Screening for chronic kidney disease in Canadian indigenous peoples is cost-effective.

Canadian indigenous (First Nations) have rates of kidney failure that are 2- to 4-fold higher than the non-indigenous general Canadian population. As such, a strategy of targeted screening and treatment for CKD may be cost-effective in this population. Our objective was to assess the cost utility of screening and subsequent treatment for CKD in rural Canadian indigenous adults by both estimated glomerular filtration rate and the urine albumin-to-creatinine ratio. A decision analytic Markov model was constructed comparing the screening and treatment strategy to usual care. Primary outcomes were presented as incremental cost-effectiveness ratios (ICERs) presented as a cost per quality-adjusted life-year (QALY). Screening for CKD was associated with an ICER of $23,700/QALY in comparison to usual care. Restricting the model to screening in communities accessed only by air travel (CKD prevalence 34.4%), this ratio fell to $7,790/QALY. In road accessible communities (CKD prevalence 17.6%) the ICER was $52,480/QALY. The model was robust to changes in influential variables when tested in univariate sensitivity analyses. Probabilistic sensitivity analysis found 72% of simulations to be cost-effective at a $50,000/QALY threshold and 93% of simulations to be cost-effective at a $100,000/QALY threshold. Thus, targeted screening and treatment for CKD using point-of-care testing equipment in rural Canadian indigenous populations is cost-effective, particularly in remote air access-only communities with the highest risk of CKD and kidney failure. Evaluation of targeted screening initiatives with cluster randomized controlled trials and integration of screening into routine clinical visits in communities with the highest risk is recommended.

Chronic kidney disease and heart disease: after 179 years, do we yet understand the link?

A definitive understanding of the link between heart and kidney disease remains elusive. Bittencourt et al. explore the association between chronic kidney disease (CKD) status, severity of coronary lesions, and clinical outcome in more than 1500 consecutive adult subjects who underwent a clinically indicated coronary computed tomography angiography for the evaluation of the coronary disease. We discuss the implications of their findings in the context of our current understanding of the development of heart disease in CKD.

Cost of the quanta SC+ hemodialysis system for self-care in the United Kingdom.

INTRODUCTION: New personal hemodialysis systems, such as the quanta SC+, are being developed; these systems are smaller and simpler to use while providing the clearances of conventional systems. Increasing the uptake of lower-intensity assistance and full self-care dialysis may provide economic benefits to the public health payer. In the United Kingdom, most hemodialysis patients currently receive facility-based dialysis costing more than £36,350 per year including patient transport. As such, we aimed to describe the annual costs of using the SC+ hemodialysis system in the United Kingdom for 3×-weekly and 3.5×-weekly dialysis regimens, for self-care hemodialysis provided both in-center and at home. METHODS: We applied a cost minimization approach. Costs for human resources, equipment, and consumables were sourced from the dialysis machine developer (Quanta Dialysis Technologies) based upon discussions with dialysis providers. Facility overhead expenses and transport costs were taken from a review of the literature. FINDINGS: Annual costs associated with the use of the SC+ hemodialysis system were estimated to be £26,642 for hemodialysis provided 3× weekly as home self-care; £30,235 for hemodialysis provided 3× weekly as self-care in-center; £29,866 for hemodialysis provided 3.5× weekly as home self-care; and £36,185 for hemodialysis provided 3.5× weekly as self-care in-center. DISCUSSION: We found that the SC+ hemodialysis system offers improved cost-effectiveness for both 3×-weekly and 3.5×-weekly self-care dialysis performed at home or as self-care in-center versus fully assisted dialysis provided 3× weekly with conventional machines in facilities.

Provider Perception of Frailty Is Associated with Dialysis Decision Making in Patients with Advanced CKD.

