Inhibition of adenylyl cyclase 8 prevents the upregulation of Orai1 channel, which improves cardiac function after myocardial infarction.

The upregulation of Orai1 and subsequent store-operated Ca2+ entry (SOCE) has been associated with adverse cardiac remodeling and heart failure (HF). However, the mechanism underlying Orai1 upregulation and its role in myocardial infarction remains unclear. Our study investigated the role of Orai1 in activating adenylyl cyclase 8 (AC8) and cyclic AMP (cAMP) response element-binding protein (CREB), as well as its contribution to cardiac dysfunction induced by ischemia and reperfusion (I/R). We found that I/R evoked an increase in the expression of Orai1 and AC8 in rats' hearts, resulting in a substantial rise in diastolic Ca2+ concentration ([Ca2+]i), and reduced ventricular contractions. The expression of Orai1 and AC8 was also increased in ventricular biopsies of post-ischemic HF patients. Mechanistically, we demonstrate that I/R activation of Orai1 stimulated AC8, which produced cAMP and phosphorylated CREB. Subsequently, p-CREB activated the ORAI1 promoter, resulting in Orai1 upregulation and SOCE exacerbation. Intramyocardial administration of AAV9 carrying AC8 short hairpin RNA decreased the expression of AC8, Orai1 and CREB, which restored diastolic [Ca2+]i and improved cardiac contraction. Therefore, our data suggests that the axis composed by Orai1/AC8/CREB plays a critical role in I/R-induced cardiac dysfunction, representing a potential new therapeutic target to limit the progression of the disease toward HF.

Early use of teduglutide in paediatric patients with intestinal failure is associated with a greater response rate: a multicenter study.

Teduglutide is a glucagon-like-peptide-2 analogue that reduces the need for parenteral support in patients with short bowel syndrome (SBS). Nevertheless, data about long-term therapy with teduglutide in children are still scarce. Our objective was to describe the real-life experience with teduglutide in children with SBS over the last 5 years in Spain. This was a national multicentre and prospective study of paediatric patients with intestinal failure (IF) treated with teduglutide for at least 3 months. The data included demographic characteristics, medical background, anthropometric data, laboratory assessments, adverse events, and parenteral nutrition (PN) requirements. Treatment response was defined as a > 20% reduction in the PN requirement. The data were collected from the Research Electronic Data Capture (REDCap) database. Thirty-one patients from seven centres were included; the median age at the beginning of the treatment was 2.3 (interquartile range (IQR) 1.4-4.4) years; and 65% of the patients were males. The most frequent cause of IF was SBS (94%). The most common cause of SBS was necrotizing enterocolitis (35%). The median residual bowel length was 29 (IQR 12-40) cm. The median duration of teduglutide therapy was 19 (IQR 12-36) months, with 23 patients (74%) treated for > 1 year and 9 treated for > 3 years. The response to treatment was analysed in 30 patients. Twenty-four patients (80%) had a reduction in their weekly PN energy > 20% and 23 patients (77%) had a reduction in their weekly PN volume > 20%. Among the responders, 9 patients (29%) were weaned off PN, with a median treatment duration of 6 (IQR 4.5-22) months. The only statistically significant finding demonstrated an association between a > 20% reduction in the weekly PN volume and a younger age at the start of treatment (p = 0.028).   Conclusions: Teduglutide seems to be an effective and safe treatment for paediatric patients with IF. Some patients require a prolonged duration of treatment to achieve enteral autonomy. Starting treatment with teduglutide at a young age is associated with a higher response rate. What is Known: •  Glucagon-like peptide-2 (GLP-2) plays a crucial role in the regulation of intestinal adaptation in short bowel syndrome (SBS). Teduglutide is a GLP-2 analog that reduces the need for parenteral support in patients with SBS. • Data about long-term therapy with teduglutide in children in real life are still scarce. What is New: • Most pediatric patients with SBS respond in a satisfactory manner to teduglutide treatment. The occurrence of long-term adverse effects is exceptional. • Starting treatment with the drug at a young age is associated with a greater response rate.

