bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrospective Use of Whole-Genome Sequencing Expands the Multicountry Outbreak Cluster of Listeria monocytogenes ST1247
Authors: Mäesaar Mihkel , Mamede Rafael , Elias Terje , Roasto Mati
Published: April 2021

Listeria monocytogenes sequence type 1247 clonal complex 8 caused a prolonged multicountry outbreak in five EU countries: Denmark, Estonia, Finland, France, and Sweden. A total of 22 disease cases were identified with onset of symptoms between July 2014 and February 2019. Five patients died due to, or with, the disease. The retrospective analysis of L. monocytogenes isolate VLTRLM2013 revealed the presence of an outbreak-related strain (cgMLST type L2-SL8-ST1247-CT4158) in ready-to-eat fish product more than a year prior to the first outbreak-related cases. Reference outbreak strain and VLTRLM2013 strain were compared using core genome and whole-genome multilocus sequence typing analyses. Genomic level differences of the persistent L. monocytogenes strains associated with a prolonged multicountry foodborne listeriosis outbreak are described. It was concluded that the persistent nature of the multicountry outbreak-related L. monocytogenes strain VLTRLM2013 together with stress island, virulence, and antibiotic resistance genes could potentially be the determining factors for the extensive and prolonged outbreak affecting five European Union countries. Our results support the systematic application of whole-genome sequencing in food and public health surveillance and further encourages its wide adoption.
Tuberculosis Drug Susceptibility, Treatment, and Outcomes for Belarusian HIV-Positive Patients with Tuberculosis: Results from a National and International Laboratory
Authors: Podlekareva Daria N. , Folkvardsen Dorte Bek , Skrahina Alena , Vassilenko Anna , Skrahin Aliaksandr , Hurevich Henadz , Klimuk Dzmitry , Karpov Igor , Lundgren Jens D. , Kirk Ole , Lillebaek Troels
Published: April 2021

Background. To cure drug-resistant (DR) tuberculosis (TB), the antituberculous treatment should be guided by Mycobacterium tuberculosis drug-susceptibility testing (DST). In this study, we compared conventional DST performed in Minsk, Belarus, a TB DR high-burden country, with extensive geno- and phenotypic analyses performed at the WHO TB Supranational Reference Laboratory in Copenhagen, Denmark, for TB/HIV coinfected patients. Subsequently, DST results were related to treatment regimen and outcome. Methods. Thirty TB/HIV coinfected patients from Minsk were included and descriptive statistics applied. Results. Based on results from Minsk, 10 (33%) TB/HIV patients had drug-sensitive TB. Two (7%) had isoniazid monoresistant TB, 8 (27%) had multidrug-resistant (MDR) TB, 5 (17%) preextensive drug-resistant (preXDR) TB, and 5 (17%) had extensive drug-resistant (XDR) TB. For the first-line drugs rifampicin and isoniazid, there was DST agreement between Minsk and Copenhagen for 90% patients. For the second-line anti-TB drugs, discrepancies were more pronounced. For 14 (47%) patients, there were disagreements for at least one drug, and 4 (13%) patients were classified as having MDR-TB in Minsk but were classified as having preXDR-TB based on DST results in Copenhagen. Initially, all patients received standard anti-TB treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol. However, this was only suitable for 40% of the patients based on DST. On average, DR-TB patients were changed to 4 (IQR 3-5) active drugs after 1.5 months (IQR 1-2). After treatment adjustment, the treatment duration was 8 months (IQR 2-11). Four (22%) patients with DR-TB received treatment for >18 months. In total, sixteen (53%) patients died during 24 months of follow-up. Conclusions. We found high concordance for rifampicin and isoniazid DST between the Minsk and Copenhagen laboratories, whereas discrepancies for second-line drugs were more pronounced. For patients with DR-TB, treatment was often insufficient and relevant adjustments delayed. This example from Minsk, Belarus, underlines two crucial points in the management of DR-TB: the urgent need for implementation of rapid molecular DSTs and availability of second-line drugs in all DR-TB high-burden settings. Carefully designed individualized treatment regimens in accordance with DST patterns will likely improve patients’ outcome and reduce transmission with drug-resistant Mycobacterium tuberculosis strains.
Multiscale Analysis of the Strength Deterioration of Loess under the Action of Drying and Wetting Cycles
Authors: Bai Yang , Ye Wanjun , Wu Yuntao , Chen Yiqian
Published: April 2021

To study the strength degradation mechanism of compacted loess during dry‐wet cycles, 0–5 dry‐wet cycles tests and many triaxial compression tests were carried out on loess with an optimal moisture content. During the dry‐wet cycles, the loess samples were analyzed by nuclear magnetic resonance and scanning electron microscopy. Studies have shown that at the macro level, with increasing numbers of wet and dry cycles and increasing cycle amplitude, the cohesive force and internal friction angle of the loess decrease, and the shear strength of the loess deteriorates significantly. At the micro level, with the number of wet and dry cycles increasing, the connection between particles changes from surface‐to‐surface contacts to point‐to‐point or point‐to‐surface contacts. The edges and corners of the particles decrease, the roundness increases, the large pores gradually decrease, the small pores gradually increase, and the fractal dimension gradually increases. In terms of microscopic view, the NMR test shows that with increasing numbers of dry‐wet cycles, the T2 peak curve increases, the curve width increases slightly, the peak area gradually increases, and the porosity increases. From the macroscopic, mesoscopic, and microscopic multiscale analysis, the structure of loess is degraded under the action of dry and wet cycles; the strength of the loess is degraded significantly after 0 to 3 cycles and then gradually stabilizes. These research results can provide a certain reference value for the management of loess collapse geological disasters in semiarid climates.
Expression of CD146 and Regenerative Cytokines by Human Placenta-Derived Mesenchymal Stromal Cells upon Expansion in Different GMP-Compliant Media
Authors: Peissert Frederik , Graf Hannah D. E. , Müller Bettina , Abruzzese Tanja , Abele Harald , Aicher Wilhelm K.
Published: April 2021

