bluuebunny/crossref_metadata_2025 huggingface dataset:
Burden of Streptococcus pneumoniae Sepsis in Children After Introduction of Pneumococcal Conjugate Vaccines: A Prospective Population-based Cohort Study
Authors: Asner Sandra A , Agyeman Philipp K A , Gradoux Eugénie , Posfay-Barbe Klara M , Heininger Ulrich , Giannoni Eric , Crisinel Pierre A , Stocker Martin , Bernhard-Stirnemann Sara , Niederer-Loher Anita , Kahlert Christian R , Hasters Paul , Relly Christa , Baer Walter , Aebi Christoph , Schlapbach Luregn J , Berger Christoph
Published: December 2018

Background

Population-based studies assessing the impact of pneumococcal conjugate vaccines (PCV) on burden of pneumococcal sepsis in children are lacking. We aimed to assess this burden following introduction of PCV-13 in a nationwide cohort study.

Methods

The Swiss Pediatric Sepsis Study (September 2011 to December 2015) prospectively recruited children <17 years of age with blood culture-proven sepsis due to Streptococcus pneumoniae, meeting criteria for systemic inflammatory response syndrome. Infection with vaccine serotype in children up to date with PCV immunization was defined as vaccine failure. Main outcomes were admission to pediatric intensive care unit (PICU) and length of hospital stay (LOS).

Results

Children with pneumococcal sepsis (n = 117) accounted for a crude incidence of 2.0 per 100 000 children (95% confidence interval [CI] 1.7–2.4) and 25% of community-acquired sepsis episodes. Case fatality rate was 8%. Forty-two (36%) patients required PICU admission. Children with meningitis (29; 25%) were more often infected by serotypes not included in PCV (69% vs 31%; P < .001). Sixteen (26%) of 62 children up to date with PCV immunization presented with vaccine failure, including 11 infected with serotype 3. In multivariable analyses, children with meningitis (odds ratio [OR] 6.8; 95% CI 2.4–19.3; P < .001) or infected with serotype 3 (OR 2.8; 95% CI 1.1–7.3; P = .04) were more often admitted to PICU. Children infected with serotype 3 had longer LOS (β coefficient 0.2, 95% CI .1–1.1; P = .01).

Conclusions

The incidence of pneumococcal sepsis in children shortly after introduction of PCV-13 remained substantial. Meningitis mostly due to non-vaccine serotypes and disease caused by serotype 3 represented significant predictors of severity.
Clinical Practice Variation Among Adult Infectious Disease Physicians in the Management of Staphylococcus aureus Bacteremia
Authors: Liu Catherine , Strnad Luke , Beekmann Susan E , Polgreen Philip M , Chambers Henry F
Published: December 2018

Infectious disease management of Staphylococcus aureus bacteremia (SAB) was surveyed through the Emerging Infections Network. Although there were areas of consensus, we found substantial practice variation in diagnostic evaluation and management of adult patients with SAB. These findings highlight opportunities for further research and guidance to define best practices.
Intensity-modulated radiotherapy at high-volume centers improves survival in patients with esophageal adenocarcinoma receiving trimodality therapy
Authors: Yang G Q , Mhaskar R , Rishi A , Naghavi A O , Frakes J M , Almhanna K , Fontaine J , Pimiento Jose M , Hoffe Sarah E
Published: December 2018

The standard of care trimodality therapy for resectable locally advanced esophageal adenocarcinoma is complex and necessitates multidisciplinary care and expertise. In this work, it is hypothesized that facility clinical volume and utilization of intensity-modulated radiotherapy (IMRT) may influence outcomes. The National Cancer Data Base was queried for patients with cT1-4-N0-3 M0 esophageal adenocarcinoma undergoing trimodality therapy from 2004 to 2013 (n = 2445). All patients received chemoradiation followed by esophagectomy at a Commission on Cancer facility. The facility volume was categorized into tertiles: high-volume centers (HVCs) in the highest 25th percentile of cases per year, intermediate-volume centers (IVCs) with the next highest 25th percentile of cases, and low- and very low-volume centers (LVCs) in the lowest 50th percentile. Overall survival (OS) was estimated using Kaplan–Meier methods and Cox proportional hazard regression. Propensity score matching to balance patient characteristics between volume centers was performed. Subgroup analysis was done comparing IMRT versus 3D conformal radiotherapy. The median follow-up was 26 months. Treatment at an HVC (hazard ratio 0.63, 95% CI 0.49–0.81, P < 0.001) was found to be independently associated with improved overall survival in multivariable analysis. Three-year OS was 58.4%, 46.2%, and 47.5% for HVCs, IVCs, and LVCs, respectively (P < 0.001). Patients at HVCs were more likely to receive IMRT over 3D chemoradiation (CRT; OR 3.45, 95% CI 2.4–5.0, P < 0.001). Patients treated using IMRT at HVCs had improved OS compared to those treated at IVCs or LVCs (HR 0.68, 95% CI 0.52–0.90, P < 0.01), while patients treated with 3D CRT at HVCs had no survival advantage over those at IVCs or LVCs (P = 0.28). Patients with locally advanced esophageal adenocarcinoma treated with IMRT and at HVCs appear to have improved survival.
The overall metastatic rate in early esophageal adenocarcinoma: long-time follow-up of surgically treated patients
Authors: Oetzmann von Sochaczewski C , Haist T , Pauthner M , Mann M , Fisseler-Eckhoff A , Braun S , Ell C , Lorenz D
Published: December 2018

