bluuebunny/crossref_metadata_2025 huggingface dataset:
β-Catenin is a pH sensor with decreased stability at higher intracellular pH
Authors: White Katharine A. , Grillo-Hill Bree K. , Esquivel Mario , Peralta Jobelle , Bui Vivian N. , Chire Ismahan , Barber Diane L.
Published: October 2018

β-Catenin functions as an adherens junction protein for cell–cell adhesion and as a signaling protein. β-catenin function is dependent on its stability, which is regulated by protein–protein interactions that stabilize β-catenin or target it for proteasome-mediated degradation. In this study, we show that β-catenin stability is regulated by intracellular pH (pHi) dynamics, with decreased stability at higher pHi in both mammalian cells and Drosophila melanogaster. β-Catenin degradation requires phosphorylation of N-terminal residues for recognition by the E3 ligase β-TrCP. While β-catenin phosphorylation was pH independent, higher pHi induced increased β-TrCP binding and decreased β-catenin stability. An evolutionarily conserved histidine in β-catenin (found in the β-TrCP DSGIHS destruction motif) is required for pH-dependent binding to β-TrCP. Expressing a cancer-associated H36R–β-catenin mutant in the Drosophila eye was sufficient to induce Wnt signaling and produced pronounced tumors not seen with other oncogenic β-catenin alleles. We identify pHi dynamics as a previously unrecognized regulator of β-catenin stability, functioning in coincidence with phosphorylation.
Action always involves attention
Authors: Wu Wayne
Published: October 2018

Jennings and Nanay (this journal, 2016) argue against my claim that action entails attention by providing putative counterexamples to the claim that action entails a Many–Many Problem. This reply demonstrates that they have misunderstood the central notion of a pure reflex on which my argument depends. A simplified form of the argument from pure reflex to the Many–Many Problem as a necessary feature of agency is given, and putative counterexamples of action without attention are addressed. Attention is present in every action. In passing, the reply discusses how we should assess intuitive claims about attention and mental processing, with emphasis on learning and the automatization of attention in its development as a skill.
Bayesian estimation of a semiparametric recurrent event model with applications to the penetrance estimation of multiple primary cancers in Li-Fraumeni syndrome
Authors: Shin Seung Jun , Li Jialu , Ning Jing , Bojadzieva Jasmina , Strong Louise C , Wang Wenyi
Published: October 2018

A common phenomenon in cancer syndromes is for an individual to have multiple primary cancers (MPC) at different sites during his/her lifetime. Patients with Li-Fraumeni syndrome (LFS), a rare pediatric cancer syndrome mainly caused by germline TP53 mutations, are known to have a higher probability of developing a second primary cancer than those with other cancer syndromes. In this context, it is desirable to model the development of MPC to enable better clinical management of LFS. Here, we propose a Bayesian recurrent event model based on a non-homogeneous Poisson process in order to obtain penetrance estimates for MPC related to LFS. We employed a familywise likelihood that facilitates using genetic information inherited through the family pedigree and properly adjusted for the ascertainment bias that was inevitable in studies of rare diseases by using an inverse probability weighting scheme. We applied the proposed method to data on LFS, using a family cohort collected through pediatric sarcoma patients at MD Anderson Cancer Center from 1944 to 1982. Both internal and external validation studies showed that the proposed model provides reliable penetrance estimates for MPC in LFS, which, to the best of our knowledge, have not been reported in the LFS literature.
Metric Properties of Parabolic Ample Bundles
Authors: Biswas Indranil , Pingali Vamsi Pritham
Published: October 2018

We introduce a notion of admissible Hermitian metrics on parabolic bundles and define positivity properties for the same. We develop Chern–Weil theory for parabolic bundles and prove that our metric notions coincide with the already existing algebro-geometric versions of parabolic Chern classes. We also formulate a Griffiths conjecture in the parabolic setting and prove some results that provide evidence in its favor for certain kinds of parabolic bundles. For these kinds of parabolic structures, we prove that the conjecture holds on Riemann surfaces. We also prove that a Berndtsson-type result holds and that there are metrics on stable bundles over surfaces whose Schur forms are positive.
Government Debt Management: The Long and the Short of It
Authors: Faraglia Elisa , Marcet Albert , Oikonomou Rigas , Scott Andrew
Published: October 2018

Standard optimal Debt Management (DM) models prescribe a dominant role for long bonds and advocate against issuing short bonds. They require very large positions in order to complete markets and assume each period that governments repurchase all outstanding bonds and reissue (r/r) new ones. These features of DM are inconsistent with U.S. data. We introduce incomplete markets via small transaction costs which serves to make optimal DM more closely resemble the data : r/r are negligible, short bond issuance substantial and persistent and short and long bonds positively co-vary. Intuitively, long bonds help smooth taxes over states and short bonds over time. Solving incomplete market models with multiple assets is challenging so a further contribution of this article is introducing a novel computational method to find global solutions.
European consensus-based recommendations for the diagnosis and treatment of rare paediatric vasculitides – the SHARE initiative
Authors: de Graeff Nienke , Groot Noortje , Brogan Paul , Ozen Seza , Avcin Tadej , Bader-Meunier Brigitte , Dolezalova Pavla , Feldman Brian M , Kone-Paut Isabelle , Lahdenne Pekka , Marks Stephen D , McCann Liza , Pilkington Clarissa , Ravelli Angelo , van Royen Annet , Uziel Yosef , Vastert Bas , Wulffraat Nico , Kamphuis Sylvia , Beresford Michael W
Published: October 2018

Objectives

The European initiative Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) aimed to optimize care for children with rheumatic diseases. Systemic vasculitides are very rare in children. Consequently, despite recent advances, paediatric-specific information is sparse. The lack of evidence-based recommendations is an important, unmet need. This study aimed to provide recommendations for diagnosing and treating children with rare forms of childhood systemic vasculitis.

