Free Radicals in Little Cigar Mainstream Smoke and the Potential Influence of Flavoring Chemicals on Free Radical Production.

Implementation of the Tobacco Control Act in 2009 banned characterizing flavors in cigarettes (except menthol and tobacco), but substitution has occurred by the continued availability of alternative flavored products (i.e., flavored little cigars). Little is known about how flavorants in noncigarette tobacco products impact human health. Thus, we investigated the impact of flavorants on free radical production in the mainstream smoke of little cigars. Gas- and particulate-phase free radical yields in mainstream smoke generated from 12 commercial little cigar brands and research little cigars and cigarettes were measured via electron paramagnetic resonance spectroscopy using the International Organization of Standardization (ISO) smoking protocol. Flavorants were extracted from unsmoked little cigars and analyzed by gas chromatography-mass spectroscopy. Gas- and particulate-phase radical yields from little cigars ranged from 13.5 to 97.6 and 0.453-1.175 nmol/unit, respectively. Comparatively, research cigarettes yielded an average of 4.9 nmol gas-phase radicals/unit and 0.292 nmol particulate-phase radicals/unit. From the products, 66 flavorants were identified, with each brand containing 4-24 individual flavorants. The free radical content was strongly correlated with the number of flavorants present in each cigar (r = 0.74, p = 0.01), indicating that highly flavored little cigars may produce higher levels of toxic free radicals. The presence of the flavorant ethyl methylphenylglycidate (strawberry) was associated with >2-fold higher levels of GP radicals (p = 0.001). Our results show that free radical delivery from little cigars is greater than that from research cigarettes and provide empirical evidence for the harmfulness of flavored tobacco products. Additionally, it demonstrates that flavorants present in combustible tobacco products can influence the levels of free radicals produced. Therefore, future tobacco product standards should consider little cigars.

Characterisation of a microelectrochemical biosensor for real-time detection of brain extracellular d-serine.

A modified development protocol and concomitant characterisation of a first generation biosensor for the detection of brain extracellular d-serine is reported. Functional parameters important for neurochemical monitoring, including sensor sensitivity, O2 interference, selectivity, shelf-life and biocompatibility were examined. Construction and development involved the enzyme d-amino acid oxidase (DAAO), utilising a dip-coating immobilisation method employing a new extended drying approach. The resultant Pt-based polymer enzyme composite sensor achieved high sensitivity to d-serine (0.76 ± 0.04 nA mm-2. µM-1) and a low µM limit of detection (0.33 ± 0.02 µM). The in-vitro response time was within the solution stirring time, suggesting potential sub-second in-vivo response characteristics. Oxygen interference studies demonstrated a 1 % reduction in current at 50 µM O2 when compared to atmospheric O2 levels (200 µM), indicating that the sensor can be used for reliable neurochemical monitoring of d-serine, free from changes in current associated with physiological O2 fluctuations. Potential interference signals generated by the principal electroactive analytes present in the brain were minimised by using a permselective layer of poly(o-phenylenediamine), and although several d-amino acids are possible substrates for DAAO, their physiologically relevant signals were small relative to that for d-serine. Additionally, changing both temperature and pH over possible in vivo ranges (34-40 °C and 7.2-7.6 respectively) resulted in no significant effect on performance. Finally, the biosensor was implanted in the striatum of freely moving rats and used to monitor physiological changes in d-serine over a two-week period.

How hot is too hot? Metabolic responses to temperature across life stages of a small ectotherm.

