bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytoglobin as a Prognostic Factor for Pancreatic Ductal Adenocarcinoma
Authors: Kono Hiroshi , Hosomura Naohiro , Amemiya Hidetake , Kawaida Hiromichi , Furuya Shinji , Akaike Hidenori , Kawaguchi Yoshihiko , Sudo Makoto , Ichikawa Daisuke
Published: October 2021

Objectives

The aim was to evaluate the relationship between cytoglobin (Cygb) expression and both clinicopathologic factors and prognosis in patients with pancreatic ductal adenocarcinoma (PDAC).

Methods

Seventy-five patients with PDAC who underwent pancreatectomy between 2009 and 2014 at our department were included. Diagnosis was based on World Health Organization standards, with staging by TNM classification of Union for International Cancer Control. Expressions of Cygb, phosphoinositide-3 kinase, phosphorylated protein kinase B, interleukin-6, and vascular endothelial growth factor were evaluated by immunohistochemical staining of resected surgical specimens and densitometrical analysis.

Results

Elevated expression of Cygb was found mainly in carcinoma cells of PDAC. Patients with low expression of Cygb showed significantly shorter disease-free survival and disease-specific survival than those with high expression. There was also a significant negative correlation between Cygb expression and the expressions of phosphoinositide 3-kinase, phosphorylated protein kinase B, interleukin-6, and vascular endothelial growth factor. In univariate analysis, Cygb expression, clinical stage, histologic tumor grade, lymphatic invasion, and vascular invasion were prognostic factors. In multivariate analysis, Cygb expression and the clinical stage were independent prognostic factors.

Conclusions

Loss of Cygb may contribute to tumor recurrence and poor prognosis of PDAC by increases in angiogenic factor.
Clinical Usefulness of [18F]-Fluoro-2-Deoxy-d-Glucose–Positron Emission Tomography/Computed Tomography for Distinguishing Between Autoimmune Pancreatitis and Pancreatic Cancer
Authors: Ohtani Masahiro , Ofuji Kazuya , Akazawa Yu , Saito Yasushi , Nosaka Takuto , Ozaki Yoshihiko , Takahashi Kazuto , Naito Tatsushi , Matsuda Hidetaka , Hiramatsu Katsushi , Nakamoto Yasunari
Published: October 2021

Objectives

We investigated the [18F]-fluoro-2-deoxy-d-glucose (FDG)–positron emission tomography (PET)/computed tomography (CT) findings of pancreatic and extrapancreatic lesions in patients with autoimmune pancreatitis (AIP) and pancreatic cancer (PC) and evaluated the usefulness of 18F-FDG–PET/CT for differentiating between AIP and PC.

Methods

Eighty-five patients, 19 with AIP and 66 with PC, who underwent 18F-FDG–PET/CT were studied retrospectively. We evaluated the maximum standardized uptake value (SUVmax), patterns and distributions of FDG activity in pancreatic lesions, as well as FDG uptake in extrapancreatic lesions.

Results

The levels of SUVmax of pancreatic lesions in PC patients were significantly higher than those in AIP patients (P < 0.05). Focal/segmental distribution of FDG activity was found in 61.1% of the AIP patients and 98.4% of the PC patients. Heterogeneous FDG activity patterns were found in 61.1% of the AIP patients and 18.7% of the PC patients. Activities of FDG in pancreatic lesions were significantly different between AIP and PC. Extrapancreatic activities of salivary glands, extraperitoneal lymph nodes, prostate, retroperitoneum, and kidneys in the AIP patients were significantly higher than those in the PC patients (P < 0.05). Multivariate analysis revealed that SUVmax (>7.08) and focal/segmental FDG distribution were independent predictors of PC (P < 0.05).

Conclusions

The 18F-FDG–PET/CT findings are useful for differentiating between AIP and PC.
Greater Cognitive-Motor Interference in Individuals Post-Stroke During More Complex Motor Tasks
Authors: Rice Jordyn , Corp Daniel T. , Swarowsky Alessandra , Cahalin Lawrence P. , Cabral Danylo F. , Nunez Christina , Koch Sebastian , Rundek Tatjana , Gomes-Osman Joyce
Published: October 2021

Background and Purpose:

Dual-task (DT) walking assessments allow for the simultaneous evaluation of cognitive and motor performance. During DT walking, individuals may experience interference in one or both tasks, known as cognitive-motor interference (CMI). The primary purpose of this study was to compare CMI between individuals post-stroke and healthy persons group during single- and dual-motor and cognitive tasks, using 2 distinct walking tasks.

Methods:

Motor performance was quantified as the total time for the Timed Up and Go (TUG) and gait speed for the 90-second walk (90W). Cognitive performance was measured as the correct response rate (CRR) during serial 7 subtractions. Participants performed the motor and cognitive tasks in isolation for the single-task (ST) and simultaneously for DT conditions, TUG-DT and 90W-DT. A repeated-measures analysis of variance assessed group (poststroke and healthy) by condition (ST and DT) interactions for the TUG, 90W, and CRR.

Results:

There were significant main effects of group and condition for both the TUG and the 90W (P < 0.05). There was also an interaction effect for the TUG, with individuals post-stroke demonstrating a larger decrement in TUG-DT performance compared with healthy persons (P < 0.05). Furthermore, a significant interaction effect was observed for the CRR, in which healthy individuals exhibited a greater decrement in performance from the ST to the 90W-DT (P < 0.05).

