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The COVID-19 pandemic prompts the government to lock down communities and spread safety nets through subsidies to control the contagion. Consequently, the strict lockdowns refrained individuals from venturing outside and impacted their reliance on the Social Amelioration Program (SAP) from the government. This study attempts to assess the effect of SAP distribution in highly populated cities in Metro Manila in the situation of possible increase of COVID-19 contagion. The geospatial analysis showed a significant association between the SAP distribution and high population density being vulnerable during the COVID-19 pandemic outbreak. The cities of Manila, Caloocan, and Quezon City pose the highest risk for individuals defined by the ratio of correct predictions to the overall occurrence of the predicted COVID-19 cases.

Social anxiety, and its most extreme condition, social anxiety disorder, is a common international problem today. The recent Covid-19 pandemic has brought relief, at least temporarily, to many social anxiety sufferers. The decrease in face-to-face social interactions and the use of face masks have reduced the usually daily discomfort of those interactions. But it has also frozen in time the practice of their social skills and served as a safe refuge from experiencing the daily symptoms of social anxiety so often. We can say, therefore, that the pandemic has served as a reinforcement of social withdrawal behaviors for people with social anxiety, both in children and in adolescents and adults.

This letter studies the peak power handling capability (PPHC) in groove gap waveguide filters based on horizontally polarized resonators. Moreover, a modification of the resonant cavity is proposed, where the central pins of the original structure are replaced by a rounded metal block. As a result of this change, the TE₁₀₁-like mode can still be excited, but the maximum electric field strength is shifted to the center of the cavity, which leads to a higher PPHC. The main advantages of the original structure are maintained, and greater robustness in the manufacturing process is achieved. Next, some guidelines for the design of the coupling windows and the dimensions of the blocks are shown to minimize the electric field strength and, consequently, maximize the PPHC. Finally, two third-order bandpass filters (with pins and with blocks) centered at 16 GHz have been manufactured and tested in a measurement campaign, where a PPHC enhancement of 8.7 dB at high pressures is achieved for the novel solution presented in this work. This work was supported in part by the University of Alicante through the Fellowship Grant UAFPU2018-054 and in part by MCIN/AEI/10.13039/501100011033 through the Sub-Projects C41 and C43 of the Coordinated Project under Grant PID2019-103982RB.

BACKGROUND: Upregulation of cAMP-dependent and cAMP-independent PKA signaling is thought to promote cystogenesis in polycystic kidney disease (PKD). PKA-I regulatory subunit RIα is increased in kidneys of orthologous mouse models. Kidney-specific knockout of RIα upregulates PKA activity, induces cystic disease in wild-type mice, and aggravates it in Pkd1(RC/RC) mice. METHODS: PKA-I activation or inhibition was compared with EPAC activation or PKA-II inhibition using Pkd1(RC/RC) metanephric organ cultures. The effect of constitutive PKA (preferentially PKA-I) downregulation in vivo was ascertained by kidney-specific expression of a dominant negative RIαB allele in Pkd1(RC/RC) mice obtained by crossing Prkar1α(R1αB/WT), Pkd1(RC/RC), and Pkhd1-Cre mice (C57BL/6 background). The effect of pharmacologic PKA inhibition using a novel, selective PRKACA inhibitor (BLU2864) was tested in mIMCD3 3D cultures, metanephric organ cultures, and Pkd1(RC/RC) mice on a C57BL/6 × 129S6/Sv F1 background. Mice were sacrificed at 16 weeks of age. RESULTS: PKA-I activation promoted and inhibition prevented ex vivo P-Ser133 CREB expression and cystogenesis. EPAC activation or PKA-II inhibition had no or only minor effects. BLU2864 inhibited in vitro mIMCD3 cystogenesis and ex vivo P-Ser133 CREB expression and cystogenesis. Genetic downregulation of PKA activity and BLU2864 directly and/or indirectly inhibited many pro-proliferative pathways and were both protective in vivo. BLU2864 had no detectable on- or off-target adverse effects. CONCLUSIONS: PKA-I is the main PKA isozyme promoting cystogenesis. Direct PKA inhibition may be an effective strategy to treat PKD and other conditions where PKA signaling is upregulated. By acting directly on PKA, the inhibition may be more effective than or substantially increase the efficacy of treatments that only affect PKA activity by lowering cAMP.

