bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantification of Flavorants and Nicotine in Waterpipe Tobacco and Mainstream Smoke and Comparison to E-cigarette Aerosol
Authors: Erythropel Hanno C , Garcia Torres Deyri S , Woodrow Jackson G , de Winter Tamara M , Falinski Mark M , Anastas Paul T , O’Malley Stephanie S , Krishnan-Sarin Suchitra , Zimmerman Julie B
Published: June 2020

Introduction

Waterpipe use remains popular among youth with the availability of flavored shisha tobacco being one of the main drivers of waterpipe use. Although waterpipe mainstream toxicant emissions are well understood, less is known about the carryover of flavorants such as vanillin, benzaldehyde, and eugenol. In this study, flavored waterpipe tobacco was analyzed for flavorants and nicotine, and subsequent carryover to mainstream smoke.

Methods

Flavorants vanillin, benzaldehyde, and eugenol, and nicotine were quantified in vanilla-, cherry-, and cinnamon-flavored shisha tobacco by gas chromatography/flame ionization detector and subsequently in waterpipe mainstream smoke generated by a smoking machine. The setup allowed for sampling before and after the water-filtration step.

Results

Flavorant and nicotine content in smoke was reduced 3- to 10-fold and 1.4- to 3.1-fold, respectively, due to water filtration. Per-puff content of filtered waterpipe mainstream smoke ranged from 13 to 46 µg/puff for nicotine and from 6 to 55 µg/puff for flavorants.

Conclusions

Although water filtration reduced flavor and nicotine content in waterpipe mainstream smoke, the detected flavorant concentrations were similar or higher to those previously reported in e-cigarette aerosol. Therefore, users could be drawn to waterpipes due to similar flavor appeal as popular e-cigarette products. Absolute nicotine content of waterpipe smoke was lower than in e-cigarette aerosol, but the differential use patterns of waterpipe (>100 puffs/session) and e-cigarette (mostly <10 puffs/session, multiple session throughout the day) probably result in higher flavorant and nicotine exposure during a waterpipe session. Strategies to reduce youth introduction and exposure to nicotine via waterpipe use may consider similar flavor restrictions as those for e-cigarettes.

Implications

Although waterpipe mainstream smoke is well characterized for toxicants content, little is known about carryover of molecules relevant for appeal and addiction: flavorants and nicotine. This study shows that flavorant content of waterpipe mainstream smoke is comparable or higher than e-cigarette aerosol flavorant content. Regulatory action to address tobacco use behaviors targeting the availability of flavors should also include other tobacco products such as flavored shisha tobacco.
ENDS Device Type and Initiation of Combustible Tobacco Products Among Adolescents
Authors: Sumbe Aslesha , Clendennen Stephanie L , Opara Samuel C , Jackson Christian D , Chen Baojiang , Wilkinson Anna V , Harrell Melissa B
Published: June 2020

Introduction

The aim of this study was to determine whether Electronic Nicotine Delivery Systems (ENDS) device type (disposable devices, replaceable cartridges, and refillables) at initial or first ENDS use predicts subsequent initiation of combustible tobacco products (cigarettes, hookah, cigars) among adolescents and/or differentiates between those who initiate use of both ENDS and combustible tobacco products at the same time.

Methods

The study examined data from the Texas Adolescent Tobacco and Marketing Surveillance System (TATAMS), a longitudinal population-based cohort of students in major metropolitan areas of Texas (n = 3907; N = 461 069). Data were collected every 6 months, from 2014 to 2018; 33.9% (n = 1324; N = 151 784) of the sample initiated ENDS use across this period. Unadjusted and adjusted logistic regression models were used to assess the odds of initiating combustible tobacco products at a subsequent or similar wave as ENDS initiation, given initial ENDS device type.

Results

After adjusting for sociodemographic factors, the odds of initiating combustible tobacco use subsequent to ENDS initiation were significantly lower among those who reported using Cartridges as their initial device type compared to those who reported Refillables as their initial device type (adjusted odds ratio = 0.42 [0.18–0.98], p = .05). In addition, after controlling for sociodemographic variables, the odds of initiating combustible tobacco use in the same wave as ENDS initiation were significantly higher among those who reported using Cartridges as their initial device type, compared with those who reported Refillables as their initial device type (adjusted odds ratio = 2.31 [1.05–5.10], p = .04). No significant differences were found in adjusted models when Disposables were compared to Refillables and Cartridges to Disposables.

Conclusion

ENDS device type differentiates between adolescents who start using combustible tobacco products at the same time as initial ENDS use, or subsequently.

Implications

Previous research has shown ENDS use predicts subsequent combustible use among adolescents, but there is lack of research on the role of specific ENDS device types and the timing of initiation. Findings from this longitudinal study show that initiation of combustible tobacco product use varies by initial ENDS device type among adolescents. These findings can become a focal point for developing interventions for adolescents and could have regulatory implications for ENDS products.
Enhanced $\Gamma(p\to K^0\mu^+)/\Gamma(p\to K^+\bar{\nu}_\mu)$ as a signature of minimal renormalizable SUSY SO (10) GUT
Authors: Haba Naoyuki , Mimura Yukihiro , Yamada Toshifumi
Published: June 2020

