bluuebunny/crossref_metadata_2025_split huggingface dataset:
5-Fluorouracil With Microneedling Modulates Wound Healing in a Murine Model: An Immunohistochemical Analysis of Mechanism and Dose Efficacy
Authors: Homer Natalie A. , Hanafy Mahmoud S. , Baer Susan C. , Watson Alison H. , Somogyi Marie , Shore John W. , Blaydon Sean , Durairaj Vikram D. , Cui Zhengrong , Nakra Tanuj 
Published: May 2022

Purpose:
The purpose of this study is to assess the dose-dependent immunohistopathological effects of intradermal microneedle-delivered 5-fluorouracil (5-FU) for postincisional wound healing in a murine model.

Methods:
A prospective experimental study was performed. Twelve hairless mice were randomized into 4 treatment groups for postincisional wound treatment: microneedling with topical saline, or microneeding with topically-applied 5-FU at concentrations of 25 mg/ml, 50 mg/ml, or 100 mg/ml. Two surgical wounds were created on each animal. Combination wound treatments were performed on postoperative days 14 and 28, and cutaneous biopsies were obtained on day 56. Specimens were analyzed by a dermatopathologist, blinded to the treatment group, for collagen thickness, lymphocytic infiltration, histiocytic response, sub-epidermal basement membrane zone thickness, and myofibroblast density.

Results:
Histopathologic evaluation showed increased collagen thickness, lymphocyte infiltration, and granuloma density in the groups undergoing microneedling treatment with 5-FU, compared to saline. Immunohistochemical analysis revealed a trend toward thicker basement membranes with higher concentrations of 5-FU used, reaching statistical significance between controls and those treated with 100 mg/ml 5-FU (p = 0.0493). A trend toward decreasing myofibroblast density with increasing doses of 5-FU was noted. No postincisional or treatment complications were observed.

Conclusions:
Our results demonstrate that microneedling is an effective topical subepithelial drug delivery system, and further suggest a beneficial dose-dependent immunomodulatory effect of 5-FU on intermediate wound healing when used in combination with microneedling. We recommend a 5-FU dose at the mid-range 50 mg/ml concentration to simultaneously maximize efficacy and minimize complication risk.
Randomized controlled trial of the significance of combined use with Ninjin’yoeito in CapeOX + Bmab therapy for patients with unresectable advanced/recurrent colorectal cancer
Authors: Motoo Yoshiharu , Shinozaki Katsunori , Takagi Tsuyoshi , Ito Shingo , Fujita Hideto , Munemoto Yoshinori , Yoshida Naohisa , Baba Eishi , Shindo Yoshiaki , Nishiuchi Takamasa , Miura Masatomo , Morita Satoshi , Tsuji Akihito 
Published: May 2022

Abstract

Background:
This randomized controlled trial is aimed at clarifying the benefit of an extract of ninjin’yoeito (NYT, traditional Japanese herbal medicine, Kampo) when combined with capecitabine plus oxaliplatin (CapeOX) plus bevacizumab (Bmab) in 150 patients with metastatic or recurrent colorectal cancer with special reference to nutritional status.

Methods/Design:
Patients with unresectable, metastatic, or recurrent colorectal cancer who plan to receive CapeOX + Bmab will be recruited. Of these patients, those who provide written informed consent will be randomly allocated to the NYT group (NYT + CapeOX + Bmab) or the control group (CapeOX + Bmab). The co-primary endpoints will be nutritional status, evaluated with CONtrolling NUTritional Status scores, and severe non-hematological adverse events, assessed using the Common Terminology Criteria for Adverse Events v5.0. The secondary endpoints will include the interaction between NYT and capecitabine; quality of life evaluated using the European Organization for Research and Treatment of Cancer-QLQ-C30; relative dose intensity of oxaliplatin, capecitabine, and bevacizumab; and plasma levels of phosphorylated neurofilament heavy chain. The two groups will include 75 patients each, and the patient recruitment period is January 1st, 2020 to December 31st, 2022.