Background and objectives 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 (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 and especially in patients who reached it before age 46. 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 five 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.

Suicidal behavior is one of the public health problems that cause most deaths in young people and has been associated with emotional and affective problems, so predictive models are required to account for the relationship between depression, anxiety, hopelessness, and alcohol consumption to propose actions for its prevention. The Plutchik Suicide Risk Scale, the CAGE Questionnaire, the Hopelessness Scale, the Depression Inventory and the Beck Anxiety Scale were applied. A total of 1.379 young people (

[EN] Multipactor has become a keylimiting factor of the final performance of satellite communication systems, due to the increase in power levels and/or operating frequency bands. As a result, the critical components of these systems must meet demanding multipactor specifications which should be considered during the design process. This paper describes the different techniques available to predict the multipactor threshold power for radio frequency (RF) and microwave passive hardware under continuous wave (CW) excitation, from cumbersome particle simulations to fast approximate methods based on circuit models. All these techniques have been described and compared together for the first time, including also a detailed description of the configuration issues of commercial particle simulators required to obtain accurate multipactor threshold predictions. The techniques are applied to both wideband and narrowband application examples. The predictions have been compared with measured thresholds of manufactured samples obtained with a novel multipactor test bed, thus allowing to highlight the advantages and limitations of each technique and particle simulator. From this paper, it will be possible to choose the most suitable procedure (and an appropriate simulator, if needed) to obtain multipactor threshold prediction of passive hardware., The work of Pablo González was supported by the FPU Fellowship of the Ministerio de Educación, Cultura y Deporte, Spanish Government, with Ref. FPU17/02901. This work was supported in part by the Ministerio de Ciencia e Innovación (MICIN, Spanish Government) under R&D Project PID2019-103982RB-C41 (funded by MICIN/AEI/10.13039/501100011033), and in part by the European Space Agency (ESA) under Project H2020-ESA-007 (funded by the European Union's Horizon 2020 Research and Innovation Program).

Resumo Este artigo objetiva investigar as práticas de fãs brasileiros do seriado norte-americano Once upon a time ao analisar os posicionamentos destes em favor do cancelamento da série por meio da hashtag #cancelouat e a continuidade de produção de fãs através da ficção nas plataformas de fanfic Spirit fanfiction e wattpad. Procura-se considerar, no universo de fãs, o ambiente virtual como um espaço de produção, colaboração e criação. Busca, com a observação dos ambientes virtuais, investigar como as práticas de participação se relacionam com as tecnologias do imaginário aqui exemplificadas pela Literatura e o campo Audiovisual. Tem como arcabouço teórico os estudos culturais com base na bibliografia de Canclini (1997) e os estudos de recepção de Jacks e Toaldo (2017), discutindo a cultura da convergência de Jenkins, (2009). Assim, tal estudo parte da percepção das práticas enquanto processo de resistências, compartilhamento e produção de conteúdos e objetos de mídia, considerando o estudo de culturas de fãs um esforço interdisciplinar que tem como conclusão primária as práticas do fandom cada vez mais pautadas no ambiente digital e ressignificadas pela participação dos sujeitos na constituição das narrativas. Palavras-chave: Once upon a time; estudos de recepção; estudos culturais; fandom; cultura da convergência. Abstract This article aims to investigate the north american series Once upon a time brazilian fans practices from a case study, up to analise their positions about the serie cancellation through a hashtag #cancelouat and the continuity of the fans production through out fiction at the Spirit Fanfiction e Wattpad platforms.. It searches to consider the virtual environment at the fans universe as a production, colaboration and creation space. It aimed to investigate how the participation practices are related to imaginary tecnologies samples here as Literature and Audio visual field. This work has as a theoritic framework the cultural studies based on Canclini´s (1997) bibliography and the reception studies from Jackins and Toaldo (2017), discussing the Jenkins convergency culture (2009). So, the study comes from the practices perceptions while a resistance, sharing and contents production and objects process from mídia, considering the fans cultural studies a interdisciplinar effort which has as a primary conclusion the fandon practices more and more done at a digital environment and re-meaningly itself through the people participation at the narratives constitution. Key words: Once upon a Time; reception studies; cultural studies; fandom; convergency culture; Resumen Este artículo tiene como objetivo investigar las prácticas de los fans brasileños de la serie norteamericana Once upon a time a partir de un caso de estudio, hasta analizar sus posiciones sobre la cancelación de la serie a través de hashtag #cancelouat y sobre la continuidad de la producción de a través de la ficción en el Spirit Fanfiction y plataformas Wattpad. Busca considerar el entorno virtual del universo de fans como un espacio de producción, colaboración y creación. Tuvo como objetivo investigar cómo las prácticas de participación se relacionan con muestras de tecnologías imaginarias como el campo de la literatura y el audiovisual. Este trabajo tiene como marco teórico los estudios culturales basados ​​en la bibliografía de Canclini (1997) y los estudios de recepción de Jackins y Toaldo (2017), discutiendo la cultura de la convergencia de Jenkins (2009). Así, el estudio parte de las percepciones de las prácticas mientras un proceso de resistencia, intercambio y producción de contenidos y objetos de mídia, considerando a los aficionados de los estudios culturales como un esfuerzo interdisciplinar que tiene como conclusión primaria las prácticas fandon cada vez más realizadas en un entorno digital y re -en sentido propio a través de la participación del pueblo en la constitución de las narrativas. Palabras clave: Éra se una vez; estudios de acogida; estudios culturales; fandom; cultura de convergencia.