The ratio of the partial widths of some dimension-5 proton decay modes can be predicted without detailed knowledge of supersymmetric (SUSY) particle masses, and this allows us to experimentally test various SUSY grand unified theory (GUT) models without discovering SUSY particles. In this paper, we study the ratio of the partial widths of the $p\to K^0\mu^+$ and $p\to K^+\bar{\nu}_\mu$ decays in the minimal renormalizable SUSY $SO(10)$ GUT, under only a plausible assumption that the 1st- and 2nd-generation left-handed squarks are mass-degenerate. In the model, we expect that the Wilson coefficients of dimension-5 operators responsible for these modes are on the same order and that the ratio of $p\to K^0\mu^+$ and $p\to K^+\bar{\nu}_\mu$ partial widths is $O(0.1)$. Hence, we may be able to detect both $p\to K^0\mu^+$ and $p\to K^+\bar{\nu}_\mu$ decays at Hyper-Kamiokande, thereby gaining a hint for the minimal renormalizable SUSY $SO(10)$ GUT. Moreover, since this partial width ratio is quite suppressed in the minimal $SU(5)$ GUT, it allows us to distinguish the minimal renormalizable SUSY $SO(10)$ GUT from the minimal $SU(5)$ GUT. In the main body of the paper, we perform a fitting of the quark and lepton masses and flavor mixings with the Yukawa couplings of the minimal renormalizable $SO(10)$ GUT, and derive a concrete prediction for the partial width ratio based on the fitting results. We find that the partial width ratio generally varies in the range $0.05$–$0.6$, confirming the above expectation.
Training cosmetology students in Arkansas to help dermatologists find skin cancers earlier: results of a cluster-randomized controlled trial
Authors: Fischbach Lori , Faramawi Mohammed F , Girard Deborah , Thapa Susan , Travers Robin
Published: June 2020

Background

We tested an educational video in cosmetology schools to increase students’ knowledge about skin cancer, sun-safety practices, identifying suspicious lesions and recommending clients consult a dermatologist when a suspicious lesion is observed.

Methods

We used a cluster-randomized controlled study design to randomize 22 cosmetology schools to receive our educational video or a publicly accessible healthy lifestyle video (control).

Results

Students who received the intervention were more likely than controls to increase their knowledge of skin cancer, risk factors and how to identify potential skin cancers (risk ratio [RR] and 95% confidence interval = 2.86 [1.58–5.20]). At follow-up, students in the intervention group were more likely than those in the control group to look for suspicious moles on their clients’ faces, scalps and necks (RRs = 1.75, 2.16 and 2.90, respectively). Additionally, students in the intervention group were more likely to communicate with clients about sun-safety practices (RR = 1.74 [1.11–2.73]) and consulting a dermatologist about suspicious moles (RR = 1.57 [1.03–2.41]).

Conclusions

Our educational video helped cosmetology students recognize potential skin cancers and talk with clients about sun safety and consulting a dermatologist about suspicious moles. Such videos may play a role in the public health surveillance of skin cancers in communities.
The incidence rate of pulmonary arterial hypertension and scleroderma renal crisis in systemic sclerosis patients with digital ulcers on endothelin antagonist receptors (ERAs) and phosphodiesterase-5 inhibitors (PDE5i)
Authors: Pestaña-Fernández Melani , Rubio-Rivas Manuel , Tolosa-Vilella Carles , Guillén-Del-Castillo Alfredo , Colunga-Argüelles Dolores , Argibay Ana , Marí-Alfonso Begoña , Marín-Ballvé Adela , Pla-Salas Xavier , Chamorro Antonio-J , Castro-Salomó Antoni , Madroñero-Vuelta Ana Belén , Sánchez-García María Esther , Sáez-Comet Luis , González-Echávarri Cristina , Ortego-Centeno Norberto , Vargas-Hitos José Antonio , Todolí-Parra José Antonio , Trapiella-Martínez Luis , Lledó Gema María , Freire Mayka , Fonollosa-Pla Vicent , Simeón-Aznar Carmen Pilar ,   for RESCLE Investigators, Autoimmune Diseases Study Group (GEAS)
Published: June 2020

Introduction

Endothelin antagonist receptors (ERAs) and phosphodiesterase-5 inhibitors (PDE5i) are beneficial in pulmonary arterial hypertension (PAH) and digital ulcers (DU) and prevent from DU recurrences. Our study aimed to determine the difference in the incidence rate of PAH and scleroderma renal crisis (SRC) in patients with SSc and DU (SSc-DU) under ERAs/PDE5i or without treatment.

Methods

We conducted a retrospective cohort study including SSc-DU patients from the Spanish Scleroderma Registry (RESCLE). The primary outcome was the incidence rate of PAH and SRC in patients under ERAs/PDE5i or not.

Results

Some 544 patients out of 1817 (29.9%) in the RESCLE database had DU, 221 (40.6%) under ERAs/PDE5i and 323 (59.4%) not. The incidence rate (95% CI) difference between patients under treatment or not under did not reach statistical significance in PAH [−0.1 (−4.8, 4.69), P = 0.988] or in SRC [0.7 (−2.2, 3.7), P = 0.620]. However, the time from the first DU to the diagnosis of SRC was delayed in treated patients [mean (s.d.) 7.6 (5.8) years vs 2.9  (5.3); P = 0.021]. The dcSSc subset was more prevalent in the treatment group (36 vs 26%; P = 0.018), along with anti-topoisomerase I antibodies (34 vs 18%; P < 0.001) and tendon friction rubs (12 vs 6%; P = 0.038), whereas the lcSSc subset was more prevalent in the no-treatment group (57 vs 66%; P = 0.031) along with ACA (37 vs 46%; P = 0.031).

