bluuebunny/crossref_metadata_2025 huggingface dataset:
Host cells with transient overexpression of MDR1 as a novel in vitro model for evaluating on-target effect for activity against the epicellular Cryptosporidium parasite
Authors: Yang Bo , Wang Dongqiang , Liu Mingxiao , Wu Xiaodong , Yin Jigang , Zhu Guan
Published: September 2021

Objectives

To rapidly generate host cells with resistance to multiple compounds for differentiating drug action on parasite target or the host cell target (i.e. on-target or off-target effect) against the zoonotic enteric parasite Cryptosporidium parvum.

Methods

Transient overexpression of a multidrug resistance protein 1 (MDR1) gene in host cells (HCT-8 cell line) was explored to increase drug tolerance of the host cells to selected anti-cryptosporidial leads. In vitro cytotoxicity and anti-cryptosporidial efficacy of selected compounds were evaluated on the parasite grown in WT parental and transiently transfected HCT-8 cells. The approach was based on the theory that, for an epicellular parasite receiving consistent exposure to compounds in culture medium, overexpressing MDR1 in HCT-8 cells would increase drug tolerance of host cells to selected compounds but would not affect the anti-cryptosporidial efficacy if the compounds acted solely on the parasite target and the drug action on host cell target played no role on the antiparasitic efficacy.

Results

Six known anti-cryptosporidial leads were tested. Transient overexpression of MDR1 increased drug tolerance of HCT-8 cells on paclitaxel, doxorubicin HCl and vincristine sulphate (2.11- to 2.27-fold increase), but not on cyclosporin A, daunorubicin HCl and nitazoxanide. Increased drug tolerance in host cells had no effect on antiparasitic efficacy of paclitaxel, but affected that of doxorubicin HCl.

Conclusions

Data confirmed that, at efficacious concentrations, paclitaxel acted mainly on the parasite target, while doxorubicin might act on both parasite and host cell targets. This model can be employed for studying the action of additional anti-cryptosporidial leads, and adapted to studying drug action in other epicellular pathogens. The limitation of the model is that the anti-cryptosporidial leads/hits need to be MDR1 substrates.
Nucleosome assembly protein 1 is a regulator of histone H1 acetylation
Authors: Yoneda Mitsuhiro , Yasui Kiyoshi , Nakagawa Takeya , Hattori Naoko , Ito Takashi
Published: September 2021

Acetylation of histone H1 is generally considered to activate transcription, whereas deacetylation of H1 represses transcription. However, the precise mechanism of the acetylation is unknown. Here, using chromatography, we identified nucleosome assembly protein 1 (NAP-1) as having inhibitory activity against histone H1 acetylation by acetyltransferase p300. We found that native NAP-1 interacts with H1 in a Drosophila crude extract. We also found that it inhibits the deacetylation of histone H1 by histone deacetylase 1. The core histones in nucleosomes were acetylated in a GAL4–VP16 transcriptional activator-dependent manner in vitro. This acetylation was strongly repressed by hypoacetylated H1 but to a lesser extent by hyperacetylated H1. Consistent with these findings, a micrococcal nuclease assay indicated that hypoacetylated H1, which represses activator-dependent acetylation, was incorporated into chromatin, whereas hyperacetylated H1 was not. To determine the contribution of NAP-1 to transcriptional regulation in vivo, we compared NAP-1 knockdown (KD) with coactivator CREB-binding protein (CBP) KD using RNA sequencing in Drosophila Schneider 2 cells. Most genes were downregulated rather than upregulated by NAP-1 KD, and those downregulated genes were also downregulated by CBP KD. Our results suggest that NAP-1 plays a role in transcriptional regulation by fine-tuning the acetylation of histone H1.
A Vacancy Chain Model of Local Managers’ Career Advancement
Authors: Yi Hongtao , Chen Catherine
Published: September 2021

Local public managers are mobile in their career trajectories. While the extant public administration literature has predominantly examined this topic from a leadership turnover perspective, few studies have approached the career trajectories of local managers from a holistic, system-level angle. This article draws upon the vacancy chain literature and frames local managers’ interconnected career trajectories within a nationwide professional job market, which we term “leadership turnover chains.” We examine factors influencing the formation of such leadership turnover chains among cities. With a dataset containing information from the resumes of 517 US local managers across 28 years, we employ panel dyadic logistic regressions to analyze the leadership turnover chains among cities. Our findings suggest that managers are more likely to move among dyads of cities that are geographically close and with similar levels of economic prosperity, population size, racial diversity, and political climate. A promotion intercity turnover tends to take place from a populous city to a less populous city, while a demotion intercity turnover exhibits an opposite pattern. This study contributes to the theory of leadership turnover of local managers, highlighting a macro vacancy chain perspective on their career trajectories.
Fourth imported rabies case since the eradication of rabies in Japan in 1957
Authors: Nosaki Yasunobu , Maeda Kentaro , Watanabe Maki , Yokoi Takamasa , Iwai Katsushige , Noguchi Akira , Tobiume Minoru , Satoh Masaaki , Kaku Yoshihiro , Sato Yuko , Kato Hirofumi , Okutani Akiko , Kawahara Madoka , Harada Michiko , Inoue Satoshi , Maeda Ken , Suzuki Tadaki , Saijo Masayuki , Takayama-Ito Mutsuyo
Published: September 2021

A 32-year-old man, who visited Japan from the Philippines in 2020, was diagnosed with rabies, the first reported case in Japan since 2006. This is the fourth imported case of rabies since 1957; one case in 1970 was imported from Nepal and two in 2006 were imported from the Philippines.
SBSA: an online service for somatic binding sequence annotation
Authors: Jiang Limin , Guo Fei , Tang Jijun , Yu Hui , Ness Scott , Duan Mingrui , Mao Peng , Zhao Ying-Yong , Guo Yan
Published: September 2021

