bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and validation of postoperative and preoperative platelets ratio (PPR) to predict the prognosis of patients undergoing surgery for colorectal cancer: A dual‐center retrospective cohort study
Authors: Yang Wei , Zheng Xiaoying , Wu Minghui , Zhang Fengming , Xu Shuizhi , Wang Xiuchao , Song Menghui , You Chang , Zhang Ting , Jiang Minghua , Ding Chunming
Published: June 2022

Background

Platelets occupy a prominent place in tumor proliferation and metastasis, and platelet count is relevant to the prognosis of tumor patients. But preoperative platelet counts cannot be standardized and individualized due to the variability among individuals, instruments, and regions, and the connection between postoperative platelet count and prognosis remains unknown. A standardized indicator of platelet count was designed to forecast the prognosis of colorectal cancer (CRC).

Methods

Five hundred and eighty six patients who suffered radical resection of CRC between 2013 and 2019 were collected. A development‐validation cohort of standardized and individualized platelet counts for prognostic assessment of CRC was designed. We first determined the ability of PPR and other peripheral blood count‐related indicators to predict the mortality of patients with CRC and validated them in a separate cohort. Kaplan–Meier analysis was executed to evaluate the survival and univariate and multivariate analyses were executed to explore the relevance. Time‐dependent ROC was measured to estimate the predictive usefulness. Decision curve analysis was used to verify the clinical net benefit.

Results

Important baseline variables showed a similar distribution in two independent queues. In the development cohort, postoperative platelet count and postoperative/preoperative platelets ratio (PPR) were independent predictors of prognosis in CRC patients. PPR showed the largest area under the curve (AUC) in evaluating 1‐year and 5‐year OS (AUC: 0.702 and 0.620) compared to others. In the validation cohort, platelet/lymphocyte ratio and PPR were validated to be independently concerned about OS of CRC patients and PPR showed the largest AUC in evaluating 1‐year and 3‐year OS (AUC: 0.663 and 0.673). PPR and joint index of platelet count and PPR showed better predictive value and clinical net benefit.

Conclusions

PPR has been identified and validated to be independently concerned about OS of patients with CRC and was a reliable and economic indicator to evaluate the prognosis.
Recognition rates, treatment recommendations and stigma attributions for clients presenting with taboo intrusive thoughts: A vignette‐based survey of psychotherapists
Authors: Canavan Réamonn
Published: June 2022

Introduction

Obsessive compulsive disorder (OCD) is a prevalent mental health disorder which is characterised by high levels of morbidity. Most individuals with OCD do not receive adequate psychotherapeutic intervention. Research suggests that taboo intrusive thoughts are less likely to be recognised as OCD in comparison to more recognisable forms. Stigma attributions are higher for individuals with taboo intrusive thoughts. The aim of this study is to examine psychotherapists' capacity to recognise different forms of OCD, their recommendations for psychotherapeutic intervention, and stigma attributions towards clients with OCD symptoms.

Methodology

Five hundred fourteen psychotherapists in Ireland were randomly assigned a vignette describing a client with different OCD presentations—paedophilia, aggressive, religious, homosexuality, contamination and symmetry. Participants gave their interpretations of the presenting symptoms, their therapy recommendations and rated their confidence in their responses. Perceived dangerousness and willingness to work with the client were also investigated.

Results

The taboo intrusive thoughts vignettes were significantly less likely to be recognised as OCD than the contamination and symmetry vignettes. Participants attributed greater levels of stigma to clients with aggressive and paedophilia intrusive thoughts. Recommendations for evidence‐based therapies were low. Participants who recognised OCD were significantly more likely to recommend an evidence‐based therapy. Confidence was a poor predictor of OCD identification and evidence‐based therapy recommendation.

Conclusions

The results suggest a lack of awareness of certain types of OCD presentation amongst psychotherapists, the meaning of the symptoms and of evidence‐based psychotherapeutic interventions for OCD. The implications of this, and possible applications of these results, are discussed.
Neuroprotective Alkamides from the Aerial Parts ofAchillea alpinaL.
Authors: Li Xiu‐Wei , Yue Hu‐Cheng , Wu Xia , Guo Qiang , Tian Jia‐Yi , Liu Zong‐Yang , Xiao Meng , Li Xiao‐Xi , Yu Lan , Li Ang , Ning Zhong‐Qi , Zan Ke , Chen Xiao‐Qing
Published: June 2022

Three new alkamides, achilleamide B‐D (1–3) along with five known alkamides (4–8) were isolated from the aerial parts ofAchillea alpinaL. Structures were elucidated by spectroscopic analysis. Modified Mosher's method and electronic circular dichroism (ECD) calculations were introduced for the absolute configuration of3. The neuroprotective effects of all the compounds were evaluated by 6‐hydroxydopamine (6‐OHDA)‐induced cell death in human neuroblastoma SH‐SY5Y cells, with concentration for 50 % of maximal effect (EC50) values of 3.16–24.75 μM, and the structure–activity relationship was conducted.
Boosted Productivity in Single‐Tile‐Based DNA Polyhedra Assembly by Simple Cation Replacement
Authors: Zhou Kaixuan , Mei Zhichao , Lei Yunxiang , Guan Zhen , Mao Chengde , Li Yulin
Published: June 2022

