Gender Disparities in End of Life Care: A Scoping Review.

Objective: Traditional gender norms and expectations may disproportionately constrain in-home palliative care received by women. This scoping review aims to canvass and evaluate the literature on gender disparities in end of life care and explore relevant themes that could inform future research and practice. Methods: A systematic search of MEDLINE, OVID, COCHRANE, and EMBASE was conducted using MeSH terms palliative care, palliative medicine, terminal care, or hospice care, combined with gender equity, sex factors, sexism, or gender disparities. Articles were limited to those in English (2010 to 2021), focusing on end of life care, gender roles, patients, and caregivers. Results: Of 624 articles identified, 15 met inclusion criteria for critical appraisal using the AMSTAR checklist for systematic reviews and NICE guidelines for quantitative and qualitative studies. Most studies were of poor to moderate quality. Thematic analyses identified 6 major themes related to gender disparities: living situation, symptom experience, care context, care preferences, caregiving, and coping strategies. Conclusion: Larger scale research of better quality is needed to fully characterize gender disparities in end of life care and understand how physicians might mitigate these disparities by building awareness of personal gender biases, providing support to families, educating them, and initiating care discussions that overturn traditional and stereotypic gendered expectations.

Differential microRNA expression, microRNA arm switching, and microRNA:long noncoding RNA interaction in response to salinity stress in soybean.

BACKGROUND: Soybean is a major legume crop with high nutritional and environmental values suitable for sustainable agriculture. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are important regulators of gene functions in eukaryotes. However, the interactions between these two types of ncRNAs in the context of plant physiology, especially in response to salinity stress, are poorly understood. RESULTS: Here, we challenged a cultivated soybean accession (C08) and a wild one (W05) with salt treatment and obtained their small RNA transcriptomes at six time points from both root and leaf tissues. In addition to thoroughly analyzing the differentially expressed miRNAs, we also documented the first case of miRNA arm-switching (miR166m), the swapping of dominant miRNA arm expression, in soybean in different tissues. Two arms of miR166m target different genes related to salinity stress (chloroplastic beta-amylase 1 targeted by miR166m-5p and calcium-dependent protein kinase 1 targeted by miR166m-3p), suggesting arm-switching of miR166m play roles in soybean in response to salinity stress. Furthermore, two pairs of miRNA:lncRNA interacting partners (miR166i-5p and lncRNA Gmax_MSTRG.35921.1; and miR394a-3p and lncRNA Gmax_MSTRG.18616.1) were also discovered in reaction to salinity stress. CONCLUSIONS: This study demonstrates how ncRNA involves in salinity stress responses in soybean by miRNA arm switching and miRNA:lncRNA interactions. The behaviors of ncRNAs revealed in this study will shed new light on molecular regulatory mechanisms of stress responses in plants, and hence provide potential new strategies for crop improvement.

Prescribed Water Intake in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Arginine vasopressin promotes kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD). Increased water intake reduces arginine vasopressin and urine osmolality and may slow kidney cyst growth. METHODS: In this randomized controlled 3-year clinical trial, we randomly assigned adults with ADPKD who had a height-corrected total kidney volume in Mayo imaging subclass categories 1B to 1E and an estimated glomerular filtration rate of 30 ml/min/1.73 m2 or greater to (1) water intake prescribed to reduce 24-hour urine osmolality to 270 mOsmol/kg or less or (2) ad libitum water intake irrespective of 24-hour urine osmolality. The primary end point was the percentage annualized rate of change in height-corrected total kidney volume. RESULTS: A total of 184 patients participated in either the ad libitum water intake group (n=92) or the prescribed water intake group (n=92). Over 3 years, there was no difference in the annualized rate of change in height-corrected total kidney volume between the ad libitum (7.8% per year; 95% confidence interval [CI], 6.6 to 9.0) and prescribed (6.8% per year; 95% CI, 5.8 to 7.7) water intake groups (mean difference, −0.97% per year; 95% CI, −2.37 to 0.44; P=0.18). The difference in mean 24-hour urine osmolality between the ad libitum and prescribed water intake groups was −91 mOsmol/kg (95% CI, −127 to −54 mOsmol/kg), with 52.3% of patients achieving adherence to the target 24-hour urine osmolality and no reduction in serum copeptin over 3 years. The frequency of adverse events was similar between groups. CONCLUSIONS: For patients with ADPKD, prescribed water intake was not associated with excess adverse events and achieved the target 24-hour urine osmolality for half of the patients but did not reduce copeptin or slow the growth of total kidney volume over 3 years compared with ad libitum water intake. (Funded by the National Health and Medical Research Council of Australia [grant GNT1138533], Danone Research, PKD Australia, the University of Sydney, and the Westmead Medical Research Foundation; Australian New Zealand Clinical Trials Registry number, ACTRN12614001216606).