Discussion and Conclusions:

Individuals post-stroke were susceptible to greater motor interference during the more complex motor task, the TUG-DT. However, the only decrements observed in cognitive performance from the ST to DT occurred in healthy individuals during the 90W-DT.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A367).
Optimizing Dolutegravir Initiation in Neonates Using Population Pharmacokinetic Modeling and Simulation
Authors: Piscitelli Joseph , Nikanjam Mina , Best Brookie M. , Acosta Edward , Mirochnick Mark , Clarke Diana F. , Capparelli Edmund V. , Momper Jeremiah D.
Published: October 2021

Background:

A knowledge gap exists for dolutegravir (DTG) pharmacokinetics and safety during the first 4 weeks of life, preventing safe and effective DTG use in neonates.

Setting:

Population pharmacokinetic modeling and simulation were used to assess newborn DTG dosing requirements during the first few days of life as a function of maternal DTG dosing history before delivery.

Methods:

DTG PK data were obtained from pregnant women and infants enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026S study. Maternal and neonate population pharmacokinetic models were separately developed. Monte Carlo simulations were performed to simulate neonatal concentrations after 2 doses of DTG after birth for infants born to mothers either receiving or not receiving DTG before delivery.

Results:

In DTG-naïve infants, a 5-mg DTG dose at birth with a second dose after 48 hours maintained median concentrations above the lower bound of the target range (0.77 μg/mL) and below the upper bound of the target range (7.34 μg/mL representing 2-fold above the adult Cmax value). In DTG-exposed infants, a 5-mg DTG dose at 24 hours after birth with a second dose after 48 hours maintained median concentrations within or nearly within the target range, even if the last maternal DTG dose was taken as soon as 6 hours or as long as 24 hours before delivery.

Conclusions:

Newborn DTG dosing requirements during the first few days of life depend on maternal DTG dosing history before delivery. These results may help the design of future clinical studies of DTG in the neonatal population.
Differential Associations Between BDNF and Memory Across Older Black and White Adults With HIV Disease
Authors: Fazeli Pariya L. , Woods Steven P. , Lambert Crystal C. , Li Wei , Hopkins Cierra N. , Vance David E.
Published: October 2021

Background:

Brain-derived neurotrophic factor (BDNF) shows consistent associations with memory across many clinical populations, including dementia. Less is understood about the association between BDNF and memory functioning in people living with HIV (PWH).

Methods:

A sample of 173 adults aged 50+ (n = 100 HIV+ and n = 73 HIV seronegative) completed a comprehensive neurobehavioral assessment and blood draw. Linear regressions predicting memory domains (learning, delayed recall, and recognition) were conducted including race (White vs. Black/African American), HIV status, BDNF, and their interactions.

Results:

For learning and delayed recall, significant (P < 0.05) main effects for race and interactions for BDNF x race and HIV status x race were found, whereas for recognition, only a BDNF x race interaction emerged. In adjusted models, BDNF x race interactions remained for learning and delayed recall. To determine effect size, correlations were conducted between BDNF and memory domains stratified by HIV serostatus and race, and small–medium associations between BDNF and learning and delayed recall (rho = 0.29, P < 0.01; rho = 0.22, P = 0.045), but no recognition (rho = 0.12, P = 0.29) were found among Black/African American PWH. BDNF was not significantly associated with memory domains in White PWH or either HIV- sample. Follow-up analyses showed BDNF-memory specificity, such that race X BDNF interactions did not emerge for other cognitive domains.

Conclusions:

While limited by cross-sectional design among a small sample, particularly of White individuals, results indicate that BDNF may serve as a promising biomarker reflecting memory functioning in PWH, particularly Black/African Americans. Further work is needed to replicate findings and determine mechanisms for racial differences in BDNF associations with memory.
Pitfalls and Practical Challenges in Imaging of the Pediatric Scrotum
Authors: Chaudhry Humaira , Siddiqi Madheea , Simpson William L. , Rosenberg Henrietta Kotlus
Published: October 2021

Ultrasound is the modality of choice for evaluation of the pediatric scrotum, as it provides excellent image quality without the use of radiation, need for sedation/anesthesia, or use of contrast material and can be used for serial examination. Ultrasound of the scrotum has proven to be useful for assessment of a wide gamut of congenital, infectious, inflammatory, endocrine, neoplastic, and traumatic abnormalities in pediatric patients of all ages from the tiniest premature infant to a fully grown young adult. This review article presents a varied spectrum of conditions that may affect the pediatric scrotum, what the radiologist needs to know to meet the challenge of limiting the differential diagnosis, and how to avoid pitfalls when imaging the scrotum.
Cost-effectiveness of Early Surgery Versus Endoscopy-first Approach for Painful Chronic Pancreatitis in the ESCAPE Trial
Authors: Kempeneers Marinus A. , Issa Yama , Bruno Marco J. , van Santvoort Hjalmar C. , Besselink Marc G. , Boermeester Marja A. , Dijkgraaf Marcel G. ,   for the Dutch Pancreatitis Study Group
Published: October 2021

Objective:

Economic evaluation of early surgery compared to the endoscopy-first approach in CP.

Background:

In patients with painful CP and a dilated main pancreatic duct, early surgery, as compared with an endoscopy-first approach, leads to more pain reduction with fewer interventions. However, it is unknown if early surgery is more cost-effective than the endoscopy-first approach.

Methods:

The multicenter Dutch ESCAPE trial randomized patients with CP and a dilated main pancreatic duct between early surgery (surgery within 6 weeks) or the endoscopy-first approach in 30 centers (April 2011–September 2016). Healthcare utilization was prospectively recorded up to 18 months after randomization. Unit costs of resources were determined, and cost-effectiveness and cost–utility analyses were performed from societal and healthcare perspectives. Primary outcomes were the costs per unit decrease on the Izbicki pain score and per gained quality-adjusted life-year.