Background Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disease, is regulated by different forms of cell death, including apoptosis and autophagy. However, the role in ADPKD of ferroptosis, a recently discovered form of cell death mediated by iron and lipid metabolism, remains elusive. Methods To determine a pathophysiologic role of ferroptosis in ADPKD, we investigated whether the absence of Pkd1 (encoding polycystin-1) affected the expression of key factors involved in the process of ferroptosis, using Western blot and qRT-PCR analysis in Pkd1 mutant renal cells and tissues. We also examined whether treatment with erastin, a ferroptosis inducer, and ferrostain-1, a ferroptosis inhibitor, affected cyst growth in Pkd1 mutant mouse models. Results We found that kidney cells and tissues lacking Pkd1 exhibit extensive metabolic abnormalities, including reduced expression of the system Xc- amino acid antiporter (critical for import of cystine), of iron exporter (ferroportin), and of GPX4 (a key and negative regulator of ferroptosis). The abnormalities also include increased expression of iron importers (TfR1, DMT1) and HO-1, which in turn result in high iron levels, low GSH and GPX4 activity, increased lipid peroxidation, and propensity to ferroptosis. We further found that erastin increased, and ferrostatin-1 inhibited ferroptotic cell death and proliferation of Pkd1-deficient cells in kidneys from Pkd1 mutant mice. A lipid peroxidation product increased in Pkd1-deficient cells, 4HNE, promoted the proliferation of survived Pkd1 mutant cells via activation of Akt, S6, Stat3, and Rb during the ferroptotic process, contributing to cyst growth. Conclusion These findings indicate that ferroptosis contributes to ADPKD progression and management of ferroptosis may be a novel strategy for ADPKD treatment.

A common strategy to reduce the cost of a filter is to use a manufacturing technique with an intermediate accuracy and use tuning elements to compensate for the manufacturing errors. However, including tuning elements in the final EM simulations, and tuning the filters after manufacturing, can be quite challenging. In this context, therefore, we review in this paper two powerful filter design procedures based on Aggressive Space Mapping (ASM), and two semi-automatic tuning techniques. As a validation, we describe in detail the design and tuning of two types of filters that are commonly used for both space and ground applications, namely, a six-pole inductive filter in rectangular waveguide, and a more complex five-pole filter based on dual-mode resonators.

