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Introduction: With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated‐dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. Methods: We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas‐directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional‐dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. Results: Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas‐directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p < 0.001) and treatment between 2016 and 2019 (aOR 2.54, p < 0.001) were associated with greater receipt of EDR, whereas use of chemotherapy (aOR 0.60, p < 0.001) was associated with less receipt. Median OS estimates for EDR and CDR were 14.5 months and 13.0 months (p < 0.0001), respectively. For radiation therapy subset patients with available survival data (n = 13,579), multivariable Cox regression correlated EDR (adjusted hazard ratio 0.85, 95% confidence interval 0.80–0.91; p < 0.001) with longer OS versus CDR. Discussion and Conclusions: Utilization of EDR has increased since 2016, but overall utilization of RT for LAPC has remained at less than one in five patients for almost two decades. These real‐world results additionally provide an estimate of effect size of EDR for future prospective trials. [ABSTRACT FROM AUTHOR]

Lytic polysaccharide monooxygenases (LPMOs) are Cu‐dependent metalloenzymes that catalyze the hydroxylation of strong C−H bonds in polysaccharides using O2 or H2O2 as oxidants (monooxygenase/peroxygenase). In the absence of C−H substrate, LPMOs reduce O2 to H2O2 (oxidase) and H2O2 to H2O (peroxidase) using proton/electron donors. This rich oxidative reactivity is promoted by a mononuclear Cu center in which some of the amino acid residues surrounding the metal might accept and donate protons and/or electrons during O2 and H2O2 reduction. Herein, we utilize a podal ligand containing H‐bond/proton donors (LH2) to analyze the reactivity of mononuclear Cu species towards O2 and H2O2. [(LH2)CuI]1+ (1), [(LH2)CuII]2+ (2), [(LH−)CuII]1+ (3), [(LH2)CuII(OH)]1+ (4), and [(LH2)CuII(OOH)]1+ (5) were synthesized and characterized by structural and spectroscopic means. Complex 1 reacts with O2 to produce 5, which releases H2O2 to generate 3, suggesting that O2 is used by LPMOs to generate H2O2. The reaction of 1 with H2O2 produces 4 and hydroxyl radical, which reacts with C−H substrates in a Fenton‐like fashion. Complex 3, which can generate 1 via a reversible protonation/reduction, binds H2O and H2O2 to produce 4 and 5, respectively, a mechanism that could be used by LPMOs to control oxidative reactivity. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to determine the immunologic profile associated with disease flares in patients with systemic lupus erythematosus (SLE) and to investigate the clinical significance of any differences observed between patients during and following a flare. Methods: Multiparameter flow cytometry was used to examine 47 immune populations within the peripheral blood of 16 healthy controls, 25 patients with clinically quiescent SLE, and 46 patients with SLE experiencing a flare at baseline and at 6‐ and 12‐month follow‐up visits. Unsupervised clustering was used to identify patients with similar immune profiles and to track changes over time. Parametric or nonparametric statistics were used when appropriate to assess the association of cellular phenotypes with clinical and laboratory parameters. Results: Five clusters of patients were identified that variably contained patients with active and quiescent SLE, and that had distinct clinical phenotypes. Patients characterized by increased T peripheral helper, activated B, and age‐associated B cells were the most likely to be flaring at baseline, as well as the most likely to remain active or flare over the subsequent year if they acquired or retained this phenotype at follow‐up. In contrast, patients who had increased T helper (Th) cells in the absence of B cell changes, or who had increased Th1 cells and innate immune populations, mostly developed quiescent SLE on follow‐up. A significant proportion of patients with SLE had depletion of many immune populations at flare and only showed increases in these populations post‐flare. Conclusion: Cellular phenotyping of patients with SLE reveals several distinct immunologic profiles that may help to stratify patients with regard to prognosis and treatment. [ABSTRACT FROM AUTHOR]

