bluuebunny/crossref_metadata_2025 huggingface dataset:
A meta-analysis evaluating the relationship between B-type Raf kinase mutation and cervical lymphatic metastasis in papillary thyroid cancer
Authors: Ma Hongzhi , Wang Ru , Fang Jugao , Zhong Qi , Chen Xiao , Hou Lizhen , Feng Ling , Chen Xiaohong , Huang Zhigang , Zhao Huanhu
Published: January 2020

Background:

B-type Raf kinase (BRAF) mutation is proved to be a critical predictive factor in papillary thyroid cancer (PTC) with aggressive characteristics. However, the association between BRAF mutation and cervical lymphatic metastasis in PTC is controversial.

Methods:

We searched papers on the study of BRAF mutation and cervical lymphatic metastasis in PTC patients through PubMed, Web of Science, Embase, and Cochranelibrary. The BRAF (+) cases, BRAF (–) cases, and cervical lymphphatic metastatic cases in both BRAF (+) and BRAF (–) groups were collected. After Quality assessment, statistical Analysis (funnel plot and Harbord evaluation, Random-effect model, heterogeneity, subgroup analysis, sensitivity analysis, and metacum analysis) were done by the Review Manager (RevMan) 5.3 and stata14 statistical software.

Results:

There were 78 cross-section studies which met our inclusion criteria. And all of them had no selection bias, publication bias, or any other bias. A significant association existed between BRAF mutation and cervical lymph node metastasis (LNM) (odds ratio [OR] = 1.63; 95% confidence interval [CI]: 1.44–1.84;P < .05). Overall, 46 studies were conducted among East Asians. Twenty four articles had provided the data of central lymph node metastasis (CLNM), 11 articles with the data of lateral lymph node metastasis (LLNM), and classic/conventional PTC (CPTC) was analyzed in 10 studies. Subgroup analyses were performed based on ethnicity, metastatic site, and subtype of PTC. Significant association between BRAF (+) mutation and cervical LNM were indicated in East Asians (OR = 1.73; 95% CI: 1.49–2.02;P < .05), in non-East Asians (OR = 1.57; 95% CI: 1.26–1.96;P < .05), and in CLNM (OR = 1.80; 95% CI: 1.56–2.07;P < .05). While no significant association was found in LLNM (OR = 1.37; 95% CI: 0.76–2.48;P = .29 > .05) and in CPTC (OR = 1.32; 95% CI: 0.97–1.80;P = .08 > .05). We did not find any other major changes when sensitivity analysis was performed. The metacum analysis showed no significant association existed before 2012. While a significant association began to exist between BRAF mutation and LNM from 2012, and this association became stable from 2017.

Conclusions:

We consider that a significant association exists between BRAF mutation and cervical LNM. Further meta-analysis on subgroup may reveal some valuable factors between BRAF gene mutation and LNM. And we do not recommend that BRAF (+) as the biomarker for LNM in PTC.
Alveolar soft part sarcoma of the right calf
Authors: Wang Bin , Wang Huanhuan , Wei Jinlong , Qu Limei , Meng Lingbin , Xin Ying , Jiang Xin
Published: January 2020

Rationale:

Alveolar soft part sarcoma (ASPS) is a rare malignant soft tissue neoplasm with controversial histogenesis. ASPS accounts for 0.5% to 1% of all soft tissue sarcomas. Because of its rarity, ASPS is easily misdiagnosed, increasing the risk of incorrect treatment.

Patient concerns:

A 6-year-old female patient presented with a history of a 2.0 × 2.5 × 3.0-cm mass in the deep soft tissues of her right lower extremity.

Diagnoses:

Histopathological features indicated the diagnosis of ASPS. Microscopically, a diffuse arrangement of tumor cells or pseudoalveolar architectures separated by thin and well-vascularized fibrous septa were observed. Immunohistochemical staining of the tumor cells indicated positivity for transcription factor E3, myogenic determination factor 1, and periodic acid–Schiff–diastase (PAS-D) and showed a Ki-67 proliferating index of approximately 20%.

Interventions:

The patient underwent enlarged resection of the tumor and was treated with radiotherapy.

Outcomes:

During the 3-year follow-up, the patient has remained in good condition, with no symptom recurrence, distant metastatic spread, or significant toxicity during or after treatment. The patient remains under regular surveillance.

Lessons:

Its low incidence, lack of characteristic clinical manifestations, and atypical location often lead to ASPS misdiagnosis and subsequent incorrect treatment. Nuclear expression of transcription factor E3 is of diagnostic value for ASPS. At present, there is no consensus on the treatment for ASPS. In-depth pathological analysis is needed to better understand the characteristics of this tumor.
Herbal medicine on cancer-related fatigue of lung cancer survivors
Authors: Kwon Chan-Young , Lee Boram , Kim Kwan-Il , Lee Beom-Joon
Published: January 2020

Background:

Lung cancer is one of the most common cancers worldwide, and approximately half of the patients with lung cancer receiving chemotherapy suffer from cancer-related fatigue (CRF). Herbal medicines (HMs) have been used in Oriental countries for centuries as tonics. Various beneficial effects of HM on fatigue and cancer have been reported. However, the effectiveness and safety of HM for CRF in lung cancer patients have not been synthesized. The purpose of this systematic review is to evaluate the effectiveness and safety of HM for CRF in patients with lung cancer, regardless of their cancer type or stage.