Conclusion

There was no difference in the incidence rate of PAH and SRC between groups. However, treatment with ERAs and/or PDE5i appeared to delay the occurrence of SRC.
Interactions between decision-making and emotion in behavioral-variant frontotemporal dementia and Alzheimer’s disease
Authors: Manuel Aurélie L , Roquet Daniel , Landin-Romero Ramon , Kumfor Fiona , Ahmed Rebekah M , Hodges John R , Piguet Olivier
Published: June 2020

Negative and positive emotions are known to shape decision-making toward more or less impulsive responses, respectively. Decision-making and emotion processing are underpinned by shared brain regions including the ventromedial prefrontal cortex (vmPFC) and the amygdala. How these processes interact at the behavioral and brain levels is still unclear. We used a lesion model to address this question. Study participants included individuals diagnosed with behavioral-variant frontotemporal dementia (bvFTD, n = 18), who typically present deficits in decision-making/emotion processing and atrophy of the vmPFC, individuals with Alzheimer’s disease (AD, n = 12) who present with atrophy in limbic structures and age-matched healthy controls (CTRL, n = 15). Prior to each choice on the delay discounting task participants were cued with a positive, negative or neutral picture and asked to vividly imagine witnessing the event. As hypothesized, our findings showed that bvFTD patients were more impulsive than AD patients and CTRL and did not show any emotion-related modulation of delay discounting rate. In contrast, AD patients showed increased impulsivity when primed by negative emotion. This increased impulsivity was associated with reduced integrity of bilateral amygdala in AD but not in bvFTD. Altogether, our results indicate that decision-making and emotion interact at the level of the amygdala supporting findings from animal studies.
The UVR Filter Octinoxate Modulates Aryl Hydrocarbon Receptor Signaling in Keratinocytes via Inhibition of CYP1A1 and CYP1B1
Authors: Phelan-Dickinson Sarah J , Palmer Brian C , Chen Yue , DeLouise Lisa A
Published: June 2020

Ultraviolet radiation (UVR) is a consistent part of the environment that has both beneficial and harmful effects on human health. UVR filters in the form of commercial sunscreens have been widely used to reduce the negative health effects of UVR exposure. Despite their benefit, literature suggests that some filters can penetrate skin and have off-target biological effects. We noted that many organic filters are hydrophobic and contain aromatic rings, making them potential modulators of Aryl hydrocarbon Receptor (AhR) signaling. We hypothesized that some filters may be able to act as agonists or antagonists on the AhR. Using a luciferase reporter cell line, we observed that the UVR filter octinoxate potentiated the ability of the known AhR ligand, 6-formylindolo[3,2-b]carbazole (FICZ), to activate the AhR. Cotreatments of keratinocytes with octinoxate and FICZ lead to increased levels of cytochrome P4501A1 (CYP1A1) and P4501B1 (CYP1B1) mRNA transcripts, in an AhR-dependent fashion. Mechanistic studies revealed that octinoxate is an inhibitor of CYP1A1 and CYP1B1, with IC50 values at approximately 1 µM and 586 nM, respectively. In vivo topical application of octinoxate and FICZ also elevated CYP1A1 and CYP1B1 mRNA levels in mouse skin. Our results show that octinoxate is able to indirectly modulate AhR signaling by inhibiting CYP1A1 and CYP1B1 enzyme function, which may have important downstream consequences for the metabolism of various compounds and skin integrity. It is important to continue studying the off-target effects of octinoxate and other UVR filters, because they are used on skin on a daily basis world-wide.
Gene Expression Thresholds Derived From Short-term Exposures Identify Rat Liver Tumorigens
Authors: Hill Thomas , Rooney John , Abedini Jaleh , El-Masri Hisham , Wood Charles E , Corton J Christopher
Published: June 2020

Traditional methods for cancer risk assessment are resource-intensive, retrospective, and not feasible for the vast majority of environmental chemicals. In this study, we investigated whether quantitative genomic data from short-term studies may be used to set protective thresholds for potential tumorigenic effects. We hypothesized that gene expression biomarkers measuring activation of the key early events in established pathways for rodent liver cancer exhibit cross-chemical thresholds for tumorigenesis predictive for liver cancer risk. We defined biomarker thresholds for 6 major liver cancer pathways using training sets of chemicals with short-term genomic data (3–29 days of exposure) from the TG-GATES (n = 77 chemicals) and DrugMatrix (n = 86 chemicals) databases and then tested these thresholds within and between datasets. The 6 pathway biomarkers represented genotoxicity, cytotoxicity, and activation of xenobiotic, steroid, and lipid receptors (aryl hydrocarbon receptor, constitutive activated receptor, estrogen receptor, and peroxisome proliferator-activated receptor α). Thresholds were calculated as the maximum values derived from exposures without detectable liver tumor outcomes. We identified clear response values that were consistent across training and test sets. Thresholds derived from the TG-GATES training set were highly predictive (97%) in a test set of independent chemicals, whereas thresholds derived from the DrugMatrix study were 96%–97% predictive for the TG-GATES study. Threshold values derived from an abridged gene list (2/biomarker) also exhibited high predictive accuracy (91%–94%). These findings support the idea that early genomic changes can be used to establish threshold estimates or “molecular tipping points” that are predictive of later-life health outcomes.
The Genome Sequence of Five Highly Pathogenic Isolates of Fusarium oxysporum f. sp. lini
Authors: Kanapin Alexander , Samsonova Anastasia , Rozhmina Tatyana , Bankin Michael , Logachev Anton , Samsonova Maria
Published: June 2020

Fusarium wilt is the most destructive fungal disease in flax, limiting flax cultivation in all the main flax and linseed growing countries. The causative agent is seedborne and soilborne fungus F. oxysporum f. sp. lini. Here, we report, for the first time, genome assemblies of five highly pathogenic isolates of Fusarium oxysporum f. sp. lini, namely monoisolate 39 and strains F329, F324, F282, F287. In addition, syntenic analysis provided a powerful approach to distinguish between core and lineage-specific parts of the genome. These results lay a solid foundation for comparative genomics studies of plant fungal pathogens, evolution of pathogenicity, and virulence factors underlying the dynamics of host-pathogen interactions, thus eventually offering solutions to Fusarium disease control.
Pyrenophora tritici-repentis Race 4 Isolates Cause Disease on Tetraploid Wheat
Authors: Guo Jingwei , Shi Gongjun , Kalil Audrey , Friskop Andrew , Elias Elias , Xu Steven S. , Faris Justin D. , Liu Zhaohui
Published: June 2020

