Pregnancy rate and reproductive hormones in humpback whale blubber: Dominant form of progesterone differs during pregnancy.

To better understand reproductive physiology of humpback whales Megaptera novaeangliae that reside in Hawai'i and Alaska, enzyme immunoassays were validated for both progesterone and testosterone in free-ranging and stranded animals (n = 185 biopsies). Concentrations were analyzed between different depths of large segments of blubber taken from skin to muscle layers of stranded female (n = 2, 1 pregnant, 1 non-pregnant) and male (n = 1) whales. Additionally, progesterone metabolites were identified between pregnant (n = 1) and non-pregnant (n = 3) females using high pressure liquid chromatography (HPLC). Progesterone concentrations were compared between juvenile (i.e., sexually immature), lactating, and pregnant females, and male whales, and pregnancy rates of sexually mature females were calculated. Based on replicate samples from ship struck animals collected at 7 depth locations, blubber containing the highest concentration of progesterone was located 1 cm below the skin for females, and the highest concentration of testosterone was in the skin layer of one male whale. HPLC of blubber samples of pregnant and non-pregnant females contain different immunoreactive progesterone metabolites, with the non-pregnant female eluate comprised of a more polar, and possibly conjugated, form of progesterone than the pregnant female. In females, concentrations of progesterone were highest in the blubber of pregnant (n = 28, 28.6 ± 6.9 ng/g), followed by lactating (n = 16, 0.9 ± 0.1 ng/g), and female juvenile (n = 5, 1.0 ± 0.2 ng/g) whales. Progesterone concentrations in male (n = 24, 0.6 ng/g ± 0.1 ng/g) tissues were the lowest all groups, and not different from lactating or juvenile females. Estimated summer season pregnancy rate among sexually mature females from the Hawai'i stock of humpback whales was 0.562 (95 % confidence interval 0.528-0.605). For lactating females, the year-round pregnancy rate was 0.243 (0.09-0.59), and varies depending on the threshold of progesterone assumed for pregnancy in the range between 3.1 and 28.5 ng/g. Our results demonstrate the synergistic value added when combining immunoreactive assays, HPLC, and long-term sighting histories to further knowledge of humpback whale reproductive physiology.

The SECURE STAIRS Framework: Preliminary Evaluation of Trauma Informed Training Developments Within the Children and Young People's Secure Estate.

The SECURE STAIRS framework promotes trauma informed understanding and training across the workforce to inform work with children and young people. A component of the framework is the 'Trauma Informed Practice with Children and Young People in Secure Settings' (TIPSS) training programme for multidisciplinary staff. Between November 2020 and May 2021, a total of 123 members of multidisciplinary staff from a Secure Children's Home (SCH) in the North East of England attended five-day TIPSS training. A pre-post repeated measures design was adopted. Paired samples t-tests were used to analyse pre- and post- questionnaires regarding self-reported levels of (i) knowledge, (ii) understanding and (iii) confidence across Attachment and Developmental Trauma, Understanding Complex Behaviour and Trauma Informed Care training modules. Staff reported significant (p ≤ .001) post-training improvements in knowledge, understanding, and confidence across all three training modules. Implications of findings are discussed, and further developments outlined.

The MELD Score Is Superior to the Maddrey Discriminant Function Score to Predict Short-Term Mortality in Alcohol-Associated Hepatitis: A Global Study.