Methods

Recommendations were developed by a consensus process in accordance with the European League Against Rheumatism standard operating procedures. A systematic literature review informed the recommendations, which were devised and evaluated by a panel of experts via an online survey, and two consensus meetings using nominal group technique. Recommendations were accepted when ⩾ 80% of experts agreed.

Results

Ninety-three relevant articles were found, and 78 recommendations were accepted in the two consensus meetings. General, cross-cutting recommendations and disease-specific statements regarding the diagnosis and treatment of childhood-onset PAN, granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and Takayasu arteritis are provided.

Conclusion

These Single Hub and Access point for paediatric Rheumatology in Europe recommendations were formulated through an evidence-based consensus process to support uniform, high-quality standard of care for children with rare forms of paediatric systemic vasculitis.
Triple-low Alerts Do Not Reduce Mortality
Authors: Sessler Daniel I. , Turan Alparslan , Stapelfeldt Wolf H. , Mascha Edward J. , Yang Dongsheng , Farag Ehab , Cywinski Jacek , Vlah Claudene , Kopyeva Tatyana , Keebler Allen L. , Perilla Mauricio , Ramachandran Mangakalaraip , Drahuschak Sean , Kaple Kristina , Kurz Andrea
Published: October 2018

EDITOR’S PERSPECTIVE

What We Already Know about This Topic

Intraoperative triple-low events (mean arterial pressure less than 75 mmHg, Bispectral Index less than 45, and minimum alveolar fraction of anesthetic less than 0.8) have been found to be associated with increased risk of mortality

What This Article Tells Us That Is New

A randomized electronic alert of triple-low events to treating clinicians did not reduce 90-day mortality

The alerts minimally influenced clinician responses, assessed as vasopressor administration or reduction in end-tidal volatile anesthetic partial pressure, and there was no association between response to alerts and mortality

Triple-low events predict mortality but do not appear to be causally related

Background

Triple-low events (mean arterial pressure less than 75 mmHg, Bispectral Index less than 45, and minimum alveolar fraction less than 0.8) are associated with mortality but may not be causal. This study tested the hypothesis that providing triple-low alerts to clinicians reduces 90-day mortality.

Methods

Adults having noncardiac surgery with volatile anesthesia and Bispectral Index monitoring were electronically screened for triple-low events. Patients having triple-low events were randomized in real time, with clinicians either receiving an alert, “consider hemodynamic support,” or not. Patients were blinded to treatment. Helpful responses to triple-low events were defined by administration of a vasopressor within 5 min or a 20% reduction in end-tidal volatile anesthetic concentration within 15 min.

Results

Of the qualifying patients, 7,569 of 36,670 (20%) had triple-low events and were randomized. All 7,569 were included in the primary analysis. Ninety-day mortality was 8.3% in the alert group and 7.3% in the nonalert group. The hazard ratio (95% CI) for alert versus nonalert was 1.14 (0.96, 1.35); P = 0.12, crossing a prespecified futility boundary. Clinical responses were helpful in about half the patients in each group, with 51% of alert patients and 47% of nonalert patients receiving vasopressors or having anesthetics lowered after start of triple low (P < 0.001). There was no relationship between the response to triple-low events and adjusted 90-day mortality.

Conclusions

Real-time alerts to triple-low events did not lead to a reduction in 90-day mortality, and there were fewer responses to alerts than expected. However, similar mortality with and without responses suggests that there is no strong relationship between responses to triple-low events and mortality.
A Cost-utility Analysis of Percutaneous Endoscopic Lumbar Discectomy for L5-S1 Lumbar Disc Herniation
Authors: Wang Dongdong , Xie Wangcheng , Cao Wenxin , He Shisheng , Fan Guoxin , Zhang Hailong
Published: October 2018

Study Design.

A cost-utility analysis (CUA).

Objective.

The aim of this study was to evaluate the cost-effectiveness of percutaneous endoscopic transforaminal discectomy (PETD) and percutaneous endoscopic interlaminar discectomy (PEID) techniques for the treatment of L5-S1 lumbar disc herniation (LDH).

Summary of Background Data.

The annual cost of treatment for lumbar disc herniation is staggering. As the two major approaches of percutaneous endoscopic lumbar discectomy (PELD): percutaneous endoscopic transforaminal discectomy (PETD) and percutaneous endoscopic interlaminar discectomy (PEID) have gained recognition for the treatment of L5-S1 lumbar disc herniation (LDH) and showed similar clinical outcome. ost-utility analysis (CUA) can help clinicians make appropriate decisions about optimal health care for L5-S1 LDH.

Methods.

Fifty and 25 patients were included in the PETD and PEID groups of the study. Patients’ basic characteristics, health care costs, and clinical outcome of PETD and PEID group were collected and analyzed. Quality-adjusted life-years (QALYs) were calculated and validated by EuroQol five-dimensional (EQ-5D) questionnaire. Cost-effectiveness was determined by the incremental cost per QALY gained.

