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The degradation of shallow ecosystems has called for efforts to understand the biodiversity and functioning of Mesophotic Ecosystems. However, most empirical studies have been restricted to tropical regions and have majorly focused on taxonomic entities (i.e., species), neglecting important dimensions of biodiversity that influence community assembly and ecosystem functioning. Here, using a subtropical oceanic island in the eastern Atlantic Ocean (Lanzarote, Canary Islands), we investigated variation in (a) alpha and (b) beta functional (i.e., trait) diversity across a depth gradient (0–70 m), as a function of the presence of black coral forests (BCFs, order Antipatharian) in the mesophotic strata, a vulnerable but often overlooked ‘ecosystem engineer’ in regional biodiversity. Despite occupying a similar volume of the functional space (i.e., functional richness) than shallow (

Background Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) are both characterized by amyloid-β (Aβ) accumulation in the brain, although Aβ deposits mostly in the brain parenchyma in AD and in the cerebrovasculature in CAA. The presence of CAA can exacerbate clinical outcomes of AD patients by promoting spontaneous intracerebral hemorrhage and ischemia leading to CAA-associated cognitive decline. Genetically, AD and CAA share the ε4 allele of the apolipoprotein E (APOE) gene as the strongest genetic risk factor. Although tremendous efforts have focused on uncovering the role of APOE4 on parenchymal plaque pathogenesis in AD, mechanistic studies investigating the role of APOE4 on CAA are still lacking. Here, we addressed whether abolishing APOE4 generated by astrocytes, the major producers of APOE, is sufficient to ameliorate CAA and CAA-associated vessel damage. Methods We generated transgenic mice that deposited both CAA and plaques in which APOE4 expression can be selectively suppressed in astrocytes. At 2-months-of-age, a timepoint preceding CAA and plaque formation, APOE4 was removed from astrocytes of 5XFAD APOE4 knock-in mice. Mice were assessed at 10-months-of-age for Aβ plaque and CAA pathology, gliosis, and vascular integrity. Results Reducing the levels of APOE4 in astrocytes shifted the deposition of fibrillar Aβ from the brain parenchyma to the cerebrovasculature. However, despite increased CAA, astrocytic APOE4 removal reduced overall Aβ-mediated gliosis and also led to increased cerebrovascular integrity and function in vessels containing CAA. Conclusion In a mouse model of CAA, the reduction of APOE4 derived specifically from astrocytes, despite increased fibrillar Aβ deposition in the vasculature, is sufficient to reduce Aβ-mediated gliosis and cerebrovascular dysfunction.

Extreme climatic events can reshape the functional structure of ecological communities, potentially altering ecological interactions and ecosystem functioning. While these shifts have been widely documented, evidence of their persistence and potential flow-on effects on ecosystem structure following relaxation of extreme events remains limited. Here, we investigate changes in the functional trait structure - encompassing dimensions of resource use, thermal affinity, and body size - of herbivorous fishes in a temperate reef system that experienced an extreme marine heatwave (MHW) and subsequent return to cool conditions. We quantify how changes in the trait structure modified the nature and intensity of herbivory-related functions (macroalgae, turf, and sediment removal), and explored the potential flow-on effects on the recovery dynamics of macroalgal foundation species. The trait structure of the herbivorous fish assemblage shifted as a result of the MHW, from dominance of cool-water browsing species to increased evenness in the distribution of abundance among temperate and tropical guilds supporting novel herbivory roles (i.e. scraping, cropping, and sediment sucking). Despite the abundance of tropical herbivorous fishes and intensity of herbivory-related functions declined following a period of cooling after the MHW, the underlying trait structure displayed limited recovery. Concomitantly, algal assemblages displayed a lack of recovery of the formerly dominant foundational species, the kelp Ecklonia radiata, transitioning to an alternative state dominated by turf and Sargassum spp. Our study demonstrates a legacy effect of an extreme MHW and exemplified the value of monitoring phenotypic (trait mediated) changes in the nature of core ecosystem processes to predict and adapt to the future configurations of changing reef ecosystems.

PURPOSE: To demonstrate prognostic utility of left atrial strain(LAS) in adult patients with repaired Tetralogy of Fallot(rTOF). METHODS: Adults patients with rTOF were prospectively enrolled in this study between years 2011-2015. Left atrium(LA) phasic functions were assessed using 2D speckle tracking echocardiography(2D-STE). Association of LA strain(LAS) with primary(any cardiovascular event) and secondary(death, heart failure or arrhythmia) composite endpoints was assessed using Cox regression analysis. RESULTS: Hundred-and-twelve rTOF patients, in whom LAS was feasible and were in sinus rhythm, were included in the final analysis (age 33±10 years, 68[61%] male). Median duration of follow-up was 8.6[4.2-9.7] years in the study group. Primary composite endpoint was reached in 48 patients (mean event-free survival time: 7.2[6.6-7.9] years), and secondary composite endpoint was reached in 22 patients (mean event-free survival time: 8.7[8.1-9.2] years). LAS-r was defined as tertile groups(1st tertilend tertile=33-44%,3rd tertile>44%). Decreasing tertiles of LAS-r was associated with primary and secondary composite endpoints in Kaplan-Meier analysis(p=0.02 and 0.002, respectively). In univariable Cox-regression, both decreasing LAS-r and LAS-r tertiles were associated with primary and secondary composite endpoints. Adjusted by initial repair age and NT-proBNP quartiles, increased LAS-r was associated with significantly decreased occurrence of experiencing any events(HR=0.97,CI:0.93-0.99,p=0.037]). Decreasing LAS-r was still associated with primary endpoint when adjusted by left atrium volume index(LAVImax)(HR=0.96,CI:0.03-0.99,p=0.01),left ventricle global longitudinal strain(LV-GLS)(0.95,95%CI:0.92-0.98,p=0.002) or right ventricle free wall longitudinal strain (RV-FWLS)(0.96,95%CI:0.93-0.99,p=0.04). CONCLUSION: Assessment of LA mechanics with the use of STE has incremental utility in determination of mortality and morbidity in rTOF, and may be implemented in clinical practice.

