bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationships among leaf flammability attributes and identifying low-leaf-flammability species at the wildland–urban interface
Authors: Krix Daniel W. , Phillips Megan L. , Murray Brad R.
Published: April 2019

Leaf flammability is a multidimensional plant functional trait with emerging importance for wildfire risk management. Understanding relationships among leaf flammability attributes not only provides information about the properties of leaves as fuels in the wildland–urban interface (WUI), it can also offer an effective way to identify low-leaf-flammability species. We examined relationships between leaf ignitibility, sustainability and combustibility among 60 plant species of the WUI of eastern Australia. We found that leaf ignitibility and sustainability worked in opposition to each other as dimensions of flammability. Species with leaves that were slow to ignite were those with leaves that sustained burning for the longest, whereas species with leaves that were fast to ignite had leaves that burned for the shortest periods of time. Low leaf combustibility was related to short leaf burning sustainability but not to ignitibility. We created an overall leaf flammability index (OLFI) to rank species on emergent properties of ignitibility, sustainability and combustibility attributes in combination. We found that low-leaf-flammability species with low OLFI values had small leaf area, high leaf mass per area and high leaf water content. Our findings have implications for species selection for green firebreaks in the WUI.
Targeted exon skipping of a
CEP290
mutation rescues Joubert syndrome phenotypes in vitro and in a murine model
Authors: Ramsbottom Simon A. , Molinari Elisa , Srivastava Shalabh , Silberman Flora , Henry Charline , Alkanderi Sumaya , Devlin Laura A. , White Kathryn , Steel David H. , Saunier Sophie , Miles Colin G. , Sayer John A.
Published: April 2019

Significance

The treatment of genetic kidney disease is challenging, as this requires both the correction of the underlying gene defect and the delivery of the treatment. Here we show that by using antisense oligonucleotides, we can induce exon skipping of a mutated exon in
CEP290
, within renal epithelial cells derived from a patient with a ciliopathy syndrome called Joubert syndrome. This treatment rescues the truncated CEP290 protein to a near full-length protein and restores the ciliary phenotype. In a
Cep290
murine model of Joubert syndrome, exon skipping is achievable with systemic treatment of an antisense oligonucleotide, which rescues both the ciliary and kidney disease phenotypes. This work paves the way toward personalized genetic therapies in patients with inherited kidney diseases.
Dresden's Musical Ruins
Authors: Sprigge Martha
Published: April 2019

In studies of memory politics in post-war Germany, the role that music played in responding to the Allied bombing of Dresden on 13–14 February 1945 has been overlooked. This article examines one of the first musical reactions to this traumatic event: Rudolf Mauersberger's mourning motet Wie liegt die Stadt so wüst (How Deserted Lies the City, 1945). I argue that Mauersberger, who served as cantor of the world-famous Kreuzchor from 1930 until his death in 1971, used allegory rather than testimony to formulate a response to the firebombing that resonated with historical customs familiar to the city's residents. When premièred in the bombed-out Kreuzkirche, Mauersberger's music provided a communal setting to confront the effects of the air war, transforming a space of destruction into one of contemplation and mourning. Both his compositional process and the performance transformed rubble (the material aftermath of the attack) into a ruin (an aesthetic object).
How cells fuse
Authors: Brukman Nicolas G. , Uygur Berna , Podbilewicz Benjamin , Chernomordik Leonid V.
Published: April 2019

Cell–cell fusion remains the least understood type of membrane fusion process. However, the last few years have brought about major advances in understanding fusion between gametes, myoblasts, macrophages, trophoblasts, epithelial, cancer, and other cells in normal development and in diseases. While different cell fusion processes appear to proceed via similar membrane rearrangements, proteins that have been identified as necessary and sufficient for cell fusion (fusogens) use diverse mechanisms. Some fusions are controlled by a single fusogen; other fusions depend on several proteins that either work together throughout the fusion pathway or drive distinct stages. Furthermore, some fusions require fusogens to be present on both fusing membranes, and in other fusions, fusogens have to be on only one of the membranes. Remarkably, some of the proteins that fuse cells also sculpt single cells, repair neurons, promote scission of endocytic vesicles, and seal phagosomes. In this review, we discuss the properties and diversity of the known proteins mediating cell–cell fusion and highlight their different working mechanisms in various contexts.
Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS
Authors: Gratia Matthieu , Rodero Mathieu P. , Conrad Cécile , Bou Samra Elias , Maurin Mathieu , Rice Gillian I. , Duffy Darragh , Revy Patrick , Petit Florence , Dale Russell C. , Crow Yanick J. , Amor-Gueret Mounira , Manel Nicolas
Published: April 2019

Cellular innate immune sensors of DNA are essential for host defense against invading pathogens. However, the presence of self-DNA inside cells poses a risk of triggering unchecked immune responses. The mechanisms limiting induction of inflammation by self-DNA are poorly understood. BLM RecQ–like helicase is essential for genome integrity and is deficient in Bloom syndrome (BS), a rare genetic disease characterized by genome instability, accumulation of micronuclei, susceptibility to cancer, and immunodeficiency. Here, we show that BLM-deficient fibroblasts show constitutive up-regulation of inflammatory interferon-stimulated gene (ISG) expression, which is mediated by the cGAS–STING–IRF3 cytosolic DNA–sensing pathway. Increased DNA damage or down-regulation of the cytoplasmic exonuclease TREX1 enhances ISG expression in BLM-deficient fibroblasts. cGAS-containing cytoplasmic micronuclei are increased in BS cells. Finally, BS patients demonstrate elevated ISG expression in peripheral blood. These results reveal that BLM limits ISG induction, thus connecting DNA damage to cellular innate immune response, which may contribute to human pathogenesis.
Direct measurement of ion chamber correction factors, kQ and kB, in a 7 MV MRI-linac
Authors: de Prez Leon , Woodings Simon , de Pooter Jacco , van Asselen Bram , Wolthaus Jochem , Jansen Bartel , Raaymakers Bas
Published: April 2019

