Design, synthesis, and in vitro biological evaluation of meta-sulfonamidobenzamide-based antibacterial LpxH inhibitors.

New antibacterial compounds are urgently needed, especially for infections caused by the top-priority Gram-negative bacteria that are increasingly difficult to treat. Lipid A is a key component of the Gram-negative outer membrane and the LpxH enzyme plays an important role in its biosynthesis, making it a promising antibacterial target. Inspired by previously reported ortho-N-methyl-sulfonamidobenzamide-based LpxH inhibitors, novel benzamide substitutions were explored in this work to assess their in vitro activity. Our findings reveal that maintaining wild-type antibacterial activity necessitates removal of the N-methyl group when shifting the ortho-N-methyl-sulfonamide to the meta-position. This discovery led to the synthesis of meta-sulfonamidobenzamide analogs with potent antibacterial activity and enzyme inhibition. Moreover, we demonstrate that modifying the benzamide scaffold can alter blocking of the cardiac voltage-gated potassium ion channel hERG. Furthermore, two LpxH-bound X-ray structures show how the enzyme-ligand interactions of the meta-sulfonamidobenzamide analogs differ from those of the previously reported ortho analogs. Overall, our study has identified meta-sulfonamidobenzamide derivatives as promising LpxH inhibitors with the potential for optimization in future antibacterial hit-to-lead programs.

Application of Global Burden of Animal Diseases methods at country level: experiences of the Ethiopia case study.

Animals play a central role in human livelihoods and welfare. Animal diseases have a great impact on the benefits humans derive from animals and can also pose a risk to human health. Better control of animal diseases generates wider societal benefits, including reducing the climate and ecological impacts of livestock and improving animal welfare. To better understand the scale of investment justified for the control and prevention of animal disease, the wide-ranging impacts of disease on animal production and health must be measured. The Global Burden of Animal Diseases (GBADs) programme is quantifying animal disease burden from the local to global levels. The GBADs programme includes country case studies for national- and local-level analysis. Ethiopia is the first case study country in which GBADs methods have been applied. GBADs'Ethiopia case study consists of three activity areas: i) stakeholder engagement; ii) livestock disease burden estimation, including data collection, analytics, evidence generation and communication; and iii) capacity building in animal health economics. At the start of the case study, various stakeholder communication platforms were used to familiarise stakeholders with GBADs and engage their support in various ways, including data access, and, through this engagement, to ensure the programme tools and outputs were relevant and useful to their needs. Existing data were retrieved from multiple sources and used to estimate disease burden. This process involved multiple steps, including estimation of biomass and economic value, the Animal Health Loss Envelope (farm-level disease burden), wider economic impacts and attribution of the disease burden to different levels of causes. This was carried out for major livestock species (cattle, sheep, goats and poultry) in Ethiopia. Capacity building on animal health economics was carried out for GBADs end users to increase competence in utilising animal health economic evidence, including GBADs outputs. This article documents experiences of the implementation of these activities in the GBADs Ethiopia case study.

