Trichoderma virens and Pseudomonas chlororaphis Differentially Regulate Maize Resistance to Anthracnose Leaf Blight and Insect Herbivores When Grown in Sterile versus Non-Sterile Soils.

Soil-borne Trichoderma spp. have been extensively studied for their biocontrol activities against pathogens and growth promotion ability in plants. However, the beneficial effect of Trichoderma on inducing resistance against insect herbivores has been underexplored. Among diverse Trichoderma species, consistent with previous reports, we showed that root colonization by T. virens triggered induced systemic resistance (ISR) to the leaf-infecting hemibiotrophic fungal pathogens Colletotrichum graminicola. Whether T. virens induces ISR to insect pests has not been tested before. In this study, we investigated whether T. virens affects jasmonic acid (JA) biosynthesis and defense against fall armyworm (FAW) and western corn rootworm (WCR). Unexpectedly, the results showed that T. virens colonization of maize seedlings grown in autoclaved soil suppressed wound-induced production of JA, resulting in reduced resistance to FAW. Similarly, the bacterial endophyte Pseudomonas chlororaphis 30-84 was found to suppress systemic resistance to FAW due to reduced JA. Further comparative analyses of the systemic effects of these endophytes when applied in sterile or non-sterile field soil showed that both T. virens and P. chlororaphis 30-84 triggered ISR against C. graminicola in both soil conditions, but only suppressed JA production and resistance to FAW in sterile soil, while no significant impact was observed when applied in non-sterile soil. In contrast to the effect on FAW defense, T. virens colonization of maize roots suppressed WCR larvae survival and weight gain. This is the first report suggesting the potential role of T. virens as a biocontrol agent against WCR.

Supplementing low protein diets with methionine or threonine during mixed Eimeria challenge.

We investigated the effects of supplementing low protein diets with methionine (Met) or threonine (Thr) during a mixed Eimeria (consisting of E. acervulina, E. maxima and E. tenella) challenge in broilers. All birds were fed the same starter diet (d1-9) and finisher diet (d28-35) which met Cobb 500 nutrient specifications. Birds were allocated to 1 of 4 dietary treatments from d9 to 28: a standard protein diet (19% CP); a low protein diet (16% CP); or the low protein diet supplemented with Met or Thr at 50% above recommendations. On d14, half of the birds were challenged, and half of the birds were unchallenged. From d14 to 28, feed intake was recorded daily and BW every 3 or 4 d. Oocyst excretion was measured daily from d18 to 27. On d21 and 28, 3 birds per pen were euthanized to assess nutrient digestibility, cytokine expression and intestinal histology. During the acute stage of the challenge, challenged birds reduced ADFI and ADG (P < 0.05). In the pre-patent and recovery stages, birds given the 16% CP diets increased ADFI (P < 0.05), meanwhile there were no differences in ADG in these stages (P > 0.05). Nutrient digestibility was reduced in challenged birds in the acute stage (P < 0.05) but tended to be greater than in unchallenged birds during the recovery stage. There was no significant effect of diet on oocyst excretion or intestinal histology (P > 0.05). Interactions were observed between diet and challenge on IL-10 and IL-21 expression in the cecal tonsils during the acute stage of the challenge (P < 0.05), due to reduced IL-10 expression in challenged Thr birds and greater IL-21 expression in challenged Met birds. Supplementation with Thr or Met had limited effects on the outcomes of a mixed Eimeria challenge but provides benefits to the host by enhancing their immune response.

Implementation of standard setting for high-stakes objective structured clinical examinations.