The output of MRI-integrated photon therapy (MRgXT) devices is measured in terms of absorbed dose to water, D
w. Traditionally this is done with reference type ion chambers calibrated in a beam quality Q
0 without magnetic field. To correct the ion chamber response for the application in the magnetic field, a factor needs to be applied that corrects for both beam quality Q and the presence of the magnetic field B, k
Q,B. This can be expressed as the product of k
Q, without magnetic field, and ion chamber magnetic field correction, k
B. k
B depends on the magnetic field strength and its direction, the direction of the beam and the orientation and type of the ion chamber. In this study, for the first time, both k
Q and k
B were measured directly for six waterproof ion chambers (3  ×  PTW 30013 and 3  ×  IBA FC65-G) in a pre-clinical 7 MV MRI-linac at 0 T and at 1.5 T. Measurements were done with the only available primary standard built for this purpose, a water calorimeter. Resulting k
Q factors for PTW and IBA chambers were 0.985(5) and 0.990(4), respectively. k
B factors were measured with the chambers in antiparallel direction to the magnetic field (|| 180°), and perpendicular direction (⊥  −90°). k
B|| and k
B⊥ for the PTW chambers were 0.985(6) and 0.963(4), respectively and for IBA chambers 0.995(4) and 0.956(4). Agreement with the available literature values was shown, partly caused by the relatively large standard deviation (SD) in those values. The values in this study are currently the only available measured values for k
Q and k
B in an MRI-linac that are directly linked to the international traceability framework for the quantity absorbed dose to water, D
w.
Performance of Matching Methods as Compared With Unmatched Ordinary Least Squares Regression Under Constant Effects
Authors: Vable Anusha M , Kiang Mathew V , Glymour M Maria , Rigdon Joseph , Drabo Emmanuel F , Basu Sanjay
Published: April 2019

Matching methods are assumed to reduce the likelihood of a biased inference compared with ordinary least squares (OLS) regression. Using simulations, we compared inferences from propensity score matching, coarsened exact matching, and unmatched covariate-adjusted OLS regression to identify which methods, in which scenarios, produced unbiased inferences at the expected type I error rate of 5%. We simulated multiple data sets and systematically varied common support, discontinuities in the exposure and/or outcome, exposure prevalence, and analytical model misspecification. Matching inferences were often biased in comparison with OLS, particularly when common support was poor; when analysis models were correctly specified and common support was poor, the type I error rate was 1.6% for propensity score matching (statistically inefficient), 18.2% for coarsened exact matching (high), and 4.8% for OLS (expected). Our results suggest that when estimates from matching and OLS are similar (i.e., confidence intervals overlap), OLS inferences are unbiased more often than matching inferences; however, when estimates from matching and OLS are dissimilar (i.e., confidence intervals do not overlap), matching inferences are unbiased more often than OLS inferences. This empirical “rule of thumb” may help applied researchers identify situations in which OLS inferences may be unbiased as compared with matching inferences.
Structural Covariance Reveals Alterations in Control and Salience Network Integrity in Chronic Schizophrenia
Authors: Spreng R Nathan , DuPre Elizabeth , Ji Jie Lisa , Yang Genevieve , Diehl Caroline , Murray John D , Pearlson Godfrey D , Anticevic Alan
Published: April 2019

Schizophrenia (SCZ) is recognized as a disorder of distributed brain dysconnectivity. While progress has been made delineating large-scale functional networks in SCZ, little is known about alterations in grey matter integrity of these networks. We used a multivariate approach to identify the structural covariance of the salience, default, motor, visual, fronto-parietal control, and dorsal attention networks. We derived individual scores reflecting covariance in each structural image for a given network. Seed-based multivariate analyses were conducted on structural images in a discovery (n = 90) and replication (n = 74) sample of SCZ patients and healthy controls. We first validated patterns across all networks, consistent with well-established functional connectivity reports. Next, across two SCZ samples, we found reliable and robust reductions in structural integrity of the fronto-parietal control and salience networks, but not default, dorsal attention, motor and sensory networks. Well-powered exploratory analyses failed to identify relationships with symptoms. These findings provide evidence of selective structural decline in associative networks in SCZ. Such decline may be linked with recently identified functional disturbances in associative networks, providing more sensitive multi-modal network-level probes in SCZ. Absence of symptom effects suggests that identified disturbances may underlie a trait-type marker in SCZ.
Disparities in Short-Term Depression Among Prefrontal Cortex Synapses Sustain Persistent Activity in a Balanced Network
Authors: Yoon Jae Young , Lee Hyoung Ro , Ho Won-Kyung , Lee Suk-Ho
Published: April 2019