Autosomal dominant polycystic kidney disease (ADPKD), with an estimated genetic prevalence between 1:400 and 1:1,000 individuals, is the third most common cause of end stage kidney disease after diabetes mellitus and hypertension. Over the last 3 decades there has been great progress in understanding its pathogenesis. This allows the stratification of therapeutic targets into four levels, gene mutation and polycystin disruption, proximal mechanisms directly caused by disruption of polycystin function, downstream regulatory and signaling pathways, and non-specific pathophysiologic processes shared by many other diseases. Dysfunction of the polycystins, encoded by the PKD genes, is closely associated with disruption of calcium and upregulation of cyclic AMP and protein kinase A (PKA) signaling, affecting most downstream regulatory, signaling, and pathophysiologic pathways altered in this disease. Interventions acting on G protein coupled receptors to inhibit of 3′,5′-cyclic adenosine monophosphate (cAMP) production have been effective in preclinical trials and have led to the first approved treatment for ADPKD. However, completely blocking cAMP mediated PKA activation is not feasible and PKA activation independently from cAMP can also occur in ADPKD. Therefore, targeting the cAMP/PKA/CREB pathway beyond cAMP production makes sense. Redundancy of mechanisms, numerous positive and negative feedback loops, and possibly counteracting effects may limit the effectiveness of targeting downstream pathways. Nevertheless, interventions targeting important regulatory, signaling and pathophysiologic pathways downstream from cAMP/PKA activation may provide additive or synergistic value and build on a strategy that has already had success. The purpose of this manuscript is to review the role of cAMP and PKA signaling and their multiple downstream pathways as potential targets for emergent therapies for ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney failure, accounting for 5%-10% of cases. Predicting which patients with ADPKD will progress rapidly to kidney failure is critical to assess the risk-benefit ratio of any intervention and to consider early initiation of long-term kidney protective measures that will maximize the cumulative benefit of slowing disease progression. Surrogate prognostic biomarkers are required to predict future decline in kidney function. Clinical, genetic, environmental, epigenetic, and radiologic factors have been studied as predictors of progression to kidney failure in ADPKD. A complex interaction of these prognostic factors determines the number of kidney cysts and their growth rates, which affect total kidney volume (TKV). Age-adjusted TKV, represented by the Mayo imaging classification, estimates each patient's unique rate of kidney growth and provides the most individualized approach available clinically so far. Tolvaptan has been approved to slow disease progression in patients at risk of rapidly progressive disease. Several other disease-modifying treatments are being studied in clinical trials. Selection criteria for patients at risk of rapid progression vary widely among countries and are based on a combination of age, baseline glomerular filtration rate (GFR), GFR slope, baseline TKV, and TKV rate of growth. This review details the approach in assessing the risk of disease progression in ADPKD and identifying patients who would benefit from long-term therapy with disease-modifying agents.

Introduction Loss-of-function variants in the CYP24A1 gene cause a rare hereditary disease characterized by reduced 24-hydroxylase enzyme activity, increased serum 1,25-dihydroxycholecalciferol levels, hypercalcemia, hypercalciuria, and nephrocalcinosis and/or nephrolithiasis. Kidney cysts in patients with CYP24A1 deficiency were first reported in a single case study from our center. However, a possible association between CYP24A1 deficiency and kidney cysts has not been described. Methods Retrospective analysis of patients with confirmed or suspected CYP24A1 deficiency and available kidney imaging. Results Among 16 patients with confirmed pathogenic variants, 38% were male and 31% were children, the median age at genetic confirmation was 38 years (range 1–66), and none had a family history of cystic kidney disease. Medullary and/or corticomedullary junction cysts were present in all cases. The median age at first detected cyst was 37 years (range 3–60). The mean and median number of cysts per patient were 5.3 and 2.5 (range 1–37), respectively. Four of 5 further patients with suspected but unconfirmed pathogenic variants had cysts. The number of cysts ≥5 mm in size was above the 97.5th percentile of an age- and sex-matched control population in 55% and 67% of patients with confirmed and suspected pathogenic variants, respectively. At least 1 cyst (≥5 mm in size) was found in 80% of children with confirmed CYP24A1 deficiency. Conclusions These observations strongly suggest an association between CYP24A1 deficiency and kidney cysts. Further studies are needed to evaluate the role of CYP24A1, vitamin D metabolism, and/or hypercalciuria in cyst formation, and whether cysts exacerbate chronic kidney disease or modify nephrocalcinosis and stone risk.