Discussion:
This trial evaluates the efficacy and safety of NYT in the maintenance of a better nutritional status and fewer adverse events during the standard chemotherapeutic regimen of CapeOX + Bmab administered to patients with advanced or recurrent colorectal cancer. The potential implications include that NYT could be a strong supportive therapy in patients with colorectal cancer receiving chemotherapy.

Trial registration number:
This study was registered in the Japan Registry of Clinical Trials (registration number: jRCTs041190071) on October 2, 2019.
CD133 increases oxidative glucose metabolism of HT29 cancer cells by mitochondrial uncoupling and its inhibition enhances reactive oxygen species-inducing therapy
Authors: Lee Jin Hee , Lee Eun Ji , Park Jin Won , Kim Mina , Jung Kyung-Ho , Cho Young Seok , Lee Kyung-Han 
Published: May 2022

Objective
A better understanding of the metabolic phenotype of stem-like cancer cells could provide targets to help overcome chemoresistance. In this study, we hypothesized that colon cancer cells with the stem cell feature of CD133 expression have increased proton leakage that influences glucose metabolism and offers protection against reactive oxygen species (ROS)-inducing treatment.

Methods and Results
In HT29 colon cancer cells, 18F-fluorodeoxyglucose (FDG) uptake was increased by CD133 selection and decreased by CD133 silencing. In CD133(+) cells, greater 18F-FDG uptake was accompanied by increased oxygen consumption rate (OCR) and reduced mitochondrial membrane potential and mitochondrial ROS, indicating increased proton leakage. The uncoupling protein inhibitor genipin reversed the increased 18F-FDG uptake and greater OCR of CD133(+) cells. The ROS-inducing drug, piperlongumine, suppressed CD133(−) cell survival by stimulating mitochondrial ROS generation but was unable to influence CD133(+) cells when used alone. However, cotreatment of CD133(+) cells with genipin and piperlongumine efficiently stimulated mitochondrial ROS for an enhanced antitumor effect with substantially reduced CD133 expression.

Conclusion
These results demonstrate that mitochondrial uncoupling is a metabolic feature of CD133(+) colon cancer cells that provides protection against piperlongumine therapy by suppressing mitochondrial ROS generation. Hence, combining genipin with ROS-inducing treatment may be an effective strategy to reverse the metabolic feature and eliminate stem-like colon cancer cells.
Geospatial Analysis of Social Determinants of Health Identifies Neighborhood Hot Spots Associated With Pediatric Intensive Care Use for Acute Respiratory Failure Requiring Mechanical Ventilation*
Authors: Najjar Nadine , Opolka Cydney , Fitzpatrick Anne M. , Grunwell Jocelyn R. 
Published: May 2022

OBJECTIVES:
Poverty, racial bias, and disparities are linked to adverse health outcomes for children in the United States. The social vulnerability and child opportunity indices are composite measures of the social, economic, education, health, and environmental qualities that affect human health for every U.S. census tract. Composite measures of social vulnerability and child opportunity were compared for neighborhood hot spots, where PICU admissions for acute respiratory failure requiring invasive mechanical ventilation were at the 90th percentile or greater per 1,000 children, versus non-hot spots.

DESIGN:
Population-based ecological study.

SETTING:
Two urban free-standing children’s hospital PICUs consisting of a 36-bed quaternary academic and a 56-bed tertiary community center, in Atlanta, GA.

PATIENTS:
Mechanically ventilated children who were 17 years of age or younger with a geocodable Georgia residential address admitted to a PICU for at least 1 day.

INTERVENTIONS:
None.

MEASUREMENTS AND MAIN RESULTS:
Residential addresses were geocoded and spatially joined to census tracts. Composite measures of social vulnerability and childhood opportunity, PICU readmission rates, and hospital length of stay were compared between neighborhood hot spots versus non-hot spots. There were 340 of 3,514 children (9.7%) who lived within a hot spot. Hot spots were associated with a higher (worse) composite social vulnerability index ranking, reflecting differences in socioeconomic status, household composition and disability, and housing type and transportation. Hot spots also had a lower (worse) composite childhood opportunity index percentile ranking, reflecting differences in the education, health and environment, and social and economic domains. Higher social vulnerability and lower childhood opportunity were not associated with readmission rates but were associated with longer total median duration of hospital days per 1,000 children in a census tract.

