Influence of familial forms of inflammatory bowel disease on the use of immunosuppressants, biological agents, and surgery in the era of biological therapies. Results from the ENEIDA project.

BACKGROUND AND AIMS: Familial inflammatory bowel disease (IBD) history is a controversial prognostic factor in IBD. We aimed to evaluate the impact of a familial history of IBD on the use of medical and surgical treatments in the biological era. METHODS: Patients included in the prospectively maintained ENEIDA database and diagnosed with IBD after 2005 were included. Familial forms were defined as those cases with at least one first-degree relative diagnosed with IBD. Disease phenotype, the use of biological agents, or surgical treatments were the main outcomes. RESULTS: A total of 5263 patients [2627 Crohn's disease (CD); 2636 ulcerative colitis (UC)] were included, with a median follow-up of 31 months. Of these, 507 (10%) corresponded to familial forms. No clinical differences were observed between familial and sporadic IBD forms except a lower age at IBD diagnosis and a higher rate of males in familial forms of UC. In CD, the proportions of patients treated with thiopurines (54.4% vs 46.7%; P = .015) and survival time free of thiopurines (P = .009) were lower in familial forms. No differences were found regarding the use of biological agents. Concerning surgery, a higher rate of intestinal resections was observed in sporadic CD (14.8% vs 9.9%, P = .027). No differences were observed in UC. CONCLUSIONS: In the era of biological therapies, familial and sporadic forms of IBD show similar phenotypes and are managed medically in a similar way; whether these is due to lack of phenotypical differences or an effect of biological therapies is uncertain. What is already known on this topic: IBD's etiopathogenesis points to an interaction between environmental and genetic factors, being familial history a controversial prognostic factor. Biological agents use and need for surgery regarding familial or sporadic forms of IBDs present conflicting results. What this study adds: Familial and sporadic forms of IBD have similar phenotypes and are managed medically and surgically in a similar way. How this study might affect research, practice or policy: Familial aggregation should not be considered a factor associated with more aggressive disease.

Near-infrared spectroscopy monitoring of neonatal cerebrovascular reactivity: where are we now?

Cerebrovascular reactivity defines the ability of the cerebral vasculature to regulate its resistance in response to both local and systemic factors to ensure an adequate cerebral blood flow to meet the metabolic demands of the brain. The increasing adoption of near-infrared spectroscopy (NIRS) for non-invasive monitoring of cerebral oxygenation and perfusion allowed investigation of the mechanisms underlying cerebrovascular reactivity in the neonatal population, confirming important associations with pathological conditions including the development of brain injury and adverse neurodevelopmental outcomes. However, the current literature on neonatal cerebrovascular reactivity is mainly still based on small, observational studies and is characterised by methodological heterogeneity; this has hindered the routine application of NIRS-based monitoring of cerebrovascular reactivity to identify infants most at risk of brain injury. This review aims (1) to provide an updated review on neonatal cerebrovascular reactivity, assessed using NIRS; (2) to identify critical points that need to be addressed with targeted research; and (3) to propose feasibility trials in order to fill the current knowledge gaps and to possibly develop a preventive or curative approach for preterm brain injury. IMPACT: NIRS monitoring has been largely applied in neonatal research to assess cerebrovascular reactivity in response to blood pressure, PaCO2 and other biochemical or metabolic factors, providing novel insights into the pathophysiological mechanisms underlying cerebral blood flow regulation. Despite these insights, the current literature shows important pitfalls that would benefit to be addressed in a series of targeted trials, proposed in the present review, in order to translate the assessment of cerebrovascular reactivity into routine monitoring in neonatal clinical practice.

Days spent on non-invasive ventilation support: can it determine when to initiate VV- ECMO? Observational study in a cohort of Covid-19 patients.

