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NASICON (sodium superionic conductor) materials are promising host compounds for the reversible capture of Na

Faradaic deionization (FDI) is a promising technology for energy-efficient water desalination using porous electrodes containing redox-active materials. Herein, we demonstrate for the first time the capability of a symmetric FDI flow cell to produce freshwater (100X lower permeability compared to common redox-flow battery electrodes, for which millimetric flow-channel widths were used exclusively in the past. Total desalination thermodynamic energy efficiency (TEE) was improved by more than ten-fold relative to unpatterned electrodes: 40.0% TEE for brackish water, 11.7% TEE for hypersaline brine, and 7.4% TEE for seawater-salinity feeds. Water transport between diluate and brine streams and charge efficiency losses resulting from (electro)chemical effects are implicated as limiting energy efficiency and water recovery, motivating their investigation for enhancing future FDI performance., 70 pages, 23 figures. Energy Environ. Sci. (2023)

Objective To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10 and 15 µg bimatoprost implant in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods This randomized, 20-month, multicenter, masked, parallel-group, phase 3 trial enrolled 528 patients with OAG or OHT and an open iridocorneal angle inferiorly in the study eye. Study eyes were administered 10 or 15 µg bimatoprost implant on day 1, week 16, and week 32, or twice-daily topical timolol maleate 0.5%. Primary endpoints were IOP and IOP change from baseline through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). Results Both 10 and 15 µg bimatoprost implant met the primary endpoint of noninferiority to timolol in IOP lowering through 12 weeks. Mean IOP reductions from baseline ranged from 6.2–7.4, 6.5–7.8, and 6.1–6.7 mmHg through week 12 in the 10 µg implant, 15 µg implant, and timolol groups, respectively. IOP lowering was similar after the second and third implant administrations. Probabilities of requiring no IOP-lowering treatment for 1 year after the third administration were 77.5% (10 µg implant) and 79.0% (15 µg implant). The most common TEAE was conjunctival hyperemia, typically temporally associated with the administration procedure. Corneal TEAEs of interest (primarily corneal endothelial cell loss, corneal edema, and corneal touch) were more frequent with the 15 than the 10 µg implant and generally were reported after repeated administrations. Loss in mean CECD from baseline to month 20 was ~ 5% in 10 µg implant-treated eyes and ~ 1% in topical timolol-treated eyes. Visual field progression (change in the mean deviation from baseline) was reduced in the 10 µg implant group compared with the timolol group. Conclusions The results corroborated the previous phase 3 study of the bimatoprost implant. The bimatoprost implant met the primary endpoint and effectively lowered IOP. The majority of patients required no additional treatment for 12 months after the third administration. The benefit-risk assessment favored the 10 over the 15 µg implant. Studies evaluating other administration regimens with reduced risk of corneal events are ongoing. The bimatoprost implant has the potential to improve adherence and reduce treatment burden in glaucoma. Clinicaltrials.gov Identifier NCT02250651. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-021-01624-9.

Distinguishing Crohn's disease (CD) from ulcerative colitis (UC) may be difficult when the disease is limited to the colon. Transmural healing is an important adjunctive measure of inflammatory bowel disease (IBD) activity. The aim of this study was to examine the role of endoscopic ultrasound (EUS) in differentiating CD versus UC and evaluating transmural disease activity.This prospective cohort enrolled 20 patients with CD (10 active, 10 inactive), 20 patients with UC (10 active, 10 inactive), and 20 controls who underwent colonoscopy from 2019 to 2021 at a tertiary care center. Measurements of bowel wall layer thickness from the rectum and cecum were obtained using a through-the-scope ultrasound catheter (Olympus UM-3R-3) at the time of colonoscopy.Compared to controls, patients with active CD (aCD) had thicker rectal submucosa and total wall layer (submucosa 1.80 [1.40-2.00] vs 0.60 [0.40-0.70] mm, total wall 3.70 [3.52-4.62] vs 2.10 [1.70-2.40] mm, respectively, P0.01). Similar significant findings were observed for the cecal wall layers. Compared to controls, patients with active UC (aUC) had thicker rectal mucosa and total wall but not submucosa nor muscularis propria layer (mucosa 1.35 [1.12-1.47] vs 0.60 [0.57-0.70] mm, total wall 3.45 [2.85-3.75] vs 2.10 [1.70-2.40] mm, respectively, P0.01). Patients with aCD compared to those with aUC had significantly thicker rectal submucosa layer (1.80 [1.40-2.00] vs 0.55 [0.40-0.75] mm, P0.01). Cut-off values of 1.1 mm for rectal submucosa in CD and 1.1 mm for rectal mucosa in UC can differentiate active from inactive disease (Sensitivity (Se) 1.0, Specificity (Sp) 1.0 and Se 0.8, Sp 0.9, respectively).EUS measurements of colon wall layers can help diagnose active CD versus UC and assess transmural disease activity.