Mesenchymal stromal cells (MSCs) have been successfully employed in clinical applications. In most studies, autologous MSCs from the bone marrow (bmMSCs) were used, and others employed autologous adipose tissue-derived stromal cells (ADSCs). Recently, clinical feasibility studies provided evidence that MSCs from human term placenta (pMSCs) can be used for homologous therapy facilitating access to regenerative cells in emergency situations, when autologous cells are not available or not suitable. We therefore investigated the expression of MSC stemness marker CD146 and the expression of neuro- and myoregenerative cytokines by human pMSCs after expansion in three different media compliant with good manufacturing protocols (GMP) in comparison to pMSCs expanded in a commercial MSC expansion media. To replace xenobiotic serum in the GMP-compliant media employed in this study, either human serum, human serum plus platelet lysate (PLL), or human plasma plus PLL was used. We report that enrichment of media with PLL accelerates pMSC proliferation but reduces the expression of the stemness marker CD146 significantly, while PLL deprivation enhanced the CD146 expression. In contrast, the reduced expression of CD146 by PLL deprivation was not observed on bmMSCs. The expression of the cytokines investigated was not modulated significantly by PLL. We conclude that accelerated expansion of pMSCs in GMP-compliant media enriched by PLL reduces the expression of stemness marker CD146, but does not influence the expression of neuro- and myoregenerative cytokines.
An Implementation of Lipschitz Simple Functions in Computer Algebra System Singular
Authors: Liu Yanan , Binyamin Muhammad Ahsan , Aslam Adnan , Arshad Minahal , Fan Chengmei , Mahmood Hassan , Liu Jia-Bao
Published: April 2021

A complete classification of simple function germs with respect to Lipschitz equivalence over the field of complex numbers ℂ was given by Nguyen et al. The aim of this article is to implement a classifier in terms of easy computable invariants to compute the type of the Lipschitz simple function germs without computing the normal form in the computer algebra system Singular.
The Readability of Patient Education Materials Pertaining to Gastrointestinal Procedures
Authors: Nawaz Mohammad S. , McDermott Laura E. , Thor Savanna
Published: April 2021

Introduction. Due to the ubiquity and ease of access of Internet, patients are able to access online health information more easily than ever. The American Medical Association recommends that patient education materials be targeted at or below the 6th grade level in order to accommodate a wider audience. In this study, we evaluate the difficulty of educational materials pertaining to common GI procedures; we analyze on the readability of online education materials for colonoscopy, flexible sigmoidoscopy, and esophagogastroduodenoscopy (EGD). Methods. Google search was performed using keywords of “colonoscopy,” “sigmoidoscopy,” and “EGD” with “patient information” at the end of each search term. The texts from a total of 18 studies, 6 for each of the procedures, were then saved. Each study was also subdivided into “Introduction,” “Preparation,” “Complications,” and if available, “Alternatives.” Furthermore, medical terminology that was properly explained, proper nouns, medication names, and other copyright text were removed in order to prevent inflation of the difficulty. Five validated readability tests were used to analyze each study and subsections: Coleman-Liau, New Dale-Chall, Flesch-Kincaid, Gunning Fog, SMOG. Results. Studies on colonoscopy, flexible sigmoidoscopy, and EGD had median readability grades of 9.7, 10.2, and 11.0, respectively. Analysis of the subsections revealed that the “Alternative” subsection was the most difficult to comprehend with a readability score of 11.4, whereas the “Introduction” subsection was the easiest to comprehend with a readability score of 9.5. Conclusion. Despite modifications to the studies that improved the readability scores, patient education materials were still significantly above the recommended 6th grade level across all websites. This study emphasizes that clear and simple language is warranted in order to create information that is suitable for most patients.
Investigation on the Efficiency of Tonic Chinese Herbal Injections for Treating Dilated Cardiomyopathy Based on Bayesian Network Meta-Analysis
Authors: Wang Kaihuan , Wang Haojia , Wu Jiarui , Duan Xiaojiao , Liu Xinkui , Zhang Dan , Liu Shuyu , Ni Mengwei , Meng Ziqi , Zhang Xiaomeng
Published: April 2021

Introduction. This network meta-analysis investigated the efficacy of six tonic Chinese herbal injections (Huangqi injection, Shenfu injection, Shengmai injection, Shenmai injection, Shenqi Fuzheng injection, and Yiqifumai injection) compared to Western medicine for the treatment of the deteriorating state associated with dilated cardiomyopathy. Methods. PubMed, the Cochrane Library, Embase, the Chinese Biological Medicine Database, China National Knowledge Infrastructure, the Wanfang Database, and the Chinese Scientific Journal Database were searched from their inception to October 15, 2020, to retrieve randomized controlled trials (RCTs). Study selection and data extraction conformed to a priori criteria. The risk of bias of the included RCTs was determined, and GRADE was used to evaluate outcomes. The network meta-analysis was calculated using WinBUGS 1.4.3 and Stata 13.0 software. The clinical effective rate, left ventricular ejection fraction, 6-minute walk test, left ventricular end-diastolic dimension, heart rate, and cardiac output were deemed outcomes. All outcomes were summarized as odds ratios or mean differences with their 95% credible intervals. The ranking probability of the interventions across various outcomes was also presented. Results. Forty RCTs and 2970 patients were enrolled. Integration of the outcome results revealed that a combination of Shenfu injection and Western medicine ranked ahead of the other injections in most outcomes, especially in the clinical effective rate (OR = 0.21, 95% CI: 0.12–0.34), left ventricular ejection fraction (MD = 7.43, 95% CI: 2.41–12.38), and 6-minute walk test (MD = 50.39, 95% CI: 25.78–76.33). Shenmai injection plus Western medicine ranked ahead of the other injections in left ventricular end-diastolic dimension (69.5%) and cardiac output (60.9%). The cluster analysis suggested that Shenfu injection plus Western medicine was the most effective intervention for dilated cardiomyopathy. Conclusions. Shenfu injection plus Western medicine may be a preferable treatment in dilated cardiomyopathy. Clinicians should also consider the specific patient’s various conditions when making diagnostic decisions. Due to an insufficient network meta-analysis, more high-quality RCTs need to be implemented to support our conclusions.
Computational Fluid Dynamics Analysis of Nasal Airway Changes after Treatment with C-Expander
Authors: Xiao Wang , Liu Siling , Lu Yanqin , Lei Lei , Liu Ning , Shen Xiaoping , He Yuhong , Liu Ousheng
Published: April 2021