BACKGROUND: The study evaluates the impact of the time between commencing non-invasive ventilation (NIV) support and initiation of venovenous extracorporeal membrane oxygenation (VV-ECMO) in a cohort of critically ill patients with coronavirus disease 2019 (COVID-19) associated acute respiratory distress syndrome (ARDS). METHODS: Prospective observational study design in an intensive Care Unit (ICU) of a tertiary hospital in Barcelona (Spain). All patients requiring VV-ECMO support due to COVID-19 associated ARDS between March 2020 and January 2022 were analysed. Survival outcome was determined at 90 days after VV-ECMO initiation. Demographic data, comorbidities at ICU admission, RESP (respiratory ECMO survival prediction) score, antiviral and immunomodulatory treatments received, inflammatory biomarkers, the need for vasopressors, the thromboprophylaxis regimen received, and respiratory parameters including the length of intubation previous to ECMO and the length of each NIV support (high-flow nasal cannula, continuous positive airway pressure and bi-level positive airway pressure), were also collated in order to assess risk factors for day-90 mortality. The effect of the time lapse between NIV support and VV-ECMO on survival was evaluated using logistic regression and adjusting the association with all factors that were significant in the univariate analysis. RESULTS: Seventy-two patients finally received VV-ECMO support. At 90 days after commencing VV-ECMO 35 patients (48%) had died and 37 patients (52%) were alive. Multivariable analysis showed that at VV-ECMO initiation, age (p = 0.02), lactate (p = 0.001), and days from initiation of NIV support to starting VV-ECMO (p = 0.04) were all associated with day-90 mortality. CONCLUSIONS: In our small cohort of VV-ECMO patients with COVID-19 associated ARDS, the time spent between initiation of NIV support and VV-ECMO (together with age and lactate) appeared to be a better predictor of mortality than the time between intubation and VV-ECMO.

Pre-existing Autoantibodies Neutralizing High Concentrations of Type I Interferons in Almost 10% of COVID-19 Patients Admitted to Intensive Care in Barcelona.

BACKGROUND: It is important to predict which patients infected by SARS-CoV-2 are at higher risk of life-threatening COVID-19. Several studies suggest that neutralizing auto-antibodies (auto-Abs) against type I interferons (IFNs) are predictive of critical COVID-19 pneumonia. OBJECTIVES: We aimed to test for auto-Abs to type I IFN and describe the main characteristics of COVID-19 patients admitted to intensive care depending on whether or not these auto-Abs are present. METHODS: Retrospective analysis of all COVID-19 patients admitted to an intensive care unit (ICU) in whom samples were available, from March 2020 to March 2021, in Barcelona, Spain. RESULTS: A total of 275 (70.5%) out of 390 patients admitted to ICU were tested for type I IFNs auto-antibodies (α2 and/or ω) by ELISA, being positive in 49 (17.8%) of them. Blocking activity of plasma diluted 1/10 for high concentrations (10 ng/mL) of IFNs was proven in 26 (9.5%) patients. Almost all the patients with neutralizing auto-Abs were men (92.3%). ICU patients with positive results for neutralizing IFNs auto-Abs did not show relevant differences in demographic, comorbidities, clinical features, and mortality, when compared with those with negative results. Nevertheless, some laboratory tests (leukocytosis, neutrophilia, thrombocytosis) related with COVID-19 severity, as well as acute kidney injury (17 [65.4%] vs. 100 [40.2%]; p = 0.013) were significantly higher in patients with auto-Abs. CONCLUSION: Auto-Abs neutralizing high concentrations of type I IFNs were found in 9.5% of patients admitted to the ICU for COVID-19 pneumonia in a hospital in Barcelona. These auto-Abs should be tested early upon diagnosis of SARS-CoV-2 infection, as they account for a significant proportion of life-threatening cases.