Persistent activity of cue-representing neurons in the prefrontal cortex (PFC) is regarded as a neural basis for working memory. The contribution of short-term synaptic plasticity (STP) at different types of synapses comprising the cortical network to persistent activity, however, remains unclear. Characterizing STP at synapses of the rat PFC layer 5 network, we found that PFC synapses exhibit distinct STP patterns according to presynaptic and postsynaptic identities. Excitatory postsynaptic currents (EPSCs) from corticopontine (Cpn) neurons were well sustained throughout continued activity, with stronger depression at synapses onto fast-spiking interneurons than those onto pyramidal cells. Inhibitory postsynaptic currents (IPSCs) were sustained at a weaker level compared with EPSC from Cpn synapses. Computational modeling of a balanced network incorporating empirically observed STP revealed that little depression at recurrent excitatory synapses, combined with stronger depression at other synapses, could provide the PFC with a unique synaptic mechanism for the generation and maintenance of persistent activity.
Adherence and Viral Suppression Among Participants of the Patient-centered Human Immunodeficiency Virus (HIV) Care Model Project: A Collaboration Between Community-based Pharmacists and HIV Clinical Providers
Authors: Byrd Kathy K , Hou John G , Bush Tim , Hazen Ron , Kirkham Heather , Delpino Ambrose , Weidle Paul J , Shankle Michael D , Camp Nasima M , Suzuki Sumihiro , Clay Patrick G ,   Patient-centered HIV Care Model Team, Aguirre Michael , Akinbosoye Osayi , Bamberger David M , Bluml Ben , Bullock Katura , Burrell Diane C , Bush Tim , Bush Clifton , Byrd Kathy K , Cadwell Chad , Camp Nasima M , Cardarelli Roberto , Clark Terri , Clay Patrick G , Crim Andrew , Cure Angela , Darin Kristin , Dean Traci , Delpino Ambrose , DeMayo Michael , Elrod Shara , Eschmann Ashley L , Farmer David , Farnan Rose , Free Heather , Gudzelak Andrew , Halbur Andrew , Hardnett Felicia , Hazen Ronald , Hilker Heidi , Hou John , Hujdich Brian , Johnson Lisa , Kirkham Heather , Lecounte James , Lio Sayuri , Lo Guanzhong , Middleton Sondra , Mills Brittany , Nguyen Christopher M , Ortiz Linda , Pietrandoni Glen , Scarsi Kimberly K , Schommer Jon , Shankle Michael D , Shrestha Ram , Smith Daron , Suzuki Sumihiro , Taitel Michael S , Teferi Gebeyehu N , Tomer Vikas , Torres Louis , Weidle Paul J , Whitfield Carmelita , Willman Jason E
Published: April 2019

Background

Human immunodeficiency virus (HIV) viral suppression (VS) decreases morbidity, mortality, and transmission risk.

Methods

The Patient-centered HIV Care Model integrated community-based pharmacists with HIV medical providers and required them to share patient clinical information, identify therapy-related problems, and develop therapy-related action plans.

Proportions adherent to antiretroviral therapy (proportion of days covered [PDC] ≥90%) and virally suppressed (HIV RNA <200 copies/mL), before and after model implementation, were compared. Factors associated with postimplementation VS were determined using multivariable logistic regression; participant demographics, baseline viral load, and PDC were explanatory variables. PDC was modified to account for time to last viral load in the year postimplementation, and stratified as <50%, 50% to <80%, 80% to <90%, and ≥90%.

Results

The 765 enrolled participants were 43% non-Hispanic black, 73% male, with a median age of 48 years; 421 and 649 were included in the adherence and VS analyses, respectively. Overall, proportions adherent to therapy remained unchanged. However, VS improved a relative 15% (75% to 86%, P < .001). Higher PDC (adjusted odds ratio [AOR], 1.74 per 1-level increase in PDC category [95% confidence interval {CI}, 1.30–2.34]) and baseline VS (AOR, 7.69 [95% CI, 3.96–15.7]) were associated with postimplementation VS. Although non-Hispanic black persons (AOR, 0.29 [95% CI, .12–.62]) had lower odds of suppression, VS improved a relative 23% (63% to 78%, P < .001).

Conclusions

Integrated care models between community-based pharmacists and primary medical providers may identify and address HIV therapy–related problems and improve VS among persons with HIV.
Influenza A Reinfection in Sequential Human Challenge: Implications for Protective Immunity and “Universal” Vaccine Development
Authors: Memoli Matthew J , Han Alison , Walters Kathie-Anne , Czajkowski Lindsay , Reed Susan , Athota Rani , Angela Rosas Luz , Cervantes-Medina Adriana , Park Jae-Keun , Morens David M , Kash John C , Taubenberger Jeffery K
Published: April 2019

Background

Identification of correlates of protection against human influenza A virus infection is important in development of broadly protective (“universal”) influenza vaccines. Certain assumptions underlie current vaccine developmental strategies, including that infection with a particular influenza A virus should offer long-term or lifelong protection against that strain, preventing reinfection. In this study we report observations made when 7 volunteers participated in sequential influenza challenge studies where they were challenged intranasally using the identical influenza A(H1N1)pdm09 virus approximately 1 year apart. We evaluate and describe the outcomes of these 7 rechallenge participants and discuss what these results may suggest about correlates of protection and development of more broadly protective influenza vaccines.

Methods

Seven participants were enrolled in 2 viral challenge studies at 7.5- to 18.5-month intervals. Both challenge studies used the identical lot of influenza A (H1N1)pdm09 virus administered intranasally. We evaluated pre- and postchallenge hemagglutination inhibition, neuraminidase inhibition, and stalk antibody titers; peripheral blood leukocyte host gene expression response profiles; daily viral detection via nasal wash; and clinical signs and symptoms.

Results

At least 3 of 7 participants demonstrated confirmed laboratory evidence of sequential infection, with 5 of 7 demonstrating clinical evidence.

Conclusions

The data presented in this report demonstrate that sequential infection with the identical influenza A virus can occur and suggest it may not be rare. These data raise questions about immune memory responses in an acute superficial respiratory mucosal infection and their implications in development of broadly protective influenza vaccines. Further investigation of these observations is warranted.

