FOCUS: Future of fecal calprotectin utility study in inflammatory bowel disease

AIMTo evaluate the perspective of gastroenterologists regarding the impact of fecal calprotectin (FC) on the management of patients with inflammatory bowel disease (IBD).METHODSPatients with known IBD or symptoms suggestive of IBD for whom the physician identified that FC would be clinically useful were recruited. Physicians completed an online “pre survey” outlining their rationale for the test. After receipt of the test results, the physicians completed an online “post survey” to portray their perceived impact of the test result on patient management. Clinical outcomes for a subset of patients with follow-up data available beyond the completion of the “post survey” were collected and analyzed.RESULTSOf 373 test kits distributed, 290 were returned, resulting in 279 fully completed surveys. One hundred and ninety patients were known to have IBD; 147 (77%) with Crohn’s Disease, 43 (21%) Ulcerative Colitis and 5 (2%) IBD unclassified. Indications for FC testing included: 90 (32.2%) to differentiate a new diagnosis of IBD from Irritable Bowel Syndrome (IBS), 85 (30.5%) to distinguish symptoms of IBS from IBD in those known to have IBD and 104 (37.2%) as an objective measure of inflammation. FC levels resulted in a change in management 51.3% (143/279) of the time which included a significant reduction in the number of colonoscopies (118) performed (P < 0.001). Overall, 97.5% (272/279) of the time, the physicians found the test sufficiently useful that they would order it again in similar situations. Follow-up data was available for 172 patients with further support for the clinical utility of FC provided.CONCLUSIONThe FC test effected a change in management 51.3% of the time and receipt of the result was associated with a reduction in the number of colonoscopies performed.     

Control of heart rate by cAMP sensitivity of HCN channels

“Pacemaker” f-channels mediating the hyperpolarization-activated nonselective cation current I_f are directly regulated by cAMP. Accordingly, the activity of f-channels increases when cellular cAMP levels are elevated (e.g., during sympathetic stimulation) and decreases when they are reduced (e.g., during vagal stimulation). Although these biophysical properties seem to make f-channels ideal molecular targets for heart rate regulation by the autonomic nervous system, the exact contribution of the major I_f-mediating cardiac isoforms HCN2 and HCN4 to sinoatrial node (SAN) function remains highly controversial. To directly investigate the role of cAMP-dependent regulation of hyperpolarization activated cyclic nucleotide activated (HCN) channels in SAN activity, we generated mice with heart-specific and inducible expression of a human HCN4 mutation (573X) that abolishes the cAMP-dependent regulation of HCN channels. We found that hHCN4–573X expression causes elimination of the cAMP sensitivity of I_f and decreases the maximum firing rates of SAN pacemaker cells. In conscious mice, hHCN4–573X expression leads to a marked reduction in heart rate at rest and during exercise. Despite the complete loss of cAMP sensitivity of I_f, the relative extent of SAN cell frequency and heart rate regulation are preserved. Our data demonstrate that cAMP-mediated regulation of I_f determines basal and maximal heart rates but does not play an indispensable role in heart rate adaptation during physical activity. Our data also reveal the pathophysiologic mechanism of hHCN4–573X–linked SAN dysfunction in humans.     

Cardiac troponins predict mortality and cardiovascular outcomes in patients with peripheral artery disease: A systematic review and meta‐analysis of adjusted observational studies

BackgroundA significant proportion of patients (pts) with peripheral artery disease (PAD) have concomitant coronary artery disease and polyvascular involvement contributes to increased risk of death and unfavorable cardiovascular events.HypothesisCardiac troponins are associated with adverse cardiovascular outcomes in PAD pts.MethodsWe systematically searched Medline and Scopus to identify all observational cohort studies published before June 2021 (combining terms “troponin,” “peripheral artery disease,” “peripheral arterial disease,” “intermittent claudication,” and “critical limb ischemia”) that evaluated the prognostic impact of troponin rise on admission on all‐cause mortality and/or major cardiovascular events (MACEs; composite of myocardial infarction, stroke, and cardiovascular death) in PAD pts followed up at least 6 months. A meta‐analysis was conducted using the generic inverse variance method. Heterogeneity between studies was investigated using Cochrane''s Q test and I ² statistic.ResultsEight studies were included in the final analysis (5313 pts) with a median follow‐up of 27 months (interquartile range: 12–59 months). The prevalence of troponin positivity was 5.3% (range: 4.4%–8.7%) in pts with intermittent claudication, and 62.6% (range: 33.6%–85%) in critical limb ischemia. Elevated troponins were significantly associated with an increased risk of all‐cause mortality (hazard ratio [HR]: 2.85, 95% confidence interval [CI]: 2.28–3.57; I ² = 50.97%), and MACE (HR: 2.58, 95% CI: 2.04–3.26; I ² = 4.00%) without publication bias (p = .24 and p = .10, respectively).ConclusionTroponin rise on admission is associated with adverse long‐term cardiovascular outcomes in symptomatic PAD.     