Results.

The mean total cost of the PETD group was $5275.58 ± 292.98 and the PEID group was $5494.45 ± 749.24. No significant differences were observed in hospitalization expenses, laboratory and radiographic evaluations expenses, surgical expenses, and drug costs. Surgical equipment and materials costs, and anesthesia expense in the PEID group were significantly higher than in the PETD group (P < 0.001). Clinical outcomes, including Oswestry Disability Index (ODI), Visual Analogue Scale (VAS) scores, and Japanese Orthopaedic Association (JOA), also showed no significant differences between the two groups. The cost-effectiveness ratio of PETD and PEID were $6816.05 ± 717.90/QALY and $7073.30 ± 1081.44/QALY, respectively. The incremental cost-effectiveness ratios (ICERs) of PEID over PETD was $21887.00/QALY.

Conclusion.

Observed costs per QALY gained for L5-S1 LDH with PETD or PEID were similar for patients, demonstrating that the two different approaches of PELD are equally cost-effective and valuable interventions.

Level of Evidence: 5
Group and Individual-level Change on Health-related Quality of Life in Chiropractic Patients With Chronic Low Back or Neck Pain
Authors: Hays Ron D. , Spritzer Karen L. , Sherbourne Cathy D. , Ryan Gery W. , Coulter Ian D.
Published: October 2018

Study Design.

A prospective observational study.

Objective.

The aim of this study was to evaluate group-level and individual-level change in health-related quality of life among persons with chronic low back pain or neck pain receiving chiropractic care in the United States.

Summary of Background Data.

Chiropractors treat chronic low back and neck pain, but there is limited evidence of the effectiveness of their treatment

Methods.

A 3-month longitudinal study of 2024 patients with chronic low back pain or neck pain receiving care from 125 chiropractic clinics at six locations throughout the United States was conducted. Ninety-one percent of the sample completed the baseline and 3-month follow-up survey (n = 1835). Average age was 49, 74% females, and most of the sample had a college degree, were non-Hispanic White, worked full-time, and had an annual income of $60,000 or more. Group-level (within-group t tests) and individual-level (coefficient of repeatability) changes on the Patient-Reported Outcomes Measurement Information System (PROMIS-29) v2.0 profile measure was evaluated: six multi-item scales (physical functioning, pain, fatigue, sleep disturbance, social health, emotional distress) and physical and mental health summary scores.

Results.

Within-group t tests indicated significant group-level change (P < 0.05) for all scores except for emotional distress, and these changes represented small improvements in health (absolute value of effect sizes ranged from 0.08 for physical functioning to 0.20 for pain). From 13% (physical functioning) to 30% (PROMIS-29 v2.0 Mental Health Summary Score) got better from baseline to 3 months later according to the coefficient of repeatability.

Conclusion.

Chiropractic care was associated with significant group-level improvement in health-related quality of life over time, especially in pain. But only a minority of the individuals in the sample got significantly better (“responders”). This study suggests some benefits of chiropractic on functioning and well-being of patients with low back pain or neck pain.

Level of Evidence: 3
Economic Evaluation of Venovenous Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome*
Authors: Barrett Kali A. , Hawkins Neil , Fan Eddy
Published: October 2018

Objectives:

Venovenous extracorporeal membrane oxygenation is increasingly being used to support patients with severe acute respiratory distress syndrome, but its cost-effectiveness is unknown. We assessed the cost-utility of venovenous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome in adults compared with standard lung protective ventilation from the perspective of the healthcare system.

Design:

We conducted a cost-utility analysis with a cohort state transition decision model using a lifetime time horizon, 1.5% discount rate, and outcomes reported as cost per quality-adjusted life year. Literature reviews were conducted to inform the model variables. Deterministic and probabilistic sensitivity analyses were conducted to assess uncertainty in the model.

Setting:

Canadian publicly funded healthcare system.

Patients:

Hypothetical cohort of adults with severe acute respiratory distress syndrome.

Interventions:

Venovenous extracorporeal membrane oxygenation or standard lung protective ventilation.

Measurements and Main Results:

In our model, the use of venovenous extracorporeal membrane oxygenation compared with lung protective ventilation resulted in a gain of 5.2 life years and 4.05 quality-adjusted life years, at an additional lifetime cost of $145,697 Canadian dollars. The incremental cost-effectiveness ratio was $36,001/quality-adjusted life year. Sensitivity analyses show that the incremental cost-effectiveness ratio is sensitive to the efficacy of extracorporeal membrane oxygenation therapy and costs.

Conclusions:

Based on current data, venovenous extracorporeal membrane oxygenation is cost-effective for patients with severe acute respiratory distress syndrome. Additional evidence on the efficacy of venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome and in different subgroups of patients will allow for greater certainty in its cost-effectiveness.
Predictors of Metastases in Rectal Neuroendocrine Tumors: Results of a National Cohort Study
Authors: Concors Seth J. , Sinnamon Andrew J. , Folkert Ian W. , Mahmoud Najjia N. , Fraker Douglas L. , Paulson E. Carter , Roses Robert E.
Published: October 2018

BACKGROUND:

Rectal neuroendocrine tumors are often found incidentally. Local excision alone has been advocated for lesions ≤2 cm; however, the evidence base for this approach is limited.

OBJECTIVE:

Associations among tumor size, degree of differentiation, and presence of distant metastatic disease were examined.

DESIGN:

This was a retrospective cohort study.