Les animaux représentent une part substantielle des moyens de subsistance et contribuent de manière essentielle au bien-être humain. Les bénéfices que l'humanité peut retirer des animaux sont toutefois compromis par les maladies animales, qui font aussi peser un risque sur la santé publique. Les avantages sociétaux d'un meilleur contrôle des maladies animales dépassent la portée strictement sanitaire et recouvrent notamment l'atténuation de l'impact climatique et environnemental des animaux d'élevage et l'amélioration du bien-être animal. Pour mieux appréhender l'échelle des investissements requis pour contrôler et prévenir les maladies animales, il convient de mesurer les impacts très divers de ces maladies sur la production et la santé animales. Le programme " Impact mondial des maladies animales " (GBADs) procède actuellement à la quantification de la charge des maladies animales, du niveau local au niveau mondial. Il comprend aussi des études de cas conduites dans des pays choisis pour une analyse à l'échelle nationale, voire locale. L'Ethiopie est le premier pays à avoir fait l'objet d'une étude de cas nationale reprenant les méthodes du GBADs. L'étude comportait trois volets d'activités : i) la mobilisation des parties prenantes ; ii) l'estimation de la charge des maladies chez les animaux d'élevage, notamment la collecte de données, leur analyse, l'apport d'éléments probants et la communication ; et iii) le renforcement des capacités en économie de la santé animale. Au lancement de l'étude, plusieurs plateformes de communication professionnelles ont été utilisées pour mieux faire connaître le GBADs aux différents acteurs et solliciter leur soutien de diverses manières, en particulier en termes d'accès aux données, et pour s'assurer, grâce à cette mobilisation, que les outils et les résultats du programme étaient pertinents pour eux et répondaient à leurs besoins. Les données existantes ont été recueillies auprès de multiples sources et ont permis d'estimer la charge sanitaire. Ce processus comportait plusieurs étapes, dont l'estimation de la biomasse et de la valeur économique, la définition de l'enveloppe des pertes sanitaires animales (charge sanitaire à l'échelle des exploitations), l'appréciation des effets économiques au sens large et la répartition de la charge sanitaire en fonction des niveaux des causes attribuées. Les analyses portaient sur les principales espèces d'animaux d'élevage (bovins, ovins, caprins et volailles) en Ethiopie. Des activités de renforcement des capacités en économie de la santé animale ont été proposées aux utilisateurs finaux du GBADs afin de les former à l'utilisation des preuves économiques en santé animale. Les auteurs expliquent comment s'est déroulée la mise en oeuvre de ces activités lors de l'étude du GBADs conduite en Ethiopie.

Los animales desempeñan un papel fundamental en los medios de subsistencia y el bienestar humanos. En este sentido, las enfermedades animales tienen un gran impacto en los beneficios que los humanos obtienen de los animales y también pueden suponer un riesgo para la salud humana. Un mejor control de las enfermedades animales genera beneficios sociales más amplios, como la reducción del impacto climático y ecológico de la ganadería y la mejora del bienestar animal. Para comprender mejor la magnitud de la inversión justificada para el control y la prevención de las enfermedades animales, es preciso medir las amplias repercusiones de las enfermedades en la producción y la sanidad animal. El programa sobre el impacto global de las enfermedades animales (GBADs) cuantifica el impacto de las enfermedades animales desde el nivel local hasta el mundial. El programa GBADs incluye estudios de casos por países a fin de realizar un análisis a escala nacional y local. Etiopía es el primer país en el que se han aplicado los métodos del GBADs. El estudio de caso del GBADs en dicho país se divide en tres áreas de actividad: i) la participación de las partes interesadas; ii) la estimación del impacto de las enfermedades del ganado, incluida la recopilación de datos, el análisis, la generación de pruebas y la comunicación; y iii) el desarrollo de capacidades en el ámbito de la economía de la sanidad animal. Al inicio del estudio de caso, se utilizaron diversas plataformas de comunicación con las partes interesadas para familiarizarlas con el GBADs y recabar su apoyo a través de diversas vías, entre las que se incluía el acceso a los datos, y, mediante esta colaboración, garantizar que las herramientas y los resultados del programa fueran pertinentes y útiles para sus necesidades. Se obtuvieron datos de diversas fuentes que se utilizaron para estimar el impacto de las enfermedades. Este proceso implicó múltiples pasos, incluida la estimación de la biomasa y el valor económico, la cartera de pérdidas en sanidad animal (impacto de las enfermedades a nivel de explotación), los impactos económicos más amplios y la atribución del impacto de las enfermedades a diferentes categorías de causas. Esto se llevó a cabo para las principales especies ganaderas (bovinos, ovinos, caprinos y aves de corral) en Etiopía. Se realizaron actividades de capacitación en economía de la sanidad animal para los usuarios finales con el fin de aumentar su competencia en la utilización de los datos económicos sobre sanidad animal, incluidos los resultados del GBADs. Este artículo documenta las experiencias de la puesta en práctica de estas actividades en el estudio de caso del GBADs en Etiopía.

Characterization of a human thyroid microtissue model for testing thyroid disrupting chemicals.