The ascomycete fungus Pyrenophora tritici-repentis is the causal agent of tan spot of wheat. The disease can occur on both common wheat (Triticum aestivum) and durum wheat (T. turgidum ssp. durum) and has potential to cause significant yield and quality losses. The fungal pathogen is known to produce necrotrophic effectors (NEs) that act as important virulence factors. Based on the NE production and virulence on a set of four differentials, P. tritici-repentis isolates have been classified into eight races. Race 4 produces no known NEs and is avirulent on the differentials. From a fungal collection in North Dakota, we identified several isolates that were classified as race 4. These isolates caused no or little disease on all common wheat lines including the differentials; however, they were virulent on some durum cultivars and tetraploid wheat accessions. Using two segregating tetraploid wheat populations and quantitative trait locus mapping, we identified several genomic regions significantly associated with disease caused by two of these isolates, some of which have not been previously reported. This is the first report that race 4 is virulent on tetraploid wheat, likely utilizing unidentified NEs. Our findings further highlight the insufficiency of the current race classification system for P. tritici-repentis.
Systematic Analysis of Copy-Number Variations Associated With Early Pregnancy Loss
Authors: Wang Y. , Li Y. , Chen Y. , Zhou R. , Sang Z. , Meng L. , Tan J. , Qiao F. , Bao Q. , Luo D. , Peng C. , Wang Y. S. , Luo C. , Hu P. , Xu Z.
Published: June 2020

(Abstracted from Ultrasound Obstet Gynecol 2020;55:96–104)

Early pregnancy loss is most commonly caused by embryonic numerical and structural chromosomal abnormalities, which explain more than 50% of miscarriages. In more recent years, submicroscopic copy-number variations (CNVs) have also been identified in some early miscarriage specimens.
Fetal Fraction and Noninvasive Prenatal Testing: What Clinicians Need to Know
Authors: Hui Lisa , Bianchi Diana W.
Published: June 2020

(Abstracted from Prenat Diagn 2020;40:155–163)

Fetal fraction (FF) is defined as the percentage of total maternal plasma cell-free (cf) DNA that is derived from the fetoplacental unit (FF = fetal cfDNA/[fetal cfDNA + maternal cfDNA]). The measured FF is dependent on both biological factors and bioinformatics algorithms and is used in interpretation of DNA sequencing results in noninvasive prenatal testing (NIPT).
Surgical Technique: Closed Reduction and Percutaneous Pinning of Posterolaterally Displaced Supracondylar Humerus Fractures
Authors: Prusick Vincent W. , Gibian Joseph T. , Ross Kirsten E. , Moore-Lotridge Stephanie N. , Rees Andrew B. , Mencio Gregory A. , Stutz Christopher M. , Schoenecker Jonathan G.
Published: June 2020

Gartland type III posterolateral (IIIB) supracondylar humerus fractures are common among the pediatric population and can lead to concomitant injury, including compromise of the brachial artery and median nerve and long-term deformity, such as cubitus varus. These fractures can be difficult to reduce, and there is little consensus regarding the optimal technique for closed reduction and percutaneous pinning. Here, we discuss the management of Gartland III posterolateral supracondylar humerus fractures, including an in-depth technical description of the methods of operative fixation. We describe a lateral pin-only fixation technique for Gartland III posterolateral supracondylar humerus fractures that uses the intact periosteum during reduction of the distal fragment to assist in realigning the medial and lateral columns anatomically. We also discuss a safe method for placing a medial-based pin if there is persistent rotational instability at the fracture site after placement of the laterally based pins.
Comparison of Early Fatigue Failure of the TFNa and Gamma 3 Cephalomedullary Nails in the United States From 2015 to 2019
Authors: Klima Matthew L.
Published: June 2020

Objectives:

To compare reports of implant fatigue failure submitted to the FDA of 2 commonly used cephalomedullary nails.

Methods:

In total, 2724 medical device reports from the FDA's MAUDE database from Jan 2015 to Oct 2019 were reviewed for the Trochanteric Femoral Nail–Advanced (TFNa) and Gamma 3 implants.

Results:

Data from 342 implant failures included in the MAUDE database were analyzed. TFNa and Gamma 3 had 183 and 159 reported fatigue failures, respectively. All failed implants fractured in the same location through the proximal screw aperture. Time from implantation to failure was on average 2 months shorter for TFNa implants that were reported fractured than for Gamma 3 implants reported, a difference that was statistically significant (P < 0.05). In total, 100 implants were reported to have failed within the first 4 months (53 and 47 for TFNa and Gamma 3, respectively). For Gamma 3 implants that failed in the first 4 months, almost all of the available manufacturers' inspection reports revealed implant notches at the point of failure from drilling. For TFNa implants that failed early, only one reported notch was noted in the available inspection reports.

Conclusions:

In contrast to other studies regarding fatigue failure, reported failures in both TFNa and Gamma 3 occurred earlier than can be attributed to delayed or nonunion. The reported failures of the TFNa in the MAUDE database occurred earlier than did those of the Gamma 3. Early failures of the Gamma 3 seemed to be the result of iatrogenic implant notching.

