Impact of Tumor-Infiltrating Lymphocytes on Overall Survival in Merkel Cell Carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin. As the clinical course can be variable, prognostic markers are needed to better stratify patients. Prior literature, composed of small series with limited sample size, has demonstrated that tumor-infiltrating lymphocytes (TILs) are an important prognostic marker in MCC. To validate these findings on a population level, we sought to analyze and report the prognostic value of TILs in a large national data set. MATERIALS AND METHODS: A retrospective observational cohort study was conducted of patients with nonmetastatic MCC from 2010 to 2015 using the National Cancer Database. Individual variables trending toward significance using a univariable analysis were included in a multivariable Cox proportional hazards model to assess their independent effect on overall survival (OS). TILs were subclassified into none, nonbrisk, and brisk and the survival analysis was performed. Propensity score-weighted multivariable analysis (PS MVA) was performed to adjust for additional confounding. RESULTS: A total of 2,182 patients met inclusion criteria: 611 (28.0%) were identified as having TILs present, and 1,571 (72.0%) had TILs absent in the tumor. On MVA, subdivision of TIL status into nonbrisk (hazard ratio [HR], 0.750; 95% confidence interval [CI], 0.602-0.933) and brisk (HR, 0.499; 95% CI, 0.338-0.735) was associated with incrementally improved OS compared with no TILs. The association of nonbrisk and brisk TILs with improved OS was retained on PS MVA (Nonbrisk: HR, 0.720; 95% CI, 0.550-0.944; Brisk: HR, 0.483; 95% CI, 0.286-0.814). CONCLUSION: The presence of nonbrisk and brisk TILs is associated with incrementally improved OS in patients with nonmetastatic MCC in a large national data set. This pathologic feature can aid with risk stratification, estimation of prognosis, and, importantly, decision-making with respect to treatment intensification in high-risk patients. IMPLICATIONS FOR PRACTICE: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy with variable clinical course. Prognostic markers are needed to better risk stratify patients. We present the largest retrospective observational cohort study of patients with nonmetastatic MCC using the National Cancer Database. Our analysis demonstrates an association between increasing degrees of tumor-infiltrating lymphocytes and incrementally improved survival. These conclusions improve pathologic risk stratification, and decision-making with respect to treatment intensification. Intensification may include adjuvant radiation therapy to the primary site after wide excision despite small tumor size, to the nodal basin in sentinel lymph node-negative patients, or offering closer follow-up.

Radiotherapy Remains Underused in the Treatment of Soft-Tissue Sarcomas: Disparities in Practice Patterns in the United States.

BACKGROUND: Practice patterns of radiation therapy (RT) use for soft-tissue sarcoma (STS) remain quite variable, despite clinical practice guidelines recommending the addition of RT to surgery for patients with high-grade STS, particularly for larger tumors. Using the National Cancer Database (NCDB), we assessed patterns of overall RT use, neoadjuvant versus adjuvant treatment, and specific RT modalities in this population. PATIENTS AND METHODS: Patients aged ≥18 years with stage II/III STS in 2004 through 2015 were identified from the NCDB. Patterns of care were assessed using multivariable logistic regression analysis. RESULTS: Of 27,426 total patients, 11,654 (42%) were treated with surgery alone versus 15,772 (58%) with RT in addition to surgery, with no overall increase in RT use over the study period. Notable clinical predictors of receipt of RT included tumor size (>5 cm), grade III, and tumors arising in the extremities. Conversely, female sex, older age (≥70 years), Black race, noncommercial insurance coverage, farther distance to treatment, and poor performance status were negative predictors of RT use. Of those receiving RT, 27% were treated with neoadjuvant RT and 73% with adjuvant RT. The proportion of those receiving neoadjuvant RT increased over time. Relevant factors associated with neoadjuvant RT included treatment at academic centers, larger tumor size, and extremity tumors. Of those who received RT with a modality specified as either intensity-modulated RT (IMRT) or 3D conformal RT (3DCRT), 61% were treated with IMRT and 39% with 3DCRT. The proportion of patients treated with IMRT increased over time. Relevant factors associated with IMRT use included treatment at academic centers, commercial insurance coverage, and larger and nonextremity tumors. CONCLUSIONS: Although use of neoadjuvant RT and IMRT has increased over time, a significant number of patients with STS are not receiving adjuvant or neoadjuvant RT. Our findings also note potential sociodemographic disparities and highlight the concern that not all patients with STS are being equally considered for RT.