Batoids, distributed from shallow to abyssal depths, are considerably vulnerable to anthropogenic threats. Data deficiencies on the distribution patterns of batoids, however, challenge their effective management and conservation. In this study, we took advantage of the particular geological and geomorphological configuration of the Canary Islands, across an east‐to‐west gradient in the eastern Atlantic Ocean, to assess whether patterns in the occurrence and abundance of batoids varied between groups of islands (western, central, and eastern). Data were collected from shallow (, Differences in the abundance of batoids across an oceanic archipelago suggest that “whole” archipelago management strategies are unlikely to provide adequate conservation. Management plans should be adjusted individually per island.

Shark depredation, whereby hooked fish are partially or completely consumed before they can be retrieved, occurs globally in commercial and recreational fisheries. Depredation can damage fishing gear, injure sharks, cause additional mortality to targeted fish species and result in economic losses to fishers. Knowledge of the mechanisms behind depredation is limited. We used a 13 yr dataset of fishery-dependent commercial daily logbook data for the Mackerel Managed Fishery in Western Australia, which covers 15° of latitude and 10000 km of coastline, to quantify how fishing effort and environmental variables influence depredation. We found that shark depredation rates were relatively low in comparison with previous studies and varied across the 3 management zones of the fishery, with 1.7% of hooked fish being depredated in the northern Zone 1, 2.5% in the central Zone 2 and 5.7% in the southern Zone 3. Generalized additive mixed models found that measures of commercial fishing activity and a proxy for recreational fishing effort (distance from town centre) were positively correlated with shark depredation across Zones 1 and 2. Depredation rates increased during the 13 yr period in Zones 2 and 3, and were higher at dawn and dusk, suggesting crepuscular feeding in Zone 1. This study provides one of the first quantitative assessments of shark depredation in a commercial fishery in Western Australia, and for a trolling fishery globally. The results demonstrate a correlation between fishing effort and depredation, suggesting greater fishing effort in a concentrated area may change shark behaviour, leading to high rates of depredation.

Translational Psychiatry 11(1), 467 (2021). doi:10.1038/s41398-021-01591-5, Published by Nature Publishing Group, London

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are biliary tract pathologies with increased risk of HCC, although HCC is more commonly associated with viral hepatitis and steatohepatitis. HCC risk stratification in PBC/PSC populations may help select patients for surveillance. We hypothesized that metabolic syndrome associated diagnoses and co-morbid nonalcoholic fatty liver disease (NAFLD) may be risk factors for HCC in patients with PBC and PSC. We undertook a multi-institutional case control study of PSC (19 cases, 38 controls) and PBC (39 cases and controls) patients with advanced fibrosis, matched for known HCC risk factors of age and sex, who had native liver explant or resection specimens. In the PSC population, HCC risk was significantly associated with multiple metabolic syndrome associated diagnoses (OR 13, p = 0.02), hyperlipidemia (OR 29, p = 0.03), and obesity (OR 6.8, p = 0.01). In the PBC cohort, only type 2 diabetes was a risk factor for HCC (OR 4.7, p = 0.03). In the PSC cohort, thick fibrous septae were associated with HCC risk (OR 3.4, p = 0.04). No other pathologic features of the nonneoplastic liver were significantly associated with HCC, including features of NAFLD such as macrovesicular steatosis, pericellular fibrosis, and steatohepatitis. Metabolic syndrome associated diagnoses, specifically type 2 diabetes among PBC patients, is associated with HCC risk in patients with biliary type cirrhosis. However, we found no evidence that HCC risk is related to co-morbid NAFLD, indicating a likely distinct mechanism of metabolic syndrome-associated carcinogenesis in these populations.

Este artículo contiene 16 páginas, 5 figuras, 1 tabla., Aim The influence of niche and neutral mechanisms on the assembly of ecological communities have long been debated. However, we still have a limited knowledge on their relative importance to explain patterns of diversity across latitudinal gradients (LDG). Here, we investigate the extent to which these ecological mechanisms contribute to the LDG of reef fishes. Location Eastern Atlantic Ocean. Taxon Reef-associated ray-finned fishes. Methods We combined abundance data across ~60° of latitude with functional trait data and phylogenetic trees. A null model approach was used to decouple the influence of taxonomic diversity (TD) on functional (FD) and phylogenetic (PD) diversity. Standardized effect sizes (SES FD and SES PD) were used to explore patterns of overdispersion, clustering and randomness. Information theoretic approaches were used to investigate the role of large- (temperature, geographic isolation, nitrate and net primary productivity) and local-scale (human population and depth) drivers. We further assessed the role of demographic stochasticity and its interaction with species trophic identity and dispersal capacity. Results Taxonomic diversity peaked at ~15°–20°N, with a second mode of lower magnitude at ~45°N; a pattern that was predicted by temperature, geographic isolation and productivity. Tropical regions displayed a higher proportion of overdispersed assemblages, whilst clustering increased towards temperate regions. Phylogenetic and functional overdispersion were associated with warmer, productive and isolated regions. Demographic stochasticity also contributed largely to community assembly, independently of ecoregions, although variation was dependent on the trophic identity and body size of species. Main conclusions Niche-based processes linking thermal and resource constraints to local coexistence mechanisms have contributed to the LDG in reef fishes. These processes do not act in isolation, stressing the importance of understanding interactions between deterministic and stochastic factors driving community structure in the face of rapid biodiversity change., This study was partially supported by Portuguese national funds from FCT—Foundation for Science and Technology through project UIDB/04326/2020. C.R. and P.N. were financially supported by the Oceanic Observatory of Madeira Project (M1420-01-0145-FEDER-000001—Observatório Oceânico da Madeira-OOM). D.A.S. was supported by a UKRI Future Leaders Fellowship (MR/S032827/1). P.J.M. was supported by a Marie Curie Career Integration Grant (PCIG10-GA-2011-303685). T.W. received funding from the Australian Research Council (DP170100023).