The overall metastatic potential of surgically treated early esophageal adenocarcinoma has not been studied in detail. This paper therefore assessed lymph node metastases at surgery, loco regional and distant metastases, in order to assess the metastatic potential of early esophageal adenocarcinoma. Two hundred and seventeen patients (53 T1a, 164 T1b; median follow-ups 87 and 75 months, 187 males) diagnosed with early esophageal adenocarcinoma and treated with esophagectomy in our tertiary center's database between July 2000 and December 2015 were included. All metastatic events were retrospectively analyzed, their topographic distribution was assessed, and the overall metastatic rate was calculated. Lymph node metastases occurred in 39 patients (18%) and 29 (13.4%) developed recurrences. Lymph node metastases were absent in m1 and m2 tumors and rare in m3 (1/18), m4 (5/21), and sm1 (4/42), but more frequent in sm2 (11/44) and sm3 tumors (18/78). Locoregional recurrences were exceedingly rare in m3 (2/18), m4 (1/21), sm1 (1/42), and sm2 (2/44), but frequent in sm3 (12/78). In contrast, distant metastases were more frequent with 2/18 in m3, 1/21 in m4, 4/42 in sm1, 4/44 in sm2, and 13/78 in sm3. Overall metastatic rates of 11.9% in sm1 (submucosal layer divided into equal thirds), 27.3% in sm2, and 32.1% in sm3 tumors were calculated. This first report of the metastatic potential of early esophageal adenocarcinoma provides a meticulous assessment of the overall metastatic risk. Metastatic events pose a relevant risk in surgically treated patients with esophageal adenocarcinoma with distant metastases being more frequent than locoregional recurrences.
Outcomes of octogenarians with esophageal cancer: an analysis of the National Cancer Database
Authors: Bakhos C T , Salami A C , Kaiser L R , Petrov R V , Abbas A E
Published: December 2018

The optimal treatment of esophageal cancer in octogenarians is controversial. While the safety of esophagectomy has been demonstrated in elderly patients, surgery and multimodality therapy are still offered to a select group. Additionally, the long-term outcomes in octogenarians have not been thoroughly compared to those in younger patients. We sought to compare the outcomes of esophageal cancer treatment between octogenarians and non-octogenarians in the National Cancer Database (2004–2014). The major endpoints were early postoperative mortality and long-term survival. A total of 107,921 patients were identified [octogenarian—16,388 (15.2%)]. Compared to non-octogenarians, octogenarians were more likely to be female, of higher socioeconomic status, and had more Charlson comorbidities (p < 0.001 for all). Octogenarians were significantly less likely to undergo esophagectomy (11.5% vs. 33.3%; p < 0.001) and multimodality therapy (2.0% vs. 18.5%; p < 0.001), a trend that persisted following stratification by tumor stage and Charlson comorbidities. Both 30-day and 90-day mortality were higher in the octogenarian group, even after multivariable adjustment (p ≤ 0.001 for both). Octogenarians who underwent multimodality therapy had worse long-term survival when compared to younger patients, except for those with stage III tumors and no comorbidities (HR: 1.29; p = 0.153). Within the octogenarian group, postoperative mortality was lower in academic centers, and the long-term survival was similar between multimodality treatment and surgery alone (HR: 0.96; p = 0.62). In conclusion, octogenarians are less likely to be offered treatment irrespective of tumor stage or comorbidities. Although octogenarians have higher early mortality and poorer overall survival compared to younger patients, outcomes may be improved when treatment is performed at academic centers. Multimodality treatment did not seem to confer a survival advantage compared to surgery alone in octogenarians, and more prospective studies are necessary to better elucidate the optimal treatment in this patient population.
Sampling inequalities for anisotropic tensor product grids
Authors: Rieger Christian , Wendland Holger
Published: December 2018

We derive sampling inequalities for discrete point sets that are of anisotropic tensor product form. Such sampling inequalities can be used to prove convergence for arbitrary stable reconstruction processes. As usual in the context of high-dimensional problems, our sampling inequalities are expressed in terms of the number of data sites, i.e., the number of points in the sparse grid. To this end, new bounds on specific monotone sets and on the number of points in an anisotropic sparse grid are derived.
Comparative Transcriptomics Reveals Patterns of Adaptive Evolution Associated with Depth and Age Within Marine Rockfishes (Sebastes)
Authors: Heras Joseph , Aguilar Andres
Published: December 2018

The genetic underpinnings that contribute to ecological adaptation and speciation are not completely understood, especially within marine ecosystems. These evolutionary processes can be elucidated by studying adaptive radiations, because they provide replicates of divergence within a given environment or time-frame. Marine rockfishes (genus Sebastes) are an adaptive radiation and unique model system for studying adaptive evolution in the marine realm. We investigated molecular evolution associated with ecological (depth) and life history (lifespan) divergence in 2 closely related clades of Sebastes. Brain transcriptomes were sequenced via RNA-Seq from 3 species within the subgenus Pteropodus and a pair of related congeners from the subgenus Sebastosomus in order to identify patterns of adaptive evolution. De novo assemblies from these transcriptomes were used to identify 3867 orthologous clusters, and genes subject to positive selection were identified based on all 5 species, depth, and lifespan. Within all our analyses, we identified hemoglobin subunit α to be under strong positive selection and is associated with the depth of occurrence. In our lifespan analysis we identified immune function genes under positive selection in association with maximum lifespan. This study provides insight on the molecular evolution of rockfishes and these candidate genes may provide a better understanding of how these subgenera radiated within the Northeast Pacific.
Geometrical compression: a new method to enhance the BOSS galaxy bispectrum monopole constraints
Authors: Gualdi Davide , Gil-Marín Héctor , Manera Marc , Joachimi Benjamin , Lahav Ofer
Published: December 2018

