Oral supplementation with postbiotics modulates the immune response produced by myxomatosis vaccination in wild rabbits.

Rabbits (Oryctolagus cuniculus) are vitally important species in the Iberian Peninsula ecosystem. However, since 1950, there has been a significant population decline, with major repercussions. This situation is mainly due to the presence of infectious diseases, such as myxomatosis, which is expanding and is characterized by severe and fatal clinical manifestations. Current control measures, mainly those based on vaccinations, are ineffective. Therefore, new strategies need to be developed and implemented. This study aimed to evaluate whether supplementation with postbiotic products modulates the immune response in wild rabbits vaccinated against myxomatosis. For this purpose, two groups of rabbits were established: a control group fed with standard feed ad libitum from weaning (28 days) until two months of age, and a treated group, which was fed under the same conditions but supplemented with postbiotics (3 kg/Tm). All the studied rabbits were vaccinated against this disease during weaning. In addition, a blood samples were obtained from all animals immediately before vaccination and 30 days later, which allowed us to evaluate the level of antibodies against myxomatosis virus (ELISA detection) and the relative expression of gene encoding to cytokines related to the immune response (IL6, TNFα and IFNγ), at both times of the experience. Weight and length measurements were also taken at both times to calculate body index and mean daily gain (MDG). No statistically significant differences in growth parameters were observed. There were also no differences in the serological response among groups. However, a relative underexpression of gene codifying to TNFα (p-value = 0.03683) and a higher expression on IFNγ (p-value = 0.045) were observed in the treated group. This modulation in cytokines could lead to less severe lesions in wild rabbit naturally infected with myxomatosis virus.

Activation of Piezo1 Inhibits Kidney Cystogenesis.

The disruption of calcium signaling associated with polycystin deficiency has been proposed as the primary event underlying the increased abnormally patterned epithelial cell growth characteristic of Polycystic Kidney Disease. Calcium can be regulated through mechanotransduction, and the mechanosensitive cation channel Piezo1 has been implicated in sensing of intrarenal pressure and in urinary osmoregulation. However, a possible role for PIEZO1 in kidney cystogenesis remains undefined. We hypothesized that cystogenesis in ADPKD reflects altered mechanotransduction, suggesting activation of mechanosensitive cation channels as a therapeutic strategy for ADPKD. Here, we show that Yoda-1 activation of PIEZO1 increases intracellular Ca 2+ and reduces forskolin-induced cAMP levels in mIMCD3 cells. Yoda-1 reduced forskolin-induced IMCD cyst surface area in vitro and in mouse metanephros ex vivo in a dose-dependent manner. Knockout of polycystin-2 dampened the efficacy of PIEZO1 activation in reducing both cAMP levels and cyst surface area in IMCD3 cells. However, collecting duct-specific Piezo1 knockout neither induced cystogenesis in wild-type mice nor affected cystogenesis in the Pkd1 RC/RC model of ADPKD. Our study suggests that polycystin-2 and PIEZO1 play a role in mechanotransduction during cystogenesis in vitro , and ex vivo , but that in vivo cyst expansion may require inactivation or repression of additional suppressors of cystogenesis and/or growth. Our study provides a preliminary proof of concept for PIEZO1 activation as a possible component of combination chemotherapy to retard or halt cystogenesis and/or cyst growth.

Los trastornos de la personalidad ¿realidad o ficción? El sombrío futuro de su diagnóstico / Personality disorders: reality or fiction? The bleak future of your diagnosis