Background Conventional HER2-targeting therapies improve outcomes for patients with HER2-positive breast cancer (BC), defined as tumors showing HER2 protein overexpression by immunohistochemistry and/or ERBB2 gene amplification determined by in situ hybridization (ISH). Emerging HER2-targeting compounds show benefit in some patients with neither HER2 protein overexpression nor ERBB2 gene amplification, creating a need for new assays to select HER2-low tumors for treatment with these compounds. We evaluated the analytical performance of a targeted mass spectrometry-based assay for quantifying HER2 protein in formalin-fixed paraffin-embedded (FFPE) and frozen BC biopsies. Methods We used immunoaffinity-enrichment coupled to multiple reaction monitoring-mass spectrometry (immuno-MRM-MS) to quantify HER2 protein (as peptide GLQSLPTHDPSPLQR) in 96 frozen and 119 FFPE BC biopsies. We characterized linearity, lower limit of quantification (LLOQ), and intra- and inter-day variation of the assay in frozen and FFPE tissue matrices. We determined concordance between HER2 immuno-MRM-MS and predicate immunohistochemistry and ISH assays and examined the benefit of multiplexing the assay to include proteins expressed in tumor subcompartments (e.g., stroma, adipose, lymphocytes, epithelium) to account for tissue heterogeneity. Results HER2 immuno-MRM-MS assay linearity was ≥103, assay coefficient of variation was 7.8% (FFPE) and 5.9% (frozen) for spiked-in analyte, and 7.7% (FFPE) and 7.9% (frozen) for endogenous measurements. Immuno-MRM-MS-based HER2 measurements strongly correlated with predicate assay HER2 determinations, and concordance was improved by normalizing to glyceraldehyde-3-phosphate dehydrogenase. HER2 was quantified above the LLOQ in all tumors. Conclusions Immuno-MRM-MS can be used to quantify HER2 in FFPE and frozen BC biopsies, even at low HER2 expression levels.

Mismatch repair (MMR) immunohistochemistry (IHC) is frequently used to inform prognosis, select (immuno-)therapy, and identify patients for heritable cancer syndrome testing. However, false-negative and false-positive MMR IHC interpretations have been described.Following identification of discordant MMR IHC and DNA-based microsatellite instability testing in a patient with colorectal carcinoma, we retrospectively reviewed institutional archives to identify patient samples with similar discrepancies.We report a patient with metastatic colorectal carcinoma who initially received immunotherapy on the basis of apparent isolated loss of MLH1 by IHC; notably,This study confirms that rare germline polymorphisms can result in incorrect IHC results, potentially affecting selection of optimal therapy and the decision to pursue germline testing. This case further highlights the need for expert molecular pathologic review and communication between clinical and molecular oncology teams.

Study question Can we use MPA as a pituitary inhibitor instead of the GnRH antagonist in ovarian stimulation protocols in non-oncological fertility preservation and PGT-A cycles? Summary answer MPA can act as a substitute of GnRH antagonist for pituitary suppression in FP and PGT-A cycles, since the results are similar between both groups. What is known already Progestin-primed ovarian stimulation (PPOS) protocols using exogenous progesterone to replace GnRH analogs during the follicular phase of OS have emerged as an efficient alternative to prevent LH from peaking and have been used successfully in different types of patients. Fertility preservation (FP) and preimplantation genetic testing (PGT-A) have become new emerging areas of assisted reproduction. FP gives women the ability to have children using their own gametes after age-related fertility decline, while PGT-A appears to improve reproductive outcomes in advanced maternal age at increased risk of aneuploid embryos. However, few data are available for both indications regarding PPOS cycle outcomes. Study design, size, duration Multicenter, retrospective, observational, cohort study conducted in eleven IVIRMA centers attached to private universities. We included a total of 4,961 cycles of non-oncological fertility preservation that were distributed as follows: n = 494 were stimulated under a PPOS protocol while n = 4,467 received a GnRH antagonist. Regarding PGT-A cycles, we analyzed 12,461 treatments, of which n = 686 and n = 11,775 received MPA and GnRH antagonist, respectively. Cycles were performed from January 2017 to December 2021. Participants/materials, setting, methods Patients were divided according to the protocol used for preventing premature luteinization during follicular phase of OS. In the MPA group, participants received 10 mg daily administered orally, while in the control group, women received an antagonist once the main follicle reached 13 mm. In FP cycles, ovarian response specific parameters were evaluated, such as endocrine profile and mature oocytes; in PGT-A treatments, main variables were number of biopsied and aneuploid embryos and reproductive outcomes. Main results and the role of chance Regarding FP's baseline characteristics, age was statistically but not clinically significant between the two groups. Length of ovarian stimulation and total dose of hMG administered were similar in both groups, despite the significantly higher total dose of FSH administered in MPA compared to the GnRH antagonist group (p = 0.008) . Number of mature oocytes retrieved (10.2 [95% CI 9.6-10.8] vs 9 [95% CI 8.8-9.2]) was significantly higher in MPA compared to antagonist group; this trend continued regardless of age (≤ 35 or > 35 years). PGT-A cycles followed the same tendency in terms of demographic characteristics. Length of OS was comparable between groups, whilst the total dose of rFSH and hp-HMG administered in the MPA were significantly higher than that in the GnRH antagonist group. Although the number of MII was comparable and despite the lower number of embryos biopsied in the MPA group (4.5±0.2 vs 4.7±0.06, p = 0.031) the number of aneuploid embryos was similar between the two groups (2.3±0.1 vs 2.4±0.04, p = 0.474), as well as implantation (56% vs. 54% p = 0.359) and clinical pregnancy rate (64.1% vs. 62.1, p = 0.316). The miscarriage rate was significantly lower in the group treated with MPA compared to GnRH antagonists (4.7% vs. 8.2%, p = 0.001). Limitations, reasons for caution The retrospective nature of this study may be a reason for caution and only association, not causation, can be inferred from the results. Despite being the largest sample size ever reported with PPOS in no oncological FP and PGT-A, the number of patients included is still low. Wider implications of the findings The administration of PPOS yielded similar or even better results than those observed with GnRH antagonists in terms of oocytes retrieved, rate of aneuploid embryos or clinical results. Therefore, PPOS could be recommended for ovarian stimulation in non-oncological FP and PGT-A cycles as it allows for a more patient-friendly approach. Trial registration number Not applicable