INTRODUCTION: Several scoring systems predict mortality in alcohol-associated hepatitis (AH), including the Maddrey discriminant function (mDF) and model for end-stage liver disease (MELD) score developed in the United States, Glasgow alcoholic hepatitis score in the United Kingdom, and age, bilirubin, international normalized ratio, and creatinine score in Spain. To date, no global studies have examined the utility of these scores, nor has the MELD-sodium been evaluated for outcome prediction in AH. In this study, we assessed the accuracy of different scores to predict short-term mortality in AH and investigated additional factors to improve mortality prediction. METHODS: Patients admitted to hospital with a definite or probable AH were recruited by 85 tertiary centers in 11 countries and across 3 continents. Baseline demographic and laboratory variables were obtained. The primary outcome was all-cause mortality at 28 and 90 days. RESULTS: In total, 3,101 patients were eligible for inclusion. After exclusions (n = 520), 2,581 patients were enrolled (74.4% male, median age 48 years, interquartile range 40.9-55.0 years). The median MELD score was 23.5 (interquartile range 20.5-27.8). Mortality at 28 and 90 days was 20% and 30.9%, respectively. The area under the receiver operating characteristic curve for 28-day mortality ranged from 0.776 for MELD-sodium to 0.701 for mDF, and for 90-day mortality, it ranged from 0.773 for MELD to 0.709 for mDF. The area under the receiver operating characteristic curve for mDF to predict death was significantly lower than all other scores. Age added to MELD obtained only a small improvement of AUC. DISCUSSION: These results suggest that the mDF score should no longer be used to assess AH's prognosis. The MELD score has the best performance in predicting short-term mortality.

Substantial long-term loss of alpha and gamma diversity of lake invertebrates in a landscape exposed to a drying climate.

Many regions across the globe are shifting to more arid climates. For shallow lakes, decreasing rainfall volume and timing, changing regional wind patterns and increased evaporation rates alter water regimes so that dry periods occur more frequently and for longer. Drier conditions may affect fauna directly and indirectly through altered physicochemical conditions in lakes. Although many studies have predicted negative effects of such changes on aquatic biodiversity, empirical studies demonstrating these effects are rare. Global warming has caused severe climatic drying in southwestern Australia since the 1970s, so we aimed to determine whether lakes in this region showed impacts on lake hydroperiod, water quality, and α, ß and γ diversity of lake invertebrates from 1998 to 2011. Seventeen lakes across a range of salinities were sampled biennially in spring in the Wheatbelt and Great Southern regions of Western Australia. Multivariate analyses were used to identify changes in α, ß and γ diversity and examine patterns in physicochemical data. Salinity and average rainfall partially explained patterns in invertebrate richness and assemblage composition. Climatic drying was associated with significant declines in lake depth, increased frequency of dry periods, and reduced α and γ diversity (γ declined from ~300 to ~100 taxa from 1998 to 2011 in the 17 wetlands). In contrast, ß diversity remained consistently high, because each lake retained a distinct fauna. Mean α diversity per-lake declined both in lakes that dried and lakes that did not dry out, but lakes which retained a greater proportion of their maximum depth retained more α diversity. Accumulated losses in α diversity caused the decline in γ diversity likely through shrinking habitat area, fewer stepping stones for dispersal and loss of specific habitat types. Biodiversity loss is thus likely from lakes in drying regions globally. Management actions will need to sustain water depth in lakes to prevent biodiversity loss.

Myxobolus spp. (Cnidaria: Myxozoa) in introduced yellow perch Perca flavescens (Mitchill, 1814).

We surveyed introduced yellow perch Perca flavescens (Mitchill, 1814) from the Willamette River, OR, USA, to determine if these fish have co-introduced myxosporean parasites. Mature parasite myxospores were observed in brains of 3/19 fish, and were morphologically and molecularly consistent with Myxobolus neurophilus (Guilford 1963), a parasite known from yellow perch in their native range. We identified another Myxobolus species from the gill filaments of 1/22 fish. The spores from the gill filaments were oval-shaped, 11.7 (10.7-12.3) µm long × 8.6 (7.7-9.0) µm wide × 5.2 (4.6-5.6) µm thick, with two oval-shaped polar capsules 5.7 (5.1-6.5) µm × 2.7 (2.4-3.2) µm, each containing a polar tubule with 8-9 turns. Small-subunit ribosomal DNA sequences from each of four plasmodia were identical, and 4.0% different (over 1800 nucleotides) from the closest known myxosporeans. Interestingly, these sequences had overlapping peaks in their chromatograms, which suggested that DNA from multiple species was present. Hence, we isolated and sequenced three individual myxospores and found that they too had mixed chromatograms, which indicated presence of at least two sequence types of small-subunit ribosomal DNA in each spore (GenBank accession MK592012, MK592013), a rare character among described myxosporeans. The spore morphology, morphometry, tissue tropism, and DNA sequence supported a diagnosis of a novel species, Myxobolus doubleae n. sp. This parasite is unknown from yellow perch in its native range, despite extensive historical surveys, which suggests that introduced yellow perch might have acquired an endemic Myxobolus species via spillback from another fish host.