Level of Evidence:

Therapeutic Level III. See instructions for authors for a complete description of levels of evidence.
Distal Femur Replacement Versus Surgical Fixation for the Treatment of Geriatric Distal Femur Fractures: A Systematic Review
Authors: Salazar Brett P. , Babian Aaron R. , DeBaun Malcolm R. , Githens Michael F. , Chavez Gustavo A. , Goodnough L. Henry , Gardner Michael J. , Bishop Julius A.
Published: June 2020

Objectives:

The management of geriatric distal femur fractures is controversial, and both primary distal femur replacement (DFR) and surgical fixation (SF) are viable treatment options. The purpose of this study was to compare patient outcomes after these treatment strategies.

Data Sources:

PubMed, Embase, and Cochrane databases were searched for English language articles up to April 24, 2020, identifying 2129 papers.

Study Selection:

Studies evaluating complications in elderly patients treated for distal femur fractures with either immediate DFR or SF were included. Studies with mean patient age <55 years, nontraumatic indications for DFR, or SF with nonlocking plates were excluded.

Data Extraction:

Two studies provided Level II or III evidence, whereas the remaining 28 studies provided Level IV evidence. Studies were formally evaluated for methodological quality using established criteria. Treatment failure between groups was compared using an incidence rate ratio.

Data Synthesis:

Treatment failure was defined for both SF and arthroplasty as complications requiring a major reoperation for reasons such as mechanical failure, nonunion, deep infection, aseptic loosening, or extensor mechanism disruption. There were no significant differences in complication rates or knee range of motion between SF and DFR.

Conclusions:

SF and DFR for the treatment of geriatric distal femur fractures demonstrate similar overall complication rates. Given the available evidence, no strong conclusions on the comparative effectiveness between the 2 treatments can be definitively made. More rigorous prospective research comparing SF vs. DFR to treat acute geriatric distal femur fractures is warranted.

Level of Evidence:

Therapeutic Level IV. See instructions for authors for a complete description of levels of evidence.
Effect of the topical administration of N-(2-(4-bromophenylamino)-5-(trifluoromethyl)phenyl)nicotinamide compound in a murine subcutaneous melanoma model
Authors: Vale Juliana Alves do , de Souza Ana Paula Martins , Lima Graziela Domingues Almeida , Gonçalves Victor Hugo Sousa , Moreira Gabriela Alves , Barros Marcus Vinícius de Andrade , Pereira Wagner Luiz , Merchid Nara Clara Lazaroni e , Fietto Juliana Lopes Rangel , Bressan Gustavo Costa , Teixeira Róbson Ricardo , Machado-Neves Mariana
Published: June 2020

Conventional treatments for metastatic melanomas are still ineffective and generate numerous side effects, justifying the search for new therapies. The antimetastatic effect of the named N-(2-(4-bromophenylamino)-5-(trifluoromethyl)phenyl)nicotinamide (SRVIC30) compound has been previously demonstrated in murine melanoma. Herein, we aimed to evaluate its effect when topically administrated in a murine subcutaneous melanoma model. For that, mice C57BL/6 were injected subcutaneously with 2 × 105 B16-F10 cells. Topical treatment began when tumors became visible on animal’s back. Therefore, tumor volume was measured three times a week until it reaches 12 mm3 approximately. At this point, 40 mg oil-in-water cream (Lanette) without (control mice; n = 10) or with SRVIC30 compound (SRVIC30 group; n = 10 animals) were spread daily over the tumor external surface using a small brush for 14 days. The treatments increased the percentage of peroxidase antioxidant enzyme and dead cells via caspase-3 activation, with a consequent deposit of collagen fibers in the tumors. In addition, the skin of treated animals showed the presence of inflammatory infiltrate. Finally, SRVIC30 did not show signs of toxicity. Thus, we concluded that the topic administration of SRVIC30 was able to influence crucial anticancer processes such as tumor cells apoptosis and surrounding microenvironment.
Mutational profile in circulating tumor DNA in a patient affected by low-risk endometrial cancer: predictable tool of relapse?
Authors: Malentacchi Francesca , Turrini Irene , Zepponi Francesca , Fantappiè Giulia , Sorbi Flavia , Antonuzzo Lorenzo , Fambrini Massimiliano , Noci Ivo , Pillozzi Serena
Published: June 2020

Endometrial cancer is the commonest gynecological cancer, the majority is endometrioid type, diagnosed at an early stage with 69–88% 5-year survival. Low-grade endometrial cancers have low recurrence rates and often do not receive adjuvant therapy; however, a subset of these patients will have poor outcomes and would benefit from adjuvant treatment has been challenging. We evaluate the circulating cell-free DNA (ccfDNA) in a patient with low-risk endometrial cancer in order to identify the presence of molecular markers associated with risk of recurrence. The evaluation of mutation profile was performed by next-generation sequencing (NGS) in primary tumor formalin-fixed paraffin-embedded (FFPE) tissue and in circulating tumor DNA (ctDNA). We identified a specific mutational profile in ctDNA, different from primary tumor tissue suggesting that the clone involved in the relapse may be different in comparison to the most represented in the primary tumor. These findings open new prospective and new wonderings. The molecular characterization of tissue may be useful for setting new target personalized therapy even in the treatment of endometrial cancer, moreover, endometrial cancer at low risk should be not underestimated for the incidence of relapse, and for this evaluation the molecular characterization may be useful. Moreover, these results suggest that the single analysis of primary tumors may be not sufficient for setting a specific personalized therapy targeted to avoid the relapse but may be necessary to join the molecular characterization of liquid biopsy to primary tissue.
Metformin induces caspase-dependent and caspase-independent apoptosis in human bladder cancer T24 cells
Authors: Jang Ji Hoon , Sung Eon-Gi , Song In-Hwan , Lee Tae-Jin , Kim Joo-Young
Published: June 2020

