Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease.

Long non-coding RNA (lncRNA) genes have well-established and important impacts on molecular and cellular functions. However, among the thousands of lncRNA genes, it is still a major challenge to identify the subset with disease or trait relevance. To systematically characterize these lncRNA genes, we used Genotype Tissue Expression (GTEx) project v8 genetic and multi-tissue transcriptomic data to profile the expression, genetic regulation, cellular contexts, and trait associations of 14,100 lncRNA genes across 49 tissues for 101 distinct complex genetic traits. Using these approaches, we identified 1,432 lncRNA gene-trait associations, 800 of which were not explained by stronger effects of neighboring protein-coding genes. This included associations between lncRNA quantitative trait loci and inflammatory bowel disease, type 1 and type 2 diabetes, and coronary artery disease, as well as rare variant associations to body mass index.

CasPEDIA Database: a functional classification system for class 2 CRISPR-Cas enzymes.

CRISPR-Cas enzymes enable RNA-guided bacterial immunity and are widely used for biotechnological applications including genome editing. In particular, the Class 2 CRISPR-associated enzymes (Cas9, Cas12 and Cas13 families), have been deployed for numerous research, clinical and agricultural applications. However, the immense genetic and biochemical diversity of these proteins in the public domain poses a barrier for researchers seeking to leverage their activities. We present CasPEDIA (http://caspedia.org), the Cas Protein Effector Database of Information and Assessment, a curated encyclopedia that integrates enzymatic classification for hundreds of different Cas enzymes across 27 phylogenetic groups spanning the Cas9, Cas12 and Cas13 families, as well as evolutionarily related IscB and TnpB proteins. All enzymes in CasPEDIA were annotated with a standard workflow based on their primary nuclease activity, target requirements and guide-RNA design constraints. Our functional classification scheme, CasID, is described alongside current phylogenetic classification, allowing users to search related orthologs by enzymatic function and sequence similarity. CasPEDIA is a comprehensive data portal that summarizes and contextualizes enzymatic properties of widely used Cas enzymes, equipping users with valuable resources to foster biotechnological development. CasPEDIA complements phylogenetic Cas nomenclature and enables researchers to leverage the multi-faceted nucleic-acid targeting rules of diverse Class 2 Cas enzymes.

Evidence of a genetic background predisposing to complex regional pain syndrome type 1.

BACKGROUND: Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition. METHODS: Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n=34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n=50). Gene expression of peripheral blood macrophages was assessed. RESULTS: In the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher's p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls. CONCLUSION: A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1.

Development of a selection assay for small guide RNAs that drive efficient site-directed RNA editing.

A major challenge confronting the clinical application of site-directed RNA editing (SDRE) is the design of small guide RNAs (gRNAs) that can drive efficient editing. Although many gRNA designs have effectively recruited endogenous Adenosine Deaminases that Act on RNA (ADARs), most of them exceed the size of currently FDA-approved antisense oligos. We developed an unbiased in vitro selection assay to identify short gRNAs that promote superior RNA editing of a premature termination codon. The selection assay relies on hairpin substrates in which the target sequence is linked to partially randomized gRNAs in the same molecule, so that gRNA sequences that promote editing can be identified by sequencing. These RNA substrates were incubated in vitro with ADAR2 and the edited products were selected using amplification refractory mutation system PCR and used to regenerate the substrates for a new round of selection. After nine repetitions, hairpins which drove superior editing were identified. When gRNAs of these hairpins were delivered in trans, eight of the top ten short gRNAs drove superior editing both in vitro and in cellula. These results show that efficient small gRNAs can be selected using our approach, an important advancement for the clinical application of SDRE.

A catalog of GWAS fine-mapping efforts in autoimmune disease.