BACKGROUND AND OBJECTIVES: Frailty is common in patients with CKD. Little is known about the prevalence of frailty and its effect on prognosis and decisions surrounding dialysis modalities in patients with advanced CKD (eGFR<30 ml/min per 1.73 m2). Our objective was to determine the agreement between different frailty measures and physical function and their association with dialysis modality choice (home based versus in-center) and all-cause mortality in patients with advanced CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our study was a prospective, multicenter, cohort study. In 603 patients with advanced CKD, we collected demographics, comorbidities, and laboratory results in addition to objective (Fried frailty criteria) and subjective measures of frailty (physician and nurse impressions) and physical function (Short Physical Performance Battery). Logistic regression and Cox proportional hazards models were used to evaluate the association of frailty with dialysis modality choice and all-cause mortality, respectively. RESULTS: The prevalence of frailty varied with assessment tool used (Fried frailty criteria, 34%; Short Physical Performance Battery, 55%; physician impression, 44%; nurse impression, 36%). The agreement between all frailty and physical function measures was poor. We had 227 patients reach kidney failure and decide on a dialysis therapy, and 226 patients died during a mean follow-up of 1455 days. After adjusting for age, sex, and comorbid conditions, the Fried criteria and Short Physical Performance Battery were associated with a two-fold higher risk of all-cause mortality (hazard ratio, 1.96; 95% confidence interval, 1.47 to 2.61 and hazard ratio, 1.96; 95% confidence interval,1.42 to 2.76, respectively). Patients deemed as frail by physician and nurse frailty impressions were three to four times more likely to choose in-center dialysis (odds ratio, 3.41; 95% confidence interval, 1.56 to 7.44; odds ratio, 3.87; 95% confidence interval, 1.76 to 8.51, respectively). CONCLUSIONS: We found that the agreement between objective and subjective measures of frailty and physical function was poor. Objective measures of frailty and physical function were associated with mortality, and subjective measures of frailty were associated with dialysis modality choice.

Association of Membership at a Medical Fitness Facility With Adverse Health Outcomes.

INTRODUCTION: Interventions that increase physical activity behavior can reduce morbidity and prolong life, but long-term effects in large populations are unproven. This study investigates the association of medical fitness facility membership and frequency of attendance with all-cause mortality and rate of hospitalization. METHODS: A propensity weighted retrospective cohort study was conducted by linking individuals who attended medical fitness facilities in Winnipeg, Canada to provincial health administrative databases. Members aged ≥18 years who had ≥1 year of provincial health coverage from their index date between January 1, 2005 and December 31, 2015 were included. Controls were assigned a pseudo-index date at random on the basis of the frequency distribution of index dates in the intervention group. Members were stratified into low-frequency attenders (<1 weekly visit), moderate-frequency attenders (1-3 weekly visits), and high-frequency attenders (>3 weekly visits). The primary outcomes were time to all-cause mortality and rate of hospitalizations. Statistical analyses were performed between 2018 and 2020. RESULTS: Among 19,300 adult members and 515,810 controls, members had a 60% lower risk of all-cause mortality during the first 651 days and 48% after 651 days. Membership was associated with a 13% lower risk of hospitalizations. A dose-response effect was apparent because higher weekly attendance was associated with a lower risk of hospitalizations (low frequency: 9%, moderate frequency: 20%, high frequency: 39%). CONCLUSIONS: Membership at a medical fitness facility was associated with a reduced risk of all-cause mortality and hospitalizations. Healthcare systems should consider the medical fitness model as a preventative public health strategy to encourage physical activity participation.

Hemodialysis With the Quanta SC+: Efficacy and Safety of a Self-care Hemodialysis Machine.