Host-parasite relationship of Ortholinea lauquen sp. nov. (Cnidaria: Myxozoa) and the fish Galaxias maculatus in northwestern Patagonia, Argentina.

Galaxias maculatus (Jenyns, 1842) is a widespread freshwater fish and an important component of the economically important whitebait fisheries across the Southern Hemisphere. We report a new myxosporean parasite (Cnidaria: Myxozoa) infecting the kidney of G. maculatus from northwestern Patagonia (Argentina). Ortholinea lauquen sp. nov. was characterized using myxospore morphology, morphometrics and small subunit rDNA (ssrDNA) sequence data. Our ssrDNA phylogenetic analyses showed that O. lauquen sp. nov. is a member of the oligochaete-freshwater urinary tract clade and basal to a clade containing 4 different spore morphotypes (Chloromyxum, Myxidium, Zschokkella, Hoferellus). We explored host-parasite relationships at the macro- and microscale by analyzing the distribution, tissue tropism and pathology of O. lauquen sp. nov. Prevalence was relatively low (7%) by microscopy, but PCR detection revealed hidden levels of infection (49%), with the highest detection in lakes Morenito and Moreno (63-90%, Río Negro Province). The only locality negative by both microscopy and PCR was the Caleufu River (Neuquén Province), suggesting differences in fish life history traits (landlocked vs. potamodromous) or preference of the putative obligate invertebrate host for lentic habitats. O. lauquen sp. nov. sporulates in the renal tubules and occasionally in the glomerular space. The plasmodia frequently occluded the tubule lumina, and cellular necrosis and disintegration of the epithelium were observed. O. lauquen sp. nov. could represent a potential threat to G. maculatus culture under intensive farming conditions.

Pathological findings and survey for pathogens associated with reproductive failure in perinatal Steller sea lions Eumetopias jubatus.

Steller sea lions (SSLs) Eumetopias jubatus experienced a population decline in the 1960s, leading to the listing of the western stock as endangered and the eastern stock as threatened under the US Endangered Species Act. A decrease of births in the western stock beginning in the late 1960s indicates that reproductive failure may have contributed to the decline. We evaluated the role pathogens play in spontaneous abortions, premature births and neonatal deaths in SSLs. Archived tissues from carcasses (n = 19) collected in Alaska from 2002 to 2015 were tested by PCR for Coxiella burnetii, Brucella spp., Chlamydia and morbilliviruses. Animals examined included 47% premature pups, 32% aborted fetuses, 11% neonates and 11% intrauterine fetuses. Gross necropsy and histology findings were summarized in the context of the PCR findings. Tissues were negative for Chlamydia and C. burnetii. Brucella spp. were detected in the lung tissues of 3 animals, including 1 positive for the ST27 strain, the first detection of Brucella spp. DNA in SSLs. Phocine distemper virus was detected in 3 animals in 2 skin lesions and 1 placenta by hemi-nested diagnostic qRT-PCR. Both skin and the placental lesions had vesiculoulcerative changes, and 1 skin lesion contained inclusion bodies in syncytia and upon histologic examination, suggesting that the lesions may be associated with an infection reminiscent of phocine distemper virus, the first in SSLs. We highlight the continuing need for disease surveillance programs to improve our understanding of the prevalence and potential population impacts of these infectious disease agents for pinnipeds in Alaskan waters.

[Compliance of nursing professional practices related to drug preparation and administration: A cross-sectional and longitudinal descriptive study]. / Observations des pratiques des professionnelles en soins infirmiers liées à la préparation et à l'administration des médicaments : une étude descriptive transversale et longitudinale.