Genome-wide association studies (GWASs) have enabled unbiased identification of genetic loci contributing to common complex diseases. Because GWAS loci often harbor many variants and genes, it remains a major challenge to move from GWASs' statistical associations to the identification of causal variants and genes that underlie these association signals. Researchers have applied many statistical and functional fine-mapping strategies to prioritize genetic variants and genes as potential candidates. There is no gold standard in fine-mapping approaches, but consistent results across different approaches can improve confidence in the fine-mapping findings. Here, we combined text mining with a systematic review and formed a catalog of 85 studies with evidence of fine mapping for at least one autoimmune GWAS locus. Across all fine-mapping studies, we compiled 230 GWAS loci with allelic heterogeneity estimates and predictions of causal variants and trait-relevant genes. These 230 loci included 455 combinations of locus-by-disease association signals with 15 autoimmune diseases. Using these estimates, we assessed the probability of mediating disease risk associations across genes in GWAS loci and identified robust signals of causal disease biology. We predict that this comprehensive catalog of GWAS fine-mapping efforts in autoimmune disease will greatly help distill the plethora of information in the field and inform therapeutic strategies.

U.S. Preparedness and Response to Increasing Clade I Mpox Cases in the Democratic Republic of the Congo - United States, 2024.

Clade I monkeypox virus (MPXV), which can cause severe illness in more people than clade II MPXVs, is endemic in the Democratic Republic of the Congo (DRC), but the country has experienced an increase in suspected cases during 2023-2024. In light of the 2022 global outbreak of clade II mpox, the increase in suspected clade I cases in DRC raises concerns that the virus could spread to other countries and underscores the importance of coordinated, urgent global action to support DRC's efforts to contain the virus. To date, no cases of clade I mpox have been detected outside of countries in Central Africa where the virus is endemic. CDC and other partners are working to support DRC's response. In addition, CDC is enhancing U.S. preparedness by raising awareness, strengthening surveillance, expanding diagnostic testing capacity for clade I MPXV, ensuring appropriate specimen handling and waste management, emphasizing the importance of appropriate medical treatment, and communicating guidance on the recommended contact tracing, containment, behavior modification, and vaccination strategies.

A data-driven approach to multiple-stressor impact assessment for a marine protected area.

The coastal environment is not managed in a way that considers the impact of cumulative threats, despite being subject to threats from all realms (marine, land, and atmosphere). Relationships between threats and species are often nonlinear; thus, current (linear) approaches to estimating the impact of threats may be misleading. We developed a data-driven approach to assessing cumulative impacts on ecosystems and applied it to explore nonlinear relationships between threats and a temperate reef fish community. We used data on water quality, commercial fishing, climate change, and indicators of recreational fishing and urbanization to build a cumulative threat map of the northern region in New South Wales, Australia. We used statistical models of fish abundance to quantify associations among threats and biophysical covariates and predicted where cumulative impacts are likely to have the greatest impact on fish. We also assessed the performance of no-take zones (NTZs), to protect fish from cumulative threats across 2 marine protected area networks (marine parks). Fishing had a greater impact on fish than water quality threats (i.e., percent increase above the mean for invertivores was 337% when fishing was removed and was 11% above the mean when water quality was removed inside NTZs), and fishing outside NTZs affected fish abundances inside NTZs. Quantifying the spatial influence of multiple threats enables managers to understand the multitude of management actions required to address threats.

Una estrategia basada en datos para la evaluación de impacto de múltiples estresores en un área marina protegida Resumen Los ambientes costeros no se manejan de manera que se considere el impacto de las amenazas acumulativas, a pesar de que se enfrentan a amenazas de todos los entornos (marinas, terrestres y atmosféricas). Las relaciones entre las amenazas y las especies casi siempre son no lineales; por lo tanto, las estrategias actuales (lineales) para estimar el impacto de las amenazas pueden ser engañosas. Desarrollamos una estrategia basada en datos para evaluar el impacto acumulativo sobre los ecosistemas y la aplicamos para explorar las relaciones no lineales entre las amenazas y la comunidad de peces de arrecifes templados. Usamos datos de la calidad del agua, pesca comercial, cambio climático e indicadores de pesca recreativa y urbanización para construir un mapa acumulativo de amenazas de la región norte de Nueva Gales del Sur, Australia. Usamos modelos estadísticos de la abundancia de peces para cuantificar las asociaciones entre las amenazas y las covarianzas biofísicas y pronosticamos en dónde es probable que los impactos acumulativos sean mayores sobre los peces. También evaluamos el desempeño de las zonas de veda para así proteger a los peces de las amenazas acumulativas en dos redes de áreas marinas protegidas (parques marinos). La pesca tuvo un mayor impacto que la calidad del agua sobre los peces (es decir, el incremento del porcentaje por encima de la media de depredadores de invertebrados fue de 337% cuando se eliminó la pesca y fue de 11% por encima de la media cuando se eliminó la calidad del agua dentro de las zonas de veda) y la pesca fuera de las zonas de veda afectó la abundancia de los peces dentro de ellas. La cuantificación de la influencia espacial de las múltiples amenazas permite que los gestores entiendan la multitud de acciones de manejo que se requieren para abordar las amenazas.