Autosomal dominant polycystic kidney disease (ADPKD), primarily due to PKD1 or PKD2 mutations, causes progressive kidney cyst development and kidney failure. There is significant intrafamilial variability likely due to the genetic background and environmental/lifestyle factors; variability that can be modeled in PKD mice. Here, we characterized mice homozygous for the PKD1 hypomorphic allele, p.Arg3277Cys (Pkd1(RC/RC)), inbred into the BALB/cJ (BC) or the 129S6/SvEvTac (129) strains, plus F1 progeny bred with the previously characterized C57BL/6J (B6) model; F1(BC/B6) or F1(129/B6). By one-month cystic disease in both the BC and 129 Pkd1(RC/RC) mice was more severe than in B6 and continued with more rapid progression to six to nine months. Thereafter, the expansive disease stage plateaued/declined, coinciding with increased fibrosis and a clear decline in kidney function. Greater severity correlated with more inter-animal and inter-kidney disease variability, especially in the 129-line. Both F1 combinations had intermediate disease severity, more similar to B6 but progressive from one-month of age. Mild biliary dysgenesis, and an early switch from proximal tubule to collecting duct cysts, was seen in all backgrounds. Preclinical testing with a positive control, tolvaptan, employed the F1(129/B6)-Pkd1(RC/RC) line, which has moderately progressive disease and limited isogenic variability. Magnetic resonance imaging was utilized to randomize animals and provide total kidney volume endpoints; complementing more traditional data. Thus, we show how genetic background can tailor the Pkd1(RC/RC) model to address different aspects of pathogenesis and disease modification, and describe a possible standardized protocol for preclinical testing.

Background Tumor-associated macrophages (TAMs) are critical components of the tumor microenvironment (TME) in prostate cancer. Commonly used orthotopic models do not accurately reflect the complete TME of a human patient or the natural initiation and progression of a tumor. Therefore, genetically engineered mouse models are essential for studying the TME as well as advancing TAM-targeted therapies. Two common transgenic (TG) models of prostate cancer are Hi-Myc and transgenic adenocarcinoma of the mouse prostate (TRAMP), but the TME and TAM characteristics of these models have not been well characterized. Methods To advance the Hi-Myc and TRAMP models as tools for TAM studies, macrophage infiltration and characteristics were assessed using histopathologic, flow cytometric, and expression analyses in these models at various timepoints during tumor development and progression. Results In both Hi-Myc and TRAMP models, macrophages adopt a more pro-tumor phenotype in higher histological grade tumors and in older prostate tissue. However, the Hi-Myc and TRAMP prostates differ in their macrophage density, with Hi-Myc tumors exhibiting increased macrophage density and TRAMP tumors exhibiting decreased macrophage density compared to age-matched wild type mice. Conclusions The macrophage density and the adenocarcinoma cancer subtype of Hi-Myc appear to better mirror patient tumors, suggesting that the Hi-Myc model is the more appropriate in vivo TG model for studying TAMs and TME-targeted therapies.

[EN] This paper studies the corona discharge power thresholds in microstrip bandpass filters (BPFs) and, in particular, is focused on a solution based on lambda/2 cover-ended resonators to enhance their peak power handling capability (PPHC). First, a parametric analysis is carried out to evaluate the variation of the maximum electric field and the unloaded quality factor (Q(u)) as a function of the cover's geometrical dimensions (i.e. height, length, and width). Next, several microstrip BPFs centered at 1.6 GHz are designed, and their behaviors under moderate-to-high applied RF power signals are simulated to corroborate the previous study. A suitable number and size of covers are selected to enhance PPHC without barely degrading the filters' electrical performance and, consequently, without hardly increasing the insertion losses. Finally, two third-order filters with covers and without covers (benchmark prototype) are manufactured, by way of illustration, and they are tested in the European High-Power RF Space Laboratory to validate the good performance of the proposed solution, where a PPHC enhancement of 3.1 dB at high pressures is achieved as compared to the benchmark prototype., This work has been supported by the University of Alicante through the fellowship grant UAFPU2018-054 and by the "Ministerio de Ciencia e Innovacion" through the sub-projects C41 and C43 of the coordinated project PID2019-103982RB. The authors would like to thank Val Space Consortium for its contribution - Laboratories funded by the European Development Fund - A way of making Europe.