To understand how global warming will impact biodiversity, we need to pay attention to those species with higher vulnerability. However, to assess vulnerability we also need to consider the thermoregulatory mechanisms, body size and thermal tolerance of species. Studies addressing thermal tolerance on small ectotherms have mostly focused on insects, while other arthropods such as arachnids remain understudied. Here, we quantified the physiological thermal sensitivity of the pseudoscorpion Dactylochelifer silvestris using a respirometry setup with a ramping temperature increase. Overall, we found that D. silvestris has a much lower metabolic rate than other organisms of similar size. As expected, metabolic rate increased with body size, with adults having larger metabolic rates, but the overall metabolic scaling exponent was low. Both the temperature at which metabolism peaked and the critical thermal maxima were high (above 44°C) and comparable to those of other arachnids. The activation energy, which characterizes the rising portion of the thermal sensitivity curve, was 0.66 eV, consistent with predictions for insects and other taxa in general. Heat tolerances and activation energy did not differ across life stages. We conclude that D. silvestris has low metabolic rates and a high thermal tolerance, which would likely influence how all stages and sexes of this species could endure climate change.

A Potential Role for MAGI-1 in the Bi-Directional Relationship Between Major Depressive Disorder and Cardiovascular Disease.

PURPOSE OF REVIEW: Major Depressive Disorder (MDD) is characterized by persistent symptoms such as fatigue, loss of interest in activities, feelings of sadness and worthlessness. MDD often coexist with cardiovascular disease (CVD), yet the precise link between these conditions remains unclear. This review explores factors underlying the development of MDD and CVD, including genetic, epigenetic, platelet activation, inflammation, hypothalamic-pituitary-adrenal (HPA) axis activation, endothelial cell (EC) dysfunction, and blood-brain barrier (BBB) disruption. RECENT FINDINGS: Single nucleotide polymorphisms (SNPs) in the membrane-associated guanylate kinase WW and PDZ domain-containing protein 1 (MAGI-1) are associated with neuroticism and psychiatric disorders including MDD. SNPs in MAGI-1 are also linked to chronic inflammatory disorders such as spontaneous glomerulosclerosis, celiac disease, ulcerative colitis, and Crohn's disease. Increased MAGI-1 expression has been observed in colonic epithelial samples from Crohn's disease and ulcerative colitis patients. MAGI-1 also plays a role in regulating EC activation and atherogenesis in mice and is essential for Influenza A virus (IAV) infection, endoplasmic reticulum stress-induced EC apoptosis, and thrombin-induced EC permeability. Despite being understudied in human disease; evidence suggests that MAGI-1 may play a role in linking CVD and MDD. Therefore, further investigation of MAG-1 could be warranted to elucidate its potential involvement in these conditions.

Does Aspirin Use Reduce the Risk for Ovarian Cancer?

Ovarian cancer is an aggressive malignancy and the leading cause of death among gynecologic cancers. Researchers have evaluated prophylactic medications that potentially avert the manifestation of ovarian cancer, but currently, there are no reliable screening measures for this disease. Nevertheless, the largest study involving aspirin use and ovarian cancer reported a substantive risk reduction from enduring aspirin use. Since there are countervailing data to impugn the potential benefits of aspirin use in staving off ovarian cancer, further research should scrutinize the use of this medication as a prophylactic intervention, especially in women who are at higher risk for developing the disease.

Benchmarking of a multi-biomarker low-volume panel for Alzheimer's Disease and related dementia research.

Alzheimer's Disease (AD) biomarker measurement is key to aid in the diagnosis and prognosis of the disease. In the research setting, participant recruitment and retention and optimization of sample use, is one of the main challenges that observational studies face. Thus, obtaining accurate established biomarker measurements for stratification and maximizing use of the precious samples is key. Accurate technologies are currently available for established biomarkers, mainly immunoassays and immunoprecipitation liquid chromatography-mass spectrometry (IP-MS), and some of them are already being used in clinical settings. Although some immunoassays- and IP-MS based platforms provide multiplexing for several different coding proteins there is not a current platform that can measure all the stablished and emerging biomarkers in one run. The NUcleic acid Linked Immuno-Sandwich Assay (NULISA™) is a mid-throughput platform with antibody-based measurements with a sequencing output that requires 15µL of sample volume to measure more than 100 analytes, including those typically assayed for AD. Here we benchmarked and compared the AD-relevant biomarkers including in the NULISA against validated assays, in both CSF and plasma. Overall, we have found that CSF measures of Aß42/40, NfL, GFAP, and p-tau217 are highly correlated and have similar predictive performance when measured by immunoassay, mass-spectrometry or NULISA. In plasma, p-tau217 shows a performance similar to that reported with other technologies when predicting amyloidosis. Other established and exploratory biomarkers (total tau, p-tau181, NRGN, YKL40, sTREM2, VILIP1 among other) show a wide range of correlation values depending on the fluid and the platform. Our results indicate that the multiplexed immunoassay platform produces reliable results for established biomarkers in CSF that are useful in research settings, with the advantage of measuring additional novel biomarkers using minimal sample volume.