Cations such as divalent magnesium ion (Mg2+) play an essential role in DNA self‐assembly. However, the strong electrostatic shielding effect of Mg2+would be disadvantageous in some situations that require relatively weak interactions to allow a highly reversible error‐correcting mechanism in the process of assembly. Herein, by substituting the conventional divalent Mg2+with monovalent sodium ion (Na+), we have achieved one‐pot high‐yield assembly of tile‐based DNA polyhedra at micromolar concentration of tiles, at least 10 times higher than the DNA concentrations reported previously. This strategy takes advantage of coexisting counterions and is expected to surmount the major obstacle to potential applications of such DNA nanostructures: large‐scale production.
Iridium‐Catalyzed Direct Reductive Amination of Ketones and Secondary Amines: Breaking the Aliphatic Wall
Authors: Jouffroy Matthieu , Nguyen Thi‐Mo , Cordier Marie , Blot Marielle , Roisnel Thierry , Gramage‐Doria Rafael
Published: June 2022

Invited for the cover of this issue are Matthieu Jouffroy from Discovery Process Research at Janssen Pharmaceutica N.V. and the group of Rafael Gramage‐Doria at the University of Rennes. The image depicts an Ir‐based catalytic system “fueled” by hydrogen for the direct reductive amination of ketones and secondary amines, allowing complex aliphatic tertiary amines to be prepared and, so, new chemical space to be reached. Read the full text of the article at 10.1002/chem.202201078.
Nonbonding/Bonding Molecular Orbital Regulation of Nitrogen‐Boron‐Oxygen‐embedded Blue/Green Multiresonant TADF Emitters with High Efficiency and Color Purity
Authors: Liu Guanting , Sasabe Hisahiro , Kumada Kengo , Arai Hiroki , Kido Junji
Published: June 2022

In this study, we synthesized and characterized multiresonant thermally activated delayed fluorescent (TADF) materials embedded with nitrogen‐boron‐oxygen (N−B−O), exhibiting color‐tunability between blue and green, namely NBO, m‐DiNBO, and p‐DiNBO. The three emitter materials showed a high photoluminescence quantum yield (PLQY) and a state‐of‐the‐art narrow full width at half maximum (FWHM) of 96 %/25 nm, 87 %/17 nm, and 99 %/19 nm, respectively. For m‐DiNBO and p‐DiNBO, the emission color could be tuned from blue to green by regulating the nonbonding/bonding molecular orbital characters. Owing to the expanded planar molecular structure, m‐DiNBO and p‐DiNBO showed high horizontal dipole ratio (Θ) of 88 % and 92 %, respectively. OLEDs were prepared with NBO, m‐DiNBO, and p‐DiNBO, exhibiting high external quantum efficiencies of 16.8 %, 24.2 %, and 21.6 %, respectively. NBO and m‐DiNBO exhibited pure‐blue emission with CIE coordinates of (0.137, 0.142) and (0.126, 0.098), respectively. p‐DiNBO showed pure‐green emission with a CIE coordinate of (0.258, 0.665).
Ether unterbricht Signalweiterleitung bei der Fliegenfalle
Authors: Feil Sylvia
Published: June 2022

Ethernarkosen wirken nicht nur beim Menschen. Auch Die fleischfressende Venusfliegenfalle lässt sich so betäuben: Mit Ether narkotisierte Fliegenfallen klappen nicht mehr zu. Die Hypothese zu dieser schon bekannten Beobachtung war, dass Glutamat‐Rezeptoren, die an der Weiterleitung von Signalen beteiligt sind, blockiert werden. Tatsächlich wurde nun ein Zusammenhang gezeigt zwischen mechanisch ausgelösten Ca2+‐basierten Aktionspotenzialen und deren Weiterleitung im Blatt durch Glutamat. Die weiterführende Idee ist, daraus ein pflanzliches Modell für Studien zu Signalwegen bei der Reizweiterleitung zu entwickeln.
Preoperative therapy for pancreatic adenocarcinoma—precision beyond anatomy
Authors: Seo Y. David , Katz Matthew H. G.
Published: June 2022

Despite recent advances in the systemic treatment of gastrointestinal tumors, pancreatic adenocarcinoma (PDAC) remains a challenging disease, with 5‐year survival just over 10%. Pancreatectomy in patients meeting defined anatomic criteria can result in cure; however, perioperative morbidity and mortality, as well as high rates of both local and distant recurrence even after “potentially curative” resection, have limited survival. Although perioperative chemotherapy has been shown to improve patients' longevity and chance for cure, debate continues about whether the preoperative or adjuvant approach is most effective in treatment of localized PDAC. Large, randomized multicenter trials in patients with resectable and borderline resectable PDAC have evaluated an evolving therapeutic landscape with mixed results. Importantly, these landmark studies share the fundamentally flawed assumption that tumor anatomical characteristics are an indicator of behavior and natural history. Concurrent biologic and translational research has revealed that rather than a single disease, PDAC represents a phenotypically variable group of malignancies arising in physiologically diverse patients. Ongoing novel trials have begun to capture this heterogeneity both in patient selection as well as the measurement of response by using genomic, transcriptional and radiomic markers. By moving away from classic anatomic descriptors to a more nuanced landscape of biomarkers predictive of tumor behavior and response, we can further refine the questions asked in preoperative trials and translate the answers to clinically meaningful precision therapy in localized PDAC.
Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling
Authors: Li Liyang , Liu Yifei , Liu Xuanqi , Zheng Nannan , Gu Yutong , Song Yuanlin , Wang Xiangdong
Published: June 2022

Background

Hypercholesterolemia is found in patients with chronic lung inflammation, during which airway epithelial cells play important roles in maintenance of inflammatory responses to pathogens. The present study aims at molecular mechanisms by which cholesterol changes airway epithelial sensitivity in response to smoking.