CONCLUSIONS:
Social determinants of health identified by geospatial analyses are associated with acute respiratory failure requiring invasive mechanical ventilation in critically ill children. Interventions addressing the neighborhood social vulnerability and child opportunity are needed to decrease disparities in intensive care admissions for acute respiratory failure requiring mechanical ventilation.
The National Disaster Medical System and military combat readiness: A scoping review
Authors: Lee Clark J. , Allard Rhonda J. , Adeniji Adeteju A. , Quintanilla Norma , Kirsch Thomas D. 
Published: May 2022

ABSTRACT
A scoping review was conducted to describe the history of the National Disaster Medical System (NDMS) in the context of US military medical preparedness for a large-scale overseas military conflict. National Disaster Medical System civilian hospitals would serve as backups to military treatment facilities if both US Department of Defense and US Department of Veterans Affairs hospitals reached capacity during such a conflict. Systematic searches were used to identify published works discussing the NDMS in the scientific and gray literature. Results were limited to publicly available unclassified English language works from 1978 to January 2022; no other restrictions were placed on the types of published works. Full-text reviews were conducted on identified works (except student papers and dissertations) to determine the extent to which they addressed NDMS definitive care. Data charting was performed on a final set of papers to assess how these works addressed NDMS definitive care. The search identified 54 works published between 1984 and 2022. More than half of the publications were simple descriptions of the NDMS (n = 30 [56%]), and most were published in academic or professional journals (n = 38 [70%]). Only nine constituted original research. There were recurrent criticisms of and recommendations for improving the definitive care component of the NDMS. The lack of published literature on NDMS definitive care supports the assertion that the present-day NDMS may lack the capacity and military-civilian interoperability necessary to manage the casualties resulting from a large-scale overseas military conflict.
Estimating the distribution of COVID-19-susceptible, -recovered, and -vaccinated individuals in Germany up to April 2022
Authors: Maier Benjamin F. , Rose Annika H. , Burdinski Angelique , Klamser Pascal , Neuhauser Hannelore , Wichmann Ole , Schaade Lars , Wieler Lothar H. , Brockmann Dirk 
Published: May 2022

AbstractAfter having affected the population for two years, the COVID-19 pandemic has reached a phase where a considerable number of people in Germany have been either infected with a SARS-CoV-2 variant, vaccinated, or both. Yet the full extent to which the population has been in contact with either virus or vaccine remains elusive, particularly on a regional level, because (a) infection counts suffer from under-reporting, and (b) the overlap between the vaccinated and recovered subpopulations is unknown. Since previous infection, vaccination, or especially a combination of both reduce the risk of severe disease, a high share of individuals with SARS-CoV-2 immunity lowers the probability of severe outbreaks that could potentially overburden the public health system once again, given that emerging variants do not escape this reduction in susceptibility. Here, we estimate the share of immunologically naïve individuals by age group for each of the 16 German federal states by integrating an infectious disease model based on weekly incidences of SARS-CoV-2 infections in the national surveillance system and vaccine uptake, as well as assumptions regarding under-ascertainment. We estimate a median share of 7.0% of individuals in the German population have neither been in contact with vaccine nor any variant as of March 31, 2022 (quartile range [3.6%– 9.8%]). For the adult population at higher risk of severe disease, this figure is reduced to 3.5% [1.3%–5.5%] for ages 18–59 and 4.3% [2.7%–5.8%] for ages 60 and above. However, estimates vary between German states mostly due to heterogeneous vaccine uptake. Excluding Omicron infections from the analysis, 16.1% [14.0%–17.8%] of the population in Germany, across all ages, are estimated to be immunologically naïve, highlighting the large impact the Omicron wave had until the beginning of spring in 2022.
Ribavirin antiviral combination therapy in COVID 19, a single-center experience
Authors: Singh Budha O , Chikara Gaurav , Panda Prasan Kumar , Bahurupi Yogesh Arvind , Saha Sarama , Pai Venkatesh S. 
Published: May 2022