Radiotherapy dose response in bulky relapsed/refractory large B-cell lymphoma.

PURPOSE: To assess whether a radiotherapy (RT) dose affects response in bulky tumors in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). METHODS: Data from r/r DLBCL patients treated with salvage- or palliative-intent RT (2008-2020) at a single institution were examined. Index lesion size ≥7.5 cm was defined as bulky. Equivalent doses in 2 Gray (Gy) fractions (EQD2) were calculated to compare doses between conventional and hypofractionated (HF, ≥2.5 Gy/fraction) schemes. Objective response rates (ORR) were compared using non-parametric Mann-Whitney U test or Kruskal-Wallis tests with Dunn's multiple comparison corrections. Freedom from local progression (FFLP) was assessed using Kaplan-Meier and Cox proportional hazard regression analyzes. RESULTS: 183 courses of 151 unique patients were included (salvage: 37%, palliative: 63%). Non-bulky and bulky tumors were irradiated in 109 (60%) and 74 (40%) courses, respectively. Median EQD2 was 33 Gy (IQR=23-39 Gy) with HF in 84 (46%) cases. Of those with post-RT imaging (80%), the ORR was 59% with a trend towards worsened ORR in bulky tumors (50% vs. 65%, p=0.077). For bulky tumors, RT regimens with EQD2s >30 Gy were associated with better ORR (≤30 Gy vs. >30 Gy: 27% vs. 64%, p=0.0073), whereas a lower EQD2 cut-off was sufficient for non-bulky tumors (≤20 Gy vs. >20 Gy: 38% vs. 75%, p=0.0011). On multivariable regression, bulky tumor size was associated with worsened FFLP (HR=2.07, 95% CI=1.16-3.68, p=0.014), while high EQD2s >30 Gy were associated with better FFLP (HR=0.48, 95% CI=0.25-0.93, p=0.031). Bulky tumors treated with EQD2s ≤30 Gy had the lowest median FFLP (4.0 months), while EQD2s >30 Gy had an unreached median FFLP (p=0.0047). CONCLUSIONS: Bulky r/r DLBCL tumors were associated with less favorable tumor control outcomes in the salvage and palliative settings. RT regimens with higher EQD2s (>30 Gy) should be considered if durable local control of bulky tumors is desired.

Three SARS-CoV-2 spike protein variants delivered intranasally by measles and mumps vaccines are broadly protective.

As the new SARS-CoV-2 Omicron variants and subvariants emerge, there is an urgency to develop intranasal, broadly protective vaccines. Here, we developed highly efficacious, intranasal trivalent SARS-CoV-2 vaccine candidates (TVC) based on three components of the MMR vaccine: measles virus (MeV), mumps virus (MuV) Jeryl Lynn (JL1) strain, and MuV JL2 strain. Specifically, MeV, MuV-JL1, and MuV-JL2 vaccine strains, each expressing prefusion spike (preS-6P) from a different variant of concern (VoC), were combined to generate TVCs. Intranasal immunization of IFNAR1-/- mice and female hamsters with TVCs generated high levels of S-specific serum IgG antibodies, broad neutralizing antibodies, and mucosal IgA antibodies as well as tissue-resident memory T cells in the lungs. The immunized female hamsters were protected from challenge with SARS-CoV-2 original WA1, B.1.617.2, and B.1.1.529 strains. The preexisting MeV and MuV immunity does not significantly interfere with the efficacy of TVC. Thus, the trivalent platform is a promising next-generation SARS-CoV-2 vaccine candidate.