Perturbation of thyroid hormone (T4) synthesis is known to cause numerous developmental, metabolic, and cognitive disorders in humans. Due to species differences in sensitivity to chemical exposures, there is a need for human-based in vitro approaches that recapitulate thyroid cellular architecture and T4 production when screening. To address these limitations, primary human thyrocytes, isolated from healthy adult donor tissues and cryopreserved at passage one (p'1) were characterized for cellular composition, 3D follicular architecture, and thyroglobulin (TG)/T4 expression and inhibition by prototype thyroid disrupting chemicals (TDC). Flow analysis of the post-thaw cell suspension showed >80% EpCAM-positive cells with 10%-50% CD90-positive cells. When seeded onto 96-well Matrigel®-coated plates and treated with bovine thyroid stimulating hormone (TSH), thyrocytes formed 3D microtissues during the initial 4-5 days of culture. The microtissues exhibited a stable morphology and size over a 14-day culture period. TG and T4 production were highest in microtissues when the proportion of CD90-positive cells, seeding density and thyroid stimulating hormone concentrations were between 10%-30%, 6K-12K cells per well, and 0.03-1 mIU/mL, respectively. At maximal TG and T4 production levels, average microtissue diameters ranged between 50 and 200 µm. The T4 IC50 values for two prototype TPO inhibitors, 6-propyl-2-thiouracil and methimazole, were ∼0.7 µM and ∼0.5 µM, respectively, in microtissue cultures treated between days 9 and 14. Overall, p'1 cryopreserved primary human thyrocytes in 3D microtissue culture represent a promising new model system to prioritize potential TDC acting directly on the thyroid as part of a weight-of-evidence hazard characterization.

Developing work readiness in university graduates: a case study in mapping a university curriculum to work readiness domains in an Australian physiotherapy degree.

BACKGROUND: Recent research has identified six domains of work readiness: Practical Wisdom, Interpersonal Capabilities, Personal Attributes, Organisational Acumen, Profession Specific Knowledge and Skills, and Professionally Relevant Experiences. OBJECTIVE: Using a case study, the aim of this study was to demonstrate the process of curriculum mapping to evaluate the alignment of a university program to the work readiness framework. METHODS: A retrospective audit of curriculum material for one cohort of Macquarie University's Doctor of Physiotherapy (DPT) was undertaken. Curriculum was categorized as declared, delivered, or assessed, mapped to the six work readiness domains through qualitative content analysis, and then quantitatively scored and expressed as percentages of maximum possible scores per unit, and average units scores per semester. RESULTS: Mapping curriculum to a six domain work readiness framework revealed declared, delivered, and assessed curriculum within all six work readiness domains, with varying contributions across the degree. Mapping revealed that the Profession Specific Knowledge and Skills domain had the highest coverage of declared (M = 63%, SD = 12), delivered (M = 88%, SD = 11) and assessed (M = 80%, SD = 7) curriculum, highlighting a strength of the program. The Personal Attributes domain had the lowest coverage of declared (M = 5%, SD = 5), delivered (M = 48%, SD = 24) and assessed (M = 29%, SD = 20) curriculum, highlighting opportunities for development. CONCLUSION: Mapping curriculum to a work readiness framework allows universities to consider alignment, and the strength and opportunities for the improvement of work readiness within its curriculum.

Regional Differences in Microbial Infiltration of Brain Tissue from Alzheimer's Disease Patients and Control Individuals.

Alzheimer's disease (AD) is characterized by cognitive decline and neuropathology including amyloid beta (Aß) plaques and neurofibrillary tangles (tau). Factors initiating or driving these pathologies remain unclear, though microbes have been increasingly implicated. Our data and others' findings indicate that microbes may be common constituents of the brain. It is notable that Aß and tau have antimicrobial properties, suggesting a response to microbes in the brain. We used 16S rRNA sequencing to compare major bacterial phyla in post-mortem tissues from individuals exhibiting a range of neuropathology and cognitive status in two brain regions variably affected in AD. Our data indicate that strong regional differences exist, driven in part by the varied presence of Proteobacteria and Firmicutes. We confirmed our data using ELISA of bacterial lipopolysaccharide (LPS) and lipoteichoic acid in the same brain tissue. We identified a potential association between the composition of phyla and the presence of neuropathology but not cognitive status. Declining cognition and increasing pathology correlated closely with serum LPS, but not brain levels of LPS, although brain LPS showed a strong negative correlation with cerebral amyloid angiopathy. Collectively, our data suggest a region-specific heterogeneity of microbial populations in brain tissue potentially associated with neurodegenerative pathology.

Self-purification in tropical upland rivers as affected by environmental factors: the case of Balili River in Benguet, Philippines.