The use of the C-expander is an effective treatment modality for maxillary skeletal deficiencies which can cause ailments and significantly reduce life expectancy in late adolescents and young adults. However, the morphological and dynamic effects on the nasal airway have not been reported. The main goal of this study was to evaluate the nasal airway changes after the implementation of a C-expander. A sample of nine patients (8 females, 1 male, age range from 15 to 29 years) was included. The morphology parameters and nasal airway ventilation parameters of pretreatment and posttreatment were measured. All study data were normally distributed. A paired

t

-test was used to evaluate the changes before and after treatment. After expansion, the mean and standard deviation values of intercanine maxillary width (CMW) and intermolar maxillary width (MMW) increased from

35.75
±
2.48

 mm and

54.20
±
3.17

 mm to

37.87
±
2.26

 mm (

P
<
0.05

) and

56.65
±
3.10

 mm (

P
<
0.05

), respectively. The nasal cavity volume increased from

20320.00
±
3468.25

 mm3 to

23134.70
±
3918.84

 mm3 (

P
<
0.05

). The nasal pressure drop decreased from

36.34
±
3.99

 Pa to

30.70
±
3.17

 Pa (

P
<
0.05

), while the value of the maximum velocity decreased from

6.50
±
0.31

 m/s to

5.85
±
0.37

 m/s (

P
<
0.05

). Nasal resistance dropped remarkably from

0.16
±
0.14

 Pa/ml/s to

0.08
±
0.06

 Pa/ml/s (

P
<
0.05

). The use of C-expander can effectively broaden the area and volume of the nasal airway, having a positive effect in the reduction of nasal resistance and improvement of nasal airway ventilation. For patients suffering from maxillary width deficiency and respiratory disorders, a C-expander may be an alternative method to treat the disease.
Factors Influencing Utilization of HIV Testing Services among Boda‐Boda Riders in Kabarole District, Southwestern Uganda: A Cross‐Sectional Study
Authors: Ssekankya Vicent , Githaiga Stanley Kamau , Aleko Timothy , Munguciada Esther Faith , Nabakka Vivian Patience , Kyalisiima Jolly Justine , Ndyabakira Alex , Migisha Richard
Published: April 2021

Background. HIV testing is an important step for entry and linkage into HIV care. Utilization of HIV testing services among transport workers may be challenging, because of the mobile nature of their jobs. We assessed utilization of HIV testing services and identified factors influencing the utilization of HIV testing services among motorcycle taxi (boda‐boda) riders in Fort Portal Municipality, Kabarole District, Southwestern Uganda. Methods. We conducted a cross‐sectional study among boda‐boda riders, aged 18 years and above, from July 15 to July 29, 2020. We recruited participants through simple random sampling. Data were captured using a self‐administered questionnaire. Binary logistic regression was used to identify factors associated with utilization of HIV testing services. Results. Of the 315 participants who received questionnaires, 305 (97%) responded. The mean age of the participants was 32 (±7.1) years and ranged from 18 to 55 years. Of the 305 participants, 238 reported having taken an HIV test and received results in the past 12 months, for an HIV testing utilization rate of 78.0% (95% CI: 73.0–82.6%). In multivariable analysis, participants who were less likely to utilize HIV testing services were those aged ≥30 years (aOR = 0.33; 95% CI: 0.16–0.70, P = 0.004) and those who had HIV‐related stigma (aOR = 0.27; 95% CI: 0.08–0.88, P = 0.030). Participants who were more likely to utilize HIV testing services were those who knew HIV status of their primary partners (aOR = 4.23; 95% CI: 1.24–14.49, P = 0.022) and those who had good knowledge on HIV/AIDS (aOR = 3.94; 95% CI: 1.65–9.41, P = 0.002). Conclusions. Utilization of HIV testing services among the boda‐boda riders in Fort Portal Municipality, Southwestern Uganda, was high. More efforts should focus on targeting older boda‐boda riders for HIV testing, reduction of HIV‐related stigma, improving knowledge on HIV/AIDS, and encouraging communication and disclosure between partners, in order to consolidate the gains made in HIV testing services in this bridge population.
An Interactive Pain Application (MServ) Improves Postoperative Pain Management
Authors: Gordon-Williams Richard , Trigo Andreia , Bassett Paul , Williams Amanda , Cone Stephen , Lees Martin , Brandner Brigitta
Published: April 2021