Introduction Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst growth and a loss of functioning renal mass, but a decline in glomerular filtration rate (GFR) and onset of end-stage renal disease (ESRD) occur late in the disease course. There is therefore a great need for early prognostic biomarkers in this disorder. Methods We measured baseline serum fibroblast growth factor 23 (FGF23) levels in 192 patients with ADPKD from the Consortium for Radiologic Imaging Studies of PKD (CRISP) cohort that were followed for a median of 13 years and tested the association between FGF23 levels and change over time in height-adjusted total kidney volume (htTKV), GFR, and time to the composite endpoints of ESRD, death, and doubling of serum creatinine. Results Patients in the highest quartile for baseline FGF23 level had a higher rate of increase in htTKV (0.95% per year, P = 0.0016), and faster rate of decline in GFR (difference of −1.03 ml/min/1.73 m2 per year, P = 0.005) compared with the lowest quartile, after adjusting for other covariates, including htTKV and genotype. The highest quartile of FGF23 was also associated with a substantial increase in risk for the composite endpoint of ESRD, death, or doubling of serum creatinine (hazard ratio [HR] of 2.45 in the fully adjusted model, P = 0.03). Conclusion FGF23 is a prognostic biomarker for disease progression and clinically important outcomes in ADPKD, and has additive value to established imaging and genetic biomarkers., Graphical abstract

Mice with disruption of Pkd1 in osteoblasts demonstrate reduced bone mineral density, trabecular bone volume and cortical thickness. To date, the bone phenotype in adult patients with autosomal dominant polycystic kidney disease (ADPKD) with stage I and II chronic kidney disease has not been investigated. To examine this, we characterized biochemical markers of mineral metabolism, examined bone turnover and biology, and estimated risk of fracture in patients with ADPKD. Markers of mineral metabolism were measured in 944 patients with ADPKD and other causes of kidney disease. Histomorphometry and immunohistochemistry were compared on bone biopsies from 20 patients with ADPKD with a mean eGFR of 97 ml/ min/1.73m(2) and 17 healthy individuals. Furthermore, adults with end stage kidney disease (ESKD) initiating hemodialysis between 2002–2013 and estimated the risk of bone fracture associated with ADPKD as compared to other etiologies of kidney disease were examined. Intact fibroblast growth factor 23 was higher and total alkaline phosphatase lower in patients with compared to patients without ADPKD with chronic kidney disease. Compared to healthy individuals, patients with ADPKD demonstrated significantly lower osteoid volume/bone volume (0.61 vs. 1.21%) and bone formation rate/bone surface (0.012 vs. 0.026 μm(3)/μm(2)/day). ESKD due to ADPKD was not associated with a higher risk of fracture as compared to ESKD due to diabetes (age adjusted incidence rate ratio: 0.53 (95% confidence interval 0.31, 0.74) or compared to other etiologies of kidney disease. Thus, individuals with ADPKD have lower alkaline phosphatase, higher circulating intact fibroblast growth factor 23 and decreased bone formation rate. However, ADPKD is not associated with higher rates of bone fracture in ESKD.

In this letter, we propose a new device that integrates the functions of a microwave filter and switch (F&S). The key component of the F&S is a modified tuning pin (MTP) that can be used to tune or to detune a cavity or an aperture. In addition to theory, a prototype is also manufactured and tested, showing how the switching function of the new device can be easily controlled remotely.

Introduction Cystic expansion damaging the parenchyma is thought to lead to end-stage kidney disease (ESKD) in autosomal dominant polycystic kidney disease (ADPKD). Here we characterized genotypic and phenotypic attributes of ADPKD at time of ESKD. Methods This is a retrospective cross-sectional study of patients with ADPKD with ESKD evaluated at Mayo Clinic with available abdominal computed tomography (CT) or magnetic resonance imaging (MRI). Kidney volumes were measured (total kidney volume adjusted for height [HtTKV]), Mayo Image Class (MIC) calculated, ADPKD genotype determined, and clinical and laboratory features obtained from medical records. Results Differences in HtTKV at ESKD were associated with patient age and sex; older patients and women had smaller HtTKV at ESKD. HtTKV at ESKD was observed to be 12.3% smaller with each decade of age (P < 0.01); but significant only in women (17.8%, P < 0.01; men 6.9%, P = 0.06). Patients with onset of ESKD at 61 years had different characteristics, with a shift from youngest to oldest in male to female enrichment, MIC from 1D/1E to 1B/1C, likely fully penetrant PKD1 mutations from 95% to 42%, and presence of macrovascular disease from 8% to 40%. Macrovascular disease was associated with smaller kidneys in female patients. Conclusion HtTKV at ESKD was smaller with advancing age in patients with ADPKD, particularly in women. These novel findings provide insight into possible underlying mechanisms leading to ESKD, which differ between younger and older individuals. Cystic growth is the predominant mechanism in younger patients with ESKD, whereas aging-related factors, including vascular disease, becomes potentially important as patients age., Graphical abstract