SETTINGS:

This study was conducted using a nationwide cohort.

PATIENTS:

A total of 4893 patients with rectal neuroendocrine tumors were identified in the National Cancer Database (2006–2015).

MAIN OUTCOME MEASURES:

Logistic regression analyses were used to evaluate associations among tumor size, degree of differentiation, and presence of regional and distant metastatic disease. Cut point analysis was performed to identify an optimal size threshold predictive of distant metastatic disease.

RESULTS:

Of patients included for analysis, 3880 (79.3%) had well-differentiated tumors, 540 (11.0%) had moderately differentiated tumors, and 473 (9.7%) had poorly differentiated tumors. On logistic regression, increasing size was associated with a higher likelihood of pathologically confirmed lymph node involvement (among patients undergoing proctectomy), and both size and degree of differentiation were independently associated with a higher likelihood of distant metastatic disease. The association between tumor size and distant metastatic disease was stronger for well-differentiated and moderately differentiated tumors (OR = 1.4; p < 0.001 for both) than for poorly differentiated tumors (OR = 1.1; p = 0.010). For well-differentiated tumors, the optimal cut point for the presence of distant metastatic disease was 1.15 cm (area under the curve = 0.88; 88% sensitive and 88% specific). Tumors ≥1.15 cm in diameter were associated with a substantially increased incidence of distant metastatic disease (72/449 (13.8%)). For moderately differentiated tumors, the optimal cut point was also 1.15 cm (area under the curve = 0.87, 100% sensitive and 75% specific).

LIMITATIONS:

This study was limited by its retrospective design.

CONCLUSIONS:

Tumor size and degree of differentiation are predictive of regional and distant metastatic disease in rectal neuroendocrine tumors. Patients with tumors >1.15 cm are at substantial risk of distant metastasis and should be staged and managed accordingly. See Video Abstract at http://links.lww.com/DCR/A778.
PARS PLANA VITRECTOMY FOR THE TREATMENT OF TRACTIONAL AND DEGENERATIVE LAMELLAR MACULAR HOLES
Authors: Figueroa Marta S. , Govetto Andrea , Steel David H. , Sebag J. , Virgili Gianni , Hubschman Jean Pierre
Published: October 2018

Purpose:

Functional and anatomical outcomes of vitrectomy with membrane peeling were compared in tractional lamellar macular holes (LMH)/macular pseudoholes (MPH) versus degenerative LMH.

Methods:

This multicenter retrospective study enrolled patients with a minimum follow-up of 6 months. The association of spectral domain optical coherence tomography parameters with preoperative and postoperative best-corrected visual acuity was analyzed.

Results:

Seventy-seven (74.8%) tractional LMH/MPH and 26 (25.2%) degenerative LMH were included. Preoperative best-corrected visual acuity was better in tractional LMH/MPH (0.39 ± 0.2 logarithm of the minimal angle of resolution, 20/50 Snellen equivalent) than degenerative LMH (0.56 ± 0.2 logarithm of the minimal angle of resolution, 20/66 Snellen equivalent; P < 0.001). Premacular membranes were found in all tractional LMH/MPH, whereas LMH-associated epiretinal proliferation (LHEP) was present in all degenerative LMH. Primary anatomical success was achieved in 97/103 eyes (94.2%), with foveal restoration occurring earlier in degenerative LMH (1.6 ± 2.3 vs. 3.3 ± 3.6 months; P = 0.025). Best-corrected visual acuity improved in both tractional LMH/MPH and degenerative LMH (P < 0.001 and P = 0.012, respectively) but was better in tractional LMH/MPH (P = 0.001).

Conclusion:

The presence of premacular membranes and absence of LMH-associated epiretinal proliferation in all tractional LMH/MPH further distinguishes this from degenerative LMH. Best-corrected visual acuity improved in both subgroups but more so in tractional LMH/MPH. Complete anatomical restoration of foveal microanatomy was rare in degenerative LMH, reflecting significant morphological and pathophysiological differences between the two lesions.
INTRAVITREAL ANTI–VASCULAR ENDOTHELIAL GROWTH FACTOR FOR THE MANAGEMENT OF NEOVASCULARIZATION IN RETINOBLASTOMA AFTER INTRAVENOUS AND/OR INTRAARTERIAL CHEMOTHERAPY
Authors: Stathopoulos Christina , Gaillard Marie-Claire , Moulin Alexandre , Puccinelli Francesco , Beck-Popovic Maja , Munier Francis L.
Published: October 2018

Purpose:

To report the use of anti–vascular endothelial growth factor in the management of retinoblastoma.

Methods:

Retrospective review of 35 eyes (33 patients) treated with at least one intravitreal anti–vascular endothelial growth factor (ranibizumab and/or aflibercept) for new iris (n = 26) and/or retinal neovascularization (n = 21) after intravenous chemotherapy and/or intraarterial chemotherapy.