Methods and analysis:

A comprehensive search will be conducted in 12 electronic medical databases including 5 English-language databases (Medline via PubMed, EMBASE via Elsevier, the Cochrane Central Register of Controlled Trials [CENTRAL], the Allied and Complementary Medicine Database [AMED] via EBSCO, and the Cumulative Index to Nursing and Allied Health Literature [CINAHL] via EBSCO), 4 Korean-language databases (Oriental Medicine Advanced Searching Integrated System [OASIS], Koreanstudies Information Service System [KISS], Research Information Service System [RISS], and Korea Citation Index [KCI]), 2 Chinese-language databases (China National Knowledge Infrastructure [CNKI] and Wanfang Data), and 1 Japanese-language database (CiNii). Only randomized controlled trials (RCTs) and quasi-RCTs on HM for CRF will be allowed. The severity of fatigue assessed using a validated tool will be considered as theprimary outcome. The secondary outcomes will include the patients’ quality of life, activities of daily life, incidence of adverse events, and total effective rate. Two independent researchers will perform the study selection, data extraction, and quality assessment. RevMan version 5.3 will be used for data synthesis. The methodological quality of the included RCTs will be assessed using the Cochrane Collaboration's risk of bias tool. In the meta-analysis, for dichotomous data and continuous data, risk ratio and mean difference, respectively, will be estimated with their 95% confidence intervals. According to the heterogeneity, either a fixed-effects or a random-effects model will be used.

Ethics and dissemination:

Ethical approval is not required because individual patient data are not included. The findings of this systematic review will be disseminated through a peer-reviewed publication or conference presentation.

PROSPERO registration number:

CRD42019141660.
Tripterygium wilfordii multiglycosides combined with prednisone in the treatment of idiopathic membranous nephropathy
Authors: Jin Yuxia , Zhang Jiayuan , Wang Yunxia , Xiao Xiao , Zhang Qi
Published: January 2020

Aim:

The aim of this review is to assess the efficacy and safety of tripterygium wilfordii multiglycosides combined with prednisone in the treatment of idiopathic membranous nephropathy.

Background:

Tripterygium wilfordii multiglycosides, a Chinese patent medicine, is widely in-depth research in China, and is proved to have anti-inflammatory and immunosuppressive effect. It has been extensively used in China for the treatment of autoimmune diseases, such as idiopathic membranous nephropathy (IMN). However, there has no relevant systematic review studied on its effects and safety been reported. We plan to perform a systematically reviewing to assess the efficacy and safety of tripterygium wilfordii multiglycosides combined with hormones in the treatment of IMN.

Methods:

Seven electronic databases will be searched to identify eligible trials. Randomized controlled trials (RCTs) that compared tripterygium wilfordii multiglycosides combined with prednisone versus standard therapy are included. Methodological quality is assessed using the Cochrane Collaboration Risk of Bias tool. A random- or fixed-effect model is used to analyze outcomes that are expressed as risk ratios (RRs) or mean differences (MD), and the I
2 statistic is used to assess heterogeneity.

Results:

A high-quality synthesis of current evidence of tripterygium wilfordii multiglycosides combined with prednisone in the treatment of idiopathic membranous nephropathy will be provided in this study.

Conclusion:

This systematic review will provide evidence of whether tripterygium wilfordii multiglycosides is an effective intervention for idiopathic membranous nephropathy.

PROSPERO registration number: No.CRD42018118179.
Complications of hardware removal in pediatric upper limb surgery
Authors: Scheider Philipp , Ganger Rudolf , Farr Sebastian
Published: January 2020

Previous studies indicated that hardware removal may lead to increased morbidity and therefore, at least in adults, remains questionable for certain indications. However, risks such as corrosion or local reactions may be less likely in younger patients with current, improved hardware materials. We sought to retrospectively determine complication rates of hardware removal in pediatric upper limb surgery, and establish potential risk factors for increased morbidity.

All children and adolescents who underwent inpatient hardware removal under anesthesia after previous upper limb surgery between 2002 and 2016 were retrospectively evaluated. The following details were extracted at the latest follow-up: demographics, implant location, hardware material, duration of surgery, duration of hardware in situ, and any complications graded according to Goslings et al (grade 0–5) and Sink et al (grade 1–5), respectively. Correlations were calculated to establish potential relationships between specific outcome parameters (e.g., location, duration of surgery etc.) and complication grades.

A total of 2089 children were evaluated of whom 317 patients with 449 interventions (mean age 9.4 years) fulfilled the inclusion criteria for this study. Overall, 203 K-wires (46%), 97 plates (22%), 102 external fixators (23%), 32 intramedullary nails (7%), 6 screws (1%), 4 cerclages (1%) and 1 pin (0.2%) were removed; most common locations were the forearm (34%) and humerus (24%). The mean duration of surgery was 40 minutes (± 50.9), mean time in situ was 194 days (± 319.6). Complication rates were low overall, with most being grade 0 (n = 372; 83%) or 1 (n = 60; 13%) according to Goslings et al and grade 1 (n = 386; 86%) and 2 (n = 42; 9%) according to Sink et al. No severe complications were observed. The following predictors were related to the severity of the complications in linear regression analysis: more distal localizations, external fixators, longer duration of surgery and female sex.

Hardware removal under anesthesia in the pediatric upper extremity has produced a low complication rate with no severe complications and can thus be considered to be safe. Increased morbidity occurred in more distal localizations, external fixators, longer surgeries and females.

