2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease" provides recommendations to guide clinicians in the treatment of patients with lower extremity peripheral artery disease across its multiple clinical presentation subsets (ie, asymptomatic, chronic symptomatic, chronic limb-threatening ischemia, and acute limb ischemia). METHODS: A comprehensive literature search was conducted from October 2020 to June 2022, encompassing studies, reviews, and other evidence conducted on human subjects that was published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through May 2023 during the peer review process, were also considered by the writing committee and added to the evidence tables where appropriate. STRUCTURE: Recommendations from the "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with peripheral artery disease have been developed.

Scientism, trust, value alignment, views of nature, and U.S. public opinion about gene drive mosquitos.

Gene drive could be a powerful tool for addressing problems of conservation, agriculture, and human health caused by insect and animal pests but is likely to be controversial as it involves the release of genetically modified organisms. This study examined the social determinants of opinion of gene drive. We asked a representative sample of the U.S. public to respond to a description of a hypothetical application of a gene-drive mosquito to the problem of malaria and examined the relationship of these responses with demographic and ideological beliefs. We found strong general approval for the use of gene-drive mosquitos to address malaria, coinciding with the concern about a possible environmental impact of modified mosquitos and that gene drives represent "too much power over nature." Among the determinants we measured, respondent acceptance of scientism and trust that scientists are advancing the public's interest were the greatest predictors of views of gene drive.

The importance of species-specific and temperature-sensitive parameterisation of A/Ci models: A case study using cotton (Gossypium hirsutum L.) and the automated 'OptiFitACi' R-package.

Leaf gas exchange measurements are an important tool for inferring a plant's photosynthetic biochemistry. In most cases, the responses of photosynthetic CO2 assimilation to variable intercellular CO2 concentrations (A/Ci response curves) are used to model the maximum (potential) rate of carboxylation by ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco, Vcmax) and the rate of photosynthetic electron transport at a given incident photosynthetically active radiation flux density (PAR; JPAR). The standard Farquhar-von Caemmerer-Berry model is often used with default parameters of Rubisco kinetic values and mesophyll conductance to CO2 (gm) derived from tobacco that may be inapplicable across species. To study the significance of using such parameters for other species, here we measured the temperature responses of key in vitro Rubisco catalytic properties and gm in cotton (Gossypium hirsutum cv. Sicot 71) and derived Vcmax and J2000 (JPAR at 2000 µmol m-2 s-1 PAR) from cotton A/Ci curves incrementally measured at 15°C-40°C using cotton and other species-specific sets of input parameters with our new automated fitting R package 'OptiFitACi'. Notably, parameterisation by a set of tobacco parameters produced unrealistic J2000:Vcmax ratio of <1 at 25°C, two- to three-fold higher estimates of Vcmax above 15°C, up to 2.3-fold higher estimates of J2000 and more variable estimates of Vcmax and J2000, for our cotton data compared to model parameterisation with cotton-derived values. We determined that errors arise when using a gm,25 of 2.3 mol m-2 s-1 MPa-1 or less and Rubisco CO2-affinities in 21% O2 (KC 21%O2) at 25°C outside the range of 46-63 Pa to model A/Ci responses in cotton. We show how the A/Ci modelling capabilities of 'OptiFitACi' serves as a robust, user-friendly, and flexible extension of 'plantecophys' by providing simplified temperature-sensitivity and species-specificity parameterisation capabilities to reduce variability when modelling Vcmax and J2000.

Examining relationships between parent-reported factors and recurring ear symptoms among Aboriginal and Torres Strait Islander children.