Background. Most patients have moderate or severe pain after surgery. Opioids are the cornerstone of treating severe pain after surgery but cause problems when continued long after discharge. We investigated the efficacy of multifunction pain management software (MServ) in improving postoperative pain control and reducing opioid prescription at discharge. Methods. We recruited 234 patients to a prospective cohort study into sequential groups in a nonrandomised manner, one day after major thoracic or urological surgery. Group 1 received standard care (SC, n = 102), group 2 were given a multifunctional device that fed back to the nursing staff alone (DN, n = 66), and group 3 were given the same device that fed back to both the nursing staff and the acute pain team (DNPT, n = 66). Patient-reported pain scores at 24 and 48 hours and patient-reported time in severe pain, medications, and satisfaction were recorded on trial discharge. Findings. Odds of having poor pain control (>1 on 0–4 pain scale) were calculated between standard care (SC) and device groups (DN and DNPT). Patients with a device were significantly less likely to have poor pain control at 24 hours (OR 0.45, 95% CI 0.25, 0.81) and to report time in severe pain at 48 hours (OR 0.62, 95% CI 0.47–0.80). Patients with a device were three times less likely to be prescribed strong opioids on discharge (OR 0.35, 95% CI 0.13 to 0.95). Interpretation. Using an mHealth device designed for pain management, rather than standard care, reduced the incidence of poor pain control in the postoperative period and reduced opioid prescription on discharge from hospital.
Progression of Nonmotor Symptoms in Parkinson’s Disease by Sex and Motor Laterality
Authors: Kurlawala Zimple , Shadowen Paul H. , McMillan Joseph D. , Beverly Levi J , Friedland Robert P.
Published: April 2021

Nonmotor symptoms (NMS) in Parkinson’s disease (PD) can start up to a decade before motor manifestations and strongly correlate with the quality of life. Understanding patterns of NMS can provide clues to the incipient site of PD pathology. Our goal was to systematically characterize the progression of NMS in PD (n = 489), compared to healthy controls, HC (n = 241), based on the sex of the subjects and laterality of motor symptom onset. Additionally, NMS experienced at the onset of PD were also compared to subjects with scans without dopaminergic deficit, SWEDD (n = 81). The Parkinson’s Progression Markers Initiative (PPMI) database was utilized to analyze several NMS scales. NMS experienced by PD and SWEDD cohorts were significantly higher than HC and both sex and laterality influenced several NMS scales at the onset of motor symptoms. Sex Differences. PD males experienced significant worsening of sexual, urinary, sleep, and cognitive functions compared to PD females. PD females reported significantly increased thermoregulatory dysfunction and anxious mood over 7 years and significantly more constipation during the first 4 years after PD onset. Laterality Differences. At onset, PD subjects with right-sided motor predominance reported significantly higher autonomic dysfunction. Subjects with left-sided motor predominance experienced significantly more anxious mood at onset which continued as Parkinson’s progressed. In conclusion, males experienced increased NMS burden in Parkinson’s disease. Laterality of motor symptoms did not significantly influence NMS progression, except anxious mood. We analyzed NMS in a large cohort of PD patients, and these data are valuable to improve PD patients’ quality of life by therapeutically alleviating nonmotor symptoms.
Application of Rapid Rehabilitation Nursing in Perioperative Period of Laparoscopic Radical Prostatectomy for Prostate Cancer Patients
Authors: Liu Huimin , Yang Ke , Gong Fanghua , Wu Yan , Tang Sanhui
Published: April 2021

The purpose of the study is to explore the application of rapid rehabilitation nursing strategy in the perioperative period of laparoscopic radical prostatectomy for patients with prostate cancer. A total of 120 patients with prostate cancer undergoing laparoscopic radical prostatectomy were randomly divided into two groups, with 60 cases per group. The control group was given routine nursing care, and the experimental group received rapid rehabilitation nursing strategies. The stress hormone (cortisol and norepinephrine) levels, patient satisfaction, length of hospitalization, hospitalization costs, and postoperative complication were compared between the two groups before and after nursing. The serum cortisol and norepinephrine levels in the control group before nursing were similar to those in the experimental group (

P
>
0.05

). The stress hormone levels in the experimental group were lower than those in the control group (

P
<
0.05

). It was found that the experimental group had reduced operation time, less intraoperative blood loss, shortened exhaust time, and hospitalization stay and was earlier to eat and to get out of bed than the control group (

P
<
0.05

). The time for the patients in the experimental group to pull out the drainage tube was significantly shorter than that of the control group (

P
<
0.05

), and the hospitalization costs were fewer than the control group (

P
<
0.05

). The rates of postoperative complications including nausea, vomiting, bleeding, and fever in the experimental group were significantly lower than those in the control group (

P
<
0.05

). In conclusion, the study suggests that rapid rehabilitation nursing strategies can reduce the stress hormone levels, shorten the length of hospitalization, reduce hospitalization costs, reduce postoperative complication rates, and improve patient satisfaction for prostate cancer patients undergoing laparoscopic radical prostatectomy, in support of clinical application.
Patient Experience of Interpersonal Processes of Care and Subsequent Utilization of Hormone Therapy for Non-Metastatic Breast Cancer
Authors: Poon BY , Kroenke CH , Hillyer GC , Lamerato LE , Stewart AL , Neugut AI , Hershman DL , Kushi LH
Published: April 2021