Artificial Neural Network-Based Failure Pressure Prediction of API 5L X80 Pipeline with Circumferentially Aligned Interacting Corrosion Defects Subjected to Combined Loadings

Conventional pipeline corrosion assessment methods produce conservative failure pressure predictions for pipes under the influence of both internal pressure and longitudinal compressive stress. Numerical approaches, on the other hand, are computationally expensive. This work provides an assessment method (empirical) for the failure pressure prediction of a high toughness corroded pipe subjected to combined loading, which is currently unavailable in the industry. Additionally, a correlation between the corrosion defect geometry, as well as longitudinal compressive stress and the failure pressure of a pipe based on the developed method, is established. An artificial neural network (ANN) trained with failure pressure from FEA of an API 5L X80 pipe for varied defect spacings, depths, defect lengths, and longitudinal compressive loads were used to develop the equation. With a coefficient of determination (R²) of 0.99, the proposed model was proven to be capable of producing accurate predictions when tested against arbitrary finite element models. The effects of defect spacing, length, and depth, and longitudinal compressive stress on the failure pressure of a corroded pipe with circumferentially interacting defects, were then investigated using the suggested model in a parametric analysis.     

Molecular Characterization of the First Alternavirus Identified in Fusarium oxysporum

A novel mycovirus named Fusarium oxysporum alternavirus 1(FoAV1) was identified as infecting Fusarium oxysporum strain BH19, which was isolated from a fusarium wilt diseased stem of Lilium brownii. The genome of FoAV1 contains four double-stranded RNA (dsRNA) segments (dsRNA1, dsRNA 2, dsRNA 3 and dsRNA 4, with lengths of 3.3, 2.6, 2.3 and 1.8 kbp, respectively). Additionally, dsRNA1 encodes RNA-dependent RNA polymerase (RdRp), and dsRNA2- dsRNA3- and dsRNA4-encoded hypothetical proteins (ORF2, ORF3 and ORF4), respectively. A homology BLAST search, along with multiple alignments based on RdRp, ORF2 and ORF3 sequences, identified FoAV1 as a novel member of the proposed family “Alternaviridae”. Evolutionary relation analyses indicated that FoAV1 may be related to alternaviruses, thus dividing the family “Alternaviridae” members into four clades. In addition, we determined that dsRNA4 was dispensable for replication and may be a satellite-like RNA of FoAV1—and could perhaps play a role in the evolution of alternaviruses. Our results provided evidence for potential genera establishment within the proposed family “Alternaviridae”. Additionally, FoAV1 exhibited biological control of Fusarium wilt. Our results also laid the foundations for the further study of mycoviruses within the family “Alternaviridae”, and provide a potential agent for the biocontrol of diseases caused by F. oxysporum.     

Female-specific flightless phenotype for mosquito control

Dengue and dengue hemorrhagic fever are increasing public health problems with an estimated 50–100 million new infections each year. Aedes aegypti is the major vector of dengue viruses in its range and control of this mosquito would reduce significantly human morbidity and mortality. Present mosquito control methods are not sufficiently effective and new approaches are needed urgently. A “sterile-male-release” strategy based on the release of mosquitoes carrying a conditional dominant lethal gene is an attractive new control methodology. Transgenic strains of Aedes aegypti were engineered to have a repressible female-specific flightless phenotype using either two separate transgenes or a single transgene, based on the use of a female-specific indirect flight muscle promoter from the Aedes aegypti Actin-4 gene. These strains eliminate the need for sterilization by irradiation, permit male-only release (“genetic sexing”), and enable the release of eggs instead of adults. Furthermore, these strains are expected to facilitate area-wide control or elimination of dengue if adopted as part of an integrated pest management strategy.     