Efficient annotation of alterations in binding sequences of molecular regulators can help identify novel candidates for mechanisms study and offer original therapeutic hypotheses. In this work, we developed Somatic Binding Sequence Annotator (SBSA) as a full-capacity online tool to annotate altered binding motifs/sequences, addressing diverse types of genomic variants and molecular regulators. The genomic variants can be somatic mutation, single nucleotide polymorphism, RNA editing, etc. The binding motifs/sequences involve transcription factors (TFs), RNA-binding proteins, miRNA seeds, miRNA-mRNA 3′-UTR binding target, or can be any custom motifs/sequences. Compared to similar tools, SBSA is the first to support miRNA seeds and miRNA-mRNA 3′-UTR binding target, and it unprecedentedly implements a personalized genome approach that accommodates joint adjacent variants. SBSA is empowered to support an indefinite species, including preloaded reference genomes for SARS-Cov-2 and 25 other common organisms. We demonstrated SBSA by annotating multi-omics data from over 30,890 human subjects. Of the millions of somatic binding sequences identified, many are with known severe biological repercussions, such as the somatic mutation in TERT promoter region which causes a gained binding sequence for E26 transformation-specific factor (ETS1). We further validated the function of this TERT mutation using experimental data in cancer cells. Availability:http://innovebioinfo.com/Annotation/SBSA/SBSA.php.
SARS-CoV-2 Epidemiology on a Public University Campus in Washington State
Authors: Weil Ana A , Sohlberg Sarah L , O’Hanlon Jessica A , Casto Amanda M , Emanuels Anne W , Lo Natalie K , Greismer Emily P , Magedson Ariana M , Wilcox Naomi C , Kim Ashley E , Back Lewis , Frazar Christian D , Pelle Ben , Sibley Thomas R , Ilcisin Misja , Lee Jover , Ryke Erica L , Craft J Chris , Schwabe-Fry Kristen M , Fay Kairsten A , Cho Shari , Han Peter D , Heidl Sarah J , Pfau Brian A , Truong Melissa , Zhong Weizhi , Srivatsan Sanjay R , Harb Katia F , Gottlieb Geoffrey S , Hughes James P , Nickerson Deborah A , Lockwood Christina M , Starita Lea M , Bedford Trevor , Shendure Jay A , Chu Helen Y
Published: September 2021

Background

We aimed to evaluate a testing program to facilitate control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission at a large university and measure spread in the university community using viral genome sequencing.

Methods

Our prospective longitudinal study used remote contactless enrollment, daily mobile symptom and exposure tracking, and self-swab sample collection. Individuals were tested if the participant was exposed to a known SARS-CoV-2-infected person, developed new symptoms, or reported high-risk behavior (such as attending an indoor gathering without masking or social distancing), if a member of a group experiencing an outbreak, or at enrollment. Study participants included students, staff, and faculty at an urban public university during the Autumn quarter of 2020.

Results

We enrolled 16 476 individuals, performed 29 783 SARS-CoV-2 tests, and detected 236 infections. Seventy-five percent of positive cases reported at least 1 of the following: symptoms (60.8%), exposure (34.7%), or high-risk behaviors (21.5%). Greek community affiliation was the strongest risk factor for testing positive, and molecular epidemiology results suggest that specific large gatherings were responsible for several outbreaks.

Conclusions

A testing program focused on individuals with symptoms and unvaccinated persons who participate in large campus gatherings may be effective as part of a comprehensive university-wide mitigation strategy to control the spread of SARS-CoV-2.
Coronavirus Disease 2019 Vaccine Impact on Rates of Severe Acute Respiratory Syndrome Coronavirus 2 Cases and Postvaccination Strain Sequences Among Health Care Workers at an Urban Academic Medical Center: A Prospective Cohort Study
Authors: Bouton Tara C , Lodi Sara , Turcinovic Jacquelyn , Schaeffer Beau , Weber Sarah E , Quinn Emily , Korn Cathy , Steiner Jacqueline , Schechter-Perkins Elissa M , Duffy Elizabeth , Ragan Elizabeth J , Taylor Bradford P , Miller Nancy , Davidoff Ravin , Hanage William P , Connor John , Pierre Cassandra , Jacobson Karen R
Published: September 2021

Background

Coronavirus disease 2019 (COVID-19) vaccine trials and post-implementation data suggest that vaccination decreases infections. We examine vaccination’s impact on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case rates and viral diversity among health care workers (HCWs) during a high community prevalence period.

Methods

In this prospective cohort study, HCW received 2 doses of BNT162b2 or mRNA-1273. We included confirmed cases among HCWs from 9 December 2020 to 23 February 2021. Weekly SARS-CoV-2 rates per 100,000 person-days and by time from first injection (1–14 and ≥15 days) were compared with surrounding community rates. Viral genomes were sequenced.

Results

SARS-CoV-2 cases occurred in 1.4% (96/7109) of HCWs given at least a first dose and 0.3% (17/5913) of HCWs given both vaccine doses. Adjusted rate ratios (95% confidence intervals) were 0.73 (.53–1.00) 1–14 days and 0.18 (.10–.32) ≥15 days from first dose. HCW ≥15 days from initial dose compared to 1-14 days were more often older (46 vs 38 years, P = .007), Latinx (10% vs 8%, P = .03), and asymptomatic (48% vs 11%, P = .0002). SARS-CoV-2 rates among HCWs fell below the surrounding community, an 18% vs 11% weekly decrease, respectively (P = .14). Comparison of 50 genomes from post–first dose cases did not indicate selection pressure toward known spike antibody escape mutations.