Background/aims Clostridioides difficile infection (CDI) remains a diagnostic challenge in patients with inflammatory bowel disease (IBD). We tested novel biomarkers to differentiate CDI from colonization in patients without (CDI-only) and with IBD (IBD-CDI). Methods Samples were enzyme immunoassay (EIA)-tested for glutamate dehydrogenase (GDH) and toxin, followed by reflex PCR. Quantitative GDH [(qGDH) - a novel indicator of Clostridium difficile load] and stool lactoferrin were tested at days 0, 3 and 10 during antibiotic treatment. Samples were also analyzed for toxin B cytotoxicity neutralization assay (CNA) and toxigenic culture, gold standards to detect free toxin and virulent bacteria, respectively. Results Forty-five symptomatic patients (28 CDI-only, 13 with Crohn's disease, 4 with ulcerative colitis) were recruited with 3 sequential samples available for 36 (21 CDI-only, 15 IBD-CDI). Thirty-nine of 45 (87%) cases were toxigenic culture-positive. In the CDI-only group, 78.6% were positive for EIA-toxin, 21.4% were PCR-positive while 82.1% were CNA-positive. In the IBD-CDI group, only one patient (6%) was EIA-toxin positive and 17.6% CNA-positive. The median qGDH level at day 0 was higher in CNA-positive patients compared to CNA-negative patients (1111 vs. 146 ng/g, P = 0.004) and dropped together with lactoferrin from day 0 to 10. CDI eradication improved symptoms in 72.2% of patients with CDI-only. In 60% of patients with IBD-CDI, eradication was ineffective, with symptoms improving in 89% of them after IBD therapy intensification. Conclusion In patients with IBD-CDI, PCR-only positivity might mainly reflect colonization rather than disease. C. difficile load by qGDH correlates with CNA-detected toxin and together with stool lactoferrin might differentiate CDI from colonization in patients with IBD.

Over the past few years, the detection of biological analytes has intensively been studied to understand the biodiagnostics of various diseases [1]. Some of the analytes that have been used as biomarkers for specific diseases include cell-free nucleic acids, (for example, DNA), messenger RNA (mRNA) and microRNA (miRNA) [2]-[5], circulating tumor-specific nucleic acids [circulating tumor DNA (ctDNA) and ctRNA] [6]-[8], exosomes [9], [10], and circulating tumor cells [11]. These biomolecules are known to be effective indicators that can diagnose the presence of a potential disease even if their concentration changes slightly [12].

Despite aggressive medical therapy, many patients with Crohn’s disease require surgical intervention over time. After surgical resection, disease recurrence is common. Ileo-colonoscopy and the Rutgeerts score are commonly used for diagnosis and monitoring of post-operative endoscopic recurrence. The latter is the precursor of clinical recurrence and therefore it impacts prognosis and patient management. However, due to the limited length of bowel assessed by ileo-colonoscopy, this procedure can miss out-of-reach, more proximal lesions in the small bowel. This limitation introduces an important uncertainty when evaluating post-operative relapse by ileo-colonoscopy. In addition, the Rutgeerts score ‘per se’ bears a number of ambiguities. Here we will discuss the pros and cons of ileo-colonoscopy and other imaging studies including wireless capsule endoscopy to diagnose and manage post-operative recurrence of Crohn’s disease. A number of studies provide evidence that wireless capsule endoscopy is a potentially more accurate as well as less invasive and less costly alternative to conventional techniques including ileo-colonoscopy. Published version

Entrustable professional activities have emerged as a means for the evaluation of resident competency that is expressed in terms of the assessed need for supervision. Recently, 19 physical medicine and rehabilitation-specific entrustable professional activities were published (Am J Phys Med Rehabil. 2017;96:762-764). The electrodiagnostic entrustable professional activity and six new electrodiagnostic entrustable professional activities subcategories (observable practice activities) were piloted as an entrustable professional activities/observable practice activities set within five residency programs. Survey-based (quantitative) and open-ended (qualitative) feedback was collected from participants. Participating attendings found this method feasible and generally reported satisfaction with the entrustable professional activities/observable practice activities as a means of providing feedback to residents. Residents were less clear on the added value of this approach. Qualitative data supported the need for adjustments to the entrustment scale to allow for more gradations within supervisory levels, a standardized orientation of residents to the use of observable practice activities and an increased quantity of assessments for each observable practice activities category to allow for demonstration of resident progress toward independence. Use of the electrodiagnostic entrustable professional activity/observable practice activities set shows promise as a means for observational competency assessment in the outpatient setting. However, feedback acquired through this pilot study suggests changes that could be made to improve future implementation.

In electromembrane desalination processes such as electrodialysis (ED) and ion concentration polarization (ICP) desalination, ion-depleted boundary layers constitute the desalted, product stream, yet also cause high resistivity and voltage drop. Directly manipulating fluid flow streams is a new method to break this fundamental trade-off for electromembrane desalination. In this work, we are introducing a novel electromembrane desalination architecture that allows a feed stream to return to the feed inlet side of the membrane (hereby named as return-flow (RF) architecture) to improve the energy efficiency by re-distributing and controlling the depleted boundary layer, even at high current values. The technical feasibility of this idea was examined in ICP desalination process (RF-ICP) with a wide range of feed salinity from 10 to 70 g/L. For a partial desalination, RF-ICP (∼75 cm2 of membrane area) has achieved similar power consumption compared to batch-ED with 3 times bigger membrane area (200 cm2) with a higher area efficiency for salt removal, which translates into lower optimal desalination cost. The techno-economic analysis of RF-ICP have been performed for the treatment of 70 g/L brine waste. For partial desalination of 70 g/L brine down to 35 g/L, RF-ICP desalination achieved overall water cost as low as $2.57/m3 ($0.41/barrel). This could translate into reduction in total water cost up to 31% for zero brine release scenarios, depending on the concentrated brine treatment cost. These results show that return-flow architecture can improve the performance of electromembrane desalination, enabling more flexible water treatment for many real-world applications.