OBJECTIVES: Evaluate the compliance of practices of nursing professionals related to the preparation and administration of drugs in 2018. Discuss the evolution of compliance practices from 2014 to 2018. METHODS: Prospective transversal observational study. Based on an observation grid with 55 compliance criteria, we conducted direct observation of medication doses prepared and administered by nursing professionals. For each compliance criterion, the auditor could indicate whether the practice was compliant, non-compliant or not applicable. A convenience target of 250 observations has been set. RESULTS: A total of 252 doses of drugs were observed between March 1, 2018 and April 29, 2018. Drug doses were observed by day (52 %), evening (30 %) or night (18 %) mainly nurses (80 %) working on regular shifts (94 %). Just over half of the doses required preparation by a nurse (58 %) and almost half of the doses were administered parenterally (48 %). In 2018, the observed compliance rate of the drug circuit ranged from 25.0 % to 86.3 %. CONCLUSION: This descriptive study shows a compliance rate of practices of nursing professionals related to the preparation and administration of drugs, which varies from 25.0 % to 86.3 % by observed stage of the drug circuit. 2018. The study identified 15 action actions for continuous improvement.

Effect of Ichthyophonus on blood plasma chemistry of spawning Chinook salmon and their resulting offspring in a Yukon River tributary.

Ichthyophonus is a protozoan parasite of Alaska Chinook salmon Oncorhynchus tshawytscha. In this study, we determined whether spawning Chinook salmon in the Yukon River drainage exhibited a measurable stress response (i.e. elevated plasma cortisol concentrations) and detectable changes in selected blood plasma chemistry parameters when infected with Ichthyophonus. The resulting alevin were also analyzed for any differences in blood plasma chemistry caused by parental infection with Ichthyophonus. In 2010, 2011, and 2012, spawning adult Chinook salmon were collected from the Salcha River, Alaska, USA, and the prevalence of Ichthyophonus in these fish was 7.8, 6.3, and 8.3%, respectively. Fish with no clinical signs of Ichthyophonus and Ichthyophonus-positive parents were cross-fertilized to investigate potential second-generation effects as a result of Ichthyophonus infection. We found no significant difference in cortisol concentrations in blood plasma between Ichthyophonus-positive and -negative adults or between alevin from Ichthyophonus-positive and -negative parents. There were no significant differences in blood plasma parameters (e.g. alanine aminotransferase, creatine kinase, glucose) of Ichthyophonus-negative and -positive adults, with the exception of aspartate aminotransferase, which was significantly higher in plasma of Ichthyophonus-negative adults. All clinical chemistry parameters for alevin resulting from both Ichthyophonus-negative and -positive parents were not significantly different. Based on this study, which has a limited sample size and low prevalence of Ichthyophonus, offspring of Chinook salmon appear to suffer no disadvantage as a result of Ichthyophonus infection in their parents on the Salcha River.

Seroprevalence of Brucella antibodies in harbor seals in Alaska, USA, with age, regional, and reproductive comparisons.

Populations of harbor seal Phoca vitulina in the Gulf of Alaska have dramatically declined during the past 4 decades. Numbers of seals in Glacier Bay, in southeast Alaska, USA, have also declined despite extensive protection. Causes of the declines and slow recovery are poorly understood. Brucellosis is a zoonotic disease that adversely affects reproduction in many domestic species. We measured the seroprevalence of Brucella antibodies in 554 harbor seals in 3 Alaska locations: Prince William Sound (PWS), Glacier Bay (GB), and Tracy Arm Fords Terror (TAFT) Wilderness Area. Objectives included testing for regional, sex, age, and female reproductive state differences in Brucella antibody seroprevalence, persistence in titers in recaptured seals, and differences in titers between mother seals and their pups. Overall, 52% of adults (AD), 53% of subadults (SA), 77% of yearlings (YRL), and 26% of <5 mo old pups were seropositive. Matched mother-pup samples were consistent with dependent pups acquiring maternal passive immunity to Brucella. Results show higher seroprevalence (64%) for AD and SA seals in the depressed and declining populations in PWS and GB than in TAFT (29%). Lactating females were less likely to be seropositive than other AD females, including pregnant females. Further research is needed to seek evidence of Brucella infection in Alaskan harbor seals, identify effects on neonatal viability, and assess zoonotic implications for Alaska Natives who rely on harbor seals for food.