No impact of surviving sepsis campaign care bundles in reducing sepsis-associated acute kidney injury
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BACKGROUND: The impact of Surviving Sepsis Campaign (SSC) care bundles in reducing sepsis-associated acute kidney injury (SA-AKI) was evaluated. METHODS: We conducted an observational single-center cohort study. Accomplishment of SSC care bundles was registered in all patients with severe sepsis admitted to the critical care department of a university hospital during three different periods. The main outcome measured was SA-AKI incidence defined as any worsening of AKI stage within the first 7 days from onset of sepsis. RESULTS: Among 260 patients with severe sepsis or septic shock finally meeting inclusion criteria, 82 (31.5%) patients developed SA-AKI. None of the SSC care tasks significantly decreased SA-AKI incidence, although a trend was observed with an initial better blood glucose control as well as with a more protective ventilation strategy. Hypotension requiring fluid challenge (hazard ratio (HR), 2.3; 95% confidence interval (CI), 1.2 - 4.2) and the presence of an abdominal sepsis etiology (HR, 1.8; 95% CI, 1.1 - 3.1) were independently associated with SA-AKI. Patients who developed SA-AKI had a higher 90-day mortality rate (62.2 vs. 40.4%). CONCLUSION: In a cohort of septic patients, none of the SSC care tasks significantly decreased SA-AKI incidence within the first week after onset of sepsis.
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New developments in cerebral blood flow autoregulation analysis in preterm infants: a mechanistic approach.

BACKGROUND: Impaired autoregulation capacity implies that changes in cerebral perfusion follow changes in blood pressure; however, no analytical method has explored such a signal causality relationship in infants. We sought to develop a method to assess cerebral autoregulation from a mechanistic point of view and explored the predictive capacity of the method to classify infants at risk for adverse outcomes. METHODS: The partial directed coherence (PDC) method, which considers synchronicity and directionality of signal dependence across frequencies, was used to analyze the relationship between spontaneous changes in mean arterial pressure (MAP) and the cerebral tissue oxygenation index (TOI). PDCMAP>>TOI indicated that changes in TOI were induced by MAP changes, and PDCTOI>>MAP indicated the opposite. RESULTS: The PDCMAP>>TOI and PDCTOI>>MAP values differed. PDCMAP>>TOI adjusted by gestational age predicted low superior vena cava flow (≤41 ml/kg per min), with an area under the receiver operating characteristic curve of 0.72 (95% CI: 0.63-0.81; P < 0.001), whereas PDCTOI>>MAP did not. The adjusted pPDCMAP>>TOI (the average value per patient) predicted severe intracranial hemorrhage and mortality. CONCLUSION: PDCMAP>>TOI allows for a noninvasive physiological interpretation of the pressure autoregulation process in neonates. PDCMAP>>TOI is a good classifier for infants at risk of brain hypoperfusion and adverse outcomes.

Measurement of ceftazidime concentration in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry. Application to critically ill patients and patients with osteoarticular infections.

Ceftazidime is an antibiotic belonging to the third generation of the cephalosporin family. It is indicated in the treatment of serious, simple or mixed bacterial infections, and its administration in continuous or intermittent infusion allows optimization of the concentration of antibiotic to keep it above the minimum inhibitory concentration. We developed and validated a chromatographic method by ultra-performance liquid chromatography-tandem mass spectrometry to measure ceftazidime concentration in human plasma. Following extraction with acetonitrile and 1,2-dichloroethane, the chromatographic separation was achieved using an Acquity ® UPLC ® BEH(TM) (2.1 × 100 mm i.d., 1.7 µm) reverse-phase C18 column, with a water-acetonitrile linear gradient containing 0.1% formic acid at a 0.4 mL/min flow rate. Ceftazidime and its internal standard (cefotaxime) were detected by electrospray ionization mass spectrometry in positive ion multiple reaction monitoring mode using mass-to-charge transitions of 547.0 → 467.9/396.1 and 456.0 → 395.8/324.1, respectively. The limit of quantification was 0.58 mg/L and linearity was observed in the range 0.58-160 mg/L. Coefficients of variation and absolute relative biases were <9.8 and 8.4%. The mean recovery for ceftazidime was 74.4 ± 8.1%. Evaluation of the matrix effect showed ion enhancement, and no carry-over was observed. The validated method could be applied to daily clinical laboratory practice to measure the concentration of ceftazidime in plasma.