Conclusions

Our results indicate an early positive impact of vaccines on SARS-CoV-2 case rates. Post-vaccination isolates did not show unusual genetic diversity or selection for mutations of concern.
Efficient and high-throughput pseudorecombinant-chimeric Cucumber mosaic virus-based VIGS in maize
Authors: Li Huangai , Zhang Danfeng , Xie Ke , Wang Yan , Liao Qiansheng , Hong Yiguo , Liu Yule
Published: September 2021

Virus-induced gene silencing (VIGS) is a versatile and attractive approach for functional gene characterization in plants. Although several VIGS vectors for maize (Zea mays) have been previously developed, their utilities are limited due to low viral infection efficiency, insert instability, short maintenance of silencing, inadequate inoculation method, or abnormal requirement of growth temperature. Here, we established a Cucumber mosaic virus (CMV)-based VIGS system for efficient maize gene silencing that overcomes many limitations of VIGS currently available for maize. Using two distinct strains, CMV-ZMBJ and CMV-Fny, we generated a pseudorecombinant-chimeric (Pr) CMV. Pr CMV showed high infection efficacy but mild viral symptoms in maize. We then constructed Pr CMV-based vectors for VIGS, dubbed Pr CMV VIGS. Pr CMV VIGS is simply performed by mechanical inoculation of young maize leaves with saps of Pr CMV-infected Nicotiana benthamiana under normal growth conditions. Indeed, suppression of isopentenyl/dimethylallyl diphosphate synthase (ZmIspH) expression by Pr CMV VIGS resulted in non-inoculated leaf bleaching as early as 5 d post-inoculation (dpi) and exhibited constant and efficient systemic silencing over the whole maize growth period up to 105 dpi. Furthermore, utilizing a ligation-independent cloning (LIC) strategy, we developed a modified Pr CMV-LIC VIGS vector, allowing easy gene cloning for high-throughput silencing in maize. Thus, our Pr CMV VIGS system provides a much-improved toolbox to facilitate efficient and long-duration gene silencing for large-scale functional genomics in maize, and our pseudorecombination-chimera combination strategy provides an approach to construct efficient VIGS systems in plants.
Genome Sequence of the Agrobacterium salinitolerans DG3-1 Isolated from Cotton Roots
Authors: Hao Haiting , Wang Zhe , Gou Changqing , Sha Shuaishuai , Yan Chengcai , Niu Dongdong , Wang Lan , Feng Hongzu
Published: September 2021

Agrobacterium salinitolerans DG3-1 is an endophytic bacterium isolated from cotton root tissue. Our previous work has shown that it can inhibit the growth of Fusarium and Verticillium wilt pathogens as well as increase the chlorophyll content of cotton leaves. Here, we reported the complete genome sequence of strain DG3-1, which was analyzed by sequence reads generated from Nanopore PromethION and Illumina NovaSeq PE150 platforms. This genome sequence could be used to clarify the possible mechanism of DG3-1 at the gene level.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
The Impact of Elsinoë ampelina Infection on Key Metabolic Properties in Vitis vinifera ‘Red Globe’ Berries via Multiomics Approaches
Authors: Li Zhi , Gao Linlin , Chang Pingping , Chen Ziqiu , Zhang Xiuming , Yin Wuchen , Fan Yanchun , Wang Xiping
Published: September 2021

Grape anthracnose caused by Elsinoë ampelina (Shear) is one of the most serious fungal diseases that lead to the quality reduction and yield losses of grape (Vitis vinifera ‘Red Globe’) berries. In the present study, metabolome and transcriptome analyses were conducted using grape berries in the field after infection with E. ampelina at 7, 10, and 13 days to identify the metabolic properties of berries. In total, 132 metabolites with significant differences and 6,877 differentially expressed genes were detected and shared by three comparisons. The analyses demonstrated that phenylpropanoid, flavonoid, stilbenoid, and nucleotide metabolisms were enriched in E. ampelina-infected grape berries but not amino acid metabolism. Phenolamide, terpene, and polyphenole contents also accumulated during E. ampelina infection. The results provided evidence of the enhancement of secondary metabolites such as resveratrol, α-viniferin, ε-viniferin, and lignins involved in plant defense. The results showed the plant defense-associated metabolic reprogramming caused by E. ampelina infection in grape berry and provided a global metabolic mechanism under E. ampelina stimulation.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Imaging of Tuberculosis in Children
Authors: Rana Pratyaksha , Bhatia Anmol , Saxena Akshay Kumar , Sodhi Kushaljit Singh
Published: September 2021

Tuberculosis (TB) is highly prevalent worldwide, and it affects children and adults equally, causing significant morbidity and mortality. Imaging plays a crucial role in diagnosis and management. Knowledge of imaging modalities available, imaging manifestations of both pulmonary and extrapulmonary tuberculosis, is vital for the radiologist for timely diagnosis among children with TB.
Distal Humerus Fractures in the Elderly: When to Fix and When to Replace?
Authors: Mayer Ryan , Choo Andrew , Zuelzer David
Published: September 2021

Distal humerus fractures in the elderly population can be difficult to manage because of substantial articular comminution, poor bone quality, and soft tissue compromise. Important patient considerations for treatment include physiologic age, mental status, activity level, and independence with activities of daily living. Elderly patients may be reliant on their upper extremity as a weight-bearing limb when using a walker or rising to stand which creates additional demand. The goal of surgical treatment is to recreate a stable, painless elbow with a functional range of motion to preserve independence for daily activities and mobilization. The main surgical treatment options are open reduction and internal fixation and arthroplasty. Here, we discuss indications and operative goals in each clinical scenario.
Cephalomedullary Nailing of Pertrochanteric Femur Fractures using a Large Distractor and Standard Radiolucent Table
Authors: Davison Brian L.
Published: September 2021

Background:

Cephalomedullary nailing is used to treat pertrochanteric fractures of the femur. A fracture or traction table is generally used to obtain and maintain fracture reduction. Some patients because of body habitus or ipsilateral foot or ankle pathology are not well suited for standard fracture table use. This study describes a technique and the results of using the large distractor on a standard radiolucent table to treat pertrochanteric femur fractures with a cephalomedullary implant.