Study question Is partial premature ovulation (PPO) detection during the oocyte pick-up (OPU) a sign of poor prognosis in in vitro fertilization (IVF) cycles with own oocytes? Summary answer PPO halves the number of metaphase II oocytes available for an IVF treatment without reducing their quality, demonstrated by unaltered fertilization and top-quality blastocyst rates. What is known already PPO detected during the OPU procedure has not been extensively studied in the literature. This phenomenon may result in a reduction in the number and/or competence of the oocytes retrieved, due to the potential loss of the already expelled oocytes, as well as the likely dominance exerted by the ruptured follicle/s in the rest of the cohort. Despite this, several authors have demonstrated that competent oocytes can be retrieved from these already ruptured follicles, suggesting that oocyte extrusion frequently does not occur after follicle rupture. The potential negative effect exerted in the rest of sibling oocytes remains unknown. Study design, size, duration Retrospective cohort analysis performed in IVIRMA Valencia (Spain), including 8994 cycles of controlled ovarian stimulation (COS) for an IVF treatment with fresh own oocytes, between January 2016 and May 2021. OPU procedures for oocyte cryopreservation, as well as mixed cycles with both fresh and frozen oocytes, were discarded. PPO diagnosis was based on ultrasound visualization of any already formed corpus luteum structure/s, a lower follicular count than expected, and/or free fluid. Participants/materials, setting, methods Female patients undergoing OPU after COS for a fresh IVF treatment. Cycles in which PPO has been detected will be compared with a random, and of the same size, sample without PPO. Mean number of oocytes, metaphase II, fertilized oocytes and top-quality embryos, as well as IVF success rates, will be compared between both groups. Patients’ basal characteristics and COS parameters will be analyzed in order to detect any potential early indicator of PPO. Main results and the role of chance PPO was detected in 123 of the 8994 cycles (1.37%) performed. A random control group of 123 cycles without PPO was selected. Patients’ mean age was 37.6±3.6, with a BMI of 23.3±4.1 kg/m2 and an anti-mullerian hormone of 1.62±1.3 ng/mL. Patient’s basal characteristics and COS parameters were statistically comparable among groups (p > 0.05), except for lower serum estradiol levels (2037.64 vs. 1582.24 pg/mL; p = 0.004) in the PPO group on the last ultrasound prior to OPU. Patients with PPO showed lower aspiration rates (88.95% vs. 55.78% in the PPO gr.), as well as a reduced mean number of oocytes (10.69 vs. 5.68 in the PPO gr.), metaphase II (8.41 vs. 4.33 in the PPO gr.), fertilized oocytes (6.23 vs. 3.26 in the PPO gr.) and top-quality blastocysts (2.77 vs. 1.35 in the PPO gr.) (p = 0.000). In contrast, maturation (80.72% vs. 76.57% in the PPO gr.), fertilization (73.52% vs. 75.18% in the PPO gr.) and top-quality blastocyst rates (44.03% vs. 38.68% in the PPO gr.) were statistically similar between both groups (p > 0.05). Limitations, reasons for caution The main limitations of the present study are its retrospective design and its small sample size, derived from the low frequency of the PPO phenomenon in our clinic. Larger prospective studies should be proposed in order to accurately define the negative impact of PPO in IVF success rates. Wider implications of the findings PPO clearly reduces the number of oocytes available for an IVF treatment, although it does not seem to impair the competence of the remaining cohort. Once PPO is detected, cycle cancellation may not be worth the associated loss of money, time and morale, especially given its low prevalence (around 1%). Trial registration number Not applicable

Carbon monoxide (CO) has long been considered a toxic gas but is now a recognized bioactive gasotransmitter with potent immunomodulatory effects. Although inhaled CO is currently under investigation for use in patients with lung disease, this mode of administration can present clinical challenges. The capacity to deliver CO directly and safely to the gastrointestinal (GI) tract could transform the management of diseases affecting the GI mucosa such as inflammatory bowel disease or radiation injury. To address this unmet need, inspired by molecular gastronomy techniques, we have developed a family of gas-entrapping materials (GEMs) for delivery of CO to the GI tract. We show highly tunable and potent delivery of CO, achieving clinically relevant CO concentrations in vivo in rodent and swine models. To support the potential range of applications of foam GEMs, we evaluated the system in three distinct disease models. We show that a GEM containing CO dose-dependently reduced acetaminophen-induced hepatocellular injury, dampened colitis-associated inflammation and oxidative tissue injury, and mitigated radiation-induced gut epithelial damage in rodents. Collectively, foam GEMs have potential paradigm-shifting implications for the safe therapeutic use of CO across a range of indications.