Clinical characteristics and outcomes of hyponatraemia associated with oral water intake in adults: a systematic review.

INTRODUCTION: Excessive water intake is rarely associated with life-threatening hyponatraemia. The aim of this study was to determine the clinical characteristics and outcomes of hyponatraemia associated with excess water intake. METHODS: This review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All studies (case reports, observational or interventional studies) reporting excess water intake and hyponatraemia in adults (1946-2019) were included. RESULTS: A total of 2970 articles were identified and 177 were included (88.7% case reports), consisting of 590 patients. The mean age was 46±16 years (95% CI 44 to 48 years), 47% female, 52% had a chronic psychiatric disorder and 31% had no underlying condition. The median volume of water consumed and serum sodium at presentation was 8 L/day (95% CI 8.9 to 12.2 L/day) and 118 mmol/L (95% CI 116 to 118 mmol/L), respectively. The motivator for increased water consumption was psychogenic polydipsia (55%); iatrogenic (13%); exercise (12%); habitual/dipsogenic polydipsia (7%) and other reasons (13%). The clinical features on presentation were severe in 53% (seizures, coma); moderate in 35% (confusion, vomiting, agitation) and mild in 5% (dizziness, lethargy, cognitive deficit) and not reported in 5% of studies. Treatment was supportive in 41% of studies (fluid restriction, treatment of the underlying cause, emergency care), and isotonic and hypertonic saline was used in 18% and 28% of cases, respectively. Treatment-related complications included osmotic demyelination (3%) and rhabdomyolysis (7%), and death occurred in 13% of cases. CONCLUSION: Water intoxication is associated with significant morbidity and mortality and requires daily intake to substantially exceed population-based recommendations. The limitations of this analysis are the low quality and high risk of bias of the included studies. PROSPERO REGISTRATION NUMBER: A pre-existing protocol in the international prospective register of systematic reviews was updated to incorporate any new amendments and reregistered at http://www.crd.york.ac.uk/PROSPERO (registration no. CRD42019129809).

Effect of Early and Delayed Commencement of Paricalcitol in Combination with Enalapril on the Progression of Experimental Polycystic Kidney Disease.

Vitamin D secosteroids are intranuclear regulators of cellular growth and suppress the renin-angiotensin system. The aim of this study was to test the hypothesis that the vitamin D receptor agonist, paricalcitol (PC), either alone or with enalapril (E) (an angiotensin-converting enzyme inhibitor), reduces the progression of polycystic kidney disease. Preventative treatment of Lewis polycystic kidney (LPK) and Lewis control rats with PC (0.2 µg/kg i.p. 5 days/week) or vehicle from postnatal weeks 3 to 10 did not alter kidney enlargement. To evaluate the efficacy in established disease, LPK rats received either PC (0.8 µg/kg i.p; 3 days/week), vehicle, E (50 mg/L in water) or the combination of PC + E from weeks 10 to 20. In established disease, PC also did not alter the progression of kidney enlargement, kidney cyst growth or decline in renal function in LPK rats. Moreover, the higher dose of PC was associated with increased serum calcium and weight loss. However, in established disease, the combination of PC + E reduced systolic blood pressure and heart-body weight ratio compared to vehicle and E alone (p < 0.05). In conclusion, the combination of PC + E attenuated cardiovascular disease but caused hypercalcaemia and did not alter kidney cyst growth in LPK rats.

Long-term dietary nitrate supplementation does not reduce renal cyst growth in experimental autosomal dominant polycystic kidney disease.