A major data gap in tropical river ecology is the limited documentation of natural water purification of upstream rivers. This study documented the improvement of water quality of downstream Balili River as affected by environmental factors and macrophyte diversity using a mixed-method approach (water quality assessment, plant inventory, field observation, canonical correspondence analysis, community interview). Results showed that the distance from pollution plays a significant role in the self-purification of the river while the floral diversity maintains the riparian from further contaminating the water and at the same time absorbing air pollutants. Generally, the pollution reduction and %change is exponential at 2 and 3 km from point source then taper at 4 and 5 km. At 3 km from the point source, 30% improvement in TDS, BOD and salinity, 25% for EC, 20% in TSS, 35% in WQI, 36% in CPI, and 50% for DO were noted. Key factors that influence the self-purification process in the river were distance from pollution source, elevation, human disturbance (as indicated by %tree canopy) and temperature. These findings highlight the importance of distance from pollution sources and floral diversity in driving water quality improvements, with implications for sustainable water resource management in tropical regions.

This study documented the improvement of water quality of downstream Balili River as affected by environmental factors and macrophyte diversity ­ as contribution to the major data gap in tropical river ecology which currently has limited documentation on natural water purification of upstream rivers. The study also shows the mosaic interplay of water quality, plant diversity, distance from pollution, human disturbance, and air quality in understudied tropical river. Further, this study is unique in documenting the downstream of Balili River since majority of the previous studies were concentrated in the upstream portion of the river.

Economic losses due to foot-and-mouth disease (FMD) in Ethiopian cattle.

Ethiopia's cattle population is among the largest in Africa and is burdened by frequent foot-and-mouth disease (FMD) outbreaks. FMD is caused by several distinct and highly contagious viral strains that can result in acute disease in cattle, causing losses in productivity and impeding international trade. This economic simulation study considered four main sources of losses due to FMD in cattle: reduced milk yield, draft power yield, fertility, and increased mortality. Economic losses were estimated per case across age-sex strata in 89 Ethiopian administrative zones for the years 2010-2021 using a wide range of data to estimate distributions for 30 input variables in a series of Monte Carlo simulations. It was estimated that an average case of FMD in Ethiopian cattle results in losses (mean values reported followed 95 % confidence intervals in brackets) of US dollars (USD) 11 (USD 7-USD 16) per case. Losses resulting from an average outbreak were estimated to be USD 2300 (USD 1400-USD 3300), while national annual losses were estimated to be USD 0.9 Mil. (USD 0.2 Mil.-USD 2.3 Mil.). Per cow-year, based on a national cow population of approximately 39 Mil. head, these estimated annual losses are equivalent to losses of only USD 0.02 (USD 0.01-USD 0.06). Nationally, these losses were significantly less than previously estimated in the literature, with currently estimated losses more accurately reflecting the economic burden of FMD in Ethiopian cattle over the past decade. The relatively small estimated losses suggest that control efforts based on widespread vaccination in countries with primarily extensive cattle production systems, such as Ethiopia, are unlikely to be economically sound. Sensitivity analyses suggested losses would be far greater in intensive systems, and that certainty surrounding incidence rates is paramount to the formulation of economically sound animal healthpolicy in regions with endemic FMD.

Induced plant resistance and its influence on natural enemy use of plant-derived foods.

In response to herbivory, plants employ several inducible defenses to mitigate herbivore damage. These plant-induced responses can trigger subtle changes in plant metabolite composition, altering the profiles of plant-produced exudates such as (extra-) floral nectar and plant guttation. Natural enemies consume these plant-produced exudates, which serve as consistent and nutrient-dense food sources. There is mounting evidence that natural enemies' access to plant-produced exudates impacts their fitness, performance, and life history traits. Nonetheless, the role of induced plant defense on plant-produced exudates and the subsequent effect on natural enemies remains under-researched. This review, thus, highlights the potential role of induced plant defense on the profiles of plant-produced exudates, with a particular emphasis on altered metabolic changes affecting resource nutritional value and consequently the fitness and performance of natural enemies. Future directions and potential implications in biological control practices are also highlighted.

Prevalence and risk factors for gingivitis in a cohort of UK companion cats aged up to 6 years.