Results:

In total, 88 patients were included in the analysis, with 44 patients randomized to each group. Total costs were lower in the early surgery group but did not reach statistical significance (mean difference €−4,815 (95% bias-corrected and accelerated confidence interval €−13,113 to €3411; P = 0.25). Early surgery had a probability percentage of 88.4% of being more cost-effective than the endoscopy-first approach at a willingness-to-pay threshold of €0 per day per unit decrease on the Izbicki pain score. The probability percentage per additional gained quality-adjusted life-year was 75.7% at a willingness-to-pay threshold of €50,000.

Conclusion:

In patients with painful CP and a dilated main pancreatic duct, early surgery was more cost-effective than the endoscopy-first approach.
Efficacy of Extended Modification in Left Hemihepatectomy for Advanced Perihilar Cholangiocarcinoma
Authors: Otsuka Shimpei , Mizuno Takashi , Yamaguchi Junpei , Onoe Shunsuke , Watanabe Nobuyuki , Shimoyama Yoshie , Igami Tsuyoshi , Uehara Kay , Yokoyama Yukihiro , Nagino Masato , Ebata Tomoki
Published: October 2021

Objective:

The aim of this study was to verify the prognostic impact of the tumor exposure at the liver transection margin (LTM) in left-sided perihilar cholangiocarcinoma and the impact of middle hepatic vein (MHV) resection on this exposure.

Background:

In perihilar cholangiocarcinoma, tumors are unexpectedly exposed at the LTM during left hemihepatectomy (LH).

Methods:

Patients who underwent LH for perihilar cholangiocarcinoma during 2002 to 2018 were retrospectively evaluated. LH was classified into conventional and extended types, which preserved and resected the MHVs, respectively. Positive LTM was defined as the involvement of invasive carcinoma at the liver transection plane and/or the adjacent Glissonean pedicle exposed. The clinicopathologic features and survival outcomes were compared between procedures.

Results:

Among 236 patients, conventional and extended LHs were performed in 198 and 38 patients, respectively. The LTM was positive in 31 (13%) patients, with an incidence of 14% versus 8% (P = 0.432) and 24% versus 0% in advanced tumors (P = 0.011). Tumor size ≥ 18 mm (P = 0.041), portal vein invasion (P = 0.009), and conventional LH (P = 0.028) independently predicted positive LTM. In patients with negative LTM, the survival was comparable between the two groups: 60.4% versus 59.2% at 3 years (P = 0.206), which surpassed 17.7% for those with positive LTM in the conventional group (P < 0.001). Multivariable analysis demonstrated that LTM status was an independent prognostic factor (P = 0.009) along with ductal margin status (P = 0.030).

Conclusions:

The LTM status is an important prognostic factor in perihilar cholangiocarcinoma. Extended LH reduced the risk of tumor exposure at the LTM with a subsequent improvement in the survival, particularly in advanced tumors.
Extraocular Muscle Volumetry for Assessment of Thyroid Eye Disease
Authors: Bontzos Georgios , Papadaki Efrosini , Mazonakis Michael , Maris Thomas G. , Tsakalis Nikolaos G. , Drakonaki Eleni E. , Detorakis Efstathios T.
Published: October 2021

Background:

In this study we evaluate the diagnostic accuracy of extraocular muscle volumetry in detecting thyroid eye disease and to compare the results with simple measurements of maximal medial rectus (MR) diameter.

Methods:

Cross-sectional study that included 47 eyes of 47 patients with thyroid eye disease and 47 healthy controls. Patients underwent slitlamp examination and imaging consisting of computed tomography scans. Image segmentation and volume measurements were performed by 2 independent researchers. Intraobserver and interobserver reliability testing was also conducted.

Results:

Total extraocular muscle volume was 7.31 ± 1.88 cm3 and medial volume was 2.38 ± 0.73 cm3 in the study group. In this group, the maximum measured diameter of the MR was 6.67 ± 0.35 mm. MR volume was statistically associated with maximum MR diameter (r = 9.78; P < 0.001). Both MR volume and maximum MR diameter measurements showed good predictive efficacy as shown using receiver operator characteristic curve analysis.

Conclusions:

Complications of thyroid eye disease are often sight threatening, and timely diagnosis is crucial for the management of the entity and its sequelae. The results of this study imply that simple measurements of maximum MR diameter are sensitive enough to establish diagnosis.
Remote monitoring of progression in early Parkinson’s disease: reliability and validity of the Roche PD Mobile Application v2
Authors: Lipsmeier Florian , Taylor Kirsten I. , Postuma Ronald B. , Volkova-Volkmar Ekaterina , Kilchenmann Timothy , Mollenhauer Brit , Bamdadian Atieh , Popp Werner L. , Cheng Wei-Yi , Zhang Yan Ping , Wolf Detlef , Schjodt-Eriksen Jens , Boulay Anne , Svoboda Hanno , Zago Wagner , Pagano Gennaro , Lindemann Michael
Published: October 2021