El diagnóstico categorial de los trastornos de la personalidad (TTPP) ha sido criticado por diversas razones, entras las que se encuentran el solapamiento de síntomas entre distintos trastornos, su elevada comorbilidad o el carácter dicotómico de su diagnóstico. Estas críticas han llevado al desarrollo de un planteamiento dimensional en las últimas versiones de los sistemas de clasificación, DSM-5/DSM-5-TR y CIE-11, considerando dos aspectos: el funcionamiento de la personalidad y una serie de rasgos patológicos. A pesar de la cuantiosa literatura publicada desde principio de este siglo sobre esta propuesta dimensional, no está claro, a día de hoy, que tenga alguna utilidad clínica. La vaga, abstracta y poco operativizable exposición de lo que constituye el funcionamiento de la personalidad y la compleja y forzada designación de rasgos mayores y menores (facetas) en el DSM-5/DSM-5-TR o sólo mayores y opcionales en la CIE-11, complican el diagnóstico dimensional de los TTPP. En este trabajo se discuten todas estas cuestiones en un intento de aportar algo de luz para un futuro menos sombrío que el actual panorama de los TTPP.(AU)

The categorical diagnosis of personality disorders (PDs) has been criticized forvarious reasons, among which are overlapping of symptoms between differentdisorders, their high comorbidity, and the dichotomous nature of their diagnosis.These criticisms have led to the development of a dimensional approach in thelatest versions of the classification systems, DSM-5/DSM-5-TR and ICD-11,considering two substantial aspects for its new diagnosis: personality functioning,and a series of pathological features. Despite the large amount of literature thathas been published since the beginning of this century on this dimensionalproposal, it is not clear, to date, that this approach enhances clinical utility. Thevague, abstract, and inoperative exposition of what constitutes personalityfunctioning and the complex and forced designation of major and minor traits(facets) in the DSM-5/DSM-5-TR, and only major and optional traits in the ICD-11,complicate, in an unusual way, the dimensional diagnosis of PDs. This paperdiscusses all of these issues in an attempt to shed some light on the potentially darkfuture of the current PDs panorama.(AU)

El papel de la impulsividad en la orientación al suicidio de universitarios con antecedentes de conducta autolesiva / The role of impulsivity in suicidal orientation of university students with a history of self-injurious behavior

El objetivo de esta investigación fue describir el efecto de la depresión, la desesperanza y la impulsividad sobre la orientación al suicidio y el papel de la impulsividad como mediador de la orientación suicida en universitarios con antecedentes de conductas autolesivas. Participaron 1.645 jóvenes entre los 18 y 29 años, de dos ciudades colombianas. Se seleccionaron 218 jóvenes (M= 21,00; DT= 2,99) que informaron de al menos un intento de suicidio en el último año, quienes contestaron el “Inventario de orientación suicida”, la “Escala de desesperanza de Beck”, el “Inventario de depresión de Beck” y la “Escala de impulsividad de Barratt”. La depresión, la desesperanza y la impulsividad explicaron el 63% de la variación de la orientación al suicidio (R2= 0,635; IC 95% [0,555; 0,713]; p= 0,001). La impulsividad medió con depresión en aquellos casos en los que la orientación suicida era alta, cuyos efectos totales, directos e indirectos, fueron estadísticamente significativos (p< 0,001). La impulsividad desempeña un papel mediador entre la depresión y la desesperanza en la predicción de la orientación suicida.(AU)

The aim of this research was to describe the effect of depression,hopelessness, and impulsivity on orientation to suicide and the role of impulsivityas a mediator of suicidal orientation in university students with a history of self-injury behaviors. 1645 young people between 18 and 29 years old participated,from two Colombian cities. 218 young people were selected (M= 21.00; SD= 2.99)who reported at least one suicide attempt in the last year, who answered the“Suicidal Orientation Inventory”, the “Beck Hopelessness Scale”, the “BeckDepression Inventory” and the “Barratt Impulsivity Scale”. Depression,hopelessness, and impulsivity explained 63% of the variation in suicidal orientation (R 2 = .635, IC 95% [.555, .713], p= .001). Impulsivity mediated with depression inthose cases in which suicidal orientation was high, whose total, direct and indirecteffects were statistically significant (p< .001). Impulsivity plays a mediating rolebetween depression and hopelessness in predicting suicidal orientation.K EY WORDS : depression, hopelessness, impulsivity, suicidality, college youth.(AU)

CD74 Promotes Cyst Growth and Renal Fibrosis in Autosomal Dominant Polycystic Kidney Disease.