Results:

Most eyes (n = 31/35, 89%) were Group D or E. Previous treatments were salvage intraarterial chemotherapy after intravenous chemotherapy (n = 21/35, 60%), first-line intraarterial chemotherapy (n = 7/35, 20%), and first-line intravenous chemotherapy (n = 7/35, 20%). Associated clinical features were retinal ischemia (94%), retinal detachment (51%), active tumor (34%), intravitreal hemorrhage (43%), and/or glaucoma (17%). Mean 1.6 anti–vascular endothelial growth factor injections/eye were given; 28 eyes received ranibizumab, 2 aflibercept, and 5 both agents. Eight eyes underwent complementary treatments of ischemic retina. Resolution of neovascularization was observed in 28 eyes (n = 28/35, 80%). Globe salvage was achieved in 51% (n = 18/35), including 25% of those with active tumor (n = 3/12). One eye became phthisic. Sixteen eyes were enucleated, nine for tumor relapse/progression. Five eyes had high-risk histopathologic risk factors and received adjuvant intravenous chemotherapy. All patients are alive with no extraocular extension nor metastases (mean follow-up 3.7 years, range 1.1–7.6).

Conclusion:

Intravitreal anti–vascular endothelial growth factor contributed to a globe salvage rate of 51% by providing conditions to continue conservative treatment.
Predicting Engagement With Online Walking Promotion Among Metropolitan and Rural Cancer Survivors
Authors: Frensham Lauren J. , Parfitt Gaynor , Dollman James
Published: October 2018

Background

Physical activity has numerous associated benefits for cancer survivors. Compared with their urban counterparts, rural Australians experience a health disadvantage, including poorer survival rate after diagnosis of cancer.

Objective

The aims of this study were to test the effectiveness of an online 12-week walking intervention designed for cancer survivors and explore region-specific psychological predictors of behavior change.

Methods

This was a quasi-randomized controlled trial of an online resource designed according to Social Cognitive Theory and Self-determination Theory, based on individualized goal setting. Measures of habitual walking, motivation, and self-efficacy were taken at baseline, postintervention, and 3-month follow-up in an intervention group (n = 46) and active control group (n = 45). The control group was provided a pedometer but did not have access to the online program.

Results

An increase in steps/day at 12 weeks was observed in both groups, with a larger increase in the intervention group; these increases were not sustained at the 3-month follow-up. Psychological predictors of maintained change in steps per day (motivation, barrier self-efficacy, and relapse self-efficacy) did not differ between metropolitan and rural participants. Changes in steps per day among intervention participants were predicted by changes in relapse self-efficacy and barrier self-efficacy.

Conclusions

The intervention was successful in increasing physical activity postintervention; however, changes were not maintained at follow-up. There were no region-specific predictors of engagement in the intervention.

Implications for Practice

Nurses are seamlessly positioned to promote health interventions like walking. Nurses should reframe physical activity with patients so that relapse is seen as common and possibly inevitable when adopting a regular physical activity habit.
A Patient Decision Aid for Men With Localized Prostate Cancer
Authors: Stacey Dawn , Taljaard Monica , Breau Rodney H. , Baba Nicole , Blackmore Terry , Boland Laura , Carley Meg , Wu Robert Chi , Smylie Jennifer , Légaré France
Published: October 2018

Background

There are multiple options for men diagnosed with localized prostate cancer. Patient decision aids (PtDAs) help empower individuals and reduce unwarranted practice variation, but few are used in clinical practice.

Objective

We compared 2 programs implementing PtDAs for men with localized prostate cancer.

Methods

This was a comparative case study. Case 1 was a hospital prostate pathway and case 2 was a provincial prostate pathway with 2 locations (2a, 2b). Nurses provided the men with PtDAs and answered questions. Data sources were as follows: (a) 2 years administrative data for men with localized prostate cancer, (b) clinicians survey and interviews, and (c) patients/spouses interviews. Analysis was within and across cases.

Results

The PtDA was used with 23% of men in case 1 (95% confidence interval, 19.8%–26.1%) and 98% of men in case 2a (95% confidence interval, 96.5%–99.8%). The pathway was not implemented in case 2b. Men given the PtDA had positive experiences. Many clinicians supported the use of PtDAs, some adapted their discussions with patients, and others did not support the use of PtDAs. To increase use in case 1, participants identified needing a Canadian PtDA available electronically and endorsed by all clinicians. In case 2b, the provincial prostate pathway needed to be implemented.

Conclusions

There was variable uptake of the PtDAs between the cases. Men who received the PtDA had positive outcomes. Several strategies were identified to increase or sustain PtDA use.

Implications for Practice

Nurses have a key role in supporting men making decisions about prostate cancer treatment by providing PtDAs, answering questions, and advocating for men's preferences.
Opioid Agonist Treatment and Improved Outcomes at Each Stage of the HIV Treatment Cascade in People Who Inject Drugs in Ukraine
Authors: Mazhnaya Alyona , Marcus Ruthanne , Bojko Martha J. , Zelenev Alexei , Makarenko Iuliia , Pykalo Iryna , Filippovych Sergii , Dvoriak Sergii , Altice Frederick L.
Published: October 2018

Background:

The HIV treatment cascade is a crucial tool to guide HIV prevention and treatment strategies. The extent to which opioid agonist treatments (OATs) such as methadone and buprenorphine influence this cascade was examined in a nationwide study of people who inject drugs (PWID) in Ukraine.

Setting:

Cross-sectional stratified survey of PWID followed by HIV and hepatitis C virus testing in 5 Ukrainian cities.

Methods:

Opioid-dependent PWID (N = 1613) were sampled from January 2014 to March 2015. Analysis was confined to 520 participants with HIV, with 184 (35.4%) prescribed OAT. Weighted logistic regression models were used to assess independent factors associated with the 5 steps in the HIV treatment cascade.