Methods

Human bronchial epithelial cells (HBEs) were stimulated with cigarette smoke extract (CSE) and mice were exposed to CS/lipopolysaccharide (LPS) as models in vitro and in vivo. Severe COPD patients and healthy volunteers were also enrolled and the level of cholesterol in plasma was detected by metabolomics. Filipin III and elisa kits were used to stain free cholesterol. Mitochondrial function was detected by mitotracker green, mitotracker green, and Seahorse. Mitochondrial morphology was detected by high content screening and electron microscopy. The mRNA and protein levels of mitochondrial dynamics‐related proteins were detected by RT‐qPCR and Western blot,respectively. BODIPY 493/503 was used to stain lipid droplets. Lipidomics was used to detect intracellular lipid components. The mRNA level of interleukin (IL)‐6 and IL‐8 were detected by RT‐qPCR.

Results

We found that the cholesterol overload was associated with chronic obstructive pulmonary disease (COPD) and airway epithelia‐driven inflammation, evidenced by hypercholesterolemia in patients with COPD and preclinical models, alteration of lipid metabolism‐associated genes in CSE‐induced airway epithelia and production of ILs. External cholesterol altered airway epithelial sensitivity of inflammation in response to CSE, through the regulation of STARD3‐MFN2 pathway, cholesterol re‐distribution, altered transport and accumulation of cholesterol, activities of lipid transport regulators and disorder of mitochondrial function and dynamics. MFN2 down‐regulation increased airway epithelial sensitivity and production of ILs after smoking, at least partially by injuring fatty acid oxidation and activating mTOR phosphorylation.

Conclusions

Our data provide new insights for understanding molecular mechanisms of cholesterol‐altered airway epithelial inflammation and for developing diagnostic biomarkers and therapeutic targets to improve patient outcomes.
Demographic responses to climate‐driven variation in habitat quality across the annual cycle of a migratory bird species
Authors: Saracco James F. , Cormier Renée L. , Humple Diana L. , Stock Sarah , Taylor Ron , Siegel Rodney B.
Published: June 2022

The demography and dynamics of migratory bird populations depend on patterns of movement and habitat quality across the annual cycle. We leveraged archival GPS‐tagging data, climate data, remote‐sensed vegetation data, and bird‐banding data to better understand the dynamics of black‐headed grosbeak (Pheucticus melanocephalus) populations in two breeding regions, the coast and Central Valley of California (Coastal California) and the Sierra Nevada mountain range (Sierra Nevada), over 28 years (1992–2019). Drought conditions across the annual cycle and rainfall timing on the molting grounds influenced seasonal habitat characteristics, including vegetation greenness and phenology (maturity dates). We developed a novel integrated population model with population state informed by adult capture data, recruitment rates informed by age‐specific capture data and climate covariates, and survival rates informed by adult capture–mark–recapture data and climate covariates. Population size was relatively variable among years for Coastal California, where numbers of recruits and survivors were positively correlated, and years of population increase were largely driven by recruitment. In the Sierra Nevada, population size was more consistent and showed stronger evidence of population regulation (numbers of recruits and survivors negatively correlated). Neither region showed evidence of long‐term population trend. We found only weak support for most climate–demographic rate relationships. However, recruitment rates for the Coastal California region were higher when rainfall was relatively early on the molting grounds and when wintering grounds were relatively cool and wet. We suggest that our approach of integrating movement, climate, and demographic data within a novel modeling framework can provide a useful method for better understanding the dynamics of broadly distributed migratory species.
Alkylated Polycyclic Aromatic Compounds in Road Runoff Are an Environmental Risk and Should Be Included in Future Investigations
Authors: Grung Merete , Lindman Sofie , Kringstad Alfhild , Girardin Viviane , Meland Sondre
Published: June 2022

Polycyclic aromatic compounds (PACs) and metals are important contaminants in road runoff. Vital mitigation measures against aquatic contamination from road runoff include the use of sedimentation ponds. However, it has been demonstrated that ecosystems in sedimentation ponds might be affected by road runoff. Sediments from six natural ponds and 27 sedimentation ponds were investigated to determine the environmental risk of contaminants. The amount of traffic on the respective roads associated with the sedimentation ponds was correlated with the environmental concentrations. Quantification included seven metals, the 16 US Environmental Protection Agency polycyclic aromatic hydrocarbons, alkylated PACs, dibenzothiophene, benzo[e]pyrene, and perylene. The environmental risk was assessed according to the European Union Water Framework Directive guidelines. Sedimentation ponds had a higher level of contaminants than natural ponds, and environmental risks were dominated by the concentration of PACs. Alkylated PACs contributed to the environmental risk posed by PACs and should be included in future monitoring. Only Cu and Zn were measured at concentrations above the environmental quality standards (EQSs), while 13 PACs exceeded the EQS. Sediment concentrations of Cu, Zn, and most PACs correlated significantly with the amount of traffic. The sources of PACs were determined by source apportionment ratios between PACs. Alkylation and pyrogenic indices showed that sources in natural ponds were of mostly pyrogenic origin, whereas in sedimentation ponds they were predominantly petrogenic. Asphalt was the probable main source of PACs. A hierarchical clustering technique was used to investigate both the environmental risks and the pattern of PACs in the ponds and revealed that a few sedimentation ponds were not protecting the environment as intended because the upper sediment layers had not been regularly dredged. Environ Toxicol Chem 2022;41:1838–1850. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
Optimal power allocation for non‐orthogonal multiple access enabled full‐duplex underlay cognitive relay networks under partial relay selection
Authors: Aswathi V , Babu A V
Published: June 2022