We present a novel method to compress galaxy clustering three-point statistics and apply it to redshift space galaxy bispectrum monopole measurements from BOSS DR12 CMASS data considering a k-space range of $0.03-0.12\, h/\mathrm{Mpc}$. The method consists in binning together bispectra evaluated at sets of wavenumbers forming closed triangles with similar geometrical properties: the area, the cosine of the largest angle, and the ratio between the cosines of the remaining two angles. This enables us to increase the number of bispectrum measurements, for example by a factor of 23 over the standard binning (from 116 to 2734 triangles used), which is otherwise limited by the number of mock catalogues available to estimate the covariance matrix needed to derive parameter constraints. The $68{{\ \rm per\ cent}}$ credible intervals for the inferred parameters (b1, b2, f, σ8) are thus reduced by $\left(-39{{\ \rm per\ cent}},-49{{\ \rm per\ cent}},-29{{\ \rm per\ cent}},-22{{\ \rm per\ cent}}\right)$, respectively. We find very good agreement with the posteriors recently obtained by alternative maximal compression methods. This new method does not require the a-priori computation of the data vector covariance matrix and has the potential to be directly applicable to other three-point statistics (e.g. galaxy clustering, weak gravitational lensing, 21-cm emission line) measured from future surveys such as DESI, Euclid, PFS, and SKA.
Radiative shocks in disk accretion
Authors: Fukue Jun
Published: December 2018

Radiative shock waves standing in disk accretion flows are examined under the equilibrium diffusion approximation (1T limit) in the optically thick case, taking into account the hydrostatic equilibrium in the vertical direction. In contrast to the usual one-dimensional shock, where the gas density of the post-shock region increases due to the shock compression, if the shock is sufficiently strong, the gas density in the post-shock region often decreases due to the vertical expansion behind the shock front. However, the surface density behaves like the gas density in the usual shocks, and increases up to 7 in the radiation pressure dominated shock. Hence, the vertical optical depth in the post-shock region rises, in spite of the reduction of the gas density. In addition, similar to the usual radiative shock, there appears a radiative precursor in the pre-shock region before the shock front, due to the radiative diffusion effect. We derive the overall jump conditions for the radiative shock in disk accretion flows, and solve the structure of the radiative precursor for both the gas and radiation pressure dominated cases. The solutions are quite fundamental in disk-accretion shock problems, and should be developed in various aspects.
Influenza virus and atherosclerosis
Authors: Peretz A , Azrad M , Blum A
Published: December 2018

Influenza viruses infect the upper respiratory system, causing usually a self-limited disease with mild respiratory symptoms. Acute lung injury, pulmonary microvascular leakage and cardiovascular collapse may occur in severe cases, usually in the elderly or in immunocompromised patients. Acute lung injury is a syndrome associated with pulmonary oedema, hypoxaemia and respiratory failure. Influenza virus primarily binds to the epithelium, interfering with the epithelial sodium channel function. However, the main clinical devastating effects are caused by endothelial dysfunction, thought to be the main mechanism leading to pulmonary oedema, respiratory failure and cardiovascular collapse. A significant association was found between influenza infection and acute myocardial infarction (AMI). The incidence of admission due to AMI during an acute viral infection was six times as high during the 7 days after laboratory confirmation of influenza infection as during the control interval (10-fold in influenza B, 5-fold in influenza A, 3.5-fold in respiratory syncytial virus and 2.7-fold for all other viruses). Our review will focus on the mechanisms responsible for endothelial dysfunction during influenza infection leading to cardiovascular collapse and death.
A Rare Case of Gender Parity in Academia
Authors: Lynn Freda B , Noonan Mary C , Sauder Michael , Andersson Matthew A
Published: December 2018

In academia, women trail men in nearly every major professional reward, such as earnings, publications, and funding. Bibliometric studies, however, suggest that citations are unique with regard to gender inequality: female penalties have been reported, but gender parity or even female premiums are routinely documented as well. Two questions follow from this puzzle. First, does gender matter for citations in sociology and neighboring social science disciplines? No theoretically informed study of gender and citations exists for the social science core. We begin to fill this gap by analyzing roughly 10,000 publications in economics, political science, and sociology. In contrast to many big data studies, we estimate the effect of author gender on citations alongside other author-, article-, journal-, and (sub)field-level predictors. Our results strongly suggest that when male and female authors publish articles that are comparably positioned to receive citations, their publications do in fact accrue citations at the same rate. This finding raises a second question: Why would gender matter “everywhere but here”? We hypothesize that the answer is related to the mechanisms (e.g., self-selection, biased assessments of commitment) that are activated in the context of some professional rewards but not citations. We discuss why a null gender finding should not be discarded as an anomaly but rather approached as an analytical opportunity.
Survey in Nurseries and Irrigation Water Reservoirs as Sources of Oomycetes Found in Avocado Orchards in the Canary Islands
Authors: Rodríguez-Padrón Cristina , Rodríguez Ana , Siverio Felipe
Published: December 2018