RATIONALE & OBJECTIVE: Most patients with kidney failure receive hemodialysis 3 times per week in a facility. More frequent and longer duration dialysis prescriptions improve a number of key outcome measures. These prescriptions are best suited to self-care and home regimens. The Quanta SC+ hemodialysis system is a novel device with demonstrated ease of use for patients and health care practitioners through human factors testing. The primary objective of this study is to report the efficacy and safety of the SC+ system using conventional hemodialysis prescriptions. STUDY DESIGN: Nonrandomized observational study. SETTING & PARTICIPANTS: Prevalent hemodialysis patients in 4 sites in the United Kingdom were recruited to switch from their current device to the SC+ system with no other changes to their prescription. INTERVENTIONS: SC+ hemodialysis system. OUTCOMES: Efficacy data were collected in terms of dialysis adequacy, urea reduction ratios, and net fluid removal accuracy. RESULTS: 60 patients were enrolled in the study, resulting in 1,333 evaluable treatments. The threshold single-pool Kt/V of 1.2 was exceeded in 96.6% of treatments in patients receiving 3-times-weekly regimens, whereas the threshold standard Kt/V of 2.1 was exceeded in 94% of treatments and 97.6% of treatments in patients without significant residual kidney function. Ultrafiltration accuracy was determined by measuring net fluid removal and validated to be within acceptable limits. The adverse event profile during treatment was typical of hemodialysis. There were no serious adverse events. LIMITATIONS: Few patients on high-frequency treatment regimens were enrolled. CONCLUSIONS: The SC+ system delivers safe and effective hemodialysis across a range of patients and dialysis prescriptions. It is one of the smallest systems available and has validated usability for patients to perform self-care safely with minimal training. This device may encourage patients to feel empowered to take on home hemodialysis, unlocking beneficial clinical and patient-reported outcomes associated with these modalities.

Isolation of halimedatrial: chemical defense adaptation in the calcareous reef-building alga halimeda.

Halimedatrial, a structurally unprecedented diterpenoid trialdehyde, has been identified as the major secondary metabolite in six species of the calcareous reef-building alga Halimeda. In laboratory bioassays, halimedatrial is toxic toward reef fishes, significantly reduces feeding in herbivorous fishes, and has cytotoxic and antimicrobial activities. The widespread occurrence of halimedatrial and its potent biological activities suggest that this metabolite represents a chemical defense adaptation in this pantropical marine alga.

Interspecific Variation in Coral Settlement and Fertilization Success in Response to Hydrogen Peroxide Exposure.

Hydrogen peroxide (H2O2) is involved in the regulation of numerous reproductive and morphogenic processes across an array of taxa. Extracellular H2O2 can be widespread in oceanic waters, and elevated sea surface temperatures can cause increased levels of intracellular H2O2 within cnidarian tissue, but it remains unclear how this compound affects early life-history processes in corals, such as fertilization, metamorphosis, and settlement. To evaluate the effects of H2O2 on multiple stages of recruitment, experiments were conducted using Caribbean corals with various reproductive modes, including the brooders Porites astreoides and Favia fragum and the broadcast-spawning species Acropora palmata and Orbicella franksi. H2O2 accelerated settlement in all brooding species tested. Concentrations of 1000 µmol l-1 H2O2 caused close to 100% settlement in all larval age classes, regardless of exposure duration. As larvae aged, the required threshold of H2O2 capable of inducing settlement decreased. In contrast, H2O2 concentrations of 100 µmol l-1 or greater caused a significant reduction in metamorphosis and settlement in the larvae of spawners. Furthermore, fertilization of their gametes was inhibited in the presence of H2O2 concentrations as low as 100 µmol l-1. In Porites astreoides larvae, internal levels of H2O2 reached a maximal value of 75 µmol l-1 following 48 h of incubation at 31 °C. This concentration was found to significantly alter settlement rates in both brooding coral species and likely induced a cellular cascade in the settlement signaling pathway. The results of this study suggest that temperature stress influences H2O2 production, which in turn impacts coral settlement. While it is unlikely that the current levels of externally derived concentrations of oceanic H2O2 are affecting coral larvae, internal concentrations (produced under heat stress) have the capacity to impact recruitment under a changing climate.

Induction of Larval Settlement in the Reef Coral Porites astreoides by a Cultivated Marine Roseobacter Strain.