Similar improvements in 5-km performance and maximal oxygen uptake with submaximal and maximal 10-20-30 training in runners, but increase in muscle oxidative phosphorylation occur only with maximal effort training.

OBJECTIVE: The aim of the present study was to examine whether 10-20-30 training (consecutive 1-min intervals consisting of 30 s at low-speed, 20 s at moderate-speed, and 10 s at high-speed), performed with submaximal effort during the 10-s high-speed runs, would lead to improved performance as well as increased maximum oxygen uptake (VO2 -max) and muscle oxidative phosphorylation (OXPHOS). In addition, to examine to what extent the effects would compare to 10-20-30 running conducted with maximal effort. DESIGN: Nineteen males were randomly assigned to 10-20-30 running performed with either submaximal (SUBMAX; n = 11) or maximal (MAX; n = 8) effort, which was conducted three times/week for 6 weeks (intervention; INT). Before and after INT, subjects completed a 5-km running test and a VO2 -max test, and a biopsy was obtained from m. vastus lateralis. RESULTS: After compared to before INT, SUBMAX and MAX improved (p < 0.05) 5-km performance by 3.0% (20.8 ± 0.4 (means±SE) vs. 21.5 ± 0.4 min) and 2.3% (21.2 ± 0.4 vs. 21.6 ± 0.4 min), respectively, and VO2 -max was ~7% higher (p < 0.01) in both SUBMAX (57.0 ± 1.3 vs. 53.5 ± 1.1 mL/min/kg) and MAX (57.8 ± 1.2 vs. 53.7 ± 0.9 mL/min/kg), with no difference in the changes between groups. In SUBMAX, muscle OXPHOS was unchanged, whereas in MAX, muscle OXPHOS subunits (I-IV) and total OXPHOS (5.5 ± 0.3 vs 4.7 ± 0.3 A.U.) were 9%-29% higher (p < 0.05) after compared to before INT. CONCLUSION: Conducting 10-20-30 training with a non-maximal effort during the 10-s high-speed runs is as efficient in improving 5-km performance and VO2 -max as maximal effort exercise, whereas increase in muscle OXPHOS occur only when the 10-s high-speed runs are performed with maximal effort.

Relative contributions of the supraspinatus cord and strap tendons to shoulder abduction and translation.

BACKGROUND: The supraspinatus (SS) is formed by a larger anterior bipennate muscle with a cord-like tendon and a posterior unipennate muscle with a strap-like tendon. There is a tendinous connection between the 2 SS subunits. Yet, the relative mechanical contribution of the SS cord and SS strap musculotendinous units to load transmission and subsequent shoulder abduction force is unknown. We hypothesized that a simulated SS cord vs. an SS strap tear would generate less shoulder abduction force and, further, an intact SS cord would offset the expected abduction loss from an SS strap tear, but the inverse would not be true. MATERIALS AND METHODS: Twenty fresh-frozen cadaveric specimens were tested in a shoulder simulator with physiological load vectors applied to the upper and lower subscapularis, SS cord, SS strap, infraspinatus, and teres minor. The roles of the SS cord and SS strap muscles were delineated by varying their loads, while keeping constant loads on other muscles. The randomized testing trials included a native condition and 4 test cases that simulated tears by dropping the load and force transfer via the SS cord-to-SS strap connection by adding the load. Testing was completed at both 0° and 30° of abduction. During each test, shoulder abduction force, rotator cuff strains, and humeral translation were measured. RESULTS: Simulated isolated SS cord and SS strap tears led to a significantly lower shoulder abduction force (P < .001). A simulated cord tear at 0° and 30° reduced the abduction force by 53% and 38%, respectively. A simulated strap tear at 0° and 30° dropped the abduction force by 27% and 23%, respectively. The decline in the abduction force was larger for the SS cord tear vs. SS strap tear (P ≤ .001). An SS cord tear with full-load transfer to the strap was able to recover to native values at both 0° and 30° (P ≥ .288). Likewise, an SS strap tear with full-load transfer to the SS cord showed a similar recovery to native values at both 0° and 30° (P ≥ .155). During full-load transfer, the tendon strain followed the loading pattern. An SS cord tear or SS strap tear did not cause a change in humeral translation (P ≥ .303). DISCUSSION: The mechanical findings support the efficacy of nonoperative treatment of small (<10 mm) SS tears,11 because an intact SS strap tendon can effectively offset the abduction loss of a torn SS cord tear and vice versa.