Nursery stocks and irrigation water are important sources of Phytophthora spp. In this study, 20 irrigation water reservoirs and 10 avocado nurseries were surveyed in the Canary Islands between 2013 and 2015 to investigate their potential role in disseminating pathogenic species in avocado orchards. Phytophthora multivora was isolated from one of the irrigation reservoirs, whereas, in two surveys conducted in nurseries, Phytophthora cinnamomi, the primary pathogen in avocado, was detected in addition to other Phytophthora species (P. lacustris, P. multivora, P. nicotianae, P. niederhauserii, and P. palmivora) and Phytopythium vexans. The species recovered from nurseries were isolated mostly from propagated plants but also from nursery irrigation water, soil used for substrate preparation, and soil samples collected in orchards that supply seeds for seedling propagation. Species recovered from nurseries correlated with those found in avocado orchards in a previous study, except for P. lacustris, suggesting that nurseries could be involved in their dissemination in avocado orchards. The improved sanitary status of nurseries resulted in reduced incidence in the second survey, indicating the importance of nursery monitoring to reduce infestations.
Shifting Strategies: Using Film to Improve Therapeutic Communication and Nursing Education
Authors: Moosvi Karen , Garbutt Susan
Published: December 2018

Narrative pedagogy successfully transformed a previously discordant mental health clinical rotation into a reflective and engaged learning process. Use of the film “Wit” early in the clinical semester was popular with subsequent cohorts of students and helped better engage them in practicing therapeutic communication techniques. This article is an exemplar of the application of narrative pedagogy as a means of embracing the phenomenon of therapeutic communication in health care.
Simulation as a Method of Competency Assessment Among Health Care Providers: A Systematic Review
Authors: Keddington Amanda S. , Moore Jill
Published: December 2018

AIM

The aim of this study was to review and assess current research on simulation as a method of competency assessment among health care professionals and the efficacy of simulation-based competency assessment compared to standard methods.

BACKGROUND

Simulation has been proven to be an effective instructional methodology for many health care specialties. However, there is a limited amount of research on simulation as a method of competency assessment.

METHOD

Articles regarding competency assessment by simulation in health care professionals were reviewed from academic databases based on inclusion/exclusion criteria.

RESULTS

The effectiveness of simulation as a method of competency assessment needs further study in order to provide conclusive evidence of benefits. Assessment of high-risk, low-frequency skills promotes patient safety in situations that may occur infrequently enough to prevent continued practice of skills.

CONCLUSION

This systematic review indicates that simulation may be a safe and effective method of competency assessment in health care professionals.
Using the Two-Minute Assessment With Debriefing to Optimize Traditional Patient Care Clinical Experiences
Authors: Veesart Amanda , Johnson Kyle
Published: December 2018

Traditional patient care clinical experiences present numerous challenges to faculty in prelicensure nursing education. This article presents an adapted nontraditional clinical activity for use in patient care clinical experiences. The Two-Minute Assessment With Debriefing incorporates peer collaboration and attributes of debriefing, including assimilation, accommodation, and anticipation. Nursing students in acute care facilities are assigned to either traditional or nontraditional care, with the group ideally split in half. The use of nontraditional clinical activities with reflection has been supported as a strategy to engage higher order thinking about patient care while allowing focused faculty time with students in traditional patient care.
Technology Use Patterns Among Patients Enrolled in Inpatient Detoxification Treatment
Authors: Tofighi Babak , Leonard Noelle , Greco Peter , Hadavand Aboozar , Acosta Michelle C. , Lee Joshua D.
Published: December 2018

Background:

Technology-based interventions offer a practical, low-cost, and scalable approach to optimize the treatment of substance use disorders (SUDs) and related comorbidities (HIV, hepatitis C infection). This study assessed technology use patterns (mobile phones, desktop computers, internet, social media) among adults enrolled in inpatient detoxification treatment.

Methods:

A 49-item, quantitative and qualitative semi-structured survey assessed for demographic characteristics, technology use patterns (ie, mobile phone, text messaging [TM], smart phone applications, desktop computer, internet, and social media use), privacy concerns, and barriers to technology use. We used multivariate logistic regression models to assess the association between respondent demographic and clinical characteristics and their routine use of technologies.

Results:

Two hundred and six participants completed the survey. Nearly all participants reported mobile phone ownership (86%). Popular mobile phone features included TM (96%), web-browsers (81%), and accessing social media (61%). There was high mobile phone (3.3 ± 2.98) and phone number (2.6 ± 2.36) turnover in the preceding 12 months. Nearly half described daily or weekly access to desktop computers (48%) and most reported internet access (67%). Increased smartphone ownership was associated with higher education status (P = 0.022) and homeless respondents were less likely to report mobile phone ownership (P = 0.010) compared to participants with any housing status (ie, own apartment, residing with friends, family, or in a halfway house). Internet search engines were used by some participants (39.4%, 71/180) to locate 12 step support group meetings (37%), inpatient detoxification programs (35%), short- or long-term rehabilitation programs (32%), and outpatient treatment programs (4%).

Conclusions:

Technology use patterns among this hard-to-reach sample of inpatient detoxification respondents suggest high rates of mobile phone ownership, TM use, and moderate use of technology to facilitate linkage to addiction treatment services.
Prevalence, Incidence, and Factors Associated With Substance Use Among Medical Students: A 2-Year Longitudinal Study
Authors: Moutinho Ivana Lúcia Damásio , Lucchetti Alessandra Lamas Granero , Ezequiel Oscarina da Silva , Lucchetti Giancarlo
Published: December 2018

Objectives:

Although there are a number of studies about substance use by medical students, the majority are still cross-sectional. We aimed to investigate prevalence, 2-year incidence, and factors associated with substance use during medical training.