Study question Is the individualised follitropin delta regimen based on serum anti-Müllerian hormone (AMH) concentration and body weight effective and safe in a long GnRH agonist protocol? Summary answer Per started stimulation, the live birth rate following fresh transfer was 43% and the cumulative live birth rate following fresh and frozen transfers was 58%. What is known already Individualised follitropin delta treatment in a GnRH antagonist protocol reduces the incidence of OHSS and/or preventive interventions without compromising live birth rates. In a multinational, double-blind, randomised trial (RAINBOW, NCT03564509) exploring the efficacy and safety of choriogonadotropin beta in women undergoing ovarian stimulation in a long GnRH agonist protocol, the control group was treated with the same individualised follitropin delta regimen based on AMH (Elecsys AMH Plus Immunoassay) and body weight. Women had one stimulation cycle and were followed up to live birth following the fresh and all frozen blastocyst transfers performed within one year after start of stimulation. Study design, size, duration Analysis of fresh and cumulative live birth rates in 104 women (30–42 years, AMH 5-35 pmol/L) down-regulated with 0.1 mg/day triptorelin and stimulated in one cycle with a fixed individualised daily dose of follitropin delta. Triggering was performed when 3 follicles ≥17 mm. Oocytes were inseminated by ICSI; blastocyst transfer was on day 5 and remaining blastocysts were cryopreserved on day 5/6 and subsequently used for frozen transfers. Participants/materials, setting, methods Data collection included live birth and neonatal health follow-up for all transfers of fresh or frozen embryos performed within one year after the start of stimulation. The data presented are based on all women who were down-regulated and started stimulation. The cumulative live birth rate was calculated as the percentage of women starting stimulation that had at least one live born neonate. Main results and the role of chance Of 104 women starting stimulation, 101 had triggering. Two subjects were cancelled due to poor response and one due to adverse event. Nine subjects had transfer cancellations; six due to no day 5 blastocyst available, and one each due to risk of OHSS, adverse event, and other reason. The average daily dose of follitropin delta was 11.0±1.6 and the duration of stimulation was 10.3±1.6 days. The mean number of oocytes was 12.5±6.4; the mean number of blastocysts was 5.1±3.4; and 85% had at least one good-quality blastocyst. Following mostly single blastocyst transfer (95%), the ongoing pregnancy rate (10–11 weeks after transfer) was 43% per started stimulation. There were six cases of early OHSS (5.8%) graded as mild (3) and moderate (3) and six cases with late OHSS (5.8%) graded as moderate (3) and severe (3). In total, 92% of women had at least one fresh or frozen transfer and 150 blastocyst transfers were performed (92 fresh and 58 frozen transfers). Per started stimulation, the live-birth rate following fresh transfer was 43% and the cumulative live-birth rate following fresh and all frozen transfers was 58%. There were three neonates with congenital anomalies following fresh transfer and none following frozen transfer. Limitations, reasons for caution This is the first clinical trial investigating the individualised follitropin delta regimen in a long GnRH agonist protocol. A final evaluation of this regimen requires comparative data. Accordingly, a randomised trial comparing follitropin delta in a long GnRH agonist protocol vs. in a GnRH antagonist protocol is currently ongoing (NCT03809429). Wider implications of the findings The use of individualised follitropin delta dosing based on AMH and body weight in a long GnRH agonist protocol resulted in high fresh and cumulative live birth rates, and with an incidence of OHSS similar to previously reported for other FSH products in long GnRH agonist protocols. Trial registration number NCT03564509

Study question Is there an optimal serum progesterone (P) threshold in frozen embryo transfer (FET) modified natural cycles when luteal phase support (LPS) is given? Summary answer Serum P measured on the day of ET is not related with ongoing pregnancy outcome when doing a modified natural cycle with LPS. What is known already Recent publications showed that there is a minimum threshold of serum P that needs to be reached in artificial cycles to optimize pregnancy rates. When using micronized vaginal P (MVP), about 30% of patients show low levels of serum P ( Study design, size, duration Prospective cohort unicentric study performed in IVI RMA Valencia (Spain), including 244 cycles from February 2020 to January 2021. Participants/materials, setting, methods Infertile patients 6.5mm). MVP was used for LPS (200mg/12h). Ongoing pregnancy rate (OPR) was correlated with serum P levels on the FET day, measured within two hours before transfer. Main results and the role of chance A total of 241 patients were analyzed. Mean age was 38.1 + 3.8 years, with a mean BMI of 23.3 + 3.9. On the rec-hCG day the mean leading follicle size was 17.7±0.1 mm. The endometrium displayed a trilaminar pattern, with a mean thickness of 7.8±3.3 mm, and mean P and estradiol (E2) levels were 0.30±0.03 ng/ml and 249.39±11.03 pg/ml, respectively. A mean of 1.1 blastocysts were transferred (90.9% were single embryo transfers), 27.4% (66) from donated and 72.6 % (175) from own oocytes. On the day of FET, the mean serum P and E2 levels were 26.19 + 8.97ng/mL and 154.12 + 96.08pg/mL, respectively. The overall OPR was 51.5% (124). OPR according to quartiles of serum P (ng/mL) was 56.7% (Q1, P 20.2-24.8), 51.7% (Q3, P > 24.8-31.1), 50.0% (Q4, P > 31.1), p = 0.78). Multivariate logistic regression showed that serum P was not related with OPR after adjusting for age, BMI, E2 and origin of oocytes (aOR:0.98, 95% CI:0.93-1.04, p = 0.47). Only 2 patients had serum P levels below 10 ng/mL, with values of 8.6 and 8.8 ng/mL on the ET day and had a negative pregnancy test. Limitations, reasons for caution As part of our routine clinical practice, MVP (200mg/12h) is given for LPS in patients undergoing a FET in the context of a modified natural cycle. Thus, these results cannot be extrapolated to LPS-free or any other LPS protocol in FET modified natural cycles. Wider implications of the findings The majority of patients undergoing FET in modified natural cycles when using LPS have adequate levels of serum P and thus, do not have an impact on pregnancy outcome. According to our data, there is no need to measure serum P levels on the luteal phase of modified natural cycles. Trial registration number NCT04259996