Introduction: Polynucleotides (PN) are becoming more prominent in aesthetic medicine. However, the structural characteristics of PN have not been published and PN from different companies may have different structural characteristics. This study aimed to elucidate the structural attributes of DOT™ PN and distinguish differences with polydeoxyribonucleotides (PDRN) using high‐resolution scanning electron microscopy (SEM) imaging. Materials and methods: DOT™ PN was examined using a Quanta 3‐D field emission gun (FEG) Scanning Electron Microscope (SEM). Sample preparation involved cryogenic cooling, cleavage, etching, and metal coating to facilitate high‐resolution imaging. Cryo‐FIB/SEM techniques were employed for in‐depth structural analysis. Results: PDRN exhibited an amorphous structure without distinct features. In contrast, DOT™ PN displayed well‐defined polyhedral shapes with smooth, uniformly thick walls. These cells were empty, with diameters ranging from 3 to 8 micrometers, forming a seamless tessellation pattern. Discussion: DOT™ PN's distinct geometric tessellation design conforms to the principles of biotensegrity, providing both structural reinforcement and integrity. The presence of delicate partitions and vacant compartments hints at possible uses in the field of pharmaceutical delivery systems. Within the realms of beauty enhancement and regenerative medicine, DOT™ PN's capacity to bolster cell growth and tissue mending could potentially transform approaches to rejuvenation treatments. Its adaptability becomes apparent when considering its contributions to drug administration and surgical procedures. Conclusion: This study unveils the intricate structural scaffold features of DOT™ PN for the first time, setting it apart from PDRN and inspiring innovation in biomedicine and materials science. DOT™ PN's unique attributes open doors to potential applications across healthcare and beyond. [ABSTRACT FROM AUTHOR]

Objective: Homicide is the extreme endpoint along the continuum of interpersonal violence. Violence in healthcare settings and directed toward healthcare workers has been a growing concern. Analysis of health professionals' homicides is needed to inform prevention interventions. Methods: Decedent numbers, age, and sex in the National Violent Death Reporting System are reported for 10 types of health professionals: advance practice registered nurses, dentists, nurses, pharmacists, physicians, physician assistants, psychiatrists, psychologists, social workers, and veterinarians. Results: Between 2003 and 2020, 944 homicides of these professionals were reported to the NVDRS. Nearly 80% of victims were women; 53% of homicides involved guns. Nurses, social workers, physicians, and pharmacists comprised the most victims. In 2020, nurses, social workers, pharmacists, and psychologists had the highest homicide rates relative to their workforce size. Few of these homicides were related to professionals' work. The number of homicides within these professions correlated highly with the size of professions' workforces. Conclusions: Health professionals' homicides constitute a small proportion of US homicides generally at lower rates than seen in the general population. Age is likely one of the protective factors. Future, more comprehensive data will provide greater insights into emerging trends to inform strategies to mitigate homicide risk in health professionals. Prevention needs to go beyond healthcare settings and address societal roots of violence. [ABSTRACT FROM AUTHOR]

Background: An intradermal injection is a medical procedure that involves administering a small amount of medication or substance into the dermal layer of the skin. This research focused on identifying the most suitable injection needle for precise intradermal administration of skin boosters. Methods: The study involved conducting intradermal injections on four cadavers and participants using a 2 mm length, 34‐gauge needle (N‐Finders, Inc., South Korea). During the cadaveric study, the polynucleotide prefilled syringe was dyed green, and an anatomist performed dissections, removing only the skin layer. Ultrasonographic observations were carried out to ensure accurate intradermal injection placement. Results: In all four cadavers, the facial injections at the anterior cheek region were precisely administered intradermally at a 30‐degree injection angle. However, the 90‐degree injection was found just below the dermal layer upon skin layer removal. Discussion: The findings suggest that using a 2 mm needle length allows for easy and convenient intradermal injections. [ABSTRACT FROM AUTHOR]

Background: Polynucleotides (PN) are increasingly used for the treatment of facial erythema in the Republic of Korea. However, there are limited pre‐clinical and clinical data on the efficacy of polynucleotides for facial erythema. In this study, we investigated the current practice and perceived effectiveness of polynucleotide treatment for facial erythema among cosmetic physicians. Methods: By conducting a survey among clinicians who use PN in clinical practice, we explored the current practices and assessed the perceived effectiveness of polynucleotides in treating facial erythema. Results: A total of 557 physicians who used polynucleotides for facial erythema participated in the survey. Polynucleotides were used by 84.4%, 66.4%, and 47.4% of physicians for facial erythema caused by inflammatory facial dermatosis, repeated laser/microneedle radiofrequency, and steroid overuse, respectively. Among those users, 88.1%, 90%, and 83.7% respectively in those same categories answered that polynucleotides were "highly effective" or "effective." Furthermore, they agreed that polynucleotides have the following properties: wound healing/regeneration (95.8%), protection of skin barrier (92.2%), hydration (90.5%), vascular stabilization (81.0%), and anti‐inflammation (79.5%). Conclusion: Our findings showed that cosmetic physicians in the Republic of Korea have used PN as a part of combination treatment for facial erythema resulting from inflammatory facial dermatosis and repeated laser/ microneedle radiofrequency, rather than from steroid overuse. Also, most clinicians agreed that PN was effective for treatment of facial erythema. Given the lack of pre‐clinical and clinical trial evidence, the empirical responses of practicing physicians provide useful information to guide clinical practice and further research. [ABSTRACT FROM AUTHOR]