Methods:

This longitudinal study included medical students in 4 different waves (with each wave equaling 1 semester). Socio-demographic data, Duke Religion Index (DUREL), DASS-21, and the “Alcohol, Smoking and Substance Involvement Screening Test” (ASSIST) were used.

Results:

A total of 327 (56.2%) medical students were followed for 2 years. Prevalence of lifetime substance use was 89.9% for alcohol, 34.5% for cannabis, and 17.1% for sedatives. Tobacco had the greatest incidence of use over the 2 years (16.4%), followed by alcohol (13.8%) and cannabis (13.8%). At least 24% of the students would need an intervention for alcohol use, 11.4% for tobacco, and 6.5% for cannabis. Alcohol use during wave 4 was associated with organizational religiosity, and alcohol and tobacco use at the baseline; tobacco use during wave 4 was associated with age, non-organizational religiosity, and cannabis and tobacco use at the baseline; and cannabis use during wave 4 was associated with cannabis and tobacco use at the baseline.

Conclusions:

Our results indicate an increase in the incidence of lifetime substance use during medical training. Prior use of substance was associated with a higher chance of use after 2 years, while age and religiousness seem to reduce the chance of use.
Value of Cervical Disk Arthroplasty
Authors: Tarazona Daniel A. , Schroeder Gregory D. , Vaccaro Alexander R. , Radcliff Kris E.
Published: December 2018

Over the last decade, several of the Food and Drug Administration-regulated investigational device exemption (IDE) trials have compared multiple cervical disk arthroplasty (CDA) devices to anterior cervical decompression and fusion (ACDF) showing comparable and even superior patient-reported outcomes. CDA has been an increasingly attractive option because of the positive outcomes and the motion-preserving technology. However, with the large burden that health care expenditures place on the economy, the focus is now on the value of treatment options. Cost-effectiveness studies assess value by evaluating both outcomes and cost, and recently several have been conducted comparing CDA and ACDF. The results have consistently shown that CDA is a cost-effective alternative, however, in comparison to ACDF the results remain inconclusive. The lack of incorporation of disease specific measures into health state utility values, the inconsistent methods of calculating cost, and the fact that a vast majority of the results have come from industry-sponsored studies makes it difficult to form a definitive conclusion. Despite these limitations, both procedures have proven to be safe, effective, and cost-efficient alternatives.
Stereotactic radiosurgery combined with immune checkpoint inhibitors or kinase inhibitors for patients with multiple brain metastases of malignant melanoma
Authors: Stera Susanne , Balermpas Panagiotis , Blanck Oliver , Wolff Robert , Wurster Stefan , Baumann Rene , Szücs Marcella , Loutfi-Krauss Britta , Wilhelm Maria-Lisa , Seifert Volker , Rades Dirk , Rödel Claus , Dunst Jürgen , Hildebrandt Guido , Arnold Andreas , Meissner Markus , Kähler Katharina C.
Published: December 2018

The aim was to evaluate toxicity and oncological outcome of combined stereotactic radiosurgery (SRS) and immunotherapy or targeted therapy in patients with multiple brain metastases originating from malignant melanoma. Despite the fact that both SRS and kinase inhibitors or immune checkpoint inhibitors are considered standard treatment options for this indication, the optimal combination and sequence of these modalities remains largely unknown, especially for patients with a high number of brain metastases. For this retrospective analysis, conducted in two large SRS dedicated centers, we identified patients with brain metastases from malignant melanoma and simultaneous application of immunotherapy or targeted therapy within 30 days of SRS. Forty-eight patients with a total of 250 lesions (median: 3) were treated in 65 single fraction SRS sessions from 2012 to 2018. After a median follow-up of 8.3 months (range: 1.2–43.6 months), the 6-month and 1-year overall survival rates were 75.3 and 50.8%, respectively. The local control rate at one year was 89.5%. Immunotherapy and the application of systemic treatment directly before or concomitant to SRS were both associated with improved overall survival (P=0.037 and 0.045, respectively). We observed four grade III toxicities, of which only two can be clearly attributed to the combined treatment. Various combinations of SRS and kinase inhibitors or immune checkpoint inhibitors appear feasible and provide promising oncological results and safety profiles for treating few (n=1–4) and also multiple (n≥5) melanoma brain metastases.
Prognostic significance of distant metastasis-free interval in patients with relapsed melanoma treated with BRAF with or without MEK inhibitors
Authors: Bafaloukos Dimitrios , Papaxoinis George , Linardou Helena , Diamantopoulos Panagiotis , Laskarakis Apostolos , Anastasopoulou Amalia , Sergentanis Theodoros N. , Tarampikou Anthi , Tsoutsos Dimosthenis , Gogas Helen
Published: December 2018

This retrospective cohort study assessed the prognostic significance of distant metastasis-free interval (DMFI) in patients with relapsed BRAF-mutant melanoma treated with BRAF with or without MEK inhibitors (BRAFi ± MEKi). Patients with a DMFI of up to 24 months were compared with those with DMFI of more than 24 months, with regard to their postrelapse progression-free survival (PR-PFS) and overall survival (PR-OS). In total, 109 patients were included in the study. Median DMFI was 25.3 (range: 3.4–188.2) months. Median PR-PFS in patients with DMFI of more than 24 months was 7.9 months [95% confidence interval (CI): 6.2–9.7] compared with 5.4 (95% CI: 4.2–6.7) months of those with shorter DMFI (P = 0.016). Median PR-OS was 15.6 months (95% CI: 13.6–17.6) in patients with DMFI of more than 24 months and 12.0 months (95% CI: 9.0–15.0) with DMFI of up to 24 months (P = 0.289). Multivariate Cox regression analysis showed that DMFI was independently and strongly associated with improved PR-PFS (adjusted hazard ratio = 3.21, 95% CI: 1.78–5.77, ≤ 24 vs. > 24 months) and longer PR-OS (adjusted hazard ratio: 2.09, 95% CI: 1.15–3.80, ≤ 24 vs. > 24 months). The present cohort study is one of the first to confirm the association of DMFI of more than 24 months with an indolent disease course, as shown by longer PR-PFS and PR-OS, in patients with relapsed stage IV melanoma treated by BRAF inhibitor/MEK inhibitor.
Proliferation index and pseudoprogression as predictors of the therapeutic efficacy of suicide gene therapy for canine melanoma
Authors: Fondello Chiara , Agnetti Lucrecia , Glikin Gerardo C. , Finocchiaro Liliana M.E.
Published: December 2018