Augmentation of endogenous nitric oxide (NO) synthesis, either by the classical L-arginine-NO synthase pathway, or the recently discovered entero-salivary nitrate-nitrite-NO system, may slow the progression of autosomal dominant polycystic kidney disease (ADPKD). To test this hypothesis, the expression of NO in human ADPKD cell lines (WT 9-7, WT 9-12), and the effect of L-arginine on an in vitro model of three-dimensional cyst growth using MDCK cells, was examined. In addition, groups of homozygous Pkd1RC/RC mice (a hypomorphic genetic ortholog of ADPKD) received either low, moderate or high dose sodium nitrate (0.1, 1 or 10 mmol/kg/day), or sodium chloride (vehicle; 10 mmol/kg/day), supplemented drinking water from postnatal month 1 to 9 (n = 12 per group). In vitro, intracellular NO, as assessed by DAF-2/DA fluorescence, was reduced by >70% in human ADPKD cell lines, and L-arginine and the NO donor, sodium nitroprusside, both attenuated in vitro cyst growth by up to 18%. In contrast, in Pkd1RC/RC mice, sodium nitrate supplementation increased serum nitrate/nitrite levels by ~25-fold in the high dose group (P<0.001), but kidney enlargement and percentage cyst area was not altered, regardless of dose. In conclusion, L-arginine has mild direct efficacy on reducing renal cyst growth in vitro, whereas long-term sodium nitrate supplementation was ineffective in vivo. These data suggest that the bioconversion of dietary nitrate to NO by the entero-salivary pathway may not be sufficient to influence the progression of renal cyst growth in ADPKD.

Up-Regulation of DNA Damage Response Signaling in Autosomal Dominant Polycystic Kidney Disease.

DNA damage and alterations in DNA damage response (DDR) signaling could be one of the molecular mechanisms mediating focal kidney cyst formation in autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to test the hypothesis that markers of DNA damage and DDR signaling are increased in human and experimental ADPKD. In the human ADPKD transcriptome, the number of up-regulated DDR-related genes was increased by 16.6-fold compared with that in normal kidney, and by 2.5-fold in cystic compared with that in minimally cystic tissue (P < 0.0001). In end-stage human ADPKD tissue, γ-H2A histone family member X (H2AX), phosphorylated ataxia telangiectasia and radiation-sensitive mutant 3 (Rad3)-related (pATR), and phosphorylated ataxia telangiectasia mutated (pATM) localized to cystic kidney epithelial cells. In vitro, pATR and pATM were also constitutively increased in human ADPKD tubular cells (WT 9-7 and 9-12) compared with control (HK-2). In addition, extrinsic oxidative DNA damage by hydrogen peroxide augmented γ-H2AX and cell survival in human ADPKD cells, and exacerbated cyst growth in the three-dimensional Madin-Darby canine kidney cyst model. In contrast, DDR-related gene expression was only transiently increased on postnatal day 0 in Pkd1RC/RC mice, and not altered at later time points up to 12 months of age. In conclusion, DDR signaling is dysregulated in human ADPKD and during the early phases of murine ADPKD. The constitutive expression of the DDR pathway in ADPKD may promote survival of PKD1-mutated cells and contribute to kidney cyst growth.

Horseshoe crab genomes reveal the evolution of genes and microRNAs after three rounds of whole genome duplication.

Whole genome duplication (WGD) has occurred in relatively few sexually reproducing invertebrates. Consequently, the WGD that occurred in the common ancestor of horseshoe crabs ~135 million years ago provides a rare opportunity to decipher the evolutionary consequences of a duplicated invertebrate genome. Here, we present a high-quality genome assembly for the mangrove horseshoe crab Carcinoscorpius rotundicauda (1.7 Gb, N50 = 90.2 Mb, with 89.8% sequences anchored to 16 pseudomolecules, 2n = 32), and a resequenced genome of the tri-spine horseshoe crab Tachypleus tridentatus (1.7 Gb, N50 = 109.7 Mb). Analyses of gene families, microRNAs, and synteny show that horseshoe crabs have undergone three rounds (3R) of WGD. Comparison of C. rotundicauda and T. tridentatus genomes from populations from several geographic locations further elucidates the diverse fates of both coding and noncoding genes. Together, the present study represents a cornerstone for improving our understanding of invertebrate WGD events on the evolutionary fates of genes and microRNAs, at both the individual and population level. We also provide improved genomic resources for horseshoe crabs, of applied value for breeding programs and conservation of this fascinating and unusual invertebrate lineage.