The progression of autosomal dominant polycystic kidney disease (ADPKD), an inherited kidney disease, is associated with renal interstitial inflammation and fibrosis. CD74 has been known not only as a receptor of macrophage migration inhibitory factor (MIF) it can also have MIF independent functions. In this study, we report unknown roles and function of CD74 in ADPKD. We show that knockout of CD74 delays cyst growth in Pkd1 mutant kidneys. Knockout and knockdown of CD74 (1) normalize PKD associated signaling pathways, including ERK, mTOR and Rb to decrease Pkd1 mutant renal epithelial cell proliferation, (2) decrease the activation of NF-κB and the expression of MCP-1 and TNF-alpha (TNF-α) which decreases the recruitment of macrophages in Pkd1 mutant kidneys, and (3) decrease renal fibrosis in Pkd1 mutant kidneys. We show for the first time that CD74 functions as a transcriptional factor to regulate the expression of fibrotic markers, including collagen I (Col I), fibronectin, and α-smooth muscle actin (α-SMA), through binding on their promoters. Interestingly, CD74 also regulates the transcription of MIF to form a positive feedback loop in that MIF binds with its receptor CD74 to regulate the activity of intracellular signaling pathways and CD74 increases the expression of MIF in ADPKD kidneys during cyst progression. We further show that knockout of MIF and targeting MIF with its inhibitor ISO-1 not only delay cyst growth but also ameliorate renal fibrosis through blocking the activation of renal fibroblasts and CD74 mediated the activation of TGF-ß-Smad3 signaling, supporting the idea that CD74 is a key and novel upstream regulator of cyst growth and interstitial fibrosis. Thus, targeting MIF-CD74 axis is a novel therapeutic strategy for ADPKD treatment.

Toxicity of particulate emissions from residential biomass combustion: An overview of in vitro studies using cell models.

This article aims to critically review the current state of knowledge on in vitro toxicological assessments of particulate emissions from residential biomass heating systems. The review covers various aspects of particulate matter (PM) toxicity, including oxidative stress, inflammation, genotoxicity, and cytotoxicity, all of which have important implications for understanding the development of diseases. Studies in this field have highlighted the different mechanisms that biomass combustion particles activate, which vary depending on the combustion appliances and fuels. In general, particles from conventional combustion appliances are more potent in inducing cytotoxicity, DNA damage, inflammatory responses, and oxidative stress than those from modern appliances. The sensitivity of different cell lines to the toxic effects of biomass combustion particles is also influenced by cell type and culture conditions. One of the main challenges in this field is the considerable variation in sampling strategies, sample processing, experimental conditions, assays, and extraction techniques used in biomass burning PM studies. Advanced culture systems, such as co-cultures and air-liquid interface exposures, can provide more accurate insights into the effects of biomass combustion particles compared to simpler submerged monocultures. This review provides critical insights into the complex field of toxicity from residential biomass combustion emissions, underscoring the importance of continued research and standardisation of methodologies to better understand the associated health hazards and to inform targeted interventions.

Genetic diversity of SNPs associated with candidate genes for heat stress in Coreño Creole cattle in Mexico.

Mexican Coreño Creole cattle are an important genetic resource adapted to local environmental conditions, so the study of their genetic diversity is essential to know their status and implement conservation programs and their use for crossbreeding. This study evaluated the genetic diversity of heat stress tolerance characteristics of Coreño Creole cattle, and a gene ontology enrichment was performed to know the biological processes in which candidate genes are involved. A total of 48 samples from three localities of Nayarit were genotyped using 777 K Illumina BovineHD BeadChip and 34 single nucleotide polymorphisms associated with candidate genes were selected. Genetic diversity was analyzed using allelic frequencies, expected heterozygosity (He), and Wright's fixation index (FST) using PLINK v1.9 software. Candidate genes were uploaded to the open-source GOnet for pathway analysis and linkage to biological processes. Coreño Creole cattle showed low genetic diversity (He = 0.35), the average FST obtained was 0.044, and only eight markers had allele frequencies higher than 0.80 in the three locations. We found that the genes GOT1 and NCAD are related in the biological processes of stress response, cell differentiation, and homeostatic process. The results revealed that Coreño Creole cattle have low genetic diversity; this could be due to the isolation of these populations.