SUMMARYTranscription initiation by RNA polymerase II (Pol II) requires preinitiation complex (PIC) assembly at gene promoters. In the dynamic nucleus where thousands of promoters are broadly distributed in chromatin, it is unclear how ten individual components converge on any target to establish the PIC. Here, we use live-cell, single-molecule tracking in S. cerevisiae to document subdiffusive, constrained exploration of the nucleoplasm by PIC components and Mediator’s key functions in guiding this process. On chromatin, TBP, Mediator, and Pol II instruct assembly of a short-lived PIC, which occurs infrequently but efficiently at an average promoter where initiation-coupled disassembly may occur within a few seconds. Moreover, PIC exclusion by nucleosome encroachment underscores regulated promoter accessibility by chromatin remodeling. Thus, coordinated nuclear exploration and recruitment to accessible targets underlies dynamic PIC establishment in yeast. Collectively, our study provides a global spatio-temporal model for transcription initiation in live cells.

Objectives: Targeting tumor necrosis factor (TNF) with biologic agents, such as infliximab and adalimumab, is a widely used and effective therapeutic strategy in inflammatory bowel disease (IBD). Unfortunately, a significant number of patients fail to respond or lose response over time to these agents. Previous studies have defined multiple complex roles for canonical NF-kappa B signaling in the pathogenesis of IBD. However, preliminary evidence suggests that the lesser defined noncanonical NF-kappa B signaling pathway also contributes to disease pathogenesis and response to anti-TNF agents. The objective of this study was to evaluate this hypothesis in Crohn's disease (CD) and ulcerative colitis (UC) patients. Design: A total of 27 subjects with IBD (19 with CD and 8 with UC) and 15 control subjects were tested. Clinical criteria, patient history, and endoscopic disease activity were factors used to categorize patients and define therapeutic response. Biopsy specimens were collected during colonoscopy and expression was determined for 88 target genes known to be associated with noncanonical NF-kappa B signaling and IBD. Results: Noncanonical NF-kappa B signaling was significantly upregulated in IBD patients and was associated with increased gastrointestinal inflammation, epithelial cell death, lymphocyte migration, and Nod-like receptor signaling. Furthermore, noncanonical NF-kappa B signaling was further upregulated in patients unresponsive to anti-TNF agents and was suppressed in responsive patients. MAP3K14, NFKB2, CCL19, CXCL12, and CXCL13 were significantly dysregulated, as were genes that encode pathway regulators, such as CYLD, NLRP12, and BIRC2/3. Conclusion: Our study identifies a previously uncharacterized role for the understudied noncanonical NF-kappa B signaling pathway in the pathogenesis of IBD and anti-TNF therapy responsiveness. The genes and pathways identified may ultimately prove useful in IBD management and could potentially be used as biomarkers of drug response. Carilion Research Advancement Program (RAP) Grant 13 Role of the Non-Canonical NFkB Inflammatory Cascade in Therapeutic Response and Pathogenesis of IBD Published version Carilion Research Advancement Program (RAP) Grant 13 Role of the Non-Canonical NFkB Inflammatory Cascade in Therapeutic Response and Pathogenesis of IBD.

Introduction: Fecal lactoferrin (FL) is a timely and accurate marker of inflammation in ulcerative colitis (UC) and Crohn’s disease (CD). The aim of this study was to verify whether FL can predict primary nonresponse (PNR) to biologic agents during induction. Methods: Retrospective outcome review in 27 patients (13 with CD and 14 with UC) tested for baseline FL and retested within a week after the first and second induction doses. Clinical/biochemical outcomes were evaluated at end of induction and at follow-up (3–24 months). Results: Compared to baseline, changes of the Harvey-Bradshaw (CD) and Partial Mayo Scoring (UC) indices at end of induction separated responders (18/27 or 67%) from nonresponders (9/17 or 33%). In all patients, the initial FL value at induction decreased compared to baseline, continuing to decrease after the following dose in clinical responders while bouncing back in the others. Models targeting the 2 consecutively decreased FL values or the second FL value compared to baseline or the second FL value compared to the first were able to accurately predict response at end of induction. Follow-up assessment confirmed clinical remission in initial responders (with FL values reduced on the average by 94 ± 10% compared to baseline). Conclusions: In CD and UC patients during induction with biologic agents, early FL measurements accurately separate clinical responders from those experiencing PNR. The method described here offers several potential advantages over other strategies to assess and manage these patients.