Assessment of Dietary Sodium Intake Using the Scored Salt Questionnaire in Autosomal Dominant Polycystic Kidney Disease.

The excess intake of dietary sodium is a key modifiable factor for reducing disease progression in autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to test the hypothesis that the scored salt questionnaire (SSQ; a frequency questionnaire of nine sodium-rich food types) is a valid instrument to identify high dietary salt intake in ADPKD. The performance of the SSQ was evaluated in adults with ADPKD with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 during the screening visit of the PREVENT-ADPKD trial. High dietary sodium intake (HSI) was defined by a mean 24-h urinary sodium excretion ≥ 100 mmol/day from two collections. The median 24-h urine sodium excretion was 132 mmol/day (IQR: 112-172 mmol/d) (n = 75; mean age: 44.6 ± 11.5 years old; 53% female), and HSI (86.7% of total) was associated with male gender and higher BMI and systolic blood pressure (p < 0.05). The SSQ score (73 ± 23; mean ± SD) was weakly correlated with log10 24-h urine sodium excretion (r = 0.29, p = 0.01). Receiving operating characteristic analysis showed that the optimal cut-off point in predicting HSI was an SSQ score of 74 (area under the curve 0.79; sensitivity 61.5%; specificity 90.0%; p < 0.01). The evaluation of the SSQ in participants with a BMI ≥ 25 (n = 46) improved the sensitivity (100%) and the specificity (100%). Consumers with an SSQ score ≥ 74 (n = 41) had higher relative percentage intake of processed meats/seafood and flavourings added to cooking (p < 0.05). In conclusion, the SSQ is a valid tool for identifying high dietary salt intake in ADPKD but its value proposition (over 24-h urinary sodium measurement) is that it may provide consumers and their healthcare providers with insight into the potential origin of sodium-rich food sources.

Millipede genomes reveal unique adaptations during myriapod evolution.

The Myriapoda, composed of millipedes and centipedes, is a fascinating but poorly understood branch of life, including species with a highly unusual body plan and a range of unique adaptations to their environment. Here, we sequenced and assembled 2 chromosomal-level genomes of the millipedes Helicorthomorpha holstii (assembly size = 182 Mb; shortest scaffold/contig length needed to cover 50% of the genome [N50] = 18.11 Mb mainly on 8 pseudomolecules) and Trigoniulus corallinus (assembly size = 449 Mb, N50 = 26.78 Mb mainly on 17 pseudomolecules). Unique genomic features, patterns of gene regulation, and defence systems in millipedes, not observed in other arthropods, are revealed. Both repeat content and intron size are major contributors to the observed differences in millipede genome size. Tight Hox and the first loose ecdysozoan ParaHox homeobox clusters are identified, and a myriapod-specific genomic rearrangement including Hox3 is also observed. The Argonaute (AGO) proteins for loading small RNAs are duplicated in both millipedes, but unlike in insects, an AGO duplicate has become a pseudogene. Evidence of post-transcriptional modification in small RNAs-including species-specific microRNA arm switching-providing differential gene regulation is also obtained. Millipedes possesses a unique ozadene defensive gland unlike the venomous forcipules found in centipedes. We identify sets of genes associated with the ozadene that play roles in chemical defence as well as antimicrobial activity. Macro-synteny analyses revealed highly conserved genomic blocks between the 2 millipedes and deuterostomes. Collectively, our analyses of millipede genomes reveal that a series of unique adaptations have occurred in this major lineage of arthropod diversity. The 2 high-quality millipede genomes provided here shed new light on the conserved and lineage-specific features of millipedes and centipedes. These findings demonstrate the importance of the consideration of both centipede and millipede genomes-and in particular the reconstruction of the myriapod ancestral situation-for future research to improve understanding of arthropod evolution, and animal evolutionary genomics more widely.