Results:

Compared with PWID not on OAT (N = 336), participants who prescribed OAT (N = 184) were significantly more likely to be diagnosed (91% vs. 71%), linked (81% vs. 52%), and retained (69% vs. 35%) in HIV care, and prescribed (56% vs. 31%) and optimally (>95% of doses) adherent to antiretroviral therapy (41% vs. 22%). Receiving OAT contributed most as an independent factor with every step of the cascade. Other steps in the HIV treatment cascade were influenced by age, depression, and geographical variability.

Conclusions:

OAT remains an essential and effective strategy to not only treat patients with opioid use disorder, but also a crucial strategy to engage PWID in care to meet UNAIDS 90-90-90 targets. Geographical differences suggest local structural impediments. With low OAT coverage prescribed for 2.9% of the estimated 347,000 PWID in Ukraine, OAT expansion requires strategic interventions that target the individual, clinical care settings, policies, and funding.
Importance of Normalization of CA19-9 Levels Following Neoadjuvant Therapy in Patients With Localized Pancreatic Cancer
Authors: Tsai Susan , George Ben , Wittmann David , Ritch Paul S. , Krepline Ashley N. , Aldakkak Mohammed , Barnes Chad A. , Christians Kathleen K. , Dua Kulwinder , Griffin Michael , Hagen Catherine , Hall William A. , Erickson Beth A. , Evans Douglas B.
Published: October 2018

Objective:

Carbohydrate antigen 19-9 (CA19-9) is a prognostic marker for patients with pancreatic cancer (PC), but its value as a treatment biomarker is unclear.

Summary Background Data:

Although CA19-9 is an established prognostic marker for patients with PC, it is unclear how CA19-9 monitoring should be used to guide multimodality treatment and what level of change in CA19-9 constitutes a meaningful treatment response.

Methods:

CA19-9 measurements at diagnosis (pretx), after completion of all planned neoadjuvant therapy (preop), and after surgery (postop) were analyzed in patients with localized PC who had an elevated CA19-9 (≥35 U/dL) at diagnosis. Patients were classified by: 1) quartiles of pretx CA19-9 (Q1-4); 2) proportional changes in CA19-9 (ΔCA19-9) after the completion of neoadjuvant therapy; 3) normalization (CA19-9 <35 U/dL) of preop CA19-9; and 4) normalization of postop CA19-9.

Results:

Among 131 patients, the median overall survival (OS) was 30 months; 68 months for the 33 patients in Q1 of pretx CA19-9 (<80 U/dL) compared with 25 months for the 98 patients in Q2-4 (P = 0.03). For the 98 patients in Q2-4, preop CA19-9 declined (from pretx) in 86 (88%), but there was no association between the magnitude of ΔCA19-9 and OS (P = 0.77). Median OS of the 98 patients who did (n = 29) or did not (n = 69) normalize their preop CA19-9 were 46 and 23 months, respectively (P = 0.02). Of the 69 patients with an elevated preop CA19-9, 32 (46%) normalized their postop CA19-9. Failure to normalize preop or postop CA19-9 was associated with a 2.77-fold and 4.03-fold increased risk of death, respectively (P < 0.003) as compared with patients with normal preop CA19-9.

Conclusions:

Following neoadjuvant therapy, normalization of CA19-9, rather than the magnitude of change, is the strongest prognostic marker for long-term survival.
Risk factors for avoidable transfer to a pediatric trauma center among patients 2 years and older
Authors: Snyder Christopher W. , Kauffman Jeremy D. , Pracht Etienne E. , Danielson Paul D. , Ciesla David J. , Chandler Nicole M.
Published: October 2018

BACKGROUND

Effective and sustainable pediatric trauma care requires systems of regionalization and interfacility transfer. Avoidable transfer, also known as secondary overtriage, occurs when a patient is transferred to a regional trauma center after initial evaluation at another facility that is capable of providing definitive care. The purpose of this study was to identify risk factors for avoidable transfer among pediatric trauma patients in southwest Florida.

METHODS

All pediatric trauma patients 2 years and older transferred from outlying hospitals to the emergency department of a single state-designated pediatric trauma center between 2009 and 2017 were obtained from the institutional registry. Transfers were classified as avoidable if the patient suffered only minor injuries (International Classification of Diseases—9th Rev. Injury Severity Score > 0.9), did not require invasive procedures or intensive care unit monitoring, and was discharged within 48 hours. Demographics and injury characteristics were compared for avoidable and nonavoidable transfers. Logistic regression was used to estimate the independent effects of age, sex, insurance type, mechanism of injury, diagnosis, within region versus out-of-region residence, suspected nonaccidental trauma, and abnormal Glasgow Coma Scale score on the risk of avoidable transfer.

RESULTS

A total of 3,876 transfer patients met inclusion criteria, of whom 1,628 (42%) were classified as avoidable. Among avoidable transfers, 29% had minor head injuries (isolated skull fractures, concussions, and mild traumatic brain injury not otherwise specified), and 58% received neurosurgery consultation. On multivariable analysis, the strongest risk factors for avoidable transfer were diagnoses of isolated skull fracture or concussion. Suspected nonaccidental trauma was predictive of nonavoidable transfer.

CONCLUSION

Among injured children 2 years and older, those with minor head injuries were at greatest risk for avoidable transfer. Many were transferred because of a perceived need for evaluation by a pediatric neurosurgeon. Future projects seeking to reduce avoidable transfers should focus on children with isolated skull fractures and concussions, in whom there is no suspicion of nonaccidental trauma.