Association of Age with Efficacy of Immunotherapy in Metastatic Melanoma.

Management of melanoma has been revolutionized by the use of immune checkpoint inhibitors. Immune system changes associated with aging may affect the efficacy of immune-based therapies. Using the National Cancer Database, we evaluated the impact of age on the receipt and efficacy of modern immunotherapies in patients with metastatic melanoma. We identified 11,944 patients from 2011-2015, of whom 25% received immunotherapy. Older (≥60 years), compared with younger, patients were less likely to receive immunotherapy (odds ratio, 0.69; 95% confidence interval [CI], 0.61-0.78; p < .001). Immunotherapy was associated with a survival benefit in both younger and older patients (<60 years: hazard ratio [HR], 0.64; 95% CI, 0.57-0.72; p < .001; ≥60 years: HR, 0.55; 95% CI, 0.50-0.60; p < .001). Importantly, there was a statistically significant interaction between age and survival with immunotherapy, where a greater benefit was observed for older patients (pinteraction = 0.013). Further work studying the age-related response to immunotherapy is warranted.

Consensus Report on Shigella Controlled Human Infection Model: Clinical Endpoints.

The Shigella controlled human infection model (CHIM) is valuable for assessing candidate Shigella vaccine efficacy and potentially accelerating regulatory approval. The Shigella CHIM is currently being conducted at 3 sites in the United States using Shigella flexneri 2a strain 2457T and Shigella sonnei strain 53G. Shigellosis can present variably as watery diarrhea alone or with dysentery, and can be accompanied by manifestations including fever, abdominal cramps, tenesmus, and malaise. For comparability, it is important to harmonize the primary clinical endpoint. An expert working group was convened on 2 February 2018 to review clinical data from Shigella CHIM studies performed to date and to develop a consensus primary endpoint. The consensus endpoint enabled "shigellosis" to present as severe diarrhea or moderate diarrhea or dysentery. The latter 2 criteria are met when concurrent with fever of 38.0°C and/or vomiting, and/or a constitutional/enteric symptom graded at least as "moderate" severity. The use of a blinded independent committee to adjudicate the primary endpoint by subject was also regarded as important. As safety of volunteers in challenge studies is of paramount importance and treatment timing can affect primary outcomes, a standard for early antibiotic administration was established as follows: (1) when the primary endpoint is met; (2) if a fever of ≥39.0°C develops; or (3) if the study physician deems it appropriate. Otherwise, antibiotics are given at 120 hours postinfectious challenge. The working group agreed on objective and subjective symptoms to be solicited, and standardized methods for assessing subject-reported severity of symptoms.

Gold nanoparticle-mediated signal amplification of liquid crystal biosensors for dopamine.

A unique design strategy was developed for the detection of dopamine using a newly synthesized amphiphile containing boronic acid head group at the aqueous-liquid crystal (LC) interface. The optical signal of LC for the detection of dopamine was highly amplified in the presence of functionalized gold nanoparticles.

Solvation effect on binding modes of model lignin dimer compounds on MWW 2D-zeolite.