Clinical Trials Registration

NCT01646138; NCT01971255.
Uniportal video-assisted thoracic surgery lobectomy: a consensus report from the Uniportal VATS Interest Group (UVIG) of the European Society of Thoracic Surgeons (ESTS)
Authors: Bertolaccini Luca , Batirel Hasan , Brunelli Alessandro , Gonzalez-Rivas Diego , Ismail Mahmoud , Ucar Antonio Martin , Ng Calvin S H , Scarci Marco , Sihoe Alan D L , Ugalde Paula A , Abu Akar Firas , Bedetti Benedetta , Nadal Sergio Bolufer , Brandolini Jury , Crucitti Pierfilippo , Enyedi Attila , Fernando Hiran C , Furak Jozsef , Gallego-Poveda Javier , Galvez-Munos Carlos , Hanke Ivo , Hernandez-Arenas Luis A , Janik Miroslav , Juhos Peter , Libretti Lidia , Lucciarini Paolo , Macrì Paolo , Margaritora Stefano , Mahoozi Hamid Reza , Nachira Dania , Pardolesi Alessandro , Pischik Vadim , Sagan Dariusz , Schreurs Hermien , Sekhniaidze Dmitrii , Socci Laura , Tosi Davide , Turna Akif , Vannucci Fernando , Zielinski Marcin , Rocco Gaetano
Published: April 2019

OBJECTIVES

Our goal was to report the results of the first consensus paper among international experts in uniportal video-assisted thoracoscopic surgery (UniVATS) lobectomy obtained through a Delphi process, the objective of which was to define and standardize the main procedural steps, optimize its indications and perioperative management and identify elements to assist in future training.

METHODS

The 40 members of the working group were convened and organized on a voluntary basis by the Uniportal VATS Interest Group (UVIG) of the European Society of Thoracic Surgeons (ESTS). An e-consensus finding exercise using the Delphi method was applied to require 75% agreement for reaching consensus on each question. Repeated iterations of anonymous voting continued for 3 rounds.

RESULTS

Overall, 31 international experts from 18 countries completed all 3 rounds of questionnaires. Although a technical quorum was not achieved, most of the responders agreed that the maximum size of a UniVATS incision should be ≤4 cm. Agreement was reached on many points outlining the currently accepted definition of a UniVATS lobectomy, its indications and contraindications, perioperative clinical management and recommendations for training and future research directions.

CONCLUSIONS

The UVIG Consensus Report stated that UniVATS offers a valid alternative to standard VATS techniques. Only longer follow-up and randomized controlled studies will predict whether UniVATS represents a valid alternative approach to multiport VATS for major lung resections or whether it should be performed only in selected cases and by selected centres. The next step for the ESTS UVIG is the establishment of a UniVATS section inside the ESTS databases.
Impact of force magnitude on effectiveness in cervical headgear therapy: a cephalometric analysis
Authors: Talvitie Tuula H , Helminen Mika , Karsila Susanna , Varho Reeta , Signorelli Luca , Pirttiniemi Pertti , Peltomäki Timo
Published: April 2019

Aim

The main aim of this study was to study the impact of different force magnitudes on effectiveness in cervical headgear (CHG) therapy.

Materials and methods

Forty patients were treated with CHG with light (L; 300 g) or heavy (H; 500 g) force in this controlled clinical trial. Patients were asked to wear CHG for 10 hours/day for 10 months. The inner bow of the CHG was expanded (3–4 mm) and the long outer bow bent (10–20 degree) upward in relation to the inner bow. Adherence to instructions and force magnitude in CHG use was monitored by electronic module (Smartgear, Swissorthodontics, Switzerland). Lateral cephalograms were taken before (T1) and after (T2) the treatment and studied with modified Pancherz analysis using a Planmeca Romexis Ceph module (Planmeca, Finland).

Results

In both groups, skeletal and dental effects were seen. The only statistically significant difference in cephalometric analysis was the inclination of upper incisors at T1 (P = 0.010) and at T2 (P = 0.011). In both groups, a reduction in Sella-Nasion- point A (SNA) angle was found: L group T1 82.7degree (SD ± 3.6degree), T2 82.0degree (SD ± 3.5 degree) and H group T1 82.6 degree (SD ± 4.7 degree), T2 81.5 degree (SD ± 4.5 degree), but no statistically significant difference between the groups. Children in the L group used CHG statistically significantly more than those in the H group (10.0 ± 1.5 hour, and 8.3 ± 2.1 hour, respectively, P = 0.002).

Conclusion

Children with lower force CHG seem to adhere better to instructions for CHG use. After 10 months of use, no statistically significant differences were found in dental or skeletal outcome. However, in the H group, the outcome was achieved with less daily hours of use.
New-onset left bundle branch block after transcatheter aortic valve replacement is associated with adverse long-term clinical outcomes in intermediate-risk patients: an analysis from the PARTNER II trial
Authors: Nazif Tamim M , Chen Shmuel , George Isaac , Dizon Jose M , Hahn Rebecca T , Crowley Aaron , Alu Maria C , Babaliaros Vasilis , Thourani Vinod H , Herrmann Howard C , Smalling Richard W , Brown David L , Mack Michael J , Kapadia Samir , Makkar Raj , Webb John G , Leon Martin B , Kodali Susheel K
Published: April 2019

Aims

Transcatheter aortic valve replacement (TAVR) is now an established therapy for intermediate-risk surgical candidates with symptomatic, severe aortic stenosis. The clinical impact of new-onset left bundle branch block (LBBB) after TAVR remains controversial and has not been studied in intermediate-risk patients. We therefore sought to analyse outcomes associated with new LBBB in a large cohort of intermediate-risk patients treated with TAVR.