Level of Evidence:Therapeutic, Level IV.
Safety and efficacy of immune checkpoint inhibitors in patients with HBV/HCV infection and advanced-stage cancer
Authors: Pu Dan , Yin Liyuan , Zhou Yuwen , Li Wen , Huang Lin , Cai Liang , Zhou Qinghua
Published: January 2020

Background:

Cancer patients with hepatitis B or C virus (HBV/HCV) infection are commonly seen in clinical practice, however, the data of safety and efficacy of immune checkpoint inhibitors (ICIs) among them are sparse, because active HBV/HCV infected patients were generally excluded by clinical trials and the correlation between previous infection and treatment-related adverse events was rarely reported. This review is the first to summarize the results on the safety and efficacy of immune checkpoint inhibitors (ICIs) in HBV/HCV infected cancer patients.

Method:

We searched literature and conference abstracts in PubMed and Embase followed the PRISMA guideline, using the keywords hepatitis B, hepatitis C, immune checkpoint inhibitor, ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, tremelimumab. Studies described patients with HBV/HCV infection treated with ICIs for advanced stage cancer were included.

Findings:

One hundred eighty six patients were identified from 14 articles (8 case reports, 4 case series, 2 trials). Eighty nine patients had HBV infection and 98 had HCV infection (1 both had HBV and HCV). The majority of patients were treated with PD-1 inhibitor monotherapy (140 of 186, 75.3%) and anti-CTLA-4 monotherapy (36 of 186, 19.4%). No treatment-related death was reported. The incidence of grade 3 or 4 hepatic transaminase elevating (HTE) in HBV and HCV infected patients were 3.4% (3/89) and 17.3% (17/98), respectively. 2.8% patients without antivirus therapy experienced virus load increasing, and 1.9% presented virus-related hepatitis. In terms of efficacy, 22 of 118 (18.6%) patients with liver cancer, 11 of 34 (32.4%) with melanoma, 1 of 6 (16.7%) with NSCLC showed objective responses (CR and PR) to ICIs in spite of lines of therapies.

Conclusion:

ICIs is considered to be safe and effective in advanced cancer patients with hepatitis B or C infection, but still has possibilities to reactive hepatitis virus due to uncertain mechanisms. We recommend that those with viral hepatitis be monitored closely and treated with antiviral therapy if indicated before or during ICIs treatment.
Preoperative assessment of contrast-enhanced spectral mammography of diagnosed breast cancers after sonographic biopsy
Authors: Cheung Yun-Chung , Juan Yu-Hsiang , Lo Yung-Feng , Lin Yu-Ching , Yeh Chih-Hua , Ueng Shir-Hwa
Published: January 2020

To assess the feasibility of using contrast-enhanced spectral mammography (CESM) for operative planning of patients with breast cancers who were initially diagnosed by sonographic guided biopsy.

With the approval of the Institutional Review Board of our hospital, we retrospectively reviewed the data on patients with breast cancers who underwent CESM and contrast-enhanced magnetic resonance imaging (CE-MRI) prior to operation and were followed up for at least 5 years postoperatively. The patients with breast cancer diagnosed by sonographic guided biopsy without mammography were included for analysis. The size and number of cancers on low-energy mammograms (LE-MG), recombined subtracted mammograms (RSM), and CE-MRI were recorded and compared with microscopic histopathologic data and at least 5 years of clinical follow-up data.

Fifty-one cancerous breasts of 46 patients were included in the analysis. All the principal cancers could be detected by RSM or CE-MRI; however, only 45 were by LE-MG. The Pearson correlation coefficients for the size on microscopy were 0.44 for LE-MG, 0.77 for RSM, and 0.84 for CE-MRI (all P-values ≤.001). Regarding the microscopic reports, RSM or CE-MRI had sensitivities of 100% and a positive predictive value of 63.6% for multicentric cancers. One breast cancer with partial mastectomy recurred after 3 years of follow-up.

CESM was feasible for assessing the cancer extension and multicentric cancers as secondary examination in patients with diagnosed breast cancers after sonographic biopsy.
Primary anorectal malignant melanoma
Authors: Xu Xingdong , Ge Ting , Wang Gang
Published: January 2020

Introduction:

Anorectal malignant melanoma (AMM) is a rare and aggressive malignance with poor prognosis, yet no consensus of treatment exists to date. Abdominoperineal resection surgery (APR) is the standard treatment of anorectal malignant melanoma, capable of controlling lymphatic spread and obtaining a large negative margin for local control but it can lead to complications. Wide local excision (WLE) allows for quicker recovery and has minimal impact on bowel function (i.e., bypassing the need for a stoma).

Patient concerns:

A 66-year-old male patient presented with a 2-months history of painless rectal bleeding.

Diagnosis:

The characteristic finding from colonoscopy and magnetic resonance imaging led to a diagnosis of colorectal cancer. Immunohistochemistry analyses confirmed malignant melanoma. The tumor was classified as: HMB-45(+), S-100(+), CD117(±), PCK(−), ki-67(+, 10%).

Interventions:

The patient underwent abdominoperineal resection with no other adjuvant therapy.

Outcomes:

The patient is doing well at 24 month after the operation, with no signs of recurrence.