A Global Positioning System Used to Monitor the Physical Performance of Elite Beach Handball Referees in a Spanish Championship.

Beach handball is a fully developed sporting discipline on all five continents which has attracted the attention of researchers in the last decade, resulting in a proliferation of different studies focusing on players but not on referees. The main objective of this cross-sectional research was to determine the physical demands on elite male beach handball referees in four different competitions: U18 male; U18 female; senior male; and senior female. Twelve elite federated male referees (age: 30.86 ± 8 years; body height: 175.72 ± 4.51 cm; body weight: 80.18 ± 17.99 kg; fat percentage: 20.1 ± 4.41%; national or international experience) belonging to the Technical Committee of the Royal Spanish Handball Federation were recruited for this the study. The physical demands required of referees in official matches were measured by installing a GPS device. The sampling frequency used to record their speed and distance was 15 Hz. A triaxial accelerometer (100 Hz) was used to determine their acceleration. An analysis of variance (ANOVA) between competitions with post hoc comparisons using the Bonferroni adjustment was used to compare among categories. A higher distance covered in zone 1 and speeds of 0 to 6 km-h-1 were recorded. Most accelerations and decelerations occurred in zones 0 and 1 (zone 0: 0 to 1 m·s-2; zone 1: 1 to 2 m·s-2). The lack of differences (p > 0.05) between most analysed variables suggest quite similar physical demands of the four analysed competitions. These results provide relevant information to design optimal training plans oriented to the real physical demands on referees in an official competition.

Measurement of Near-Field Radiative Heat Transfer at Deep Sub-Wavelength Distances using Nanomechanical Resonators.

Near-field radiative heat transfer (NFRHT) measurements often rely on custom microdevices that can be difficult to reproduce after their original demonstration. Here we study NFRHT using plain silicon nitride (SiN) membrane nanomechanical resonators─a widely available substrate used in applications such as electron microscopy and optomechanics─and on which other materials can easily be deposited. We report measurements down to a minimal distance of 180 nm between a large radius of curvature (15.5 mm) glass radiator and a SiN membrane resonator. At such deep sub-wavelength distance, heat transfer is dominated by surface polariton resonances over a (0.25 mm)2 effective area, which is comparable to plane-plane experiments employing custom microfabricated devices. We also discuss how measurements using nanomechanical resonators create opportunities for simultaneously measuring near-field radiative heat transfer and thermal radiation forces (e.g., thermal corrections to Casimir forces).

A Comprehensive Review of the Current State of Robot-assisted Laparoscopic Salvage Prostatectomy.