[Selection and optimal sequence of critical elements for medication review: A simulation with hospital pharmacy residents]. / Sélection et séquence optimale des éléments critiques de validation des ordonnances : une simulation avec des résidents en pharmacie hospitalière.

OBJECTIVES: The main objective of this study was to compare the responses of pharmacy residents regarding critical steps for medication order review, in the presence or absence of clinical pharmacists on patient care units, to describe the sequence of these steps and to compare them to an optimal sequence. The secondary objectives were to test this sequence in a simulation and to assess the residents' level of agreement on medication order review. METHODS: Twenty-two validation steps were selected from guidelines. A simulation on order review was organized in three steps: selecting elements judged to be necessary or not for the order review critical path, then organizing this sequence in chronological order, implementation of this critical path on two simulated practical cases, resident perceptions about order review in their training. RESULTS: Forty-one residents participated in the activity. Responses were heterogeneous regarding the elements' sequence and the time required for the review of a simulated case (3-13minutes). A majority of residents considered that their training was insufficient (29/41), that pharmacists validated differently (27/41), and that it was impossible to review the 22 proposed items for each prescription (30/41). CONCLUSIONS: This article highlights heterogeneous medication order review practices among pharmacy residents, due to a lack of training in their curriculum according to them. It is essential to acquire medication order review standard both locally and nationally.

CRISPR/Cas9 DNA cleavage at SNP-derived PAM enables both in vitro and in vivo KRT12 mutation-specific targeting.

CRISPR/Cas9-based therapeutics hold the possibility for permanent treatment of genetic disease. The potency and specificity of this system has been used to target dominantly inherited conditions caused by heterozygous missense mutations through inclusion of the mutated base in the short-guide RNA (sgRNA) sequence. This research evaluates a novel approach for targeting heterozygous single-nucleotide polymorphisms (SNPs) using CRISPR/Cas9. We determined that a mutation within KRT12, which causes Meesmann's epithelial corneal dystrophy (MECD), leads to the occurrence of a novel protospacer adjacent motif (PAM). We designed an sgRNA complementary to the sequence adjacent to this SNP-derived PAM and evaluated its potency and allele specificity both in vitro and in vivo. This sgRNA was found to be highly effective at reducing the expression of mutant KRT12 mRNA and protein in vitro. To assess its activity in vivo we injected a combined Cas9/sgRNA expression construct into the corneal stroma of a humanized MECD mouse model. Sequence analysis of corneal genomic DNA revealed non-homologous end-joining repair resulting in frame-shifting deletions within the mutant KRT12 allele. This study is the first to demonstrate in vivo gene editing of a heterozygous disease-causing SNP that results in a novel PAM, further highlighting the potential for CRISPR/Cas9-based therapeutics.

[Assessment of perception about medication reconciliation among healthcare professionals at Saint-Justine hospital]. / Évaluation de la perception des professionnels de santé vis-à-vis du bilan comparatif des médicaments au CHU Sainte-Justine.

OBJECTIVES: Our main objective is to assess nurses and doctors perception about medication reconciliation. METHODS: This is a descriptive and cross-sectional study. We have created three surveys, one for each health worker (nurses, doctors, resident, pharmacists). Each survey consists of single or multi-choice closed questions. A four-point Likert scale was used to collect the perception. Descriptive statistics have been calculated. RESULTS: A total of 114 nurses, 98 doctors and residents and 26 pharmacists from all care services, replied to the survey. The majority of doctors (58%), pharmacists (60%) and nurses (52%) recognized the relevance and utility of medication reconciliation in healthcare safety. However, few healthcare professionals (6% of doctors, 13% of nurses et 46% of pharmacists) know that medication reconciliation is a required organizational practice. Only 25% of doctors always consult the best possible medication history after a patient admission while the majority do not use it because of unreliability issues. So, there have been some major changes to optimize medication reconciliation process in our hospital. CONCLUSION: This study shows a increasing interest to medication reconciliation by healthcare professionals. However, the use of medication reconciliation remains marginal.

Getting food policy on the Mayoral table: a comparison of two election cycles in New York and London.