LEVEL OF EVIDENCE

Therapeutic/care management, level IV.
ICTV Virus Taxonomy Profile: Deltavirus
Authors: Magnius Lars , Taylor John , Mason William S. , Sureau Camille , Dény Paul , Norder Helene ,   ICTV Report Consortium
Published: October 2018

Hepatitis delta virus, the only member of the only species in the genus Deltavirus, is a unique human pathogen. Its ~1.7 kb circular negative-sense RNA genome encodes a protein, hepatitis delta antigen, which occurs in two forms, small and large, both with unique functions. Hepatitis delta virus uses host RNA polymerase II to replicate via double rolling circle RNA synthesis. Newly synthesized linear RNAs are circularized after autocatalytic cleavage and ligation. Hepatitis delta virus requires the envelope of the helper virus, hepatitis B virus (family Hepadnaviridae), to produce infectious particles. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of Deltavirus which is available at www.ictv.global/report/deltavirus.
Genetic diversity in the env V1-V2 region of proviral quasispecies from long-term controller MHC-typed cynomolgus macaques infected with SHIV
SF162P4cy
Authors: Capone Alessia , Lo Presti Alessandra , Sernicola Leonardo , Farcomeni Stefania , Ferrantelli Flavia , Maggiorella Maria T. , Mee Edward T. , Rose Nicola J. , Cella Eleonora , Ciccozzi Massimo , Ensoli Barbara , Borsetti Alessandra
Published: October 2018

Intra-host evolution of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) has been shown by viral RNA analysis in subjects who naturally suppress plasma viremia to low levels, known as controllers. However, little is known about the variability of proviral DNA and the inter-relationships among contained systemic viremia, rate of reservoir reseeding and specific major histocompatibility complex (MHC) genotypes, in controllers. Here, we analysed the proviral DNA quasispecies of the env V1-V2 region, in PBMCs and in anatomical compartments of 13 long-term controller monkeys after 3.2 years of infection with simian/human immunodeficiency virus (SHIV)SF162P4cy. A considerable variation in the genetic diversity of proviral quasispecies was present among animals. Seven monkeys exhibited env V1-V2 proviral populations composed of both clusters of identical ancestral sequences and new variants, whereas the other six monkeys displayed relatively high env V1-V2 genetic diversity with a large proportion of diverse novel sequences. Our results demonstrate that in SHIVSF162P4cy-infected monkeys there exists a disparate pattern of intra-host viral diversity and that reseeding of the proviral reservoir occurs in some animals. Moreover, even though no particular association has been observed between MHC haplotypes and the long-term control of infection, a remarkably similar pattern of intra-host viral diversity and divergence was found within animals carrying the M3 haplotype. This suggests that in animals bearing the same MHC haplotype and infected with the same virus, viral diversity follows a similar pattern with similar outcomes and control of infection.
A simple microbiome in the European common cuttlefish, Sepia officinalis
Authors: Lutz Holly L. , Ramírez-Puebla S. Tabita , Abbo Lisa , Durand Amber , Schlundt Cathleen , Gottel Neil , Sjaarda Alexandra K. , Hanlon Roger T. , Gilbert Jack A. , Mark Welch Jessica L.
Published: October 2018

The European common cuttlefish, Sepia officinalis, is used extensively in biological and biomedical research yet its microbiome remains poorly characterized. We analyzed the microbiota of the digestive tract, gills, and skin in mariculture-raised S. officinalis using a combination of 16S rRNA amplicon sequencing, qPCR and fluorescence spectral imaging. Sequencing revealed a highly simplified microbiota consisting largely of two single bacterial amplicon sequence variants (ASVs) of Vibrionaceae and Piscirickettsiaceae. The esophagus was dominated by a single ASV of the genus Vibrio. Imaging revealed bacteria in the family Vibrionaceae distributed in a discrete layer that lines the esophagus. This Vibrio was also the primary ASV found in the microbiota of the stomach, cecum, and intestine, but occurred at lower abundance as determined by qPCR and was found only scattered in the lumen rather than in a discrete layer via imaging analysis. Treatment of animals with the commonly-used antibiotic enrofloxacin led to a nearly 80% reduction of the dominant Vibrio ASV in the esophagus but did not significantly alter the relative abundance of bacteria overall between treated versus control animals. Data from the gills was dominated by a single ASV in the family Piscirickettsiaceae, which imaging visualized as small clusters of cells. We conclude that bacteria belonging to the Gammaproteobacteria are the major symbionts of the cuttlefish Sepia officinalis cultured from eggs in captivity, and that the esophagus and gills are major colonization sites.