Phenogrouping heart failure with preserved or mildly reduced ejection fraction using electronic health record data.

BACKGROUND: Heart failure (HF) with preserved or mildly reduced ejection fraction includes a heterogenous group of patients. Reclassification into distinct phenogroups to enable targeted interventions is a priority. This study aimed to identify distinct phenogroups, and compare phenogroup characteristics and outcomes, from electronic health record data. METHODS: 2,187 patients admitted to five UK hospitals with a diagnosis of HF and a left ventricular ejection fraction ≥ 40% were identified from the NIHR Health Informatics Collaborative database. Partition-based, model-based, and density-based machine learning clustering techniques were applied. Cox Proportional Hazards and Fine-Gray competing risks models were used to compare outcomes (all-cause mortality and hospitalisation for HF) across phenogroups. RESULTS: Three phenogroups were identified: (1) Younger, predominantly female patients with high prevalence of cardiometabolic and coronary disease; (2) More frail patients, with higher rates of lung disease and atrial fibrillation; (3) Patients characterised by systemic inflammation and high rates of diabetes and renal dysfunction. Survival profiles were distinct, with an increasing risk of all-cause mortality from phenogroups 1 to 3 (p < 0.001). Phenogroup membership significantly improved survival prediction compared to conventional factors. Phenogroups were not predictive of hospitalisation for HF. CONCLUSIONS: Applying unsupervised machine learning to routinely collected electronic health record data identified phenogroups with distinct clinical characteristics and unique survival profiles.

Stomal Stenosis After Continent Urinary Diversion in Bladder Exstrophy: Risk Factors and Management.

OBJECTIVE: To identify risk factors for stenosis and compare management strategies for stenosis etiology and to examine the efficacy of each approach. Patients with classic bladder exstrophy (CBE), a rare genitourinary malformation, may require construction of a continent urinary stoma (CUS) if incontinence persists. Stomal stenosis is a challenging complication as it is common, progressive and recurrent. METHODS: CBE patients who underwent CUS were retrospectively reviewed for risk factors for stenosis including stoma type, prior midline laparotomy number, and umbilicoplasty suture material. Stenosis etiology and management strategies were further reviewed. RESULTS: A total of 260 CBE patients underwent CUS creation. Stenosis developed in 65 patients (25.0%) at a median interval of 1.9 years. Etiology included scar contracture (n=41), keloid (n=17), and hypertrophic scar (n=7). Multifilament suture was the only variable associated with an increased risk of stenosis compared to monofilament suture (p=0.009). Almost all patients required surgical intervention. Most scar contractures underwent stomal incision with success in 100%. Hypertrophic scars and keloids responded best to excision with local tissue rearrangement (66.7%). At last follow-up, all patients achieved success. CONCLUSION: Stomal stenosis is common and challenging for the reconstructive surgeon. Strategies to prevent and effectively manage this are greatly desired. Use of multifilament suture for the umbilicoplasty increased stenosis perhaps from a greater inflammatory response and scarring, while monofilament suture may reduce its incidence. Stomal incision for treating scar contractures, and excision with local tissue rearrangement for hypertrophic scars and keloids may improve successful primary surgical intervention.

Climate change and environmental sustainability in otolaryngology: A state-of-the-art review.