Cities and Mayors are increasingly being recognized as important in shaping social policy and improving social well-being. And municipal food policies are increasingly important as a tool to reduce food insecurity and prevent diet-related chronic diseases. Thus city governments have a unique ability to improve local food environments. To realize this potential for improving urban food environments, nutrition advocates will need to find innovative approaches for influencing municipal food policy. This paper examines Mayoral elections as a vehicle to advance food policy. To explore this strategy, Mayoral elections in two cities, New York City (NYC) and London, during two recent cycles were compared. To gather evidence multiple sources were used including campaign documents, media and opinion polls as well as the authors' own observations as food policy observers and participants in the two cities. Mayoral governance differs between NYC and London, with the Mayor in NYC having greater powers of management and administration, whilst the London Mayor has a more strategic role and may need to also use 'influence'. Food policy and related issues did not feature strongly in the first election cycles in either city. However by the 2012 and 2013 elections food issues were definitely 'on the table' and featured in main candidates' campaign literature. These latter elections also saw the importance of food advocates coming together to form common alliances and place food issues higher on the municipal agenda. In this way, food policy has become part of the election dialogue in both cities and candidates are expected to consider food policy issues. This analysis leads to make observations which could guide advocates as to how to use Mayoral elections to raise policy objectives for the benefit of public health.

Skeletal findings in the first 12 months following initiation of glucocorticoid therapy for pediatric nephrotic syndrome.

UNLABELLED: Incident vertebral fractures and lumbar spine bone mineral density (BMD) were assessed in the 12 months following glucocorticoid initiation in 65 children with nephrotic syndrome. The incidence of vertebral fractures was low at 12 months (6 %) and most patients demonstrated recovery in BMD Z-scores by this time point. INTRODUCTION: Vertebral fracture (VF) incidence following glucocorticoid (GC) initiation has not been previously reported in pediatric nephrotic syndrome. METHODS: VF was assessed on radiographs (Genant method); lumbar spine bone mineral density (LS BMD) was evaluated by dual-energy X-ray absorptiometry. RESULTS: Sixty-five children were followed to 12 months post-GC initiation (median age, 5.4 years; range, 2.3-17.9). Three of 54 children with radiographs (6 %; 95 % confidence interval (CI), 2-15 %) had incident VF at 1 year. The mean LS BMD Z-score was below the healthy average at baseline (mean ± standard deviation (SD), -0.5 ± 1.1; p = 0.001) and at 3 months (-0.6 ± 1.1; p < 0.001), but not at 6 months (-0.3 ± 1.3; p = 0.066) or 12 months (-0.3 ± 1.2; p = 0.066). Mixed effect modeling showed a significant increase in LS BMD Z-scores between 3 and 12 months (0.22 SD; 95 % CI, 0.08 to 0.36; p = 0.003). A subgroup (N = 16; 25 %) had LS BMD Z-scores that were ≤-1.0 at 12 months. In these children, each additional 1,000 mg/m(2) of GC received in the first 3 months was associated with a decrease in LS BMD Z-score by 0.39 at 12 months (95 % CI, -0.71 to -0.07; p = 0.017). CONCLUSIONS: The incidence of VF at 1 year was low and LS BMD Z-scores improved by 12 months in the majority. Twenty-five percent of children had LS BMD Z-scores ≤-1.0 at 12 months. In these children, LS BMD Z-scores were inversely associated with early GC exposure, despite similar GC exposure compared to the rest of the cohort.

Zinc Supplementation Trial in Pediatric Chronic Kidney Disease: Effects on Circulating FGF-23 and Klotho.