Cloud radio access network (C-RAN) is an evolutionary radio network architecture in which a cloud-computing-based baseband (BB) signal-processing unit is shared among distributed low-cost wireless access points. This architecture offers a number of significant improvements over the traditional RANs, including better network scalability, spectral, and energy efficiency. As such C -RAN has been identified as one of the enabling technologies for the next-generation mobile networks. This chapter focuses on examining the energy-efficient transmission strategies of the C-RAN for cellular systems. In particular, we present optimization algorithms for the problem of transmit beamforming designs maximizing the network energy efficiency. In general, the energy efficiency maximization in C-RANs inherits the difficulty of resource allocation optimizations in interference-limited networks, i.e., it is an intractable non convex optimization problem. We first introduce a globally optimal method based on monotonic optimization (MO) to illustrate the optimal energy efficiency performance of the considered system. While the global optimization method requires extremely high computational effort and, thus, is not suitable for practical implementation, efficient optimization techniques achieving near -optimal performance are desirable in practice. To fulfill this gap, we present three low -complexity approaches based on the state-of-the-art local optimization framework, namely, successive convex approximation (SCA).

We consider downlink transmission whereby a multiantenna base station simultaneously transmits data to multiple single-antenna users. We focus on slow flat fading channel where the channel state information is imperfect, the channel estimation error is unbounded and its statistics are known. The aim is to design beamforming vectors such that the sum rate is maximized under the constraints on probability of successful transmission for each user and maximum transmit power. The optimization problem is intractable due to the chance constraints. To this end, we propose an efficient solution drawn upon stochastic optimization. In particular, we first use the step function and its smooth approximation to get an approximate nonconvex stochastic program of the considered problem. We then develop an iterative procedure to solve the stochastic program based on the stochastic successive convex approximation framework. The numerical results show that the proposed solution can achieve remarkable sum rate gains compared to the conventional one.

Modified Vaccinia Ankara (MVA) is a highly attenuated poxvirus vector that is widely used to develop vaccines for infectious diseases and cancer. We developed a novel vaccine platform based on a unique three-plasmid system to efficiently generate recombinant MVA vectors from chemically synthesized DNA. In response to the ongoing global pandemic caused by SARS coronavirus-2 (SARS-CoV-2), we used this novel vaccine platform to rapidly produce fully synthetic MVA (sMVA) vectors co-expressing SARS-CoV-2 spike and nucleocapsid antigens, two immunodominant antigens implicated in protective immunity. Mice immunized with these sMVA vectors developed robust SARS-CoV-2 antigen-specific humoral and cellular immune responses, including potent neutralizing antibodies. These results demonstrate the potential of a novel vaccine platform based on synthetic DNA to efficiently generate recombinant MVA vectors and to rapidly develop a multi-antigenic poxvirus-based SARS-CoV-2 vaccine candidate.

Introduction: Management of inflammatory bowel diseases (IBDs) – both Crohn’s disease (CD) and ulcerative colitis (UC) – during pregnancy can be challenging since most monitoring tools available in nonpregnant patients are contraindicated. Objectives: The aim of the study was to test whether fecal inflammatory markers – specifically fecal lactoferrin – physiologically change during normal pregnancy as a prerequisite to use them to monitor IBD activity during pregnancy. Methods: Fecal lactoferrin was tested in healthy pregnant and nonpregnant women from the same geographic area and age range (18–40 years) – all negative for clinical gastrointestinal tract inflammation. A retrospective review of fecal lactoferrin levels contrasted with the Simple Endoscopic Score for CD, and the Disease Activity Index for UC was also performed in women with active IBDs within the same age range and geographical area. Results: In 30 nonpregnant subjects, fecal lactoferrin levels were 0.87 ± 1.08 μg/g. In 49 pregnant subjects, levels were 0.59 ± 0.83, 0.87 ± 1.13, and 0.85 ± 1.06 μg/g during the first, second, and third trimester, respectively (p = 0.64), with average levels for the 3 trimesters of 0.81 ± 1.04 μg/g (p = 0.61 compared to nonpregnant subjects). Sequential fecal lactoferrin levels (n = 26) did not differ from one trimester to the other in the individual subjects (p = 0.80). In 45 female IBD patients (27 with CD and 18 with UC), fecal lactoferrin levels were correlated with disease activity as defined by the endoscopic scores: 218, 688, and 1,175 μg/g for CD and 931, 2,088, and 2,509 μg/g for UC, respectively, for mild, moderate, and severe activity. Conclusions: Fecal lactoferrin levels during normal pregnancy are superimposable to those of nonpregnant women and significantly below levels in women of the same childbearing age with active IBDs. Additional published data – reviewed in this atricle – and our own indicate that fecal lactoferrin and other markers can be potentially used to monitor disease activity in pregnant IBD patients.

The H2A.Z histone variant, a genome-wide hallmark of permissive chromatin, is enriched near transcription start sites in all eukaryotes. H2A.Z is deposited by the SWR1 chromatin remodeler and evicted by unclear mechanisms. We tracked H2A.Z in living yeast at single-molecule resolution, and found that H2A.Z eviction is dependent on RNA Polymerase II (Pol II) and the Kin28/Cdk7 kinase, which phosphorylates Serine 5 of heptapeptide repeats on the carboxy-terminal domain of the largest Pol II subunit Rpb1. These findings link H2A.Z eviction to transcription initiation, promoter escape and early elongation activities of Pol II. Because passage of Pol II through +1 nucleosomes genome-wide would obligate H2A.Z turnover, we propose that global transcription of noncoding RNAs prior to premature termination, in addition to transcription of mRNAs, are responsible for eviction of H2A.Z. Such usage of yeast Pol II suggests a general mechanism coupling eukaryotic transcription to erasure of the H2A.Z epigenetic signal.