BACKGROUND AND OBJECTIVE: Salvage robot assisted radical prostatectomy (sRARP) is performed for patients with biochemical or biopsy proven, localized prostate cancer recurrences after radiation or ablative therapies. Traditionally, sRARP has been avoided by lower volume surgeons due to technical demand and high complication rates. Post-radiation sRARP outcomes studies exist but remain few in number. With increasing use of whole gland and focal ablative therapies, updates on sRARP in this setting are needed. The aim of this narrative review is to provide an overview of recently reviewed studies on the oncologic outcomes, functional outcomes, and complications after post-radiation and post-ablative sRARP. Tips and tricks are provided to guide surgeons who may perform sRARP. MATERIALS AND METHODS: We performed a non-systematic literature search of PubMed and MEDLINE for the most relevant articles pertaining to the outlined topics from 2010-2022 without limitation on study design. Only case reports, editorial comments, letters, and manuscripts in non-English languages were excluded. Key Content and Findings: Salvage robotic radical prostatectomy is performed in cases of biochemical recurrence after radiation or ablative therapies. Oncologic outcomes after sRARP are worse compared to primary surgery (pRARP) though improvements have been made with the robotic approach when compared to open salvage prostatectomy. Higher pre-sRARP PSA levels and more advanced pathologic stage portend worse oncologic outcomes. Patients meeting low-risk, EAU-biochemical recurrence criteria have improved oncologic outcomes compared to those with high-risk BCR. While complication rates in sRARP are higher compared to pRARP, Retzius sparing approaches may reduce complication rates, particularly rectal injuries. In comparison to the traditional open approach, sRARP is associated with a lower rate of bladder neck contracture. In terms of functional outcomes, potency rates after sRARP are poor and continence rates are low, though Retzius sparing approaches demonstrate acceptable recovery of urinary continence by 1 year, post-operatively. CONCLUSIONS: Advances in the robotic platform and improvement in robotic experience have resulted in acceptable complication rates after sRARP. However, oncologic and functional outcomes after sRARP in both the post-radiation and post-ablation settings are worse compared to pRARP. Thus, when engaging in shared decision making with patients regarding the initial management of localized prostate cancer, patients should be educated regarding oncologic and functional outcomes and complications in the case of biochemically recurrent prostate cancer that may require sRARP.

Bartonella spp. in different species of bats from Misiones (Argentina).

The aim of this study was to detect vector-borne pathogens (Anaplasmataceae family, Rickettsia genus, and Bartonella genus) in bats from Misiones (Argentina). Thirty-three specimens were captured over 8 days using mist nets. Twenty (60.6%) blood samples were positive (11/13 Artibeus lituratus, 4/10 Desmodus rotundus, 4/8 Carollia perspicillata, and 1/2 Myotis nigricans) by PCR for the gltA gene fragment of Bartonella. All samples were negative by PCR for the Anaplasmataceae family and Rickettsia genus. The phylogenetic analysis showed seven Bartonella genotypes. The three genotypes obtained from A. lituratus, 2 from C. perspicillata, and 1 from D. rotundus were related to Bartonella spp. from New World bats, while the sequence obtained from M. nigricans was related to Old World bats. We identified a considerable diversity of Bartonella genotypes in a small number of bats, thus further research is required to better understand the complex bat-pathogen interaction.

Modified Oblique Lobenhoffer (MOL) approach for posterolateral and posteromedial column access in tibial plateau fractures: a detailed cadaveric anatomical study.

BACKGROUND: Tibial plateau fractures involving posteromedial (PM) and posterolateral (PL) columns are complex injuries that require an appropriate approach. The management of the PL column in these cases can be controversial, and limitations using deep posteromedial interval approaches have been referenced. In this paper, a modification of the Lobenhoffer approach, designed to optimize the access to the PL column, is described in detail. The aim of this study was to assess the feasibility of this approach in a cadaveric anatomical study. MATERIALS AND METHODS: In total, five fresh-frozen cadaveric specimens were used for detailed anatomical study surrounding the approach. Relationships with cutaneous and deep neurovascular structures were evaluated. The exposure area of the PL and PM columns using this approach was assessed. RESULTS: The cadaveric study showed safe and adequate exposure. Oblique skin and fascia incision just medial to the posterior midline was safe to protect the medial sural cutaneous nerve and the small saphenous vein. Elevation of the popliteus and tibialis posterior muscles offered safe protection of the anterior tibial artery and popliteal neurovascular bundle during retractor placement. Adequate full proximal exposure of the PM and PL columns, including the posterolateral lateral (PLL) and posterolateral central (PLC) segments, was obtained in all specimens. CONCLUSIONS: The Modified Oblique Lobenhoffer (MOL) approach can be a feasible option to access PL and PM columns in tibial plateau fractures. LEVEL OF EVIDENCE: IV.