OBJECTIVES: Prospectively collected data were used to estimate the prevalence of gingivitis in a cohort of companion cats aged up to 6 years and to investigate factors associated with the risk of gingivitis in cats aged 3 to 4 years. MATERIALS AND METHODS: Data were obtained from a longitudinal study of domestic cats (the Bristol Cats Study), using owner-completed questionnaires and veterinary surgeon-completed oral health scores. Prevalence estimates of veterinary-reported gingivitis for cats aged up to 6 years old (n = 1534) were calculated for different age groups. Cat signalment, diet and dental care were assessed for association with gingivitis in cats aged 3 to 4 years (n = 317) using univariable and multiple logistic regression. RESULTS: The prevalence of gingivitis increased with age and ranged from 24.5% (<12 months old) to 56.3% (5 to 6 years old). Odds of gingivitis in cats aged 3 to 4 years were higher in cats fed a wet only or mixed wet/dry diet compared to dry only (odds ratio: 2.7; 95% confidence interval: 1.4 to 5.1), cats not reported to hunt compared to reported hunters (odds ratio: 2.1; 95% confidence interval: 1.0 to 4.2), cats reported to dribble whilst being stroked at age 6 months compared to reported non-dribblers (odds ratio: 3.2; 95% confidence interval: 1.3 to 8.4) and cats with orange variants in their coat colour compared to non-orange cats (odds ratio: 2.3; 95% confidence interval: 1.0 to 5.3). CLINICAL SIGNIFICANCE: These results will help veterinary surgeons identify cats that may be at a greater risk of gingivitis and provide an evidence base to inform dietary and oral healthcare recommendations aimed at promoting gingival health in cats.

COVID-19 effects on horses in-transition: A survey analysis of United States equine industry perspectives.

The welfare of unwanted horses presents a significant concern for the equine industry. However, there is a lack of research on how unwanted horses are affected by major crises. The drastic changes that resulted from the COVID-19 pandemic presented ample opportunity to investigate how unwanted horses are impacted by challenging circumstances. Study objectives were to evaluate the COVID-19 pandemic's impact on the unwanted horse population and determine the current perceptions of horses in-transition. A 23-question online survey designed using QualtricsTM was administered electronically to adults living in the United States. Questions pertained to effects on equine ownership, equine management, event participation, and perceptions of unwanted horses. Frequency analysis combined with Chi-squared analyses and analyses of variance identified the impacts of COVID-19 on horse owners, non-horse owners, and equine professionals. From survey results, equine ownership, management practices, and time spent with horses proved to be unaffected (P < 0.001) by the coronavirus pandemic. A decreased ability to participate in equine events was evident across all groups (P ≤ 0.03). Financial hardship, unmanageable behavior, and injury were cited as leading causes for horses becoming "in-transition." Euthanasia was the transitioning method perceived as most accessible, while donation to an equine program was least accessible. Based on results, the COVID-19 pandemic had negligible impact on the number of unwanted horses in the United States. Long-term effects of COVID-19 on equine ownership and management decisions should be considered to provide a deeper base of knowledge for how major crises affect the horse in-transition population.

Salivary toxicity from PSMA-targeted radiopharmaceuticals: What we have learned and where we are going.

Clinical trials of prostate-specific membrane antigen (PSMA) targeted radiopharmaceuticals have shown encouraging results. Some agents, like lutetium-177 [177Lu]Lu-PSMA-617 ([177Lu]Lu-PSMA-617), are already approved for late line treatment of metastatic castration-resistant prostate cancer (mCRPC). Projections are for continued growth of this treatment modality; [177Lu]Lu-PSMA-617 is being studied both in earlier stages of disease and in combination with other anti-cancer therapies. Further, the drug development pipeline is deep with variations of PSMA-targeting radionuclides, including higher energy alpha particles conjugated to PSMA-honing vectors. It is safe to assume that an increasing number of patients will be exposed to PSMA-targeted radiopharmaceuticals during the course of their cancer treatment. In this setting, it is important to better understand and mitigate the most commonly encountered toxicities. One particularly vexing side effect is xerostomia. In this review, we discuss the scope of the problem, inventories to better characterize and monitor this troublesome side effect, and approaches to preserve salivary function and effectively palliate symptoms. This article aims to serve as a useful reference for prescribers of PSMA-targeted radiopharmaceuticals, while also commenting on areas of missing data and opportunities for future research.