State of the Science and Ethical Considerations for Preimplantation Genetic Testing for Monogenic Cystic Kidney Diseases and Ciliopathies.

There is a broad phenotypic spectrum of monogenic polycystic kidney diseases (PKDs). These disorders often involve cilia-related genes and lead to the development of fluid-filled cysts and eventual kidney function decline and failure. Preimplantation genetic testing for monogenic (PGT-M) disorders has moved into the clinical realm. It allows prospective parents to avoid passing on heritable diseases to their children, including monogenic PKD. The PGT-M process involves embryo generation through in vitro fertilization, with subsequent testing of embryos and selective transfer of those that do not harbor the specific disease-causing variant(s). There is a growing body of literature supporting the success of PGT-M for autosomal-dominant and autosomal-recessive PKD, although with important technical limitations in some cases. This technology can be applied to many other types of monogenic PKD and ciliopathies despite the lack of existing reports in the literature. PGT-M for monogenic PKD, like other forms of assisted reproductive technology, raises important ethical questions. When considering PGT-M for kidney diseases, as well as the potential to avoid disease in future generations, there are regulatory and ethical considerations. These include limited government regulation and unstandardized consent processes, potential technical errors, high cost and equity concerns, risks associated with pregnancy for mothers with kidney disease, and the impact on all involved in the process, including the children who were made possible with this technology.

Concerning the presumptive identification of Candida kefyr on Uriselect™4 agar.

OBJECTIVE: Non-albicans Candida species, such as Candida kefyr, are emerging pathogens. Chromogenic media are highly useful for the diagnosis of urinary tract infections (UTIs). The aim was to describe the behavior of this specie on a non-specific chromogenic medium. METHODS: A retrospective study of cases of candiduria detected in the Microbiology laboratory of the Virgen de las Nieves Hospital in Granada (Spain) between 2016 and 2021 (N=2,130). Urine samples were quantitatively seeded on non-selective UriSelect™4 chromogenic agar. RESULTS: Between 2016 and 2021, C. kefyr was the seventh most frequent Candida species responsible for candiduria in our setting (n=15). The macroscopic appearance of C. kefyr colonies, punctiform and bluish, allowed the direct identification of these microorganisms. CONCLUSIONS: This study provides the first description of the specific behavior of C. kefyr on UriSelect™4 agar, which differentiates it from other Candida species based on its enzymatic characteristics.

Sex, Genotype, and Liver Volume Progression as Risk of Hospitalization Determinants in Autosomal Dominant Polycystic Liver Disease.

BACKGROUND & AIMS: Autosomal dominant polycystic liver disease is a rare condition with a female preponderance, based mainly on pathogenic variants in 2 genes, PRKCSH and SEC63. Clinically, autosomal dominant polycystic liver disease is characterized by vast heterogeneity, ranging from asymptomatic to highly symptomatic hepatomegaly. To date, little is known about the prediction of disease progression at early stages, hindering clinical management, genetic counseling, and the design of randomized controlled trials. To improve disease prognostication, we built a consortium of European and US centers to recruit the largest cohort of patients with PRKCSH and SEC63 liver disease. METHODS: We analyzed an international multicenter cohort of 265 patients with autosomal dominant polycystic liver disease harboring pathogenic variants in PRKCSH or SEC63 for genotype-phenotype correlations, including normalized age-adjusted total liver volumes and polycystic liver disease-related hospitalization (liver event) as primary clinical end points. RESULTS: Classifying individual total liver volumes into predefined progression groups yielded predictive risk discrimination for future liver events independent of sex and underlying genetic defects. In addition, disease severity, defined by age at first liver event, was considerably more pronounced in female patients and patients with PRKCSH variants than in those with SEC63 variants. A newly developed sex-gene score was effective in distinguishing mild, moderate, and severe disease, in addition to imaging-based prognostication. CONCLUSIONS: Both imaging and clinical genetic scoring have the potential to inform patients about the risk of developing symptomatic disease throughout their lives. The combination of female sex, germline PRKCSH alteration, and rapid total liver volume progression is associated with the greatest odds of polycystic liver disease-related hospitalization.