We consider uplink multiuser wireless communications systems, where the base station (BS) receiver is equipped with a large-scale antenna array and resolution adaptive analog-to-digital converters (ADCs). The aim is to maximize the energy efficiency (EE) at the BS subject to constraints on the users’ quality-of-service. The approach is to jointly optimize both the number of quantization bits at the ADCs and the on/off modes of the radio frequency (RF) processing chains. The considered problem is a discrete nonlinear program, the optimal solution of which is difficult to find. We develop an efficient algorithm based on the discrete branch-reduce-and-bound (DBRnB) framework. It finds the globally optimal solutions to the problem. In particular, we make some modifications, which significantly improve the convergence performance. The numerical results demonstrate that optimizing jointly the number of quantization bits and on/off mode can achieve remarkable EE gains compared to only optimizing the number of quantization bits.

Inflammatory bowel disease (IBD) patients are at increased risk of developing Clostridioides difficile infection (CDI). Common methods to diagnose CDI involve a combination of tests including the toxin A/B enzyme immunoassay (Toxin) and toxin gene polymerase chain reaction assay (PCR). Disease outcomes in Toxin+ versus Toxin-PCR+ IBD patients remain unclear. This study aimed to examine the response to antibiotics and risk of IBD therapy escalation in Toxin+ versus Toxin-PCR+ patients. IBD patients at an academic center with CDI diagnosis based on Toxin+ or Toxin-PCR+ from 2012 to 2017 were identified. Comparisons of response to antibiotics within 30 days and escalation of IBD therapy within 90 days of CDI diagnosis between these two groups were analyzed by Chi-square analysis. Multivariable regression analysis examined factors associated with antibiotic response. Among 92 patients included, 61% had Crohn’s disease and 39% had ulcerative colitis. 70% tested Toxin-PCR+. 60% received vancomycin or fidaxomicin to treat CDI. 82% of Toxin+ patients responded to antibiotics compared to 25% of Toxin-PCR+ patients (p

We consider a secure transmission including a transmitter, a receiver and an eavesdropper, each being equipped with multiple antennas. The aim is to develop a low-complexity and scalable method to find a globally optimal solution to the problem of secrecy rate maximization under a total power constraint at the transmitter. In principle, the original formulation of the problem is nonconvex. However, it can be equivalently translated into finding a saddle point of a minimax convex-concave program. An existing approach finds the saddle point using the Newton method, whose computational cost increases quickly with the number of transmit antennas, making it unsuitable for large scale antenna systems. To this end, we propose an iterative algorithm based on alternating optimization, which is guaranteed to converge to a saddle point, and thus achieves a globally optimal solution to the considered problem. In particular, each subproblem of the proposed iterative method admits a closed-form solution. We analytically show that the iteration cost of our proposed method is much cheaper than that of the known solution. As a result, numerical results demonstrate that the proposed method remarkably outperforms the existing one in terms of the overall run time.

Background In Crohn's disease (CD) a small bowel study-in addition to colonoscopy-is considered necessary for diagnosis/staging. In this study we re-examined the role of capsule endoscopy (CE), colonoscopy, imaging tests [magnetic resonance enterography/computed tomographic enterography (MRE/CTE)], and inflammatory markers [fecal lactoferrin and C-reactive protein (FL/CRP)] in CD patients who had undergone intestinal resection and in those who never had surgery. Methods In this retrospective study 43 consecutive patients underwent CE because of staging/symptoms unexplained by colonoscopy/imaging. We compared colonoscopy, imaging, and FL/CRP with CE and evaluated the impact of the latter on clinical management and outcomes. Results In patients who never had surgery imaging was negative with a positive CE in 8/15 (53%) of cases. Colonoscopy was insufficient for disease staging in 10/20 (50%) cases. CRP and FL were normal with a positive CE in 35% and 28% of cases, respectively. CE findings changed the management in 6/20 (30%) of cases, with 83% showing clinical/biochemical improvement after up to 15 months of follow-up. In postoperative patients CE was positive with negative imaging in 6/8 (75%) cases. Colonoscopy was insufficient for disease staging in 13/22 (59%) cases. CRP and FL were normal in 42% and 31.8% of patients with positive CE. In these patients CE findings changed the management in 12/23 (52%) cases with 83% of them showing clinical/biochemical improvement after up to 18 months of follow-up. Conclusions Omitting CE from diagnostic/staging algorithms in CD tends to underdiagnose clinically significant small bowel lesions, thus impacting on patients' management and outcomes. 10.1093/ibd/izy048_video1izy048.video15794820403001.