Successful larval settlement and recruitment by corals is critical for the survival of coral reef ecosystems. Several closely related strains of γ-proteobacteria have been identified as cues for coral larval settlement, but the inductive properties of other bacterial taxa naturally occurring in reef ecosystems have not yet been explored. In this study, we assayed bacterial strains representing taxonomic groups consistently detected in corals for their ability to influence larval settlement in the coral Porites astreoides. We identified one α-proteobacterial strain, Roseivivax sp. 46E8, which significantly increased larval settlement in P. astreoides. Logarithmic growth phase (log phase) cell cultures of Roseivivax sp. 46E8 and filtrates (0.22µm) from log phase Roseivivax sp. 46E8 cultures significantly increased settlement, suggesting that an extracellular settlement factor is produced during active growth phase. Filtrates from log phase cultures of two other bacterial isolates, Marinobacter sp. 46E3, and Cytophaga sp. 46B6, also significantly increased settlement, but the cell cultures themselves did not. Monospecific biofilms of the three strains did not result in significant increases in larval settlement. Organic and aqueous/methanol extracts of Roseivivax sp. 46E8 cultures did not affect larval settlement. Examination of filtrates from cell cultures showed that Roseivivax sp. 46E8 spontaneously generated virus-like particles in log and stationary phase growth. Though the mechanism of settlement enhancement by Roseivivax sp. 46E8 is not yet elucidated, our findings point to a new aspect of coral-Roseobacter interactions that should be further investigated, especially in naturally occurring, complex microbial biofilms on reef surfaces.

Prey nutritional quality and the effectiveness of chemical defenses against tropical reef fishes.

Many coral-reef seaweeds and sessile invertebrates produce both secondary chemicals and mineral or fibrous skeletal materials that can reduce their susceptibility to consumers. Although skeletal materials often have been assumed to function as physical defenses, their deterrent effectiveness may derive from their reduction of prey nutritional quality as well as from noxiousness of the skeletal material itself. To test the relative importance of prey nutritional quality and chemical defenses in susceptibility to predation, we offered reef fishes on Guam a choice of artificial foods varying in nutritional quality (4% versus 22% protein) and in secondary chemistry (spanning approximately natural concentration ranges). Field feeding assays were performed with pachydictyol A from the pantropical brown seaweed genus Dictyota, manoalide from the Micronesian sponge Luffariella variabilis, and a brominated diphenyl ether from the Micronesian sponge Dysidea sp. The results indicated that chemical defenses were less effective in high- than in low-quality foods. In paired assays with metabolite-free controls, all three compounds at natural concentrations significantly reduced feeding by reef fishes only in assays using low-quality food, and not in assays with high-quality food. When fishes were offered an array of artificial foods varying in both food quality and metabolite concentration, food quality significantly affected fish feeding in all three cases, while secondary chemistry was significant in only one. Thus differences in nutritional quality, within the natural range among reef organisms, can be comparable to or greater in importance than secondary chemistry in affecting feeding preferences of their consumers. Reduced nutritional quality may be an important selective advantage of producing indigestible structural materials, in addition to their roles as physical support and defense, in coral reef organisms.

Isolation of new brominated sesquiterpene feeding deterrents from tropical green algaNeomeris annulata (Dasycladaceae: Chlorophyta).

We investigated the natural products chemistry and feeding deterrent effects of brominated sesquiterpenes produced by Pacific collections of the calcareous tropical green algaNeomeris annulata. Assays conducted with whole algae showed thatN. annulata was not susceptible to grazing by natural populations of herbivorous fishes on Guam. Crude extracts and column chromatography fractions containing the brominated sesquiterpenes deterred feeding by herbivorous fishes at natural concentrations in field assays on Guam. Two majorN. annulata sesquiterpenes isolated from Guam collections and three related sesquiterpenes previously reported from Bermuda all deterred fish feeding at the high end of their natural concentration ranges, with the exception of one metabolite from Bermuda collections of the alga that differed structurally from the other compounds. The results support our hypothesis that the compounds produced byNeomeris function as chemical defenses against herbivores. The alga produces both structural defenses (CaCO3 in the form of aragonite) and secondary metabolites that defend against herbivory by reef fishes.

The structure of ulithiacyclamide B. Antitumor evaluation of cyclic peptides and macrolides from Lissoclinum patella.