Benchmarking multi-ancestry prostate cancer polygenic risk scores in a real-world cohort.

Prostate cancer is a heritable disease with ancestry-biased incidence and mortality. Polygenic risk scores (PRSs) offer promising advancements in predicting disease risk, including prostate cancer. While their accuracy continues to improve, research aimed at enhancing their effectiveness within African and Asian populations remains key for equitable use. Recent algorithmic developments for PRS derivation have resulted in improved pan-ancestral risk prediction for several diseases. In this study, we benchmark the predictive power of six widely used PRS derivation algorithms, including four of which adjust for ancestry, against prostate cancer cases and controls from the UK Biobank and All of Us cohorts. We find modest improvement in discriminatory ability when compared with a simple method that prioritizes variants, clumping, and published polygenic risk scores. Our findings underscore the importance of improving upon risk prediction algorithms and the sampling of diverse cohorts.

Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria.

Here, we describe the identification of an antibiotic class acting via LpxH, a clinically unexploited target in lipopolysaccharide synthesis. The lipopolysaccharide synthesis pathway is essential in most Gram-negative bacteria and there is no analogous pathway in humans. Based on a series of phenotypic screens, we identified a hit targeting this pathway that had activity on efflux-defective strains of Escherichia coli. We recognized common structural elements between this hit and a previously published inhibitor, also with activity against efflux-deficient bacteria. With the help of X-ray structures, this information was used to design inhibitors with activity on efflux-proficient, wild-type strains. Optimization of properties such as solubility, metabolic stability and serum protein binding resulted in compounds having potent in vivo efficacy against bloodstream infections caused by the critical Gram-negative pathogens E. coli and Klebsiella pneumoniae. Other favorable properties of the series include a lack of pre-existing resistance in clinical isolates, and no loss of activity against strains expressing extended-spectrum-ß-lactamase, metallo-ß-lactamase, or carbapenemase-resistance genes. Further development of this class of antibiotics could make an important contribution to the ongoing struggle against antibiotic resistance.

Cosmic mysteries and the hydrogen 21-cm line: bridging the gap with lunar observations.

The hydrogen 21-cm signal is predicted to be the richest probe of the young Universe, including those eras known as the cosmic Dark Ages, the Cosmic Dawn (when the first star and black hole formed) and the Epoch of Reionization. This signal holds the key to deciphering processes that take place at the early stages of cosmic history. In this opinion piece, we discuss the potential scientific merit of lunar observations of the 21-cm signal and their advantages over more affordable terrestrial efforts. The Moon is a prime location for radio cosmology which will enable precision observations of the low-frequency radio sky. The uniqueness of such observations is that they will provide an unparalleled opportunity to test cosmology and the nature of dark matter using the Dark Ages 21-cm signal. No less enticing is the opportunity to obtain a much clearer picture of the Cosmic Dawn than that currently achievable from the ground, which will allow us to determine the properties of the first stars and black holes. This article is part of a discussion meeting issue 'Astronomy from the Moon: the next decades (part 2)'.

Characteristics and outcomes of a hospitalized cohort with reduced mortality from COVID-19, White Mountain apache tribal lands, April 1 - July 31, 2020.

BACKGROUND: Widespread transmission of COVID-19 continues to threaten public health, particularly of rural, American Indian communities. Although COVID-19 risk factors for severe disease and clinical characteristics are well described in the general population, there has been little shared on hospitalized American Indian populations. METHODS: In this observational study, we performed chart extractions on all persons hospitalized with COVID-19 from April 1 through July 31, 2020 among an exclusively American Indian population living on or near Tribal lands in eastern Arizona. We provide descriptive statistics for the cohort stratified by presentation, comparing those who self-presented or were referred by an outreach program. Exploratory analyses were performed to identify risk factors for morbidity and mortality. RESULTS: During the observation period, 2262 persons were diagnosed with COVID-19 and 490 (22%) were hospitalized. Hospitalized persons had a median age of 54 years; 92% had at least one comorbidity, 72% had greater than one comorbidity, and 60% had a BMI of > 30. Most persons required supplemental oxygen (83%), but the majority (62%) only required nasal cannula and only 11% were intubated. The case fatality rates were 1.7% for the population, 7.1% among hospitalizations, and 9.3% among hospitalized patients 50 years and older. All rates that are significantly lower than those reported nationally during the same period. CONCLUSIONS: We observed a cohort of American Indian patients hospitalized secondary to COVID-19 with greater number of comorbidities compared to the general population but with lower mortality rates. We posit that the primary driver of mortality reduction for this population and the hospitalized cohort was a community-based referral program that led to disproportionately lower fatality rates among the oldest persons.