Digital health technologies (DHTs) enable remote and therefore frequent measurement of motor signs, potentially providing reliable and valid estimates of motor sign severity and progression in Parkinson’s disease (PD). The Roche PD Mobile Application v1 was revised to v2 to include more measures of bradykinesia, and bradyphrenia and speech tests, to optimize suitability for early-stage PD. It was studied in 316 early-stage PD participants who performed daily active tests at home then carried a smartphone and wore a smartwatch throughout the day for passive monitoring (studyNCT03100149). Adherence was excellent (96.29%). All pre-specified sensor features exhibited good-to-excellent test-retest reliability (median intraclass correlation coefficient = 0.9), and correlated with corresponding Movement Disorder Society - Unified Parkinson’s Disease Rating Scale items (rho: 0.12–0.71). These findings demonstrate the preliminary reliability and validity of remote at-home quantification of motor sign severity with the Roche PD Mobile Application v2 in individuals with early PD.
Sampling Statistical Errors in Big Data Research: 3 Cases of Breast Cancer Research
Authors: Cho Han-Jun , Jeong Eui Seok
Published: October 2021

Breast cancer is a major cause of female death, and various big data analysis methods have been applied to breast cancer. This study lists cases in which big data analysis was applied to breast cancer research. In addition, statistics and percentages from each specific sample were proposed. However, research on the use of big data has a blind spot that relies on sample characteristics. Therefore, before sampling big data, statistical inference should be discussed more precisely through pre-examination and sample statistical errors should be reduced by professional statistical evaluation of the analysis method. In particular, the control and experimental groups should be statistically equivalent.
Dual modulation of phase-transitioning licenses the Bicc1 network of ciliopathy proteins to bind specific target mRNAs
Authors: Rothé Benjamin , Fortier Simon , Constam Daniel B.
Published: October 2021

Perturbations in biomolecular condensates that form by phase-transitioning are linked to a growing number of degenerative diseases. For example, mutations in a multivalent interaction network of the Ankyrin (ANK) and sterile alpha motif (SAM) domain-containing ANKS3 and ANKS6 proteins with the RNA-binding protein Bicaudal-C1 (Bicc1) associate with laterality defects and chronic kidney diseases known as ciliopathies. However, insights into the mechanisms that control RNA condensation in ribonucleoprotein particles (RNPs) are scarce. Here, we asked whether heterooligomerization modulates Bicc1 binding to RNA. Reconstitution assays in vitro and live imaging in vivo show that a K homology (KH) repeat of Bicc1 self-interacts and synergizes with SAM domain self-polymerization independently of RNA to concentrate bound mRNAs in gel-like granules that can split or fuse with each other. Importantly, emulsification of Bicc1 by ANKS3 inhibited binding to target mRNAs, whereas condensation by ANKS6 co-recruitment increased it by liberating the KH domains from ANKS3. Our findings suggest that the perturbation of Bicc1-Anks3-Anks6 RNP dynamics is a likely cause of associated ciliopathies.
2-Deoxy-D-Glucose as an Adjunct to Standard of Care in the Medical Management of COVID-19: A Proof-of-Concept & Dose-Ranging Randomised Clinical Trial
Authors: Bhatt Anant Narayan , Shenoy Srinivas , Munjal Sagar , Chinnadurai Vijayakumar , Agarwal Apurva , Kumar A. Vinoth , Shanavas A , Kanwar Ratnesh , Chandna Sudhir
Published: October 2021

Objective

To evaluate the efficacy and safety of 2-deoxy-D-glucose (2-DG) in the treatment of COVID-19.

Participants

110 adults aged 18 to 65 years with moderate to severe COVID-19.

Interventions

63, 90, and 126 mg/kg/day 2-DG plus standard of care (SOC) versus SOC only.

Main Outcome Measures

Times to maintaining SpO2 ≥94% on room air discharge, clinical recovery, vital signs normalisation, improvement by 1 and 2 points on WHO 10-point ordinal scale, negative conversion on RT-PCR, intensive care, and mortality.

Results

Patients treated with 90 mg/kg/day 2-DG plus SOC showed better outcomes. Time to maintaining SpO2 ≥94% was significantly shorter in the 2-DG 90 mg compared to SOC (median 2.5 days vs 5 days, Hazard ratio [95% confidence interval]=2.3 [1.14, 4.64], p=0.0201). Times to discharge from isolation ward, to clinical recovery, and to vital signs normalisation were significantly shorter for the 2-DG 90 mg group.

All three doses of 2-DG were well tolerated. Thirty-three (30.3%) patients reported 65 adverse events and were mostly (86%) mild.

Conclusion

2-DG 90 mg/kg/day as adjunct to SOC showed clinical benefits over SOC alone in the treatment of moderate to severe COVID-19. The promising trends observed in current phase-II study encourage confirmatory evaluation of the efficacy and safety of 2-DG in a larger phase-III trial.
Lipoprotein and metabolite associations to breast cancer risk in the HUNT2 study
Authors: Debik Julia , Schaefer Hartmut , Andreassen Trygve , Wang Feng , Fang Fang , Cannet Claire , Spraul Manfred , Bathen Tone F. , Giskeødegård Guro F.
Published: October 2021

Background

The aim of this study was to investigate if serum lipoprotein and metabolic profiles of healthy women can predict the risk of developing breast cancer in the future, and to gain a better understanding of the etiology of the disease.

Methods

From a cohort of 70 000 participants within the Trøndelag Health Study (HUNT study), we identified 1199 women who developed breast cancer within a 22 year follow-up period. Through a nested case-control study design, future breast cancer patients and matching controls (n = 2398) were analysed. Using nuclear magnetic resonance (NMR) spectroscopy, 28 metabolites and 112 lipoprotein subfractions were quantified from prediagnostic serum samples. Logistic regression was used to test metabolites and lipoprotein subfractions for associations with breast cancer risk and partial least-squares discriminant analysis (PLS-DA) models were built to predict future disease.