Background: Zinc status, its role in bone metabolism and efficacy of deficiency correction has not been well studied in children with chronic kidney disease (CKD). Objectives: The primary objective was to investigate whether 3 months of oral zinc supplementation corrects zinc deficiency in children with CKD who have native or transplanted kidneys. The secondary objective was to compare circulating intact FGF-23 (iFGF-23), c-terminal FGF-23 (cFGF-23), and Klotho between zinc-sufficient and zinc-deficient children with CKD and to assess the relationship between circulating zinc, iFGF-23, cFGF-23, Klotho, bone biomarkers, copper, and phosphate excretion pre-supplementation and post-supplementation of zinc. Methods: Forty-one children (25 male and 16 female, age 12.94 ± 4.13 years) with CKD in native or transplanted kidneys were recruited through 2 pediatric nephrology divisions in Ontario, Canada. Of those, 14 patients (9 native CKD, 5 transplant CKD) with identified zinc deficiency (64% enrollment rate) received zinc citrate supplement for 3 months: 10 mg orally once (4-8 years) or twice (9-18 years) daily. Results: Zinc deficiency (plasma concentration < 11.5 µmol/L) was found in 22 patients (53.7%). A linear regression model suggested that zinc concentration reduced by 0.026 µmol/L (P = .04) for every 1-unit of estimated glomerular filtration rate (eGFR) drop. Zinc deficiency status was associated with higher serum iFGF-23; however, this was predominantly determined by the falling GFR. Zinc deficient and sufficient children had similar circulating c-FGF-23 and alpha-Klotho. Normalization of plasma zinc concentration was achieved in 8 (5 native CKD and 3 transplant CKD) out of 14 treated patients rising from 10.04 ± 1.42 to 12.29 ± 3.77 µmol/L (P = .0038). There were no significant changes in other biochemical measures in all treated patients. A statistically significant (P = .0078) rise in c-FGF-23 was observed only in a subgroup of 11 children treated with zinc but not receiving calcitriol. Conclusions: Zinc status is related to kidney function and possibly connected to bone metabolism in patients with CKD. However, it plays a minor role in fine-tuning various metabolic processes. In this exploratory non-randomized study, 3 months supplementation with zinc corrected deficiency in just over half of patients and only modestly affected bone metabolism in asymptomatic CKD patients.

Contexte: Le statut du zinc, son rôle dans le métabolisme osseux et l'efficacité de la correction d'une carence n'ont pas encore été bien étudiés chez les enfants atteints d'insuffisance rénale chronique (IRC). Objectifs: L'objectif principal était d'examiner si une supplémentation orale en zinc pendant trois mois pouvait corriger une carence chez les enfants atteints d'IRC avec des reins natifs ou transplantés. Les objectifs secondaires étaient de comparer les taux circulants de FGF-23 intact (iFGF-23), de FGF-23 c-terminal (cFGF-23) et de Klotho d'enfants atteints d'IRC et ayant des niveaux corrects ou déficients en zinc, puis d'évaluer la relation entre le zinc circulant, l'iFGF-23, le cFGF-23, le Klotho, les biomarqueurs osseux et l'excrétion de cuivre et de phosphate avant et après la supplémentation en zinc. Méthodologie: Un total de 41 enfants (25 garçons et 16 filles, âgés de 12,94 ±4,13 ans) atteints d'IRC avec reins natifs ou transplantés ont été recrutés par deux divisions de néphrologie pédiatrique en Ontario, au Canada. De ceux-ci, 14 patients (9 avec reins natifs; 5 avec reins transplantés) qui présentaient une carence en zinc (taux d'inclusion de 64 %) ont reçu un supplément de citrate de zinc pendant trois mois à raison de 10 mg par voie orale une fois (4 à 8 ans) ou deux fois (9 à 18 ans) par jour. Résultats: Une carence en zinc (concentration plasmatique < 11,5 µmol/L) a été constatée chez 22 patients (53,7 %). Un modèle de régression linéaire a suggéré que la concentration de zinc diminue de 0,026 µmol/L (P = 0,04) pour chaque chute d'une unité de DFGe. Le statut de carence en zinc était associé à un taux sérique d'iFGF-23 plus élevé; cependant, cela était principalement déterminé par la baisse du DFG. Tous les enfants, avec ou sans carence en zinc, avaient des taux circulants similaires de c-FGF-23 et d'alpha-Klotho. La normalisation de la concentration plasmatique de zinc a été obtenue chez 8 patients (5 avec reins natifs; 3 avec reins transplantés) sur les 14 qui ont été traités, passant de 10,04 ±1,42 à 12,29 ±3,77 µmol/L (P = 0,003 8). Aucun changement significatif n'a été observé dans les autres mesures biochimiques chez les patients traités. Une augmentation statistiquement significative (P = 0,007 8) du taux de c-FGF-23 a été observée uniquement dans un sous-groupe de 11 enfants traités avec du zinc, mais ne recevant pas de calcitriol. Conclusion: Le statut du zinc est lié à la fonction rénale et peut être lié au métabolisme osseux chez les patients atteints d'IRC. Il joue toutefois un rôle mineur dans le réglage fin de divers processus métaboliques. Dans cet essai exploratoire non randomisé, une supplémentation en zinc pendant trois mois a permis de corriger la carence chez un peu plus de la moitié des patients et n'a eu qu'un effet modeste sur le métabolisme osseux chez les patients asymptomatiques atteints d'IRC.