Purpose: We examined the association between patient experience of care and utilization of hormone therapy (HT) in the treatment of non-metastatic hormone-receptor positive (HR+) breast cancer. Methods: Patients newly diagnosed with non-metastatic breast cancer were recruited from 2006 to 2010 for a longitudinal multisite cohort study in New York, NY, Detroit, MI, and Northern California. Of 1,145 patients surveyed, 797 had HR+ tumors eligible for HT and all necessary data. We assessed patient experience 4 to 8 weeks after recruitment using 6 subscales of the Interpersonal Processes of Care (IPC) survey: compassion, discrimination, and hurriedness in communication, as well as concern elicitation, result explanation, and patient-centered decision-making. Subscales ranged from 1 to 5 where higher values indicated better experiences. HT for 5 years is standard care for HR+ breast cancer so utilization was defined as time from diagnosis to HT initiation and time from HT initiation to early discontinuation before 5 years as calculated from follow-up survey responses. We evaluated the relationship between patient experience and utilization using Cox proportional hazard models, controlling for education, income, insurance, marital status, social support, site of care, age at diagnosis, stage, grade, tumor size, Charlson comorbidity index, and chemotherapy. Results: Median age at diagnosis was 59 years (interquartile range 51–66) with the majority diagnosed at clinical stage 1 (54%) and with low or moderate grade disease (78%). Less hurried communication was associated with increased probability of HT initiation (Hazards Ratio (HR) 1.15; 95% Confidence Interval (CI) 1.03, 1.30; p = 0.018). Conversely, more patient-centered decision-making was associated with increased probability of early discontinuation (HR 1.29; CI, 1.03, 1.63; p = 0.028). All other associations were null. Conclusion: While unhurried communication was associated with initiation of hormone therapy, patient-centered decision-making was associated with early discontinuation. Different aspects of patient experience may have vastly different relationships with patient utilization of health services. Actionable assessments of patient experience may require measurement along multiple dimensions.
Recommending Inequality? Patterns of US Healthcare Providers' HPV Vaccine Recommendations
Authors: Kong WY , Bustamante G , Margolis M , McRee AL , Pallotto IK , Gilkey MB
Published: April 2021

Purpose: Infrequent provider recommendations continue to be a key barrier to human papillomavirus (HPV) vaccination, including among adolescents at higher risk for future HPV cancers. To inform future provider- training programs, our study sought to synthesize the findings of existing studies of disparities in provider recommendation of HPV vaccination among adolescents. Methods: We conducted a systematic review of studies that quantitatively assessed the prevalence of provider recommendation of HPV vaccination among US parents of adolescents aged 9–17. We excluded studies that were not empirical, not peer-reviewed, or collected data before 2012. Following PRISMA guidelines, two independent coders extracted and screened 3,158 unique titles and abstracts from multiple databases. Next, two independent coders reviewed the full text of eligible studies, systematically collecting data using a standardized abstraction form. We resolved coding disagreements via discussion with the whole team. Results: Fifty-four of 252 reviewed studies met eligibility criteria, including 33 studies of parents and 21 studies of providers. Parental report of receiving a provider recommendation for HPV vaccination ranged from 22% to 78%. These studies most often assessed disparities by adolescents' sex, with almost all finding that provider recommendations were less common for boys vs. girls. Most studies of provider reports confirmed disparate recommendations by sex. Fewer studies stratified recommendation disparities by income or race/ethnicity; these studies found that recommendations were less common among lower-income households, but reported mixed findings by race/ethnicity. Geographic assessments found variation across states and urbanicity, with recommendations being lower including in some Southern states and in rural areas. Conclusion: Findings suggest differences in provider recommendation by sex, household income, geography, and possibly race/ethnicity, in spite of national guidelines for routine HPV vaccination. National efforts to improve provider communication about HPV vaccination should focus on improving recommendation consistency, especially for populations such as lower-income and rural adolescents who are at higher risk for future HPV cancers.
Pilot Clinical Trial of Perioperative Durvalumab and Tremelimumab in the Treatment of Resectable Colorectal Cancer Liver Metastases
Authors: Kanikarla Marie Preeti , Haymaker Cara , Parra Edwin Roger , Kim Young Uk , Lazcano Rossana , Gite Swati , Lorenzini Daniele , Wistuba Ignacio I. , Tidwell Rebecca S. Slack , Song Xiaofei , Foo Wai Chin , Maru Dipen M. , Chun Yun Shin , Futreal Andy , Kee Bryan , Menter David , Solis Luisa , Tzeng Ching-Wei , Parseghian Christine , Raghav Kanwal , Morris Van , Chang Chia-Chi , Jenq Robert , Tam Alda , Bernatchez Chantale , Kopetz Scott , Vauthey Jean-Nicolas , Overman Michael J.
Published: April 2021

Purpose:

Despite the prognostic importance of immune infiltrate in colorectal cancer, immunotherapy has demonstrated limited clinical activity in refractory metastatic proficient mismatch-repair (pMMR) colorectal cancer. This study explores combining anti–CTLA-4 and an anti–PD-L1 therapy in the preoperative management of resectable colorectal cancer liver metastases with the intent to improve immune responses in this disease setting.

Patients and Methods:

Patients with resectable colorectal cancer liver-only metastases received one dose of tremelimumab and durvalumab preoperatively followed by single-agent durvalumab postoperatively. Primary objectives were to determine feasibility and safety.

Results:

A total of 24 patients were enrolled between November 2016 and November 2019. Twenty-three patients received treatment [21 pMMR and 2 deficient mismatch-repair (dMMR)] and subsequently 17 (74%; 95% CI: 53%–88%) underwent surgical resection. Grade 3/4 treatment-related immune toxicity and postoperative grade 3/4 toxicity were seen in 5/23 (22%; 95% CI: 10%–44%) and 2/17 (12%; 95% CI: 2%–38%) patients. The median relapse-free survival (RFS) was 9.7 (95% CI: 8.1–17.8) months, and overall survival was 24.5 (95% CI: 16.5–28.4) months. Four patients demonstrated complete pathologic response, two dMMR patients and two POLE mutation patients. Pre- and post-tumor tissue analysis by flow cytometry, immunofluorescence, and RNA sequencing revealed similar levels of T-cell infiltration, but did demonstrate evidence of CD8+ and CD4+ activation posttreatment. An increase in B-cell transcriptome signature and B-cell density was present in posttreatment samples from patients with prolonged RFS.