A digital health intervention for cardiovascular disease management in primary care (CONNECT) randomized controlled trial.

Digital health applications (apps) have the potential to improve health behaviors and outcomes. We aimed to examine the effectiveness of a consumer web-based app linked to primary care electronic health records (EHRs). CONNECT was a multicenter randomized controlled trial involving patients with or at risk of cardiovascular disease (CVD) recruited from primary care (Clinical Trial registration ACTRN12613000715774). Intervention participants received an interactive app which was pre-populated and refreshed with EHR risk factor data, diagnoses and, medications. Interactive risk calculators, motivational messages and lifestyle goal tracking were also included. Control group received usual health care. Primary outcome was adherence to guideline-recommended medications (≥80% of days covered for blood pressure (BP) and statin medications). Secondary outcomes included attainment of risk factor targets and eHealth literacy. In total, 934 patients were recruited; mean age 67.6 (±8.1) years. At 12 months, the proportion with >80% days covered with recommended medicines was low overall and there was no difference between the groups (32.8% vs. 29.9%; relative risk [RR] 1.07 [95% CI, 0.88-1.20] p = 0.49). There was borderline improvement in the proportion meeting BP and LDL targets in intervention vs. control (17.1% vs. 12.1% RR 1.40 [95% CI, 0.97-2.03] p = 0.07). The intervention was associated with increased attainment of physical activity targets (87.0% intervention vs. 79.7% control, p = 0.02) and e-health literacy scores (72.6% intervention vs. 64.0% control, p = 0.02). In conclusion, a consumer app integrated with primary health care EHRs was not effective in increasing medication adherence. Borderline improvements in risk factors and modest behavior changes were observed.

Infection patterns of dengue, Zika and endosymbiont Wolbachia in the mosquito Aedes albopictus in Hong Kong.

BACKGROUND: The mosquito Aedes albopictus is a vector of dengue and Zika viruses. Insecticide-resistant mosquito populations have evolved in recent decades, suggesting that new control strategies are needed. Hong Kong has a monsoon-influenced humid subtropical climate, which favours the spread of mosquitoes. However, baseline information on the composition and dynamics of the occurrence of endosymbiont Wolbachia in local Ae. albopictus is lacking, hindering the development of scientifically-informed control measures. This study identifies the presence and absence of dengue and Zika viruses, and Wolbachia infection in Aedes albopictus in Hong Kong. METHODS: Oviposition traps were set at 57 areas in Hong Kong, and both immature and adult mosquitoes were collected on a monthly basis between April 2018 and April 2019 as the study sample. Each individual mosquito in this sample was processed and screened for the presence of the dengue and Zika viruses and the endosymbionts Wolbachia wAlbA and wAlbB with PCR. RESULTS: Totals of 967 and 984 mosquitoes were tested respectively for the presence of dengue and Zika viruses, and no trace of either infection was found in these samples. The presence of wAlbA and wAlbB was also tested in 1582 individuals. Over 80% of these individuals were found to be stably infected with Wolbachia throughout the thirteen-month collection period (~ 47% singly-infected; ~ 36.8% doubly infected with both wAlbA and wAlbB). CONCLUSIONS: The high degree of Wolbachia wAlbA and wAlbB infection in Ae. albopictus mosquitoes in Hong Kong, coupled with the absence of any signs of infection by dengue and Zika viruses, contrasts significantly with the pattern of mosquito infection in other parts of Asia. Further studies of the infection pattern in local mosquitoes are warranted before mosquito control strategies used in other regions are implemented in Hong Kong.

Micro-RNA Clusters Integrate Evolutionary Constraints on Expression and Target Affinities: The miR-6/5/4/286/3/309 Cluster in Drosophila.