Results

Among premenopausal women (554 cases) 14 lipoprotein subfractions were associated with long-term breast cancer risk. In specific, different subfractions of VLDL particles (in particular VLDL-2, VLDL-3 and VLDL-4) were inversely associated with breast cancer. For total VLDL: apolipoprotein B, cholesterol, free cholesterol and phospholipids were inversely associated with premenopausal breast cancer risk, and in addition total and HDL-4 triglycerides. No significant association was found in postmenopausal women.

Conclusions

We identified several associations between lipoprotein subfractions and long-term risk of breast cancer in premenopausal women. Inverse associations between several VLDL subfractions and breast cancer risk were found, revealing an altered metabolism in the endogenous lipid pathway many years prior to a breast cancer diagnosis.
Pattern of fibrin stabilizing factor (FXIII) expression in placentas of women suffering with gestational diabetes mellitus in Saint John, New Brunswick
Authors: Mercer Victoria J. , Obenson Kenneth
Published: October 2021

Gestational diabetes mellitus (GDM) affects 2-5% of all pregnancies and is known to place the fetus at risk for adverse fetal outcomes. Previous studies have reported the increased presence of villous immaturity in the placentas of women with gestational diabetes. Villous immaturity poses a great risk of restricted diffusion capacity across the placenta and may be a marker for some of the placental insufficiency associated with diabetes mellitus. The present study looks at the possibility of using fibrin stabilizing factor, or Factor XIII (FXIII), as a biomarker of villous immaturity. The aim of the present study is to establish a baseline pattern of FXIII expression in placentas of women in Saint John, NB with GDM, without villous immaturity using a scoring formula adapted from surgical pathology. While the small sample size precludes definitive conclusions regarding the expression of FXIII in normal placentas in women with GDM, there appears to a baseline of strong FXIII expression in normal placental tissues from the second and third trimester of pregnancy. Further study using a larger sample size is required to determine if a correlation exists between level of FXIII expression and degree of villous maturity in patients with GDM, which could improve the histologic assessment of placental development.
Comparing lateral flow testing with a rapid RT-PCR method for SARS-CoV-2 detection in the UK
Authors: Taylor Andrew , Calvez Ronan , Atkins Mark , Fink Colin G
Published: October 2021

In late 2019, SARS-CoV-2 emerged in the Wuhan province of China. Rapid global spread led to the Covid-19 pandemic. Rapid and accurate detection of SARS-CoV-2 has become a vitally important tool in controlling the spread of the virus. Lateral flow devices (LFDs) offer the potential advantage of speed and on-site testing. The sensitivity of these devices compared to the gold standard RT-PCR has been questioned. We compared the performance of the Innova lateral flow kit, recommended by the UK government, with our rapid in-house RT-PCR protocol using stored positive patient samples. The LFD device was found to be 6,000-10,000 times less sensitive than RT-PCR for the detection of SARS-CoV-2. Overall, the LFD detected 46.2% of the positives detected by RT-PCR. 50% of the LFD results were observed to be weak positives, only visible after careful examination by experienced laboratory staff. At lower viral loads, such as 10,000-100,000 RNA copies/ml, the LFD detected 22.2% of positives. In addition, two strong positives (3 and 1.5 million RNA copies/ml) were not detected by the LFD. The argument for use of LFD kits, despite their lack of sensitivity, is that they detect infectious virus and hence contagious individuals. At present, there is a lack of scientific evidence supporting this claim. The LFD used in the UK fails to identify individuals with considerable viral loads and has been subject to a class I recall by the US FDA but is still approved and recommended for use by the UK government. We believe that using LFD testing for assessing SARS-CoV-2 infection risk is a strategy which has risks that outweigh any benefits.
Psychiatric polygenic risk scores: Child and adolescent psychiatrists’ knowledge, attitudes, and experiences
Authors: Pereira Stacey , Muñoz Katrina A. , Small Brent J. , Soda Takahiro , Torgerson Laura N. , Sanchez Clarissa E. , Austin Jehannine , Storch Eric A. , Lázaro-Muñoz Gabriel
Published: October 2021

Objective

Psychiatric polygenic risk scores (PRS) have the potential to transform aspects of psychiatric care and prevention, but there are concerns about their implementation. We sought to assess child and adolescent psychiatrists’ (CAP) experiences, perspectives, and potential uses of psychiatric PRS.

Methods

A survey of 960 US-based practicing CAP.

Results

Most respondents (54%) believed psychiatric PRS are currently at least slightly useful and 87% believed they will be so in five years. Yet, 77% rated their knowledge of PRS as poor or very poor. Ten percent have had a patient/family bring PRS to them, and 25% would request PRS if a patient/caregiver asked. Respondents endorsed different actions in response to a hypothetical child with a top 5th percentile psychiatric PRS but no diagnosis: 48% would increase prospective monitoring of symptoms, 42% would evaluate for current symptoms, and 4% would prescribe medications. Most respondents were concerned that high PRS results could lead to overtreatment and negatively impact patients’ emotional well-being.