Role of Helicobacter pylori infection in autoimmune systemic rheumatic diseases

The relationship between infection and autoimmunity has been increasingly defined over the last 20 years. The systemic rheumatic diseases are characterized by dysregulation of the immune system resulting in a loss of tolerance to self-antigen. The exact etiology for the majority of these diseases is unknown; however, a complex combination of host and environmental factors are believed to play a pivotal role. Helicobacter pylori (H. pylori) is one of the most widely studied infectious agents proposed as agents triggering autoimmune response. The persistent presence of H. pylori in the gastric mucosa results in chronic immune system activation with ongoing cytokine signaling, infiltration of gastric mucosa by neutrophils, macrophages, lymphocytes, as well as production of antibodies and effector T-cells. Various mechanisms have been proposed in an attempt to explain the extra-intestinal manifestations of H. pylori infections. These include: molecular mimicry, endothelial cell damage, superantigens and microchimerism. I performed a systematic literature review using the keywords “rheumatoid arthritis”, “Sjögren’s syndrome”, “systemic sclerosis”, “systemic lupus erythematosus”, “Helicobacter pylori” and “pathogenesis”. A systematic literature search was carried out in MEDLINE; EMBASE; Cochrane Library and ACR/EULAR meeting abstracts. In systemic rheumatic diseases H. pylori infection prevalence alone should not be expected to provide sufficient evidence for or against a pathologic role in the disease. In this article I review studies examining the potential involvement of H. pylori infection in autoimmune systemic rheumatic diseases. Further studies of the immunological response to H. pylori and its role in the pathogenesis of systemic rheumatic diseases are warranted.     

Molecular code for protein insertion in the endoplasmic reticulum membrane is similar for N(in)-C(out) and N(out)-C(in) transmembrane helices

Transmembrane α-helices in integral membrane proteins can have two orientations in the membrane: N_in–C_out or N_out–C_in. Previous studies of model N_out–C_in transmembrane segment have led to a detailed, quantitative picture of the “molecular code” that relates amino acid sequence to membrane insertion efficiency in vivo [Hessa T, et al. (2007) Molecular code for transmembrane helix recognition by the Sec61 translocon. Nature 450:1026–1030], but whether the same code applies also to N_in–C_out transmembrane helices is unknown. Here, we show that the contributions of individual amino acids to the overall efficiency of membrane insertion are similar for the two kinds of helices and that the threshold hydrophobicity for membrane insertion can be up to ≈1 kcal/mol lower for N_in–C_out compared with N_out–C_in transmembrane helices, depending on the neighboring helices.     

Hybrid therapy for Helicobacter pylori infection: A systemic review and meta-analysis

AIM: To compare the effectiveness of hybrid therapy with other recommended regimens using meta-analysis.METHODS: Bibliographical searches for randomized trials comparing hybrid and other therapies were performed in PubMed, the Cochrane Library and relevant congresses up to February 2015 using the following keywords (all fields and/or MeSH): (“Helicobacter pylori” or “H. pylori”) and (“hybrid therapy” or “sequential-concomitant therapy”). Meta-analyses were performed with Cochrane Review Manager 5.1. The random effect model proposed by DerSimonian and Laird and the Mantel-Haenszel method were used to estimate the pooled relative risk and 95%CI of the efficacy outcomes between hybrid therapy and other eradication therapies.RESULTS: Eight studies (2516 subjects) met entry criteria. The antimicrobial resistance in the study groups ranged from 6.9% to 23.5%. The mean cure rates of hybrid therapy by intention-to-treat (ITT) and per-protocol analyses were 88.5% (n = 1207; range: 80.0% to 97.4%) and 93.3% (n = 1109; range: 85.7% to 99.1%), respectively. Meta-analysis showed there was no significant difference in ITT eradication rate between hybrid and sequential therapy (relative risk: 1.01; 95%CI: 0.92-1.11). Subgroup analysis revealed hybrid therapy was more effective than sequential therapy in the non-Italian populations (95%CI: 1.01-1.18) and was only less effective in one, Italian population (95%CI: 0.83-0.98). There was no significant difference in eradication rate between hybrid therapy and concomitant therapy (95%CI: 0.93-1.02). No head-to-head comparisons of hybrid therapy and standard triple therapy or bismuth quadruple therapy were found. However, a multicenter, randomized trial showed that reverse hybrid therapy was superior to standard triple therapy (95.5% vs 88.6% ITT; P = 0.011).CONCLUSION: Hybrid therapy appears to be an effective, safe, and well-tolerated treatment for H. pylori infection in the era of increasing antibiotic resistance.     