Integrating socioeconomic and ecological data into restoration practice.

Driven by the United Nations Decade on Restoration and international funding initiatives, such as the Mangrove Breakthrough, investment in mangrove restoration is expected to increase. Yet, mangrove restoration efforts frequently fail, usually because of ad hoc site-selection processes that do not consider mangrove ecology and the socioeconomic context. Using decision analysis, we developed an approach that accounts for socioeconomic and ecological data to identify sites with the highest likelihood of mangrove restoration success. We applied our approach in the Biosphere Reserve Marismas Nacionales Nayarit, Mexico, an area that recently received funding for implementing mangrove restoration actions. We identified 468 potential restoration sites, assessed their restorability potential based on socioeconomic and ecological metrics, and ranked sites for implementation with spatial optimization. The metrics we used included favorable conditions for propagules to establish and survive under sea-level rise, provision of ecosystem services, and community dynamics. Sites that were selected based on socioeconomic or ecological metrics alone had lower likelihood of mangrove restoration success than sites that were selected based on integrated socioeconomic and ecological metrics. For example, selecting sites based on only socioeconomic metrics captured 16% of the maximum attainable value of functioning mangroves able to provide propagules to potential restoration sites, whereas selecting sites based on ecological and socioeconomic metrics captured 46% of functioning mangroves. Our approach was developed as part of a collaboration between nongovernmental organizations, local government, and academics under rapid delivery time lines given preexisting mangrove restoration implementation commitments. The systematic decision process we used integrated socioeconomic and ecological considerations even under short delivery deadlines, and our approach can be adapted to help mangrove restoration site-selection decisions elsewhere.

Integración de datos socioeconómicos y ecológicos en las prácticas de restauración Resumen Se espera que la inversión en la restauración de los manglares incremente debido a la Década de Restauración de las Naciones Unidad y las iniciativas internacionales de financiamiento, como The Mangrove Breakthrough. Sin embargo, los esfuerzos de restauración de manglares fallan con frecuencia, generalmente por los procesos de selección de sitios ad­hoc que no consideran la ecología del manglar y el contexto socioeconómico. Usamos el análisis de decisiones para desarrollar una estrategia que considera los datos socioeconómicos y ecológicos para identificar los sitios con mayor probabilidad de éxito de restauración. Aplicamos nuestra estrategia en la Reserva de la Biósfera Marismas Nacionales Nayarit, México, un área que recibió financiamiento reciente para la restauración del manglar. Identificamos 468 sitios potencialmente restaurables, evaluamos su potencial de restauración con base en medidas ecológicas y socioeconómicas y clasificamos los sitios para la implementación con la optimización espacial. Las medidas que usamos incluían las condiciones favorables para que los propágulos se establezcan y sobrevivan con el incremento en el nivel del mar, el suministro de servicios ambientales y las dinámicas de la comunidad. Los sitios seleccionados sólo con base en las medidas ecológicas o socioeconómicas tuvieron una menor probabilidad de éxito de restauración que los sitios que se seleccionaron con base en medidas socioeconómicas y ecológicas integradas. Por ejemplo, la selección de sitios con base sólo en las medidas socioeconómicas capturó el 16% del máximo valor alcanzable de manglares funcionales capaces de proporcionar propágulos a los sitios potenciales de restauración, mientras que la selección basada en medidas ecológicas y socioeconómicas capturó el 46% de los manglares funcionales. Desarrollamos nuestra estrategia como parte de una colaboración entre organizaciones no gubernamentales, el gobierno local y académicos sujetos a una fecha pronta de entrega debido a los compromisos preexistentes para la restauración de manglares. El proceso de decisión sistemática que usamos integró las consideraciones ecológicas y socioeconómicas incluso con plazos cortos de entrega. Nuestra estrategia puede adaptarse para apoyar en la selección de sitios de restauración de manglares en otros sitios.