Methods and results

A total of 2043 patients underwent TAVR in the PARTNER II trial and S3 intermediate-risk registry and survived to hospital discharge. Patients were excluded from the current analysis due to baseline conduction disturbances, pre-existing permanent pacemaker (PPM), and new PPM during the index hospitalization. Clinical outcomes at 2 years were compared between patients with and without persistent, new-onset LBBB at hospital discharge, and multivariable analysis was performed to identify predictors of mortality. Among 1179 intermediate-risk patients, new-onset LBBB at discharge occurred in 179 patients (15.2%). Patients with new LBBB were similar to those without except for more frequent diabetes and more frequent treatment with SAPIEN 3 vs. SAPIEN XT. At 2 years, new LBBB was associated with increased rates of all-cause mortality (19.3% vs. 10.8%, P = 0.002), cardiovascular mortality (16.2% vs. 6.5%, P < 0.001), rehospitalization, and new PPM implantation. By multivariable analysis, new LBBB remained an independent predictor of 2-year all-cause [hazard ratio (HR) 1.98, 95% confidence interval (95% CI) 1.33, 2.96; P < 0.001] and cardiovascular (HR 2.66 95% CI 1.67, 4.24; P < 0.001) mortality. New LBBB was also associated with worse left ventricular systolic function at 1 and 2-year follow-up.

Conclusions

In a large cohort of intermediate-risk patients from the PARTNER II trial and registry, persistent, new-onset LBBB occurred in 15.2% of patients without baseline conduction disturbances or pacemaker. New LBBB was associated with adverse clinical outcomes at 2 years, including all-cause and cardiovascular mortality, rehospitalization, new pacemaker implantation, and worsened left ventricular systolic function.

Clinical Trial Registration

ClinicalTrials.gov #NCT01314313 and NCT03222128.
Diastolic pressure ratio: new approach and validation vs. the instantaneous wave-free ratio
Authors: Johnson Nils P , Li Wenguang , Chen Xi , Hennigan Barry , Watkins Stuart , Berry Colin , Fearon William F , Oldroyd Keith G
Published: April 2019

Aims

The instantaneous wave-free ratio (iFR) and whole-cycle Pd/Pa investigate coronary physiology during non-hyperaemic conditions. To test for unique physiologic properties of the wave-free period when making resting coronary pressure measurements, we compared post hoc a diastolic pressure ratio (dPR) and Pd/Pa against iFR for numerical similarity and test/retest repeatability.

Methods and results

Eight hundred and ninety-three lesions from 833 subjects were included from the VERIFY 2 and CONTRAST studies. Diastolic pressure ratio and a linear transform of Pd/Pa were compared against iFR for diagnostic performance. Mean difference between dPR and iFR [Δ = −0.006 ± 0.011, r  2 = 0.993, area under receiver operating characteristic (ROC) curve (AUC) = 0.997] mirrored the difference of two iFR measurements repeated immediately (Δ = <0.001 ± 0.004, r  2 = 0.998, AUC = 1.00). Minor variations in the definition of dPR changed its value by <1–2% over a broad range of the cardiac cycle. A linear transform of Pd/Pa showed very good diagnostic performance (Δ = −0.012 ± 0.031, r  2 = 0.927, AUC = 0.979). Post hoc iFR values were validated against real-time iFR values and matched almost exactly (average Δ = <0.001 ± 0.004, 99.6% within ±0.01).

Conclusions

Our dPR offers numerical equivalency to iFR. Despite different technical approaches for identifying the relevant period of diastole, the agreement between dPR and iFR and the insensitivity of dPR to minor variations in its definition further confirm numerical equivalency among resting metrics.
Company-level determinants of disability retirement: a multilevel study of Finnish private sector workplaces
Authors: Laaksonen Mikko , Rantala Juha , Liukko Jyri , Polvinen Anu , Varis Jarno , Kesälä Meeri , Kuivalainen Susan
Published: April 2019

Background

We examined whether the risk for disability retirement varies between companies over and above the individual-level characteristics of their employees and which company-level characteristics are associated with the risk for any, full or partial disability retirement.

Methods

A 30% random sample of Finnish private sector companies with at least 10 employees was used (5567 companies and 301 313 employees). The risk for disability retirement over 6 years was analyzed using multilevel logistic regression. Company size and industry, as well as gender, age, education and social class measured both at the individual- and the company-level were used as explanatory variables.

Results

3.8% of the variance in the risk for disability retirement was attributed to the company level after controlling for individual-level characteristics of the employees. Company-level variance was much larger in partial (11.7%) than in full (4.2%) disability retirement. After controlling for all individual- and company-level characteristics, those working in health and social work activities had increased risk for both full and partial disability retirement. The risk for full disability retirement increased by decreasing educational level of the company. The risk for partial disability retirement increased by increasing company size and was elevated in companies with the highest proportion of women.

Conclusions

After controlling for the individual-level characteristics, variation in the risk for disability retirement between companies was modest. The more substantial variation in partial disability pension suggests that companies have a marked role in advancing working with partial disabilities.
Trajectories of mobility limitations over 24 years and their characterization by shift work and leisure-time physical activity in midlife
Authors: Prakash K C , Neupane Subas , Leino-Arjas Päivi , Härmä Mikko , von Bonsdorff Mikaela B , Rantanen Taina , von Bonsdorff Monika E , Hinrichs Timo , Seitsamo Jorma , Ilmarinen Juhani , Nygård Clas-Håkan
Published: April 2019

Background

We aimed to investigate trajectories of mobility limitations (MLs) over a period of 24 years. In addition, we aimed to study how shift work and leisure-time physical activity (LTPA) in midlife predict assignment to MLs trajectories separately for those retired on statutory pensions (SPs) and on disability pensions (DPs).