Global warming is facilitating the range expansion of tropical herbivores, causing a tropicalization of temperate marine ecosystems, where tropical herbivores can suppress habitat‐forming macrophytes, supporting the resilience of canopy‐free ecosystem states. However, currently we lack a thorough understanding of the mechanisms that, on one hand, support the persistence of tropical herbivores and on the other support the recovery of temperate foundation species in tropicalized ecosystems, a required knowledge to predict potential regime shifts and reversals to the baseline state of the ecosystem. This study tested processes behind the persistence of the tropicalization of temperate reefs which experienced a complete loss of their kelp forests and an influx of tropical herbivores following a marine heatwave in 2011. For this, we assessed the feedback mechanisms that maintain turf‐dominated states (recruitment of tropical herbivores, browsing and grazing rates and turf cover) and those that resist it (kelp recruitment, survival and reproductiveness). We found that the reefs remained tropicalized with high abundances of turf and tropical herbivores after 9 years from the regime shift. The rabbitfish Siganus fuscescens and the chub Kyphosus bigibbus were the most important herbivores whose persistence was supported by the adjacent reef lagoon, where seagrass meadows and the backreef habitats hosted juveniles of both species, particularly rabbitfish. Tropical herbivores exerted a strong top–down control on turf seaweed and kelp during herbivory assays, rapidly consuming kelp individuals in open areas. However, in topographical refuges in the reefs, herbivory was low and kelp individuals survived, with some having reproductive tissue. Synthesis. Our findings incorporate the importance of nursery grounds for tropical herbivores and herbivory refugia for kelp individuals into the tropicalization model, where the former increases the resilience of canopy‐free states and the latter might facilitate recovering kelp populations. The restoration of abundant warm‐resistant kelp populations in shelters could provide local sources of propagules to recolonize open spaces; however, our results suggest that the reduction of herbivory and the provision of turf‐free substratum would be necessary to boost the recovery of kelp forests.

CONTEXT: Different polymorphisms of the endothelial nitric oxide synthase gene (NOS3) have been related to diabetic kidney disease. OBJECTIVE: To evaluate the association between advanced diabetic chronic kidney disease (ACKD) and the rs1799983 and rs2070744 poymorphisms of NOS3 in a population from the Gran Canaria island. DESIGN: Cross-sectional case-control study. SUBJECTS AND METHODS: Polymorphisms were genotyped in 152 subjects with ACKD secondary to type 2 diabetes [estimated glomerular filtration rate (eGFR)

Our aims were to assess performance of duodenal intraepithelial lymphocyte counting for diagnosis of Helicobacter pylori (H. pylori) gastritis, and effects of eradication therapy on intraepithelial lymphocytosis. Paired duodenal and gastric biopsies from subjects with a pathologic diagnosis of H. pylori gastritis were reviewed. Higher duodenal intraepithelial lymphocyte counts were observed in 40 subjects with H. pylori gastritis (26 ± 5 per villus) than 52 subjects negative for H. pylori (12 ± 2 per villus). After successful eradication therapy, duodenal lymphocytes were indistinguishable from H. pylori–negative subjects, whereas they remained elevated after failed eradication therapy. This study confirms previous reports of increased duodenal intraepithelial lymphocytes in patients with concurrent Helicobacter pylori gastritis. Intraepithelial lymphocyte counts of > 15 per villus or > 10 per 100 enterocytes were predictive of infection. Duodenal lymphocytosis decreases significantly after successful eradication therapy but remains elevated when treatment fails.

The polymorphic drug-metabolizing enzyme CYP2D6, which is responsible for the metabolism of most psychoactive compounds, is expressed not only in the liver, but also in the brain. The effects of its marked genetic polymorphism on the individual capacity to metabolize drugs are well known, but its role in metabolism of neural substrates affecting behavior personality or cognition, suggested by its CNS expression, is a long-standing unresolved issue. To verify earlier findings suggesting a potential effect on attentional processes, we collected functional imaging data, while N = 415 participants performed a simple task in which the reward for correct responses varied. CYP2D6 allelic variants predicting higher levels of enzymatic activity level were positively associated with cortical activity in occipito-parietal areas as well as in a right lateralized network known to be activated by spatial attentional tasks. Reward-related modulation of activity in cortical areas was more pronounced in poor metabolizers. In conjunction with effects on reaction times, our findings provide evidence for reduced cognitive efficiency in rapid metabolizers compared to poor metabolizers in on-task attentional processes manifested through differential recruitment of a specific neural substrate.

In the province of KwaZulu-Natal in South Africa, isiZulu is a dominant language, yet it is not used as the language of teaching and learning in schools. The linguistic rights of isiZulu-speaking l...