Bladder cancer (BC) is the sixth most common cancer in men. Moreover, chemotherapy for BC leads to various side effects. Metformin is known to induce apoptosis in vitro in many types of cancer. Furthermore, it has feasibility as a drug repositioning used for the treatment of cancer. The molecular mechanism of metformin mediating apoptosis in BC is still unclear. In this study, we showed that metformin stimulated the caspase-dependent apoptotic signaling pathway in T24 cells, a human BC cell line. Moreover, the induced apoptosis was partially inhibited by a general caspase inhibitor, z-VAD-fmk, which suggested that metformin-induced apoptosis in T24 cells is partially caspase-independent. Notably, we observed the nuclear translocation of apoptosis-inducing factors (AIFs) in metformin-promoted apoptosis, which is a typical characteristic of the caspase-independent apoptotic pathway. In addition, we found that metformin-mediated apoptosis occurred via degradation of the cellular FADD-like interleukin-1β-converting enzyme inhibitory protein (c-FLIP) by facilitating ubiquitin/proteasome-mediated c-FLIPL degradation. Furthermore, treatment with the reactive oxygen species scavenger N-acetylcysteine, failed to suppress metformin-induced apoptosis and c-FLIPL protein degradation in metformin-treated T24 cells. In conclusion, these results indicate that metformin-induced apoptosis was mediated through AIF-promoted caspase-independent pathways as well as caspase-dependent pathways in T24 cells. As such, metformin could be used as a possible apoptotic agent for the treatment of BC.
Prognostic Value of P25/30 Cortical Somatosensory Evoked Potential Amplitude After Cardiac Arrest*
Authors: Oh Sang Hoon , Oh Joo Suk , Jung Hyun Ho , Park Jungtaek , Kim Ji Hoon , Park Jeong Ho , Wee Jung Hee , Kim Seong Hoon , Choi Seung Pill , Park Kyu Nam
Published: June 2020

Objectives:

The aim of this study was to evaluate the prognostic performance of the peak amplitude of P25/30 cortical somatosensory evoked potentials in predicting nonawakening in targeted temperature management-treated cardiac arrest patients.

Design:

Prospective analysis.

Setting:

Four academic tertiary care hospitals.

Patients:

Eighty-seven cardiac arrest survivors after targeted temperature management.

Interventions:

Analysis of the amplitude of P25/30.

Measurements and Main Results:

In all participants, somatosensory evoked potentials were recorded after rewarming, and bilaterally absent pupillary and corneal reflexes were evaluated at 72 hours after the return of spontaneous circulation. We analyzed the amplitudes of the N20 and P25/30 peaks and the N20–P25/30 complex in cortical somatosensory evoked potentials. Upon hospital discharge, 87 patients were dichotomized into the awakening and nonawakening groups. The lowest amplitudes of N20, P25/30, and N20–P25/30 in the awakening patients were 0.17, 0.45, and 0.73 μV, respectively, and these thresholds showed a sensitivity of 70.5% (95% CI, 54.8–83.2%), 86.4% (95% CI, 72.7–94.8%), and 75.0% (95% CI, 59.7–86.8%), respectively, for nonawakening. The area under the curve of the P25/30 amplitude was significantly higher than that of the N20 amplitude (0.955 [95% CI, 0.912–0.998] vs 0.894 [95% CI, 0.819–0.969]; p = 0.036) and was comparable with that of the N20–P25/30 amplitude (0.931 [95% CI, 0.873–0.989]). Additionally, adding resuscitation variables or an absent brainstem reflex to the P25/30 amplitude showed a trend toward improving prognostic performance compared with the use of other somatosensory evoked potential amplitudes (area under the curve, 0.958; 95% CI, 0.917–0.999 and area under the curve, 0.974; 95% CI, 0.914–0.996, respectively).

Conclusions:

Our results provide evidence that the absence of the P25/30 peak and a reduction in the P25/30 amplitude may be considered prognostic indicators in these patients.
“Eavesdropping”
Authors: Beneteau Erin , Haldar Shefali , Mishra Sonali R. , Pratt Wanda
Published: June 2020

Healthcare providers in the hospital setting must discuss patient information to ensure continuity of care and patient safety. This study explores how patients perceive the information they hear discussed between healthcare providers and how the concept of “eavesdropping” can be addressed by healthcare providers and in the field of medical informatics. Using an inductive analysis of interviews with 14 adult inpatients, research findings indicate that patients value receiving information in the hospital setting, including information received through eavesdropping. Patient eavesdropping opportunities include “eavesdropping by design” events, such as during bedside shift changes and handoffs, as well as unintended “unintended eavesdropping” events, such as listening to healthcare provider conversations outside of the patient's room. Healthcare providers and medical informaticists have opportunities to address eavesdropping in the inpatient setting. Informatics systems that address “eavesdropping by design” and “unintended eavesdropping opportunities” can improve patient-provider communication and satisfy patient preferences for receiving medical information.
A Case Report of Papillary Digital Adenocarcinoma With BRAFV600E Mutation and Quantified Mutational Burden
Authors: Trager Megan H. , Jurkiewicz Magdalena , Khan Shaheer , Niedt George W. , Geskin Larisa J. , Carvajal Richard D.
Published: June 2020

Papillary digital adenocarcinoma (PDA) is a rare eccrine tumor that is most often found on the digits. Few case reports have described PDAs located on atypical sites. It is now accepted that PDAs cannot be distinguished from benign adenomas based on histological features, and it is recommended to excise all of these lesions. Even with excision, recurrence and metastasis rates are high. Only limited genomic analyses have been performed to date, and no driver mutations have been identified. We report a case of a 63-year-old woman with a PDA on the right forearm. Biopsy showed moderate cytologic atypia and mitotic figures. Next-generation DNA sequencing of the tumor showed a BRAFV600E mutation and high tumor mutational burden (5.51 mutations/Mb). This mutation is known for its response to small molecular inhibitors of BRAF and Mitogen-activated protein kinase kinase. Such therapy may be a consideration should our patient develop recurrent unresectable disease.
Acquired Epidermodysplasia Verruciformis in the Setting of Renal Transplant
Authors: Henning Ania , Weaver Joshua , Reedy Matthew
Published: June 2020