Randomized, Placebo-Controlled Trial of Dobutamine for Low Superior Vena Cava Flow in Infants.

OBJECTIVE: To gather information for a future confirmatory trial of dobutamine (DB) for circulatory impairment (ie, low superior vena cava [SVC] flow). STUDY DESIGN: A total of 127 infants born at < 31 weeks gestational age were serially scanned from birth to 96 hours after birth. The infants were randomly assigned to 2 groups and were treated with DB (stepwise dose increase, 5-10-15-20 µg/kg/min) or placebo if they had an SVC flow < 41 mL/kg/min within the first 24 hours after birth. The primary outcome measures were the achievement and maintenance of an SVC flow ≥ 41 mL/kg/min. Secondary outcome measures were the short-term evolution of clinical and biochemical variables, near-infrared spectroscopy, cranial Doppler ultrasound, and clinical outcomes. RESULTS: SVC flow increased throughout the first 96 hours for the entire cohort. All of the randomized infants (n = 28) except 2 achieved and maintained an SVC flow ≥ 41 mL/kg/min after intervention; however, the infants treated with DB (n = 16) showed a higher heart rate and improved base excess compared with those treated with placebo (n = 12). Low SVC flow was associated with low gestational age (P = .02) and poor condition at birth (P = .02). Low SVC flow significantly increased the risk of severe ischemic events (OR, 13; 95% CI, 2.4-69.2; P < .01). CONCLUSION: This exploratory trial demonstrates a tendency toward improved short-term clinical and biochemical perfusion variable outcomes in infants with low SVC flow treated with DB. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01605279) and the European Clinical Trials Database (EurodraCT 2009-010901-35).

Surgical site infection in critically ill patients with secondary and tertiary peritonitis: epidemiology, microbiology and influence in outcomes.

BACKGROUND: Surgical site infection (SSI) remains a significant problem in the postoperative period that can negatively affect clinical outcomes. Microbiology findings are typically similar to other nosocomial infections, with differences dependent on microbiology selection due to antibiotic pressure or the resident flora. However, this is poorly understood in the critical care setting. We therefore aimed to assess the incidence, epidemiology and microbiology of SSI and its association with outcomes in patients with severe peritonitis in the intensive care unit (ICU). METHODS: We prospectively studied 305 consecutive patients admitted to our surgical ICU from 2010 to 2014 with a diagnosis of secondary or tertiary peritonitis. We collected the following data: SSI diagnosis, demographics, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Simplified Acute Physiology Score (SAPS) II score, type of surgery, microbiology, antibiotic treatment and outcomes. Microbiological sampling was done by means of swabs. RESULTS: We identified 269 episodes of SSI in 162 patients (53.1%) aged 64.4 ± 14.3 years, of which 200 episodes occurred in men (64.6%). The mean APACHE II and SAPS II scores were 19.7 ± 7.8 and 36.5 ± 16.1 respectively. The mean ICU and hospital stays were 19.8 ± 24.8 and 21.7 ± 30 days respectively. Pseudomonas spp. (n = 52, 19.3%), Escherichia coli (n = 55, 20.4%) and Candida spp. (n = 46, 17.1%) were the most frequently isolated microorganisms, but gram-positive cocci (n = 80, 29.7%) were also frequent. Microorganisms isolated from SSIs were associated with a higher incidence of antibiotic resistance (64.9%) in ICU patients, but not with higher in-hospital mortality. However, patients who suffered from SSI had longer ICU admissions (odds ratio = 1.024, 95% confidence interval 1.010-1.039, P = 0.001). CONCLUSIONS: The incidence of SSI in secondary or tertiary peritonitis requiring ICU admission is very high. Physicians may consider antibiotic-resistant pathogens, gram-positive cocci and fungi when choosing empiric antibiotic treatment for SSI, although more studies are needed to confirm our results due to the inherent limitations of the microbiological sampling with swabs performed in our research. The presence of SSI may be associated with prolonged ICU stays, but without any influence on overall mortality.