Facial infrared thermography as an index of social anxiety.

Previous research on physiological indices of social anxiety has offered unclear results. In this study, participants with low and high social anxiety performed five social interaction tasks while being recorded with a thermal camera. Each task was associated with a dimension assessed by the Social Anxiety Questionnaire for Adults (1 = Interactions with strangers. 2 = Speaking in public/Talking with people in authority, 3 = Criticism and embarrassment, 4 = Assertive expression of annoyance, disgust or displeasure, 5 = Interactions with the opposite sex). Mixed-effects models revealed that the temperature of the tip of the nose decreased significantly in participants with low (vs. high) social anxiety (p < 0.001), while no significant differences were found in other facial regions of interest: forehead (p = 0.999) and cheeks (p = 0.999). Furthermore, task 1 was the most effective at discriminating between the thermal change of the nose tip and social anxiety, with a trend for a higher nose temperature in participants with high social anxiety and a lower nose temperature for the low social anxiety group. We emphasize the importance of corroborating thermography with specific tasks as an ecological method, and tip of the nose thermal change as a psychophysiological index associated with social anxiety.

Evaluation of advanced imaging biomarkers at kidney failure in patients with ADPKD: a pilot study.

Background: Autosomal dominant polycystic kidney disease (ADPKD) presents with variable disease severity and progression. Advanced imaging biomarkers may provide insights into cystic and non-cystic processes leading to kidney failure in different age groups. Methods: This pilot study included 39 ADPKD patients with kidney failure, stratified into three age groups (<46, 46-56, >56 years old). Advanced imaging biomarkers were assessed using an automated instance cyst segmentation tool. The biomarkers were compared with an age- and sex-matched ADPKD cohort in early chronic kidney disease (CKD). Results: Ht-total parenchymal volume correlated negatively with age at kidney failure. The median Ht-total parenchymal volume was significantly lower in patients older than 56 years. Cystic burden was significantly higher at time of kidney failure, especially in patients who reached it before age 46 years. The cyst index at kidney failure was comparable across age groups and Mayo Imaging Classes. Advanced imaging biomarkers showed higher correlation with Ht-total kidney volume in early CKD than at kidney failure. Cyst index and parenchymal index were relatively stable over 5 years prior to kidney failure, whereas Ht-total cyst volume and cyst parenchymal surface area increased significantly. Conclusion: Age-related differences in advanced imaging biomarkers suggest variable pathophysiological mechanisms in ADPKD patients with kidney failure. Further studies are needed to validate the utility of these biomarkers in predicting disease progression and guiding treatment strategies.

Residential combustion of coal: Effect of the fuel and combustion stage on emissions.

Worldwide coal is still used for household heating purposes not only because it is available and cheap but also due to behavioural issues. Regional variability in fuels and combustion appliances make accurate emission estimates from this source hard to achieve. In the present study, gaseous (CO, VOCs, SO2 and NOX) and particulate matter (TSP) emission factors (EFs) were determined for Spanish household coal combustion covering three commercial coals and distinct combustion stages and mimicking usage patterns in real households. TSP samples were analysed to determine water-soluble inorganic ions, metal(loid)s, and organic and elemental carbon (OC and EC). Additionally, the morphology of the emitted particles was also characterised. CO (3.43-169 g kg-1), NOX (1.29-6.00 g kg-1) and SO2 (8.96-22.3 g kg-1) EFs showed no trend regarding the combustion stage or coal type tested. On the other hand, VOC, TSP and EC EFs were higher for the ignition/devolatilisation combustion stage, regardless of the fuel tested. TSP EFs (0.085-1.08 g kg-1) increased with increasing coal volatile matter while the opposite trend was recorded for VOC emissions (0.045-3.39 gC kg-1). TSP carbonaceous matter was dominated by EC while OC represented a small fraction of the particulate mass emitted (less than 8 %wt.). Inorganic compounds composed an important fraction of the TSP samples. Sulphate particulate mass fractions (8.66-22.9 %wt.) appeared to increase with coal S-content. Coal combustion released particles with diverse morphologies, including silicate-rich particles, ferro- and glassy-spheres. This study provides novel emission factors to update emission inventories of residential coal combustion. Additionally, detailed chemical profiles were obtained for source apportionment.