This article considers non‐orthogonal multiple access (NOMA) enabled full‐duplex (FD) underlay cognitive relay networks (ie, NOMA‐FDCRNs) with partial relay selection scheme. The secondary network, where NOMA is used, consists of a secondary base station (SBS) sending messages to two secondary users (SUs), that is, a near SU (SU1) and a far SU (SU2), by utilizing a dedicated relay selected from a set of FD decode‐and‐forward nodes. We obtain analytical expressions for the outage probabilities (OPs) of the SUs and then deduce the asymptotic OP expressions as well. Further, expressions are obtained for the optimal power allocation (OPA) coefficients at the SBS and at the relay that separately maximizes the throughput of the secondary network in NOMA‐FDCRN. Furthermore, the jointly optimal power allocation (JOPA) coefficients that maximize the throughput are also determined. The analyses consider (i) imperfect successive interference cancelation conditions, (ii) the tolerable interference limit of the primary receiver, (iii) the secondary nodes' maximum transmit power values, (iv) interference generated by the primary transmitter, and (v) the residual self‐interference (RSI) at the FD relay. It is shown that the proposed OPA coefficients at the SBS and the JOPA can mitigate the impact of RSI and significantly improve the OP and throughput performance. The numerical results show that the proposed JOPA approach provides 32% and 106% improvement of throughput compared to random power allocation (RPA) and equal power allocation (EPA) strategies, respectively. The OP of SU1 and SU2 reduce by 68% and 73%, respectively, under the proposed JOPA compared to RPA, while compared to EPA, the OP of SU1 and SU2 reduce by 96% and 97%, respectively.
If Not Now, Then When? Taking Disability Seriously in Bioethics
Authors: Mukherjee Debjani , Tarsney Preya S. , Kirschner Kristi L.
Published: June 2022

The impression of bioethicists as “dangerous,” as articulated in Mouth Magazine in 1994, has continued to be a theme in the disability movement. We respond to three common responses by bioethicists to this impression—namely, this is from the past, and bioethicists are different now; this is an angry and extremist position; and the Americans with Disabilities Act and other disability rights and justice efforts have solved historical inequities. We draw on the historical record and on our collective experiences as bioethicists engaged in clinical consultation and education and as the founding, former, and current directors of a program focused on disability and rehabilitation ethics to argue that ableism and unexamined assumptions about people with disabilities have persisted in bioethics despite decades of counternarratives, research, and divergent perspectives. Ableism and such assumptions can lead to health care decisions that are prone to bias, mistreatment, and a lack of consideration of viable options for living with disability. As the field of bioethics moves toward certification examinations and as new generations join the field's ranks, these problems need to be rectified with solutions at the individual, interpersonal, and structural levels. It is past time to take disability seriously.
Probiotic‐derived nanoparticles inhibit ALD through intestinal miR194 suppression and subsequent FXR activation
Authors: Jiang Mengwei , Li Fengyuan , Liu Yunhuan , Gu Zelin , Zhang Lihua , Lee Jiyeon , He Liqing , Vatsalya Vatsalya , Zhang Huang‐Ge , Deng Zhongbin , Zhang Xiang , Chen Shao‐Yu , Guo Grace L. , Barve Shirish , McClain Craig J. , Feng Wenke
Published: June 2022

Background and Aims:

Intestinal farnesoid X receptor (FXR) plays a critical role in alcohol‐associated liver disease (ALD). We aimed to investigate whether alcohol‐induced dysbiosis increased intestinal microRNA194 (miR194) that suppressed Fxr transcription and whether Lactobacillus rhamnosus GG–derived exosome‐like nanoparticles (LDNPs) protected against ALD through regulation of intestinal miR194‐FXR signaling in mice.

Approach and Results:

Binge‐on‐chronic alcohol exposure mouse model was utilized. In addition to the decreased ligand‐mediated FXR activation, alcohol feeding repressed intestinal Fxr transcription and increased miR194 expression. This transcriptional suppression of Fxr by miR194 was confirmed in intestinal epithelial Caco‐2 cells and mouse enteriods. The alcohol feeding–reduced intestinal FXR activation was further demonstrated by the reduced FXR reporter activity in fecal samples and by the decreased fibroblast growth factor 15 (Fgf15) messenger RNA (mRNA) in intestine and protein levels in the serum, which caused an increased hepatic bile acid synthesis and lipogeneses. We further demonstrated that alcohol feeding increased‐miR194 expression was mediated by taurine‐upregulated gene 1 (Tug1) through gut microbiota regulation of taurine metabolism. Importantly, 3‐day oral administration of LDNPs increased bile salt hydrolase (BSH)‐harboring bacteria that decreased conjugated bile acids and increased gut taurine concentration, which upregulated Tug1, leading to a suppression of intestinal miR194 expression and recovery of FXR activation. Activated FXR upregulated FGF15 signaling and subsequently reduced hepatic bile acid synthesis and lipogenesis and attenuated ALD. These protective effects of LDNPs were eliminated in intestinal Fxr

ΔIEC
and Fgf15

−/−
mice. We further showed that miR194 was upregulated, whereas BSH activity and taurine levels were decreased in fecal samples of patients with ALD.