The arrival of non-indigenous species into new areas is one of the main processes altering the oceans globally. Macrorhynchia philippina is a large-sized colonial hydrozoan of an invasive nature. To obtain a deeper understanding of the process of colonization of new areas, it is essential to describe the ecological pattern through scales of temporal and spatial variation. In this study, we describe the colonization by M. Philippina of an oceanic island (Gran Canaria Island, Canary Islands, eastern Atlantic). We describe the abundance and size structure patterns of M. Philippina in three nearshore habitats, rocky reefs, seagrass meadows and rhodolith seabeds, at times before (2014), during (2016) and after (2017) the demographic explosion of this species. On rocky reefs and rhodolith seabeds, the abundance of colonies increased dramatically in 2017 rel­ative to 2014, e.g. from 0 to 138 colonies/100 m2. On seagrass meadows, however, the colonies were smaller. In summary, M. Philippina shows an ecological plasticity to rapidly colonize different types of nearshore habitats, but with varying success. La aparición de especies exóticas es uno de los principales factores que alteran los océanos de forma global. Mac­rorhynchia philippina es un hidrozoo colonial de tamaño grande y naturaleza invasora. Para tener un mejor conocimiento del proceso de colonización es fundamental describir los patrones ecológicos a escalas de variación temporal y espacial. En este estudio, describimos el proceso de colonización por M. Philippina en una isla oceánica (Gran Canaria, Islas Canarias, Atlántico oriental). Se describen los patrones de abundancia y estructura de tallas de M. Philippina en tres hábitats costeros: arrecifes rocosos, praderas de fanerógamas marinas y fondos de rodolitos, antes (2014), durante (2016) y después (2017) de la explosión demográfica de la especie. Sobre arrecifes rocosos y en fondos de rodolitos, la abundancia de las colonias se incrementó drásticamente en 2017 con relación a 2014, e.g. desde 0 hasta 138 colonias/100 m2; este incremento fue menor en las praderas de fanerógamas marinas. En las praderas marinas, la longitud de las colonias fue más pequeña que sobre ar­recifes rocosos y fondos de rodolitos. Consecuentemente, la colonización rápida por M. Philippina demuestra su plasticidad ecológica para colonizar diferentes tipos de hábitats costeros, aunque con diferente éxito.

Purpose To assess estradiol (E2) and progesterone levels during ovarian stimulation determined by third-generation (Gen III) and second-generation (Gen II) Elecsys® immunoassays. Methods E2 and progesterone concentrations were measured using Elecsys® Gen III and Gen II immunoassays, and progesterone concentrations on the day of ovulation triggering were determined by LC–MS/MS. This was a retrospective, non-interventional study conducted at European tertiary referral infertility clinics in women aged 18–45 years, with a body mass index 18–35 kg/m2, regular menses, and both ovaries. Results Serum samples were obtained from 230 women classified by oocyte retrieval as poor (33.0%; 0–3 oocytes), normal (40.9%; 4–15 oocytes), or high (26.1%; > 15 oocytes) responders. E2 and progesterone levels increased during ovarian stimulation, with greatest increases observed in high responders. Elecsys® Gen III and Gen II assay results were highly correlated for E2 (Pearson’s r = 0.99) and progesterone (r = 0.89); Gen III results were lower than Gen II for both E2 and progesterone. On the day of triggering, Gen III E2 and progesterone levels showed a difference of − 15.0% and − 27.9%, respectively. Progesterone levels (on day of triggering) measured by LC–MS/MS correlated better with Gen III (0.98) than Gen II (0.90). Mean relative differences for Gen III and Gen II assays versus LC–MS/MS were 14.6% and 62.8%, respectively. Conclusion E2 and progesterone levels determined with Elecsys® Gen II and III assays were highly correlated; results were lower for Gen III versus Gen II. Differences observed for progesterone on the day of triggering may be clinically relevant.

Introduction: Activation of the kynurenine pathway (KP) has been reported in patients with pulmonary arterial hypertension (PAH) undergoing PAH therapy. We aimed to determine KP-metabolism in treatment-naïve PAH patients, investigate its prognostic values, evaluate the effect of PAH therapy on KP-metabolites and identify cytokines responsible for altered KP-metabolism. Methods: KP-metabolite levels were determined in plasma from PAH patients (median follow-up 42 months) and in rats with monocrotaline- and Sugen/hypoxia-induced PH. Blood sampling of PAH patients was performed at the time of diagnosis, six months and one year after PAH therapy. Results: KP activation with lower tryptophan, higher kynurenine (Kyn), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA), and anthranilic acid was observed in treatment-naïve PAH patients compared with controls. A similar KP-metabolite profile was observed in monocrotaline, but not Sugen/hypoxia-induced PAH. Human lung primary cells (microvascular endothelial cells, pulmonary artery smooth muscle cells, and fibroblasts) were exposed to different cytokines in vitro. Following exposure to interleukin-6 (IL-6)/IL-6 receptor a (IL-6Ra) complex, all cell types exhibit a similar KP-metabolite profile as observed in PAH patients. PAH therapy partially normalized this profile in survivors after one year. Increased KP-metabolites correlated with higher pulmonary vascular resistance, shorter six-minute walking distance, and worse functional class. High levels of Kyn, 3-HK, QA, and KA measured at the latest time-point were associated with worse long-term survival. Conclusion: KP-metabolism was activated in treatment-naïve PAH patients, likely mediated through IL-6/IL-6Ra signaling. KP-metabolites predict response to PAH therapy and survival of PAH patients.

Understanding the extent to which species’ traits mediate patterns of community assembly is key to predict the effect of natural and anthropogenic disturbances on ecosystem functioning. Here, we apply a trait-based community assembly framework to understand how four different habitat configurations (kelp forests, Sargassum spp. beds, hard corals, and turfs) shape the trophic and energetic dynamics of reef fish assemblages in a tropical–temperate transition zone. Specifically, we tested (i) the degree of trait divergence and convergence in each habitat, (ii) which traits explained variation in species’ abundances, and (iii) differences in standing biomass (kg ha−1), secondary productivity (kg ha−1 day−1) and turnover (% day−1). Fish assemblages in coral and kelp habitats displayed greater evidence of trait convergence, while turf and Sargassum spp. habitats displayed a higher degree of trait divergence, a pattern that was mostly driven by traits related to resource use and thermal affinity. This filtering effect had an imprint on the trophic and energetic dynamics of reef fishes, with turf habitats supporting higher fish biomass and productivity. However, these gains were strongly dependent on trophic guild, with herbivores/detritivores disproportionately contributing to among-habitat differences. Despite these perceived overall gains, turnover was decoupled for fishes that act as conduit of energy to higher trophic levels (i.e. microinvertivores), with coral habitats displaying higher rates of fish biomass replenishment than turf despite their lower productivity. This has important implications for biodiversity conservation and fisheries management, questioning the long-term sustainability of ecological processes and fisheries yields in increasingly altered marine habitats.