Epidermodysplasia verruciformis (EV) is a rare dermatologic condition that is clinically characterized by flat, cutaneous, verrucous papules, pityriasis versicolor-like lesions, and similar lichenoid papules. There are 2 forms of EV: a classic inherited genodermatosis and a secondary acquired form. EV predisposes individuals to infections with certain types of human papillomavirus virus and subsequently increases the risk of cutaneous squamous cell carcinoma. The acquired form occurs in immunosuppressed patients, particularly in patients infected with HIV; however, it has also been described in patients who have undergone stem cell and solid organ transplantation. We report an additional case of renal transplantation and immunosuppressive therapy-associated acquired EV (AEV) in a 78-year-old man with multiple flesh-colored to violaceous, flat-topped papules distributed on the face and trunk clinically mimicking lichen planus. Biopsy was typical for that of EV, demonstrating enlarged keratinocytes with a blue–gray cytoplasm, a thickened granular layer, acanthosis, and hyperkeratosis. Herein, we discuss an unusual presentation of an AEV-mimicking lichen planus with review of the literature.
Partial and full deletion of nicotinic acetylcholine receptor α4 and β2 subunits reduces sensitivity to acute nicotine administration and development of tolerance following chronic nicotine administration
Authors: Marks Michael J. , Loetz Esteban , Ortiz Nick C. , Herder Penelope A. , Collins Allan C.
Published: June 2020

The diversity of nicotinic cholinergic receptor (nAChR) subunits underlies the complex responses to nicotine. Mice differing in the expression of α4 and β2 subunits, which are most widely expressed in brain, were evaluated for the responses to acute nicotine administration on Y-maze crossings and rears, open-field locomotion and body temperature following chronic treatment with nicotine (0, 0.25, 1.0 and 4.0 mg/kg/h). Deletion or partial deletion of the α4, β2 or both nAChR subunits reduced the sensitivity of mice to acute nicotine administration. This reduced sensitivity was gene dose-dependent. Modification of α4 subunit expression elicited a greater reduction in sensitivity than the modification of β2 subunit expression. No measurable tolerance was observed for mice of any genotype following chronic treatment with 0.25 mg/kg/h nicotine. Modest tolerance was noted following treatment with 1.0 mg/kg/h. Greater tolerance was observed following treatment with 4.0 mg/kg/h. The extent of tolerance differed among the mice depending on genotype: wild-type (α4++and β2++) developed measurable tolerance for all four tests. Heterozygotes (α4+−, β2+−and α4+−/β2+−) developed tolerance for only Y-maze crossings and body temperature. Null mutants (α4− −and β2− −) did not become tolerant. However, following chronic treatment with 4.0 mg/kg/h nicotine, wild type, α4+−and α4− −mice displayed increased Y-maze crossings following acute administration of 0.5 mg/kg nicotine that may reflect the activity of α6β2*-nAChR. These results confirm the importance of the α4 and β2 nAChR subunits in mediating acute and chronic effects of nicotine on locomotion and body temperature in the mouse.
Low-Dose Ticagrelor in Patients With High Ischemic Risk and Previous Myocardial Infarction: A Multicenter Prospective Real-World Observational Study
Authors: Cesaro Arturo , Taglialatela Vittorio , Gragnano Felice , Moscarella Elisabetta , Fimiani Fabio , Conte Marzia , Barletta Valeria , Monda Emanuele , Limongelli Giuseppe , Severino Salvatore , Cirillo Plinio , Calabrò Paolo
Published: June 2020

Prolonged dual antiplatelet therapy after 12 months in patients with previous myocardial infarction (MI) is attractive to reduce long-term ischemic complications. In the PEGASUS-TIMI 54, the use of low-dose ticagrelor (60 mg b.i.d.) plus aspirin after 12 months from MI reduced the risk of ischemic events, at the price of limited increase on bleeding complications. However, data on the use of low-dose ticagrelor in real-world practice lack. We aim at providing data on prescription/eligibility criteria and outcomes in patients receiving low-dose ticagrelor in the real-world setting. We enrolled consecutive patients eligible for ticagrelor 60 mg according to Italian national regulation in 3 high-volume centers and collected 1-year outcomes. The primary objective of the study is to generate real-world data about clinical characteristics, eligibility criteria, major adverse cardiovascular events, bleeding, and adverse event in patients receiving low-dose ticagrelor from our cohort. One hundred eighty-one patients were consecutively enrolled with a median follow-up of 18 months. The most used and the least used prescription criteria were multivessel coronary disease (72.4%) and chronic kidney disease (15.5%), respectively. At 1-year follow-up, the rate of major adverse cardiovascular events was 4.97%; of these, 3.86% of patients had a MI, and 1.1% had a stroke/transient ischemic attack, whereas no major bleeding occurred. In conclusion, in a real-world study, including patients with previous MI, low-dose ticagrelor for prolonged dual antiplatelet therapy showed to be effective and safe, with no major bleeding occurring at follow-up.
Current Perspectives of Anticoagulation in Patients With COVID-19
Authors: Gavioli Elizabeth M. , Sikorska Gabriela , Man Ammy , Rana Jay , Vider Etty
Published: June 2020