BACKGROUND AND PURPOSE: To describe one institution's approach to transformation of high-stakes objective structure clinical examinations (OSCEs) from norm-referenced to criterion-referenced standards setting and to evaluate the impact of these changes on OSCE performance and pass rates. EDUCATIONAL ACTIVITY AND SETTING: The OSCE writing team at the college selected a modified Angoff method appropriate for high-stakes assessments to replace the two standard deviation method previously used. Each member of the OSCE writing team independently reviewed the analytical checklist and calculated a passing score for active stations on OSCEs. Then the group met to determine a final pass score for each station. The team also determined critical cut points for each station, when indicated. After administration of the OSCEs, scores, pass rates, and need for remediation were compared to the previous norm-referenced method. Descriptive statistics were used to summarize the data. FINDINGS: OSCE scores remained relatively unchanged when switched to a criterion-referenced method, but the number of remediators increased up to 2.6 fold. In the first year, the average score increased from 86.8% to 91.7% while the remediation rate increased from 2.8% to 7.4%. In the third year, the average increased from 90.9% to 92% while the remediation rate increased from 6% to 15.6%. Likewise, the fourth-year average increased from 84.9% to 87.5% while the remediation rate increased from 4.4% to 9%. SUMMARY: Transition to a modified Angoff method did not impact average OSCE score but did increase the number of remediations.

Combination of BeGraft and Solaris Stent Grafts for the Covered Endovascular Reconstruction of Aortic Bifurcation-BS-CERAB Technique.

Background: This study examines the impact of the use of the combination of BeGraft and Solaris stent grafts on the outcomes during the covered endovascular reconstruction of aortic bifurcation (BS-CERAB) technique and extension to the iliac arteries. Methods: Consecutive patients with aortoiliac occlusive disease who underwent endovascular treatment using BS-CERAB between January 2020 and December 2023 were included. Patient demographics, symptoms, lesion characteristics, and procedural and follow-up details were collected and analyzed. Perioperative complications and reinterventions were also identified. Results: A total of 42 patients met the inclusion criteria (32 men, 76.2%, median age 72 years, range 59-85). Indications for treatment were intermittent claudication (42.9%) and critical limb ischemia (57.1%). Procedure success was achieved in all cases. The median patient follow-up time was 14 months (1-36). One patient died at a 10-month follow-up due to lung cancer. The mean pre-operative ABI increased from 0.37 ± 0.19 before intervention to 0.71 ± 1.23 post-operatively at 12 months (p = 0.037). The estimated primary patency rates at 3, 6, and 12 months were 90.5%, 85.7%, and 81.0% and primary assisted patency rates were 90.5%, 90.5%, and 85.7%, respectively. Secondary patency was 95.2% at 3 and 6 months and 90.5% at a 12-month follow-up. Active cancer (p = 0.023, OR 2.12 95%CI 1.14-3.25) was a risk factor for restenosis. Conclusions: This mid-term experience shows that the CERAB technique using the combination of BeGraft and Solaris stents grafts, for the endovascular treatment of severe aortoiliac atherosclerotic disease, may allow an effective reconstruction of the aortic bifurcation and iliac arteries related to high-patency and lower-reintervention rates.

Comprehensive Analysis of Methyl-ß-D-ribofuranoside: A Multifaceted Spectroscopic and Theoretical Approach.

This study presents a comprehensive analysis of the vibrational spectra of methyl-ß-D-ribofuranoside. Employing a combination of inelastic neutron scattering, Raman, and infrared spectroscopy allows for the observation of all modes regardless of the selection rules. The experimental techniques were complemented by density functional theory computational methods using both gas-phase (Gaussian) and solid-state (CRYSTAL, CASTEP) approaches to provide an unambiguous assignment of the defining vibrational features. Two distinct structures of the molecule were identified in the unit cell, differentiated mainly by the orientation of the furanose ring O-H bonds. The low-energy region of the spectrum (<400 cm-1) is dominated by lattice vibrations and functional group rotation, while the midenergy region is dominated by out-of-plane bending motions of the furanose ring (400-900 cm-1) and by C-H bending in the methyl and methylene groups (1400-1600 cm-1). The high-energy region (>2800 cm-1) encompasses the C-H and O-H stretching modes and offers convincing evidence of at least one H-bonding interaction between the two structures of methyl-ß-D-ribofuranoside.