Conclusion:

AMM is a rare malignance, and is easy to misdiagnose. The therapy approach remains controversial. Every effort should be made to ensure prompt diagnosis and to define the optimally effective standard therapy approach.
Nonsystemic vasculitic neuropathy in a patient with IgG-monoclonal gammopathy of undetermined significance
Authors: Kinno Ryuta , Osakabe Yuyuko , Takahashi Seiya , Kurokawa Shinji , Owan Yoshiyuki , Ono Kenjiro , Baba Yasuhiko
Published: January 2020

Rationale:

Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell proliferative disorder that consistently precedes multiple myeloma. Peripheral neuropathy in patients with IgG-MGUS tends to vary in clinical phenotype. We report a rare case of a patient with IgG-MGUS who had nonsystemic vasculitic neuropathy (NSVN).

Patient concerns:

A 56-year-old Japanese woman presented with progressive sensory ataxia with episodic paresthesia. Her clinical and laboratory values were compatible with IgG-MGUS. A nerve conduction study suggested possible chronic inflammatory demyelinating polyneuropathy. However, intravenous immunoglobulin therapy was not effective. A sural nerve biopsy specimen revealed mildly reduced myelinated fiber density and myelin ovoid formation, with epineural arterioles infiltrated by inflammatory cells.

Diagnoses:

We accordingly diagnosed her condition as NSVN.

Interventions:

She was accordingly started on oral prednisolone (40 mg/d) at 3 months after the onset of her neurological symptoms.

Outcomes:

At 1 year after the oral prednisolone treatment was begun, the patient's neurological symptoms showed no worsening.

Lessons:

These findings indicate NSVN as a possible cause of peripheral neuropathy in patients with IgG-MGUS. Cumulatively, our findings highlight the need for a nerve biopsy for peripheral neuropathy in patients with IgG-MGUS as a possible cause of NSVN. The early diagnosis of NSVN is expected to be beneficial for such patients.
Variations by Education Status in Relationships Between Alcohol/Pregnancy Policies and Birth Outcomes and Prenatal Care Utilization: A Legal Epidemiology Study
Authors: Roberts Sarah C. M. , Mericle Amy A. , Subbaraman Meenakshi S. , Thomas Sue , Kerr William , Berglas Nancy F.
Published: January 2020

Context:

Previous research finds that some state policies regarding alcohol use during pregnancy (alcohol/pregnancy policies) increase low birth weight (LBW) and preterm birth (PTB), decrease prenatal care utilization, and have inconclusive relationships with alcohol use during pregnancy.

Objective:

This research examines whether effects of 8 alcohol/pregnancy policies vary by education status, hypothesizing that health benefits of policies will be concentrated among women with more education and health harms will be concentrated among women with less education.

Methods:

This study uses 1972-2015 Vital Statistics data, 1985-2016 Behavioral Risk Factor Surveillance System data, policy data from National Institute on Alcohol Abuse and Alcoholism's Alcohol Policy Information System and original legal research, and state-level control variables. Analyses include multivariable logistic regressions with education-policy interaction terms as main predictors.

Results:

The impact of alcohol/pregnancy policies varied by education status for PTB and LBW for all policies, for prenatal care use for some policies, and generally did not vary for alcohol use for any policy. Hypotheses were not supported. Five policies had adverse effects on PTB and LBW for high school graduates. Six policies had adverse effects on PTB and LBW for women with more than high school education. In contrast, 2 policies had beneficial effects on PTB and/or LBW for women with less than high school education. For prenatal care, patterns were generally similar, with adverse effects concentrated among women with more education and beneficial effects among women with less education. Although associations between policies and alcohol use during pregnancy varied by education, there was no clear pattern.

Conclusions:

Effects of alcohol/pregnancy policies on birth outcomes and prenatal care use vary by education status, with women with more education typically experiencing health harms and women with less education either not experiencing the harms or experiencing health benefits. New policy approaches that reduce harms related to alcohol use during pregnancy are needed. Public health professionals should take the lead on identifying and developing policy approaches that reduce harms related to alcohol use during pregnancy.
A Multilevel Workforce Study on Drivers of Turnover and Training Needs in State Health Departments: Do Leadership and Staff Agree?
Authors: Leider Jonathon P. , Coronado Fátima , Bogaert Kyle , Sellers Katie
Published: January 2020

Objectives:

To characterize agreement between senior governmental public health staff and their subordinates concerning drivers for staff turnover, and skill importance and ability.

Design:

Data were combined from 2 national surveys conducted in 2017; one was a nationally representative, individual-level survey of public health workers, and one was an individual-level survey of their leadership.

Setting:

State health agencies.

Participants:

Respondents who held scientific, nonsupervisory positions at state health agency central offices (n = 3606) were matched with leadership (n = 193) who provided programmatic area oversight.

Main Outcome Measures:

Drivers of turnover and training needs are the primary outcomes examined in this article.

Results:

Leaders and their staff agreed on the main 2 drivers of turnover (low salary and lack of opportunities for advancement), but discordance was observed for other major drivers of turnover. Substantial discordance was observed between leaders and their staff in terms of perceived staff proficiency with selected skills.