Conclusion

Findings indicate emerging use of psychiatric PRS within child and adolescent psychiatry in the US. Thus, it is critical to examine the ethical and clinical challenges that PRS may generate and begin efforts to promote their informed and responsible use.
Poly-glutamine-dependent self-association as a potential mechanism for regulation of androgen receptor activity
Authors: Roggero Carlos M. , Esser Victoria , Duan Lingling , Rice Allyson M. , Ma Shihong , Raj Ganesh V. , Rosen Michael K. , Liu Zhi-Ping , Rizo Josep
Published: October 2021

The androgen receptor (AR) plays a central role in prostate cancer. Development of castration resistant prostate cancer (CRPC) requires androgen-independent activation of AR, which involves its large N-terminal domain (NTD) and entails dramatic epigenetic changes depending in part on histone lysine demethylases (KDMs) that interact with AR. The AR-NTD is rich in low-complexity sequences, including a polyQ repeat. Longer polyQ sequences were reported to decrease transcriptional activity and to protect against prostate cancer. However, the molecular mechanisms underlying these observations are unclear. Using NMR spectroscopy, here we identify weak interactions between the AR-NTD and the KDM4A catalytic domain, and between the AR ligand-binding domain and a central KDM4A region that also contains low-complexity sequences. We also show that the AR-NTD can undergo liquid-liquid phase separation in vitro, with longer polyQ sequences phase separating more readily. Moreover, longer polyQ sequences hinder nuclear localization in the absence of hormone and increase the propensity for formation of AR-containing puncta in the nucleus of cells treated with dihydrotestosterone. These results lead us to hypothesize that polyQ-dependent liquid-liquid phase separation may provide a mechanism to decrease the transcriptional activity of AR, potentially opening new opportunities to design effective therapies against CRPC.
The genetic history of Mayotte and Madagascar cattle breeds mirrors the complex pattern of human exchanges in Western Indian Ocean
Authors: Magnier Jessica , Druet Tom , Naves Michel , Ouvrard Melissa , Raoul Solene , Janelle Jérôme , Moazami-Goudarzi Katayoun , Lesnoff Matthieu , Tillard Emmanuel , Gautier Mathieu , Flori Laurence
Published: October 2021

Despite their central economic and cultural role, the origin of cattle populations living in Indian Ocean islands still remains poorly documented. Here, we unravel the demographic and adaptive histories of the extant Zebus from the Mayotte and Madagascar islands using high-density SNP genotyping data. We found that these populations are very closely related and both display a predominant indicine ancestry. They diverged in the 16thcentury at the arrival of European people who transformed the trade network in the area. Their common ancestral cattle population originates from an admixture between an admixed African zebu population and an Indian zebu that occurred around the 12thcentury at the time of the earliest contacts between human African populations of the Swahili corridor and Austronesian people from Southeast Asia in Comoros and Madagascar. A steep increase of the estimated population sizes from the beginning of the 16thto the 17thcentury coincides with the expansion of the cattle trade. By carrying out genome scans for recent selection in the two cattle populations from Mayotte and Madagascar, we identified sets of candidate genes involved in biological functions (cancer, skin structure and UV-protection, nervous system and behavior, organ development, metabolism and immune response) broadly representative of the physiological adaptation to tropical conditions. Overall, the origin of the cattle populations from Western Indian Ocean islands mirrors the complex history of human migrations and trade in this area.
A resistome roadmap: from the human body to pristine environments
Authors: Maestre-Carballa Lucia , Navarro-López Vicente , Martínez-Garcia Manuel
Published: October 2021

A comprehensive characterization of the human body resistome (sets of antibiotic resistance genes (ARGs)) is yet to be done and paramount for addressing the antibiotic microbial resistance threat. Here, we study the resistome of 771 samples from five major body parts (skin, nares, vagina, gut and oral cavity) of healthy subjects from the Human Microbiome Project and addressed the potential dispersion of ARGs in pristine environments. A total of 28,731 ARGs belonging to 344 different ARG types were found in the HMP proteome dataset (n=9.1×107 proteins analyzed). Our study reveals a distinct resistome profile (ARG type and abundance) between body sites and high inter-individual variability. Nares had the highest ARG load (≈5.4 genes/genome) followed by the oral cavity, while the gut showed one of the highest ARG richness (shared with nares) but the lowest abundance (≈1.3 genes/genome). Fluroquinolone resistance genes were the most abundant in the human body, followed by macrolide-lincosamide-streptogramin (MLS) or tetracycline. Most of the ARGs belonged to common bacterial commensals and multidrug resistance trait was predominant in the nares and vagina. Our data also provide hope, since the spread of common ARG from the human body to pristine environments (n=271 samples; 77 Gb of sequencing data and 2.1×108 proteins analyzed) thus far remains very unlikely (only one case found in an autochthonous bacterium from a pristine environment). These findings broaden our understanding of ARG in the context of the human microbiome and the One-Health Initiative of WHO uniting human host-microbes and environments as a whole.

Importance

The current antibiotic resistance crisis affects our health and wealth at a global scale and by 2050 predictions estimate 10 million deaths attributed to antibiotic resistance worldwide. Remarkably, a comprehensive analysis of ARG diversity and prevalence in different human body sites is yet to be done. Undoubtedly, our body and human built-environment have antibiotic resistant bacteria than can also be transported to other environments. Hence, the analysis of Human Microbiome Project dataset provides us not only the opportunity to explore in detail the ARGs diversity and prevalence in different parts of our body but also to provide some insights into the dispersion of ARGs from human to natural populations inhabiting pristine environments. Thus, our data would help to stablish a baseline in ARG surveillance protocols to asses further changes in antibiotic resistances in our society.
Membrane phosphoinositides stabilize GPCR-arrestin complexes and provide temporal control of complex assembly and dynamics
Authors: Janetzko John , Kise Ryoji , Barsi-Rhyne Benjamin , Siepe Dirk H. , Heydenreich Franziska M. , Masureel Matthieu , Kawakami Kouki , Christopher Garcia K. , von Zastrow Mark , Inoue Asuka , Kobilka Brian K.
Published: October 2021