Correction: Structural and Functional Analysis of the Symmetrical Type I Restriction Endonuclease R.EcoR124INT.

[This corrects the article DOI: 10.1371/journal.pone.0035263.].

Lung Cancer Survival Trends in the Veterans Health Administration.

INTRODUCTION: Lung cancer survival is improving in the United States. We investigated whether there was a similar trend within the Veterans Health Administration (VHA), the largest integrated healthcare system in the United States. MATERIALS AND METHODS: Data from the Veterans Affairs Central Cancer Registry were analyzed for temporal survival trends using Kaplan-Meier estimates and linear regression. RESULTS: A total number of 54,922 Veterans were identified with lung cancer diagnosed from 2010 to 2017. Histologies were classified as non-small-cell lung cancer (NSCLC) (64.2%), small cell lung cancer (SCLC) (12.9%), and 'other' (22.9%). The proportion with stage I increased from 18.1% to 30.4%, while stage IV decreased from 38.9% to 34.6% (both P < .001). The 3-year overall survival (OS) improved for stage I (58.6% to 68.4%, P < .001), stage II (35.5% to 48.4%, P < .001), stage III (18.7% to 29.4%, P < .001), and stage IV (3.4% to 7.8%, P < .001). For NSCLC, the median OS increased from 12 to 21 months (P < .001), and the 3-year OS increased from 24.1% to 38.3% (P < .001). For SCLC, the median OS remained unchanged (8 to 9 months, P = .10), while the 3-year OS increased from 9.1% to 12.3% (P = .014). Compared to White Veterans, Black Veterans with NSCLC had similar OS (P = .81), and those with SCLC had higher OS (P = .003). CONCLUSION: Lung cancer survival is improving within the VHA. Compared to White Veterans, Black Veterans had similar or higher survival rates. The observed racial equity in outcomes within a geographically and socioeconomically diverse population warrants further investigation to better understand and replicate this achievement in other healthcare systems.

Riociguat in patients with sickle cell disease and hypertension or proteinuria (STERIO-SCD): a randomised, double-blind, placebo controlled, phase 1-2 trial.

BACKGROUND: Although nitric oxide based therapeutics have been shown in preclinical models to reduce vaso-occlusive events and improve cardiovascular function, a clinical trial of a phosphodiesterase 5 inhibitor increased rates of admission to hospital for pain. We aimed to examine if riociguat, a direct stimulator of the nitric oxide receptor soluble guanylate cyclase, causes similar increases in vaso-occlusive events. METHODS: This was a phase 1-2, randomised, double blind, placebo-controlled trial. Eligible patients were 18 years or older, had confirmed sickle cell disease documented by haemoglobin electrophoresis or HPLC fractionation (haemoglobin SS, SC, Sß-thalassemia, SD, or SO-Arab), and stage 1 hypertension or proteinuria. Participants were randomly assigned 1:1 to receive either riociguat or matching placebo via a web-based system to maintain allocation concealment. Both treatments were administered orally starting at 1·0 mg three times a day up to 2·5 mg three times a day (highest tolerated dose) for 12 weeks. Dose escalation by 0·5 mg was considered every 2 weeks if systolic blood pressure was greater than 95 mm Hg and the participant had no signs of hypotension; otherwise, the last dose was maintained. The primary outcome was the proportion of participants who had at least one adjudicated treatment-emergent serious adverse event. The analysis was performed by the intention-to-treat. This trial is registered with ClinicalTrials.gov (NCT02633397) and was completed. FINDINGS: Between April 11, 2017, and Dec 31, 2021, 165 participants were screened and consented to be enrolled into the study. Of these, 130 participants were randomly assigned to either riociguat (n=66) or placebo (n=64). The proportion of participants with at least one treatment-emergent serious adverse event was 22·7% (n=15) in the riociguat group and 31·3% (n=20) in the placebo group (difference -8·5% [90% CI -21·4 to 4·5]; p=0·19). A similar pattern emerged in other key safety outcomes, sickle cell related vaso-occlusive events (16·7 [n=11] vs 21·9% [n=14]; difference -5·2% [-17·2 to 6·5]; p=0·42), mean pain severity (3·18 vs 3·32; adjusted mean difference -0·14 [-0·70 to 0·42]; p=0·69), and pain interference (3·15 vs 3·12; 0·04 [-0·62 to 0·69]; p=0·93) at 12 weeks were similar between groups. Regarding the key clinical efficacy endpoints, participants taking riociguat had a blood pressure of -8·20 mm Hg (-10·48 to -5·91) compared with -1·24 (-3·58 to 1·10) in those taking placebo (-6·96 mm Hg (90% CI -10·22 to -3·69; p<0·001). INTERPRETATION: Riociguat was safe and had a significant haemodynamic effect on systemic blood pressure. The results of this study provide measures of effect and variability that will inform power calculations for future trials. FUNDING: Bayer Pharmaceuticals.