OVERTURE: A Worldwide, Prospective, Observational Study of Disease Characteristics in Patients With ADPKD.

Introduction: The course of autosomal dominant polycystic kidney disease (ADPKD) varies greatly among affected individuals, necessitating natural history studies to characterize the determinants and effects of disease progression. Therefore, we conducted an observational, longitudinal study (OVERTURE; NCT01430494) of patients with ADPKD. Methods: This prospective study enrolled a large international population (N = 3409) encompassing a broad spectrum of ages (12-78 years), chronic kidney disease (CKD) stages (G1-G5), and Mayo imaging classifications (1A-1E). Outcomes included kidney function, complications, quality of life, health care resource utilization, and work productivity. Results: Most subjects (84.4%) completed ≥12 months of follow-up. Consistent with earlier findings, each additional l/m of height-adjusted total kidney volume (htTKV) on magnetic resonance imaging (MRI) was associated with worse outcomes, including lower estimated glomerular filtration rate (eGFR) (regression coefficient 17.02, 95% confidence interval [CI] 15.94-18.11) and greater likelihood of hypertension (odds ratio [OR] 1.25, 95% CI 1.17-1.34), kidney pain (OR 1.22, 95% CI 1.11-1.33), and hematuria (OR 1.35, 95% CI 1.21-1.51). Greater baseline htTKV was also associated with worse patient-reported health-related quality of life (e.g., ADPKD Impact Scale physical score, regression coefficient 1.02, 95% CI 0.65-1.39), decreased work productivity (e.g., work days missed, regression coefficient 0.55, 95% CI 0.18-0.92), and increased health care resource utilization (e.g., hospitalizations, OR 1.48, 95% CI 1.33-1.64) during follow-up. Conclusion: Although limited by a maximum 3-year duration of follow-up, this observational study characterized the burden of ADPKD in a broad population and indicated the predictive value of kidney volume for outcomes other than kidney function.

Autosomal Dominant Polycystic Kidney Disease Therapies on the Horizon.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of numerous kidney cysts which leads to kidney failure. ADPKD is responsible for approximately 10% of patients with kidney failure. Overwhelming evidence supports that vasopressin and its downstream cyclic adenosine monophosphate signaling promote cystogenesis, and targeting vasopressin 2 receptor with tolvaptan and other antagonists ameliorates cyst growth in preclinical studies. Tolvaptan is the only drug approved by Food and Drug Administration to treat ADPKD patients at the risk of rapid disease progression. A major limitation of the widespread use of tolvaptan is aquaretic events. This review discusses the potential strategies to improve the tolerability of tolvaptan, the progress on the use of an alternative vasopressin 2 receptor antagonist lixivaptan, and somatostatin analogs. Recent advances in understanding the pathophysiology of PKD have led to new approaches of treatment via targeting different signaling pathways. We review the new pharmacotherapies and dietary interventions of ADPKD that are promising in the preclinical studies and investigated in clinical trials.

Epidemiology of ataxia and hereditary spastic paraplegia in Spain: A cross-sectional study.