In our veterinary clinical trials, the combination of systemic immunotherapy with local herpes simplex virus thymidine kinase/ganciclovir suicide gene (SG) treatment induced tumor pseudoprogression as part of a strong local antitumor response. This phenomenon could be owing to tumor inflammation, increased vascular permeability and to different tumor growth rates before, during and after SG therapy. The proliferation index (PI: the fraction of viable cells in S, G2/M, and hyperdiploid phases) would reflect the in-vivo and in-vitro proportion of proliferating melanoma cells in the absence of treatment (PIB) or in response to SG (PISG). The extent of in-vivo and in-vitro melanoma cells responses to SG exhibited a reverse correlation with PIB and a direct correlation with PISG. Then, the final SG outcome depended on the balance between PIB-dependent ‘regrowth resistance’ versus ‘regrowth sensitivity’ to SG treatment. In all the cell lines derived from canine tumors presenting partial responses to SG treatment, PISG prevailed over PIB. Conversely, as more aggressive was the tumor (greater PIB of the cell line), the more the balance displacement towards ‘regrowth resistance’ over SG ‘regrowth sensitivity’. All these parameters could have a prognostic value for SG treatment response and provide a glimpse at the clinical benefit of this therapy.
Is Anacetrapib Better Than Its CETP Inhibitor Counterparts?
Authors: Grabie Mordechai , Tai Cheng-Hung , Frishman William H.
Published: December 2018

Cholesterol metabolism and transport has been a major focus in cardiovascular disease risk modification over the past several decades. Hydroxymethylglutaryl-CoA reductase inhibitors (statins) have been the most commonly used agents, with the greatest benefit in reducing both the primary and secondary risks of cardiovascular disease. However, heart disease remains the leading cause of death in both men and women in the United States. Further investigation and intervention are required to further reduce the risk for cardiovascular disease and cardiovascular-related deaths. This review will focus on high-density lipoprotein metabolism and transport, looking particularly at cholesteryl ester transfer protein (CETP) inhibitors. While studies of the other CETP inhibitors in its class have not shown a significant improvement in the prevention of primary or secondary cardiovascular risk, anacetrapib, the fourth and latest of the CETP inhibitors to be investigated, may be more promising.
Antihypertrophic Effects of Nebivolol on Neonatal Cardiomyocyte Hypertrophy Models
Authors: Ozakca Isil
Published: December 2018

The antihypertrophic effect of nebivolol over cardioselective beta-blockers (β-blockers) is attributed to the activation of cardiac nitric oxide signaling. However, the precise role of nebivolol on hypertrophied cardiomyocytes remains unclear. In the current study, in vitro cardiomyocyte hypertrophy model was induced with isoprenaline (10 μM), angiotensin II (1 μM), and phenylephrine (20 μM) in neonatal cardiomyocytes isolated from 0- to 2-day-old Sprague–Dawley rats. In addition to hypertrophic agents, cardiomyocytes were treated with nebivolol (1 μM), metoprolol (10 μM), N(ω)-nitro-l-arginine methyl ester (l-NAME) (100 μM), KT5823 (1 μM), DETA-NONOate (1–10 μM), and BAY412272 (10 μM). After 24 hours of treatment, cardiomyocyte size and transcriptional changes in cardiac hypertrophy markers were evaluated. Cardiomyocyte size increased equally in response to all hypertrophic agents. Nebivolol reduced the enhancement in cell size in response to both isoprenaline and angiotensin II; metoprolol did not. The antihypertrophic effect of nebivolol was prevented with l-NAME blockage indicating the role of NOS signaling on cardiomyocyte hypertrophy. The increased mRNA levels of atrial natriuretic peptide induced by isoprenaline decreased with nebivolol, but both β-blockers reduced the angiotensin II–induced increase in atrial natriuretic peptide expression. Combined, these results reveal that by activating NOS signaling, nebivolol exerts antihypertrophic effects on neonatal cardiomyocytes independent from the action mechanism of hypertrophic stimulus.
MACULAR ATROPHY IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
Authors: Rebhun Carl B. , Moreira-Neto Carlos , Gune Shamika , Hill Lauren , Duker Jay S. , Waheed Nadia K.
Published: December 2018

Purpose:

To determine optical coherence tomography signs associated with macular atrophy (MA) in eyes with neovascular age-related macular degeneration and pigment epithelial detachments treated with vascular endothelial growth factor inhibitors.

Methods:

Optical coherence tomography scans from a subgroup of the pigment epithelial detachment cohort of the HARBOR study were analyzed for MA. Two groups were formed based on MA presence/absence at Month 24. Then, optical coherence tomography scans from each baseline visit were graded with standard reading center grading parameters including ellipsoid zone disruption, intraretinal cysts, subretinal fluid, and MA or nascent MA in the study and fellow eyes.