A striking feature of micro-RNAs is that they are often clustered in the genomes of animals. The functional and evolutionary consequences of this clustering remain obscure. Here, we investigated a micro-RNA cluster miR-6/5/4/286/3/309 that is conserved across drosophilid lineages. Small RNA sequencing revealed expression of this micro-RNA cluster in Drosophila melanogaster leg discs, and conditional overexpression of the whole cluster resulted in leg appendage shortening. Transgenic overexpression lines expressing different combinations of micro-RNA cluster members were also constructed. Expression of individual micro-RNAs from the cluster resulted in a normal wild-type phenotype, but either the expression of several ancient micro-RNAs together (miR-5/4/286/3/309) or more recently evolved clustered micro-RNAs (miR-6-1/2/3) can recapitulate the phenotypes generated by the whole-cluster overexpression. Screening of transgenic fly lines revealed downregulation of leg-patterning gene cassettes in generation of the leg-shortening phenotype. Furthermore, cell transfection with different combinations of micro-RNA cluster members revealed a suite of downstream genes targeted by all cluster members, as well as complements of targets that are unique for distinct micro-RNAs. Considered together, the micro-RNA targets and the evolutionary ages of each micro-RNA in the cluster demonstrate the importance of micro-RNA clustering, where new members can reinforce and modify the selection forces on both the cluster regulation and the gene regulatory network of existing micro-RNAs. Key words: micro-RNA, cluster, evolution.

Regression of Peritubular Capillaries Coincides with Angiogenesis and Renal Cyst Growth in Experimental Polycystic Kidney Disease.

BACKGROUND/AIM: The natural history of the renal microvasculature changes in PKD is not known. The aim of this study was to test the hypothesis that angiogenesis is coupled with kidney cyst expansion, and the loss of peritubular capillary networks precedes the onset of interstitial fibrosis. METHODS: The renal microvasculature (RECA-1 and CD34) was evaluated in groups of Lewis polycystic kidney (LPK) rats and juvenile cystic kidney (jck) mice during the early, mid and late stage of disease. In addition, LPK rats and jck mice received sirolimus to determine if the reduction in renal cyst growth is in part mediated by the suppression of angiogenesis. RESULTS: In LPK rats, the loss of peritubular capillaries occurred in early-stage disease and paralleled cyst formation whereas in jck mice it was delayed to the mid stage. In both models, vasa recta were displaced by growing cysts and regressed in LPK rats with disease progression but lengthened in jck mice. Cortical and medullary capillary neoangiogenesis occurred during the early stage in both models and persisted with progression. Treatment with sirolimus reduced cyst enlargement but did not alter the progression of renal microvasculature changes in either model. CONCLUSION: Regression of peritubular capillaries and disruption of vasa recta occur in parallel with angiogenesis and the progressive enlargement of kidney cysts. These data suggest that the regrowth of peritubular capillaries together with inhibition of angiogenesis are potential strategies to be considered in the treatment of PKD.

Chromosomal-level reference genome of the incense tree Aquilaria sinensis.

Trees in the genus Aquilaria (Thymelaeaceae) are known as lign aloes, and are native to the forests of southeast Asia. Lign aloes produce agarwood as an antimicrobial defence. Agarwood has a long history of cultural and medicinal use, and is of considerable commercial value. However, due to habitat destruction and over collection, lign aloes are threatened in the wild. We present a chromosomal-level assembly for Aquilaria sinensis, a lign aloe endemic to China known as the incense tree, based on Illumina short-read, 10X Genomics linked-read, and Hi-C sequencing data. Our 783.8 Mbp A. sinensis genome assembly is of high physical contiguity, with a scaffold N50 of 87.6 Mbp, and high completeness, with a 95.8% BUSCO score for eudicotyledon genes. We include 17 transcriptomes from various plant tissues, providing a total of 35,965 gene models. We reveal the first complete set of genes involved in sesquiterpenoid production, plant defence, and agarwood production for the genus Aquilaria, including genes involved in the biosynthesis of sesquiterpenoids via the mevalonic acid (MVA), 1-deoxy-D-xylulose-5-phosphate (DXP), and methylerythritol phosphate (MEP) pathways. We perform a detailed repeat content analysis, revealing that transposable elements account for ~61% of the genome, with major contributions from gypsy-like and copia-like LTR retroelements. We also provide a comparative analysis of repeat content across sequenced species in the order Malvales. Our study reveals the first chromosomal-level genome assembly for a tree in the genus Aquilaria and provides an unprecedented opportunity to address a variety of applied, genomic and evolutionary questions in the Thymelaeaceae more widely.

