High exposure of global tree diversity to human pressure.

Safeguarding Earth's tree diversity is a conservation priority due to the importance of trees for biodiversity and ecosystem functions and services such as carbon sequestration. Here, we improve the foundation for effective conservation of global tree diversity by analyzing a recently developed database of tree species covering 46,752 species. We quantify range protection and anthropogenic pressures for each species and develop conservation priorities across taxonomic, phylogenetic, and functional diversity dimensions. We also assess the effectiveness of several influential proposed conservation prioritization frameworks to protect the top 17% and top 50% of tree priority areas. We find that an average of 50.2% of a tree species' range occurs in 110-km grid cells without any protected areas (PAs), with 6,377 small-range tree species fully unprotected, and that 83% of tree species experience nonnegligible human pressure across their range on average. Protecting high-priority areas for the top 17% and 50% priority thresholds would increase the average protected proportion of each tree species' range to 65.5% and 82.6%, respectively, leaving many fewer species (2,151 and 2,010) completely unprotected. The priority areas identified for trees match well to the Global 200 Ecoregions framework, revealing that priority areas for trees would in large part also optimize protection for terrestrial biodiversity overall. Based on range estimates for >46,000 tree species, our findings show that a large proportion of tree species receive limited protection by current PAs and are under substantial human pressure. Improved protection of biodiversity overall would also strongly benefit global tree diversity.

Strategies to enhance the response of liver cancer to pharmacological treatments.

In contrast to other types of cancers, there is no available efficient pharmacological treatment to improve the outcomes of patients suffering from major primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma. This dismal situation is partly due to the existence in these tumors of many different and synergistic mechanisms of resistance, accounting for the lack of response of these patients, not only to classical chemotherapy but also to more modern pharmacological agents based on the inhibition of tyrosine kinase receptors (TKIs) and the stimulation of the immune response against the tumor using immune checkpoint inhibitors (ICIs). This review summarizes the efforts to develop strategies to overcome this severe limitation, including searching for novel drugs derived from synthetic, semisynthetic, or natural products with vectorial properties against therapeutic targets to increase drug uptake or reduce drug export from cancer cells. Besides, immunotherapy is a promising line of research that is already starting to be implemented in clinical practice. Although less successful than in other cancers, the foreseen future for this strategy in treating liver cancers is considerable. Similarly, the pharmacological inhibition of epigenetic targets is highly promising. Many novel "epidrugs," able to act on "writer," "reader," and "eraser" epigenetic players, are currently being evaluated in preclinical and clinical studies. Finally, gene therapy is a broad field of research in the fight against liver cancer chemoresistance, based on the impressive advances recently achieved in gene manipulation. In sum, although the present is still dismal, there is reason for hope in the non-too-distant future.

Synthesis, Characterization, and Potential Usefulness in Liver Function Assessment of Novel Bile Acid Derivatives with Near-Infrared Fluorescence (NIRBAD).

Conventional serum markers often fail to accurately detect cholestasis accompanying many liver diseases. Although elevation in serum bile acid (BA) levels sensitively reflects impaired hepatobiliary function, other factors altering BA pool size and enterohepatic circulation can affect these levels. To develop fluorescent probes for extracorporeal noninvasive hepatobiliary function assessment by real-time monitoring methods, 1,3-dipolar cycloaddition reactions were used to conjugate near-infrared (NIR) fluorochromes with azide-functionalized BA derivatives (BAD). The resulting compounds (NIRBADs) were chromatographically (FC and PTLC) purified (>95%) and characterized by fluorimetry, 1H NMR, and HRMS using ESI ionization coupled to quadrupole TOF mass analysis. Transport studies using CHO cells stably expressing the BA carrier NTCP were performed by flow cytometry. Extracorporeal fluorescence was detected in anesthetized rats by high-resolution imaging analysis. Three NIRBADs were synthesized by conjugating alkynocyanine 718 with cholic acid (CA) at the COOH group via an ester (NIRBAD-1) or amide (NIRBAD-3) spacer, or at the 3α-position by a triazole link (NIRBAD-2). NIRBADs were efficiently taken up by cells expressing NTCP, which was inhibited by taurocholic acid (TCA). Following i.v. administration of NIRBAD-3 to rats, liver uptake and consequent release of NIR fluorescence could be extracorporeally monitored. This transient organ-specific handling contrasted with the absence of release to the intestine of alkynocyanine 718 and the lack of hepatotropism observed with other probes, such as indocyanine green. NIRBAD-3 administration did not alter serum biomarkers of hepatic and renal toxicity. NIRBADs can serve as probes to evaluate hepatobiliary function by noninvasive extracorporeal methods.