Determination of sensed and paced atrial-ventricular delay in cardiac resynchronization therapy.

BACKGROUND: Optimization of atrial-ventricular delay (AVD) during atrial sensing (SAVD) and pacing (PAVD) provides the most effective cardiac resynchronization therapy (CRT). We demonstrate a novel electrocardiographic methodology for quantifying electrical synchrony and optimizing SAVD/PAVD. METHODS: We studied 40 CRT patients with LV activation delay. Atrial-sensed to RV-sensed (As-RVs) and atrial-paced to RV-sensed (Ap-RVs) intervals were measured from intracardiac electrograms (IEGM). LV-only pacing was performed over a range of SAVD/PAVD settings. Electrical dyssynchrony (cardiac resynchronization index; CRI) was measured at each setting using a multilead ECG system placed over the anterior and posterior torso. Biventricular pacing, which included multiple interventricular delays, was also conducted in a subset of 10 patients. RESULTS: When paced LV-only, peak CRI was similar (93 ± 5% vs. 92 ± 5%) during atrial sensing or pacing but optimal PAVD was 61 ± 31 ms greater than optimal SAVD. The difference between As-RVs and Ap-RVs intervals on IEGMs (62 ± 31 ms) was nearly identical. The slope of the correlation line (0.98) and the correlation coefficient r (0.99) comparing the 2 methods of assessing SAVD-PAVD offset were nearly 1 and the y-intercept (0.63 ms) was near 0. During simultaneous biventricular (BiV) pacing at short AVD, SAVD and PAVD programming did not affect CRI, but CRI was significantly (p < .05) lower during atrial sensing at long AVD. CONCLUSIONS: A novel methodology for measuring electrical dyssynchrony was used to determine electrically optimal SAVD/PAVD during LV-only pacing. When BiV pacing, shorter AVDs produce better electrical synchrony.

Ecosystem restructuring along the Great Barrier Reef following mass coral bleaching.

Global warming is markedly changing diverse coral reef ecosystems through an increasing frequency and magnitude of mass bleaching events1-3. How local impacts scale up across affected regions depends on numerous factors, including patchiness in coral mortality, metabolic effects of extreme temperatures on populations of reef-dwelling species4 and interactions between taxa. Here we use data from before and after the 2016 mass bleaching event to evaluate ecological changes in corals, algae, fishes and mobile invertebrates at 186 sites along the full latitudinal span of the Great Barrier Reef and western Coral Sea. One year after the bleaching event, reductions in live coral cover of up to 51% were observed on surveyed reefs that experienced extreme temperatures; however, regional patterns of coral mortality were patchy. Consistent declines in coral-feeding fishes were evident at the most heavily affected reefs, whereas few other short-term responses of reef fishes and invertebrates could be attributed directly to changes in coral cover. Nevertheless, substantial region-wide ecological changes occurred that were mostly independent of coral loss, and instead appeared to be linked directly to sea temperatures. Community-wide trophic restructuring was evident, with weakening of strong pre-existing latitudinal gradients in the diversity of fishes, invertebrates and their functional groups. In particular, fishes that scrape algae from reef surfaces, which are considered to be important for recovery after bleaching2, declined on northern reefs, whereas other herbivorous groups increased on southern reefs. The full impact of the 2016 bleaching event may not be realized until dead corals erode during the next decade5,6. However, our short-term observations suggest that the recovery processes, and the ultimate scale of impact, are affected by functional changes in communities, which in turn depend on the thermal affinities of local reef-associated fauna. Such changes will vary geographically, and may be particularly acute at locations where many fishes and invertebrates are close to their thermal distribution limits7.

Sarcopenia versus clinical frailty scale in predicting the risk of postoperative mortality after emergency laparotomy: a retrospective cohort study.