Screening uptake of colonoscopy versus fecal immunochemical testing in first-degree relatives of patients with non-syndromic colorectal cancer: A multicenter, open-label, parallel-group, randomized trial (ParCoFit study).

BACKGROUND: Colonoscopy screening is underused by first-degree relatives (FDRs) of patients with non-syndromic colorectal cancer (CRC) with screening completion rates below 50%. Studies conducted in FDR referred for screening suggest that fecal immunochemical testing (FIT) was not inferior to colonoscopy in terms of diagnostic yield and tumor staging, but screening uptake of FIT has not yet been tested in this population. In this study, we investigated whether the uptake of FIT screening is superior to the uptake of colonoscopy screening in the familial-risk population, with an equivalent effect on CRC detection. METHODS AND FINDINGS: This open-label, parallel-group, randomized trial was conducted in 12 Spanish centers between February 2016 and December 2021. Eligible individuals included asymptomatic FDR of index cases <60 years, siblings or ≥2 FDR with CRC. The primary outcome was to compare screening uptake between colonoscopy and FIT. The secondary outcome was to determine the efficacy of each strategy to detect advanced colorectal neoplasia (adenoma or serrated polyps ≥10 mm, polyps with tubulovillous architecture, high-grade dysplasia, and/or CRC). Screening-naïve FDR were randomized (1:1) to one-time colonoscopy versus annual FIT during 3 consecutive years followed by a work-up colonoscopy in the case of a positive test. Randomization was performed before signing the informed consent using computer-generated allocation algorithm based on stratified block randomization. Multivariable regression analysis was performed by intention-to-screen. On December 31, 2019, when 81% of the estimated sample size was reached, the trial was terminated prematurely after an interim analysis for futility. Study outcomes were further analyzed through 2-year follow-up. The main limitation of this study was the impossibility of collecting information on eligible individuals who declined to participate. A total of 1,790 FDR of 460 index cases were evaluated for inclusion, of whom 870 were assigned to undergo one-time colonoscopy (n = 431) or FIT (n = 439). Of them, 383 (44.0%) attended the appointment and signed the informed consent: 147/431 (34.1%) FDR received colonoscopy-based screening and 158/439 (35.9%) underwent FIT-based screening (odds ratio [OR] 1.08; 95% confidence intervals [CI] [0.82, 1.44], p = 0.564). The detection rate of advanced colorectal neoplasia was significantly higher in the colonoscopy group than in the FIT group (OR 3.64, 95% CI [1.55, 8.53], p = 0.003). Study outcomes did not change throughout follow-up. CONCLUSIONS: In this study, compared to colonoscopy, FIT screening did not improve screening uptake by individuals at high risk of CRC, resulting in less detection of advanced colorectal neoplasia. Further studies are needed to assess how screening uptake could be improved in this high-risk group, including by inclusion in population-based screening programs. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT02567045).

Coupled C, H, N, S and Fe biogeochemical cycles operating in the continental deep subsurface of the Iberian Pyrite Belt.

Microbial activity is a major contributor to the biogeochemical cycles that make up the life support system of planet Earth. A 613 m deep geomicrobiological perforation and a systematic multi-analytical characterization revealed an unexpected diversity associated with the rock matrix microbiome that operates in the subsurface of the Iberian Pyrite Belt (IPB). Members of 1 class and 16 genera were deemed the most representative microorganisms of the IPB deep subsurface and selected for a deeper analysis. The use of fluorescence in situ hybridization allowed not only the identification of microorganisms but also the detection of novel activities in the subsurface such as anaerobic ammonium oxidation (ANAMMOX) and anaerobic methane oxidation, the co-occurrence of microorganisms able to maintain complementary metabolic activities and the existence of biofilms. The use of enrichment cultures sensed the presence of five different complementary metabolic activities along the length of the borehole and isolated 29 bacterial species. Genomic analysis of nine isolates identified the genes involved in the complete operation of the light-independent coupled C, H, N, S and Fe biogeochemical cycles. This study revealed the importance of nitrate reduction microorganisms in the oxidation of iron in the anoxic conditions existing in the subsurface of the IPB.