Dynamic Configuration on a Chiral-at-Rhodium Catalyst Featuring a Flexible Tetradentate Ligand.

The unique dynamic configuration of an enantioselective chiral-at-metal catalyst based on Rh(III) and a non-chiral tetradentate ligand is described and resolved. At room temperature, the catalyst undergoes a dynamic configuration process leading to the formation of two interconvertible metal-stereoisomers, remarkably without racemization. Density functional theory (DFT) calculations indicate that this metal-isomerization proceeds via a concerted transition state, which features a trigonal bipyramidal geometry stabilized by the tetradentate ligand. Furthermore, the resolved enantiopure complex shows high catalytic enantioinduction in the Friedel-Crafts reaction, achieving enantiomeric ratios as high as 99 : 1.

RNA editing of microtubule-associated protein tau circular RNAs promotes their translation and tau tangle formation.

Aggregation of the microtubule-associated protein tau characterizes tauopathies, including Alzheimer's disease and frontotemporal lobar degeneration (FTLD-Tau). Gene expression regulation of tau is complex and incompletely understood. Here we report that the human tau gene (MAPT) generates two circular RNAs (circRNAs) through backsplicing of exon 12 to either exon 7 (12→7 circRNA) or exon 10 (12→10 circRNA). Both circRNAs lack stop codons. The 12→7 circRNA contains one start codon and is translated in a rolling circle, generating a protein consisting of multimers of the microtubule-binding repeats R1-R4. For the 12→10 circRNA, a start codon can be introduced by two FTLD-Tau mutations, generating a protein consisting of multimers of the microtubule-binding repeats R2-R4, suggesting that mutations causing FTLD may act in part through tau circRNAs. Adenosine to inosine RNA editing dramatically increases translation of circRNAs and, in the 12→10 circRNA, RNA editing generates a translational start codon by changing AUA to AUI. Circular tau proteins self-aggregate and promote aggregation of linear tau proteins. Our data indicate that adenosine to inosine RNA editing initiates translation of human circular tau RNAs, which may contribute to tauopathies.

Unpredictable tunneling in a retarded bistable potential.

We have studied the rich dynamics of a damped particle inside an external double-well potential under the influence of state-dependent time-delayed feedback. In certain regions of the parameter space, we observe multistability with the existence of two different attractors (limit cycle or strange attractor) with well separated mean Lyapunov energies forming a two-level system. Bifurcation analysis reveals that, as the effects of the time-delay feedback are enhanced, chaotic transitions emerge between the two wells of the double-well potential for the attractor corresponding to the fundamental energy level. By computing the residence time distributions and the scaling laws near the onset of chaotic transitions, we rationalize this apparent tunneling-like effect in terms of the crisis-induced intermittency phenomenon. Further, we investigate the first passage times in this regime and observe the appearance of a Cantor-like fractal set in the initial history space, a characteristic feature of hyperbolic chaotic scattering. The non-integer value of the uncertainty dimension indicates that the residence time inside each well is unpredictable. Finally, we demonstrate the robustness of this tunneling intermittency as a function of the memory parameter by calculating the largest Lyapunov exponent.

Minimally invasive ultrasound-assisted cutting thread tenotomy of the deep digital flexor tendon in horses: An ex vivo study.

OBJECTIVE: To evaluate the feasibility and limitations associated with a minimally invasive ultrasound-assisted cutting thread technique for tenotomy of the deep digital flexor tendon (DDFT) in horses. STUDY DESIGN: Ex vivo study. SAMPLE POPULATION: Twenty cadaveric forelimbs. METHODS: Forelimbs were placed on a jig to mimic a standing semiflexed position and the midmetacarpal region was prepared to perform tenotomy of the DDFT using a percutaneous technique with a cutting thread. For that purpose, the thread was placed percutaneously around the DDFT (first dorsally and then palmarly) with the aid of a curved 20 gauge spinal needle. Tendon palpation/manipulation and ultrasonographic assessment assisted thread placement. Procedure time and skin puncture size were recorded. Limbs were then dissected to evaluate the degree of DDFT transection and the presence of any iatrogenic lesions. RESULTS: The DDFT was completely transected in all cases. Minor lesions of the superficial digital flexor tendon were found in 11/20 limbs and considered clinically irrelevant. However, the neurovascular bundle was damaged in 6/20 limbs (four limbs had nerve damage and two limbs had a nerve and either a palmar artery or vein damaged). The skin puncture hole sizes ranged from undetectable to 5 mm long. The average duration of the procedure was 7 min and 38 s (range: 4 min 56 s to 10 min 19 s). CONCLUSION: A DDFT tenotomy can be performed reliably with a percutaneous cutting thread technique. However, refinement of the technique is required to minimize iatrogenic damage. CLINICAL SIGNIFICANCE: The reported technique allows a DDFT tenotomy to be performed in a minimally invasive manner and has the potential to be clinically applicable.