Summary The histone chaperone FACT occupies transcribed regions where it plays prominent roles in maintaining chromatin integrity and preserving epigenetic information. How it is targeted to transcribed regions, however, remains unclear. Proposed models include docking on the RNA polymerase II (RNAPII) C-terminal domain (CTD), recruitment by elongation factors, recognition of modified histone tails, and binding partially disassembled nucleosomes. Here, we systematically test these and other scenarios in Saccharomyces cerevisiae and find that FACT binds transcribed chromatin, not RNAPII. Through a combination of high-resolution genome-wide mapping, single-molecule tracking, and mathematical modeling, we propose that FACT recognizes the +1 nucleosome, as it is partially unwrapped by the engaging RNAPII, and spreads to downstream nucleosomes aided by the chromatin remodeler Chd1. Our work clarifies how FACT interacts with genes, suggests a processive mechanism for FACT function, and provides a framework to further dissect the molecular mechanisms of transcription-coupled histone chaperoning.

Inflammatory bowel disease (IBD) patients are at increased risk of developing Clostridioides difficile infection (CDI). Common methods to diagnose CDI involve a combination of tests including the toxin A/B enzyme immunoassay (Toxin) and toxin gene polymerase chain reaction assay (PCR). Disease outcomes in Toxin+ versus Toxin-PCR+ IBD patients remain unclear.This study aimed to examine the response to antibiotics and risk of IBD therapy escalation in Toxin+ versus Toxin-PCR+ patients.IBD patients at an academic center with CDI diagnosis based on Toxin+ or Toxin-PCR+ from 2012 to 2017 were identified. Comparisons of response to antibiotics within 30 days and escalation of IBD therapy within 90 days of CDI diagnosis between these two groups were analyzed by Chi-square analysis. Multivariable regression analysis examined factors associated with antibiotic response.Among 92 patients included, 61% had Crohn's disease and 39% had ulcerative colitis. 70% tested Toxin-PCR+. 60% received vancomycin or fidaxomicin to treat CDI. 82% of Toxin+ patients responded to antibiotics compared to 25% of Toxin-PCR+ patients (p 0.001). 21% of Toxin+ patients required IBD therapy escalation compared to 63% of Toxin-PCR+ patients (p 0.001). When adjusted for the types of antibiotics used, IBD subtypes, and immunosuppression status, positivity to Toxin (OR 14.85, CI 4.62-47.72) was the most significant predictor of response to antibiotics.Toxin+ compared to Toxin-PCR+ IBD patients had a significantly higher rate of response to antibiotics and lower chances of requiring IBD therapy escalation. Future outcome studies involving CDI in IBD patients should be stratified by modality of diagnosis.

While much progress has been made in the last two decades in the treatment and the management of inflammatory bowel diseases (IBD)—both ulcerative colitis (UC) and Crohn’s Disease (CD)—as of today these conditions are still diagnosed only after they have become symptomatic. This is a major drawback since by then the inflammatory process has often already caused considerable damage and the disease might have become partially or totally unresponsive to medical therapy. Late diagnosis in IBD is due to the lack of accurate, non-invasive indicators that would allow disease identification during the pre-clinical stage—as it is often done in many other medical conditions. Here, we will discuss what is known about the biologic onset and pre-clinical CD with an emphasis on studies conducted in patients’ first degree relatives. We will then review the possible strategies to diagnose IBD very early in time including screening, available disease markers and imaging, and the possible clinical implications of treating these conditions at or close to their biologic onset. Later, we will review the potential impact of conducting translational research in IBD during the pre-clinical stage, especially focusing on the role of the microbiome in disease etiology and pathogenesis. Finally, we will highlight possible future developments in the field and how they can impact IBD management and our scientific knowledge of these conditions. Published version

While much progress has been made in the last two decades in the treatment and the management of inflammatory bowel diseases (IBD)—both ulcerative colitis (UC) and Crohn’s Disease (CD)—as of today these conditions are still diagnosed only after they have become symptomatic. This is a major drawback since by then the inflammatory process has often already caused considerable damage and the disease might have become partially or totally unresponsive to medical therapy. Late diagnosis in IBD is due to the lack of accurate, non-invasive indicators that would allow disease identification during the pre-clinical stage—as it is often done in many other medical conditions. Here, we will discuss what is known about the biologic onset and pre-clinical CD with an emphasis on studies conducted in patients’ first degree relatives. We will then review the possible strategies to diagnose IBD very early in time including screening, available disease markers and imaging, and the possible clinical implications of treating these conditions at or close to their biologic onset. Later, we will review the potential impact of conducting translational research in IBD during the pre-clinical stage, especially focusing on the role of the microbiome in disease etiology and pathogenesis. Finally, we will highlight possible future developments in the field and how they can impact IBD management and our scientific knowledge of these conditions.