Effects of Fixture Configurations and Weld Strength Mismatch on J-Integral Calculation Procedure for SE(B) Specimens

This work presents the development of a J-integral estimation procedure for deep and shallow cracked bend specimens based upon plastic η_pl factors for a butt weld made in an S690 QL high strength low alloyed steel. Experimental procedures include the characterization of average material properties by tensile testing and evaluation of base and weld metal resistance to stable tearing by fracture testing of square SE(B) specimens containing a weld centerline notch. J-integral has been estimated from plastic work using a single specimen approach and the normalization data reduction technique. A comprehensive parametric finite element study has been conducted to calibrate plastic factor η_pl and geometry factor λ for various fixture and weld configurations, while a corresponding plastic factor γ_pl was computed on the basis of the former two. The modified η_pl and γ_pl factors were then incorporated in the J computation procedure given by the ASTM E1820 standard, for evaluation of the plastic component of J and its corresponding correction due to crack growth, respectively. Two kinds of J-R curves were computed on the basis of modified and standard η_pl and γ_pl factors, where the latter are given by ASTM E1820. A comparison of produced J-R curves for the base material revealed that variations in specimen fixtures can lead to ≈10% overestimation of computed fracture toughness J_Ic. Furthermore, a comparison of J-R curves for overmatched single-material idealized welds revealed that the application of standard η_pl and γ_pl factors can lead to the overestimation of computed fracture toughness J_Ic by more than 10%. Similar observations are made for undermatched single material idealized welds, where fracture toughness J_Ic is overestimated by ≈5%.     

The Surface of Nanoparticle Silicon as Studied by Solid-State NMR

The surface structure and adjacent interior of commercially available silicon nanopowder (np-Si) was studied using multinuclear, solid-state NMR spectroscopy. The results are consistent with an overall picture in which the bulk of the np-Si interior consists of highly ordered (“crystalline”) silicon atoms, each bound tetrahedrally to four other silicon atoms. From a combination of ¹H, ²⁹Si and ²H magic-angle-spinning (MAS) NMR results and quantum mechanical ²⁹Si chemical shift calculations, silicon atoms on the surface of “as-received” np-Si were found to exist in a variety of chemical structures, with apparent populations in the order (a) (Si–O–)₃Si–H > (b) (Si–O–)₃SiOH > (c) (HO–)_nSi(Si)_m(–OSi)_4−m−n ≈ (d) (Si–O–)₂Si(H)OH > (e) (Si–O–)₂Si(–OH)₂ > (f) (Si–O–)₄Si, where Si stands for a surface silicon atom and Si represents another silicon atom that is attached to Si by either a Si–Si bond or a Si–O–Si linkage. The relative populations of each of these structures can be modified by chemical treatment, including with O₂ gas at elevated temperature. A deliberately oxidized sample displays an increased population of (Si–O–)₃Si–H, as well as (Si–O–)₃SiOH sites. Considerable heterogeneity of some surface structures was observed. A combination of ¹H and ²H MAS experiments provide evidence for a substantial population of silanol (Si–OH) moieties, some of which are not readily H-exchangeable, along with the dominant Si–H sites, on the surface of “as-received” np-Si; the silanol moieties are enhanced by deliberate oxidation. An extension of the DEPTH background suppression method is also demonstrated that permits measurement of the T₂ relaxation parameter simultaneously with background suppression.     

Conjugate points on a limiting extremal

Theorem 1, together with the author's extensions of the Sturmian Comparison Theorems, will suffice to establish the basic Theorem 27.3, p. 211 of Global Variational Analysis: Weierstrass Integrals on a Riemannian Manifold. Mathematical Notes, Princeton University Press, Princeton, N.J., 1976. Here and in the preceding reference there is given a Weierstrass Integral on a compact, connected, Riemannian manifold M_n, conditioned as in the above reference. Let γ be an arbitrary extremal of J joining a point P to a point Q, ≠ P on M_n. An extremal ζ of J joining A to B is termed nondegenerate if A and B are not conjugate on ζ. The index of ζ is by definition the “count” of conjugate points of A on ζ definitely preceding B.     