Lignin as a potential renewable source of biofuels, chemicals, and other value-added products has gained much attention. However, the complexity of lignin structure poses a significant challenge for developing efficient valorization techniques. As most processes involve solvothermal conditions to minimize energy cost, lignin depolymerization is governed by reaction conditions (temperature and pressure) and solvents. In this work, binding of ß-O-4 linkage consisting lignin dimers on MWW two-dimensional (2D) zeolite is investigated using periodic density functional theory. Furthermore, the effect of different terminated surfaces (H:OH% = 100:0; 50:50; 0:100%), different temperatures (323, 353, 373 K), and different solvents (water and methanol) on the binding modes is quantified. Our work shows that in the gas phase the binding strength increases 10-15 kcal/mol upon increasing the number of hydroxyl groups on the surface. Also, the phenolic dimer binds more strongly than the nonphenolic dimer, and the binding strength of model compounds increases in the presence of the solvent. Analysis of structural changes in the presence of the solvent reveals that the aromatic rings are parallel to the zeolite surface and primary interaction with zeolite is through the hydroxyl groups near the ß-O-4 linkage. Furthermore, while the solvation energy decreases with increasing temperature, the opposite trend is observed for the binding energy with the surface.

Assessment of an optimized manufacturing process for inactivated quadrivalent influenza vaccine: a phase III, randomized, double-blind, safety and immunogenicity study in children and adults.

BACKGROUND: GSK has modified the licensed monovalent bulk manufacturing process for its split-virion inactivated quadrivalent influenza vaccine (IIV4) to harmonize the process among different strains, resulting in an increased number of finished vaccine doses, while compensating for the change from inactivated trivalent influenza vaccine (IIV3) to IIV4. To confirm the manufacturing changes do not alter the profile of the vaccine, a clinical trial was conducted to compare IIV4 made by the currently licensed process with a vaccine made by the new (investigational) process (IIV4-I). The main objectives were to compare the reactogenicity and safety of IIV4-I versus IIV4 in all age groups, and to demonstrate the non-inferiority of the hemagglutination-inhibition (HI) antibody responses based on the geometric mean titer ratio of IIV4-I versus IIV4 in children. METHODS: The Phase III, randomized, double-blind, multinational study included three cohorts: adults (18-49 years; N = 120), children (3-17 years; N = 821), and infants (6-35 months; N = 940). Eligible subjects in each cohort were randomized 1:1 to receive IIV4-I or IIV4. Both vaccines contained 15 µg of hemagglutinin antigen for each of the four seasonal virus strains. Adults and vaccine-primed children received one dose of vaccine, and vaccine-unprimed children received two doses of vaccine 28 days apart. All children aged ≥9 years were considered to be vaccine-primed and received one dose of vaccine. RESULTS: The primary immunogenicity objective of the study was met in demonstrating immunogenic non-inferiority of IIV4-I versus IIV4 in children. The IIV4-I was immunogenic against all four vaccine strains in each age cohort. The reactogenicity and safety profile of IIV4-I was similar to IIV4 in each age cohort, and there was no increase in the relative risk of fever (≥38 °C) with IIV4-I versus IIV4 within the 7-day post-vaccination period in infants (1.06; 95% Confidence Interval: 0.75, 1.50; p = 0.786). CONCLUSIONS: The study demonstrated that in adults, children, and infants, the IIV4-I made using an investigational manufacturing process was immunogenic with a reactogenicity and safety profile that was similar to licensed IIV4. These results support that the investigational process used to manufacture IIV4-I is suitable to replace the current licensed process. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02207413 ; trial registration date: August 4, 2014.

Two transcription factors, Pou4f2 and Isl1, are sufficient to specify the retinal ganglion cell fate.