Laparoscopic cryptorchidectomy using a resorbable self-locking loop device in dorsally recumbent horses.

OBJECTIVE: To report the use and feasibility of a self-locking resorbable loop device for cryptorchidectomy. STUDY DESIGN: Clinical prospective study. POPULATION: Twenty horses. METHODS: Horses suspected to have an abdominal testicle/s after admission work-up were enrolled. Horses were anesthetized in dorsal recumbency and a standard laparoscopic technique was performed. The looped device was inserted into the abdomen, glided around the testis/cord and tightened. Then, the spermatic cord was transected prior testis removal. Surgical procedure details and remarks, perioperative complications and total surgical time were recorded. Short- (>3 weeks) and long-term (>6 months) follow-ups were obtained by telephone questionnaire. RESULTS: Median total surgical time was 67 min (range: 43-189 min) and significantly shortened after the first four horses. The loop device was easily glided around 13/20 abdominal testes and required more time and technical skills around larger testes (≥3 years). Excellent intraoperative hemostasis was achieved in 17 horses. Three horses demonstrated mild intraoperative bleeding that required retightening, device replacement or adding a second device, respectively. Three horses developed mild postoperative hemoabdomen identified ultrasonographically and were successfully managed medically. Follow-up revealed no significant complications related to the procedure. One horse was euthanized for colic 4 months after surgery and one died of hemolytic shock 17 months postoperatively. CONCLUSION: This device represents another method to perform equine cryptorchidectomy that requires minimal training and laparoscopic expertise but demands knowledge of the device and application to prevent complications. CLINICAL SIGNIFICANCE: Laparoscopic cryptorchidectomy using this device is an alternative technique for horses <3 years.

Leveraging transcriptomics to develop bronchopulmonary dysplasia endotypes: a concept paper.

IMPACT: Bronchopulmonary dysplasia has multiple definitions that are currently based on phenotypic characteristics. Using an unsupervised machine learning approach, we created BPD subclasses (e.g., endotypes) by clustering whole microarray data. T helper 17 cell differentiation was the most significant pathway differentiating the BPD endotypes. INTRODUCTION: Bronchopulmonary dysplasia (BPD) is the most common complication of extreme prematurity. Discovery of BPD endotypes in an unbiased format, derived from the peripheral blood transcriptome, may uncover patterns underpinning this complex lung disease. METHODS: An unsupervised agglomerative hierarchical clustering approach applied to genome-wide expression of profiling from 62 children at day of life five was used to identify BPD endotypes. To identify which genes were differentially expressed across the BPD endotypes, we formulated a linear model based on least-squares minimization with empirical Bayes statistics. RESULTS: Four BPD endotypes (A, B,C,D) were identified using 7,319 differentially expressed genes. Across BPD endotypes, 5,850 genes had a p value < 0.05 after multiple comparison testing. Endotype A consisted of neonates with a higher gestational age and birthweight. Endotypes B-D included neonates between 25 and 26 weeks and a birthweight range of 640 to 940 g. Endotype D appeared to have a protective role against BPD compared to Endotypes B and C (36% vs. 62% vs. 60%, respectively). The most significant pathway focused on T helper 17 cell differentiation. CONCLUSION: Bioinformatic analyses can help identify BPD endotypes that associate with clinical definitions of BPD.

Effects of human milk on body composition and growth in very low birthweight infants.