BACKGROUND Studies have demonstrated a potential role for fecal biomarkers such as fecal calprotectin (FC) and fecal lactoferrin (FL) in monitoring inflammatory bowel diseases (IBD) - Crohn’s disease (CD) and ulcerative colitis (UC). However, their correlation to endoscopic scores, disease severity and affected intestinal surface has not been extensively investigated. AIM To correlate FL, and for comparison white blood cell (WBC) and C-reactive protein (CRP), with endoscopic scores, disease extent and location in CD and UC. METHODS Retrospective analysis in 188 patients who had FL, CRP and WBC determined within 30 d of endoscopy. Disease location, disease extent (number of intestinal segments involved), disease severity (determined by endoscopic scores), timing of FL testing in relation to colonoscopy, as well as the use of effective fast acting medications (steroids and biologics) between colonoscopy and FL measurement, were recorded. RESULTS In 131 CD and 57 UC patients, both CRP and FL - but not WBC - distinguished disease severity (inactive, mild, moderate, severe). In patients receiving fast-acting (steroids or biologics) treatment in between FL and colonoscopy, FL showed a higher correlation to endoscopic scores when tested before vs after the procedure (r = 0.596, P < 0.001, vs r = 0.285, P = 0.15 for the Simple Endoscopic Score for CD; and r = 0.402, P = 0.01 vs r = 0.054 P = 0.84 for Disease Activity Index). Finally, FL was significantly correlated with the diseased mucosal surface (colon-ileocolon > small bowel) and the number of inflamed colon segments. CONCLUSION FL and CRP separated disease severity categories with FL showing lower discriminating P-values. FL showed a close correlation with the involved mucosal surface and with disease extent and was more closely correlated to endoscopy when determined before the procedure – this indicating that inflammatory activity changes associated with therapy might be rapidly reflected by FL levels. FL can accurately and timely characterize intestinal inflammation in IBD.

Background:For people living with HIV, major guidelines in high-income countries recommend testing for transmitted drug resistance (TDR) to guide the choice of first-line antiretroviral therapy (ART). However, individuals who fail a first-line regimen can now be switched to one of several effective regimens. Therefore, the virological and clinical benefit of TDR testing needs to be evaluated.Methods:We included individuals from the HIV-CAUSAL Collaboration who enrolled

© 2018 The Authors We tested the hypotheses that increasing the number of anti-herbivore resistance loci in crop plants will increase resistance strength, increase the spectrum of resistance (the number of species affected), and increase resistance stability. We further examined the potential ecological costs of pyramiding resistance under benign environments. In our experiments, we used 14 near-isogenic rice lines with zero (T65: recurrent parent), one, two or three resistance loci introgressed through marker-assisted selection. Lines with two or more loci that were originally bred for resistance to the green rice leafhopper, Nephotettix cincticeps, significantly reduced egg-laying by the green leafhopper, N. virescens. Declines in egg-number and in nymph weight were correlated with the numbers of resistance loci in the rice lines. To test the spectrum of resistance, we challenged the lines with a range of phloem feeders including the zig-zag leafhopper, Recilia dorsalis, brown planthopper, Nilaparvata lugens, and whitebacked planthopper, Sogatella furcifera. There was an increase in the number of tested species showing significant declines in egg-laying and nymph survival on lines with increasing numbers of loci. In a screen house trial that varied rates of nitrogenous fertilizer, a line with three loci had stable resistance against the green leafhopper and the grain yields of infested plants were maintained or increased (overcompensation). Under benign conditions, plant growth and grain yields declined with increasing numbers of resistance loci. However, under field conditions with natural exposure to herbivores, there were no significant differences in final yields. Our results clearly indicate the benefits, including unanticipated benefits such as providing resistance against multiple herbivore species, of pyramiding anti-herbivore resistance genes/loci in crop plants. We discuss our results as part of a review of existing research on pyramided resistance against leafhoppers and planthoppers in rice. We suggest that potential ecological costs may be overcome by the careful selection of gene combinations for pyramiding, avoidance of high (potentially redundant) loci numbers, and introgression of loci into robust plant types such as hybrid rice varieties.

We proposed several energy-efficient resource allocation algorithms for the downlink of an orthogonal frequency-division-multiple-access (OFDMA) based femtocell heterogeneous networks (HetNets). Heterogeneous QoS and fairness in rate are investigated in the proposed resource allocation problem. A dense deployment of femtocells in the coverage area of a central macrocell is considered and energy usage of both femtocell and macrocell users are optimized simultaneously. We aim to maximize the weighted sum of the individual energy efficiencies (WSEEMax) and the network energy efficiency (NEEMax) while satisfying the following: (1) minimum throughput for delay-sensitive (DS) users, (2) fairness constraint for delay-tolerant (DT) users, (3) required constraints of OFDMA systems. The problem is formulated in three different forms: mixed 0—1 integer programming formulation, time-sharing formulation and sparsity-inducing formulation. The proposed resource block (RB) and power optimization problems are combinatorial and highly non-convex due to the fractional form of the objective function, the integer constraint of OFDMA RBs and non-affine fairness. We adopt the successive convex approximation (SCA) approach and transform the problems into a sequence of convex subproblems. With the proposed algorithms, we show that the overall joint RB and power allocation schemes converge to suboptimal solutions. Numerical examples confirm the merits of the proposed algorithms.