Prostate-Specific Membrane Antigen-Targeting Alpha Emitter via Antibody Delivery for Metastatic Castration-Resistant Prostate Cancer: A Phase I Dose-Escalation Study of 225Ac-J591.

PURPOSE: Novel therapies are needed to extend survival in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA), a cell surface antigen overexpressed in PC, provides a validated target. This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) for 225Ac-J591, anti-PSMA monoclonal antibody J591 radiolabeled with the alpha emitter actinium-225. METHODS: Following investigational new drug-enabling preclinical studies, we enrolled patients with progressive mCRPC that was refractory to or who refused standard treatment options (including androgen receptor pathway inhibitor and had received or been deemed ineligible for taxane chemotherapy). No selection for PSMA was performed. Patients received a single dose of 225Ac-J591 at one of seven dose-escalation levels followed by expansion at the highest dose. Primary end point of dose-escalation cohort was determination of dose-limiting toxicity (DLT) and RP2D. RESULTS: Radiochemistry and animal studies were favorable. Thirty-two patients received 225Ac-J591 in an accelerated dose-escalation design (22 in dose escalation, 10 in expansion). One patient (1 of 22; 4.5%) experienced DLT in cohort 6 (80 KBq/kg) but none in cohort 7; MTD was not reached, and RP2D was the highest dose level (93.3 KBq/kg). The majority of high-grade adverse events (AEs) were hematologic with an apparent relationship with administered radioactivity. Nonhematologic AEs were generally of low grade. Prostate-specific antigen (PSA) declines and circulating tumor cell (CTC) control were observed: 46.9% had at least 50% PSA decline at any time (34.4% confirmed PSA response), and protocol-defined CTC count response occurred in 13 of 22 (59.1%). CONCLUSION: To our knowledge, this is the first-in-human phase I dose-escalation trial of a single dose of 225Ac-J591 in 32 patients with pretreated progressive mCRPC demonstrated safety and preliminary efficacy signals. Further investigation is underway.

Mild traumatic brain injury in Drosophila melanogaster alters reactive oxygen and nitrogen species in a sex-dependent manner.

Traumatic brain injury (TBI) is an outside force causing a modification in brain function and/or structural brain pathology that upregulates brain inducible nitric oxide synthase (iNOS), instigating increased levels of nitric oxide activity which is implicated in secondary pathology leading to behavioral deficits (Hall et al., 2012; Garry et al., 2015; Kozlov et al., 2017). In mammals, TBI-induced NO production activates an immune response and potentiates metabolic crisis through mitochondrial dysfunction coupled with vascular dysregulation; however, the direct influence on pathology is complicated by the activation of numerous secondary cascades and activation of other reactive oxygen species. Drosophila TBI models have demonstrated key features of mammalian TBI, including temporary incapacitation, disorientation, motor deficits, activation of innate immunity (inflammation), and autophagy responses observed immediately after injury (Katzenberger et al., 2013; Barekat et al., 2016; Simon et al., 2017; Anderson et al., 2018; Buhlman et al., 2021b). We hypothesized that acute behavioral phenotypes would be associated with deficits in climbing behavior and increased oxidative stress. Because flies lack mammalian-like cardiovascular and adaptive immune systems, we were able to make our observations in the absence of vascular disruption and adaptive immune system interference in a system where highly targeted interventions can be rapidly evaluated. To demonstrate the induction of injury, ten-day-old transgenic flies received an injury of increasing angles from a modified high impact trauma (HIT) device where angle-dependent increases occurred for acute neurological behavior assessments and twenty-four-hour mortality, and survival was significantly decreased. Injury caused sex-dependent effects on climbing activity and measures of oxidative stress. Specifically, after a single 60-degree HIT, female flies exhibited significant impairments in climbing activity beyond that observed in male flies. We also found that several measures of oxidative stress, including Drosophila NOS (dNOS) expression, protein nitration, and hydrogen peroxide production were significantly decreased in female flies. Interestingly, protein nitration was also decreased in males, but surpassed sham levels with a more severe injury. We also observed decreased autophagy demand in vulnerable dopaminergic neurons in female, but not male flies. In addition, mitophagy initiation was decreased in females. Collectively, our data suggest that TBI in flies induces acute behavioral phenotypes and climbing deficits that are analogous to mammalian TBI. We also observed that various indices of oxidative stress, including dNOS expression, protein tyrosine nitration, and hydrogen peroxide levels, as well as basal levels of autophagy, are altered in response to injury, an effect that is more pronounced in female flies.