Methods:

The described technique was used to reduce and stabilize pertrochanteric femur fractures with a cephalomedullary implant. All fractures were reduced on a radiolucent table using the large bone distractor with 5 or 6 mm threaded pin in supra-acetabular area of the pelvis and a 5 mm threaded pin in the distal femur. Results for the first 36 patients treated with this technique are reviewed.

Results:

All fractures were able to be reduced and stabilized using the technique. The average total operative time was 89 minutes and the average time from incision to wound closure was 53 minutes. Thirty patients were followed until fracture union and healed without further surgical intervention. One patient developed a nonunion with implant failure, 4 patients died, and 1 was lost to follow up.

Conclusions:

Pertrochanteric femur fractures can be reduced and stabilized using this technique if the surgeon feels the fracture table is not a good option.
Impact of neoadjuvant chemoradiotherapy on the local recurrence and distant metastasis pattern of locally advanced rectal cancer: a propensity score-matched analysis
Authors: Yu Liang , Xu Tian-Lei , Zhang Lin , Shen Shuo-Hao , Zhu Yue-Lu , Fang Hui , Zhang Hai-Zeng
Published: September 2021

Background:

Previous studies have demonstrated different predominant sites of distant metastasis between patients with and without neoadjuvant chemoradiotherapy (NCRT). This study aimed to explore whether NCRT could influence the metastasis pattern of rectal cancer through a propensity score-matched analysis.

Methods:

In total, 1296 patients with NCRT or post-operative chemoradiotherapy (PCRT) were enrolled in this study between January 2008 and December 2015. Propensity score matching was used to correct for differences in baseline characteristics between the two groups. After propensity score matching, the metastasis pattern, including metastasis sites and timing, was compared and analyzed.

Results:

After propensity score matching, there were 408 patients in the PCRT group and 245 patients in the NCRT group. NCRT significantly reduced local recurrence (4.1% vs. 10.3%, P = 0.004), but not distant metastases (28.2% vs. 27.9%, P = 0.924) compared with PCRT. In both the NCRT and PCRT groups, the most common metastasis site was the lung, followed by the liver. The NCRT group developed local recurrence and distant metastases later than the PCRT group (median time: 29.2 [18.8, 52.0] months vs. 18.7 [13.3, 30.0] months, Z = –2.342, P = 0.019; and 21.2 [12.2, 33.8] vs. 16.4 [9.3, 27.9] months, Z = –1.765, P = 0.035, respectively). The distant metastases occurred mainly in the 2nd year after surgery in both the PCRT group (39/114, 34.2%) and NCRT group (21/69, 30.4%). However, 20.3% (14/69) of the distant metastases appeared in the 3rd year in the NCRT group, while this number was only 13.2% (15/114) in the PCRT group.

Conclusions:

The predominant site of distant metastases was the lung, followed by the liver, for both the NCRT group and PCRT group. NCRT did not influence the predominant site of distant metastases, but the NCRT group developed local recurrence and distant metastases later than the PCRT group. The follow-up strategy for patients with NCRT should be adjusted and a longer intensive follow-up is needed.
Efficacy and safety of obinutuzumab for the first-line treatment of follicular lymphoma: a subgroup analysis of Chinese patients enrolled in the phase III GALLIUM study
Authors: Hong Xiaonan , Song Yuqin , Shi Yuankai , Zhang Qingyuan , Guo Wei , Wu Gang , Li Junmin , Feng Jifeng , Kinkolykh Anastasiia , Knapp Andrea , Lin Tongyu
Published: September 2021

Backgrounds:

GALLIUM is a global phase III study that demonstrated significant improvements in progression-free survival (PFS) for obinutuzumab plus chemotherapy (G-chemo) vs. rituximab plus chemotherapy (R-chemo) in previously untreated patients with follicular lymphoma (FL). This study aimed to report the results of a subgroup of patients in China.

Methods:

Patients were randomized to G-chemo or R-chemo. Responders received maintenance therapy for 2 years or until disease progression. The primary endpoint was investigator (INV)-assessed PFS. Secondary endpoints included the overall response rate (ORR) and complete response rate (CRR) at the end of induction chemotherapy, overall survival (OS), and safety.

Results:

Overall, 58 patients with FL were randomized to the G-chemo (n = 25) and R-chemo arms (n = 33). The INV-assessed PFS rate at 3 years was 81.8% in the G-chemo arm, vs. 70.2% in the R-chemo arm (hazard ratio 0.35; 95% confidence interval: 0.09–1.34; P = 0.1120). The INV-assessed CRRs (without positron emission tomography [PET]) in these arms were 24.0% and 21.2%, respectively, whereas the ORRs were 80.0% and 90.9%, respectively. INV-assessed CRR-PET was 52.6% in the G-chemo, vs. 60.9% in the R-chemo. Median OS was not reached in either arm. Grade 3 to 5 adverse events were more frequent in the R-chemo arm (97.0% vs. 88.0%).