Methods

Subjects who responded MLs questionnaires (1985–2009, N = 3048) in Finnish Longitudinal Study on Aging Municipal Employees were included in this prospective cohort study. LTPA and shift work were measured during baseline. International Classification of Functioning was used to code MLs. Growth mixture modeling was used to identify the trajectories of MLs. Odds ratio (OR) and their 95% Confidence interval (CI) were assessed by using multinomial logistic regression.

Results

We identified four trajectories of MLs, namely low persistent, low increasing, high decreasing and high persistent. Among the SP recipients, shift work with night shifts was associated with an increased risk (adjusted OR 1.49; 95% CI 1.03–2.14) of belonging to the high persistent MLs trajectory. The inactive LTPA (SP: OR 5.99, 95% CI 3.39–10.58, DP: OR 6.81, 95% CI 2.52–18.43) was similarly associated with high persistent MLs trajectory.

Conclusion

Nearly two-thirds of the people retired due to disability belonged to high MLs trajectory. High persistent MLs trajectory was associated with physical inactivity in midlife among those retired on SP and on DP. Shift work with night shift predicted high persistent MLs in SP strata. Active involvement in LTPA during midlife could be beneficial to spend MLs free later life.
Comparative Efficacy of Vedolizumab and Adalimumab in Ulcerative Colitis Patients Previously Treated With Infliximab
Authors: Favale Agnese , Onali Sara , Caprioli Flavio , Pugliese Daniela , Armuzzi Alessandro , Macaluso Fabio Salvatore , Orlando Ambrogio , Viola Anna , Fries Walter , Rispo Antonio , Castiglione Fabiana , Mocci Giammarco , Chicco Fabio , Usai Paolo , Calabrese Emma , Biancone Livia , Monteleone Giovanni , Fantini Massimo Claudio ,   Italian Group for the study of Inflammatory Bowel Disease (IG-IBD)
Published: April 2019

Background

Adalimumab (ADA) and vedolizumab (VDZ) have shown efficacy in moderate to severe ulcerative colitis (UC) patients who failed infliximab (IFX). Although, a comparative efficacy evaluation of ADA and VDZ in this clinical setting is currently missing.

Aim

The aim of this study is to compare the efficacy of ADA and VDZ in patients affected by UC who failed IFX.

Methods

Clinical records of UC patients from 8 Italian IBD referral centers who failed IFX and were candidates to receive either ADA or VDZ were retrospectively reviewed. The primary end point was therapeutic failure at week 52. Secondary end points included therapy discontinuation at weeks 8, 24 and 52, the discontinuation-free survival, and safety.

Results

One hundred sixty-one UC patients, 15 (9.2%) primary, 83 (51.6%) secondary IFX failures, and 63 (39.2%) IFX intolerants were included. Sixty-four (40%) patients received ADA and 97 (60%) VDZ as second line therapy. At week 52, 37.5% and 28.9% of patients on ADA and VDZ, respectively, had therapeutic failure (P = 0.302). However, the failure rate was significantly higher in the ADA group as compared with VDZ group among IFX secondary failures (48.0% ADA vs 22.4%VDZ, P = 0.035). The therapy discontinuation-free survival was significantly higher in the group of IFX secondary failures who received VDZ as compared with ADA at both the univariate (P = 0.007) and multivariate survival analysis (OR 2.79; 95% CI, 1.23–6.34; P = 0.014). No difference in the failure and biologic discontinuation-free survival was observed in the IFX primary failure and intolerant subgroups.

Conclusion

Vedolizumab might be the therapy of choice in those UC patients who showed secondary failure to IFX.
Association of Infliximab Levels With Mucosal Healing Is Time-Dependent in Crohn’s Disease: Higher Drug Exposure Is Required Postinduction Than During Maintenance Treatment
Authors: Feng Ting , Chen Baili , Ungar Bella , Qiu Yun , Zhang Shenghong , He Jinshen , Lin Sinan , He Yao , Zeng Zhirong , Ben-Horin Shomron , Chen Minhu , Mao Ren
Published: April 2019

Background

Infliximab levels have been reported to be associated with mucosal healing (MH) in Crohn’s disease (CD). However, whether the association differs between postinduction (week 14) and maintenance (week 30) has seldom been investigated. We aimed to analyze the association between serum infliximab trough levels and MH at the 2 different time points.

Methods

A retrospective study of CD patients treated with infliximab in a tertiary referral center between January 2012 and May 2018 was conducted. MH was defined as absence of ulceration by endoscopy. Correlations between infliximab level and MH were investigated at 2 specific time points, weeks 14 and 30.

Results

Median infliximab levels were higher in patients with MH than those without at weeks 14 (7.5 vs 1.5 μg/mL; P < 0.001) and 30 (5.9 vs 0.5 μg/mL; P < 0.001). The median levels in patients with MH at week 14 were higher than at week 30 (7.5 vs 5.9 μg/mL; P < 0.05). Multivariate analysis showed that infliximab level was independently associated with MH (both P < 0.001 at weeks 14 and 30). Infliximab level above 4.85 μg/mL and 2.85 μg/mL identified patients with MH at week 14 (area under the curve [AUC], 0.796; P < 0.001) and week 30 (AUC, 0.780; P < 0.001) with 80% specificity. The rates of MH reached a plateau (>85%) when infliximab levels were above 10 and 6 μg/mL at weeks 14 and 30, respectively.