OBJECTIVES: To compare predictive significance of sarcopenia and clinical frailty scale (CFS) in terms of postoperative mortality in patients undergoing emergency laparotomy METHODS: In compliance with STROCSS statement standards, a retrospective cohort study with prospective data collection approach was conducted. The study period was between January 2017 and January 2022. All adult patients with non-traumatic acute abdominal pathology who underwent emergency laparotomy in our centre were included. The primary outcome was 30-day mortality and secondary outcomes were in-hospital mortality and 90-day mortality. The predictive value of sarcopenia and CFS were compared using the receiver operating characteristic (ROC) curve analysis and multivariable binary logistic regression analysis. RESULTS: A total of 1043 eligible patients were included. The risk of 30-day mortality, in-hospital mortality, and 90-day mortality were 8%, 10%, and 11%, respectively. ROC curve analysis suggested that sarcopenia is a significantly stronger predictor of 30-day mortality (AUC: 0.87 vs. 0.70, P<0.0001), in-hospital mortality (AUC: 0.79 vs. 0.67, P=0.0011), and 90-day mortality (AUC: 0.79 vs. 0.67, P=0.0009) compared with CFS. Moreover, multivariable binary logistic regression analysis identified sarcopenia as an independent predictor of mortality [coefficient: 4.333, OR: 76.16 (95% CI 37.06-156.52), P<0.0001] but not the CFS [coefficient: 0.096, OR: 1.10 (95% CI 0.88-1.38), P=0.4047]. CONCLUSIONS: Sarcopenia is a stronger predictor of postoperative mortality compared with CFS in patients undergoing emergency laparotomy. It cancels out the predictive value of clinical frailty scale in multivariable analyses; hence among the two variables, sarcopenia deserves to be included in preoperative predictive tools.

The Gut Microbiome Modulates Body Temperature Both in Sepsis and Health.

Rationale: Among patients with sepsis, variation in temperature trajectories predicts clinical outcomes. In healthy individuals, normal body temperature is variable and has decreased consistently since the 1860s. The biologic underpinnings of this temperature variation in disease and health are unknown. Objectives: To establish and interrogate the role of the gut microbiome in calibrating body temperature. Methods: We performed a series of translational analyses and experiments to determine whether and how variation in gut microbiota explains variation in body temperature in sepsis and in health. We studied patient temperature trajectories using electronic medical record data. We characterized gut microbiota in hospitalized patients using 16S ribosomal RNA gene sequencing. We modeled sepsis using intraperitoneal LPS in mice and modulated the microbiome using antibiotics, germ-free, and gnotobiotic animals. Measurements and Main Results: Consistent with prior work, we identified four temperature trajectories in patients hospitalized with sepsis that predicted clinical outcomes. In a separate cohort of 116 hospitalized patients, we found that the composition of patients' gut microbiota at admission predicted their temperature trajectories. Compared with conventional mice, germ-free mice had reduced temperature loss during experimental sepsis. Among conventional mice, heterogeneity of temperature response in sepsis was strongly explained by variation in gut microbiota. Healthy germ-free and antibiotic-treated mice both had lower basal body temperatures compared with control animals. The Lachnospiraceae family was consistently associated with temperature trajectories in hospitalized patients, experimental sepsis, and antibiotic-treated mice. Conclusions: The gut microbiome is a key modulator of body temperature variation in both health and critical illness and is thus a major, understudied target for modulating physiologic heterogeneity in sepsis.

Chirality matters: stereo-defined phosphorothioate linkages at the termini of small interfering RNAs improve pharmacology in vivo.

A critical challenge for the successful development of RNA interference-based therapeutics therapeutics has been the enhancement of their in vivo metabolic stability. In therapeutically relevant, fully chemically modified small interfering RNAs (siRNAs), modification of the two terminal phosphodiester linkages in each strand of the siRNA duplex with phosphorothioate (PS) is generally sufficient to protect against exonuclease degradation in vivo. Since PS linkages are chiral, we systematically studied the properties of siRNAs containing single chiral PS linkages at each strand terminus. We report an efficient and simple method to introduce chiral PS linkages and demonstrate that Rp diastereomers at the 5' end and Sp diastereomers at the 3' end of the antisense siRNA strand improved pharmacokinetic and pharmacodynamic properties in a mouse model. In silico modeling studies provide mechanistic insights into how the Rp isomer at the 5' end and Sp isomer at the 3' end of the antisense siRNA enhance Argonaute 2 (Ago2) loading and metabolic stability of siRNAs in a concerted manner.