Binding of arrestin to phosphorylated G protein-coupled receptors (GPCRs) is crucial for modulating signaling. Once internalized some GPCRs may complex with arrestin, while others interact transiently; this difference affects receptor signaling and recycling. Cell-based and in vitro biophysical assays reveal the role of membrane phosphoinositides (PIPs) in arrestin recruitment and GPCR-arrestin complex dynamics. We find that GPCRs broadly stratify into two groups, one requiring PIP-binding for arrestin recruitment and one that does not. Plasma membrane PIPs potentiate an active conformation of arrestin and stabilize GPCR-arrestin complexes by promoting a receptor core-engaged state of the complex. As allosteric modulators of GPCR-arrestin complex dynamics, membrane PIPs allow for additional conformational diversity beyond that imposed by GPCR phosphorylation alone. The dependance on membrane PIPs provides a mechanism for arrestin release from transiently associated GPCRs, allowing their rapid recycling, while explaining how stably associated GPCRs are able to engage G proteins at endosomes.
A nesprin-4/kinesin-1 cargo model for nuclear positioning in cochlear outer hair cells
Authors: Taiber Shahar , Gozlan Oren , Cohen Roie , Andrade Leonardo R. , Gregory Ellen F. , Starr Daniel A. , Moran Yehu , Hipp Rebecca , Kelley Matthew W. , Manor Uri , Sprinzak David , Avraham Karen B.
Published: October 2021

Nuclear positioning is important for the functionality of many cell types and is mediated by interactions of cytoskeletal elements and nucleoskeleton proteins. Nesprin proteins, part of the linker of nucleoskeleton and cytoskeleton (LINC) complex, have been shown to participate in nuclear positioning in multiple cell types. Outer hair cells (OHCs) in the inner ear are specialized sensory epithelial cells that utilize somatic electromotility to amplify auditory signals in the cochlea. Recently, nesprin-4 (encoded by Syne4) was shown to play a crucial role in nuclear positioning in OHCs. Syne4 deficiency in humans and mice leads to mislocalization of the OHC nuclei and cell death resulting in deafness. However, it is unknown how nesprin-4 mediates the position of the nucleus, and which other molecular components are involved in this process. Here, we show that the interaction of nesprin-4 and the microtubule motor kinesin-1 is mediated by a conserved 4 amino-acid motif. Using in-vivo AAV gene delivery, we show that this interaction is critical for nuclear positioning and hearing in mice. Nuclear mislocalization and cell death of OHCs coincide with the onset of hearing and electromotility and are solely restricted to outer, but not inner, hair cells. Likewise, the C. elegans functional homolog of nesprin-4, UNC-83, uses a similar motif to mediate interactions between migrating nuclei and kinesin-1. Overall, our results suggest that OHCs require unique cellular machinery for proper nuclear positioning at the onset of electromotility. This machinery relies on the interaction between nesprin-4 and kinesin-1 motors supporting a microtubule cargo model for nuclear positioning.
Computational and experimental studies of the breathing motion of a protein loop: implications in PfAMA1-PfRON2 late-stage binding event
Authors: Sinha Suman , Biswas Anamika , Mondal Jagannath , Mandal Kalyaneswar
Published: October 2021

Protein-protein interactions are important targets for various drug discovery campaigns. One such promising and therapeutically pertinent protein-protein complex is PfAMA1-PfRON2 involved in malarial parasite invasion into human red blood cells. A thorough understanding of the interactions between these macromolecular binding partners is crucial for designing better therapeutics against this age-old disease. Although crystal structures of several PfAMA1-PfRON2 complexes are available, the mechanism of how domain II loop associates with PfRON2 is not clear. The current work investigates how the domain II loop of PfAMA1 exerts its effect on the alpha helix of the PfRON2, thus influencing the overall kinetics of this intricate recognition phenomenon. To this end, we have computationally simulated the dynamics and free energetics of domain II loop closing processes and identified a set of key amino acid residues of PfRON2 helix which are essential for binding. The subsequent evaluation of the binding affinity of Ala-substituted PfRON2 peptide ligands by surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) validates the relative importance of the residues in context. Together, the combination of computational and experimental investigation reveals that the domain II loop of PfAMA1 is in fact responsible for arresting the PfRON2 molecule from egress, K2027 and D2028 of PfRON2 being the determinant residues for the capturing event. Our study provides a comprehensive understanding of the molecular recognition event between PfAMA1 and PfRON2, specifically in the post binding stage, which could potentially open up new avenues to drug discovery against malaria.

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High Resolution Slide-seqV2 Spatial Transcriptomics Enables Discovery of Disease-Specific Cell Neighborhoods and Pathways
Authors: Marshall Jamie L. , Noel Teia , Wang Qingbow S. , Bazua-Valenti Silvana , Chen Haiqi , Murray Evan , Subramanian Ayshwarya , Vernon Katherine A. , Liguori Katie , Keller Keith , Stickels Robert R. , McBean Breanna , Heneghan Rowan M. , Weins Astrid , Macosko Evan Z. , Chen Fei , Greka Anna
Published: October 2021

High resolution spatial transcriptomics is a transformative technology that enables mapping of RNA expression directly from intact tissue sections; however, its utility for the elucidation of disease processes and therapeutically actionable pathways remain largely unexplored. Here we applied Slide-seqV2 to mouse and human kidneys, in healthy and in distinct disease paradigms. First, we established the feasibility of Slide-seqV2 in human kidney by analyzing tissue from 9 distinct donors, which revealed a cell neighborhood centered around a population ofLYVE1+macrophages. Second, in a mouse model of diabetic kidney disease, we detected changes in the cellular organization of the spatially-restricted kidney filter and blood flow regulating apparatus. Third, in a mouse model of a toxic proteinopathy, we identified previously unknown, disease-specific cell neighborhoods centered around macrophages. In a spatially-restricted subpopulation of epithelial cells, we also found perturbations in 77 genes associated with the unfolded protein response (UPR). Our studies illustrate and experimentally validate the utility of Slide-seqV2 for the discovery of disease-specific cell neighborhoods.