RAPID-ADPKD (Retrospective epidemiological study of Asia-Pacific patients with rapId Disease progression of Autosomal Dominant Polycystic Kidney Disease): study protocol for a multinational, retrospective cohort study.

INTRODUCTION: Patients with autosomal dominant polycystic kidney disease (ADPKD) reach end-stage renal disease in their fifth decade on average. For effective treatment and early intervention, identifying subgroups with rapid disease progression is important in ADPKD. However, there are no epidemiological data on the clinical manifestations and disease progression of patients with ADPKD from the Asia-Pacific region. METHODS AND ANALYSIS: The RAPID-ADPKD (Retrospective epidemiological study of Asia-Pacific patients with rapId Disease progression of Autosomal Dominant Polycystic Kidney Disease) study is a multinational, retrospective, observational cohort study of patients with ADPKD in the Asia-Pacific region (Australia, China, Hong Kong, South Korea, Taipei and Turkey). This study was designed to identify the clinical characteristics of patients with ADPKD with rapid disease progression. Adult patients with ADPKD diagnosed according to the unified ultrasound criteria and with an estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 at baseline will be included. The cohort will include patients with ≥2 records of eGFR and at least 24 months of follow-up data. Demographic information, clinical characteristics, comorbidities, medications, eGFR, radiological findings that allow calculation of height-adjusted total kidney volume, ADPKD-related complications and the Predicting Renal Outcomes in autosomal dominant Polycystic Kidney Disease (PRO-PKD) score will be collected. Rapid progression will be defined based on the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) guideline. All other patients without any of these criteria will be classified to be of slow progression. Clinical characteristics will be compared between patients with rapid progression and those with slow progression. The incidence of complications and the effects of race and water intake on renal progression will also be analysed. The planned sample size of the cohort is 1000 patients, and data from 600 patients have been collected as of 30 May 2019. ETHICS AND DISSEMINATION: This study was approved or is in the process of approval by the institutional review boards at each participating centre. The results will be presented in conferences and published in a journal, presenting data on the clinical characteristics, risk factors for disease progression and patterns of complications of ADPKD in Asian populations.

Role of cyclin-dependent kinase 2 in the progression of mouse juvenile cystic kidney disease.

A hallmark of polycystic kidney diseases (PKDs) is aberrant proliferation, which leads to the formation and growth of renal cysts. Proliferation is mediated by cyclin-dependent kinases (Cdks), and the administration of roscovitine (a pan-Cdk inhibitor) attenuates renal cystic disease in juvenile cystic kidney (jck) mice. Cdk2 is a key regulator of cell proliferation, but its specific role in PKD remains unknown. The aim of this study was to test the hypothesis that Cdk2 deficiency reduces renal cyst growth in PKD. Three studies were undertaken: (i) a time course (days 28, 56, and 84) of cyclin and Cdk activity was examined in jck mice and compared with wild-type mice; (ii) the progression was compared in jck mice with or without Cdk2 ablation from birth; and (iii) the effect of sirolimus (an antiproliferative agent) on Cdk2 activity in jck mice was investigated. Renal disease in jck mice was characterized by diffuse tubular cyst growth, interstitial inflammation and fibrosis, and renal impairment, peaking on day 84. Renal cell proliferation peaked during earlier stages of disease (days 28-56), whereas the expression of Cdk2-cyclin partners (A and E) and Cdk1 and 2 activity, was maximal in the later stages of disease (days 56-84). Cdk2 ablation did not attenuate renal disease progression and was associated with persistent Cdk1 activity. In contrast, the postnatal treatment of jck mice with sirolimus reduced both Cdk2 and Cdk1 activity and reduced renal cyst growth. In conclusion, (i) the kinetics of Cdk2 and Cdk2-cyclin partners did not correlate with proliferation in jck mice; and (ii) the absence of Cdk2 did not alter renal cyst growth, most likely due to compensation by Cdk1. Taken together, these data suggest that Cdk2 is dispensable for the proliferation of cystic epithelial cells and progression of PKD.