Algal turfs are expected to increasingly dominate the benthos of coral reefs in the Anthropocene, becoming important sources of reef productivity. The sediments trapped within algal turfs are known to determine turf condition and influence a range of key ecological processes, particularly the feeding behavior of fishes. Yet, our understanding of the interactions between turfs, sediments and fishes is largely derived from offshore reef systems, where turfs typically contain relatively low sediment loads. Here, we expand on this knowledge by characterizing the properties of turfs and their interactions with fishes on a large, mainland fringing reef system, Ningaloo Reef. Algal turfs varied in algal biomass, height and percent of organic content in the sediment between sites, while the total inorganic and organic sediment loads were comparable. Despite being located in an arid climate with low riverine sediment inputs, turfs in Ningaloo contained an average of 3.5 kg m−2 of inorganic sediment, one of the highest loads reported in the literature. Yet, turf feeding rates by fishes in our study were comparable to locations where inorganic sediment loads are substantially lower. Feeding was dominated by herbivorous fishes (> 80% of the bites on average), with surgeonfishes being the dominant herbivore feeders (72% of the herbivore bites). In particular, the sediment sucker Acanthurus grammoptilus and the cropper Acanthurus triostegus—which crops off algal filaments protruding above the sediment layer—were the dominant and most commonly observed feeders. Our results suggest that cropping and sediment-sucking surgeonfishes are able to feed on turfs with high sediment loads, an ability that may prove advantageous in sediment-laden turf-dominated-reefs of the future.

Sharks play a key role in the structure and functioning of marine ecosystems. More ecological information is essential to implement responsible management and conservation actions on this fauna, particularly at a regional level for threatened species.

Centrizonal hepatocyte dropout has been described in diverse liver pathologies, including viral hepatitis, venous outflow obstruction, and allograft cellular rejection. However, its clinical significance remains uncertain.We designed a clinicopathological study of 206 allograft liver biopsies with centrizonal hepatocyte dropout. Centrizonal hepatocyte dropout was associated most frequently with cellular rejection (n = 62), asymptomatic/protocol biopsies (n = 56), immediate post-transplantation biopsies (n = 21), biliary obstruction (n = 14), and viral hepatitis (n = 13). The differential diagnosis is informed by timing post-transplantation, biliary imaging and laboratory test results. 'Cholestatic' and 'hepatocytic' laboratory patterns were associated with biliary obstruction and cellular rejection, respectively. A mixed pattern peaking after biopsy was observed in viral hepatitis cases. In the context of cellular rejection, dropout was not associated with the time interval to normalisation of serum alanine aminotransferase (ALT), but was associated with shorter transplant-free survival (hazard ratio 4, P = 0.01) than that of histological severity-matched controls. In time zero allograft biopsies, time to ALT normalisation was prolonged (median, 15 versus 11 days, P = 0.002) in allografts with centrizonal dropout, with no effect on retransplant-free survival.Centrizonal hepatocyte dropout has low clinicopathological diagnostic specificity. However, it correlates with adverse clinical outcomes in allograft cellular rejection and time zero biopsies.

Predicates like "coloring-the-star" denote events that have a temporal duration and a culmination point (telos). When combined with perfective aspect (e.g., "Valeria has colored the star"), a culmination inference arises implying that the action has stopped, and the star is fully colored. While the perfective aspect is known to constrain the conceptualization of the event as telic, many reading studies have demonstrated that readers do not make early commitments as to whether the event is bounded or unbounded. A few visual-world studies tested the processing of telic predicates during online sentence processing, demonstrating an early integration of aspectual and temporal cues. By employing the visual-world paradigm, we tested the incremental processing of the perfective aspect in Italian in two eye-tracking studies in which listeners heard durative predicates in the perfective form in a scenario showing a completed and a non-completed event. Differently from previous studies, we compared telic durative predicates such as "coloring-the-star" to punctual predicates such as "lighting-the-candle." While for punctual predicates, the inferences of telicity (the event has a telos) and of culmination (the telos is reached) are lexically encoded in the perfective verb, for durative predicates, the degree of event completion (visually encoded) needs to be integrated with perfective aspect (linguistically encoded) for the culmination inference derivation. By modulating the interaction of visual and linguistic stimuli across the two experiments, we show that the verb's perfective aspect triggers the culmination inference incrementally during sentence processing, offering novel evidence for the continuous integration of linguistic processing with real-world visual information.

Gallbladder carcinoma is an uncommon malignancy with an overall 5-year survival of less than 5%. Gallbladder carcinoma has been strongly linked with cholelithiasis and chronic inflammation. Case reports and series have described cholecystitis with acute (neutrophilic) inflammation in association with gallbladder carcinoma, although a clear relationship to patient outcome has not been established. Our series included 8 cases of gallbladder carcinoma with high tumor-associated neutrophils (>25 per high power field) that were associated with shorter patient survival (Cox regression coefficient 6.2, p = 0.004) than age- and stage-matched controls. High tumor-associated neutrophils were not associated with gallbladder rupture/perforation or increased bacterial load measured by 16S PCR. Neutrophilic inflammation with gallbladder carcinoma correlates to shorter survival, independent of patient age and stage of carcinoma. The findings suggest that the degree of neutrophilic inflammation may have prognostic significance in specimens from patients with gallbladder carcinoma after cholecystectomy. Further studies with larger case numbers are needed to confirm and generalize these findings.