Conclusions

Infliximab levels correlated with MH at weeks 14 and 30 in CD patients. Higher levels might be required to achieve MH at postinduction than during maintenance treatment.
The Inflammatory Bowel Disease Medical Home: From Patients to Populations
Authors: Click Benjamin , Regueiro Miguel
Published: April 2019

This review explores the concept, experience, and future of value-based, patient-centered specialty medical homes using inflammatory bowel disease as a model chronic disease.
Thirty years from Tiananmen: China, Hong Kong, and the ongoing experiment to preserve liberal values in an authoritarian state
Authors: Chan Cora
Published: April 2019

The 1989 Tiananmen Square Massacre marked China out as an exception in the chapter of world history that saw the fall of international communism. The massacre crystalized the mistrust between China and Hong Kong into an open ideological conflict—Leninist authoritarianism versus liberal democracy—that has colored relations between the two since then. This article tracks the hold that authoritarianism has gained over liberal values in Hong Kong in the past thirty years and reflects on what needs to be done in the next thirty years for the balance to be re-tilted and sustained beyond 2047, when China’s fifty-year commitment to preserving Hong Kong’s autonomy expires. Still surviving (just) as a largely liberal (though by no means fully democratic) jurisdiction after two decades of Chinese rule, Hong Kong is a testing ground for whether China can respect liberal values, how resilient such values are to the alternative authoritarian vision offered by an economic superpower, and the potential for establishing a liberal-democratic pocket within an authoritarian state. The territory’s everyday wrestle with Chinese pressures speaks to the liberal struggles against authoritarian challenges (in their various guises) that continue to plague the world thirty years after the end of the Cold War.​
‘Somehow This Whole Process Became so Artificial’: Exploring the Transitional Justice Implementation Gap in Uganda
Authors: Macdonald Anna
Published: April 2019

Abstract∞

This article explores a key challenge in contemporary international efforts to promote transitional justice (TJ) in nontransitioning, conflict-affected states: the ‘implementation gap,’ in which policies are designed and funded but neither enacted nor implemented. Findings based on long-term qualitative fieldwork in Uganda indicate the implementation gap is co-constituted by technocratic donor approaches and domestic elite political maneuvering in a semi-authoritarian regime. The interaction between the two produces two forms of political artifice: ‘isomorphic mimicry’ and ‘calculated stasis,’ which stall the emergence of substantive TJ reform. Findings are relevant to the wide range of nontransitioning contexts where TJ is promoted by international donors and have important implications for its claimed potential to catalyze or restore civic trust in political systems in the aftermath of massive human rights violations.
An Open-Label, Randomized, Active-Controlled Trial of 8 Versus 12 Weeks of Elbasvir/Grazoprevir for Treatment-Naive Patients With Chronic Hepatitis C Genotype 1b Infection and Mild Fibrosis (EGALITE Study): Impact of Baseline Viral Loads and NS5A Resistance-Associated Substitutions
Authors: Huang Chung-Feng , Hung Chao-Hung , Cheng Pin-Nan , Bair Ming-Jong , Huang Yi-Hsiang , Kao Jia-Horng , Hsu Shih-Jer , Lee Pei-Lun , Chen Jyh-Jou , Chien Rong-Nan , Peng Cheng-Yuan , Lin Chun-Yen , Hsieh Tsai-Yuan , Cheng Chun-Han , Dai Chia-Yen , Huang Jee-Fu , Chuang Wan-Long , Yu Ming-Lung
Published: April 2019

Background

A 12-week grazoprevir/elbasvir regimen is highly effective against hepatitis C virus genotype 1 (HCV-1) infection. The efficacy of an 8-week regimen for treatment-naive HCV-1–infected patients with mild fibrosis has not been determined.

Methods

Treatment-naive HCV-1b–infected patients with mild fibrosis were randomly assigned to receive 8 (n = 41) or 12 (n = 41) weeks of grazoprevir/elbasvir therapy. The primary end point was a sustained virologic response, defined as an HCV RNA level of < 12 IU/mL, at posttreatment week 12 (SVR12).

Results

SVR12 was achieved by 87.8% of patients (36 of 41) in the 8-week arm and 100% (41 of 41) in the 8-week arm of the full-analysis population and by 90.0% (36 of 40) and 100% (41 of 41), respectively, in the per-protocol population (all P = .055). In the 8-week arm, a significantly lower SVR12 rate was observed among patients with a high HCV-1b load, defined as ≥1 500 000 IU/mL (79% vs 100%; P = .042), and among those with a baseline Y93H resistance-associated substitution (RAS) frequency of >15% in HCV nonstructural protein 5A (NS5A; 40.0% vs 97.1%; P = .004). Between-group analysis demonstrated that, among patient with a high HCV-1b load and a baseline Y93H RAS frequency of >15%, those in the 8-week arm had a substantially lower SVR12 rate than those in the 12-week arm (40.0% vs 100.0%). All 4 HCV-1b relapses had a Y93H RAS frequency of >99% at posttreatment week 12.

Conclusions

Twelve weeks of grazoprevir/elbasvir therapy is highly effective for treatment-naive patients with mild fibrosis. A truncated, 8-week grazoprevir/elbasvir regimen might be applied for those with low viral loads or without a significant NS5A RAS frequency.

Clinical trials registration

NCT03186365.
Patient education in relation to informational needs and postoperative complications in surgical patients
Authors: Koivisto Jaana-Maija , Saarinen Ira , Kaipia Antti , Puukka Pauli , Kivinen Katri , Laine Kirsi-Marja , Haavisto Elina
Published: April 2019

Objective

To study surgical patients’ informational expectations and the level of received knowledge at the time of hospital discharge. To examine if there is an association with postoperative complications and the patient´s level of received knowledge.

Design

Comparative descriptive design.