BACKGROUND: Climate change has been identified by the World Health Organization (WHO) as the greatest existing threat to human health. Given the direct exposure of the upper aerodigestive system to pollutants, patients in otolaryngology are at high risk for increased disease burden in the setting of climate change and worsening air quality. Given this and the environmental impact of surgical care, it is essential for surgeons to understand their role in addressing climate health through quality-driven clinical initiatives, education, advocacy, and research. METHODS: A state-of-the-art review was performed of the existing literature on the otolaryngologic health impacts of climate change and environmental sustainability efforts in surgery with specific attention to studies in otolaryngology - head and neck surgery. FINDINGS: Climate variables including heat and air pollution are associated with increased incidence of allergic rhinitis, chronic rhinosinusitis and head and neck cancer. A number of studies have shown that sustainability initiatives in otolaryngology are safe and provide direct cost benefit. CONCLUSION: Surgeons have the opportunity to lead on climate health and sustainability to address the public health burden of climate change.

Harnessing myelin water fraction as an imaging biomarker of human cerebral aging, neurodegenerative diseases, and risk factors influencing myelination: A review.

Myelin water fraction (MWF) imaging has emerged as a promising magnetic resonance imaging (MRI) biomarker for investigating brain function and composition. This comprehensive review synthesizes the current state of knowledge on MWF as a biomarker of human cerebral aging, neurodegenerative diseases, and risk factors influencing myelination. The databases used include Web of Science, Scopus, Science Direct, and PubMed. We begin with a brief discussion of the theoretical foundations of MWF imaging, including its basis in MR physics and the mathematical modeling underlying its calculation, with an overview of the most adopted MRI methods of MWF imaging. Next, we delve into the clinical and research applications that have been explored to date, highlighting its advantages and limitations. Finally, we explore the potential of MWF to serve as a predictive biomarker for neurological disorders and identify future research directions for optimizing MWF imaging protocols and interpreting MWF in various contexts. By harnessing the power of MWF imaging, we may gain new insights into brain health and disease across the human lifespan, ultimately informing novel diagnostic and therapeutic strategies.

Unveiling the Antianemic Activity, Physicochemical Aspects, Antioxidant Properties, and Mineral Profile of Petroselinum crispum L.

Anemia is a widespread global health concern necessitating effective, accessible, and natural interventions. The potential of medicinal plants to address anemia has garnered significant interest. Among these plants, parsley (Petroselinum crispum (Petroselinum crispum) L.) stands out as an edible and herbal-based option for combating anemia. Aim of the study: This study investigated the potential of P. crispum (PC-Ext) as an emerging antianemic product, focusing on its physicochemical attributes, antioxidant properties, and mineral profile. Both qualitative and quantitative analyses of the phenolic compounds in P. crispum were conducted by using high-performance liquid chromatography with a diode array detector (HPLC-DAD). Anemia was induced in rats by intravenous injections of phenylhydrazine, administered at a dose of 40 mg/kg for two consecutive days. The antianemic activity of PC-Ext was assessed at a dose of 500 mg/kg twice daily for 5 weeks by estimating blood parameters, such as serum iron and ferritin. Additionally, the osmotic fragility test measured the capacity of red blood cells to withstand osmotic shock of various concentrations of saline. Aqueous extract of P. crispum was rich in phytochemical compounds, including syringic acid, quercetin, catechin, gallic acid, and luteolin. The findings demonstrate the effectiveness of P. crispum in ameliorating phenylhydrazine-induced reductions in red blood cell count (RBCs), hemoglobin (Hb), and hematocrit (HCT) levels. Consequently, PC-Ext exhibits significant activity against phenylhydrazine-induced anemia in rats, as demonstrated by its ability to prevent hemolysis. Iron estimation within PC-Ext further confirms its utility in addressing both iron deficiency and ferritin-deficiency anemia. Therefore, PC exhibits a favorable effect against both types of anemia, iron deficiency, and hemolysis. The results of this study provide robust scientific validation for ethnomedicinal use and the potential utility of P. crispum, positioning it as a promising source for future pharmaceutical development.

Long-distance communication can enable collective migration in a dynamic seascape.