Conclusions:

This multilevel assessment of workplace perceptions offers evidence around training needs and drivers of turnover in state health agencies. Although staff and leaders agree on some major drivers of turnover, other potential reasons for leaving cited by staff, and the difference in perceptions of skills, can help target job satisfaction, training, and retention efforts in state health agencies.
Trends Over Time and Jurisdiction Variability in Supplemental Security Income and State Supplementary Payment Programs for Children With Disabilities
Authors: Robinson Lara R. , McCord Russell F. , Cloud Lindsay K. , Kaminski Jennifer W. , Cook Amy , Amoroso Jessica , Watts Maya Hazarika , Kotzky Kim , Barry Caroline M. , Johnson Rebecca , Kelleher Kelly J.
Published: January 2020

Context:

Nearly 1.2 million children with disabilities received federally administered Supplemental Security Income (SSI) payments in 2017. Based on a robust review of research and evaluation evidence and microsimulations, The National Academies of Sciences, Engineering, and Medicine committee identified modifications to SSI (ie, increasing the federal SSI benefit maximum by one-third or two-thirds) as 1 of 10 strategies that could reduce the US child poverty rate, improving child health and well-being on a population level.

Objective:

Describing the availability and amount of SSI and State Supplementary Payment (SSP) program benefits to support families of children with disabilities may be a first step toward evaluating The National Academies of Sciences, Engineering, and Medicine–proposed modification to SSI as a potential poverty alleviation and health improvement tool for children with disabilities and their families.

Design:

We used public health law research methods to characterize the laws (statutes and state agency regulations) governing the federal SSI program and SSP programs in the 50 states and District of Columbia from January 1, 1996, through November 1, 2018.

Results:

The number of jurisdictions offering supplementary payments (SSP) was relatively stable between 1996 and 2018. In 2018, 23 US jurisdictions legally mandated that SSP programs were available for children. Among the states with SSP payment amounts in their codified laws, SSP monthly benefit amounts ranged from $8 to $64.35 in 1996 and $3.13 to $60.43 in 2018.

Conclusion:

Our initial exploration of SSI-related policies as a tool for improving the economic stability of children with disabilities and their families suggests that current SSPs, in combination with SSI, would not rise to the level of SSI increases proposed by The National Academies of Sciences, Engineering, and Medicine. Understanding more about how SSI and SSP reach children and work in combination with other federal and state income security programs may help identify policies and strategies that better support children with disabilities in low-income households.
Ultrasound-Guided Procedures in Rheumatology Daily Practice
Authors: Cipolletta Edoardo , Filippucci Emilio , Incorvaia Antonella , Schettino Martina , Smerilli Gianluca , Di Battista Jacopo , Tesei Giulia , Cosatti Micaela Ana , Di Donato Eleonora , Tardella Marika , Di Matteo Andrea , Di Carlo Marco , Grassi Walter
Published: January 2020

Background/Objective

The aims of this study were to describe in detail the ultrasound (US)-guided procedures in our daily rheumatology practice, to evaluate the feasibility and accuracy of US-guided procedures, and to test the efficacy of our disinfection protocol in preventing infectious complications.

Methods

This was a cross-sectional and monocentric study. Information regarding patients' age, sex, body mass index, rheumatic disease, US pathological findings, aspirated and/or injected anatomical site, US equipment (ie, probe type and frequency), and needle type was consecutively collected for each US-guided procedure in a third-level rheumatology center.

Results

A total of 643 US-guided procedures were performed, with a mean of 5.2 procedures per working-day. In 94.2% of the patients, only one procedure was carried out, whereas in 5.8%, more than one. The mean time was 7 ± 2.5 minutes. Ultrasound-guided procedures were highly accurate (accuracy rate higher than 95%) and safe (adverse events were reported in 0.8%). Our disinfection protocol was effective in preventing infectious complications. Probes with frequency values between 8 to 13 MHz and 20-, 21-, and 22-gauge needles were the most frequently used at shoulder, knee, wrist, elbow, and ankle level. High-frequency linear probes (ranging between 18 and 22 MHz) and 23- and 25-gauge needles were used for injecting small joints of the hands and feet. Convex low-frequency probe (2–7 MHz) and 18- and 20-gauge needles were the most used for performing hip joint aspirations and/or injections.

Conclusions

This study reports useful information for setting up a service providing US-guided procedures in rheumatology and supports the feasibility, accuracy, and safety of US-guided procedures.
Experimental evolution selects clinically relevant antibiotic resistance in biofilms but with collateral tradeoffs
Authors: Trampari Eleftheria , Holden Emma , Wickham Gregory , Ravi Anuradha , Prischi Filippo , Martins Leonardo de Oliveira , Savva George , Bavro Vassiliy , Webber Mark
Published: January 2020

The widespread usage of antimicrobials in modern clinical, veterinary and industrial practices has selected for the emergence of antibiotic-resistant bacteria, which are increasingly hard to treat with currently available antibiotics. Most bacteria in nature exist in aggregated communities known as biofilms, which are inherently highly tolerant to antibiotics. There is currently a limited understanding of how biofilms evolve in response to antimicrobial pressure. Here we used a biofilm evolution model as a tool to study the effects of antimicrobial exposure on biofilms compared to planktonic cultures. We showed that biofilms of the model foodborne pathogen, Salmonella Typhimurium rapidly evolve in response to exposure to three clinically important antibiotics. Adaptation to antibiotic stress imposed a marked cost in biofilm formation, particularly evident for populations exposed to cefotaxime and azithromycin. By pairing the evolution model with whole-genome sequencing, we were able to identify and characterise two distinct mechanisms of resistance to cefotaxime and azithromycin. Among others, we identified novel substitutions within the multidrug efflux transporter, AcrB (R717L and Q176K) and validated their impact in drug export as well as changes in regulators of this efflux system. We showed that the model biofilm system selects clinically-important mechanisms of resistance and can be used to help predict how biofilms evolve under antimicrobial pressure.
Plasma activated liquids: New decontamination solutions
Authors: Tsoukou Evanthia , Bourke Paula , Boehm Daniela
Published: January 2020

In the field of new decontaminants, there is an increasing consensus that improved disinfection of environmental surfaces is needed in patient care facilities as an important component in the overall strategy for prevention of HAI. The interaction of cold atmospheric plasma, i.e. an ionized gas, with liquids results in complex physical and chemical processes, which offer a source of short-lived and long-lived reactive chemical species that are critical for microbial inactivation. These solutions may fulfil the urgent need for new decontaminant solutions for special purposes such as disinfection of surfaces, or use as an antiseptic for body surfaces.