Objective: Elevated levels of serum interferon‐α (IFNα) and the disruption of B cell tolerance are central to systemic lupus erythematosus (SLE) immunopathogenesis; however, the relationship between these 2 processes remains unclear. The purpose of this study was to investigate the impact of elevated IFNα levels on B cell tolerance mechanisms in vivo and determine whether any changes observed were due to the direct effect of IFNα on B cells. Methods: Two classical mouse models of B cell tolerance were used in conjunction with an adenoviral vector encoding IFNα to mimic the sustained elevations of IFNα seen in SLE. The role of B cell IFNα signaling, T cells, and Myd88 signaling was determined using B cell–specific IFNα receptor–knockout, CD4+ T cell–depleted, or Myd88‐knockout mice, respectively. Flow cytometry, enzyme‐linked immunosorbent assay, real‐time quantitative polymerase chain reaction, and cell cultures were used to study the effects of elevated IFNα on the immunologic phenotype. Results: Elevation of serum IFNα disrupts multiple B cell tolerance mechanisms and leads to autoantibody production. This disruption was dependent upon B cell expression of IFNα receptor. Many of the IFNα‐mediated alterations also required the presence of CD4+ T cells as well as Myd88, suggesting that IFNα acts directly on B cells to modify their response to Myd88 signaling and their ability to interact with T cells. Conclusion: The results provide evidence that elevated IFNα levels act directly on B cells to facilitate autoantibody production and further highlight the importance of IFN signaling as a potential therapeutic target in SLE. [ABSTRACT FROM AUTHOR]

Studies on PN have been published previously in the treatment of periorbital rhytides[7] and post-surgery scars[2]; however, this is the first study using PN as a volumizing treatment for fat atrophy in vivo. In addressing iatrogenic subcutaneous fat atrophy, PN injection therapy yielded highly satisfactory outcomes with ease of use, positive patient compliance, and no significant known side effects. High-viscosity PN injections show potential beyond scar treatment, providing robust biomechanical responses via its 3-D scaffold structure which can enhance clinical outcomes. [Extracted from the article]

Background/Purpose: Risk‐stratified pancreatectomy clinical pathways using regional anesthesia and multimodality analgesia have decreased overall opioid use, but the additional benefits of robotic surgery in opioid reduction for pancreatoduodenectomy (PD) are unknown. We compared the inpatient opioid use between robotic PD and open PD. Methods: Patients undergoing open PD within a protocol evaluating preincisional regional anesthetic block bundles were compared to consecutively‐treated patients undergoing robotic PD identified from a prospectively maintained single‐institutional database. Clinical characteristics, operative outcomes, pain scores and inpatient oral morphine equivalent (OME) use were compared between patients treated with robotic or open PD. Patients with a history of continuous‐release opioid dependence were excluded. Results: Of 114 total patients, 25 underwent robotic PD and 89 underwent open PD. Intraoperative opioid use was not different (P =.87), nor were cumulative pain scores. Robotic PD patients used significantly fewer OMEs per day on postoperative days 1–4 (P =.039), used fewer total OMEs during hospitalization (robotic: median = 79, IQR 42.5–141; open: median = 126, IQR 61.3–203.8; P =.0036) and were discharged with fewer OMEs (robotic: median = 0, IQR 0–43.8; open: median = 25, IQR 0–75; P =.009) despite a shorter length of stay (robotic: median = 4, open: median = 5, P =.002). Conclusions: Robotic PD patients required fewer inpatient OMEs than open PD while maintaining similar pain scores. A higher percentage of robotic PD patients tapered off of opioids prior to discharge than open surgery patients treated with a standardized opioid reduction protocol despite a shorter length of stay. These results provide a rationale for choosing robotic PD when feasible to minimize opioid use. [ABSTRACT FROM AUTHOR]