IMPORTANCE

Microbes can play critical roles in the physiology of their animal hosts, as evidenced in cephalopods by the role of Vibrio (Aliivibrio) fischeri in the light organ of the bobtail squid and the role of Alpha- and Gammaproteobacteria in the reproductive system and egg defense in a variety of cephalopods. We sampled the cuttlefish microbiome throughout the digestive tract, gills, and skin and found dense colonization of an unexpected site, the esophagus, by a microbe of the genus Vibrio, as well as colonization of gills by Piscirickettsiaceae. This finding expands the range of organisms and body sites known to be associated with Vibrio and is of potential significance for understanding host-symbiont associations as well as for understanding and maintaining the health of cephalopods in mariculture.
The key parameters that govern translation efficiency
Authors: Erdmann-Pham Dan D. , Dao Duc Khanh , Song Yun S.
Published: October 2018

Translation of mRNA into protein is a fundamental yet complex biological process with multiple factors that can potentially affect its efficiency. In particular, different genes can have quite different initiation rates, while site-specific elongation rates can vary substantially along a given transcript. Here, we analyze a stochastic model of translation dynamics to identify the key parameters that govern the overall rate of protein synthesis and the efficiency of ribosome usage. The mathematical model we study is an interacting particle system that generalizes the Totally Asymmetric Simple Exclusion Process (TASEP), where particles correspond to ribosomes. While the TASEP and its variants have been studied for the past several decades through simulations and mean field approximations, a general analytic solution has remained challenging to obtain. By analyzing the so-called hydrodynamic limit, we here obtain exact closed-form expressions for stationary currents and particle densities that agree well with Monte Carlo simulations. In addition, we provide a complete characterization of phase transitions in the system. Surprisingly, phase boundaries depend on only four parameters: the particle size, and the first, last and minimum particle jump rates. Relating these theoretical results to translation, we formulate four design principles that detail how to tune these parameters to optimize translation efficiency in terms of protein production rate and resource usage. We then analyze ribosome profiling data of S. cerevisiae and demonstrate that its translation system is generally efficient, consistent with the design principles we found. We discuss implications of our findings on evolutionary constraints and codon usage bias.
Dynamic load balancing enables large-scale flux variability analysis
Authors: Guebila Marouen Ben
Published: October 2018

Genome-scale metabolic models (GSMMs) of living organisms are used in a wide variety of applications pertaining to health and bioengineering. They are formulated as linear programs (LP) that are often under-determined. Flux Variability Analysis (FVA) characterizes the alternate optimal solution (AOS) space enabling thereby the assessment of the robustness of the solution. fastFVA (FFVA), the C implementation of MATLAB FVA, allowed to gain substantial speed up, although, the parallelism was managed through MATLAB. Here veryfastFVA (VFFVA) is presented, which is a pure C implementation of FVA, that relies on lower level management of parallelism through a hybrid MPI/OpenMP. The flexibility of VFFVA allowed to gain a threefold speedup factor and to decrease memory usage 14 fold in comparison to FFVA. Finally, VFFVA allows processing a higher number of GSMMs in faster times accelerating thereby biomedical modeling and simulation. VFFVA is available online athttps://github.com/marouenbg/VFFVA.
Assessing reliability of intra-tumor heterogeneity estimates from single sample whole exome sequencing data
Authors: Abécassis Judith , Hamy Anne-Sophie , Laurent Cécile , Sadacca Benjamin , Bonsang-Kitzis Hélène , Reyal Fabien , Vert Jean-Philippe
Published: October 2018

Tumors are made of evolving and heterogeneous populations of cells which arise from successive appearance and expansion of subclonal populations, following acquisition of mutations conferring them a selective advantage. Those subclonal populations can be sensitive or resistant to different treatments, and provide information about tumor aetiology and future evolution. Hence, it is important to be able to assess the level of heterogeneity of tumors with high reliability for clinical applications.

In the past few years, a large number of methods have been proposed to estimate intra-tumor heterogeneity from whole exome sequencing (WES) data, but the accuracy and robustness of these methods on real data remains elusive. Here we systematically apply and compare 6 computational methods to estimate tumor heterogeneity on 1,697 WES samples from the cancer genome atlas (TCGA) covering 3 cancer types (breast invasive carcinoma, bladder urothelial carcinoma, and head and neck squamous cell carcinoma), and two distinct input mutation sets. We observe significant differences between the estimates produced by different methods, and identify several likely confounding factors in heterogeneity assessment for the different methods. We further show that the prognostic value of tumor heterogeneity for survival prediction is limited in those datasets, and find no evidence that it improves over prognosis based on other clinical variables.

In conclusion, heterogeneity inference from WES data on a single sample, and its use in cancer prognosis, should be considered with caution. Other approaches to assess intra-tumoral heterogeneity such as those based on multiple samples may be preferable for clinical applications.
Detection of introduced and resident marine species using environmental DNA metabarcoding of sediment and water
Authors: Holman Luke E. , de Bruyn Mark , Creer Simon , Carvalho Gary , Robidart Julie , Rius Marc
Published: October 2018

Environmental DNA (eDNA) surveys are increasingly being used for biodiversity monitoring, principally because they are sensitive and can provide high resolution community composition data. Despite considerable progress in recent years, eDNA studies examining how different environmental sample types can affect species detectability remain rare. Comparisons of environmental samples are especially important for providing best practice guidance on early detection and subsequent mitigation of non-indigenous species. Here we used eDNA metabarcoding of COI (cytochrome c oxidase subunit I) and 18S (nuclear small subunit ribosomal DNA) genes to compare community composition between sediment and water samples in artificial coastal sites across the United Kingdom. We first detected markedly different communities and a consistently greater number of distinct operational taxonomic units in sediment compared to water. We then compared our eDNA datasets with previously published rapid assessment biodiversity surveys and found excellent concordance among the different survey techniques. Finally, our eDNA surveys detected many non-indigenous species, including several newly introduced species, highlighting the utility of eDNA metabarcoding for both early detection and temporal / spatial monitoring of non-indigenous species. We conclude that careful consideration on environmental sample type is needed when conducting eDNA surveys, especially for studies assessing community change.