Conclusions:

Our results demonstrated that gut microbiota–mediated miR194 regulation contributes to ALD pathogenesis and to the protective effects of LDNPs through modulating intestinal FXR signaling.
Clinical outcomes and prognostic factors for patients with high‐risk gastrointestinal stromal tumors treated with 3‐year adjuvant imatinib
Authors: Bang Yeong Hak , Ryu Min‐Hee , Kim Hyung‐Don , Lee Hyung Eun , Kang Yoon‐Koo
Published: June 2022

Three years of adjuvant imatinib is the current standard for patients with high‐risk gastrointestinal stromal tumors (GIST). We aimed to investigate the safety and efficacy profiles of 3‐year imatinib, focusing on the prognostic value of various factors. In this registry‐based study, 222 patients with high‐risk GIST who underwent surgical resection followed by 3 years of adjuvant imatinib between 2010 and 2018 were included. The imatinib dose was reduced in 39 (17.6%), and 13 (5.9%) discontinued imatinib due to toxicity. With a median follow‐up duration of 65.7 months, 5‐year recurrence‐free survival (RFS) and overall survival (OS) were 73.2% and 93.9%, respectively. Tumor rupture, tumor size of >10 cm, mitotic index of >10/50 high power fields (HPF) were independent factors for short RFS. Patient subgroups stratified by the risk factors showed distinct RFS (P < .001): patients without the above risk factors or those with only a tumor size of >10 cm showed favorable RFS (5‐year RFS 83.8% and 92.3%, respectively), whereas those with tumor rupture or those with tumor size of >10 cm and mitotic index of >10/50 HPF showed prominently poor RFS (5‐year RFS of 54.8% and 47.9%, respectively). Three years of adjuvant imatinib treatment was generally tolerable and effective, which were consistent with the clinical outcomes of previous reports. The presence of tumor rupture, large tumor and high mitotic count was independently associated with poor RFS. Based on these risk factors, different management strategies, such as different durations of adjuvant imatinib, deserve further investigation.
Combined risk factors and risk of upper gastrointestinal cancer mortality in the Linxian general population
Authors: Yang Huan , Wang Xiao‐Kun , Wang Jian‐Bing , Zhao Fang‐Hui , Fan Jin‐Hu , Qiao You‐Lin , Taylor Philip R. , Abnet Christian C.
Published: June 2022

We aimed to explore the association of combined risk factors with risk of death from upper gastrointestinal (UGI) cancer, including esophageal squamous cell carcinoma (ESCC), gastric cardia carcinoma (GCC) and gastric noncardia carcinoma (GNCC) in the Linxian Nutrition Intervention Trial (NIT) cohort. The NIT cohort included 29 584 healthy adults. A combined risk score (CRS) was calculated using a point system method based on 10 risk factors collected at baseline, including gender, smoking, alcohol drinking, body mass index, family history of UGI cancer, drinking tap water, tooth loss and consumption of fresh fruit, eggs and meat. Possible score ranged from 0 to 31, and higher score indicated as poorer health status. Subjects were divided into three groups by the CRS (<12 points, 12 to 20 points and >20 points). The group of CRS <12 points was considered as the reference. During the 30‐year follow‐up, we identified 4553 UGI cancer deaths. Compared to subjects with a CRS <12 points, the adjusted HRs for CRS of 12 to 20 points and >20 points were 1.69 (95% CI: 1.56‐1.83) and 3.06 (95% CI: 2.82‐3.33) for UGI cancer mortality, respectively (Ptrend < .001). Comparable associations were also observed for ESCC, GCC and GNCC mortality. Results remained similar across different age groups (Pinteraction > .05). All HRs observed in the second half follow‐up period were stronger than that observed in the first half follow‐up period. Our study indicated that higher CRS was associated with increased risk of UGI cancer mortality. Appropriate measures should be taken to reduce unhealthy lifestyles.
Whole Exome Sequencing in Two Southeast Asian Families With Atypical Femur Fractures
Authors: Zhou Wei , Nguyen Hanh H. , van de Laarschot Denise M. , Howe Tet Sen , Koh Joyce S.B. , Milat Frances , van Rooij Jeroen G.J. , Verlouw Joost A.M. , van der Eerden Bram C.J. , Stevenson Mark , Thakker Rajesh V. , Zillikens M. Carola , Ebeling Peter R.
Published: June 2022

Atypical femur fractures (AFFs) are rare complications of anti‐resorptive therapy. Devastating to the affected individual, they pose a public health concern because of reduced uptake of an effective treatment for osteoporosis due to patient concern. The risk of AFF is increased sixfold to sevenfold in patients of Asian ethnicity compared with Europeans. Genetic factors may underlie the AFF phenotype. Given the rarity of AFFs, studying familial AFF cases is valuable in providing insights into any genetic predisposition. We present two Singaporean families, one comprising a mother (1‐a) and a daughter (1‐b), and the other comprising two sisters (2‐a and 2‐b). All four cases presented with bisphosphonate‐associated AFF. Whole‐exome sequencing (WES) was performed on 1‐b, 2‐a, and 2‐b. DNA for 1‐a was not available. Variants were examined using a candidate gene approach comprising a list of genes previously associated with AFF in the literature, as well as using unbiased filtering based on dominant and/or recessive inheritance patterns. Using a candidate gene approach, rare variants shared between all three cases were not identified. A rare variant in TMEM25, shared by the two sisters (2‐a and 2‐b), was identified. A rare heterozygous PLOD2 variant was present in the daughter case with AFF (1‐b), but not in the sisters. A list of potential genetic variants for AFF was identified after variant filtering and annotation analysis of the two sisters (2‐a and 2‐b), including a Gly35Arg variant in TRAF4, a gene required for normal skeletal development. Although the findings from this genetic analysis are inconclusive, a familial aggregation of AFFs is suggestive of a genetic component in AFF pathogenesis. We provide a comprehensive list of rare variants identified in these AFF familial cases to aid future genetic studies. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Performance Status Modifies the Association Between Vitamin D Receptor Activator and Mortality or Fracture: A Prospective Cohort Study on the Japanese Society for Dialysis Therapy (JSDT) Renal Data Registry
Authors: Murashima Miho , Hamano Takayuki , Nishiyama Takeshi , Tsuruya Kazuhiko , Ogata Satoshi , Kanda Eiichiro , Abe Masanori , Masakane Ikuto , Nitta Kosaku
Published: June 2022