Management of locoregionally advanced head and neck cancers (HNCs) remains a challenge. Some groups have attempted to use stereotactic radiotherapy (SBRT) to deliver "boost" treatment following conventional radiotherapy to improve local control (LC) and overall survival (OS), while aiming for acceptable toxicities. Medline, EMBASE, and Cochrane Library databases were queried for SBRT as curative‐intent planned boost in HNC after conventional radiotherapy. Individual studies were reviewed from inception until January 2021, extracting patient, treatment, and outcome data. Nine studies met inclusion criteria, representing 454 unique patients treated with curative intent across multiple head and neck sites with conventional radiotherapy. At 3 years, median LC was 92% (90%–98%), and median OS was 80% (75%–91%). Seven treatment‐related grade 5 toxicities (1.5%) were reported. Despite acceptable LC and OS rates, there were severe treatment‐related late toxicities. As such, SBRT boost should only be used in investigational settings until more data is available. [ABSTRACT FROM AUTHOR]

Background: Enhanced recovery after surgery (ERAS) protocols have been associated with improved postoperative outcomes but require further validation in thoracic surgery. This study evaluated outcomes of patients undergoing pulmonary resection before and after implementation of an ERAS protocol. Methods: Electronic medical records were queried for all patients undergoing pulmonary resection between April 2017 and April 2019. Patients were grouped into pre- and post-ERAS cohorts based on dates of operation. The ERAS protocol prioritized early mobilization, limited invasive monitoring, euvolemia, and non-narcotic analgesia. Primary outcome measures included intensive care unit (ICU) utilization, postoperative pain metrics, and perioperative morbidity. Regression analyses were performed to identify predictors of morbidity. Subgroup analyses were performed by pulmonary risk profile and surgical approach. Results: A total of 64 pre- and 67 post-ERAS patients were included in the study. ERAS implementation was associated with reduced postoperative ICU admission (pre: 65.6% vs. post: 19.4%, p < 0.0001), shorter ICU median length of stay (LOS) (pre: 1 vs. post: 0, p < 0.0001), and decreased opioid usage measured by median morphine milligram equivalents (pre: 40.5 vs. post: 20.0, p < 0.0001). Post-ERAS patients also reported lower visual analog scale (VAS) pain scores on postoperative days (POD) 1 and 2 (pre: 6.3/5.6 vs. post: 5.3/4.2, p = 0.04/0.01) as well as average VAS pain score over POD0-2 (pre: 6.2 vs. post: 5.2, p = 0.005). Conclusions: Implementation of an ERAS protocol for pulmonary resection, which dictated reduced ICU admissions, did not increase major postoperative morbidity. Additionally, ERAS-enrolled patients reported improved postoperative pain control despite decreased opioid utilization. [ABSTRACT FROM AUTHOR]

Prestige Biopharma Ltd (Singapore) has developed HD201, a proposed biosimilar to reference product trastuzumab. As a part of the stepwise approach to ensure comparability between the biosimilar candidate and the reference medicinal product, a phase I study in healthy subjects was conducted to demonstrate the pharmacokinetic (PK) equivalence (NCT03776240). The primary objective of the study was to demonstrate (PK) equivalence of HD201, EU‐Herceptin®, and US‐Herceptin® given at 6 mg/kg as a 90‐min i.v. infusion to healthy male subjects. A pairwise comparisons based on the primary endpoint AUC0–inf and secondary PK endpoints, AUC0–last and Cmax were undertaken. PK equivalence was to be concluded if the 90% confidence interval (CI) for the ratio of geometric means for each criterion were within the equivalence margin of 80% to 125%. Secondary objectives included assessment of other PK parameters, safety, tolerability, and immunogenicity in the three arms. A total of 105 healthy male subjects (35/treatment) were randomized in this study. The 90% CI for the ratios of AUC0–inf, Cmax and AUC0–last, were within 80%–125% for the comparisons of HD201 to EU‐Herceptin® or US‐Herceptin® and EU‐Herceptin® to US‐Herceptin®. The frequency of subjects with TEAEs of special interest was slightly lower in the HD201 group (20.0%) compared to the other treatment groups (EU‐Herceptin®: 34.3%; US‐Herceptin®: 31.4%). Only 1 subject (EU‐Herceptin® group) developed anti‐drug antibodies prior to dosing. Overall, HD201 demonstrates PK similarity to both EU‐Herceptin® and US‐Herceptin®. The three study drugs also demonstrated similar safety profiles.TROIKA‐1: A Double‐blind, Randomized, Parallel Group, Study aimed to demonstrate the equivalent pharmacokinetic profile of HD201, a potential biosimilar candidate to trastuzumab, versus EU‐Herceptin® and US‐Herceptin® in Healthy Male Subjects. [ABSTRACT FROM AUTHOR]