From bench to bedside: Improving the clinical safety of GalNAc-siRNA conjugates using seed-pairing destabilization.

Preclinical mechanistic studies have pointed towards RNA interference-mediated off-target effects as a major driver of hepatotoxicity for GalNAc-siRNA conjugates. Here, we demonstrate that a single glycol nucleic acid or 2'-5'-RNA modification can substantially reduce small interfering RNA (siRNA) seed-mediated binding to off-target transcripts while maintaining on-target activity. In siRNAs with established hepatotoxicity driven by off-target effects, these novel designs with seed-pairing destabilization, termed enhanced stabilization chemistry plus (ESC+), demonstrated a substantially improved therapeutic window in rats. In contrast, siRNAs thermally destabilized to a similar extent by the incorporation of multiple DNA nucleotides in the seed region showed little to no improvement in rat safety suggesting that factors in addition to global thermodynamics play a role in off-target mitigation. We utilized the ESC+ strategy to improve the safety of ALN-HBV, which exhibited dose-dependent, transient and asymptomatic alanine aminotransferase elevations in healthy volunteers. The redesigned ALN-HBV02 (VIR-2218) showed improved specificity with comparable on-target activity and the program was reintroduced into clinical development.

Anthropogenic pressures and life history predict trajectories of seagrass meadow extent at a global scale.

Seagrass meadows are threatened by multiple pressures, jeopardizing the many benefits they provide to humanity and biodiversity, including climate regulation and food provision through fisheries production. Conservation of seagrass requires identification of the main pressures contributing to loss and the regions most at risk of ongoing loss. Here, we model trajectories of seagrass change at the global scale and show they are related to multiple anthropogenic pressures but that trajectories vary widely with seagrass life-history strategies. Rapidly declining trajectories of seagrass meadow extent (>25% loss from 2000 to 2010) were most strongly associated with high pressures from destructive demersal fishing and poor water quality. Conversely, seagrass meadow extent was more likely to be increasing when these two pressures were low. Meadows dominated by seagrasses with persistent life-history strategies tended to have slowly changing or stable trajectories, while those with opportunistic species were more variable, with a higher probability of either rapidly declining or rapidly increasing. Global predictions of regions most at risk for decline show high-risk areas in Europe, North America, Japan, and southeast Asia, including places where comprehensive long-term monitoring data are lacking. Our results highlight where seagrass loss may be occurring unnoticed and where urgent conservation interventions are required to reverse loss and sustain their essential services.

Review of quorum-quenching probiotics: A promising non-antibiotic-based strategy for sustainable aquaculture.

The emergence of antibiotic-resistant bacteria (ARBs) and genes (ARGs) in aquaculture underscores the urgent need for alternative veterinary strategies to combat antimicrobial resistance (AMR). These measures are vital to reduce the likelihood of entering a post-antibiotic era. Identifying environmentally friendly biotechnological solutions to prevent and treat bacterial diseases is crucial for the sustainability of aquaculture and for minimizing the use of antimicrobials, especially antibiotics. The development of probiotics with quorum-quenching (QQ) capabilities presents a promising non-antibiotic strategy for sustainable aquaculture. Recent research has demonstrated the effectiveness of QQ probiotics (QQPs) against a range of significant fish pathogens in aquaculture. QQ disrupts microbial communication (quorum sensing, QS) by inhibiting the production, replication, and detection of signalling molecules, thereby reducing bacterial virulence factors. With their targeted anti-virulence approach, QQPs have substantial promise as a potential alternative to antibiotics. The application of QQPs in aquaculture, however, is still in its early stages and requires additional research. Key challenges include determining the optimal dosage and treatment regimens, understanding the long-term effects, and integrating QQPs with other disease control methods in diverse aquaculture systems. This review scrutinizes the current literature on antibiotic usage, AMR prevalence in aquaculture, QQ mechanisms and the application of QQPs as a sustainable alternative to antibiotics.

Medial temporal lobe gray matter microstructure in preclinical Alzheimer's disease.