Making short-term climate forecasts useful: Linking science and action

This paper discusses the evolution of scientific and social understanding that has led to the development of knowledge systems supporting the application of El Niño-Southern Oscillation (ENSO) forecasts, including the development of successful efforts to connect climate predictions with sectoral applications and actions “on the ground”. The evolution of “boundary-spanning” activities to connect science and decisionmaking is then discussed, setting the stage for a report of outcomes from an international workshop comprised of producers, translators, and users of climate predictions. The workshop, which focused on identifying critical boundary-spanning features of successful boundary organizations, included participants from Australia, Hawaii, and the Pacific Islands, the US Pacific Northwest, and the state of Ceará in northwestern Brazil. Workshop participants agreed that boundary organizations have multiple roles including those of information broker, convenor of forums for engagement, translator of scientific information, arbiter of access to knowledge, and exemplar of adaptive behavior. Through these roles, boundary organizations will ensure the stability of the knowledge system in a changing political, economic, and climatic context. The international examples reviewed in this workshop demonstrated an interesting case of convergent evolution, where organizations that were very different in origin evolved toward similar structures and individuals engaged in them had similar experiences to share. These examples provide evidence that boundary organizations and boundary-spanners fill some social/institutional roles that are independent of culture.     

Questing Amblyomma mixtum and Haemaphysalis juxtakochi (Acari: Ixodidae) Infected with Candidatus “Rickettsia amblyommii” from the Natural Environment in Panama Canal Basin,Panama

This work emphasizes the detection of Candidatus “Rickettsia amblyommii” in questing Haemaphysalis juxtakochi and Amblyomma mixtum. From February 2009 to December 2012, questing ticks were collected from the vegetation and leaf-litter of four protected forests and two grassy areas around the Panama Canal basin. DNA was extracted from Amblyomma mixtum, Amblyomma naponense, Amblyomma oblongoguttatum, Amblyomma pecarium, Amblyomma tapirellum, Haemaphysalis juxtakochi, and unidentified immature Amblyomma. Specific primers of citrate synthase gene gltA were used to detect and identify the rickettsiae. Amplicons with the expected band size were purified and sequenced. DNA of C. “R. amblyommii” was found in A. mixtum, H. juxtakochi and Amblyomma immatures. To our knowledge, these finding represent the first report of C. “R. amblyommii” in free-living ticks in the wilderness of Central America.     

Role of hepatitis B virus DNA integration in human hepatocarcinogenesis

Liver cancer ranks sixth in cancer incidence, and is the third leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which arises from hepatocytes and accounts for approximately 70%-85% of cases. Hepatitis B virus (HBV) frequently causes liver inflammation, hepatic damage and subsequent cirrhosis. Integrated viral DNA is found in 85%-90% of HBV-related HCCs. Its presence in tumors from non-cirrhotic livers of children or young adults further supports the role of viral DNA integration in hepatocarcinogenesis. Integration of subgenomic HBV DNA fragments into different locations within the host DNA is a significant feature of chronic HBV infection. Integration has two potential consequences: (1) the host genome becomes altered (“cis” effect); and (2) the HBV genome becomes altered (“trans” effect). The cis effect includes insertional mutagenesis, which can potentially disrupt host gene function or alter host gene regulation. Tumor progression is frequently associated with rearrangement and partial gain or loss of both viral and host sequences. However, the role of integrated HBV DNA in hepatocarcinogenesis remains controversial. Modern technology has provided a new paradigm to further our understanding of disease mechanisms. This review summarizes the role of HBV DNA integration in human carcinogenesis.     