Allergic or Not: Final Interpretation of Doubtful Patch Test Reactions From the North American Contact Dermatitis Group, 2019-2020.

Background: Doubtful patch test reactions generally do not meet criterion for positivity in patch testing. However, the North American Contact Dermatitis Group (NACDG) allows for doubtful reactions to be coded with a final determination of "allergic/positive" based on the temporal pattern, appearance, known characteristics of the allergen, and/or other supportive patch test reactions. Objectives: To analyze NACDG data from the 2019-2020 patch test cycle to identify patterns in the interpretation and relevance of doubtful reactions. Methods: The frequency and proportions of doubtful reactions were tabulated and analyzed for patterns. Statistical analyses were limited to allergens with ≥30 doubtful reactions to ensure adequate sample size. Results: Of patch-tested patients, 31.9% (1315/4121) had ≥1 doubtful reaction. Of 2538 total doubtful reactions, 46% (n = 1167) had a final interpretation of "allergic/positive." The allergens with the highest proportion of doubtful reactions at the final visit were hydroperoxides of linalool 1% (4.5%), fragrance mix I 8.0% (3.9%), and cetrimonium chloride 0.5% (3.4%). Methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) 0.02% (P < 0.001), MI 0.2% (P < 0.001), nickel sulfate hexahydrate 2.5% (P = 0.001), and neomycin sulfate 20.0% (P = 0.003) doubtful reactions were more likely to be interpreted as allergic than nonallergic. Methyldibromoglutaronitrile/phenoxyethanol 0.2% (P < 0.001), oleamidopropyl dimethylamine 0.1% (P < 0.001), formaldehyde 2.0% (P < 0.001), cetrimonium chloride 0.5% (P < 0.001), benzophenone-4 (sulisobenzone) 10% (P < 0.001), iodopropynyl butylcarbamate 0.5% (P < 0.001), cocamidopropyl betaine 1.0% (P = 0.002), and benzisothiazolinone 0.1% (P = 0.012) doubtful reactions were less likely to be interpreted as allergic. Of the 1167 doubtful reactions interpreted as allergic, 84.9% had current relevance. Conclusions: Doubtful reactions were common and approximately one half were coded with a final interpretation of "allergic/positive." Of those, most were clinically relevant. MCI/MI, MI, nickel, and neomycin were more likely to be interpreted as allergic.

Use of Dulaglutide, Semaglutide, and Tirzepatide in Diabetes and Weight Management.