INTRODUCTION: Ataxia and hereditary spastic paraplegia are rare neurodegenerative syndromes. We aimed to determine the prevalence of these disorders in Spain in 2019. PATIENTS AND METHODS: We conducted a cross-sectional, multicentre, retrospective, descriptive study of patients with ataxia and hereditary spastic paraplegia in Spain between March 2018 and December 2019. RESULTS: We gathered data from a total of 1933 patients from 11 autonomous communities, provided by 47 neurologists or geneticists. Mean (SD) age in our sample was 53.64 (20.51) years; 938 patients were men (48.5%) and 995 were women (51.5%). The genetic defect was unidentified in 920 patients (47.6%). A total of 1371 patients (70.9%) had ataxia and 562 (29.1%) had hereditary spastic paraplegia. Prevalence rates for ataxia and hereditary spastic paraplegia were estimated at 5.48 and 2.24 cases per 100 000 population, respectively. The most frequent type of dominant ataxia in our sample was SCA3, and the most frequent recessive ataxia was Friedreich ataxia. The most frequent type of dominant hereditary spastic paraplegia in our sample was SPG4, and the most frequent recessive type was SPG7. CONCLUSIONS: In our sample, the estimated prevalence of ataxia and hereditary spastic paraplegia was 7.73 cases per 100 000 population. This rate is similar to those reported for other countries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, our study provides useful data for estimating the necessary healthcare resources for these patients, raising awareness of these diseases, determining the most frequent causal mutations for local screening programmes, and promoting the development of clinical trials.

Drug repurposing in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease is characterized by progressive kidney cyst formation that leads to kidney failure. Tolvaptan, a vasopressin 2 receptor antagonist, is the only drug approved to treat patients with autosomal dominant polycystic kidney disease who have rapid disease progression. The use of tolvaptan is limited by reduced tolerability from aquaretic effects and potential hepatotoxicity. Thus, the search for more effective drugs to slow down the progression of autosomal dominant polycystic kidney disease is urgent and challenging. Drug repurposing is a strategy for identifying new clinical indications for approved or investigational medications. Drug repurposing is increasingly becoming an attractive proposition because of its cost-efficiency and time-efficiency and known pharmacokinetic and safety profiles. In this review, we focus on the repurposing approaches to identify suitable drug candidates to treat autosomal dominant polycystic kidney disease and prioritization and implementation of candidates with high probability of success. Identification of drug candidates through understanding of disease pathogenesis and signaling pathways is highlighted.

Clinical Implementation of an Artificial Intelligence Algorithm for Magnetic Resonance-Derived Measurement of Total Kidney Volume.

OBJECTIVE: To evaluate the performance of an internally developed and previously validated artificial intelligence (AI) algorithm for magnetic resonance (MR)-derived total kidney volume (TKV) in autosomal dominant polycystic kidney disease (ADPKD) when implemented in clinical practice. PATIENTS AND METHODS: The study included adult patients with ADPKD seen by a nephrologist at our institution between November 2019 and January 2021 and undergoing an MR imaging examination as part of standard clinical care. Thirty-three nephrologists ordered MR imaging, requesting AI-based TKV calculation for 170 cases in these 161 unique patients. We tracked implementation and performance of the algorithm over 1 year. A radiologist and a radiology technologist reviewed all cases (N=170) for quality and accuracy. Manual editing of algorithm output occurred at radiology or radiology technologist discretion. Performance was assessed by comparing AI-based and manually edited segmentations via measures of similarity and dissimilarity to ensure expected performance. We analyzed ADPKD severity class assignment of algorithm-derived vs manually edited TKV to assess impact. RESULTS: Clinical implementation was successful. Artificial intelligence algorithm-based segmentation showed high levels of agreement and was noninferior to interobserver variability and other methods for determining TKV. Of manually edited cases (n=84), the AI-algorithm TKV output showed a small mean volume difference of -3.3%. Agreement for disease class between AI-based and manually edited segmentation was high (five cases differed). CONCLUSION: Performance of an AI algorithm in real-life clinical practice can be preserved if there is careful development and validation and if the implementation environment closely matches the development conditions.