Conclusions:

This study demonstrates the safety of neoadjuvant combination tremelimumab and durvalumab prior to colorectal cancer liver resection. Evidence for T- and B-cell activation following this therapy was seen in pMMR metastatic colorectal cancer.
Autophagy-Dependent Sensitization of Triple-Negative Breast Cancer Models to Topoisomerase II Poisons by Inhibition of the Nucleosome Remodeling Factor
Authors: Tyutyunyk-Massey Liliya , Sun Yilun , Dao Nga , Ngo Hannah , Dammalapati Mallika , Vaidyanathan Ashish , Singh Manjulata , Haqqani Syed , Haueis Joshua , Finnegan Ryan , Deng Xiaoyan , Kirberger Steve E. , Bos Paula D. , Bandyopadhyay Dipankar , Pomerantz William C.K. , Pommier Yves , Gewirtz David A. , Landry Joseph W.
Published: April 2021

Epigenetic regulators can modulate the effects of cancer therapeutics. To further these observations, we discovered that the bromodomain PHD finger transcription factor subunit (BPTF) of the nucleosome remodeling factor (NURF) promotes resistance to doxorubicin, etoposide, and paclitaxel in the 4T1 breast tumor cell line. BPTF functions in promoting resistance to doxorubicin and etoposide, but not paclitaxel, and may be selective to cancer cells, as a similar effect was not observed in embryonic stem cells. Sensitization to doxorubicin and etoposide with BPTF knockdown (KD) was associated with increased DNA damage, topoisomerase II (TOP2) crosslinking and autophagy; however, there was only a modest increase in apoptosis and no increase in senescence. Sensitization to doxorubicin was confirmed in vivo with the syngeneic 4T1 breast tumor model using both genetic and pharmacologic inhibition of BPTF. The effects of BPTF inhibition in vivo are autophagy dependent, based on genetic autophagy inhibition. Finally, treatment of 4T1, 66cl4, 4T07, MDA-MB-231, but not ER-positive 67NR and MCF7 breast cancer cells with the selective BPTF bromodomain inhibitor, AU1, recapitulates genetic BPTF inhibition, including in vitro sensitization to doxorubicin, increased TOP2-DNA crosslinks and DNA damage. Taken together, these studies demonstrate that BPTF provides resistance to the antitumor activity of TOP2 poisons, preventing the resolution of TOP2 crosslinking and associated autophagy. These studies suggest that BPTF can be targeted with small-molecule inhibitors to enhance the effectiveness of TOP2-targeted cancer chemotherapeutic drugs.

Implications:

These studies suggest NURF can be inhibited pharmacologically as a viable strategy to improve chemotherapy effectiveness.
Radiomics Biomarkers Correlate with CD8 Expression and Predict Immune Signatures in Melanoma Patients
Authors: Aoude Lauren G. , Wong Bernadette Z.Y. , Bonazzi Vanessa F. , Brosda Sandra , Walters Shaun B. , Koufariotis Lambros T. , Naeini Marjan M. , Pearson John V. , Oey Harald , Patel Kalpana , Bradford Julia J. , Bloxham Conor J. , Atkinson Victoria , Law Phillip , Strutton Geoffrey , Bayley Gerard , Yang Samuel , Smithers B. Mark , Waddell Nicola , Miles Kenneth , Barbour Andrew P.
Published: April 2021

Treatment for metastatic melanoma includes targeted and/or immunotherapy. Although many patients respond, only a subset has complete response. As late-stage patients often have multiple tumors in difficult access sites, non-invasive techniques are necessary for the development of predictive/prognostic biomarkers. PET/CT scans from 52 patients with stage III/IV melanoma were assessed and CT image parameters were evaluated as prognostic biomarkers. Analysis indicated patients with high standard deviation or high mean of positive pixels (MPP) had worse progression-free survival (P = 0.00047 and P = 0.0014, respectively) and worse overall survival (P = 0.0223 and P = 0.0465, respectively). Whole-exome sequencing showed high MPP was associated with BRAF mutation status (P = 0.0389). RNA-sequencing indicated patients with immune “cold” signatures had worse survival, which was associated with CT biomarker, MPP4 (P = 0.0284). Multiplex immunofluorescence confirmed a correlation between CD8 expression and image biomarkers (P = 0.0028).

Implications:

CT parameters have the potential to be cost-effective biomarkers of survival in melanoma, and reflect the tumor immune-microenvironment.
Splicing Patterns in SF3B1-Mutated Uveal Melanoma Generate Shared Immunogenic Tumor-Specific Neoepitopes
Authors: Bigot Jeremy , Lalanne Ana I. , Lucibello Francesca , Gueguen Paul , Houy Alexandre , Dayot Stephane , Ganier Olivier , Gilet Jules , Tosello Jimena , Nemati Fariba , Pierron Gaelle , Waterfall Joshua J. , Barnhill Raymond , Gardrat Sophie , Piperno-Neumann Sophie , Popova Tatiana , Masson Vanessa , Loew Damarys , Mariani Pascale , Cassoux Nathalie , Amigorena Sebastian , Rodrigues Manuel , Alsafadi Samar , Stern Marc-Henri , Lantz Olivier
Published: April 2021

Disruption of splicing patterns due to mutations of genes coding splicing factors in tumors represents a potential source of tumor neoantigens, which would be both public (shared between patients) and tumor-specific (not expressed in normal tissues). In this study, we show that mutations of the splicing factor SF3B1 in uveal melanoma generate such immunogenic neoantigens. Memory CD8+ T cells specific for these neoantigens are preferentially found in 20% of patients with uveal melanoma bearing SF3B1-mutated tumors. Single-cell analyses of neoepitope-specific T cells from the blood identified large clonal T-cell expansions, with distinct effector transcription patterns. Some of these expanded T-cell receptors are also present in the corresponding tumors. CD8+ T-cell clones specific for the neoepitopes specifically recognize and kill SF3B1-mutated tumor cells, supporting the use of this new family of neoantigens as therapeutic targets.