OBJECTIVE: To compare body composition and growth in very low birthweight infants according to their source of human milk: maternal expressed breast milk (MEBM) versus donor breast milk (DBM). We hypothesized that infants fed predominately MEBM would exhibit reduced body fat percentage compared to those fed predominately DBM. METHODS: Premature infants weighing ≤1500 g on an exclusive human milk diet were enrolled in a single-center study between 2017 and 2021. Demographic data and anthropometric measurements were collected. All infants underwent body composition analysis via dual energy x-ray absorptiometry at 36 weeks corrected post menstrual age. RESULTS: A total of 60 infants were enrolled and 48 were included in the primary analysis. No differences were detected in percent body fat (14 vs. 12%, p = 0.7) or fat-free mass (2050 vs. 2130 g, p = 0.7). Both groups displayed similar growth and anthropometric measurements. Caloric and macronutrient intake between groups was similar. CONCLUSION: In the cohort of patients studied, no differences were observed in percent body fat based on primary human milk type intake in the first 28 postnatal days. Further investigation is required in a larger population of exclusive human milk fed preterm infants to determine if body composition differences exist based on an infant's primary human milk source. IMPACT: Premature infants are at risk for altered body composition at term corrected age, specifically increased body fat percentage, which may have implications for the future. To our knowledge this is the first study exploring body composition outcomes based on an infant's primary human milk source. Infants fed exclusive human milk (e.g., donor vs. maternal) displayed similar percent body fat and growth outcomes.

Expanding the Molecular Alphabet of DNA-Based Data Storage Systems with Neural Network Nanopore Readout Processing.

DNA is a promising next-generation data storage medium, but challenges remain with synthesis costs and recording latency. Here, we describe a prototype of a DNA data storage system that uses an extended molecular alphabet combining natural and chemically modified nucleotides. Our results show that MspA nanopores can discriminate different combinations and ordered sequences of natural and chemically modified nucleotides in custom-designed oligomers. We further demonstrate single-molecule sequencing of the extended alphabet using a neural network architecture that classifies raw current signals generated by Oxford Nanopore sequencers with an average accuracy exceeding 60% (39× larger than random guessing). Molecular dynamics simulations show that the majority of modified nucleotides lead to only minor perturbations of the DNA double helix. Overall, the extended molecular alphabet may potentially offer a nearly 2-fold increase in storage density and potentially the same order of reduction in the recording latency, thereby enabling new implementations of molecular recorders.

First Draft Genome Assembly of Root-Lesion Nematode Pratylenchus scribneri Generated Using Long-Read Sequencing.

Root-lesion nematodes (genus Pratylenchus) belong to a diverse group of plant-parasitic nematodes (PPN) with a worldwide distribution. Despite being an economically important PPN group of more than 100 species, genome information related to Pratylenchus genus is scarcely available. Here, we report the draft genome assembly of Pratylenchus scribneri generated on the PacBio Sequel IIe System using the ultra-low DNA input HiFi sequencing workflow. The final assembly created using 500 nematodes consisted of 276 decontaminated contigs, with an average contig N50 of 1.72 Mb and an assembled draft genome size of 227.24 Mb consisting of 51,146 predicted protein sequences. The benchmarking universal single-copy ortholog (BUSCO) analysis with 3131 nematode BUSCO groups indicated that 65.4% of the BUSCOs were complete, whereas 24.0%, 41.4%, and 1.8% were single-copy, duplicated, and fragmented, respectively, and 32.8% were missing. The outputs from GenomeScope2 and Smudgeplots converged towards a diploid genome for P. scribneri. The data provided here will facilitate future studies on host plant-nematode interactions and crop protection at the molecular level.

Minimally invasive removal of obstructive ureteral stones by intracorporeal lithotripsy in horses: 3 patients.

Three client-owned horses diagnosed with obstructive ureteral stones were referred and treated in a minimally invasive manner by retrograde ureteroscopy in conjunction with electrohydraulic lithotripsy (EHL) or laser Holmium:YAG lithotripsy (HYL). For all 3 horses, additional tests revealed variable degrees of azotemia and ureteral obstruction. Ultrasound examination (2 horses) revealed a loss of cortico-medullary distinction consistent with a chronic nephropathy. Ultrasound-guided biopsy of the right kidney in 1 horse revealed moderate glomerulosclerosis and lymphoplasmacytic nephritis. A standing anesthesia with a coccygeal epidural was done for each horse. A perineal urethrotomy was performed in 2 horses before the urethrocystoscopy. One horse was treated with Holmium:YAG laser lithotripsy and 2 others were treated using a electrohydraulic lithotripsy probe. Each procedure was successful. The ureteroscopy was successfully performed and visualization was excellent. Fragmentation of stones seemed easier with the electrohydraulic lithotripsy probe. No complications, pain, or signs of discomfort after the procedure were noticed. All 3 horses were discharged from the hospital. Key clinical message: Obstructive ureteral stones in horses can be successfully treated in a minimally invasive manner by retrograde ureteroscopy accompanied by lithotripsy. This technique is safe, not painful and did not require general anesthesia. Electrohydraulic lithotripsy appeared superior for stone fragmentation.