PURPOSE: Glucagon-like peptide 1 receptor agonists (GLP1-RA) are effective therapies in lowering glycosylated hemoglobin (HbA1c), providing cardioprotective benefits, and lowering weight. The use of GLP1-RA solely for weight-loss has become commonplace in many practices, which in turn has made it difficult in some areas for those with type 2 diabetes (T2DM) to obtain these much-needed medications. METHODS: Using recent published literature, along with clinical experience, it has become apparent that many GLP1-RAs have become difficult to obtain for patients with diabetes. FINDINGS: Many clinicians started to prescribe the brand Ozempic® (semaglutide*) and dulaglutide for weight loss despite neither of them being Food and Drug Administration (FDA) approved for this indication. Ozempic, having outperformed dulaglutide in in both HbA1c reduction and weight loss, along with FDA approval of semaglutide for weight loss, has quickly become widely used off-label for weight loss. This off-label use may have increased, despite the approval of semaglutide,† because many insurances will not cover semaglutide solely for weight management. Most recently, Eli Lilly was able to develop tirzepatide,‡ which was FDA approved in May of 2022, and they are seeking fast-track FDA approval for weight loss and are projected to gain this approval within 2023. IMPLICATIONS: Insurance coverage for weight management remains sparse, and obtaining these therapies for diabetes has now become more burdensome, with insurance companies requiring a prior authorization proving FDA-approved diagnosis of T2DM. Hopefully, should more GLP1-Ras receive approval for weight loss, along with an increase in insurance coverage, the burden on patients with diabetes will be lessened as they are able to quickly obtain this highly effective therapy.

Antiviral response and HIV-1 inhibition in sickle cell disease.

Sickle cell disease (SCD) is characterized by hemolysis, vaso-occlusion, and ischemia. HIV-1 infection was previously shown to be suppressed in SCD PBMCs. Here, we report that HIV-1 suppression is attributed to the increased expression of iron, hypoxia, and interferon-induced innate antiviral factors. Inhibition of upregulated antiviral genes, HMOX-1, CDKN1A, and CH25H, increased HIV-1 replication in SCD PBMCs, suggesting their critical role in HIV-1 suppression. Levels of IFN-ß were elevated in SCD patients. Sickle cell hemoglobin (HbS) treatment of THP-1-derived and primary monocyte-derived macrophages induced production of IFN-ß, upregulated antiviral gene expression, and suppressed HIV-1 infection. Infection with mouse-adapted EcoHIV was suppressed in the SCD mice that also exhibited elevated levels of antiviral restriction factors. Our findings suggest that hemolysis and release of HbS leads to the induction of IFN-ß production, induction of cellular antiviral state by the expression of iron and IFN-driven factors, and suppression of HIV-1 infection.

Retinoic acid signaling regulates spatiotemporal specification of human green and red cones.

Trichromacy is unique to primates among placental mammals, enabled by blue (short/S), green (medium/M), and red (long/L) cones. In humans, great apes, and Old World monkeys, cones make a poorly understood choice between M and L cone subtype fates. To determine mechanisms specifying M and L cones, we developed an approach to visualize expression of the highly similar M- and L-opsin mRNAs. M-opsin was observed before L-opsin expression during early human eye development, suggesting that M cones are generated before L cones. In adult human tissue, the early-developing central retina contained a mix of M and L cones compared to the late-developing peripheral region, which contained a high proportion of L cones. Retinoic acid (RA)-synthesizing enzymes are highly expressed early in retinal development. High RA signaling early was sufficient to promote M cone fate and suppress L cone fate in retinal organoids. Across a human population sample, natural variation in the ratios of M and L cone subtypes was associated with a noncoding polymorphism in the NR2F2 gene, a mediator of RA signaling. Our data suggest that RA promotes M cone fate early in development to generate the pattern of M and L cones across the human retina.

Real-world efficacy of single-agent belantamab mafodotin in relapsed systemic AL amyloidosis.

Systemic light chain (AL) amyloidosis is a relapsing plasma cell disorder. Therapy is limited, particularly for triple-class refractory disease. We report the use of belantamab mafodotin, a BCMA-directed drug-antibody conjugate, for relapsed AL amyloidosis, including patients traditionally excluded from clinical trials. Thirty-one patients were reviewed, with a median of three prior lines of therapy. The median follow-up was 12 months (95% CI 4-19), and a median of five doses were delivered. The best haematological overall response rate was 71%, and the complete/very good partial response was 58%. Sixty-eight percent had keratopathy and improved in all. Belantamab mafodotin has high efficacy and good tolerability in patients with relapsed AL amyloidosis.

Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes.

Knowledge of locations and activities of cis -regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our V al i dated S ystematic I ntegrati on (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state Regulatory Potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbored distinctive transcription factor binding motifs that were similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we showed that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.

Patch Testing With Nickel, Cobalt, and Chromium in Patients With Suspected Allergic Contact Dermatitis.

Background: Allergic contact dermatitis is frequently caused by metals, including multiple metals simultaneously. Objectives: To assess characteristics and associations of positive and clinically relevant patch test (PT) reactions with solitary and concurrent metal sensitization. Methods: A retrospective analysis of PT results for nickel, cobalt, and/or chromium from the North American Contact Dermatitis Group between 2001 and 2018 (n = 43,522). Results: 18.0% had a positive/allergic reaction to nickel sulfate hexahydrate, 7.3% to cobalt chloride hexahydrate, and 3.0% to potassium dichromate. 87.9% patients had a currently relevant reaction to 0, 9.4% to 1, and 2.7% to multiple metals tested. Patients with 1 versus no currently relevant reactions to metal were more likely to have a primary dermatitis site of trunk, feet, and ears; patients with currently relevant reactions to multiple metals had more dermatitis affecting the trunk and ears. Metal sources varied by co-reacting metal, especially for patients with cobalt and chromium allergy. Jewelry was the most commonly identified source of nickel and cobalt for both solitary and concurrent metal allergy. Conclusions: Sensitization to multiple metals occurred in 6% of patients. Allergen sources varied between patients with sensitivity to 1 metal versus those who had concurrent sensitivity to cobalt and/or chromium.

Quality and Readability of Spanish-Language Online Information for Aortic Aneurysm and Its Endovascular Treatment.

BACKGROUND: Aortic aneurysms represent a chronic degenerative disease with life-threatening implications. In order for patients to comprehend health related information, it must be written at a level that can be readily understood. STUDY DESIGN: In January 2023, we searched "aneurisma aorta" and "endoprótesis aorta" terms on Google, Yahoo and Microsoft/Bing. The 31th websites provided by each search engine were analyzed. Four readability measures were used to evaluate websites regarding aortic aneurysm and their endovascular treatment in Spanish language: Flesch Index, Flesch-Szigriszt Index, Fernández-Huerta Index and grading Inflesz scale. The quality on information was evaluated by the HONcode seal, the DISCERN instrument and the JAMA benchmark criteria. RESULTS: 180 websites containing the terms "aneurisma aorta" and "endoprótesis aorta" were analyzed. Among the websites retrieved, the mean Flesh index score (53.12 ± 6.09 and 47.48 ± 7.12, respectively; P = .019), the Flesch-Szigriszt index (56.39 ± 5.72 and 48.10 ± 8.33; P = .000), and the Fernández Huerta index (61.30 ± 5.59 and 53.19 ± 8.21; P = .000), corresponding to a "somewhat difficult" readability level. In addition, the Inflesz scale (2.62 ± .59 and 2.07 ± .61; P = .000) reported a "somewhat difficult" readability, higher for the websites regarding aortic aneurysm. The HONcode seal was only presented in websites regarding aortic aneurysm (16.7%), whereas none of the websites relating to aortic endoprostheses presented it (0%) (P = .000). Websites that presented the HONcode seal obtained higher DISCERN score (P = .000, 95% CI = 6.42-16.84) and JAMA score (P = .000, 95% CI = 3.44-11.32). CONCLUSION: Internet information on aortic aneurysms and aortic endoprostheses is too difficult to read for the general Spanish-speaking population and is lacking in quality.