Immobilization osteoporosis is characterized by excess bone resorption. Vitamin D receptor activators (VDRA) might have adverse effects in immobilized patients. The objective of this study was to elucidate the impact of performance status (PS) on the associations between VDRA use and outcomes among hemodialysis patients. This is a prospective cohort study. Adults on hemodialysis in the Japanese Society for Dialysis Therapy (JSDT) Renal Data Registry were included. Exposure of interest was the use of VDRA. Outcomes were all-cause mortality and hip fracture. Associations between VDRA use and mortality or hip fractures were examined by Cox and Poisson regression analyses, respectively. Among 208,512 subjects, 128,535 were on VDRA. Poor PS was associated with higher calcium (Ca), lower parathyroid hormone, and higher alkaline phosphatase levels. The association between higher Ca levels and VDRA use was stronger among those with poor PS (p interaction 0.007). Adjusted hazard ratio (HR) (95% confidence interval [CI]) for mortality and incidence rate ratio (IRR) for hip fracture was 1.02 (95% CI, 0.99–1.05) and 0.93 (0.86–1.00) among users of VDRA, respectively. The VDRA use was associated with lower mortality and incidence of hip fractures among subjects with good PS but not among subjects with poor PS (p interaction 0.03 and 0.05). Effect modification by PS was observed for cardiovascular (CV) mortality but not for non-CV mortality. In conclusion, VDRA use was associated with better outcomes only among those with good PS. These results suggest that bone and mineral disorders among hemodialysis patients should be treated differently, depending on their performance status. © 2022 American Society for Bone and Mineral Research (ASBMR).
Cork‐based permeable reactive barriers coupled to electrokinetic processes for interrupting pollutants reaching groundwater: a case study of lead‐contaminated soil
Authors: Silva Karyn NO , Henrique João MM , Vilar Vítor JP , Martínez‐Huitle Carlos A , dos Santos Elisama V
Published: June 2022

BACKGROUND

A novel, original and green technology for the remediation of lead‐contaminated soil is proposed. The treatment strategy integrates two well‐known technologies: electrokinetic (EK) remediation and permeable reactive barriers (PRBs). The novelty of the present work is based on the use of cork granules, as reactive media, in the PRBs for interrupting Pb reaching groundwater. The cork barrier (treatment zone) was emplaced near the anodic compartment to favor the retention and sorption of Pb due to the migration/diffusion effects promoted from soil to the anode during EK remediation. For this purpose, NaNO3 (0.1 mol L−1) and citric acid (0.1 mol L−1) were tested as supporting electrolytes in the cathodic reservoir, while in the anodic compartment a solution of 0.1 mol L−1 NaNO3 was used. Additionally, the influence of direct current and reverse polarity approaches on EK efficiency was evaluated.

RESULTS

Results clearly indicated that the novel cork‐based PRBs concept was efficient when coupled with EK. Nevertheless, pH conditions played a significant role in Pb sorption by cork granules as well as in the physical–chemical properties of cork under an electrical field. The transportation of Pb by EK, towards the PRB with cork granules, was favored through the use of citric acid in the catholyte and reverse polarity strategy.

CONCLUSIONS

These approaches promote a better pH control in the soil and electrode wells, being able to reach near 80% Pb removal from soil, after 14 days of experiment. Therefore, this technology can be used for in situ remediation of Pb‐contaminated groundwater. © 2022 Society of Chemical Industry (SCI).
Comparison of the prognostic effect of sarcopenia on atezolizumab plus bevacizumab and lenvatinib therapy in hepatocellular carcinoma patients
Authors: Toshida Katsuya , Itoh Shinji , Tomiyama Takahiro , Morinaga Akinari , Kosai Yukiko , Tomino Takahiro , Kurihara Takeshi , Nagao Yoshihiro , Morita Kazutoyo , Harada Noboru , Yoshizumi Tomoharu
Published: June 2022

Background and Aim

Sarcopenia has received much attention as a poor prognostic factor in various fields, and has also been reported to worsen prognosis in patients with hepatocellular carcinoma (HCC) treated with sorafenib or lenvatinib (LEN). Atezolizumab/bevacizumab (ATZ/BEV) is recommended as first‐line drug therapy for unresectable‐HCC, but the effect of sarcopenia on patients treated with ATZ/BEV is unknown.

Methods

We enrolled 98 patients treated with ATZ/BEV or LEN. Computed tomography performed before the initiation of drug therapy was used to diagnose sarcopenia in accordance with the criteria proposed by the Japanese Society of Hepatology. Patients were divided into two groups based on the presence or absence of sarcopenia in each regimen, and patient characteristics, adverse events, and prognosis were compared.

Results

In ATZ/BEV therapy, 57.1% of patients had sarcopenia. The sarcopenia group had significantly more women (P = 0.0125) and more macroscopic vascular invasion (P = 0.0270). Sarcopenia had no significant effect on progression‐free survival (PFS) and overall survival (OS). In LEN therapy, 63.4% of patients had sarcopenia. The sarcopenia group was significantly older (P = 0.0064) and had a higher number of women (P = 0.0003), a higher neutrophil–lymphocyte ratio (P = 0.0222), worse albumin–bilirubin grade (P = 0.0087), and worse best response (P = 0.0255). PFS (P = 0.0091) and OS (P = 0.0006) were worse in the sarcopenia group. In multivariate analysis, age (P = 0.0362), lymphocyte–monocyte ratio (P = 0.0365), and sarcopenia (P = 0.0268) were independent prognostic factors for OS.