Setting

The data on patients admitted for non-cardiac surgery were collected in three phases during an eight-month period.

Participants

258 in-ward non-cardiac general surgery and orthopedic surgery adult patients.

Interventions

Questionnaires before admission (knowledge expectations) and at discharge (received knowledge). A telephone interview 30 days after discharge.

Main Outcome Measures

Received knowledge (as much or more / less) compared to expectations, and its association with post-discharge complications.

Results

There were differences between patient groups in their perception of receiving enough knowledge and they were connected to gender (male vs. female OR 2.67, 95% CI 1.55–4.60, P = 0.0004) and procedure (elective orthopedic implant surgery vs. elective minor orthopedic and hand surgery: OR 3.25, 95% CI 1.72–6.17, P = 0.0003). Patients who received less knowledge than expected had more postoperative complications than those who received sufficient (as much or more than expected) information.

Conclusions

Patients differ in terms of informational needs, and preoperative education prepares the patient for the information provided postoperatively. Patient education may have an influence on recovery from surgery.
Twenty-four hour pharmacokinetic relationships for intravenous vancomycin and novel urinary biomarkers of acute kidney injury in a rat model
Authors: Avedissian Sean N , Pais Gwendolyn M , O’Donnell J Nicholas , Lodise Thomas P , Liu Jiajun , Prozialeck Walter C , Joshi Medha D , Lamar Peter C , Becher Leighton , Gulati Anil , Hope William , Scheetz Marc H
Published: April 2019

Objectives

To identify the pharmacokinetic (PK) and toxicodynamic (TD) relationship for vancomycin-induced kidney injury.

Methods

Male Sprague–Dawley rats received intravenous (iv) vancomycin. Doses ranging from 150 mg/kg/day to 400 mg/kg/day were administered as a single or twice-daily injection over 24 h (total protocol duration). Controls received iv saline. Plasma was sampled with up to eight samples in 24 h per rat. Twenty-four hour urine was collected and assayed for kidney injury molecule 1 (KIM-1), osteopontin and clusterin. Vancomycin in plasma was quantified via LC-MS/MS. PK analyses were conducted using Pmetrics for R. PK exposures during the first 24 h (i.e. AUC0–24h, Cmax 0–24h and Cmin 0–24h) were calculated. PK/TD relationships were assessed with Spearman’s rank coefficient (rs) and the best-fit mathematical model.

Results

PK/TD data were generated from 45 vancomycin-treated and 5 control rats. A two-compartment model fit the data well (Bayesian: observed versus predicted R2 = 0.97). Exposure–response relationships were found between AUC0–24h versus KIM-1 and osteopontin (R2 = 0.61 and 0.66) and Cmax 0–24h versus KIM-1 and osteopontin (R2 = 0.50 and 0.56) using a four-parameter Hill fit. Conversely, Cmin 0–24h was less predictive of KIM-1 and osteopontin (R2 = 0.46 and 0.53). A vancomycin AUC0–24h of 482.2 corresponded to a 90% of maximal rise in KIM-1.

Conclusions

Vancomycin-induced kidney injury as defined by urinary biomarkers is driven by vancomycin AUC or Cmax rather than Cmin. Further, an identified PK/TD target AUC0–24h of 482.2 mg·h/L may have direct relevance to human outcomes.
The international diffusion of expatriate dual citizenship
Authors: Vink Maarten , Schakel Arjan H , Reichel David , Luk Ngo Chun , de Groot Gerard-René
Published: April 2019

While the global increase of expatriate dual citizenship acceptance over the past decades has been widely observed, the temporal and spatial contexts of this trend have remained understudied. Based on a novel data set of expatriate dual citizenship policies worldwide since 1960, we find that dual citizenship toleration has increased in the last half century from one-third to three-quarter of states globally. We argue that these domestic policy changes should be understood in light of normative pressure in a world where restrictions on individual choice in citizenship status are increasingly contested and where liberalisation is reinforced through interdependence and diaspora politics. We apply Cox proportional hazard models to examine dual citizenship liberalisation and find that states are more likely to move to a tolerant policy if neighbouring states have done so and that they tend to do so in conjunction with extending voting rights to citizens residing abroad and receiving remittances from abroad. Contrary to other studies, we do not observe significant variation by regime type.
LC8/DYNLL1 is a 53BP1 effector and regulates checkpoint activation
Authors: West Kirk L , Kelliher Jessica L , Xu Zhanzhan , An Liwei , Reed Megan R , Eoff Robert L , Wang Jiadong , Huen Michael S Y , Leung Justin W C
Published: April 2019

The tumor suppressor protein 53BP1 plays key roles in response to DNA double-strand breaks (DSBs) by serving as a master scaffold at the damaged chromatin. Current evidence indicates that 53BP1 assembles a cohort of DNA damage response (DDR) factors to distinctly execute its repertoire of DSB responses, including checkpoint activation and non-homologous end joining (NHEJ) repair. Here, we have uncovered LC8 (a.k.a. DYNLL1) as an important 53BP1 effector. We found that LC8 accumulates at laser-induced DNA damage tracks in a 53BP1-dependent manner and requires the canonical H2AX-MDC1-RNF8-RNF168 signal transduction cascade. Accordingly, genetic inactivation of LC8 or its interaction with 53BP1 resulted in checkpoint defects. Importantly, loss of LC8 alleviated the hypersensitivity of BRCA1-depleted cells to ionizing radiation and PARP inhibition, highlighting the 53BP1-LC8 module in counteracting BRCA1-dependent functions in the DDR. Together, these data establish LC8 as an important mediator of a subset of 53BP1-dependent DSB responses.