Social information is predicted to enhance the quality of animals' migratory decisions in dynamic ecosystems, but the relative benefits of social information in the long-range movements of marine megafauna are unknown. In particular, whether and how migrants use nonlocal information gained through social communication at the large spatial scale of oceanic ecosystems remains unclear. Here we test hypotheses about the cues underlying timing of blue whales' breeding migration in the Northeast Pacific via individual-based models parameterized by empirical behavioral data. Comparing emergent patterns from individual-based models to individual and population-level empirical metrics of migration timing, we find that individual whales likely rely on both personal and social sources of information about forage availability in deciding when to depart from their vast and dynamic foraging habitat and initiate breeding migration. Empirical patterns of migratory phenology can only be reproduced by models in which individuals use long-distance social information about conspecifics' behavioral state, which is known to be encoded in the patterning of their widely propagating songs. Further, social communication improves pre-migration seasonal foraging performance by over 60% relative to asocial movement mechanisms. Our results suggest that long-range communication enhances the perceptual ranges of migrating whales beyond that of any individual, resulting in increased foraging performance and more collective migration timing. These findings indicate the value of nonlocal social information in an oceanic migrant and suggest the importance of long-distance acoustic communication in the collective migration of wide-ranging marine megafauna.

How Fellowship Training Affects Complication Rate After Shoulder Arthroplasty: A Nationwide Assessment.

BACKGROUND: Total shoulder arthroplasty is performed by orthopedic surgeons with various fellowship training backgrounds. Whether surgeons performing shoulder arthroplasty with different types of fellowship training have differing rates of complications and reoperation remains unknown. METHODS: The PearlDiver Mariner database was retrospectively queried from the years 2010-2022. Patients undergoing shoulder arthroplasty were selected using the CPT code 23472. Those undergoing revision arthroplasty and those with a history of fracture, infection, or malignancy were excluded. Fellowship was determined and verified via online search. Only surgeons who performed a minimum of 10 cases were selected; and PearlDiver was queried using their provider ID codes. Primary outcome measures included 90-day, 1-year, and 5-year rates of complication and reoperation. A Bonferroni correction was utilized in which the significance threshold was set at p≤0.00023 RESULTS: In total, 150,385 patients met the inclusion criteria and were included in the study. Analysis of surgical trends revealed that Sports Medicine and Shoulder and Elbow fellowship- trained surgeons are performing an increasing percentage of all shoulder arthroplasty over time, with each cohort exhibiting am 11.3% and 4.2% increase from 2010 to 2022, respectively. The geographic region with the highest proportion of cases performed by Sports Medicine surgeons was the West, while the Northeast has the highest proportion of cases performed by Shoulder and Elbow surgeons. Shoulder and Elbow surgeons operated on patients that were significantly younger and had fewer comorbidities. Both Shoulder and Elbow and Sports Medicine surgeons had lower rates of postoperative complications at 90 days, 1 year and 5 years in comparison to surgeons who completed another type of fellowship or no fellowship. Across each time point, the rates of individual complications between Sports Medicine and Shoulder and Elbow were comparable, but the pooled complication rate was lowest in the Shoulder and Elbow cohort. CONCLUSION: Surgeons who have completed either a Sports Medicine or Shoulder and Elbow fellowship are performing an increasing proportion of shoulder arthroplasty over time. Sports Medicine and Shoulder and Elbow-trained surgeons have significantly lower complication rates at 90 days, 1 year and 5 years postoperatively. The individual complication rates between Sports Medicine and Shoulder and Elbow are comparable, but Shoulder and Elbow has the lowest pooled complication rates overall.

Comparison of Patient Health Questionnaire-9, Edinburgh Postnatal Depression Scale and Hospital Anxiety and Depression - Depression subscale scores by administration mode: An individual participant data differential item functioning meta-analysis.