Exérèse minimalement invasive de calculs urétéraux obstructifs par lithotritie intracorporelle chez le cheval : trois patients. Trois chevaux appartenant à des clients diagnostiqués avec des calculs urétéraux obstructifs ont été référés et traités de manière peu invasive par urétéroscopie rétrograde en conjonction avec une lithotripsie électrohydraulique (EHL) ou une lithotripsie au laser Holmium:YAG (HYL). Pour les trois chevaux, des tests supplémentaires ont révélé des degrés variables d'azotémie et d'obstruction urétérale. L'échographie (deux chevaux) a révélé une perte de distinction cortico-médullaire compatible avec une néphropathie chronique. La biopsie échoguidée du rein droit chez un cheval a révélé une glomérulosclérose modérée et une néphrite lymphoplasmocytaire. Une anesthésie debout avec une péridurale coccygienne était effectuée pour chaque cheval. Une urétrotomie périnéale a été réalisée chez deux chevaux avant l'urétrocystoscopie. Un cheval a été traité par lithotripsie au laser Holmium:YAG et deux autres ont été traités à l'aide d'une sonde de lithotripsie électrohydraulique. Chaque procédure a réussi. L'urétéroscopie a été réalisée avec succès et la visualisation était excellente. La fragmentation des calculs semblait plus facile avec la sonde de lithotripsie électrohydraulique. Aucune complication, douleur ou signe d'inconfort après la procédure n'a été remarqué. Les trois chevaux ont obtenu leur congé de l'hôpital.Message clinique clé :Les calculs urétéraux obstructifs chez les chevaux peuvent être traités avec succès de manière peu invasive par urétéroscopie rétrograde accompagnée de lithotripsie. Cette technique est sûre, non douloureuse et ne nécessite pas d'anesthésie générale. La lithotritie électrohydraulique est apparue supérieure pour la fragmentation des calculs.(Traduit par Dr Serge Messier).

Genomic regions associated with virulence in Setosphaeria turcica identified by linkage mapping in a biparental population.

Northern corn leaf blight (NCLB) and sorghum leaf blight (SLB) are significant diseases of maize and sorghum, respectively, caused by the filamentous fungus Setosphaeria turcica. Strains of S. turcica are typically host-specific and infect either maize or sorghum. Host specificity in this pathogen is attributed to a single locus for maize and a second distinct locus for sorghum. To identify the genetic basis of host specificity in S. turcica, we generated a biparental population of S. turcica by crossing strains specific to maize and sorghum, phenotyped the population for leaf blight on sorghum and maize, genotyped the population to create a linkage map of S. turcica, and located candidate virulence regions. A total of 190 ascospores from 35 pseudothecia were isolated from the cross of maize and sorghum-specific strains. Greenhouse phenotyping of the biparental population (n = 144) showed independent inheritance of virulence, as indicated by a 1:1:1:1 segregation for virulence to maize, sorghum, both maize and sorghum, and avirulence to both crops. The population and host-specific parent strains were genotyped using genome skim sequencing on an Illumina NovaSeq 6000 platform resulting in over 780 million reads. A total of 32,635 variants including single nucleotide polymorphisms and indels were scored. There was evidence for a large deletion in the sorghum-specific strain of S. turcica. A genetic map consisting of 17 linkage groups spanning 3,069 centimorgans was constructed. Virulence to sorghum and maize mapped on distinct linkage groups with a significant QTL detected for virulence to maize. Furthermore, a single locus each for the in vitro traits hyphal growth rate and conidiation were identified and mapped onto two other linkage groups. In vitro traits did not correlate with in planta virulence complexity, suggesting that virulence on both hosts does not incur a fitness cost. Hyphal growth rate and conidiation were negatively correlated, indicating differences in hyphal growth versus dispersal ability for this pathogen. Identification of genetic regions underlying virulence specificity and saprotrophic growth traits in S. turcica provides a better understanding of the S. turcica- Andropogoneae pathosystem.