Conclusions:

The results of this subgroup analysis were consistent with those of the global population, and they suggest that G-chemo has a positive benefit–risk profile in patients from China with FL.

Trial registration:

ClinicalTrials.gov, No. NCT01332968.
Association between time in range and cancer mortality among patients with type 2 diabetes: a prospective cohort study
Authors: Shen Yun , Wang Chunfang , Wang Yaxin , Lu Jingyi , Chen Lei , Zhang Lei , Lu Wei , Zhu Wei , Hu Gang , Xia Tian , Zhou Jian
Published: September 2021

Background:

Little was known about the association among time in range (TIR), time above range (TAR), time below range (TBR), and cancer mortality among patients with type 2 diabetes. We aimed to investigate the association among TIR, TAR, TBR, and the risk of cancer mortality among patients with type 2 diabetes.

Methods:

A total of 6225 patients with type 2 diabetes were prospectively recruited in Shanghai, China. TIR was measured with continuous glucose monitoring at baseline and was defined as the average percentage of time in the target glucose range during a 24 h period. Cox proportion hazard regression analysis was used to determine the association between TIR and the risk of cancer mortality.

Results:

During a mean follow-up of 7.10 years, we confirmed 237 death events related to cancer. The multivariable-adjusted hazard ratio (HR) for cancer mortality was 1.32 (95% confidence interval [CI]: 1.01–1.75) in patients with TIR ≤70% compared with those with TIR >70%. When TIR was considered as a continuous variable, the multivariable-adjusted HR for cancer mortality associated with each 10% decrease in TIR was 1.07 (95% CI: 1.02–1.14). In the site-specific analysis, a significant association between TIR as a continuous variable and the risk of hepatocellular cancer was found (HR: 1.24; 95% CI: 1.09–1.41). However, no relationship between hemoglobin A1c and cancer mortality was observed (HR: 1.04; 95% CI: 0.97–1.10).

Conclusions:

The present study found an inverse association of TIR with the risk of cancer mortality among patients with type 2 diabetes. New evidence of TIR was added into the clinical practice that TIR may be an optimal target of glycemic control among patients with type 2 diabetes.
Local Recurrence Outcomes of Colorectal Cancer Oligometastases Treated With Stereotactic Ablative Radiotherapy
Authors: Benson Kathryn R.K. , Sandhu Navjot , Zhang Carrie , Ko Ryan , Toesca Diego A.S. , Lee Phoebe E. , Von Eyben Rie , Diehn Maximilian , Gensheimer Michael , Maxim Peter G. , Bush Karl , Loo Billy W. , Soltys Scott G. , Pollom Erqi L. , Chang Daniel T.
Published: September 2021

Purpose:

The aim of this study was to report local failure (LF) outcomes and associated predictors in patients with oligometastatic colorectal cancer (CRC) treated with stereotactic ablative radiotherapy (SABR).

Materials and Methods:

We retrospectively reviewed patients with CRC metastases to the brain, liver, spine, or lung treated with SABR between 2001 and 2016. Time to LF was summarized using cumulative incidence of LF curves with death as a competing risk.

Results:

The analysis included a total of 130 patients and 256 lesions. Of the metastases treated, 129 (50%) were brain, 50 (20%) liver, 49 (19%) spine, and 28 (11%) lung. Median gross tumor volume was 24 mL for liver metastases, 2 mL for brain metastases, 4 mL for spine metastases, and 1 mL for lung metastases. The overall 1, 2, and 3-year cumulative incidence of LF rates were 21.6% (16.5, 27.1), 28.2% (22.3, 34.4), and 31.5% (25.2, 38.0), respectively. LF was highest among the liver metastases (1 y: 26.0%, 2 y: 38.5%), followed by spine (1 y: 25.1%, 2 y: 31.1%), brain (1 y: 20%, 2 y: 25.2%), and lung (1 y: 13.7%, 2 y: insufficient data). Metastases from right-sided primary CRC were significantly more likely to have LF (P=0.0146, HR=2.23). Biologically effective dose>70 Gy, defined using a standard linear quadratic model using α/β ratio of 10 on the individual lesion level, and pre-SABR chemotherapy were also significant predictors of LF (P= 0.0009 and 0.018, respectively).

Conclusions:

CRC metastases treated with SABR had significantly higher rates of LF if they originated from right-sided primary CRC, compared with left-sided. Liver metastases had the highest rates of LF compared with other metastatic sites. Thus, CRC liver metastases and metastases from right-sided CRC may benefit from more aggressive radiotherapy.
Aggressive Intestinal Symptoms Caused by Metastatic Tumors Originating from Primary Gastric Cancer in Pregnancy: A Case Report
Authors: Zhao Chunlin , Ji Jingru , Lu Shenghui , Wang Fang , Yang Hailan
Published: September 2021

Gastric carcinoma is extremely rare in pregnancy and the prognosis for this malignancy tends to be dismal. We herein describe a case of gastric cancer in pregnancy to alert clinicians to this rare possibility. A 29-year-old woman developed abdominal spastic pain and diarrhea during the 26 weeks of gestation and her condition was confusing and hard to recognize. The patient was initially misdiagnosed as enterogastritis and inflammatory intestinal obstruction and was finally confirmed by exploratory laparotomy with intestinal and peritoneum metastases. Because the disease was not detected early enough and progressed rapidly, the pregnancy was terminated by cesarean section at 30 weeks of gestation, and then followed by systemic chemotherapy, but eventually succumbed to the lethal pneumonia. Therefore, it is of great significance to alert clinicians to note this rare possibility and to consider the differential diagnosis of this disease in pregnant women with a long course of gastrointestinal symptoms that cannot be explained by pregnancy alone, and cancer should be suspected and tested with sophisticated diagnostic procedures.
In-house 3D Model Printing for Acute Cranio-maxillo-facial Trauma Surgery: Process, Time, and Costs
Authors: Bergeron Léonard , Bonapace-Potvin Michelle , Bergeron François
Published: September 2021