Recent studies defined a potentially important role of the microbiome in modulating pancreatic ductal adenocarcinoma (PDAC) and responses to therapies. We hypothesized that antibiotic usage may predict outcomes in patients with PDAC. We retrospectively analyzed clinical data of patients with resectable or metastatic PDAC seen at MD Anderson Cancer from 2003 to 2017. Demographic, chemotherapy regimen and antibiotic use, duration, type, and reason for indication were recorded. A total of 580 patients with PDAC were studied, 342 resected and 238 metastatic patients, selected retrospectively from our database. Antibiotic use, for longer than 48 hrs, was detected in 209 resected patients (61%) and 195 metastatic ones (62%). On resectable patients, we did not find differences in overall survival (OS) or progression‐free survival (PFS), based on antibiotic intake. However, in the metastatic cohort, antibiotic consumption was associated with a significantly longer OS (13.3 months vs. 9.0 months, HR 0.48, 95% CI 0.34–0.7, p = 0.0001) and PFS (4.4 months vs. 2 months, HR 0.48, 95% CI 0.34–0.68, p = <0.0001). In multivariate analysis, the impact of ATB remained significant for PFS (HR 0.59, p = 0.005) and borderline statistically significant for OS (HR 0.69, p = 0.06). When we analyzed by chemotherapy regimen, we found that patients who received gemcitabine‐based chemotherapy as first‐line therapy (n = 118) had significantly prolonged OS (HR 0.4, p 0.0013) and PFS (HR 0.55, p 0.02) if they received antibiotics, while those receiving 5FU‐based chemotherapy (n = 98) had only prolonged PFS (HR 0.54, p = 0.03). Antibiotics‐associated modulation of the microbiome is associated with better outcomes in patients with metastatic PDAC. We have analyzed the effect of antibiotics' intake on two cohorts of patients with pancreatic adenocarcinoma, resectable, and metastatic. We have found that on the metastatic cohort, antibiotics use was significantly associated with better outcomes, particularly, on patients that received gemcitabine based‐chemotherapy as the first line. [ABSTRACT FROM AUTHOR]

The cover image is based on the Original Article High‐resolution 3‐D scanning electron microscopy (SEM) images of DOTTM polynucleotides (PN): Unique scaffold characteristics and potential applications in biomedicine by Michael James Kim et al., https://doi.org/10.1111/srt.13667..By Michael James Kim; Hyun‐Jun Park; Rae‐Jun Jung; Chee‐Youb Won; Seul‐Ong Ohk; Hong‐Taek Kim; Nark‐Kyung Roh and Kyu‐Ho YiReported by Author; Author; Author; Author; Author; Author; Author; Author [Extracted from the article]

Leucine Zipper EF‐hand containing transmembrane protein‐1 (LETM1) is an inner mitochondrial membrane protein that mediates mitochondrial calcium (Ca2+)/proton exchange. The matrix residing carboxyl (C)‐terminal domain contains a sequence identifiable EF‐hand motif (EF1) that is highly conserved among orthologues. Deletion of EF1 abrogates LETM1 mediated mitochondrial Ca2+ flux, highlighting the requirement of EF1 for LETM1 function. To understand the mechanistic role of this EF‐hand in LETM1 function, we characterized the biophysical properties of EF1 in isolation. Our data show that EF1 exhibits α‐helical secondary structure that is augmented in the presence of Ca2+. Unexpectedly, EF1 features a weak (~mM), but specific, apparent Ca2+‐binding affinity, consistent with the canonical Ca2+ coordination geometry, suggested by our solution NMR. The low affinity is, at least in part, due to an Asp at position 12 of the binding loop, where mutation to Glu increases the affinity by ~4‐fold. Further, the binding affinity is sensitive to pH changes within the physiological range experienced by mitochondria. Remarkably, EF1 unfolds at high and low temperatures. Despite these unique EF‐hand properties, Ca2+ binding increases the exposure of hydrophobic regions, typical of EF‐hands; however, this Ca2+‐induced conformational change shifts EF1 from a monomer to higher order oligomers. Finally, we showed that a second, putative EF‐hand within LETM1 is unreactive to Ca2+ either in isolation or tandem with EF1. Collectively, our data reveal that EF1 is structurally and biophysically responsive to pH, Ca2+ and temperature, suggesting a role as a multipartite environmental sensor within LETM1. [ABSTRACT FROM AUTHOR]