Immune biomarker evaluation of sequential tyrosine kinase inhibitor and nivolumab monotherapies in renal cell carcinoma: the phase I TRIBE trial.

Background: Predictive biomarkers for immune checkpoint blockade in the second-line treatment of metastatic renal cell carcinoma (mRCC) are lacking. Materials and methods: Patients with histologically confirmed RCC who started nivolumab after at least 4 months of tyrosine kinase inhibitors (TKIs) were recruited for this study. Serial tissue and blood samples were collected for immune biomarker evaluation. The primary endpoint was to determine the association of specific T-cell subsets with clinical outcomes tested using Wilcoxon rank sum for clinical benefit rate (CBR) and log-rank test for progression-free survival (PFS). Results: Twenty patients were included in this trial with a median age of 64 years and followed-up for a median of 12 months. The median PFS for patients who received TKI was 13.8 months, while for those subsequently treated with nivolumab following TKI therapy, the median PFS was 2.6 months. CBR of nivolumab was 20% with two partial responses. Functionally active programmed cell death protein 1+ CD4+ T cells were enriched in non-responders (q = 0.003) and associated with worse PFS on nivolumab (P = 0.04). Responders showed a significant reduction in the effector CD4+T-cell (TEF) fraction compared to non-responders at 3 months on nivolumab (0.40 versus 0.80, P = 0.0005). CD127+CD4+ T cells were enriched in patients who developed immune-related adverse effects (q = 0.003). Using in-house validated multiplex immunohistochemistry for six markers, we measured tumour-associated immune cell densities in tissue samples. Responders to nivolumab showed a significantly higher mean of immune cell densities in tissue samples compared to non-responders (346 versus 87 cells/mm2, P = 0.04). Conclusions: In this small study, analysis of tissue-based and peripheral blood immune cell subsets predicted clinical outcomes of nivolumab. Further studies are warranted with larger populations to validate these observations.

'Who's who' in renal sphaerosporids (Bivalvulida: Myxozoa) from common carp, Prussian carp and goldfish--molecular identification of cryptic species, blood stages and new members of Sphaerospora sensu stricto.

Myxozoans are a group of diverse, spore-forming metazoan microparasites bound to aquatic environments. Sphaerospora dykovae (previously S. renicola) causes renal sphaerosporosis and acute swim bladder inflammation (SBI) in juvenile Cyprinus carpio carpio, in central Europe. A morphologically similar species with comparably low pathogenicity, S. angulata has been described from C. c. carpio, Carassius auratus auratus and Carassius gibelio. To clarify uncertainties and ambiguities in taxon identification in these hosts we decided to re-investigate differences in spore morphology using a statistical approach, in combination with SSU and LSU rDNA sequence analyses. We found that developing spores of S. angulata and S. dykovae cannot be distinguished morphologically and designed a duplex PCR assay for the cryptic species that demonstrated S. dykovae is specific to C. c. carpio, whereas S. angulata infects C. a. auratus and C. gibelio. The molecular identification of myxozoan blood stages in common carp and goldfish, which had previously been ascribed to Sphaerospora spp. showed that approximately 75% of blood stages were from non-sphaerosporid coelozoic species infecting these cyprinids and more than 10% were from an alien species, Myxobilatus gasterostei, developing in sticklebacks. We hereby report non-selective myxozoan host invasion and multi-species infections, whose role in SBI still requires clarification.