Administration mode of patient-reported outcome measures (PROMs) may influence responses. We assessed if Patient Health Questionnaire-9 (PHQ-9), Edinburgh Postnatal Depression Scale (EPDS) and Hospital Anxiety and Depression Scale - Depression subscale (HADS-D) item responses and scores were associated with administration mode. We compared (1) self-administration versus interview-administration; within self-administration (2) research or medical setting versus private; and (3) pen-and-paper versus electronic; and within interview-administration (4) in-person versus phone. We analysed individual participant data meta-analysis datasets with item-level data for the PHQ-9 (N = 34,529), EPDS (N = 16,813), and HADS-D (N = 16,768). We used multiple indicator multiple cause models to assess differential item functioning (DIF) by administration mode. We found statistically significant DIF for most items on all measures due to large samples, but influence on total scores was negligible. In 10 comparisons conducted across the PHQ-9, EPDS, and HADS-D, Pearson's correlations and intraclass correlation coefficients between latent depression symptom scores from models that did or did not account for DIF were between 0.995 and 1.000. Total PHQ-9, EPDS, and HADS-D scores did not differ materially across administration modes. Researcher and clinicians who evaluate depression symptoms with these questionnaires can select administration methods based on patient preferences, feasibility, or cost.

Pulmonary transit time is a predictor of outcomes in heart failure: a cardiovascular magnetic resonance first-pass perfusion study.

BACKGROUND: Pulmonary transit time (PTT) can be measured automatically from arterial input function (AIF) images of dual sequence first-pass perfusion imaging. PTT has been validated against invasive cardiac catheterisation correlating with both cardiac output and left ventricular filling pressure (both important prognostic markers in heart failure). We hypothesized that prolonged PTT is associated with clinical outcomes in patients with heart failure. METHODS: We recruited outpatients with a recent diagnosis of non-ischaemic heart failure with left ventricular ejection fraction (LVEF) < 50% on referral echocardiogram. Patients were followed up by a review of medical records for major adverse cardiovascular events (MACE) defined as all-cause mortality, heart failure hospitalization, ventricular arrhythmia, stroke or myocardial infarction. PTT was measured automatically from low-resolution AIF dynamic series of both the LV and RV during rest perfusion imaging, and the PTT was measured as the time (in seconds) between the centroid of the left (LV) and right ventricle (RV) indicator dilution curves. RESULTS: Patients (N = 294) were followed-up for median 2.0 years during which 37 patients (12.6%) had at least one MACE event. On univariate Cox regression analysis there was a significant association between PTT and MACE (Hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.08-1.25, P = 0.0001). There was also significant association between PTT and heart failure hospitalisation (HR 1.15, 95% CI 1.02-1.29, P = 0.02) and moderate correlation between PTT and N-terminal pro B-type natriuretic peptide (NT-proBNP, r = 0.51, P < 0.001). PTT remained predictive of MACE after adjustment for clinical and imaging factors but was no longer significant once adjusted for NT-proBNP. CONCLUSIONS: PTT measured automatically during CMR perfusion imaging in patients with recent onset non-ischaemic heart failure is predictive of MACE and in particular heart failure hospitalisation. PTT derived in this way may be a non-invasive marker of haemodynamic congestion in heart failure and future studies are required to establish if prolonged PTT identifies those who may warrant closer follow-up or medicine optimisation to reduce the risk of future adverse events.

Reduction in vertical transmission rate of bean common mosaic virus in bee-pollinated common bean plants.

Vertical transmission, the transfer of pathogens across generations, is a critical mechanism for the persistence of plant viruses. The transmission mechanisms are diverse, involving direct invasion through the suspensor and virus entry into developing gametes before achieving symplastic isolation. Despite the progress in understanding vertical virus transmission, the environmental factors influencing this process remain largely unexplored. We investigated the complex interplay between vertical transmission of plant viruses and pollination dynamics, focusing on common bean (Phaseolus vulgaris). The intricate relationship between plants and pollinators, especially bees, is essential for global ecosystems and crop productivity. We explored the impact of virus infection on seed transmission rates, with a particular emphasis on bean common mosaic virus (BCMV), bean common mosaic necrosis virus (BCMNV), and cucumber mosaic virus (CMV). Under controlled growth conditions, BCMNV exhibited the highest seed transmission rate, followed by BCMV and CMV. Notably, in the field, bee-pollinated BCMV-infected plants showed a reduced transmission rate compared to self-pollinated plants. This highlights the influence of pollinators on virus transmission dynamics. The findings demonstrate the virus-specific nature of seed transmission and underscore the importance of considering environmental factors, such as pollination, in understanding and managing plant virus spread.