Exercise in a hot environment influences plasma anti-inflammatory and antioxidant status in well-trained athletes.

Exercise in thermally stressful environmental conditions can enhance oxidative stress. We sought to measure the plasma antioxidant defenses and cytokine response together with oxidative damage post-exercise in a temperate versus a hot environment. The plasma concentrations of vasoactive endothelin-1 and vascular angiogenic growth factor were also evaluated. Male athletes (n=9) volunteered to participate. The athletes randomly performed two bouts of treadmill exercise of 45min at 75-80% of maximal oxygen uptake in a climatic-controlled chamber under two different conditions: temperate environment (10-12°C, 40-55% humidity) and hot, humid environment (30-32°C, 75-78% humidity). Venous blood samples were obtained immediately pre- and post-bout and on recovery after 2h. Serum glucose, malondialdehyde and lactate concentrations were significantly increased post-exercise in hot but maintained in the temperate environment; these post-exercise values were significantly higher after exercise in hot than in temperate. Urinary 8-hydroxy-2'-deoxyguanosine concentration, plasma phosphocreatine kinase and catalase activities, creatinine and monocyte chemoattractant protein-1, and interleukin-6 significantly increased post-exercise in hot but maintained in temperate environment. The post-exercise circulating values of antioxidant enzyme paraoxonase-1 and endothelin were significantly higher in the hot than in temperate environment. Exercise in a hot and humid environment resulted in mild hyperthermia with elevated perceived exertion and thermal stress. Hyperthermic environment induced hyperglycemia, lactatecidemia and more cellular and oxidative damage than exercise in a temperate environment but also induced a post-exercise antioxidant and anti-inflammatory response in plasma. These results suggest that environmental temperature needs to be taken into account when evaluating exercise-related oxidative stress and inflammation.

New time-frequency method for cerebral autoregulation in newborns: predictive capacity for clinical outcomes.

OBJECTIVE: To describe an alternative analysis in the frequency-domain of the temporal relationship between 2 biological signals and evaluate the method's predictive capacity for classifying infants at risk for an adverse outcome. STUDY DESIGN: We studied 54 infants (mean gestational age 27 weeks) with invasive mean arterial blood pressure monitoring. The bivariate autoregressive spectral coherence (BiAR-COH) method and the spectral coherence methods were used to analyze the relationship between spontaneous changes in mean arterial blood pressure and the near-infrared tissue oxygenation index. RESULTS: The mean postnatal age at the beginning and end of the autoregulation study was 6.0 (3.0) and 29.0 (7.5) hours, respectively. The BiAR-COH was superior to the spectral coherence in predicting low superior vena cava (SVC) flow (≤ 41 mL/kg per minute), with an area under the receiver operating characteristic curve of 0.84 (95% CI, 0.77-0.90; P < .001). The BiAR-COH threshold for identifying low SVC flow was 0.577, with 0.8 sensitivity and 0.76 specificity. After adjusting for the repeated measures effect (multiple epochs) in a given patient, the averaged BiAR-COH per patient and averaged COH per patient were calculated as the average value per patient. The pBiAR-COH (but not the pCOH) was associated with intraventricular hemorrhage grades 3 and 4 and predicted mortality. CONCLUSIONS: The BiAR-COH classifier identifies low SVC flow infants who are at risk for brain hypoperfusion. The BiAR-COH is superior to frequency domain methods in predicting adverse outcomes in infants.

Temporal variability of nitrogen stable isotopes in primary uptake compartments in four streams differing in human impacts.