The major cytotoxic metabolites of Lissoclinum patella from Pohnpei have been isolated and identified. Most of the cytotoxicity is attributed to a new cyclic peptide, ulithiacyclamide B [4], which is closely related to ulithiacyclamide [1]. The proposed structure of 4 is based on spectroscopic analysis and chemical degradation. Compound 4 exhibits an IC50 of 17 ng/ml against the KB cell line but does not show selective cytotoxicity against solid tumor cells in the Corbett assay.

Evidence for chemical defense in tropical green algaCaulerpa ashmeadii (Caulerpaceae: Chlorophyta): Isolation of new bioactive sesquiterpenoids.

Results of field feeding preference studies with 12 species of tropical green algae of the genusCaulerpa showed thatC. ashmeadii was preferred least by herbivorous fishes. Chemical investigations ofC. ashmeadii demonstrated the presence of high concentrations of sesquiterpenoid metabolites. The chemical isolation and structural elucidation of five majorC. ashmeadii metabolites, as well as the results of field feeding preference, antimicrobial, and ichthyotoxicity assays demonstrating the biological activities of these metabolites are reported here.

Antipredator Defenses in Tropical Pacific Soft Corals (Coelenterata: Alcyonacea). I. Sclerites as Defenses Against Generalist Carnivorous Fishes.

Calcified sclerites are common in many invertebrate species and are frequently used as taxonomic indicators; however, little is known about the function of sclerites. To determine whether sclerites could function as antipredator defenses, we conducted field assays in which sclerites from the Indo-Pacific soft corals Sinularia maxima, S. polydactyla, and S. sp. were incorporated into an artificial diet and offered to a natural assemblage of fishes in the field. Sclerites from both the tips and bases of all three species of Sinularia reduced feeding by a natural assemblage of generalist carnivorous fishes off Guam by 27-44%; however, sclerites from the bases of the colonies were 18-51% more deterrent than tip sclerites. The greater effectiveness of sclerites from the bases of the colonies was largely attributable to their high concentrations. Sclerites in the tips of the colonies occurred in mean concentrations from 24 to 58% by dry weight and were generally less than 0.5 mm in length. Sclerites in the bases of the colonies were larger and occurred in average concentrations of 82-88%. Sinularia sclerites were increasingly effective as feeding deterrents with increasing concentration at concentrations less than 30-50% by dry weight. The effectiveness of sclerites as deterrents leveled off at higher concentrations. Sclerite morphology was also important in determining antipredator activity. Although sclerites can play a role in predator deterrence, they can also function in the structural support of colonies. Thus, the sizes, shapes, and abundances of sclerites at different locations within colonies will be determined by their functions at particular locations as well as constraints upon their use or production.

Pitipeptolides A and B, new cyclodepsipeptides from the marine cyanobacterium Lyngbya majuscula.

Two new cyclodepsipeptides have been isolated from a population of the marine cyanobacterium Lyngbya majuscula collected at Piti Bomb Holes, Guam. They appear to be unique to this particular Guamanian collection and have been named pitipeptolides A (1) and B (2). Their structures have been elucidated by spectroscopic techniques and by characterization of degradation products. Distinctive features include the presence of a 2,2-dimethyl-3-hydroxy-7-octynoic acid residue in 1 and a 2,2-dimethyl-3-hydroxy-7-octenoic acid residue in 2, previously shown to be biosynthetic signatures of cyanobacterial metabolites. Pitipeptolides A (1) and B (2) exhibit weak cytotoxicity against LoVo cancer cells, but possess moderate antimycobacterial activity and stimulate elastase activity.

Isolation of dolastatin 10 from the marine cyanobacterium Symploca species VP642 and total stereochemistry and biological evaluation of its analogue symplostatin 1.

The potent antitumor agent dolastatin 10 (1) was originally isolated from the sea hare Dolabella auricularia, and we now report its isolation from the marine cyanobacterium Symploca sp. VP642 from Palau. The chemically related analogue symplostatin 1 (2) has been reisolated from Guamanian and Hawaiian varieties of S. hydnoides and its total stereochemistry completed by determining the N,N-dimethylisoleucine unit to be L. Symplostatin 1 (2), like dolastatin 10 (1), is a potent microtubule inhibitor. The antitumor activity of 2 was assessed in vivo against several murine tumors. Symplostatin 1 (2) was effective against a drug-insensitive mammary tumor and a drug-insensitive colon tumor; however, it was only slightly effective against two MDR tumors.