As with other retinal cell types, retinal ganglion cells (RGCs) arise from multipotent retinal progenitor cells (RPCs), and their formation is regulated by a hierarchical gene-regulatory network (GRN). Within this GRN, three transcription factors--atonal homolog 7 (Atoh7), POU domain, class 4, transcription factor 2 (Pou4f2), and insulin gene enhancer protein 1 (Isl1)--occupy key node positions at two different stages of RGC development. Atoh7 is upstream and is required for RPCs to gain competence for an RGC fate, whereas Pou4f2 and Isl1 are downstream and regulate RGC differentiation. However, the genetic and molecular basis for the specification of the RGC fate, a key step in RGC development, remains unclear. Here we report that ectopic expression of Pou4f2 and Isl1 in the Atoh7-null retina using a binary knockin-transgenic system is sufficient for the specification of the RGC fate. The RGCs thus formed are largely normal in gene expression, survive to postnatal stages, and are physiologically functional. Our results indicate that Pou4f2 and Isl1 compose a minimally sufficient regulatory core for the RGC fate. We further conclude that during development a core group of limited transcription factors, including Pou4f2 and Isl1, function downstream of Atoh7 to determine the RGC fate and initiate RGC differentiation.

Vaccine for prevention of mild and moderate-to-severe influenza in children.

BACKGROUND: Commonly used trivalent vaccines contain one influenza B virus lineage and may be ineffective against viruses of the other B lineage. We evaluated the efficacy of a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages. METHODS: In this multinational, phase 3, observer-blinded study, we randomly assigned children 3 to 8 years of age, in a 1:1 ratio, to receive the QIV or a hepatitis A vaccine (control). The primary end point was influenza A or B confirmed by real-time polymerase chain reaction (rt-PCR). Secondary end points were rt-PCR-confirmed, moderate-to-severe influenza and rt-PCR-positive, culture-confirmed influenza. The vaccine efficacy and the effect of vaccination on daily activities and utilization of health care resources were assessed in the total vaccinated cohort (2584 children in each group) and the per-protocol cohort (2379 children in the QIV group and 2398 in the control group). RESULTS: In the total vaccinated cohort, 62 children in the QIV group (2.40%) and 148 in the control group (5.73%) had rt-PCR-confirmed influenza, representing a QIV efficacy of 59.3% (95% confidence interval [CI], 45.2 to 69.7), with efficacy against culture-confirmed influenza of 59.1% (97.5% CI, 41.2 to 71.5). For moderate-to-severe rt-PCR-confirmed influenza, the attack rate was 0.62% (16 cases) in the QIV group and 2.36% (61 cases) in the control group, representing a QIV efficacy of 74.2% (97.5% CI, 51.5 to 86.2). In the per-protocol cohort, the QIV efficacy was 55.4% (95% CI, 39.1 to 67.3), and the efficacy against culture-confirmed influenza 55.9% (97.5% CI, 35.4 to 69.9); the efficacy among children with moderate-to-severe influenza was 73.1% (97.5% CI, 47.1 to 86.3). The QIV was associated with reduced risks of a body temperature above 39°C and lower respiratory tract illness, as compared with the control vaccine, in the per-protocol cohort (relative risk, 0.29 [95% CI, 0.16 to 0.56] and 0.20 [95% CI, 0.04 to 0.92], respectively). The QIV was immunogenic against all four strains. Serious adverse events occurred in 36 children in the QIV group (1.4%) and in 24 children in the control group (0.9%). CONCLUSIONS: The QIV was efficacious in preventing influenza in children. (Funded by GlaxoSmithKline Biologicals; ClinicalTrials.gov number, NCT01218308.).

Design and analysis of single-mode tellurite photonic crystal fibers for stimulated Brillouin scattering based slow-light generation.

We theoretically examine two designs of single-mode (i) Er-doped tellurite and (ii) undoped tellurite photonic crystal fiber (PCF) for generation of slow light with tunable features based on stimulated Brillouin scattering. We obtained (i) Brillouin gain up to 91 dB and time delay of ∼145 ns at maximum allowable pump power of ∼775 mW in a 2 m Er-doped tellurite PCF and (ii) Brillouin gain up to ∼88 dB and time delay of ∼154 ns at maximum allowable pump power ∼21 mW in a 100 m undoped tellurite photonic crystal fiber. Simulated results clearly indicate that the doped tellurite PCF with Er enhances the maximum allowable pump power and comparable time delay can be obtained even with reduced photonic crystal fiber length. We believe that the carried out examination and simulation have potential impact on design and development of slow-light-based photonic devices applicable in telecommunication systems, enhancement of optical forces, and quantum computing.