Results:

Twenty-eight eyes from 28 patients were included in the analysis. Fourteen eyes had optical coherence tomography–based MA at Month 24 and 14 did not. Macular atrophy at Month 24 was significantly associated with 1) MA/nascent MA at baseline (P = 0.0136), 2) intraretinal cysts at baseline (P = 0.0048), and 3) collapse of pigment epithelial detachments in the study eye (P = 0.0025). Macular atrophy was not associated with ellipsoid zone disruption or subretinal fluid in the study eye at baseline.

Conclusion:

This study suggests that some optical coherence tomography findings in eyes of patients with neovascular age-related macular degeneration were present before the start of anti–vascular endothelial growth factor therapy and may predict the development of MA.
RETINAL FINDINGS IN PRESUMED INFECTIOUS POSTERIOR UVEITIS AND CORRELATION WITH POLYMERASE CHAIN REACTION RESULTS
Authors: Elyashiv Sivan M. , Samson C. Michael , Jabs Douglas A.
Published: December 2018

Purpose:

To correlate demographics, retinal lesion characteristics, and host immune status with the pathogen found on polymerase chain reaction analysis of aqueous fluid in patients with suspected infectious posterior uveitis.

Methods:

Medical records of patients who underwent anterior chamber paracentesis for suspected infectious posterior uveitis and had retinal photographs between 2014 and 2016 at a single institution were reviewed. Data collection included demographics, clinical appearance of the lesions, and polymerase chain reaction results. Fundus photographs were evaluated by two masked observers for the clinical features of the retinitis.

Results:

Twenty-eight patients were included in the study. There was substantial to almost perfect agreement on retinitis location (κ = 0.67) and number (κ = 0.76) between the masked photograph graders. Polymerase chain reaction results were positive for herpes simplex virus or varicella zoster virus in 43%, cytomegalovirus in 11%, and toxoplasmosis in 3%; 43% had negative polymerase chain reaction results. Detection of herpes simplex virus or varicella zoster virus on polymerase chain reaction of the aqueous was associated with paucifocal lesions (82%, P = 0.021) and lesions involving the peripheral retina (91%, P = 0.023), consistent with the diagnosis of acute retinal necrosis.

Conclusion:

These data suggest that the diagnosis of acute retinal necrosis can be reasonably inferred on clinical examination, providing a guide for initial empiric therapy.
INSIGHTS INTO PERIFOVEAL EXUDATIVE VASCULAR ANOMALOUS COMPLEX
Authors: Mrejen Sarah , Le Hoang Mai , Nghiem-Buffet Sylvia , Tabary Sandrine , Quentel Gabriel , Cohen Salomon Y.
Published: December 2018

Purpose:

To report a series of eight patients with perifoveal exudative vascular anomalous complex imaged with optical coherence tomography angiography and the results of anti–vascular endothelial growth factor therapy or laser photocoagulation.

Methods:

Retrospective analysis of demographic data, imaging including color pictures, spectral domain optical coherence tomography, and optical coherence tomography angiography, and fluorescein angiography, course, and outcome.

Results:

Age at onset ranged from 45 to 84 years (mean ± SD: 68.6 ± 13.7). Five cases were initially misdiagnosed. The perifoveal exudative vascular anomalous complex lesion was unique in seven eyes and located predominantly in the superficial capillary plexus in two eyes, strictly in the deep capillary plexus in two eyes, but observed at the level of both plexi (3 eyes). One patient presented two lesions, one in the superficial capillary plexus and one in the deep capillary plexus. Capillary rarefaction was observed around the lesion in six eyes. Sustainable resolution of exudation could be achieved in 2 patients, one after 2 sessions of focal thermal laser photocoagulation and one after 13 intravitreal injections of anti–vascular endothelial growth factor.

Conclusion:

The present series confirms that perifoveal exudative vascular anomalous complex corresponds to a new entity that differs from other conditions associated with capillary aneurysmal lesions. Visual improvement could be obtained after treatment with focal laser or intravitreal anti–vascular endothelial growth factor agents.
NECROSIS OF THE RETINA AND UVEAL TRACT SECONDARY TO EXPANDING GAS TAMPONADE
Authors: Rooney David M. , Oltmanns Matthew H. , Sapp Mathew R. , Morris Robert E.
Published: December 2018

Purpose:

To present a case of retinal and uveal necrosis caused by expanding gas tamponade after pars plana vitrectomy.

Methods:

Single case report.

Results:

An otherwise healthy 66-year-old woman underwent pars plana vitrectomy with intended 20% sulfur hexafluoride (SF6) tamponade for macular hole repair of her pseudophakic left eye. She developed intractable nausea, emesis and increasing left eye pain in association with gas expanded to totally fill the left eye, just hours after surgery. Extremely elevated intraocular pressure was lowered with a successful paracentesis but recurred within a few hours. She then underwent vitrectomy evacuation of all vitreous cavity gas, reformation of the anterior chamber, and silicone oil placement, normalizing intraocular pressure. Three weeks later, the left eye had no light perception, and devitalization of the retina, choroid, and iris was evident.