AbstractBackgroundCOVID 19 infection has a similar clinical spectrum of disease presentation such as SARS and MERS in the past. These led to the assumption of the possibility to treat COVID 19 infection with antivirals which had been used to treat SARS and MERS.MethodsA retrospective analysis was done on the data of SEV COVID Trial in symptomatic adult patients of COVID 19 infection with objectives to explore whether ribavirin antiviral combinations reduces the need of both noninvasive and invasive ventilators in treatment of COVID 19 infections.ResultsThe patients were categorized as “Cohort A” consisting of 40 patients and “Cohort B” of 61 patients as Cohort A being the group of patients who received the standard therapy and Cohort B the group of patients who received the ribavirin combination therapy.ConclusionThe study concluded that there was no statistically significant difference in regard to the need of noninvasive ventilation and invasive ventilation and also the development of multi-organ dysfunction in between the two Cohorts. Also, with progress of time, the proportion of patients with single organ dysfunctions in the two cohorts showed gradual recovery without any statistically significant differences.
Log-order improved in trans hammerhead ribozyme turnover rates: reevaluating therapeutic space for small catalytic RNAs
Authors: Myers Jason M. , Sullivan Jack M. 
Published: May 2022

ABSTRACTWe discovered an enhanced functionality hammerhead ribozyme (EhhRz), designed to act in trans against human rod opsin (RHO) mRNA, with turnover activity >300 nM min−1 under substrate-excess conditions and physiological Mg2+ levels (1 mM). We developed a real-time moderate-throughput fluorescence quantitative hhRz kinetic assay, which is linear with substrate and product moles and supported by gel-based measures. The EhhRz targets a CUC↓ cleavage site in a substrate with no predicted secondary/tertiary structure and demonstrates classic Michaelis-Menten turnover behavior when the substrate is in 10-fold excess (Vmax/Km up to 1.60 × 108 min−1 M−1), which is comparable to RNase A. EhhRzs show cooperative titration with a Kd of 0.73 ± 0.02 mM at cellular Mg2+ concentrations and a Hill coefficient of 1.73 ± 0.07. The upstream EhhRz antisense flank (bound to a downstream substrate flank) interacts with stem-loop II, and examinations of different variants revealed that a U7 residue in the downstream flank of the substrate is not essential for enhanced activity. Under single-turnover conditions with substrate pre-annealed to enzyme, reaction rates exceeded 1,000 min−1. These findings show that RNA catalysis approaches the efficiency of the ribosome and suggests EhhRz in trans is a druggable nucleic acid therapeutic.
Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2
Authors: Castilla-Vallmanya Laura , Centeno-Pla Mónica , Serrano Mercedes , Franco-Valls Héctor , Martínez-Cabrera Raúl , Prat-Planas Aina , Rojano Elena , Ranea Juan A. G. , Seoane Pedro , Oliva Clara , Paredes-Fuentes Abraham J. , Artuch Rafael , Grinberg Daniel , Rabionet Raquel , Balcells Susanna , Urreizti Roser 
Published: May 2022