Communicating nutraceuticals: A multi-stakeholder perspective from a developing nation.

Nutraceuticals, a combination of nutrition and pharmaceutical, have grown rapidly as a product globally. Nutraceuticals can be advertised directly to consumers as well as prescribed, and thus involve multiple stakeholders in the marketing communication process. The present study investigates the marketing communication aspects of nutraceuticals using 216 semistructured in-depth interviews including all stakeholders in the process such as company/brand, physicians, pharmacists, and consumers. The findings bring out the role of each participant in the communication process and a comprehensive picture of the same. The insights would facilitate the nutraceutical brands to understand and implement marketing effective communication strategies.

A historically-controlled Phase III study in adults to characterize the acceptability of a process change for manufacturing inactivated quadrivalent influenza vaccine.

BACKGROUND: An inactivated quadrivalent influenza vaccine (QIV) was recently licenced in the US as a thimerosal-free formulation presented in a pre-filled syringe. A multidose presentation is preferred in some settings due to reduced acquisition and cold storage costs. We assessed the immunogenicity and safety of a thimerosal-containing QIV formulated using a new manufacturing process for presentation in multidose vials. METHODS: Two Phase III non-randomized studies separately evaluated inactivated trivalent influenza vaccine (TIV; 2010-2011; historical control) and a QIV (2011-2012). The QIV contained the same strains as the TIV plus an additional B strain. Both vaccines contained thimerosal to allow multidose presentation: this preservative was added to the QIV during the final formulation step using a new process, whereas it was added to the TIV early in the manufacturing process using an established method. The TIV study included 50 and 70 subjects aged 18-60 and >60 years, respectively; the QIV study included 56 subjects in each age stratum. Immunogenicity was assessed using hemagglutination-inhibition (HI) assays. Reactogenicity was assessed during the 4-day post-vaccination periods and unsolicited adverse events (AEs) were assessed during the 21-day post-vaccination periods. RESULTS: The TIV and QIV were immunogenic in both age strata. With the QIV and TIV respectively, the seroconversion rates were 48.2-62.7% and 71.4-83.7% for influenza A, and 33.9-62.5% and 67.3-72.9% for influenza B. With the QIV and TIV respectively, the seroprotection rates were 92.9-98.2% and 98.2-100% for influenza A, and 88.6-100% and 95.9-98.6% for influenza B. Pre-vaccination titers were higher in the QIV versus TIV study which confounds a direct comparison and likely explains the lower seroconversion rates observed in the QIV study. There were no safety concerns raised with TIV or QIV. CONCLUSIONS: The thimerosal-containing QIV formulated using a new process was immunogenic, conforming to regulatory acceptance criteria, with a reactogenicity and safety profile in line with the TIV manufactured using a licensed process. These results support acceptability of a manufacturing process change in which the thimerosal preservative is added at the point at which batches are filled into multidose vials. TRIAL REGISTRATION: These trials were registered at ClinicalTrials.gov: NCT01440387; NCT01153685.

A randomized trial of candidate inactivated quadrivalent influenza vaccine versus trivalent influenza vaccines in children aged 3-17 years.