Three-dimensional (3D) printing is used extensively in cranio-maxillo-facial (CMF) surgery, but its usage is limited in the setting of acute trauma specifically, as delays in outsourcing are too great. Therefore, we developed an in-house printing solution. The purpose of this study was to describe this process for surgeons treating acute CMF trauma. This series describes the printing process, time required, and printing material costs involved for in-house printing applied to a variety of acute CMF trauma cases involving the upper, middle, and lower thirds of the face and skull. All consecutive patients requiring in-house 3D printed models in a level 1 trauma center for acute trauma surgery in mid-2019 were identified and analyzed. Nine patients requiring the printing of 12 in-house models were identified. The overall printing time per model ranged from 2 hours, 36 minutes to 26 hours, 54 minutes (mean = 7h 55 min). Filament cost was between $0.20 and $2.65 per model (mean = $0.95). This study demonstrates that in-house 3D printing can be done in a relatively short period of time, therefore allowing 3D printing usage for various acute facial fracture treatments. The rapid improvements in the usability of 3D software and printing technology will likely contribute to further adoption of these technologies by CMF-trauma surgeons.
The pleiotropic cardiovascular effects of sodium-glucose cotransporter-2 inhibitors
Authors: Tanna Monique S. , Goldberg Lee R.
Published: September 2021

Purpose of review

Throughout the history of medicine, scientists and clinicians have observed unanticipated drug effects leading at times to an entirely new use for a drug class, and other times eliminating them from practice. The sodium-glucose cotransporter-2 (SGLT2) inhibitors are one such class of drugs. These agents were initially studied as diabetic agents and their unanticipated and significant cardiovascular benefit has now created a new class of drugs for an entirely new population. Here we review the pleiotropic cardiovascular effects of SGLT2 inhibitors, the potential mechanisms of action, side effect profile and future directions.

Recent findings

Large clinical trials have evaluated the cardiovascular outcomes of SGLT2 inhibitors including myocardial infarction and strokes as well as new onset and worsening systolic heart failure.

SGLT2 inhibitors are being incorporated into the guidelines for the treatment of heart failure with the goal of preventing heart failure hospitalizations and promoting positive ventricular remodeling in patients with or without diabetes. The reduction in cardiovascular events including cardiovascular death, myocardial infarction, and other atherosclerotic effects appears to be driven by baseline risk with those who have known atherosclerosis seeing a reduction in events but those without disease seeing less benefit.
Pharmacokinetics and Safety of Ceftobiprole in Pediatric Patients
Authors: Rubino Christopher M. , Polak Mark , Schröpf Sebastian , Münch Hans Georg , Smits Anne , Cossey Veerle , Tomasik Tomasz , Kwinta Przemko , Snariene Rima , Liubsys Arunas , Gardovska Dace , Hornik Chi Dang , Bosheva Miroslava , Ruehle Christine , Litherland Karine , Hamed Kamal
Published: September 2021

Background:

Ceftobiprole, the active moiety of the prodrug ceftobiprole medocaril, is an advanced-generation, broad-spectrum, intravenous cephalosporin, which is currently approved for the treatment of adults with hospital-acquired or community-acquired pneumonia.

Methods:

Noncompartmental pharmacokinetics and safety were analyzed from 2 recently completed pediatric studies, a single-dose, phase 1 study in neonates and infants up to 3 months of age (7.5 mg/kg) and a phase 3 study in patients 3 months to 17 years of age with pneumonia (10–20 mg/kg with a maximum of 500 mg per dose every 8 hours for up to 14 days).

Results:

Total ceftobiprole plasma concentrations peaked at the end of infusion. Half life (median ranging from 1.9 to 2.9 hours) and overall exposure (median AUC ranging from 66.6 to 173 μg•h/mL) were similar to those in adults (mean ± SD, 3.3 ± 0.3 hours and 102 ± 11.9 μg•h/mL, respectively). Calculated free-ceftobiprole concentrations in the single-dose study remained above a minimum inhibitory concentration (MIC) of 4 mg/L (fT > MIC of 4 mg/L) for a mean of 5.29 hours after dosing. In the pneumonia study, mean fT > MIC of 4 mg/L was ≥5.28 hours in all dose groups. Ceftobiprole was well tolerated in both studies.

Conclusions:

Pharmacokinetic parameters of ceftobiprole characterized in the pediatric population were within the range of those observed in adults. In the pneumonia study, the lowest percentage of the dosing interval with fT > MIC of 4 mg/L was 50.8%, which suggests that pharmacokinetic-pharmacodynamic target attainment can be sufficient in pediatric patients. Ceftobiprole was well tolerated.
Urinary Proadrenomedullin and Disease Severity in Children With Suspected Community-acquired Pneumonia
Authors: Florin Todd A. , Ambroggio Lilliam , Shah Samir S. , Ruddy Richard M. , Nylen Eric S. , Balmert Lauren
Published: September 2021

Background:

Plasma proadrenomedullin (proADM) is a promising biomarker to predict disease severity in community-acquired pneumonia (CAP). Urinary biomarkers offer advantages over blood, including ease of collection. We evaluated the association between urinary proADM and disease severity in pediatric CAP.