INTRODUCTION: Typical MRI measures of neurodegeneration have limited sensitivity in early disease stages. Diffusion MRI (dMRI) microstructural measures may allow for detection in preclinical stages. METHODS: Participants had dMRI and either beta-amyloid PET or plasma biomarkers of Alzheimer's pathology within 18 months of MRI. Microstructure was measured in portions of the medial temporal lobe (MTL) with high neurofibrillary tangle (NFT) burden based on a previously developed post mortem 3D-map. Regressions examined relationships between microstructure and markers of Alzheimer's pathology in preclinical disease and then across disease stages. RESULTS: There was higher isometric volume fraction in amyloid-positive compared to amyloid-negative cognitively unimpaired individuals in high tangle MTL regions. Similarly, plasma biomarkers and 18F-flortaucipir were associated with microstructural changes in preclinical disease. Additional microstructural effects were seen across disease stages. DISCUSSION: Combining a post mortem atlas of NFT pathology with microstructural measures allows for detection of neurodegeneration in preclinical Alzheimer's disease. Highlights Typical markers of neurodegeneration are not sensitive in preclinical Alzheimer's. dMRI measured microstructure in regions with high NFT. Microstructural changes occur in medial temporal regions in preclinical disease. Microstructural changes occur in other typical Alzheimer's regions in later stages. Combining post mortem pathology atlases with in vivo MRI is a powerful framework.

Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA), updates in 2022-2023. Cerebrovascular disease and the failure of elimination of Amyloid-ß from the brain and retina with age and Alzheimer's disease: Opportunities for therapy.

This editorial summarizes advances from the Clearance of Interstitial Fluid and Cerebrospinal Fluid (CLIC) group, within the Vascular Professional Interest Area (PIA) of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART). The overarching objectives of the CLIC group are to: (1) understand the age-related physiology changes that underlie impaired clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) (CLIC); (2) understand the cellular and molecular mechanisms underlying intramural periarterial drainage (IPAD) in the brain; (3) establish novel diagnostic tests for Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), retinal amyloid vasculopathy, amyloid-related imaging abnormalities (ARIA) of spontaneous and iatrogenic CAA-related inflammation (CAA-ri), and vasomotion; and (4) establish novel therapies that facilitate IPAD to eliminate amyloid ß (Aß) from the aging brain and retina, to prevent or reduce AD and CAA pathology and ARIA side events associated with AD immunotherapy.

A Framework for Response Escalation and Emergency Response Asset Management.

The Centers for Disease Control and Prevention (CDC) responds to public health emergencies at various levels within its organization. Overtime, CDC's response capabilities have matured across the organization due to years of emergency management investment and experience across the agency. In 2019, CDC began to implement the Graduated Response Framework to formalize an approach for managing public health emergencies that recognizes its response capabilities and meets the evolving needs of the country. This brief report summarizes CDC's Graduated Response Framework structure, and how response management escalates and de-escalates according to resource needs and complexity.

Effectiveness of Platelet-Rich Plasma in Reducing Pain and Increasing Function After Acute Lateral Ankle Sprain: A Critically Appraised Topic.

CLINICAL SCENARIO: Ankle sprains are one of the most common injuries in athletics, and many lead to recurrent sprains, chronic ankle instability, and persistent symptoms. Treatment improvements are needed. Platelet-rich plasma (PRP) involves formulating autologous plasma with higher platelet concentration to be injected in the desired tissue. There is currently high-quality evidence supporting the use of PRP with lateral epicondylitis and knee osteoarthritis to accelerate the healing process and decrease pain. CLINICAL QUESTION: Does the injection of PRP relieve pain faster and improve function compared with no injection or placebo in patients with a lateral ankle sprain? SUMMARY OF KEY FINDINGS: A computerized search yielded 191 studies; of these, 3 studies fit the inclusion and exclusion criteria. PRP injection reduces pain and increases function after lateral ankle sprain 5 to 8 weeks after intervention. CLINICAL BOTTOM LINE: The use of PRP after lateral ankle sprain to decrease pain and increase function is supported with moderate evidence. STRENGTH OF RECOMMENDATION: Based on the Strength of Recommendation Taxonomy, evidence from the included studies is considered as level B, reflecting limited quality patient-oriented evidence.