Significance:

Mutations of the splicing factor SF3B1 in uveal melanoma generate shared neoantigens that are uniquely expressed by tumor cells, leading to recognition and killing by specific CD8 T cells. Mutations in splicing factors can be sources of new therapeutic strategies applicable to diverse tumors.

This article is highlighted in the In This Issue feature, p. 1861
Development of Immunotherapy Combination Strategies in Cancer
Authors: Yap Timothy A. , Parkes Eileen E. , Peng Weiyi , Moyers Justin T. , Curran Michael A. , Tawbi Hussein A.
Published: April 2021

Harnessing the immune system to treat cancer through inhibitors of CTLA4 and PD-L1 has revolutionized the landscape of cancer. Rational combination strategies aim to enhance the antitumor effects of immunotherapies, but require a deep understanding of the mechanistic underpinnings of the immune system and robust preclinical and clinical drug development strategies. We review the current approved immunotherapy combinations, before discussing promising combinatorial approaches in clinical trials and detailing innovative preclinical model systems being used to develop rational combinations. We also discuss the promise of high-order immunotherapy combinations, as well as novel biomarker and combinatorial trial strategies.

Significance:

Although immune-checkpoint inhibitors are approved as dual checkpoint strategies, and in combination with cytotoxic chemotherapy and angiogenesis inhibitors for multiple cancers, patient benefit remains limited. Innovative approaches are required to guide the development of novel immunotherapy combinations, ranging from improvements in preclinical tumor model systems to biomarker-driven trial strategies.
Tracking Cancer Evolution through the Disease Course
Authors: Bailey Chris , Black James R.M. , Reading James L. , Litchfield Kevin , Turajlic Samra , McGranahan Nicholas , Jamal-Hanjani Mariam , Swanton Charles
Published: April 2021

During cancer evolution, constituent tumor cells compete under dynamic selection pressures. Phenotypic variation can be observed as intratumor heterogeneity, which is propagated by genome instability leading to mutations, somatic copy-number alterations, and epigenomic changes. TRACERx was set up in 2014 to observe the relationship between intratumor heterogeneity and patient outcome. By integrating multiregion sequencing of primary tumors with longitudinal sampling of a prospectively recruited patient cohort, cancer evolution can be tracked from early- to late-stage disease and through therapy. Here we review some of the key features of the studies and look to the future of the field.

Significance:

Cancers evolve and adapt to environmental challenges such as immune surveillance and treatment pressures. The TRACERx studies track cancer evolution in a clinical setting, through primary disease to recurrence. Through multiregion and longitudinal sampling, evolutionary processes have been detailed in the tumor and the immune microenvironment in non–small cell lung cancer and clear-cell renal cell carcinoma. TRACERx has revealed the potential therapeutic utility of targeting clonal neoantigens and ctDNA detection in the adjuvant setting as a minimal residual disease detection tool primed for translation into clinical trials.
Overcoming Resistance to Tumor-Targeted and Immune-Targeted Therapies
Authors: Aldea Mihaela , Andre Fabrice , Marabelle Aurelien , Dogan Semih , Barlesi Fabrice , Soria Jean-Charles
Published: April 2021

Resistance to anticancer therapies includes primary resistance, usually related to lack of target dependency or presence of additional targets, and secondary resistance, mostly driven by adaptation of the cancer cell to the selection pressure of treatment. Resistance to targeted therapy is frequently acquired, driven by on-target, bypass alterations, or cellular plasticity. Resistance to immunotherapy is often primary, orchestrated by sophisticated tumor–host–microenvironment interactions, but could also occur after initial efficacy, mostly when only partial responses are obtained. Here, we provide an overview of resistance to tumor and immune-targeted therapies and discuss challenges of overcoming resistance, and current and future directions of development.

Significance:

A better and earlier identification of cancer-resistance mechanisms could avoid the use of ineffective drugs in patients not responding to therapy and provide the rationale for the administration of personalized drug associations. A clear description of the molecular interplayers is a prerequisite to the development of novel and dedicated anticancer drugs. Finally, the implementation of such cancer molecular and immunologic explorations in prospective clinical trials could de-risk the demonstration of more effective anticancer strategies in randomized registration trials, and bring us closer to the promise of cure.
The Next Decade of Immune Checkpoint Therapy
Authors: Sharma Padmanee , Siddiqui Bilal A. , Anandhan Swetha , Yadav Shalini S. , Subudhi Sumit K. , Gao Jianjun , Goswami Sangeeta , Allison James P.
Published: April 2021

Immune checkpoint therapy (ICT) can provide durable clinical responses and improve overall survival. However, only subsets of patients with specific tumor types respond to ICT. Thus, significant challenges remain, including understanding pathways of resistance, optimizing patient selection, improving management of immune-related adverse events, and identifying rational therapeutic combinations. These challenges will need a focused approach encompassing both clinical and basic research, with the integration of reverse translational studies. This integrated approach will lead to identification of potential targets for subsequent clinical trials, which will guide decisions as we develop novel combination strategies to maximize efficacy and minimize toxicities for patients.