Background: Hybrid coronary revascularization (HCR) constitutes a left internal mammary artery graft to the left anterior descending (LAD) coronary artery, coupled with percutaneous coronary intervention (PCI) for non‐LAD lesions. This management strategy is not commonly offered to patients with complex multivessel disease. Our objective was to evaluate 8‐year survival in patients with triple‐vessel disease (TVD) treated by HCR, compared with that of concurrent matched patients managed by traditional coronary artery bypass grafting (CABG) or multivessel PCI. Methods: A retrospective review was undertaken of 4805 patients with TVD who presented between January 2009 and December 2016. A cohort of 100 patients who underwent HCR were propensity‐matched with patients treated by CABG or multivessel PCI. The primary endpoint was all‐cause mortality at 8 years. Results: Patients with TVD who underwent HCR had similar 8‐year mortality (5.0%) as did those with CABG (4.0%) or multivessel PCI (9.0%). A composite endpoint of death, repeat revascularization, and new myocardial infarction, was not significantly different between patient groups (HCR 21.0% vs CABG 15.0%, P =.36; HCR 21.0% vs PCI 25.0%, P =.60). Despite a higher baseline synergy between percutaneous coronary intervention with taxus and cardiac surgery(SYNTAX) score, HCR was able to achieve a lower residual SYNTAX score than multivessel PCI (P =.001). Conclusions: In select patients with TVD, long‐term survival and FREEDOM from major adverse cardiovascular events after HCR are similar to that seen after traditional CABG or multivessel PCI. HCR should be considered for patients with multivessel disease, presuming a low residual SYNTAX score can be achieved. [ABSTRACT FROM AUTHOR]

CrossTalk opposing view: E-cigarettes expose users to adverse effects of vapours and the potential for nicotine addiction Keywords: e-cigarette; mucociliary clearance; nicotine addiction EN e-cigarette mucociliary clearance nicotine addiction 3053 3056 4 08/01/20 20200801 NES 200801 Introduction The use of e-cigarettes has risen in popularity over the past decade, especially among adolescents. Am J Physiol Lung Cell Mol Physiol 316, L470 - L486. Am J Physiol Lung Cell Mol Physiol 313, L278 - L292. [Extracted from the article]

Despite advances in cancer therapeutics, pancreatic cancer remains difficult to treat and often develops resistance to chemotherapies. We have evaluated a bioavailable genistein analogue, AXP107‐11 which has completed phase Ib clinical trial, as an approach to sensitize tumor cells to chemotherapy. Using organotypic cultures of 14 patient‐derived xenografts (PDX) of pancreatic ductal adenocarcinoma, we found that addition of AXP107‐11 indeed sensitized 57% of cases to gemcitabine treatment. Results were validated using PDX models in vivo. Further, RNA‐Seq from responsive and unresponsive tumors proposed a 41‐gene treatment‐predictive signature. Functional and molecular assays were performed in cell lines and demonstrated that the effect was synergistic. Transcriptome analysis indicated activation of G‐protein‐coupled estrogen receptor (GPER1) as the main underlying mechanism of action, which was corroborated using GPER1‐selective agonists and antagonists. GPER1 expression in pancreatic tumors was indicative of survival, and our study proposes that activation of GPER1 may constitute a new avenue for pancreatic cancer therapeutics. [ABSTRACT FROM AUTHOR]

Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these age‐related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in TSC1 knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1's activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased GDF15 is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of GDF15 via phosphorylation of STAT3. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and STAT3's phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to age‐related muscle atrophy, and GDF signaling is a proposed mechanism. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: The time interval at which Nasal Obstruction Symptom Evaluation (NOSE) scores stabilize after functional septorhinoplasty has not been determined. Our goal was to characterize longitudinal trends of patient-reported outcomes of nasal obstruction using the NOSE survey instrument following functional septorhinoplasty.Study Design: Prospective longitudinal cohort study.Methods: Adult patients (≥18 years) with nasal obstruction who underwent functional septorhinoplasty by three different surgeons at a single academic, tertiary referral center were identified. NOSE scores were obtained preoperatively and prospectively during three postoperative intervals defined as early (1-3 months), middle (4-6 months), and late (≥10 months.) Longitudinal analysis included repeated measures analysis of variance and adjustments for multiple comparisons.Results: A total of 49 patients met inclusion criteria. For the total cohort, mean NOSE scores significantly improved between preoperative and early postoperative evaluations (71.4, standard deviation [SD] ± 17.0 vs. 24.2, SD ± 19.5; P < .001) but did not significantly change between early and middle (20.6, SD ± 19.1; P = .543) or middle and late (23.1, SD ± 24.9; P > .999) time intervals.Conclusions: Patients with nasal obstruction who undergo functional septorhinoplasty can be expected to have significant improvement in self -reported nasal obstruction as early as 1 to 3 months postoperatively with a continued, durable, long-standing benefit lasting at least 10 months after surgery. Future studies can consider the 3-month time frame as a proxy for 1 year outcomes to help reduce survey burden.Level Of Evidence: 2c Laryngoscope, 129:841-846, 2019. [ABSTRACT FROM AUTHOR]