ISSUE ADDRESSED: Aboriginal and Torres Strait Islander child ear health is complex and multiple. We examined relationships between parent-reported sociodemographic, child health, health service access factors and ear symptoms among Aboriginal and Torres Strait Islander children aged 3 to 7 years. METHODS: The Longitudinal Study of Indigenous Children is a large child cohort study with annual parent-reported data collection. Generalised linear mixed model analyses examined Wave 1 (1309 children 0-5 years; 2008) predictors of being free of parent-reported ear symptoms in both Waves 2 and 3. RESULTS: A total of 1030 (78.7%) had no reported ear symptoms in either Wave 2 or 3. In the fully adjusted model, children who had been hospitalised in the past year (aOR = 2.16; 95% CI 1.19-3.93) and those with no ear symptoms (aOR = 2.94; 95% CI, 1.59-5.46) at Wave 1 had higher odds of no ear symptoms in both the subsequent waves. There were also relationships between parent main source of income-government pension or allowance as well as parents who reported no history of their own ear symptoms and higher odds of no ear symptoms in Waves 2 and 3 after partial adjustment for sociodemographic factors. CONCLUSION: These findings suggest relationships between different sociodemographic and health factors and parent-reported ear symptoms among Aboriginal and Torres Strait Islander children that warrant further investigation. So what? Children with parent-reported ear symptoms during the early years need holistic support to prevent future ear symptoms that impact health, social and educational life trajectories.

Agrobacterial Transformation Enhancement by Improved Competent Cell Preparation and Optimized Electroporation.

The introduction of plasmids into Agrobacterium cells is one of the key steps in the Agrobacterium-mediated transformation of plants for gene editing applications. Depending on chromosomal background, some Agrobacterium strains exhibit a very low transformation efficiency, which results in a low number of colonies for subsequent screening and thus limits the potential for automated high-throughput transformation processes, especially with low copy or large plasmids. This study demonstrates improvements of transformation frequency by modifying the competent cell preparation process and optimizing electroporation parameters for two Agrobacterium strains. The competent cell preparation process was modified by prolonging bacterial growth in the log phase and optimizing the endpoint cell density for cell harvest which resulted in a significant cell yield increase and transformation frequency improvement. Optimization of electroporation by fine-tuning the parameters not only resulted in a 30-fold transformation frequency increase but also revealed a strain-dependent requirement for field strength and electric pulse length. To further improve transformation of a recalcitrant strain, different concentrations of dimethyl sulfoxide (DMSO) in recovery medium were examined. The study revealed an important role of DMSO in transformed cell recovery, with 5% DMSO resulting in the highest transformation frequency. The significant improvements in Agrobacterium transformation frequency addressed a critical bottleneck towards establishing a high throughput process.

Longitudinal association of conduct and emotional problems with school exclusion and truancy: A fixed effect analysis of the UK Millennium Cohort Study.

BACKGROUND: There is a need for causally stronger research on the association between child mental health and school exclusion and truancy. This study examines school exclusion and truancy in relation to both conduct and emotional problems and considers these problems both as predictors and as outcomes of school exclusion and truancy. METHOD: The sample included 15,236 individuals from the Millennium Cohort Study, a UK longitudinal birth cohort study. Conduct and emotional problems were assessed from childhood to adolescence (age 7, 11, 14 and 17 years), and reports of school exclusion and truancy were collected at age 11 and 14. Fixed effect analyses were used. RESULTS: Increases in conduct problems and emotional symptoms were associated with subsequent exclusion (OR 1.22, [95% CI 1.08-1.37] and OR 1.16, [1.05-1.29], respectively). Emotional symptoms, but not conduct problems, predicted truancy (OR 1.17, [1.07-1.29]). These estimates were similar for males and females. Exclusion was associated with an increase in conduct problems at age 14 (0.50, [0.30-0.69]), and for males, it was associated with an increase in emotional symptoms both at age 14 (0.39, [0.12-0.65]) and 17 (0.43, [0.14-0.72]). Truancy was associated with an increase in conduct problems at age 14 (0.41, [0.28-0.55]), and for females also at age 17 (0.22, [0.03-0.42]), and it was associated with increased emotional symptoms at age 14 (0.43, [0.25-0.62]) and 17 (0.44, [0.21-0.66]), which was similar for males and females. CONCLUSION: Results indicate a bidirectional association between emotional symptoms and school exclusion and truancy, as an increase in these symptoms was associated with later truancy and exclusion, and emotional symptoms increased following both school events. For conduct problems, the association was bidirectional for school exclusion, but unidirectional for truancy as these symptoms did not lead to truancy, but an increase in conduct problems was observed after both exclusion and truancy.