In this study, we explored the bactericidal effects of plasma activated liquids (PALs) on E.coli and S. aureus strains and investigated factors which influence PALs stability over time. Liquids of interest were non-complex solutions such as water and saline. An atmospheric cold plasma system using air was employed for the generation of PALs. The solutions were compared with respect to their content of long-lived reactive chemical species and bactericidal effects.

Our results documented that PALs may carry different concentrations of chemical species and maintain diverse antimicrobial properties. The bactericidal activity of these solutions demonstrated high thermal stability and could be preserved over a 6 month period through specific sub-ambient storage conditions. Investigation of the inactivation processes in relation to the PALs’ chemical composition will enhance our knowledge on how prokaryotic and eukaryotic cells respond to these, and demonstrate how PALs could be a promising treatment method for future applications, with chemical and antimicrobial stability.
Salmonella antibiotic persistence and macrophage polarisation
Authors: Majstorovic Andrea , Hill Peter W. S. , Helaine Sophie
Published: January 2020

Salmonella enterica infections have a high incidence of relapse due in part to the high levels of antibiotic persistence. It is known that growing and non-growing (e.g. persister) Salmonella utilise the Salmonella Pathogenicity Island 2 (SPI-2) Type 3 Secretion System (T3SS) to dampen the pro-inflammatory M1 state of macrophages and push the immune cells towards an anti-inflammatory M2 state. This allows Salmonella prolonged survival in the host and facilitates relapse. However, this interplay between Salmonella survival and macrophage activation states remains incompletely understood.

Here, I present a study on the influence of the initial phenotypic state of untreated (M0), IFN-γ (M1) and IL-4/IL-10 (M2) prepolarised differentiated murine bone marrow-derived macrophages (MΦs) on the survival and proliferation of Salmonella enterica Serovar Typhimurium (S. Typhimurium). As expected, pro-inflammatory M1 MΦs kill S. Typhimurium more efficiently than M0 cells. Surprisingly, S. Typhimurium shows decreased survival within anti-inflammatory M2 MΦs compared to M0 MΦs, which appears to be SPI-2 dependent. Further investigation revealed that even though S. Typhimurium induces SPI-2 T3SS within M1 and M2 prepolarised MΦs, the timing of SPI-2 activation is affected during infection of M2 MΦs, thereby reducing the ability of bacteria to proliferate. This leads to many more antibiotic tolerant non-growing S. Typhimurium surviving to combined antibiotic and macrophage challenges in prepolarised MΦs.

Together, these results suggest that infection of M0 MΦs followed by reprogramming to M2 MΦs appears to promote the optimal conditions for S. Typhimurium proliferation; nevertheless, non-growing cells may immediately persist and survive better in prepolarised MΦs.
Ferrovibrio terrae sp. nov., isolated from soil
Authors: Ryu Dajung , Kim Minji , Han Bit , Lee Ki-Eun , Lee Byoung-Hee , Lee Eun-Young , Jung Gi-Yong , Kim So-Jeong , Park Soo-Je
Published: January 2020

Designated strain K5T was isolated from soil on Jeju Island. The bacterium was aerobic, Gram-stain-negative, oxidase-positive, catalase-low activity, motile, short-rod shaped, opaque and formed white colonies that were circular, raised and had entire margins. Strain K5T was able to grow at 15–40 °C, pH 4–9 and at 0–2 % (w/v) NaCl concentration. Phylogenetic analysis based on its 16S rRNA gene sequences indicated that strain K5T is closely related to

Ferrovibrio soli

A15T (98.9 % sequence similarity),

Ferrovibrio denitrificans

Sp-1T (98.7 %) and

Ferrovibrio xuzhouensis

LM-6T (97.4 %). The sole respiratory quinone was determined to be ubiquinone-10. The dominant fatty acids of strain K5T were summed feature 8 (C18 : 1
 ω7c / C18 : 1ω6c, 29.8 %), C19 : 0 cyclo ω8c (20.2 %) and C16 : 0 (24.4 %). DNA G+C content was 63.6 % and DNA–DNA relatedness between strain K5T and other three members of the genus

Ferrovibrio

ranged from 24 to 28 %. The major polar lipids were identified as phosphatidylglycerol, phosphatidylethanolamine and aminolipids. Moreover, polyphasic characterization revealed that strain K5T represents a novel species in the genus Ferrovibrio, for which the name Ferrovibrio terrae sp. nov. is proposed. The type strain is K5T (=KCCM 43295T=LMG 30611T).
The characterization of mobile colistin resistance (mcr) genes among 33 000 Salmonella enterica genomes from routine public health surveillance in England
Authors: Sia Cheryll M. , Greig David R. , Day Martin , Hartman Hassan , Painset Anais , Doumith Michel , Meunier Daniele , Jenkins Claire , Chattaway Marie Anne , Hopkins Katie L. , Woodford Neil , Godbole Gauri , Dallman Timothy J.
Published: January 2020