Large-scale provocation studies identify maladaptive responses to ubiquitous aeroallergens as a correlate of severe allergic rhinoconjunctivitis and asthma.

BACKGROUND: Allergic asthma (AA) and allergic rhinoconjunctivitis (ARC) are common comorbid environmentally triggered diseases. We hypothesized that severe AA/ARC reflects a maladaptive or unrestrained response to ubiquitous aeroallergens. METHODS: We performed provocation studies wherein six separate cohorts of persons (total n = 217) with ARC, with or without AA, were challenged once or more with fixed concentrations of seasonal or perennial aeroallergens in an aeroallergen challenge chamber (ACC). RESULTS: Aeroallergen challenges elicited fully or partially restrained vs. unrestrained evoked symptom responsiveness, corresponding to the resilient and adaptive vs. maladaptive AA/ARC phenotypes, respectively. The maladaptive phenotype was evoked more commonly during challenge with a non-endemic versus endemic seasonal aeroallergen. In an AA cohort, symptom responses evoked after house dust mite (HDM) challenges vs. recorded in the natural environment were more accurate and precise predictors of asthma severity and control, lung function (FEV1), and mechanistic correlates of maladaptation. Correlates included elevated levels of peripheral blood CD4+ and CD8+ T-cells, eosinophils, and T-cell activation, as well as gene expression proxies for ineffectual epithelial injury/repair responses. Evoked symptom severity after HDM challenge appeared to be more closely related to levels of CD4+ and CD8+ T-cells than eosinophils, neutrophils, or HDM-specific IgE. CONCLUSIONS: Provocation studies support the concept that resilience, adaptation, and maladaptation to environmental disease triggers calibrate AA/ARC severity. Despite the ubiquity of aeroallergens, in response to these disease triggers in controlled settings (ie, ACC), most atopic persons manifest the resilient or adaptive phenotype. Thus, ARC/AA disease progression may reflect the failure to preserve the resilient or adaptive phenotype. The triangulation of CD8+ T-cell activation, airway epithelial injury/repair processes and maladaptation in mediating AA disease severity needs more investigation.

A systematic quality appraisal of clinical practice guidelines for Ménière's disease using the AGREE II instrument.

PURPOSE: To systematically appraise clinical practice guidelines for the diagnosis and treatment of Ménière's disease using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. MATERIALS AND METHODS: A systematic literature search was performed to identify guidelines pertaining to the diagnosis and treatment of Ménière's disease. Data were abstracted from guidelines that met inclusion criteria and appraised by four independent reviewers in the six domains of quality defined by the AGREE II. Domain scores reflecting quality in each domain were calculated. Intraclass correlation coefficients (ICC) were calculated across domains to qualify interrater reliability. RESULTS: Six guidelines were found to meet inclusion criteria after a systematic literature search. Of the six clinical practice guidelines appraised using the AGREE II, the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guideline received the highest average score, with a mean of 90.7% spanning six quality domains. The guideline with the lowest average score across all domains was the European Position Statement on diagnosis and treatment of Ménière's disease, receiving an average score across domains of 34.6%. Overall quality scores of clinical practice guidelines for Ménière's disease had a standard deviation of 21.3%. Two guidelines met the quality threshold of > 60% in at least five domains, qualifying as 'high': AAO-HNS and National Institute for Health and Care Excellence. Average ICC across all six domains was 0.87, suggesting near total agreement between reviewers. CONCLUSION: Ménière's disease remains a challenging entity to diagnose and treat; few existing clinical guidelines meet the standards of quality established by the AGREE II appraisal instrument.

Clinical Practice Guidelines for the Management of Patients With Cleft Lip and Palate: A Systematic Quality Appraisal Using the Appraisal of Guidelines for Research and Evaluation II Instrument.