Conclusion

In ATZ/BEV therapy, sarcopenia does not determine prognosis, and therapeutic efficacy can be expected even in cases of sarcopenia.
Developmental disorders in children born to women with sickle cell disease: A report from the Boston Birth Cohort
Authors: Brucato Martha , Lance Eboni , Lanzkron Sophie , Wang Xiaobin , Pecker Lydia H.
Published: June 2022

Children exposed to maternal sickle cell disease (SCD) have many theoretical risks for developmental disorders, but little is known about long‐term outcomes for these children. We used the Boston Birth Cohort to compare developmental outcomes between children exposed to maternal SCD and matched, unexposed controls. Children with exposure to maternal SCD had increased risk of attention deficit hyperactivity disorder (OR 5.12, 95% CI 1.36–19.19, p = 0.02) and obesity (OR 2.74, 95% CI 1.10–6.87, p = 0.03). In utero and/or environmental exposures may help explain these findings. Further studies of outcomes of children born to women with SCD are needed.
Assessment of key characteristics, methodology, and effect size measures used in meta‐analysis of human‐health‐related animal studies
Authors: Hooijmans Carlijn R. , Donders Rogier , Magnuson Kristen , Wever Kimberley E. , Ergün Mehmet , Rooney Andrew A. , Walker Vickie , Langendam Miranda W.
Published: June 2022

Since the early 1990s the number of systematic reviews (SR) of animal studies has steadily increased. There is, however, little guidance on when and how to conduct a meta‐analysis of human‐health‐related animal studies. To gain insight about the methods that are currently used we created an overview of the key characteristics of published meta‐analyses of animal studies, with a focus on the choice of effect size measures. An additional goal was to learn about the rationale behind the meta‐analysis methods used by the review authors. We show that important details of the meta‐analyses are not fully described, only a fraction of all human‐health‐related meta‐analyses provided rationales for their decision to use specific effect size measures. In addition, our data may suggest that authors make post‐hoc decisions to switch to another effect size measure during the course of their meta‐analysis, and possibly search for significant effects. Based on analyses in this paper we recommend that review teams: 1) publish a review protocol before starting the conduct of a SR, prespecifying all methodological details (providing special attention to the planned meta‐analysis including the effect size measure and the rational behind choosing a specific effect size, prespecifying subgroups and restricting the number of subgroup analyses), 2) always use the Preferred Reporting Items for Systematic Review and Meta‐Analyses (PRISMA) checklist to report your SR of animal studies, and 3) use the random effects model (REM) in human‐health‐related meta‐analysis of animal studies, unless the assumptions for using the fixed effect model (FEM) are all met.
Critical values of soil solution Al3+ activity and pH for canola and maize cultivation in two acidic soils
Authors: Zhao Wen‐rui , Shi Ren‐yong , Hong Zhi‐neng , Xu Ren‐kou
Published: June 2022

BACKGROUND

Aluminum (Al) toxicity caused by soil acidification is the main constraint for crop growth in tropical and subtropical areas of southern China. The critical values of soil solution Al3+ activity and pH for crops in acidic soils can provide a useful reference for soil acidity amelioration.

RESULTS

A pot experiment in a greenhouse was conducted to investigate the critical values of soil solution Al3+ activity and pH for canola and maize in an Ultisol and an Alfisol. The critical values of soil solution Al3+ activity in Ultisol and Alfisol for canola were 1.5 and 10.0 μmol L−1, and 13.9 and 30.4 μmol L−1 for maize, respectively. The Al tolerance varied with soil type for the same variety of crop. There was more biomass of roots and shoots and higher plant height under the same Al3+ activity, and thus greater critical values of soil solution Al3+ activity for both crops in Alfisol than those in Ultisol, owing to higher Ca2+/Al3+, Mg2+/Al3+ and K+/Al3+ ratios in soil solution caused by higher cation exchange capacity and exchangeable base cations in Alfisol, when compared with those in Ultisol. The critical values of soil solution pH for canola and maize in Ultisol were 5.09 and 4.72, respectively; while those in Alfisol were 4.87 and 4.54, respectively.

CONCLUSION

The critical values of Al3+ activity were higher for maize than for canola and the critical values for both crops were higher in Alfisol than in Ultisol. The critical soil pH for both crops showed opposite trends to soil Al3+ activity. © 2022 Society of Chemical Industry.
DAF‐16 is involved in colonic metabolites of ferulic acid‐promoted longevity and stress resistance of Caenorhabditis elegans
Authors: Yang Wenhan , Xia Wen , Zheng Bisheng , Li Tong , Liu Rui Hai
Published: June 2022

BACKGROUND

Ferulic acid (FA) is a dietary polyphenol widely found in plant tissues. It has long been considered to have health‐promoting qualities. However, the biological properties of dietary polyphenols depend largely on their absorption during digestion, and the effects of their intestinal metabolites on human health have attracted the interest of researchers. This study evaluated the effects of three main colonic metabolites of FA – 3‐(3,4‐dihydroxyphenyl)propionic acid (3,4diOHPPA), 3‐(3‐hydroxyphenyl)propionic acid (3OHPPA) and 3‐phenylpropionic acid (3PPA) – on longevity and stress resistance in Caenorhabditis elegans.