We consider downlink transmission of a fronthaul-constrained cloud radio access network. Our aim is to maximize the system sum data rate via jointly designing beamforming and user association. The problem is basically a mixed integer non-convex programs for which a global solution requires a prohibitively high computational effort. The focus is thus on efficient solutions capable of achieving the near optimal performance with low complexity. To this end, we transform the design problem into continuous programs by two approaches: penalty and sparse approximation methods. The resulting continuous nonconvex problems are then solved by the successive convex approximation framework. Numerical results indicate that the proposed methods are near-optimal, and outperform existing suboptimal methods in terms of achieved performances and computational complexity.

We consider a multi-pair amplify-and-forward relay network where the energy-constrained relays adopting the time-switching protocol harvest energy from the radio-frequency signals transmitted by the users for assisting user data transmission. Both one-way and two-way relaying techniques are investigated. Aiming at energy efficiency (EE) fairness among the user pairs, we construct an energy consumption model incorporating rate-dependent signal processing power, the dependence on output power level of power amplifiers’ efficiency, and nonlinear energy harvesting (EH) circuits. Then, we formulate the max-min EE fairness problems in which the data rates, users’ transmit power, relays’ processing coefficient, and EH time are jointly optimized under the constraints on the quality of service and users’ maximum transmit power. To achieve efficient suboptimal solutions to these nonconvex problems, we devise monotonic descent algorithms based on the inner approximation (IA) framework, which solve a second-order-cone program in each iteration. To further simplify the designs, we propose an approach combining IA and zero-forcing beamforming, which eliminates inter-pair interference and reduces the numbers of variables and required iterations. Finally, extensive numerical results are presented to validate the proposed approaches. More specifically, the results demonstrate that ignoring the realistic aspects of power consumption might degrade the performance remarkably, and jointly designing parameters involved could significantly enhance the EE.

Introduction: Postoperative recurrence (POR) of Crohn’s disease is common after surgical resection. How to best manage POR remains uncertain.Areas covered: In this review, we will first describe the natural course and the best modalities to diagnose this surgical sequela. We will then focus on the potential risk factors for relapse and highlight the main shortcomings in the current study designs and endoscopic and clinical scoring systems, which may partly explain the unexpected outcomes of recent clinical trials. Finally, we will propose a strategy to address the management of POR.Expert commentary: Anti-tumor necrosis factor (Anti-TNF) agents are the most effective therapy to prevent POR in Crohn’s disease. Patient risk stratification and active monitoring with scheduled ileocolonoscopy are cornerstones of optimal POR management. Further studies are needed to address areas of uncertainty including timing and duration of therapy and the role of therapeutic drug monitoring in this setting.

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© 2018, The International Society of Paddy and Water Environment Engineering and Springer Japan KK, part of Springer Nature. The diversification of farming landscapes is proposed as a method to increase farm productivity while at the same time enhancing pest regulation services provided by the natural enemies of insect herbivores. In this study, areas of diversified and conventional rice fields (with 2–14 fields per area = 0.42–1.31 ha) were established at three sites in the Philippines. The diversified areas had a series (> 40 per hectare) of small (< 2 m2) vegetable patches interspersed along rice bunds (levees). The abundance of planthopper and lepidopteran pests in these areas was monitored during two consecutive cropping seasons using sweep nets with rice yield and damage recorded at the end of each season. Mortality of brown planthopper (Nilaparvata lugens) and yellow stemborer (Scirpophaga incertulas) eggs was monitored through field exposures of infested rice plants. There were no differences in rice yields between the conventional and diversified areas; however, a range of vegetables were produced as a supplementary product from the diversified rice areas. Diversification had no effect on planthopper or leaffolder (Cnaphalocrocis medinalis) abundance at the sites. Adult stemborers (Scirpophaga incertulas) were more abundant in the diversified areas; however, stemborer damage was similar between area treatments in both years. Vegetable patches did not increase parasitism of planthopper eggs; however, egg parasitism was highest close to the vegetable patches, suggesting that egg parasitoids interacted with the patches. Mortality of stemborer eggs was higher in the diversified areas than in the conventional areas. Parasitism due to Trichogramma japonicum and other egg parasitoids was also higher in the diversified areas. These results indicate the potential for vegetable patches to enhance the biological control services provided by egg parasitoids in rice fields; however, the study also indicates a need to carefully select vegetable crops that avoid any potential benefits for rice pests. We discuss the need for further research into diversified farms as a means of achieving sustainable rice production in Asia.

This paper focuses on energy-efficient coordinated multi-point (CoMP) downlink in multi-antenna multi-cell wireless communications systems. We provide an overview of transmit beamforming designs for various energy efficiency (EE) metrics including maximizing the overall network EE, sum weighted EE, and fairness EE. Generally, an EE optimization problem is a nonconvex program for which finding the globally optimal solutions requires high computational effort. Consequently, several low-complexity suboptimal approaches have been proposed. Here, we sum up the main concepts of the recently proposed algorithms based on the state-of-the-art successive convex approximation (SCA) framework. Moreover, we discuss the application to the newly posted EE problems including new EE metrics and power consumption models. Furthermore, distributed implementation developed based on alternating direction method of multipliers (ADMM) for the provided solutions is also discussed. For the sake of completeness, we provide numerical comparison of the SCA based approaches and the conventional solutions developed based on parametric transformations (PTs). We also demonstrate the differences and roles of different EE objectives and power consumption models.