BACKGROUND: Two antigenically distinct influenza B lineages have cocirculated since 2001, yet trivalent influenza vaccines (TIVs) contain 1 influenza B antigen, meaning lineage mismatch with the vaccine is frequent. We assessed a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages vs TIV in healthy children aged 3-17 years. METHODS: Children were randomized 1:1:1 to receive QIV or 1 of 2 TIVs (either B/Victoria or B/Yamagata lineage; N = 2738). Hemagglutination-inhibition assays were performed 28 days after 1 or 2 doses in primed and unprimed children, respectively. Immunological noninferiority of QIV vs TIV against shared strains, and superiority against alternate-lineage B strains was based on geometric mean titers (GMTs) and seroconversion rates. Reactogenicity and safety were also assessed (Clinicaltrials.gov NCT01196988). RESULTS: Noninferiority against shared strains and superiority against alternate-lineage B strains was demonstrated for QIV vs TIV. QIV was highly immunogenic; seroconversion rates were 91.4%, 72.3%, 70.0%, and 72.5% against A/H1N1, A/H3N2, B/Victoria, and B/Yamagata, respectively. Reactogenicity and safety of QIV was consistent with TIV. CONCLUSIONS: QIV vs TIV showed superior immunogenicity for the additional B strain without interfering with immune responses to shared strains. QIV may offer improved protection against influenza B in children compared with current trivalent vaccines.

Immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate: a phase III randomized controlled trial in children.

BACKGROUND: Mismatch between circulating influenza B viruses (Yamagata and Victoria lineages) and vaccine strains occurs frequently. METHODS: In a randomized controlled trial, immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate (QIV) versus trivalent inactivated influenza vaccine (TIV)-Victoria(Vic) and TIV-Yamagata(Yam) in children 3-17 years of age was evaluated. In an open-label study arm, QIV only was assessed in children 6-35 months of age. RESULTS: A total of 3094 children (932 QIV, 929 TIV-Vic, 932 TIV-Yam, and 301 QIV only) were vaccinated. QIV was noninferior to the TIVs for shared strains (A/H3N2 and A/H1N1) based on hemagglutination-inhibition (HI) antibodies 28 days after last vaccination, and superior for the unique B strains Victoria and Yamagata (geometric mean titer ratios 2.61, 3.78; seroconversion rate differences 33.96%, 44.63%). Among children in the randomized trial, adverse event rates were similar except for injection site pain (dose 1: 65.4% QIV, 54.6% TIV-Vic, 55.7% TIV-Yam). CONCLUSION: QIV elicited superior HI responses to the added B strains compared to TIV controls, potentially improving its effectiveness against influenza B. HI responses were similar between QIV and TIV controls for the shared strains. QIV had an acceptable safety profile relative to TIVs. CLINICAL TRIALS REGISTRATION: NCT01198756.

Abnormal uterine bleeding: The well-known and the hidden face.

Abnormal uterine bleeding (AUB) is a bleeding from the uterine corpus that is abnormal in regularity, volume, frequency or duration. It encompasses heavy menstrual bleeding, irregular menstrual bleeding and intermenstrual bleeding, which are common symptoms among women of reproductive age, impacting their overall well-being. Menstruation involves interactions between endometrial epithelial and stromal cells, immune cell influx, and changes in endometrial vasculature. These events resemble an inflammatory response with increased vessel permeability, tissue breakdown, and the arrival of innate immune cells. However, the mechanisms of menstrual cessation are poorly understood. AUB can be related to structural causes (polyp, adenomyosis, leiomyoma, malignancy/hyperplasia) and nonstructural conditions (coagulopathy, ovulatory dysfunction, endometrial, iatrogenic). While transvaginal ultrasound is the primary method for the screening of intracavitary lesions, saline infusion sonohysterography is more accurate to detect endometrial polyps and submucous leiomyomas, while hysteroscopy with biopsy remains the reference method for a definitive diagnosis. The main goals in managing AUB are addressing and correcting the underlying primary cause, if possible, and establishing a regular bleeding pattern or amenorrhea, which can be done with antifibrinolytic agents, progestins, gonadotropin-releasing hormone agonists and antagonists, or surgical interventions, each one with specific indications and limitations. Further research is necessary to assess the effectiveness and the long-term effects of various medical and surgical treatments. Meanwhile, the availability of diagnostic methods such as transvaginal ultrasound and hysteroscopy and the universal distribution of medical treatments for AUB should be prioritized by policymakers to minimize the diagnostic and treatment delay and thus reduce the risk of AUB-related anemia and the need of hysterectomy.