Background Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic disorders in humans and is characterized by numerous fluid-filled cysts that grow slowly, resulting in end-stage renal disease in the majority of patients. Preclinical studies have indicated that treatment with low-dose thiazolidinediones, such as pioglitazone, decrease cyst growth in rodent models of PKD. Methods This Phase 1b cross-over study compared the safety of treatment with a low dose (15 mg) of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone or placebo in PKD patients, with each treatment given for 1 year. The study monitored known side effects of PPAR-γ agonist treatment, including fluid retention and edema. Liver enzymes and risk of hypoglycemia were assessed throughout the study. As a secondary objective, the efficacy of low-dose pioglitazone was followed using a primary assessment of total kidney volume (TKV), blood pressure (BP) and kidney function. Results Eighteen patients were randomized and 15 completed both arms. Compared with placebo, allocation to pioglitazone resulted in a significant decrease in total body water as assessed by bioimpedance analysis {mean difference 0.16 Ω [95% confidence interval (CI) 0.24–2.96], P = 0.024} and no differences in episodes of heart failure, clinical edema or change in echocardiography. Allocation to pioglitazone led to no difference in the percent change in TKV of −3.5% (95% CI −8.4–1.4, P = 0.14), diastolic BP and microalbumin:creatinine ratio. Conclusions In this small pilot trial in people with ADPKD but without diabetes, pioglitazone 15 mg was found to be as safe as placebo. Larger and longer-term randomized trials powered to assess effects on TKV are needed.

The Plusiinae subfamily has many polyphagous species, many of which occur in South America. Chrysodeixis includens and Rachiplusia nu are two representatives that mainly occurs in soybeans, cotton, common beans, sunflower and alfalfa. A population genetic study of C. includens and R. nu collected in the Southern Cone of America was performed using a partial COI gene sequencing data and compared with specimens from other American countries. Six haplotypes were identified in C. includens populations of Brazil, Argentina, Paraguay and Uruguay, organized within a star-like haplotype network, with the most common haplotype identified as Chin_MC. R. nu populations are more diverse and stable in comparison to C. includens. Populations from Argentina and Uruguay had the highest haplotype diversity, sharing five haplotypes and putatively indicating haplotype exchange. Demographic change analysis suggested a recent population expansion of C. includens over the American continent. Some C. includens haplotypes were country-specific, suggesting population expansion in the countries where specimens were collected.

Polycystic kidney disease (PKD) has been linked to abnormal structure/function of ciliary proteins, leading to renal dysfunction. Recently, attention has been focused in the significant vascular abnormalities associated with PKD, but the mechanisms underlying this phenomenon remain elusive. Here, we seek to define the molecular events regulating the angiogenic imbalance observed in PKD. Using micro computed tomography (n=7) and protein expression analysis (n=5), we assessed the vascular density and the angiogenic profile of noncystic organs in a well-established PKD rat model (Polycystic Kidney-PCK rat). Heart and lungs of PCK rats have reduced vascular density and decreased expression of angiogenic factors compared with wild type. Similarly, PCK-vascular smooth muscle cells (VSMCs; n=4) exhibited lower levels of vascular markers. Then, using small interfering RNA (n=4), we determined the role of the ciliary protein fibrocystin in wild type-VSMCs, a critical component/regulator of vascular structure and function. Reduction of fibrocystin in wild type-VSMCs (n=4) led to an abnormal angiogenic potential similar to that observed in PCK-VSMCs. Furthermore, we investigated the involvement of the hedgehog signaling, a pathway closely linked to the primary cilium and associated with vascular development, in PKD. Mechanistically, we demonstrated that impairment of the hedgehog signaling mediates, in part, this abnormal angiogenic phenotype. Lastly, overexpression of Gli1 in PCK-VSMCs (n=4) restored the expression levels of proangiogenic molecules. Our data support a critical role of fibrocystin in the abnormal vascular phenotype of PKD and indicate that a dysregulation of hedgehog may be responsible, at least in part, for these vascular deficiencies.