RESULTS

Our results showed that 3,4diOHPPA, 3OHPPA and 3PPA extended the lifespan under normal conditions in C. elegans whereas FA did not. High doses of 3,4diOHPPA (0.5 mmol L−1), 3OHPPA (2.5 mmol L−1) and 3PPA (2.5 mmol L−1) prolonged the mean lifespan by 11.2%, 13.0% and 10.6%, respectively. Moreover, 3,4diOHPPA, 3OHPPA and 3PPA treatments promoted stress tolerance against heat, UV irradiation and paraquat. Furthermore, three metabolites ameliorated physical functions, including reactive oxygen species and malondialdehyde levels, motility and pharyngeal pumping rate. The anti‐aging activities mediated by 3,4diOHPPA, 3OHPPA and 3PPA depend on the HSF‐1 and JNK‐1 linked insulin/IGF‐1 signaling pathway, which converge onto DAF‐16.

CONCLUSION

The current findings suggest that colonic metabolites of FA have the potential for use as anti‐aging bioactivate compounds. © 2022 Society of Chemical Industry.
Automatic detection and voxel‐wise mapping of lumbar spine Modic changes with deep learning
Authors: Gao Kenneth T. , Tibrewala Radhika , Hess Madeline , Bharadwaj Upasana U. , Inamdar Gaurav , Link Thomas M. , Chin Cynthia T. , Pedoia Valentina , Majumdar Sharmila
Published: June 2022

Background

Modic changes (MCs) are the most prevalent classification system for describing magnetic resonance imaging (MRI) signal intensity changes in the vertebrae. However, there is a growing need for novel quantitative and standardized methods of characterizing these anomalies, particularly for lesions of transitional or mixed nature, due to the lack of conclusive evidence of their associations with low back pain. This retrospective imaging study aims to develop an interpretable deep learning‐based detection tool for voxel‐wise mapping of MCs.

Methods

Seventy‐five lumbar spine MRI exams that presented with acute‐to‐chronic low back pain, radiculopathy, and other symptoms of the lumbar spine were enrolled. The pipeline consists of two deep convolutional neural networks to generate an interpretable voxel‐wise Modic map. First, an autoencoder was trained to segment vertebral bodies from T1‐weighted sagittal lumbar spine images. Next, two radiologists segmented and labeled MCs from a combined T1‐ and T2‐weighted assessment to serve as ground truth for training a second autoencoder that performs segmentation of MCs. The voxels in the detected regions were then categorized to the appropriate Modic type using a rule‐based signal intensity algorithm. Post hoc, three radiologists independently graded a second dataset with the aid of the model predictions in an artificial (AI)‐assisted experiment.

Results

The model successfully identified the presence of changes in 85.7% of samples in the unseen test set with a sensitivity of 0.71 (±0.072), specificity of 0.95 (±0.022), and Cohen's kappa score of 0.63. In the AI‐assisted experiment, the agreement between the junior radiologist and the senior neuroradiologist significantly improved from Cohen's kappa score of 0.52 to 0.58 (p < 0.05).

Conclusions

This deep learning‐based approach demonstrates substantial agreement with radiologists and may serve as a tool to improve inter‐rater reliability in the assessment of MCs.
Oral and Inhaled Fosamprenavir Reverses Pepsin‐Induced Damage in a Laryngopharyngeal Reflux Mouse Model
Authors: Johnston Nikki , Samuels Tina L. , Goetz Christopher J. , Arnold Leggy A. , Smith Brian C. , Seabloom Donna , Wuertz Beverly , Ondrey Frank , Wiedmann Timothy S. , Vuksanovic Nemanja , Silvaggi Nicholas R. , MacKinnon Alexander C. , Miller James , Bock Jonathan , Blumin Joel H.
Published: June 2022

Objective

More than 20% of the US population suffers from laryngopharyngeal reflux. Although dietary/lifestyle modifications and alginates provide benefit to some, there is no gold standard medical therapy. Increasing evidence suggests that pepsin is partly, if not wholly, responsible for damage and inflammation caused by laryngopharyngeal reflux. A treatment specifically targeting pepsin would be amenable to local, inhaled delivery, and could prove effective for endoscopic signs and symptoms associated with nonacid reflux. The aim herein was to identify small molecule inhibitors of pepsin and test their efficacy to prevent pepsin‐mediated laryngeal damage in vivo.

Methods

Drug and pepsin binding and inhibition were screened by high‐throughput assays and crystallography. A mouse model of laryngopharyngeal reflux (mechanical laryngeal injury once weekly for 2 weeks and pH 7 solvent/pepsin instillation 3 days/week for 4 weeks) was provided inhibitor by gavage or aerosol (fosamprenavir or darunavir; 5 days/week for 4 weeks; n = 3). Larynges were collected for histopathologic analysis.

Results

HIV protease inhibitors amprenavir, ritonavir, saquinavir, and darunavir bound and inhibited pepsin with IC50 in the low micromolar range. Gavage and aerosol fosamprenavir prevented pepsin‐mediated laryngeal damage (i.e., reactive epithelia, increased intraepithelial inflammatory cells, and cell apoptosis). Darunavir gavage elicited mild reactivity and no discernable protection; aerosol protected against apoptosis.

Conclusions

Fosamprenavir and darunavir, FDA‐approved therapies for HIV/AIDS, bind and inhibit pepsin, abrogating pepsin‐mediated laryngeal damage in a laryngopharyngeal reflux mouse model. These drugs target a foreign virus, making them ideal to repurpose. Reformulation for local inhaled delivery could further improve outcomes and limit side effects.

Level of evidence

NA. Laryngoscope, 133:S1–S11, 2023