Novel Functional Radiomics for Prediction of Cardiac Positron Emission Tomography Avidity in Lung Cancer Radiotherapy.

PURPOSE: Traditional methods of evaluating cardiotoxicity focus on radiation doses to the heart. Functional imaging has the potential to provide improved prediction for cardiotoxicity for patients with lung cancer. Fluorine-18 (18F) fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging is routinely obtained in a standard cancer staging workup. This work aimed to develop a radiomics model predicting clinical cardiac assessment using 18F-FDG PET/CT scans before thoracic radiation therapy. METHODS: Pretreatment 18F-FDG PET/CT scans from three study populations (N = 100, N = 39, N = 70) were used, comprising two single-institutional protocols and one publicly available data set. A clinician (V.J.) classified the PET/CT scans per clinical cardiac guidelines as no uptake, diffuse uptake, or focal uptake. The heart was delineated, and 210 novel functional radiomics features were selected to classify cardiac FDG uptake patterns. Training data were divided into training (80%)/validation (20%) sets. Feature reduction was performed using the Wilcoxon test, hierarchical clustering, and recursive feature elimination. Ten-fold cross-validation was carried out for training, and the accuracy of the models to predict clinical cardiac assessment was reported. RESULTS: From 202 of 209 scans, cardiac FDG uptake was scored as no uptake (39.6%), diffuse uptake (25.3%), and focal uptake (35.1%), respectively. Sixty-two independent radiomics features were reduced to nine clinically pertinent features. The best model showed 93% predictive accuracy in the training data set and 80% and 92% predictive accuracy in two external validation data sets. CONCLUSION: This work used an extensive patient data set to develop a functional cardiac radiomic model from standard-of-care 18F-FDG PET/CT scans, showing good predictive accuracy. The radiomics model has the potential to provide an automated method to predict existing cardiac conditions and provide an early functional biomarker to identify patients at risk of developing cardiac complications after radiotherapy.

High temporal resolution in vivo blood oximetry via projection-based T2 measurement.

Measuring venous oxygen saturation (HbO2) in large blood vessels can provide important information about oxygen delivery and its consumption in vital organs. Quantification of blood's T2 value via MR can be utilized to determine HbO2 noninvasively. We propose a fast method for in vivo blood T2 quantification via computing the complex difference of velocity-encoded projections. As blood flows continuously, its signal can be robustly isolated from the surrounding tissue by computing the complex difference of two central k-space lines with different velocity encodings. This resultant signal can then be measured as a function of echo time for rapidly quantifying T2 of blood. We applied the method to quantify HbO2 in three cerebral veins at rest and in one of the veins in response to hypercapnia. Average HbO2 measurements in superior sagittal sinus (SSS), straight sinus and internal jugular vein in the group were 63 ± 3%, 68 ± 4% and 65 ± 4%, respectively. Average HbO2 values in SSS during baseline, hypercapnia, and recovery were 63 ± 2%, 79 ± 5%, and 61 ± 3%, respectively. When compared with standard T2 quantification techniques, the proposed method is fast, reliable, and robust against partial volume effects.

Immunogenicity, reactogenicity and safety of an inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccine: a phase III, randomized trial in adults aged ≥18 years.