To establish the prevalence of mobile colistin resistance (mcr) genes amongst

Salmonella enterica

isolates obtained through public health surveillance in England (April 2014 to September 2017), 33 205

S

.

enterica

genome sequences obtained from human, food, animal and environmental isolates were screened for the presence of mcr variants 1 to 8. The mcr-positive genomes were assembled, annotated and characterized according to plasmid type. Nanopore sequencing was performed on six selected isolates with putative novel plasmids, and phylogenetic analysis was used to provide an evolutionary context for the most commonly isolated clones. Fifty-two mcr-positive isolates were identified, of which 32 were positive for mcr-1, 19 for mcr-3 and 1 for mcr-5. The combination of Illumina and Nanopore sequencing identified three novel mcr-3 plasmids and one novel mcr-5 plasmid, as well as the presence of chromosomally integrated mcr-1 and mcr-3. Monophasic

S. enterica

serovar Typhimurium accounted for 27/52 (52 %) of the mcr-positive isolates, with the majority clustering in clades associated with travel to Southeast Asia. Isolates in these clades were associated with a specific plasmid range and an additional extended-spectrum beta-lactamase genotype. Routine whole-genome sequencing for public health surveillance provides an effective screen for novel and emerging antimicrobial determinants, including mcr. Complementary long-read technologies elucidated the genomic context of resistance determinants, offering insights into plasmid dissemination and linkage to other resistance genes.
Ultrafiltration Segregates Tissue Regenerative Stimuli Harboured Within and Independent of Extracellular Vesicles
Authors: Cooper TT , Sherman SE , Dayarathna T , Bell GI , Ma Jun , McRae DM , Lagugné-Labarthet F , Pasternak SH , Lajoie GA , Hess DA
Published: January 2020

The release of extracellular vesicles (EVs) from human multipotent stromal cells (MSC) has been proposed as a mechanism by which MSC mediate regenerative functionsin vivo. Our recent work has characterized MSC derived from human pancreatic tissues (Panc-MSC) that generated a tissue regenerative secretome. Despite these advancements, it remains unknown whether regenerative stimuli are released independent or within extracellular vesicles. Herein, this study demonstrates ultrafiltration is a simple method to enrich for EVs which can be injected in murine models of tissue regeneration. The enrichment of EVs from Panc-MSC conditioned media (CM) was validated using nanoscale flow cytometry and atomic force microscopy; in addition to the exclusive detection of classical EV-markers CD9, CD81, CD63 using label-free mass spectrometry. Additionally, we identified several pro-regenerative stimuli, such as WNT5A or ANGPT1, exclusive to EV-enriched CM. Endothelial cell tubule formation was enhanced in response to both Panc-MSC CM fractionsin vitroyet only intramuscular injection of EV-enriched CM demonstrated vascular regenerative functions in NOD/SCID mice with unilateral hind-limb ischemia (*<p<0.05). Furthermore, both EV-depleted and EV-enriched CM reduced hyperglycemia following intrapancreatic injection in hyperglycemic mice (**p<0.01). Collectively, understanding the functional synergy between compartments of the secretome is required to advance cell-free biotherapeutics into applications of regenerative medicine.
Can constraint closure provide a generalized understanding of community dynamics in ecosystems?
Authors: Peck Steven L. , Heiss Andrew
Published: January 2020

Since the inception of the discipline, understanding causal complexity in ecological communities has been a challenge. Here we draw insights from recent work on constraint closure that suggests ways of grappling with ecological complexity that yield generalizable theoretical insights. Using a set of evolutionary constraints on species flow through ecological communities, which include: selection, species drift, dispersal, and speciation, combined with multispecies interactions such as mutualistic interactions, and abiotic constraints, we demonstrate how constraint closure allows communities to emerge as semi-autonomous structures. Here we develop an agent-based model to explore how evolutionary constraints provide stability to ecological communities. The model is written in Netlogo, an agent based-modeling system, with advanced tools for manipulating spatially structured models and tools for tracking pattern formation. We articulate ways that ecological pattern formation, viewed through the lens of constraint closure, informs questions about stability and turnover in community ecology. The role of the chosen constraints was clear from the simulation results. It took the shape of both inducing stability and creating conditions for a more dynamic community with increases in species turnover through time. Key ecological and evolutionary variables showed overall stability in the landscape structure when plotted against the number of constraints, suggesting that these evolutionary forces act as constraints to the flow of species in such a way that constraint closure is achieved effecting semi-autonomy.

Author Summary

Ecosystems are among the most complex structures studied. They comprise elements that seem both stable and contingent. The stability of these systems depends on interactions among their evolutionary history, including the accidents of organisms moving through the landscape and microhabitats of the earth, and the biotic and abiotic conditions in which they occur. When ecosystems are stable, how is that achieved? Here we look at ecosystem stability through a computer simulation model that suggests that it may depend on what constrains the system and how those constraints are structured. Specifically, if the constraints found in an ecological community form a closed loop, that allows particular kinds of feedback may give structure to the ecosystem processes for a period of time. In this simulation model, we look at how evolutionary forces act in such a way these closed constraint loops may form. This may explain some kinds of ecosystem stability. This work will also be valuable to ecological theorists in understanding general ideas of stability in such systems.
Multiscale modelling of motility wave propagation in cell migration
Authors: Khatee Hamid , Czirok Andras , Neufeld Zoltan
Published: January 2020