Methods:

We performed a prospective cohort study of children 3 months to 18 years with CAP. Urinary proADM/creatinine (Cr) was calculated. Disease severity was defined as: mild (discharged home), mild-moderate (hospitalized but not moderate-severe or severe), moderate-severe (eg, hospitalized with supplemental oxygen and complicated pneumonia) and severe (eg, vasopressors and invasive ventilation). Outcomes were examined using logistic regression within the cohort with suspected CAP and in a subset with radiographic CAP.

Results:

Of the 427 children included, higher proADM/Cr was associated with increased odds of severe disease compared with nonsevere disease [suspected CAP, odds ratio (OR) 1.02 (95% confidence interval (CI) 1.003, 1.04); radiographic CAP, OR 1.03 (95% CI 1.01, 1.06)] when adjusted for other covariates. ProADM/Cr had an area under the receiver operating characteristic curve of 0.56 (threshold 0.9 pmol/mg) to differentiate severe from nonsevere disease in suspected CAP and 0.65 in radiographic CAP (threshold 0.82 pmol/mg). Healthy controls had less proADM in their urine (median, 0.61 pmol/mg) compared with suspected (0.87 pmol/mg, P = 0.018) and radiographic (0.73 pmol/mg, P = 0.016) CAP.

Conclusions:

Urinary proADM/Cr ratio measured at the time of emergency department visit was statistically associated with the development of severe outcomes in children with CAP, with stronger discriminatory performance in radiographic disease.
Body mass index prediction rule for mid-upper arm circumference: the atherosclerosis risk in communities study
Authors: Northuis Carin A. , Murray Thomas A. , Lutsey Pamela L. , Butler Kenneth R. , Nguyen Steve , Palta Priya , Lakshminarayan Kamakshi
Published: September 2021

Objectives

Electronic health records (EHR) are a convenient data source for clinical trial recruitment and allow for inexpensive participant screening. However, EHR may lack pertinent screening variables. One strategy is to identify surrogate EHR variables which can predict the screening variable of interest. In this article, we use BMI to develop a prediction rule for arm circumference using data from the Atherosclerosis Risk in Communities (ARIC) Study. This work applies to EHR patient screening for clinical trials of hypertension.

Methods

We included 11 585 participants aged 52–75 years with BMI and arm circumference measured at ARIC follow-up visit 4 (1996–1998). We selected the following arm circumference cutpoints based on the American Heart Association recommendations for blood pressure (BP) cuffs: small adult (≤26 cm), adult (≤34 cm) and large adult (≤44 cm). We calculated the sensitivity and specificity of BMI values for predicting arm circumference using receiver operating characteristic curves. We report the BMI threshold that maximized Youden’s Index for each arm circumference upper limit of a BP cuff.

Results

Participants’ mean BMI and arm circumference were 28.8 ± 5.6 kg/m2 and 33.4 ± 4.3 cm, respectively. The BMI-arm circumference Pearson’s correlation coefficient was 0.86. The BMI threshold for arm circumference≤26 cm was 23.0 kg/m2, arm circumference≤34 cm was 29.2 kg/m2 and arm circumference≤44 cm was 37.4 kg/m2. Only the BMI threshold for arm circumference≤34 cm varied significantly by sex.

Conclusions

BMI predicts arm circumference with high sensitivity and specificity and can be an accurate surrogate variable for arm circumference. These findings are useful for participant screening for hypertension trials. Providers can use this information to counsel patients on appropriate cuff size for BP self-monitoring.
Comparison of continuous infusion and intermittent boluses of furosemide in acute heart failure
Authors: Wang Tao , Han Yue , Song Yu
Published: September 2021

Background:

Acute heart failure (HF) is a common cause of hospital admission. This study aims to compare continuous infusion and intermittent boluses of furosemide in treating acute HF.

Methods:

This protocol of systematic review and meta-analysis has been drafted under the guidance of the preferred reporting items for systematic reviews and meta-analyses protocols. Electronic databases including Web of Science, Embase, PubMed, Wanfang, Data, Scopus, Science Direct, and Cochrane Library will be searched in June 2021 by 2 independent reviewers. The main outcomes are post-treatment daily urine output, weight, length of stay, serum sodium, potassium, and creatinine. Two researchers conducted a quality assessment in strict accordance with the risk bias assessment tool recommended by the Cochrane Handbook Version5.3. We performed the meta-analysis by Stata version 10.0 software.

Results:

The results of this systematic review and meta-analysis will be published in a peer-reviewed journal.

Conclusion:

The choice of furosemide regime in acute HF remains physician preference. Both bolus and continuous infusion yields satisfactory outcomes.
Traditional herbal medicine combined with first-line platinum-based chemotherapy for advanced non-small-cell lung cancer
Authors: Jin Hayun , Park Su Bin , Yoon Jee-Hyun , Lee Jee Young , Kim Eun Hye , Yoon Seong Woo
Published: September 2021

Background:

Non-small-cell lung cancer (NSCLC) is a major health burden in many countries. This review aimed to evaluate the efficacy of traditional herbal medicine (THM) combined with first-line platinum-based chemotherapy (PBCT) for the treatment of advanced NSCLC.

Methods:

From inception to April 2021, relevant studies were retrieved from 9 electronic databases. Randomized controlled trials (RCTs) comparing survival outcomes of THM + PBCT treatment with PBCT treatment in patients with advanced NSCLC were reviewed. The risk of bias was evaluated using the Cochrane Risk of Bias Tool. Overall survival, 1-year survival, progression-free survival or time to progression, tumor response rate, and adverse effects were analyzed.