ABSTRACT: Patients with cleft lip and/or palate require complex and longitudinal care by a multidisciplinary cleft team. Unfortunately, delivery of cleft care is often fragmented, and care practices can vary significantly. Multiple clinical practice guidelines (CPGs) have been proposed to provide a standardized framework for cleft care delivery. As CPGs have gained popularity, there has been increasing demand to maintain the quality of existing guidelines. A comprehensive search of EMBASE, MEDLINE via PubMed, Scopus, Cochrane and grey literature sources published from January 1, 1990 to December 31, 2020 was conducted to identify CPGs for the care of cleft patients. The Appraisal of Guidelines for Research and Evaluation, 2nd edition II tool was used to assess the quality of selected CPGs. Intraclass coefficients were calculated to assess agreement among appraisers. Eleven guidelines were identified for study inclusion. One guideline was classified as "high" quality by Appraisal of Guidelines for Research and Evaluation II criteria, and the remaining guidelines were classified as "average" or "low" quality. The "Clarity of Presentation" domain achieved the highest mean score (76.9% ± 11.7%) across CPGs, whereas the "Rigor of Development" domain scored the lowest (35.6% ±â€Š21.2%). Intraclass coefficients analysis reflected very good inter-rater reliability across all domains (0.853-0.987). These findings highlight significant variability in the quality of existing CPGs for the global management of patients with cleft lip and/or palate. The "Rigor of Development" domain reflects the greatest opportunity for improvement. Given these findings, future guidelines may prioritize incorporating a systematic review of existing evidence into recommendations.

Repetitive aeroallergen challenges elucidate maladaptive epithelial and inflammatory traits that underpin allergic airway diseases.

BACKGROUND: Signifying the 2-compartments/1-disease paradigm, allergic rhinoconjunctivitis (ARC) and asthma (AA) are prevalent, comorbid conditions triggered by environmental factors (eg, house dust mites [HDMs]). However, despite the ubiquity of triggers, progression to severe ARC/AA is infrequent, suggesting either resilience or adaptation. OBJECTIVE: We sought to determine whether ARC/AA severity relates to maladaptive responses to disease triggers. METHODS: Adults with HDM-associated ARC were challenged repetitively with HDMs in an aeroallergen challenge chamber. Mechanistic traits associated with disease severity were identified. RESULTS: HDM challenges evoked maladaptive (persistently higher ARC symptoms), adaptive (progressive symptom reduction), and resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Nasal airway traits, defined by low inflammation-effectual epithelial integrity, moderate inflammation-effectual epithelial integrity, and higher inflammation-ineffectual epithelial integrity, were hallmarks of the resilient, adaptive, and maladaptive evoked phenotypes, respectively. Highlighting a crosstalk mechanism, peripheral blood inflammatory tone calibrated these traits: ineffectual epithelial integrity associated with CD8+ T cells, whereas airway inflammation associated with both CD8+ T cells and eosinophils. Hallmark peripheral blood maladaptive traits were increased natural killer and CD8+ T cells, lower CD4+ mucosal-associated invariant T cells, and deficiencies along the TLR-IRF-IFN antiviral pathway. Maladaptive traits tracking HDM-associated ARC also contributed to AA risk and severity models. CONCLUSIONS: Repetitive challenges with HDMs revealed that maladaptation to disease triggers may underpin ARC/AA disease severity. A combinatorial therapeutic approach may involve reversal of loss-of-beneficial-function traits (ineffectual epithelial integrity, TLR-IRF-IFN deficiencies), mitigation of gain-of-adverse-function traits (inflammation), and blocking of a detrimental crosstalk between the peripheral blood and airway compartments.

Immunologic resilience and COVID-19 survival advantage.

BACKGROUND: The risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR). OBJECTIVE: We sought to examine whether deficits in IR that antedate or are induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection independently predict COVID-19 mortality. METHODS: IR levels were quantified with 2 novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n = 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n = 13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to COVID-19 outcomes. RESULTS: IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection was associated with underrepresentation of IHG-I (21%) versus overrepresentation (77%) of IHG-II or IHG-IV, especially in males versus females (P < .01). Presentation with IHG-I was associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non-COVID-19 cohorts, IR-preserving metrics were associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females. CONCLUSIONS: Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19.

Average conservative chaos in quantum dusty plasmas.

We consider a hydrodynamic model of a quantum dusty plasma. We prove mathematically that the resulting dust ion-acoustic plasma waves present the property of being conservative on average. Furthermore, we test this property numerically, confirming its validity. Using standard techniques from the study of dynamical systems, as, for example, the Lyapunov characteristic exponents, we investigate the chaotic dynamics of the plasma and show numerically its existence for a wide range of parameter values. Finally, we illustrate how chaotic dynamics organizes in the parameter space for fixed values of the initial conditions, as the Mach number and the quantum diffraction parameter are continuously varied.