One-Sentence Summary

High resolution Slide-seqV2 spatial transcriptomics in human and mouse kidneys.
Principal operators' farm risk attitudes in hot and cold climates
Authors: Wahdat Ahmad Zia , Gunderson Michael
Published: October 2021

Purpose

The study investigates whether there is an association between climate types and farm risk attitudes of principal operators.

Design/methodology/approach

The study exploits temperature variation in the diverse climate types across the US and defines hot- and cold-climate states. Ordered logit and generalized ordered logit models are used to model principal operators' farm risk attitudes, which are measured on a Likert scale. The study uses two datasets. The first dataset is a 2017 survey of US large commercial producers (LCPs). The second dataset provides a Köppen-Geiger climate classification of the US at a spatial resolution of 5 arcmin for a 25-year period (1986–2010).

Findings

The study finds that principal operators in hot-climate states are 4–5% more likely to have a higher willingness to take farm risk compared to principal operators in cold-climate states.

Research limitations/implications

It is likely that farm risk mitigation decisions differ between hot- and cold-climate states. For instance, the authors show that corn acres' enrollment in federal crop insurance and computers' usage for farm business are pursued more intensely in cold-climate states than in hot-climate states. A differentiation of farm risk attitude by hot- and cold-climate states may help agribusiness, the government and economists in their farm product offerings, farm risk management programs and agricultural finance models, respectively.

Originality/value

Based on Köppen-Geiger climate classification, the study introduces hot- and cold-climate concepts to understand the relationship between climate types and principal operators' farm risk attitudes.
Does independent goal interdependence impair dynamic capability? The mediating role of supplier integration and the moderating role of internal integration
Authors: Yang Linbo , Tan Joo Seng , Gan Chenjing
Published: October 2021

Purpose

Rapidly changing technological and marketing environments challenge the survival of business organizations. Developing dynamic capability is critical in helping companies respond to today's turbulent environments. Thus, fruitful studies on the antecedents of dynamic capability have been conducted. However, in the context of the supply chain, little is known about the factors that can be harmful to dynamic capability. Drawing on the theory of cooperation and competition, the first purpose of this study is to examine the relationship between independent goal interdependence with suppliers and dynamic capability by focusing on the mediating role of supplier integration. Combining the information processing theory and transaction cost economics with the theory of cooperation and competition, the second purpose of this study is to discuss and test the moderating role of internal integration.

Design/methodology/approach

Using a carefully designed questionnaire, a large-scale survey was employed to collect data in China. The senior manager (e.g. president, vice president, chief executive officer [CEO], executive or purchasing manager) of each company was asked to participate in our survey. The final valid sample in our survey consisted of 233 companies. Hierarchical multiple regression statistical analysis and bias-corrected bootstrapping methods were applied to test the correlation, mediation, moderation and moderated mediation relationships between variables.

Findings

The authors found that independent goal interdependence negatively influences dynamic capability through frustrating supplier integration. In addition, the moderated mediation model analysis shows that internal integration weakens the positive direct effect of supplier integration on dynamic capability while neutralizing the negative indirect effect of independent goal interdependence on dynamic capability. The theoretical and managerial implications of these results are discussed.

Originality/value

First, starting from the goal interdependence and supply chain management perspectives, this research not only is consistent with remote theoretical research that explains why interdependence among organizations influences the capability to enhance competitive advantage but also incorporates relevant internal and external factors that influence dynamic capability. Second, by proposing an innovative boundary factor – internal integration – this study also contributes to adjusting the predictions of the theory of cooperation and competition. Third, focusing specifically on the negative antecedent of dynamic capability can provide a better understanding of the antecedents that cause companies to have weakened dynamic capability.
Sustainable open innovation for the agri-food system: sorghum as healthy food to deal with environmental challenges
Authors: Pontieri Paola , Mennini Francesco Saverio , Magni Domitilla , Fiano Fabio , Scuotto Veronica , Papa Armando , Aletta Mariarosaria , Del Giudice Luigi
Published: October 2021

Purpose

The paper provides a new definition of healthy and functional food considering the case of sorghum, which is dealing with environmental challenges, calling for exploration of eco-conscious consumers' behavior in the free-from food innovative market.

Design/methodology/approach

Through a systematic literature review and bibliometric analysis, this article offers a deep and broad outlook on a sustainable open innovations approach for agri-food systems. The bibliometric analysis includes a total of 198 scientific papers, deeply analyzed through Bibliometrix package.

Findings

Results show increasing academic interest in sustainable innovations for the agri-food system, where the relevance of the food-grade sorghum is noticed. An open innovation approach is called for to deal with environmental challenges.

Originality/value

Theoretically, the research offers a new definition of healthy and functional food in line with current environmental challenges. It also provides a deep literature review on eco-conscious consumers and food-grade sorghum as functional food in the context of the free-from food market.