Cardiovascular disease leads to high morbidity and mortality in patients with kidney failure. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic disease with various cardiac abnormalities. Details on the cardiovascular profile of patients with ADPKD who are undergoing kidney transplantation (KT) and its progression are limited.Echocardiographic data within 2 years before KT (1993-2020), and major adverse cardiovascular events (MACEs) after transplantation were retrieved. The primary outcome is to assess cardiovascular abnormalities on echocardiography at the time of transplantation in ADPKD as compared with patients without ADPKD matched by sex (male, 59.4%) and age at transplantation (57.2 ± 8.8 years).Compared with diabetic nephropathy (DN,ADPKD transplant recipients have the most favorable cardiac profile pretransplantation with better patient survival and MACE-free survival rates but worsening valvular function and increasing sinus of Valsalva diameter, as compared with patients with other kidney diseases.

To test the efficacy of cognitive-behavioural therapy (CBT) for lifestyle modification in patients with metabolic syndrome (MetS).76 MetS patients completed this clinical trial, with 18 months follow-up. 45 participants from the experimental group (EG - CBT) and 31 to the control group (CG - usual care). The CBT programme was performed by a psychologist in a face-to-face group format, during 12 weekly sessions lasting 90 minutes. The intervention for the CG consisted of workshops with basic information about MetS and it's associated cardiovascular risk.Efficacy of (CBT) in (MetS) patients.Results showed reduction in weight (mean difference - MD -2.633, 95%CI [-4.322, -0.943]; p.003), waist circumference (MD -2.944, 95%CI [-5.090, -0.798]; p.008), body mass index (MD -0.915, 95%CI [-1.494, -0.335]; p.003), systolic (MD -0.046, 95%CI [-0.685, -0.023]; p.0002) diastolic blood pressure (MD -4.777, 95%CI [-7.750, -1.804]; p.002), and cardiovascular risk score after 18 months. An increase in adherence to the Mediterranean diet and assertiveness and a reduction in anger were observed in EG. The CG did not show any significant differences.The CBT focused on changes in lifestyle seems to be effective in the reduction of MetS and cardiovascular risk factors.Registered at clinicaltrials.gov (NCT02949622) - PROMETS (Multimodal Intervention Program for Patients with Metabolic Syndrome).

Tolvaptan is associated with risk of drug-induced liver injury when used to treat autosomal dominant polycystic kidney disease (ADPKD). After this risk was described based on the clinical trials TEMPO 3:4 and TEMPO 4:4, additional data from the REPRISE trial and a long-term extension of TEMPO 4:4, REPRISE, and other tolvaptan trials in ADPKD have become available. To further characterize the hepatic safety profile of tolvaptan, an analysis of the expanded dataset was conducted.Analysis of safety data from prospective clinical trials of tolvaptan.Multicenter clinical trials including more than 2,900 tolvaptan-treated participants, more than 2,300 with at least 18 months of drug exposure.Tolvaptan administered twice daily in split-dose regimens.Frequency of liver enzyme level increases detected by regular laboratory monitoring.In the placebo-controlled REPRISE trial, more tolvaptan- than placebo-treated participants (38 of 681 [5.6%] vs 8 of 685 [1.2%]) experienced alanine aminotransferase level increases to3× the upper limit of normal (ULN), similar to TEMPO 3:4 (40 of 957 [4.4%] vs 5 of 484 [1.0%]). No participant in REPRISE or the long-term extension experienced concurrent alanine aminotransferase level increases to3× ULN and total bilirubin increases to2× ULN ("Hy's Law" laboratory criteria). Based on the expanded dataset, liver enzyme increases most often occurred within 18 months after tolvaptan initiation and were less frequent thereafter. Increased levels returned to normal or near normal after treatment interruption or discontinuation. Thirty-eight patients were rechallenged with tolvaptan after the initial drug-induced liver injury episode, with return of liver enzyme level increases in 30; 1 additional participant showed a clinical "adaptation" after the initial episode, with resolution of the enzyme level increases despite continuation of tolvaptan.Retrospective analysis.The absence of Hy's Law cases in REPRISE and the long-term extension trial support monthly liver enzyme monitoring during the first 18 months of tolvaptan exposure and every 3 months thereafter to detect and manage enzyme level increases, as is recommended on the drug label.Otsuka Pharmaceutical DevelopmentCommercialization, Inc.Trials included in the dataset were registered at ClinicalTrials.gov with study numbers NCT00428948 (TEMPO 3:4), NCT01214421 (TEMPO 4:4), NCT02160145 (REPRISE), and NCT02251275 (long-term extension).