The role of DNA damage as a therapeutic target in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and is caused by heterozygous germ-line mutations in either PKD1 (85%) or PKD2 (15%). It is characterised by the formation of numerous fluid-filled renal cysts and leads to adult-onset kidney failure in ~50% of patients by 60 years. Kidney cysts in ADPKD are focal and sporadic, arising from the clonal proliferation of collecting-duct principal cells, but in only 1-2% of nephrons for reasons that are not clear. Previous studies have demonstrated that further postnatal reductions in PKD1 (or PKD2) dose are required for kidney cyst formation, but the exact triggering factors are not clear. A growing body of evidence suggests that DNA damage, and activation of the DNA damage response pathway, are altered in ciliopathies. The aims of this review are to: (i) analyse the evidence linking DNA damage and renal cyst formation in ADPKD; (ii) evaluate the advantages and disadvantages of biomarkers to assess DNA damage in ADPKD and finally, (iii) evaluate the potential effects of current clinical treatments on modifying DNA damage in ADPKD. These studies will address the significance of DNA damage and may lead to a new therapeutic approach in ADPKD.

Novel Picobirnaviruses in Respiratory and Alimentary Tracts of Cattle and Monkeys with Large Intra- and Inter-Host Diversity.

Picobirnaviruses (PBVs) are mostly found in animal alimentary samples. In this study, among 576 respiratory specimens from 476 mammals and 100 chickens, genogroup I PBVs were detected in three cattle and three monkeys, and a genogroup II PBV-positive sample was collected from one cattle specimen. More than one PBV sequence type was observed in two and one genogroup I PBV-positive samples from cattle and monkeys, respectively. Twenty-four complete/near-complete segments 2 (nine from respiratory and 15 from alimentary samples) from the cattle and monkey genogroup I PBVs and one complete segment 2 from the cattle genogroup II PBV were sequenced. Similar to other studies, the cattle PBVs also showed a high diversity. In contrast, the monkey PBVs observed in this study were clustered into three distinct clades. Within each clade, all the sequences showed >99% amino acid identities. This unique phenomenon is probably due to the fact that monkeys in our locality reside in separated troops with minimal inter-troop contact.

Restraint stress induced gut dysmotility is diminished by a milk oligosaccharide (2'-fucosyllactose) in vitro.

BACKGROUND: Stress causes severe dysmotility in the mammalian gut. Almost all research done to date has concentrated on prevention of stress-induced altered gut motility but not on treatment. We had previously shown that intraluminal 2'FL could acutely moderate propulsive motility in isolated mouse colonic segments. Because 2'FL appeared to modulate enteric nervous system dependent motility, we wondered if the oligosaccharide could reverse the effects of prior restraint stress, ex vivo. We tested whether 2'FL could benefit the dysmotility of isolated jejunal and colonic segments from animals subjected to prior acute restraint stress. METHODS: Jejunal and colonic segments were obtained from male Swiss Webster mice that were untreated or subjected to 1 hour of acute restraint stress. Segments were perfused with Krebs buffer and propagating contractile clusters (PCC) digitally video recorded. 2'FL or ß-lactose were added to the perfusate at a concentration of 1 mg/ml. Spatiotemporal maps were constructed from paired before and after treatment recordings, each consisting of 20 min duration and PCC analyzed for frequency, velocity and amplitude. KEY RESULTS: Stress decreased propulsive motility in murine small intestine while increasing it in the colon. 2'FL in jejunum of previously stressed mice produced a 50% increase in PCC velocity (p = 0.0001), a 43% increase in frequency (p = 0.0002) and an insignificant decrease in peak amplitude. For stressed colon, 2'FL reduced the frequency by 23% (p = 0.017) and peak amplitude by 26% (p = 0.011), and was without effect on velocity. ß-lactose had negligible or small treatment effects. CONCLUSIONS & INFERENCES: We show that the prebiotic 2'FL may have potential as a treatment for acute stress-induced gut dysmotility, ex vivo, and that, as is the case for certain beneficial microbes, the mechanism occurs in the gut, likely via action on the enteric nervous system.