The cover image is based on the Original Article I Current practices and perceived effectiveness of polynucleotides for treatment of facial erythema by cosmetic physicians i by Dagyeong Lee et al., https://doi.org/10.1111/srt.13466. [Extracted from the article]

Objectives To compare incidence of falls in an emergency department ( ED) cohort using a traditional International Classification of Diseases, Ninth Revision ( ICD-9) code-based scheme and an expanded definition that included chief complaint information and to examine the clinical characteristics of visits 'missed' in the ICD-9-based scheme. Design Retrospective electronic record review. Setting Academic medical center ED. Participants Individuals aged 65 and older seen in the ED between January 1, 2013, and September 30, 2015. Measurements Two fall definitions were applied (individually and together) to the cohort: an ICD-9-based definition and a chief complaint definition. Admission rates and 30-day mortality (per encounter) were measured for each definition. Results Twenty-three thousand eight hundred eighty older adult visits occurred during the study period. Using the most-inclusive definition ( ICD-9 code or chief complaint indicating a fall), 4,363 visits (18%) were fall related. Of these visits, 3,506 (80%) met the ICD-9 definition for a fall-related visit, and 2,664 (61%) met the chief complaint definition. Of visits meeting the chief complaint definition, 857 (19.6%) were missed when applying the ICD-9 definition alone. Encounters missed using the ICD-9 definition were less likely to lead to an admission (42.9%, 95% confidence interval ( CI) = 39.7-46.3%) than those identified (54.4%, 95% CI = 52.7-56.0%). Conclusion Identifying individuals in the ED who have fallen based on diagnosis codes underestimates the true burden of falls. Individuals missed according to the code-based definition were less likely to have been admitted than those who were captured. These findings call attention to the value of using chief complaint information to identify individuals who have fallen in the ED-for research, clinical care, or policy reasons. [ABSTRACT FROM AUTHOR]

Background The osteocutaneous radial forearm free flap (RFFF) is a versatile flap primarily used to reconstruct composite defects involving the mandible. The purpose of this study was to describe our experience with this flap for nonmandible reconstruction. Methods All patients undergoing nonmandible osseous reconstruction with free-tissue transfer were reviewed. Patients with osteocutaneous RFFF reconstructions were evaluated. The retrospective review of all osteocutaneous RFFFs was performed from 1998 to 2014. Results One hundred forty-two nonmandible osseous reconstructions were performed. Twenty-five patients underwent nonmandible osteocutaneous RFFF reconstruction. Eleven patients failed previous nonmicrovascular reconstruction. Reconstruction was for defects of the: palatomaxillary complex (n = 15), orbitomaxillary complex (n = 4), nasomaxillary complex (n = 4), larynx (n = 1), and clavicle (n = 1). There were no flap compromises. Postoperative complications included: 2 partial intraoral dehiscences; 1 recipient-site infection; and 1 seroma. Eight reconstructions required secondary procedures to improve functional and/or cosmetic outcomes. Conclusion The osteocutaneous RFFF is a robust flap that can be used to reconstruct composite defects involving bone and soft-tissue beyond the mandible. [ABSTRACT FROM AUTHOR]

The recent Zika virus ( ZIKV) epidemic is particularly challenging in the field of reproductive medicine as various biological tissues and byproducts, such as intravenous immunoglobulin G or cells are utilized during reproductive cycles, and an infected mother has an increased risk of having babies with fetal microcephaly and other congenital brain anomalies. In this review, current guidelines for prevention of sexual transmission of ZIKV, ZIKV testing, and tissue and blood product usages are summarized for physicians caring for those planning pregnancy or going through infertility treatment. [ABSTRACT FROM AUTHOR]

