response was obtained in 24 neonates, an intermediate response in 15, and no response in any of the neonates. Babies with good response showed lower values in maximum ictal fraction compared with those with intermediate response (95% CI: 5.85–8.64 vs. 9.14–19.14, P = 0.002). Neurodevelopment was considered normal in 24 children, borderline in five, and abnormal in other 10 children. Abnormal neurodevelopment was significantly associated with an abnormal EEG background, maximum ictal fraction >11 minutes, and total seizure burden >25 minutes (odds ratio 95% CI: 4.74–1708.52, P = 0.003; 1.72–200, P = 0.016; 1.72–142.86, P = 0.026, respectively) but not with the therapeutic response. Serious adverse effects were not recorded.

Conclusions:

This retrospective study suggests that the midazolam/lidocaine association could potentially be efficacious in decreasing seizure burden in term neonates with acute seizures. These results would justify testing the midazolam/lidocaine combination as a first-line treatment for neonatal seizures in future clinical trials.
First record of growth patterns in a Cambrian annelid
Authors: Osawa Hatena , Caron Jean-Bernard , Gaines Robert R.
Published: April 2023

Early annelid evolution is mostly known from 13 described species from Cambrian Burgess Shale-type Lagerstätten. We introduce a new exceptionally well-preserved polychaete,Ursactis comosagen. et sp. nov., from the Burgess Shale (Wuliuan Stage). This small species (3–15 mm) is the most abundant Cambrian polychaete known to date. Most specimens come from Tokumm Creek, a new Burgess Shale locality in northern Kootenay National Park, British Columbia, Canada.Ursactishas a pair of large palps, thin peristomial neurochaetae and biramous parapodia bearing similarly sized capillary neurochaetae and notochaetae, except for segments six to nine, which also have longer notochaetae. The number of segments in this polychaete range between 8 and 10 with larger individuals having 10 segments. This number of segments inUrsactisis remarkably small compared with other polychaetes, including modern forms. Specimens with 10 segments show significant size variations, and the length of each segment increases with the body length, indicating that body growth was primarily achieved by increasing the size of existing segments rather than adding new ones. This contrasts with most modern polychaetes, which typically have a larger number of segments through additions of segments throughout life. The inferred growth pattern inUrsactissuggests that annelids had evolved control over segment addition by the mid-Cambrian.
Modular implementation of the linear- and cubic-scaling orbital minimization methods in electronic structure codes using atomic orbitals
Authors: Lebedeva Irina V. , García Alberto , Artacho Emilio , Ordejón Pablo
Published: April 2023

We present a code modularization approach to design efficient and massively parallel cubic- and linear-scaling solvers for electronic structure calculations using atomic orbitals. The modular implementation of the orbital minimization method, in which linear algebra and parallelization issues are handled via external libraries, is demonstrated in the SIESTA code. The distributed block compressed sparse row (DBCSR) and scalable linear algebra package (ScaLAPACK) libraries are used for algebraic operations with sparse and dense matrices, respectively. The MatrixSwitch and libOMM libraries, recently developed within the Electronic Structure Library, facilitate switching between different matrix formats and implement the energy minimization. We show results comparing the performance of several cubic-scaling algorithms, and also demonstrate the parallel performance of the linear-scaling solvers, and their supremacy over the cubic-scaling solvers for insulating systems with sizes of several hundreds of atoms.
Haemolymph viscosity in hawkmoths and its implications for hovering flight
Authors: Brasovs Artis , Palaoro Alexandre V. , Aprelev Pavel , Beard Charles E. , Adler Peter H. , Kornev Konstantin G.
Published: April 2023

Viscosity determines the resistance of haemolymph flow through the insect body. For flying insects, viscosity is a major physiological parameter limiting flight performance by controlling the flow rate of fuel to the flight muscles, circulating nutrients and rapidly removing metabolic waste products. The more viscous the haemolymph, the greater the metabolic energy needed to pump it through confined spaces. By employing magnetic rotational spectroscopy with nickel nanorods, we showed that viscosity of haemolymph in resting hawkmoths (Sphingidae) depends on wing size non-monotonically. Viscosity increases for small hawkmoths with high wingbeat frequencies, reaches a maximum for middle-sized hawkmoths with moderate wingbeat frequencies, and decreases in large hawkmoths with slower wingbeat frequencies but greater lift. Accordingly, hawkmoths with small and large wings have viscosities approaching that of water, whereas hawkmoths with mid-sized wings have more than twofold greater viscosity. The metabolic demands of flight correlate with significant changes in circulatory strategies via modulation of haemolymph viscosity. Thus, the evolution of hovering flight would require fine-tuned viscosity adjustments to balance the need for the haemolymph to carry more fuel to the flight muscles while decreasing the viscous dissipation associated with its circulation.
Quantitative genetic analysis of floral traits shows current limits but potential evolution in the wild
Authors: Castellanos Maria Clara , Montero-Pau Javier , Ziarsolo Peio , Blanca Jose Miguel , Cañizares Joaquin , Pausas Juli G.
Published: April 2023

The vast variation in floral traits across angiosperms is often interpreted as the result of adaptation to pollinators. However, studies in wild populations often find no evidence of pollinator-mediated selection on flowers. Evolutionary theory predicts this could be the outcome of periods of stasis under stable conditions, followed by shorter periods of pollinator change that provide selection for innovative phenotypes. We asked if periods of stasis are caused by stabilizing selection, absence of other forms of selection or by low trait ability to respond even if selection is present. We studied a plant predominantly pollinated by one bee species across its range. We measured heritability and evolvability of traits, using genome-wide relatedness in a large wild population, and combined this with estimates of selection on the same individuals. We found evidence for both stabilizing selection and low trait heritability as potential explanations for stasis in flowers. The area of the standard petal is under stabilizing selection, but the variability is not heritable. A separate trait, floral weight, presents high heritability, but is not currently under selection. We show how a simple pollination environment coincides with the absence of current prerequisites for adaptive evolutionary change, while heritable variation remains to respond to future selection pressures.