ABSTRACTBackgroundSchaaf-Yang syndrome (SYS) is caused by truncating mutations in MAGEL2, mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterization of SYS pathophysiology at clinical, genetic and molecular levels.MethodsWe performed an extensive phenotypic and mutational revision of previously reported SYS patients. We analysed the secretion levels of amyloid-β 1-40 peptide (Aβ1-40), and performed targeted metabolomic and transcriptomic profiles in SYS patients’ fibroblasts (n=7) compared to controls (n=11). We also transfected cell lines with vectors encoding wild-type (WT) or truncated MAGEL2 to assess stability and subcellular localization of the truncated protein.ResultsFunctional studies show significantly decreased levels of secreted Aβ1-40 and intracellular glutamine in SYS fibroblasts compared to wild-type. We also identified 132 differentially expressed genes, including ncRNAs such as HOTAIR, many of them related to developmental processes and mitotic mechanisms. The truncated form of MAGEL2 displayed a stability similar to the wild-type but it was significantly switched to the nucleus, compared to a mainly cytoplasmic distribution of the wild-type MAGEL2. Based on updated knowledge we offer guidelines for clinical management of SYS patients.ConclusionA truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic gain of function effect. Aβ1-40 secretion levels and HOTAIR mRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management.Key MessagesMAGEL2 truncating mutations cause Schaaf-Yang syndrome (SYS) but the functional effects of the truncated MAGEL2 protein have been poorly defined. By expressing truncated MAGEL2 in cell lines, we now know that a truncated version of the protein is retained in the nucleus, thus exerting a gain-of-function behaviour in addition to the loss of some of its main functions. Patients’ fibroblasts show reduced levels of excreted amyloid beta 1-40 and intracellular glutamine as well as an altered transcriptomic profile, including overexpression of the major regulator HOTAIR. Based on a comprehensive review of genetic and clinical aspects of all reported cases, families and physicians will benefit from the Clinical Management Recommendations that we provide here.
Adherence trajectory as an on-treatment risk indicator among drug-resistant TB patients in the Philippines
Authors: Huddart S , Geocaniga-Gaviola DM , Crowder R , Lim AR , Lopez E , Valdez CL , Berger CA , Destura Raul , Kato-Maeda M , Cattamanchi A , Garfin AMC 
Published: May 2022

AbstractIntroductionHigh levels of treatment adherence are critical for achieving optimal treatment outcomes among patients with tuberculosis (TB), especially for drug-resistant TB (DR TB). Current tools for identifying high-risk non-adherence are insufficient. Here, we apply trajectory analysis to characterize adherence behavior early in DR TB treatment and assess whether these patterns predict treatment outcomes.MethodsWe conducted a retrospective analysis of Philippines DR TB patients treated between 2013 and 2016. To identify unique patterns of adherence, we performed group-based trajectory modelling on adherence to the first 12 weeks of treatment. We estimated the association of adherence trajectory group with six-month and final treatment outcomes using univariable and multivariable logistic regression. We also estimated and compared the predictive accuracy of adherence trajectory group and a binary adherence threshold for treatment outcomes.ResultsOf 596 patients, 302 (50.7%) had multidrug resistant TB, 11 (1.8%) extremely drug-resistant (XDR) TB, and 283 (47.5%) pre-XDR TB. We identified three distinct adherence trajectories during the first 12 weeks of treatment: a high adherence group (n=483), a moderate adherence group (n=93) and a low adherence group (n=20). Similar patterns were identified at 4 and 8 weeks. Being in the 12-week moderate or low adherence group was associated with unfavorable six-month (adjusted OR [aOR] 3.42, 95% CI 1.90 - 6.12) and final (aOR 2.71, 95% 1.73 - 4.30) treatment outcomes. Adherence trajectory group performed similarly to a binary threshold classification for the prediction of final treatment outcomes (65.9 % vs. 65.4 % correctly classified), but was more accurate for prediction of six-month treatment outcomes (79.4% vs. 60.0% correctly classified).ConclusionsAdherence patterns are strongly predictive of patient treatment outcomes. Trajectory-based analyses represent an exciting avenue of research into TB patient adherence behavior seeking to inform interventions which rapidly identify and support patients with high-risk adherence patterns.
A Statistical Definition of Epidemic Waves
Authors: Kriston Levente 
Published: May 2022

ABSTRACTThe timely identification of expected surges of cases during infectious disease epidemics is essential for allocating resources and preparing interventions. This study describes a simple way to evaluate whether an epidemic wave is likely to be present based on daily new case count data. The proposed measure compares two models that assume exponential or linear dynamics, respectively. Technically, the output of two regression analyses is used to approximate a Bayes factor, which quantifies the support for the exponential over the linear model and can be used for epidemic wave detection. The trajectory of the coronavirus epidemic in three countries is analyzed and discussed for illustration. The proposed measure detects epidemic waves at an early stage, which are otherwise visible only by inspecting the development of case count data retrospectively. In addition to informing public health decision making, the outlined approach may serve as a starting point for scientific discussions on epidemic waves.