Covalent targeting of non-cysteine residues in PI4KIIIß.

The synthesis and characterisation of fluorosulfate covalent inhibitors of the lipid kinase PI4KIIIß is described. The conserved lysine residue located within the ATP binding site was targeted, and optimised compounds based upon reversible inhibitors with good activity and physicochemical profile showed strong reversible interactions and slow onset times for the covalent inhibition, resulting in an excellent selectivity profile for the lipid kinase target. X-Ray crystallography demonstrated a distal tyrosine residue could also be targeted using a fluorosulfate strategy. Combination of this knowledge showed that a dual covalent inhibitor could be developed which reveals potential in addressing the challenges associated with drug resistant mutations.

Challenges and Prospects in Developing Future SARS-CoV-2 Vaccines: Overcoming Original Antigenic Sin and Inducing Broadly Neutralizing Antibodies.

The impacts of the COVID-19 pandemic led to the development of several effective SARS-CoV-2 vaccines. However, waning vaccine efficacy as well as the antigenic drift of SARS-CoV-2 variants has diminished vaccine efficacy against SARS-CoV-2 infection and may threaten public health. Increasing interest has been given to the development of a next generation of SARS-CoV-2 vaccines with increased breadth and effectiveness against SARS-CoV-2 infection. In this Brief Review, we discuss recent work on the development of these next-generation vaccines and on the nature of the immune response to SARS-CoV-2. We examine recent work to develop pan-coronavirus vaccines as well as to develop mucosal vaccines. We further discuss challenges associated with the development of novel vaccines including the need to overcome "original antigenic sin" and highlight areas requiring further investigation. We place this work in the context of SARS-CoV-2 evolution to inform how the implementation of future vaccine platforms may impact human health.

A next-generation intranasal trivalent MMS vaccine induces durable and broad protection against SARS-CoV-2 variants of concern.

As SARS-CoV-2 variants of concern (VoCs) that evade immunity continue to emerge, next-generation adaptable COVID-19 vaccines which protect the respiratory tract and provide broader, more effective, and durable protection are urgently needed. Here, we have developed one such approach, a highly efficacious, intranasally delivered, trivalent measles-mumps-SARS-CoV-2 spike (S) protein (MMS) vaccine candidate that induces robust systemic and mucosal immunity with broad protection. This vaccine candidate is based on three components of the MMR vaccine, a measles virus Edmonston and the two mumps virus strains [Jeryl Lynn 1 (JL1) and JL2] that are known to provide safe, effective, and long-lasting protective immunity. The six proline-stabilized prefusion S protein (preS-6P) genes for ancestral SARS-CoV-2 WA1 and two important SARS-CoV-2 VoCs (Delta and Omicron BA.1) were each inserted into one of these three viruses which were then combined into a trivalent "MMS" candidate vaccine. Intranasal immunization of MMS in IFNAR1-/- mice induced a strong SARS-CoV-2-specific serum IgG response, cross-variant neutralizing antibodies, mucosal IgA, and systemic and tissue-resident T cells. Immunization of golden Syrian hamsters with MMS vaccine induced similarly high levels of antibodies that efficiently neutralized SARS-CoV-2 VoCs and provided broad and complete protection against challenge with any of these VoCs. This MMS vaccine is an efficacious, broadly protective next-generation COVID-19 vaccine candidate, which is readily adaptable to new variants, built on a platform with a 50-y safety record that also protects against measles and mumps.

Acute exposure to total and source-specific ambient fine particulate matter and risk of respiratory disease hospitalization in Kuwait.