Sustained release of inactivated H1N1 virus from degradable microparticles for extended vaccination.

Influenza vaccines administered as intramuscularly injected inactivated viruses or intranasally administered live-attenuated viruses usually provide short-term protection against influenza infections. Biodegradable particles that provide sustained release of the antigen has been studied as an approach to extend vaccine protection. Here, we investigate sustained release of ultraviolet killed influenza virus (A/PR/8/34) (kPR8) loaded into poly(D,L-lactic-co-glycolic acid) (PLGA) microparticles. Particles were prepared using the double emulsion method, and polymer molecular weight (MW), polymer hydrophobicity, polymer concentration in the organic phase, and the amount of killed virus were varied to obtain a range of particles. Formulations included PLGA 50:50 (2-6, 7-17 kDa), PLGA 75:25 (4-15 kDa), and 50/50 PLGA 75:25 (4-15 kDa)/PCL (14 kDa). Additionally, NaOH was co-encapsulated in some cases to enhance particle degradation. The structure of the particles was explored by size measurements and electron microscopy. The kPR8 release profiles were measured using hemagglutinin ELISA. The concentration of the polymer (PLGA) in the organic phase and polymer MW significantly influenced virus loading, while polymer MW and co-encapsulation of NaOH modulated the release profiles. Mice receiving a single intramuscular injection of NaOH microparticle-encapsulated kPR8 were partially protected against a lethal influenza challenge 32 weeks post immunization. Microparticle (MP) vaccination induced a gradual increase in PR8-specific IgGs dominated by IgG1 in contrast to the rapid IgG2a-biased response elicited by soluble kPR8 immunization. Our results indicate that vaccine-NaOH co-loaded PLGA particles show potential as a single dose vaccination strategy for extended protection against influenza virus infection.

Mechanism and spectrum of inhibition of a 4´-cyano modified nucleotide analog against diverse RNA polymerases of prototypic respiratory RNA viruses.

The development of safe and effective broad-spectrum antivirals that target the replication machinery of respiratory viruses is of high priority in pandemic preparedness programs. Here, we studied the mechanism of action of a newly discovered nucleotide analog against diverse RNA-dependent RNA polymerases (RdRp) of prototypic respiratory viruses. GS-646939 is the active 5'-triphosphate (TP) metabolite of a 4'-cyano modified C-adenosine analog phosphoramidate prodrug GS-7682. Enzyme kinetics show that the RdRps of human rhinovirus type 16 (HRV-16) and enterovirus 71 (EV-71) incorporate GS-646939 with unprecedented selectivity; GS-646939 is incorporated 20-50-fold more efficiently than its natural ATP counterpart. The RdRp complex of respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) incorporate GS-646939 and ATP with similar efficiency. In contrast, influenza B RdRp shows a clear preference for ATP and human mitochondrial RNA polymerase (h-mtRNAP) does not show significant incorporation of GS-646939. Once incorporated into the nascent RNA strand, GS-646939 acts as a chain-terminator although higher NTP concentrations can partially overcome inhibition for some polymerases. Modeling and biochemical data suggest that the 4'-modification inhibits RdRp translocation. Comparative studies with GS-443902, the active triphosphate form of the 1'-cyano modified prodrugs remdesivir and obeldesivir, reveal not only different mechanisms of inhibition, but also differences in the spectrum of inhibition of viral polymerases. In conclusion, 1'-cyano and 4'-cyano modifications of nucleotide analogs provide complementary strategies to target the polymerase of several families of respiratory RNA viruses.