In Situ High-Pressure Synthesis of New Outstanding Light-Element Materials under Industrial P-T Range

High-pressure synthesis (which refers to pressure synthesis in the range of 1 to several GPa) adds a promising additional dimension for exploration of compounds that are inaccessible to traditional chemical methods and can lead to new industrially outstanding materials. It is nowadays a vast exciting field of industrial and academic research opening up new frontiers. In this context, an emerging and important methodology for the rapid exploration of composition-pressure-temperature-time space is the in situ method by synchrotron X-ray diffraction. This review introduces the latest advances of high-pressure devices that are adapted to X-ray diffraction in synchrotrons. It focuses particularly on the “large volume” presses (able to compress the volume above several mm³ to pressure higher than several GPa) designed for in situ exploration and that are suitable for discovering and scaling the stable or metastable compounds under “traditional” industrial pressure range (3–8 GPa). We illustrated the power of such methodology by (i) two classical examples of “reference” superhard high-pressure materials, diamond and cubic boron nitride c-BN; and (ii) recent successful in situ high-pressure syntheses of light-element compounds that allowed expanding the domain of possible application high-pressure materials toward solar optoelectronic and infra-red photonics. Finally, in the last section, we summarize some perspectives regarding the current challenges and future directions in which the field of in situ high-pressure synthesis in industrial pressure scale may have great breakthroughs in the next years.     

Improved Resin–Zirconia Bonding by Room Temperature Hydrofluoric Acid Etching

This in vitro study was conducted to evaluate the shear bond strength of “non-self-adhesive” resin to dental zirconia etched with hydrofluoric acid (HF) at room temperature and to compare it to that of air-abraded zirconia. Sintered zirconia plates were air-abraded (control) or etched with 10%, 20%, or 30% HF for either 5 or 30 min. After cleaning, the surfaces were characterized using various analytical techniques. Three resin cylinders (Duo-Link) were bonded to each treated plate. All bonded specimens were stored in water at 37 °C for 24 h, and then half of them were additionally thermocycled 5000 times prior to the shear bond-strength tests (n = 12). The formation of micro- and nano-porosities on the etched surfaces increased with increasing concentration and application time of the HF solution. The surface wettability of zirconia also increased with increasing surface roughness. Higher concentrations and longer application times of the HF solution produced higher bond-strength values. Infiltration of the resin into the micro- and nano-porosities was observed by scanning electron microscopy. This in vitro study suggests that HF slowly etches zirconia ceramic surfaces at room temperature, thereby improving the resin–zirconia bond strength by the formation of retentive sites.     

Acute cardiovascular hospitalizations and illness severity before and during the COVID‐19 pandemic

BackgroundCardiovascular disease (CVD) hospitalizations declined worldwide during the COVID‐19 pandemic. It is unclear how shelter‐in‐place orders affected acute CVD hospitalizations, illness severity, and outcomes.HypothesisCOVID‐19 pandemic was associated with reduced acute CVD hospitalizations (heart failure [HF], acute coronary syndrome [ACS], and stroke [CVA]), and worse HF illness severity.MethodsWe compared acute CVD hospitalizations at Duke University Health System before and after North Carolina''s shelter‐in‐place order (January 1–March 29 vs. March 30–August 31), and used parallel comparison cohorts from 2019. We explored illness severity among admitted HF patients using ADHERE (“high risk”: >2 points) and GWTG‐HF (“>10%”: >57 points) in‐hospital mortality risk scores, as well as echocardiography‐derived parameters.ResultsComparing hospitalizations during January 1–March 29 (N = 1618) vs. March 30–August 31 (N = 2501) in 2020, mean daily CVD hospitalizations decreased (18.2 vs. 16.1 per day, p = .0036), with decreased length of stay (8.4 vs. 7.5 days, p = .0081) and no change in in‐hospital mortality (4.7 vs. 5.3%, p = .41). HF hospitalizations decreased (9.0 vs. 7.7 per day, p = .0019), with higher ADHERE (“high risk”: 2.5 vs. 4.5%; p = .030), but unchanged GWTG‐HF (“>10%”: 5.3 vs. 4.6%; p = .45), risk groups. Mean LVEF was lower (39.0 vs. 37.2%, p = .034), with higher mean LV mass (262.4 vs. 276.6 g, p = .014).ConclusionsCVD hospitalizations, HF illness severity, and echocardiography measures did not change between admission periods in 2019. Evaluating short‐term data, the COVID‐19 shelter‐in‐place order was associated with reductions in acute CVD hospitalizations, particularly HF, with no significant increase in in‐hospital mortality and only minor differences in HF illness severity.