Understanding the variability of the natural abundance in nitrogen stable isotopes (expressed as δ(15)N) of primary uptake compartments (PUCs; e.g., epilithon or macrophytes) is important due to the multiple applications of stable isotopes in freshwater research and can give insights into environmental and anthropogenic factors controlling N dynamics in streams. While previous research has shown how δ(15)N of PUCs varies with δ(15)N of dissolved inorganic N (DIN) among streams, less is known about how δ(15)N of PUCs varies over time. Here, we examined monthly variation of δ(15)N of PUCs and of DIN species (nitrate and ammonium) over a year, and compared it among streams with contrasting human impacts and PUC types. Our results showed no evidence of isotopic seasonal patterns. Temporal variability in δ(15)N-PUCs increased with human impact, being the highest in the urban stream, probably influenced by the high variability of δ(15)N-DIN. Among compartments, in-stream PUCs characterized by fast turnover rates, such as filamentous algae, showed the highest temporal variability in δ(15)N values (from -3.6 to 23.2 ‰). Our study elucidates some of the environmental and biological controls of temporal variability of δ(15)N in streams, which should be taken into account when using stable isotopes as an ecological tool.

Measurement of meropenem concentration in different human biological fluids by ultra-performance liquid chromatography-tandem mass spectrometry.

Meropenem is a broad-spectrum antibiotic, often used for the empirical treatment of infections in critically ill patients with acute kidney injury. Meropenem has clinically insignificant protein binding and, as a carbapenem antibiotic, shows time-dependent bacterial killing, meaning that the unbound or free antibiotic concentration in blood should be maintained above the minimal inhibitory concentration of the pathogen for at least 40 % of the dosing interval. We developed and validated simple chromatographic methods by ultra-performance liquid chromatography-tandem mass spectrometry to measure plasma, filtrate-dialysate, and urine concentrations of meropenem. Chromatographic separation was achieved using an Acquity(®) UPLC(®) BEH(TM) (2.1 × 100 mm id, 1.7 µm) reverse-phase C(18) column, with a water/acetonitrile linear gradient containing 0.1 % formic acid at a 0.4-mL/min flow rate. Meropenem and its internal standard (ertapenem) were detected by electrospray ionization mass spectrometry in positive ion multiple reaction monitoring mode. The limits of quantification were 0.27, 0.24, and 1.22 mg/L, and linearity was observed between 0.27-150, 0.24-150, and 1.22-2,000 mg/L for plasma, filtrate-dialysate, and urine samples, respectively. Coefficients of variation and relative biases were less than 13.5 and 8.0 % for all biological fluids. Recovery values were greater than 68.3 %. Evaluation of the matrix effect showed ion suppression for meropenem and ertapenem. No carry-over was observed. The validated methods are useful for both therapeutic drug monitoring and pharmacokinetic studies. It could be applied to daily clinical laboratory practice to measure the concentration of meropenem in plasma, filtrate-dialysate, and urine.

Stream carbon and nitrogen supplements during leaf litter decomposition: contrasting patterns for two foundation species.

Leaf litter decomposition plays a major role in nutrient dynamics in forested streams. The chemical composition of litter affects its processing by microorganisms, which obtain nutrients from litter and from the water column. The balance of these fluxes is not well known, because they occur simultaneously and thus are difficult to quantify separately. Here, we examined C and N flow from streamwater and leaf litter to microbial biofilms during decomposition. We used isotopically enriched leaves ((13)C and (15)N) from two riparian foundation tree species: fast-decomposing Populus fremontii and slow-decomposing Populus angustifolia, which differed in their concentration of recalcitrant compounds. We adapted the isotope pool dilution method to estimate gross elemental fluxes into litter microbes. Three key findings emerged: litter type strongly affected biomass and stoichiometry of microbial assemblages growing on litter; the proportion of C and N in microorganisms derived from the streamwater, as opposed to the litter, did not differ between litter types, but increased throughout decomposition; gross immobilization of N from the streamwater was higher for P. fremontii compared to P. angustifolia, probably as a consequence of the higher microbial biomass on P. fremontii. In contrast, gross immobilization of C from the streamwater was higher for P. angustifolia, suggesting that dissolved organic C in streamwater was used as an additional energy source by microbial assemblages growing on slow-decomposing litter. These results indicate that biofilms on decomposing litter have specific element requirements driven by litter characteristics, which might have implications for whole-stream nutrient retention.