G-CSF is used to enhance hemato- poietic recovery after autologous stem cell transplantation (ASCT), but the optimal dose of G-CSF during engraft- ment has not been established. The medical cost of ASCT is a serious financial burden in developing countries, and G-CSF is the most costly drug used in this procedure. We evaluated whether a lower, vial-size fitted dose of lenograstim is clinically equivalent to a higher fixed dose. A prospective randomized study was performed on 33 patients (11 non-Hodgkin's lymphoma, 8 multiple myeloma, 14 breast cancer) undergoing ASCT. Patients were randomly administered 100 µg or 250 µg lenograstim daily starting on the next day of ASCT, with a minimum infusion of 3 × 106 CD34+ cells per kg. For both lenograstim doses, median time to neutrophil engraftment was 9 days and median time to PLT engraftment was 11 days. Episodes of clinically documented infections were 10 per 379 patient-days in the 100 µg per day group and 10 per 320 patient-days in the 250 µg per day group. There were no between-group differences in requirements for transfusion of RBCs or PLTs. Duration of hospitalization was 16 days for the 100 µg per day group and 17 days for the 250 µg per day group. Daily lenograstim dose per patient's body weight and total amount of lenograstim used during ASCT were both significantly lower in the 100 µg per day group. Administration of 100 µg per day of lenograstim showed comparable clinical efficacy to 250 µg per day lenograstim for immediate hematopoietic recovery after ASCT. Use of the lower dose was associated with lower overall lenograstim usage and lower cost. [ABSTRACT FROM AUTHOR]

Vitamin D has a pivotal role in regulating immune responses by promoting Th2 immune responses and suppressing Th1 responses. Propensities to a Th1 immune response and increased NK-cell levels and cytotoxicity have been reported in women with recurrent pregnancy losses (RPL). In women with RPL, vitamin D deficiency is prevalent; however, the effect of vitamin D on NK cells is largely unknown. In this study, we demonstrated that CD69+ activating receptor expression on NK cells was significantly decreased by incubation with 1,25(OH)2D3 in a dose-dependent manner, while CD158a and CD158b inhibitory receptor expression was upregulated. The degranulation marker CD107a was significantly downregulated on NK cells following incubation with 1,25(OH)2D3. NK-cell conjugation with K562 target cells was not affected by 1,25(OH)2D3; however, depolarization of perforin granules in conjugated NK cells was significantly increased. TLR4 expression on NK cells was significantly decreased and TNF-α and IFN-γ production was significantly reduced by 1,25(OH)2D3 through interference with NF-κB. Our results suggest 1,25(OH)2D3 has immune regulatory effects on NK cell cytotoxicity, cytokine secretion and degranulation process as well as TLR4 expression. Potential therapeutic application of 1,25(OH)2D3 for dysregulated NK-cell immunity should be explored in the future. [ABSTRACT FROM AUTHOR]

Objectives: A novel radiation dose reduction technology was evaluated in a cardiac catheterization laboratory during routine clinical care to determine if it could reduce radiation dose to patients undergoing coronary angiography and percutaneous coronary intervention. These results were compared to patients undergoing similar procedures in a cardiac catheterization laboratory without this technology.Background: There is a safety priority in clinical care to reduce X-ray radiation dose to patients in order to lower the risk of deterministic and stochastic effects. Dose reduction technologies must be verified in clinical settings to prove if they reduce X-ray radiation dose and to what extent.Methods: Radiation dose data and procedure characteristics of 268 consecutive patients were collected and analyzed from a cardiac catheterization laboratory with dose reduction technology installed (referred to as Lab A, n = 135) and from a cardiac catheterization laboratory without this technology (referred as Lab B, n = 133).Results: For diagnostic procedures, the median total dose-area product in Lab A was reduced by 46% (P < 0.0001) compared to Lab B, with no differences in terms of body mass index (P = 0.180), total fluoroscopy times (P = 1), number of acquired images (P = 0.920), and contrast medium (P = 0.660). For interventional procedures, the median total dose-area product in Lab A was reduced by 34% (P = 0.015) compared to Lab B, with no differences in terms of body mass index (P = 0.665), total fluoroscopy times (P = 0.765), number of acquired images (P = 0.923), and contrast medium (P = 0.969).Conclusions: This new dose reduction technology significantly reduces X-ray radiation dose without affecting fluoroscopy time, number of images, and contrast medium used during diagnostic and interventional coronary procedures. [ABSTRACT FROM AUTHOR]