Results:

Sixteen RCTs comprising 1445 patients were included. The meta-analysis indicated that THM + PBCT treatment, compared to PBCT alone, could improve overall survival (median survival ratio = 1.24, 95% confidence intervals [CI] [1.11, 1.39], P < .001), progression-free survival/time to progression (median survival ratio = 1.22, 95% CI [1.09, 1.37], P < .001), and the 1-year survival rate (risk ratio [RR] = 1.56, 95% CI [1.31, 1.86], P < .001). THM + PBCT also led to a higher tumor response rate (RR = 1.39, 95% CI [1.22, 1.59], P < .001) and lower incidence of thrombocytopenia (RR = 0.72, 95% CI [0.56, 0.92], P = .009) and nausea/vomiting (RR = 0.35, 95% CI [0.21, 0.57], P < .001), while there was no significant effect observed on leukopenia (RR = 0.68, 95% CI [0.34, 1.36], P = .27).

Conclusion:

THM, when used in combination with PBCT, might increase survival and the tumor response rate while decreasing the side effects caused by chemotherapy in patients with advanced NSCLC. However, considering the limited methodological qualities of the included trials, more rigorous RCTs are needed.
Candida meningitis in an infant after abdominal surgery successfully treated with intrathecal and intravenous amphotericin B
Authors: Yuan Lihua , Chen Feng , Sun Yao , Zhang Yong , Ji Xing , Jin Bo
Published: September 2021

Rationale:

Studies on Candida infections in the central nervous system, especially in infants and young children that did or did not have postoperative surgery, are rarely reported. Thus far, intrathecal (i.t.) amphotericin B (AmB) is not routinely recommended as a therapy for Candida meningitis. We report the first case of Candida meningitis in an infant who underwent abdominal surgery and was successfully treated with i.t. and intravenous (i.v.) AmB in the mainland of China.

Patient concerns:

Candida meningitis was confirmed by culture and immunoserological tests in a 1-day-old girl after surgery. She was treated with fluconazole for 1 month, but the patient's symptoms showed no improvement.

Diagnoses:

After surgery, the infant started having recurrent attacks of fever, and laboratory tests of the cerebrospinal fluid (CSF) revealed antigens of Candida tropicalis. CSF tests revealed a high total protein level and a low glucose level. She was diagnosed with a secondary Candida meningitis.

Interventions:

After azole therapy failure, intrathecal and intravenous AmB therapy were used as rescue therapies.

Outcomes:

After nearly 2 months of AmB treatment, all repeat CSF cultures were negative, the infant was deemed stable and was discharged home, and she continued taking voriconazole orally as an outpatient.

Lessons:

The combination of i.t. and i.v. administration of AmB can provide a safe and effective alternative to managing this rare but severe disease.
Evaluation of the in situ assay for HBV DNA
Authors: Li Chang , Zhang Wei , Shi Bisheng , Chen Gang , Zheng Ye , An Yong , Sun Mimi , Feng Yanling , Shang Qinghua , Zhang Xiaonan
Published: September 2021

The visualization of intrahepatic hepatitis B virus (HBV) DNA by in situ hybridization (ISH) has uncovered some interesting aspects of HBV life cycle at the single-cell level. In the current study, we intend to evaluate the reliability and robustness of this assay in the real-world clinical scenario and its relationship with currently available clinical biomarkers in chronic hepatitis B (CHB) patients.

In this cross-sectional study, 94 CHB patients and 10 patients with non-HBV related liver diseases were enrolled. Liver biopsies and routine histopathology analysis were performed. Intrahepatic HBV DNA and viral antigens (HBsAg and HBcAg) were detected by ISH and immunohistochemistry (IHC), respectively. The basic biochemical and virological parameters such as alanine transaminase, serum HBV DNA, and serum HBsAg were measured.

The HBV DNA-ISH assay showed 55.8% (53/94 cases) positive rate in CHB patients, no false positive was found in non-HBV related hepatitis. The IHC of HBsAg and HBcAg showed a positive rate of 94.7% (89/94 cases) and 19.5% (17/87 cases), respectively. Quantification of HBV DNA-ISH signal showed a significant correlation with serum HBV DNA (r

s
 = 0.6223, P < .0001). In addition, the staining pattern of HBV DNA in situ in the context of collagen deposition informed the histopathological progression of chronic liver disease.

The application of this ISH assay in evaluating intrahepatic viral replication in real-world CHB patients showed favorable performance. It can be a complementation to conventional liver histopathology examination and IHC detection of viral antigens. This methodology provides an intuitive assessment of virological and pathological state of CHB patients, and further supports clinical diagnosis and management.
Construction of a 5 immune-related lncRNA-based prognostic model of NSCLC via bioinformatics
Authors: Huang Ya-jie , Huang Chang-jie
Published: September 2021

Participate in tumorigenic, oncogenic, and tumor suppressive pathways through gene expression regulation. We aimed to build an immune-related long noncoding RNA (lncRNA) prognostic model to enhance nonsmall cell lung cancer (NSCLC) prognostic prediction.

The original data were collected from the cancer genome atlas database. Perl and R software were used for statistical analysis. The effects of lncRNAs expression on prognosis were analyzed by Gene Expression Profiling Interactive Analysis. Silico functional analysis were performed by DAVID Bioinformatics Resources.

The median risk score as a dividing value separated patients into high- and low-risk groups. These 2 groups had different 5-year survival rates, median survival times, and immune statuses. The 5-lncRNA signature was validated as an independent prognostic factor with high accuracy (area under the receiver operating characteristic = 0.722). Silico functional analysis connected the lncRNAs with immune-related biological processes and pathways in carcinogenesis.

The novel immune-related lncRNA prognostic model had significant clinical implication for enhancing lung adenocarcinoma outcome prediction and guiding the choice of treatment.