Surveillance and prevention of healthcare-associated infections: best practices to prevent ventilator-associated events.

INTRODUCTION: Ventilator associated pneumonia (VAP) leads to an increase in morbidity, mortality, and healthcare costs. In addition to increased evidence from the latest European and American guidelines (published in 2017 and 2022, respectively), in the last two years, several important clinical experiences have added new prevention tools to be included to improve the management of VAP. AREAS COVERED: This paper is a narrative review of new evidence on VAP prevention. We divided VAP prevention measures into pharmacological, non-pharmacological, and ventilator care bundles. EXPERT OPINION: Most of the effective strategies that have been shown to decrease the incidence of complications are easy to implement and inexpensive. The implementation of care bundles, accompanied by educational measures and a multidisciplinary team should be part of optimal management. In addition to ventilator care bundles for the prevention of VAP, it could possibly be beneficial to use ventilator care bundles for the prevention of noninfectious ventilator associated events.

Population genetics and phylogeographic history of the insular lizard Podarcis lilfordi (Gunther, 1874) from the Balearic Islands based on genome-wide polymorphic data.

Islands provide a great system to explore the processes that maintain genetic diversity and promote local adaptation. We explored the genomic diversity of the Balearic lizard Podarcis lilfordi, an endemic species characterized by numerous small insular populations with large phenotypic diversity. Using the newly available genome for this species, we characterized more than 300,000 SNPs, merging genotyping-by-sequencing (GBS) data with previously published restriction site-associated DNA sequencing (RAD-Seq) data, providing a dataset of 16 island populations (191 individuals) across the range of species distribution (Menorca, Mallorca, and Cabrera). Results indicate that each islet hosts a well-differentiated population (F ST = 0.247 ± 0.09), with no recent immigration/translocation events. Contrary to expectations, most populations harbor a considerable genetic diversity (mean nucleotide diversity, P i = 0.144 ± 0.021), characterized by overall low inbreeding values (F IS < 0.1). While the genetic diversity significantly decreased with decreasing islet surface, maintenance of substantial genetic diversity even in tiny islets suggests variable selection or other mechanisms that buffer genetic drift. Maximum-likelihood tree based on concatenated SNP data confirmed the existence of the two major independent lineages of Menorca and Mallorca/Cabrera. Multiple lines of evidence, including admixture and root testing, robustly placed the origin of the species in the Mallorca Island, rather than in Menorca. Outlier analysis mainly retrieved a strong signature of genome differentiation between the two major archipelagos, especially in the sexual chromosome Z. A set of proteins were target of multiple outliers and primarily associated with binding and catalytic activity, providing interesting candidates for future selection studies. This study provides the framework to explore crucial aspects of the genetic basis of phenotypic divergence and insular adaptation.

Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery.

BACKGROUND: Inodilators are routinely used in cardiovascular surgery with cardiopulmonary bypass (CPB). Information regarding safety and tolerability of the novel molecule, levosimendan (LEVO), in newborns is anecdotal; no pharmacokinetic data in this population are available. METHODS: This was a phase I, randomized, and blinded study. Neonates undergoing surgical repair for congenital heart defects received stepwise dose increases of milrinone (MR; 0.5-1 µg/kg/min, n = 9) or LEVO (0.1-0.2 µg/kg/min, n = 11) as an i.v. continuous infusion, starting before CPB. Infants had continuous, time-locked, physiological, and near-infrared spectroscopy (NIRS) (cerebral and peripheral) recordings during the first 24 h, and at 48 and 96 h postsurgery. Serial biochemistry and pharmacokinetic studies were performed. RESULTS: During the first 24 h postsurgery, patients showed time-related, group-independent increased cerebral tissue oxygenation and decreased diastolic blood pressure; in addition, group-dependent differences in heart rate and peripheral perfusion were found. Early postsurgery, MR-treated infants showed lower pH, higher glycemia, and higher inotrope score. The groups differed in cerebral NIRS-derived variables from 24 to 96 h. Study drug withdrawal at 96 h was more frequent with LEVO. LEVO intermediate metabolites were detected in plasma at day 14 after surgery. CONCLUSION: LEVO is well tolerated in critically ill neonates. LEVO may have advantages over MR in terms of the dosing regimen.