Morpho-Anatomy and Mathematical Modelling in Lilium philippinense Baker from Cordillera Central Range, Philippines.

The study presents the morphology, anatomy and mathematical modelling in Benguet lily (Lilium philippinense Baker), a threatened species from the Cordillera Central Range and was often misidentified with the weedy L. formosanum. The plant is an annual herb with linear, spiral leaves; pure white, perfect, funnel-shaped, showy flowers; septicidal elongated capsule; and, brown, light, winged seeds. New findings in the study include the description of the capsule and seeds, biometric measurements of the different plant organs, the significant correlation and regression model of plant height and stem diameter for certain floral measurement, and its diagnostic characteristics vis-à-vis L. formosanum. Interesting findings on the taxon's anatomy show a cross between a typical monocot and a typical dicot anatomy. It has a bifacial leaf structure (a common dicot character) but its spongy layer is not as widely spaced like in dicot leaf. The stem has a distinct cortex and pith (a dicot character) but has a scattered vascular bundles (a monocot character). Lastly, some roots have a narrow pith at the centre of the stele (a monocot character) while some roots have metaxylem elements at the centermost structure (a dicot character). Further studies need to be conducted to determine the ecological significance of these features.

European Association of Urology Guidelines on Penile Size Abnormalities and Dysmorphophobia: Summary of the 2023 Guidelines.

CONTEXT: Recommendations regarding the management of penile size abnormalities and dysmorphophobia are important in guiding evidence-based clinical practice. OBJECTIVE: To present a summary of the 2023 European Association of Urology sexual and reproductive health evidence-based recommendations for the management of penile size abnormalities and dysmorphophobia. EVIDENCE ACQUISITION: A broad and comprehensive scoping exercise covering all areas of the guidelines was performed. Databases searched included Medline, EMBASE, and the Cochrane Libraries. A level of evidence and a strength of recommendation were assigned for each recommendation according to the evidence identified. The evidence cutoff date for the 2023 guidelines is June 1, 2022. EVIDENCE SYNTHESIS: Well-structured studies reporting high level of evidence, with standardized PROMS were deficient on penile size abnormalities and dysmorphohobia. A shared definition for short penis/micropenis was also lacking. Categorisation of penile abnormalities according to congenital, acquired, and dysmorphophobic aetiology is deemed compulsory. A detailed medical and psychosexual history and precise measurements of penile size are essential in the diagnostic pathway. Patients with normal penile size who are seeking penile augmentation should be referred for psychological evaluation for potential dysmorphophobic disorders. Penile length and girth enhancements can be achieved via a multitude of treatments, but a personalised management plan is crucial for satisfactory results. Endocrinological therapies, when indicated, are effective in the prepubertal setting only. Vacuum therapy has a limited evidence base in treatment protocols, although acceptable outcomes have been reported for penile traction therapy. Surgical techniques to enhance penile length and girth have limited evidence and should only be proposed after extensive patient counselling. CONCLUSIONS: Management of penile abnormalities and dysmorphophobia is a complex issue with considerable ethical concerns. The adoption of a structured diagnostic and therapeutic pathway is crucial, as recommended in the guidelines. PATIENT SUMMARY: Requests for medical/surgical treatments to increase penis size have increased dramatically worldwide. Several conservative and surgical treatments are available. However, few patients receive clear information on the benefits and possible harms of these treatments. These guidelines aim to provide a structured path to guide both physicians and patients in the selection of appropriate treatment(s) to increase penis size.