Conclusion:

We present a case of blindness and intraocular tissue dissolution/disorganization after vitrectomy with intended 20% SF6. To our knowledge, this is the most detailed report of the under-recognized complication of expanding gas tamponade. Institutions hosting vitrectomy surgery should consider enacting a formal “Time Out” that requires all team members to witness accurate fractionation of potentially expansile gas. In the event of acute postoperative glaucoma in such eyes, a single small volume paracentesis cannot be relied upon to protect against continued gas expansion.
Thymic Stromal Lymphopoietin-Related Allergic Pathway in Patients With Vernal Keratoconjunctivitis
Authors: Zhang Zong-Duan , Deng Yu-Xuan , Ma Hui-Xiang , Chen Xiao-Gang , Chen Lin-Hua , Qu Jia
Published: December 2018

Purpose:

To investigate the expression of thymic stromal lymphopoietin (TSLP) and the relevant signaling pathways in the giant papillae obtained from patients with vernal keratoconjunctivitis (VKC) and to study the potential functional role and molecular mechanism of TSLP.

Methods:

Giant papillae from VKC patients and control samples were used to perform immunohistochemical staining and analyze the mRNA expression of TSLP and related pathway by real-time polymerase chain reaction.

Results:

TSLP was markedly expressed in the epithelial cells and some inflammatory cells of giant papillae, but not in the control conjunctival tissue. TSLP mRNA expression in the giant papillae of VKC was increased by 9.63 ± 0.99 (mean ± SD) fold compared with controls (P < 0.01). CD11c+ and OX40L+ immunoreactive cells largely infiltrated the giant papillae as observed by immunohistochemical staining. CD4+Th2 cell infiltration was observed through high immunoreactivity of CD4. Th2 cytokines (IL-4, IL-5 and IL-13) and OX40 in the VKC specimens showed increased expression. Augmented gene expression levels of CD4 (6.88 ± 1.84), OX40L (7.60 ± 1.79), OX40 (7.25 ± 1.38), IL-4 (6.89 ± 1.46), IL-5 (8.42 ± 1.55), and IL-13 (9.69 ± 1.94) were significantly different from controls (P < 0.05).

Conclusions:

Our observations provide strong evidence that TSLP may be a crucial factor that contributes to the development and progression of allergic conjunctivitis. The results also demonstrated that TSLP activates dendritic cells to prime CD4+T cells to differentiate into Th2 type and triggers Th2-dominant allergic inflammation through the TSLP/OX40L/OX40 signaling as part of immunopathogenesis of VKC.
Imaging Kayser-Fleischer Ring in Wilson Disease Using In Vivo Confocal Microscopy
Authors: Zhao Tantai , Fang Zhixue , Tian Jiao , Liu Jia , Xiao Yangyan , Li Huiling , Chen Baihua
Published: December 2018

Purpose:

This study analyzes images of Kayser–Fleischer (K-F) rings in patients with Wilson disease (WD) using in vivo confocal microscopy (IVCM) and explores whether IVCM can be a useful clinical tool in facilitating the diagnosis and characterization of K-F rings.

Methods:

One hundred four eyes of 52 patients with WD and K-F rings (K-F group) and 52 normal eyes of 52 age- and gender-matched control subjects (control group) were enrolled in the study. Both K-F and control groups consisted of 29 male patients and 23 female patients. IVCM imaging was performed, and images of the peripheral Descemet membrane were analyzed.

Results:

All patients in K-F group showed abnormal patterns in the peripheral Descemet membrane from IVCM images. These abnormalities can be generally divided into 3 types: patchy, stripy, and spotty patterns. Each patient may have a combination of these patterns, with patchy pattern being most prevalent (100%), whereas stripy and spotty patterns are present in 30% to 40% of the K-F rings. Notably, these patterns are not correlated with other systematic symptoms of WD.

Conclusions:

IVCM images can be used as an objective clinical diagnostic tool to facilitate the identification of K-F rings and the diagnosis of WD.
Long-term Follow-up of Ahmed Glaucoma Valve Tube Position Changes
Authors: Mathew David J. , Anuradha Anindya , Low Stephanie A.W. , Belkin Avner , Buys Yvonne M. , Trope Graham E.
Published: December 2018

Purpose:

To evaluate long-term (4.5 to 6 y) changes in the position of Ahmed glaucoma valve (AGV) tubes.

Materials and Methods:

Adult patients aged 18 years and above, 1 to 2 months post-AGV implantation were enrolled. Tube position was evaluated using anterior segment optical coherence tomography at baseline and final follow-up. The intracameral tube length (ICL), tube-cornea (TC) distance, and cornea-tube angle were measured. Wilcoxon-signed rank test was used to assess whether the changes in parameters from baseline were significant.

Results:

In total, 11 eyes of 9 patients were included in the analysis. Mean duration of follow-up was 5.2±0.8 years (4.4 to 6.1 y). The ICL increased from 1.58±0.40 to 1.74±0.62 mm (P=0.18). The TC decreased from 0.36±0.12 to 0.29±0.05 mm (P=0.04). The cornea-tube angle decreased from 27.76±5.57 to 24.82±5.69 degrees (P=0.08). Overall, 73% of the tubes moved toward the cornea (mean 0.11 mm, over 4.4 to 6.1 y). In total, 73% showed an increase in ICL; 45% showed an increase of >0.3 mm [mean 0.50 mm (33%) increase]. Two of 11 tubes (18%) showed no significant change in the parameters (ICL, 0.03 and 0.01 mm increase; TC, 0 and 0.01 mm increase); these tubes were noted to lie on the iris.

Conclusions:

Tubes tend to move toward the cornea over time. To avoid corneal damage and involvement of the visual axis in the future, tubes should be reasonably short and inserted tangentially, preferably in the posterior one third of the anterior chamber.