BACKGROUND: Two antigenically distinct influenza B lineages have co-circulated since the 1980s, yet inactivated trivalent influenza vaccines (TIVs) include strains of influenza A/H1N1, A/H3N2, and only one influenza B from either the Victoria or Yamagata lineage. This means that exposure to B-lineage viruses mismatched to the TIV is frequent, reducing vaccine protection. Formulations including both influenza B lineages could improve protection against circulating influenza B viruses. We assessed a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages versus TIV in adults in stable health. METHODS: A total of 4659 adults were randomized 5:5:5:5:3 to receive one dose of QIV (one of three lots) or a TIV containing either a B/Victoria or B/Yamagata strain. Hemagglutination-inhibition assays were performed pre-vaccination and 21-days after vaccination. Lot-to-lot consistency of QIV was assessed based on geometric mean titers (GMT). For QIV versus TIV, non-inferiority against the three shared strains was demonstrated if the 95% confidence interval (CI) upper limit for the GMT ratio was ≤1.5 and for the seroconversion difference was ≤10.0%; superiority of QIV versus TIV for the alternate B lineage was demonstrated if the 95% CI lower limit for the GMT ratio was > 1.0 and for the seroconversion difference was > 0%. Reactogenicity and safety profile of each vaccine were assessed. Clinicaltrials.gov: NCT01204671. RESULTS: Consistent immunogenicity was demonstrated for the three QIV lots. QIV was non-inferior to TIV for the shared vaccine strains, and was superior for the added alternate-lineage B strains. QIV elicited robust immune responses against all four vaccine strains; the seroconversion rates were 77.5% (A/H1N1), 71.5% (A/H3N2), 58.1% (B/Victoria), and 61.7% (B/Yamagata). The reactogenicity and safety profile of QIV was consistent with TIV. CONCLUSIONS: QIV provided superior immunogenicity for the additional B strain compared with TIV, without interfering with antibody responses to the three shared antigens. The additional antigen did not appear to alter the safety profile of QIV compared with TIV. This suggests that the candidate QIV is a viable alternative to TIV for use in adults, and could potentially improve protection against influenza B. TRIAL REGISTRATION: Clinical Trials.gov: NCT01204671/114269.

Contemporary evaluation of women and girls with abnormal uterine bleeding: FIGO Systems 1 and 2.

Abnormal uterine bleeding (AUB) is common, often debilitating, and may affect over 50% of reproductive-aged women and girls. Whereas AUB is a collection of symptoms that include intermenstrual bleeding and abnormalities in period duration, cycle length, and regularity, it is heavy menstrual bleeding (HMB) that is most contributory to iron deficiency and related anemia. It is apparent that AUB, in general, and HMB, in particular, remain underrecognized and underreported. FIGO created two systems for assessing and classifying AUB. FIGO System 1 defines the bleeding pattern using four primary descriptors: frequency, duration, regularity, and flow volume. FIGO System 2 provides a structured classification system of possible causes of AUB, using the acronym PALM-COEIN. "PALM" refers to structural causes of AUB (Polyp, Adenomyosis, Leiomyoma, Malignancy), and "COEI" refers to nonstructural causes (Coagulopathy, Ovulatory dysfunction, Endometrial, and Iatrogenic). The "N" is reserved for those entities that are currently not otherwise classified. Using FIGO System 1 as a gateway to FIGO System 2 streamlines the investigation of reproductive-aged women and girls with AUB. Understanding the pathogenesis of the FIGO System 2 "PALM-COEIN" causes helps interpret investigations and the onward management of AUB. Numerous evidence gaps exist concerning AUB; however, if researchers and trialists universally adopt FIGO Systems 1 and 2 for the assessment and diagnosis of AUB, clear translatable research findings can be applied globally.

Human development and reproduction in space-a European perspective.

This review summarises key aspects of the first reproductive and developmental systems Science Community White Paper, supported by the European Space Agency (ESA). Current knowledge regarding human development and reproduction in space is mapped to the roadmap. It acknowledges that sex and gender have implications on all physiological systems, however, gender identity falls outside the scope of the document included in the white paper collection supported by ESA. The ESA SciSpacE white papers on human developmental and reproductive functions in space aim to reflect on the implications of space travel on the male and female reproductive systems, including the hypothalamic-pituitary-gonadal (HPG) reproductive hormone axis, and considerations for conception, gestation and birth. Finally, parallels are drawn as to how this may impact society as a whole on Earth.