Chemical defenses of the sacoglossan mollusk Elysia rufescens and its host Alga bryopsis sp.

Sacoglossans are a group of opisthobranch mollusks that have been the source of numerous secondary metabolites; however, there are few examples where a defensive ecological role for these compounds has been demonstrated experimentally. We investigated the deterrent properties of the sacoglossan Elysia rufescens and its food alga Bryopsis sp. against natural fish predators. Bryopsis sp. produces kahalalide F, a major depsipeptide that is accumulated by the sacoglossan and that shows in vitro cytotoxicity against several cancer cell lines. Our data show that both Bryopsis sp. and Elysia rufescens are chemically protected against fish predators, as indicated by the deterrent properties of their extracts at naturally occurring concentrations. Following bioassay-guided fractionation, we observed that the antipredatory compounds of Bryopsis sp. were present in the butanol and chloroform fractions, both containing the depsipeptide kahalalide F. Antipredatory compounds of Elysia rufescens were exclusively present in the dichloromethane fraction. Further bioassay-guided fractionation led to the isolation of kahalalide F as the only compound responsible for the deterrent properties of the sacoglossan. Our data show that kahalalide F protects both Brvopsis sp. and Elysia rufescens from fish predation. This is the first report of a diet-derived depsipeptide used as a chemical defense in a sacoglossan.

Isolation and structure of the cytotoxin lyngbyabellin B and absolute configuration of lyngbyapeptin A from the marine cyanobacterium Lyngbya majuscula.

An analogue of the potent microfilament-disrupter lyngbyabellin A (1) has been isolated as a minor metabolite from the marine cyanobacterium Lyngbya majuscula collected at Apra Harbor, Guam. It possesses slightly weaker cytotoxicity than 1 and has been named lyngbyabellin B (2). Primarily NMR spectroscopy was used to determine its structure. The absolute configuration of 2 has been ascertained by chiral HPLC analysis of degradation products and by comparison with lyngbyabellin A (1). The known modified tetrapeptide lyngbyapeptin A (3) has also been found in the same extract, and its absolute stereochemistry could be determined for the first time.

Total structure determination of apratoxin A, a potent novel cytotoxin from the marine cyanobacterium Lyngbya majuscula.

Apratoxin A (1), a potent cytotoxin with a novel skeleton, has been isolated from the marine cyanobacterium Lyngbya majuscula Harvey ex Gomont. This cyclodepsipeptide of mixed peptide-polyketide biogenesis bears a thiazoline ring flanked by polyketide portions, one of which possesses an unusual methylation pattern. Its gross structure has been elucidated by spectral analysis, including various 2D NMR techniques. The absolute configurations of the amino acid-derived units were determined by chiral HPLC analysis of hydrolysis products. The relative stereochemistry of the new dihydroxylated fatty acid unit, 3,7-dihydroxy-2,5,8,8-tetramethylnonanoic acid, was elucidated by successful application of the J-based configuration analysis originally developed for acyclic organic compounds using carbon-proton spin-coupling constants ((2,3)J(C,H)) and proton-proton spin-coupling constants ((3)J(H,H)); its absolute stereochemistry was established by Mosher analysis. The conformation of 1 in solution was mimicked by molecular modeling, employing a combination of distance geometry and restrained molecular dynamics. Apratoxin A (1) possesses IC(50) values for in vitro cytotoxicity against human tumor cell lines ranging from 0.36 to 0.52 nM; however, it was only marginally active in vivo against a colon tumor and ineffective against a mammary tumor.

New steroidal alkaloids from an undescribed sponge of the genus Corticium.

Two new steroidal alkaloids, along with a previously reported one of the plakinamine class, were isolated from the sponge Corticium sp. collected from Guam. The structures of the new compounds were determined by combined spectroscopic methods. These compounds exhibited moderate cytotoxicity and antifungal activity as well as DNA- and RNA-cleaving activities.