Many epidemiologic studies concerned with acute exposure to ambient PM2.5 have reported positive associations for respiratory disease hospitalization. However, few studies have investigated this relationship in Kuwait and extrapolating results from other regions may involve considerable uncertainty due to variations in concentration levels, particle sources and composition, and population characteristics. Local studies can provide evidence for strategies to reduce risks from episodic exposures to high levels of ambient PM2.5 and generating hypotheses for evaluating health risks from chronic exposures. Therefore, using speciated PM2.5 data from local samplers, we analyzed the impact of daily total and source-specific PM2.5 exposure on respiratory hospitalizations in Kuwait using a case-crossover design with conditional quasi-Poisson regression. Total and source-specific ambient PM2.5 were modeled using 0-5-day cumulative distributed lags. For total PM2.5, we observed a 0.16% (95% confidence interval [CI] = 0.05, 0.27%) increase in risk for respiratory hospitalization per 1 µg/m3 increase in concentration. Of the source factors assessed, dust demonstrated a statistically significant increase in risk (0.16%, 95% CI = 0.04, 0.29%), and the central estimate for regional PM2.5 was positive (0.11%) but not statistically significant (95% CI = -0.11, 0.33%). No effect was observed from traffic emissions and 'other' source factors. When hospitalizations were stratified by sex, nationality, and age, we found that female, Kuwaiti national, and adult groups had higher effect estimates. These results suggest that exposure to ambient PM2.5 is harmful in Kuwait and provide some evidence of differential toxicity and effect modification depending on the PM2.5 source and population affected.

Short- and mid-term outcomes of abdominoperineal resection with perineal mesh insertion: a single-centre experience.

PURPOSE: Abdominoperineal resection (APR) remains a key procedure for the treatment of low rectal/anorectal cancers. However, perineal wound closure remains challenging, particularly in extralevator abdominoperineal resection (ELAPR) due to gapped tissue planes. Different approaches have been attempted to improve perineal wound repair. The aim of this study is to report our 6-year experience in perineal wound closure utilising biological mesh. METHODS: We conducted a retrospective study using data from our prospectively maintained database, including patients who underwent APR with perineal mesh closure between 2016 and 2021. RESULTS: 49  patients underwent APR with perineal mesh reconstruction for low rectal cancer during the 6-year period. Of these, 63% were males, with a mean age of 68 (± 11), and a mean BMI of 27.9 (± 13.7). 49% (24) of patients received neoadjuvant therapy. 88% (43) of patients underwent standard "S-APR" and only 12% (6) underwent ELAPR. Majority of procedures were laparoscopic (87.8%) with conversion rate of 6.9%. Mean length of stay was 11.7 (± 11.6). The perineal wound infection rate was 30% and only two patient required mesh removal due to entero-cutaneous perineal fistula and pelvic abscess. Perineal hernia was found in only two patients (4.1%). CRM was negative in 81.6% of the patients. Mean follow-up period was 29.2 (± 16.5) months, and disease recurrence occurred in 9 (18.3%) patients with average number of months for recurrence of 21 (± 7). Overall survival during the follow-up period was 91%. CONCLUSION: Our series shows a favourable short- and medium-term outcome with routine insertion of mesh for perineal wound closure.

Translational Bioethics and Public Input.

Translational science is justified as advancing the public's interests but has no mechanism for determining these interests. Standard social science approaches would produce either unrepresentative descriptions or a cacophony of data not easily condensed into a concrete conclusion about moving forward with a translational-science project. Here, I propose that the simplifying and structuring ethics employed by institutional review boards (IRBs) be used to create social science reports of the four to six most prominent values or principles of the public regarding a biotechnology. A board of bioethicists would weigh and balance these values to conclude whether the public supports a given translational-science innovation.

Rubisco deactivation and chloroplast electron transport rates co-limit photosynthesis above optimal leaf temperature in terrestrial plants.