The collective motion of cell monolayers within a tissue is a fundamental biological process that occurs during tissue formation, wound healing, cancerous invasion, and viral infection. Experiments have shown that at the onset of migration, the motility is self-generated as a polarization wave starting from the leading edge of the monolayer and progressively propagates into the bulk. However, it is unclear how the propagation of this motility wave is influenced by cellular properties. Here, we investigate this using a computational model based on the Potts model coupled to the dynamics of intracellular polarization. The model captures the propagation of the polarization wave initiated at the leading edge and suggests that the cells cortex can regulate the migration modes: strongly contractile cells may depolarize the monolayer, whereas less contractile cells can form swirling movement. Cortical contractility is further found to limit the cells motility, which (i) decelerates the wave speed and the leading edge progression, and (ii) destabilises the leading edge into migration fingers. Together, our model describes how different cellular properties can contribute to the regulation of collective cell migration.
Genetic regulation of the bacterial omega-3 polyunsaturated fatty acid biosynthesis pathway
Authors: Allemann Marco N. , Allen Eric E.
Published: January 2020

A characteristic among many marine Gammaproteobacteria is the biosynthesis and incorporation of omega-3 polyunsaturated fatty acids into membrane phospholipids. Biosynthesis of eicosapentaenoic (EPA) and/or docosahexaenoic (DHA) acids is accomplished using a polyketide/fatty acid synthase mechanism encoded by a set of five genespfaABCDE.This unique fatty acid synthesis (FAS) pathway co-exists with the canonical Type II dissociated fatty acid synthesis pathway, which is responsible for the biosynthesis of saturated, monounsaturated, and hydroxylated fatty acids used in phospholipid and lipid A biosynthesis. In this work, a genetic approach was undertaken to elucidate genetic regulation of thepfagenes in the model marine bacteriumPhotobacterium profundumSS9. Using a reporter gene fusion, we showed that expression of thepfaoperon is down regulated in response to exogenous fatty acids, particularly long chain monounsaturated fatty acids. This regulation occurs independently of the canonical fatty acid regulators, FabR and FadR, present inP. profundumSS9. Transposon mutagenesis and screening of a library of mutants identified a novel transcriptional regulator, which we have designatedpfaF, to be responsible for the observed regulation of thepfaoperon inP. profundumSS9. Gel mobility shift and DNase I footprinting assays confirmed that PfaF binds thepfaApromoter and identified the PfaF binding site.

Importance

The production of polyunsaturated fatty acids (PUFA) by marine Gammaproteobacteria, particularly those from deep-sea environments, has been known for decades. These unique fatty acids are produced by a polyketide-type mechanism and subsequently incorporated into the phospholipid membrane. While much research has focused on the biosynthesis genes, their products and the phylogenetic distribution of these gene clusters, no prior studies have detailed the genetic regulation of this pathway. This study describes how this pathway is regulated under various culture conditions and has identified and characterized a fatty acid responsive transcriptional regulator specific to the PUFA biosynthesis pathway.
Developing an Individualized Clinical Prediction Rules of Antihypertensive Drugs: A Study Protocol Based on Real-world Practice
Authors: Hong Dongsheng , Shi Wendan , Lu Xiaoyang , Jiaying Wu , Lou Yan , Li Lu
Published: January 2020

Background

Hypertension is one of the most urgent public health challenges, and drug therapy is the primary method to control blood pressure for patients. However, blood pressure control rate is still poor with antihypertensive drugs use. Although Clinical Prediction Rules (CPR) is useful to help clinicians make more appropriate decisions at the point of medication, the evidence is still limited in china. The objective of this study is to develop an CPR of antihypertensive drugs in individualized application of patients based on real-world practice.

Methods

A two-way cohort study has been conducted in one China’s large tertiary hospital using clinical information on patient characteristics, drug use and clinical outcome. Data extraction is through ICD-10 disease codes of hypertension from Electronic Medical Record System. Eligible patients admitted from September 2016 to August 2018 who have received at least one antihypertensive drug therapy is included. Patients were grouped into several exposure groups according to medications. COX regression model and clinical specialty survey is applied to identify Influencing Factors (IF) in different study groups, and the discriminant model was used to construct a CPR according IF. The accuracy of the CPR is analyzed by sensitivity, specificity, Youden’s index and Receiver Operating Characteristic (ROC) curve.

Discussion

Result is expected to provide valuable CPR for physicians and policymakers with respect to treating hypertension according characteristic of individual patients. By developing a predictive method for clinical outcomes and treatment costs of antihypertensive medication, we expect to discriminate those patients who would profit from specific scheme of antihypertensive drugs to minimal incidence probability of costs and complications in region of china.

Trial registration

This study was registered at www.chictr.org as a primary register of the WHO International Clinical Trials Registry Platform (ICTRP), and the registered number is ChiCTR1900026339.

Highlights

Although Clinical Prediction Rules (CPR) could recognize individual patient risk and help clinicians to make more appropriate decision at the point of medication as part of clinical decision support systems, the evidence in this respect is still limited in China.

This study is first going to construct the CPR of multiple antihypertensive drugs in real world practice of China.

The highlights of this study is aimed to provide a pragmatic method to support clinical decisions for patients who has received antihypertensive drugs before long-term diagnosis of hypertension in real world practice according to their characteristics that are accessible to clinicians.