Significance:

ICTs induce durable antitumor responses for subsets of patients with cancer. Recent evidence suggests that rational combinatorial strategies can improve response by overcoming primary and adaptive resistance mechanisms, although these may carry an increased risk of immune-mediated toxicities. This review surveys the current understanding of mechanisms of response and resistance to ICTs and active areas of investigation, and proposes a path forward to improving efficacy and minimizing toxicities through better patient selection and rational combinations.
The Promising Evolution of Targeted Therapeutic Strategies in Cancer
Authors: Peters Solange , Mok Tony , Passaro Antonio , Jänne Pasi Antero
Published: April 2021

The upcoming decade of precision medicine for cancer is moving from the translation of specific genetic findings into clinically relevant improvement to the qualitative analyses of the genomic and immune tumor microenvironment, for an integrated treatment strategy in both metastatic and early disease.
Treatment Decisions for Patients with Cancer during the COVID-19 Pandemic
Authors: Labaki Chris , Peters Solange , Choueiri Toni K.
Published: April 2021

Patients with cancer have been disproportionally affected by the COVID-19 pandemic, with high rates of severe outcomes and death. Similarly, treatment decisions in this vulnerable population have been altered to a major degree during the past year, with significant disruption of care reported. Although complex, therapeutic choices in patients with cancer in times of COVID-19 are critical, as they may save thousands of lives. A mounting body of evidence, in addition to clear recommendations by multiple international societies, can help oncologists decide appropriately the necessity to administer antineoplastic regimens, helping to avoid a surge in cancer-related deaths in the upcoming months.
Genomics and Cancer Disparities: The Justice and Power of Inclusion
Authors: Davis Melissa B.
Published: April 2021

Advances in genomic science have transformed our ability to interrogate cancer, revealing biases that drive disparities in minority populations. Cancer disparities research engages diverse ethnic group inclusion as a matter of rigor, to address underrepresentation in genomic data sources, and has led to groundbreaking work, enhancing our understanding of tumor biology.
ВІДНОВЛЕННЯ МІКРОБІОМУ ВАГІНИ ПРИ БАКТЕРІЙНОМУ ВАГІНОЗІ ІЗ ЗАСТОСУВАННЯМ ПРОБІОТИКА ДІАЛАК
Authors: Mykhaylyshyn H. I. , Klуmnyuk S. І. , Spivak M. Y. , Lazarenko L. M. , Malanchuk L. M. , Korda I. V.
Published: April 2021

Наведено результати дослідження мікробіому піхви осіб з бактерійним вагінозом до і після перорального застосування капсульної форми та вагінальних супозиторіїв пробіотика «Діалак» з вмістом штаму L. casei IMB B-7280. Цей препарат, який рекомендовано для корекції вагінальної мікробіоти, має комбіновану протизапальну та вибіркову протимікробну активність. Він має широкий спектр антагоністичної активності відносно умовно-патогенних мікроорганізмів: стафілококів, стрептококів, псевдомонад, кишкової палички тощо, ефективно пригнічує ріст грибів.
Мета дослідження – оцінити ефективність застосування пробіотика «Діалак» у жінок із бактерійним вагінозом.
Пацієнти і методи. При обстеженні жінок із бактерійним вагінозом проводився традиційний гінекологічний огляд з метою визначення загальних анамнестичних даних, зокрема з’ясування частоти, тяжкості клінічних проявів та тривалості рецидивів урогенітальної інфекції. Лабораторні методи діагностики включали мікроскопію мазків для виявлення ключових клітин, амінотест, рН виділень, класичне бактеріологічне дослідження піхвового вмісту до початку лікування та на 10-й день після завершення лікування. Проводили забір периферичної крові до лікування та через 1 міс. після пробіотикотерапії для вивчення клітинного імунітету.
Результати. Проведені дослідження свідчать, що при вагінальному та пероральному застосуванні пробіотика «Діалак» відбувається стабільне заселення слизових оболонок піхви власною мікробіотою. Клінічно доведено ефективність дії препарату проти гарднерел, мобілункуса, лактококів і вейлонел.
Висновок. Доцільність застосування пробіотика «Діалак» з вмістом штаму L. casei IMB B-7280 для лікування хворих з бактерійним вагінозом доведена клінічно. Гарна переносність біопрепарату, відсутність побічної дії, відновлення лактофлори, зручна форма використання обґрунтовують його призначення в акушерстві та гінекології для лікування хворих на бактерійні вагінози.
СУЧАСНІ АСПЕКТИ ПРОБЛЕМИ ТОКСОКАРОЗУ
Authors: Prokopiv O. V. , Sehediy L. I.
Published: April 2021

Мета роботи – проаналізувати випадки токсо­карозу у дітей з урахуванням особливостей його перебігу й даних параклінічних досліджень.
Матеріали і методи. Спостерігали 8 дітей віком 3,5-10 років з вісцеральною (6) та субклінічною (2) формами токсокарозу. Проводилось комплексне обстеження, що включало дані епіданамнезу, клінічні, загальноприйняті лабораторні, біохімічні, імунологічні (виявлення антитіл IgG до Toxocara canis у сироватці крові), інструментальні (КТ органів грудної порожнини, УЗД внутрішніх органів) методи дослідження.
Результати. Висвітлені й узагальнені літературні дані, що стосуються захворюваності, особливостей клінічного перебігу та лікування токсокарозу у дітей, причетності Tocsocara canis до виникнення абортів у вагітних, передчасних пологів і безпліддя. Описані клінічні випадки вісцерального токсокарозу у дітей та труднощі діагностики, пов’язані з розмаїттям клінічних проявів хвороби. У клінічній картині домінують неврологічні симптоми та порушення з боку бронхолегеневої системи.
Висновки. Лише настороженість щодо токсокарозу та проведення цілеспрямованих методів досліджень дають змогу діагностувати це захворювання, насамперед у дітей з бронхолегеневим і судомним синдромами. З профілактичних заходів суттєве значення належить санітарно-освітній роботі, скерованій на проведення паразитологічних досліджень собак і котів для виявлення токсокарозу.