Net photosynthetic CO2 assimilation rate (An) decreases at leaf temperatures above a relatively mild optimum (Topt) in most higher plants. This decline is often attributed to reduced CO2 conductance, increased CO2 loss from photorespiration and respiration, reduced chloroplast electron transport rate (J), or deactivation of Ribulose-1,5-bisphosphate Carboxylase Oxygenase (Rubisco). However, it is unclear which of these factors can best predict species independent declines in An at high temperature. We show that independent of species, and on a global scale, the observed decline in An with rising temperatures can be effectively accounted for by Rubisco deactivation and declines in J. Our finding that An declines with Rubisco deactivation and J supports a coordinated down-regulation of Rubisco and chloroplast electron transport rates to heat stress. We provide a model that, in the absence of CO2 supply limitations, can predict the response of photosynthesis to short-term increases in leaf temperature.

Neutralization escape of Omicron XBB, BR.2, and BA.2.3.20 subvariants.

New Omicron subvariants continue to emerge throughout the world. In particular, the XBB subvariant, which is a recombinant virus between BA.2.10.1.1 and BA.2.75.3.1.1.1, as well as the BA.2.3.20 and BR.2 subvariants that contain mutations distinct from BA.2 and BA.2.75, are currently increasing in proportion of variants sequenced. Here we show that antibodies induced by 3-dose mRNA booster vaccination as well as BA.1- and BA.4/5-wave infection effectively neutralize BA.2, BR.2, and BA.2.3.20 but have significantly reduced efficiency against XBB. In addition, the BA.2.3.20 subvariant exhibits enhanced infectivity in the lung-derived CaLu-3 cells and in 293T-ACE2 cells. Overall, our results demonstrate that the XBB subvariant is highly neutralization resistant, which highlights the need for continued monitoring of the immune escape and tissue tropism of emerging Omicron subvariants.

Enhanced evasion of neutralizing antibody response by Omicron XBB.1.5, CH.1.1, and CA.3.1 variants.

Omicron subvariants continuingly challenge current vaccination strategies. Here, we demonstrate nearly complete escape of the XBB.1.5, CH.1.1, and CA.3.1 variants from neutralizing antibodies stimulated by three doses of mRNA vaccine or by BA.4/5 wave infection, but neutralization is rescued by a BA.5-containing bivalent booster. CH.1.1 and CA.3.1 show strong immune escape from monoclonal antibody S309. Additionally, XBB.1.5, CH.1.1, and CA.3.1 spike proteins exhibit increased fusogenicity and enhanced processing compared with BA.2. Homology modeling reveals the key roles of G252V and F486P in the neutralization resistance of XBB.1.5, with F486P also enhancing receptor binding. Further, K444T/M and L452R in CH.1.1 and CA.3.1 likely drive escape from class II neutralizing antibodies, whereas R346T and G339H mutations could confer the strong neutralization resistance of these two subvariants to S309-like antibodies. Overall, our results support the need for administration of the bivalent mRNA vaccine and continued surveillance of Omicron subvariants.

Extensive Polymorphism in the Molecular Ferroelectric 18-Crown-6 Oxonium Tetrachloro-Gallium(III).

The materials property of ferroelectricity is intimately linked with symmetry-changing phase transitions. Characterizing such transitions is therefore essential for understanding molecular ferroelectrics. In this paper, we explore the temperature and thermal history dependence of polymorphic phase transitions in the multiaxial molecular ferroelectric 18-crown-6 oxonium tetrachloro-gallium(III). We have solved the structures of two previously suggested polymorphs (D and Y) ab initio from high-temperature powder diffraction data. We also report the structure of a new polymorph (X) using low-temperature powder diffraction data and identify a fifth (W) that can form on cooling. These polymorphs can be related using two distinct group-subgroup trees. Structure types A-C observed in this and related compounds can be derived from high-temperature polymorph D by group-subgroup relationships. The X and Y polymorphs can be described as child structures of a hypothetical polymorph Z using a molecular rotational distortion mode description. The ferroelectric properties of the various polymorphs can be rationalized based on our structural findings.