Thromboembolism and myocardial injury is common in patients with COVID-19. Low-molecular-weight heparin appears to be associated with a good prognosis in patients with COVID-19 and has the ability to reduce coagulation and inflammation markers. Hospitalized patients with COVID-19 should be placed on thromboprophylaxis with the option of full therapeutic anticoagulation or tissue plasminogen activator in high-risk or mechanically ventilated patients. Thromboprophylaxis should also be considered at hospital discharge for high-risk patients. Clinical judgment should be used to evaluate the bleeding and safety risk of anticoagulation in patients with COVID-19 without confirmed data.
RETINAL SENSITIVITY AND VESSEL DENSITY AFTER MACULAR HOLE SURGERY WITH THE SUPERIOR INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE
Authors: Kunikata Hiroshi , Yasuda Masayuki , Aizawa Naoko , Osada Urara , Nishiguchi Koji M. , Abe Toshiaki , Nakazawa Toru
Published: June 2020

Purpose:

To evaluate retinal vessel density and retinal sensitivity (RS) after macular hole surgery with the superior inverted internal limiting membrane flap technique.

Methods:

Retrospective, observational case series. Twenty-one patients with idiopathic macular hole underwent 27-gauge vitrectomy with the superior inverted internal limiting membrane flap technique and triamcinolone acetonide. Measurements included RS, which was measured with microperimetry, as well as retinal vessel density in the superficial capillary plexus (SCP) and deep capillary plexus (DCP), which was measured with optical coherence tomography angiography. All parameters were evaluated in the superior and inferior sectors of the macula preoperatively and 1, 3, and 6 months postoperatively.

Results:

Six months postoperatively, retinal thickness in the inferior sector was unchanged, but retinal thickness in the superior sector decreased significantly (P < 0.01). SCP vessel density in both sectors was unchanged at all postoperative time points. DCP vessel density in both sectors increased very significantly at 3 months (P < 0.01) and returned to baseline at 6 months. RS in the inferior sector increased by 47% 3 months postoperatively and by 61% 6 months postoperatively (P < 0.05 and P < 0.001, respectively), but RS in the superior sector increased only at 6 months postoperatively and only by 22% (P < 0.05).

Conclusion:

Lower recovery of RS in the superior sector suggests that internal limiting membrane peeling might affect the postoperative visual function.
INCIDENCE, PROGRESSION, AND RISK FACTORS OF EPIRETINAL MEMBRANES IN THE ELDERLY
Authors: Morillon Caroline , Le Goff Mélanie , Gattoussi Sarra , Korobelnik Jean-François , Rougier Marie-Bénédicte , Schweitzer Cédric , Delcourt Cécile , Delyfer Marie-Noëlle
Published: June 2020

Purpose:

To determine the incidence, progression rate, and risk factors for epiretinal membranes (ERMs) in a population of French elderly subjects.

Methods:

Seven hundred and thirty-five eyes of 413 participants of the population-based ALIENOR study were included between 2009 and 2010. Participants were re-evaluated every 2 years between 2011 and 2017 (i.e., three follow-up visits). The mean duration of follow-up was 5.09 years (SD, 1.8; range, 0.99–7.85). Epiretinal membranes were graded from spectral-domain optical coherence tomography images according to a standardized classification.

Results:

The incidence rate of ERMs was 9.42 per 100 eye-years (95% confidence interval, 7.36–12.05), corresponding to a 5-year cumulative incidence of 37.6%. In the final multivariable model, ERM incidence was significantly associated with vitreomacular or vitreopapillary adhesion at baseline (hazard ratio, 2.15; P = 0.02), choroidal thinning (hazard ratio, 1.04 per 10 μm decrease; P = 0.02), ERM in the contralateral eye (P = 0.02), and smoking after 85 years (hazard ratio, 6.01; P = 0.003). The 5-year cumulative progression rate was 6.9%.

Conclusion:

Incidence of ERMs was higher in our population than that previously reported, most probably because of the use of spectral-domain optical coherence tomography images. Incident ERMs were found to be associated with vitreous adhesion at baseline, choroidal thinning, ERM in the contralateral eye, and smoking after 85 years.
POSTOPERATIVE MOVEMENT OF THE FOVEA AFTER SUCCESSFUL SURGERY IN PATIENTS WITH IDIOPATHIC EPIRETINAL MEMBRANES
Authors: Datlinger Felix , Georgopoulos Michael , Aliyeva Leyla , Meyer Elias L. , Abela-Formanek Claudette , Pollreisz Andreas , Schmidt-Erfurth Ursula , Sacu Stefan
Published: June 2020

Purpose:

To evaluate the change in the fovea's postoperative location after successful pars plana vitrectomy with combined epiretinal and internal limiting membrane peeling in patients with idiopathic epiretinal membranes (iERMs).

Methods:

In this prospective study 32 eyes of 32 patients with iERMs were followed from baseline before until 3 months after surgery. Study measures included 4-m Early Treatment Diabetic Retinopathy Study best-corrected visual acuity, enhanced-depth imaging-optical coherence tomography, and intraoperative fundus photographs. Foveal movement was assessed by measuring the change in the papillofoveal distance (∆PFD).

Results:

Mean ∆PFD in the study eye was −124 µm (±138) and −272 µm (±213) one day and 3 months after surgery, respectively. Mean ∆PFD after 3 months was greater in the study than in the fellow eye (P < 0.001). ∆PFD at Month 3 did not correlate with the internal limiting membrane area peeled (P = 0.78).

Conclusion:

Foveal movement starts immediately after surgery and causes a statistically significant reduction in PFD after uneventful macular pucker surgery. ∆PFD correlates statistically significantly with baseline best-corrected visual acuity and baseline central retinal thickness. The internal limiting membrane peeling size had no significant effect on the amount of postoperative foveal dislocation.