Nitrogen stable isotopes in primary uptake compartments across streams differing in nutrient availability.

High variability in the natural abundance of nitrogen stable isotopes (δ(15)N) has been reported for primary uptake compartments (PUCs; e.g., epilithon, filamentous algae, bryophytes, macrophytes) in human-impacted aquatic ecosystems, but the origin of this variability is not yet well understood. We examined how δ(15)N of different PUC types relate to δ(15)N of dissolved inorganic nitrogen (DIN) species (nitrate and ammonium) and to the stream nutrient concentrations in which they grow. We selected 25 reaches located across the fluvial network of La Tordera catchment (NE Spain, 868.5 km(2)), encompassing a gradient of human pressures from headwaters to the river valley. δ(15)N-PUC variability was mostly explained by location within the fluvial network and was strongly related to the δ(15)N of DIN species, especially of ammonium. Models were stronger for PUCs growing within the stream channel and thus using streamwater as their main source of nutrients. Regression models including nutrient concentrations improved the prediction power for δ(15)N-PUCs, suggesting that nutrient concentrations and stoichiometry cannot be ignored in explaining the natural abundance of nitrogen isotopes in PUCs. These results provide insights into what controls variability in δ(15)N of PUCs within a stream network, with implications for the application of stables isotopes as an ecological tool.

Insular holobionts: persistence and seasonal plasticity of the Balearic wall lizard (Podarcis lilfordi) gut microbiota.

Background: Integrative studies of animals and associated microbial assemblages (i.e., the holobiont) are rapidly changing our perspectives on organismal ecology and evolution. Insular vertebrates provide ideal natural systems to understand patterns of host-gut microbiota coevolution, the resilience and plasticity these microbial communities over temporal and spatial scales, and ultimately their role in the host ecological adaptation. Methods: Here we used the endemic Balearic wall lizard Podarcis lilfordi to dissect the drivers of the microbial diversity within and across host allopatric populations/islets. By focusing on three extensively studied populations/islets of Mallorca (Spain) and fecal sampling from individually identified lizards along two years (both in spring and autumn), we sorted out the effect of islet, sex, life stage, year and season on the microbiota composition. We further related microbiota diversity to host genetics, trophic ecology and expected annual metabolic changes. Results: All the three populations showed a remarkable conservation of the major microbial taxonomic profile, while carrying their unique microbial signature at finer level of taxonomic resolution (Amplicon Sequence Variants (ASVs)). Microbiota distances across populations were compatible with both host genetics (based on microsatellites) and trophic niche distances (based on stable isotopes and fecal content). Within populations, a large proportion of ASVs (30-50%) were recurrently found along the four sampling dates. The microbial diversity was strongly marked by seasonality, with no sex effect and a marginal life stage and annual effect. The microbiota showed seasonal fluctuations along the two sampled years, primarily due to changes in the relative abundances of fermentative bacteria (mostly families Lachnospiraceae and Ruminococcaceae), without any major compositional turnover. Conclusions: These results support a large resilience of the major compositional aspects of the P. lilfordi gut microbiota over the short-term evolutionary divergence of their host allopatric populations (<10,000 years), but also indicate an undergoing process of parallel diversification of the both host and associated gut microbes. Predictable seasonal dynamics in microbiota diversity suggests a role of microbiota plasticity in the lizards' metabolic adaptation to their resource-constrained insular environments. Overall, our study supports the need for longitudinal and integrative studies of host and associated microbes in natural systems.