Effectiveness of prolonged versus standard-course of oseltamivir in critically ill patients with severe influenza infection: A multicentre cohort study.

The aim of this study is to investigate the effectiveness of prolonged versus standard course oseltamivir treatment among critically ill patients with severe influenza. A retrospective study of a prospectively collected database including adults with influenza infection admitted to 184 intensive care units (ICUs) in Spain from 2009 to 2018. Prolonged oseltamivir was defined if patients received the treatment beyond 5 days, whereas the standard-course group received oseltamivir for 5 days. The primary outcome was all-cause ICU mortality. Propensity score matching (PSM) was constructed, and the outcome was investigated through Cox regression and RCSs. Two thousand three hundred and ninety-seven subjects were included, of whom 1943 (81.1%) received prolonged oseltamivir and 454 (18.9%) received standard treatment. An optimal full matching algorithm was performed by matching 2171 patients, 1750 treated in the prolonged oseltamivir group and 421 controls in the standard oseltamivir group. After PSM, 387 (22.1%) patients in the prolonged oseltamivir and 119 (28.3%) patients in the standard group died (p = 0.009). After adjusting confounding factors, prolonged oseltamivir significantly reduced ICU mortality (odds ratio [OR]: 0.53, 95% confidence interval [CI]: 0.40-0.69). Prolonged oseltamivir may have protective effects on survival at Day 10 compared with a standard treatment course. Sensitivity analysis confirmed these findings. Compared with standard treatment, prolonged oseltamivir was associated with reduced ICU mortality in critically ill patients with severe influenza. Clinicians should consider extending the oseltamivir treatment duration to 10 days, particularly in higher-risk groups of prolonged viral shedding. Further randomized controlled trials are warranted to confirm these findings.

Adjunct Thrombolysis Enhances Brain Reperfusion following Successful Thrombectomy.

OBJECTIVE: This study was undertaken to investigate whether adjunct alteplase improves brain reperfusion following successful thrombectomy. METHODS: This single-center, randomized, double-blind, placebo-controlled study included 36 patients (mean [standard deviation] = 70.8 [13.5] years old, 18 [50%] women) with large vessel occlusion undergoing thrombectomy resulting in near-normal (expanded Thrombolysis in Cerebral Infarction [eTICI] b50/67/2c, n = 23, 64%) or normal angiographic reperfusion (eTICI 3, n = 13, 36%). Seventeen patients were randomized to intra-arterial alteplase (0.225mg/kg), and 19 received placebo. At 48 hours, patients had brain perfusion/diffusion-weighted magnetic resonance imaging (MRI) and MRI-spectroscopy. The primary outcome was the difference in the proportion of patients with areas of hypoperfusion on MRI. Secondary outcomes were the infarct expansion ratio (final to initial infarction volume), and the N-acetylaspartate (NAA) peak relative to total creatine as a marker of neuronal integrity. RESULTS: The prevalence of hypoperfusion was 24% with intra-arterial alteplase, and 58% with placebo (adjusted odds ratio = 0.20, 95% confidence interval [CI] = 0.04-0.91, p = 0.03). Among 14 patients with final eTICI 3 scores, hypoperfusion was found in 1 of 7 (14%) in the alteplase group and 3 of 7 (43%) in the placebo group. Abnormal brain perfusion was associated with worse functional outcome at day 90. Alteplase significantly reduced the infarct expansion ratio compared with placebo (median [interquartile range (IQR)] = 0.7 [0.5-1.2] vs 3.2 [1.8-5.7], p = 0.01) and resulted in higher NAA peaks (median [IQR] = 1.13 [0.91-1.36] vs 1.00 [0.74-1.22], p < 0.0001). INTERPRETATION: There is a high prevalence of areas of hypoperfusion following thrombectomy despite successful reperfusion on angiography. Adjunct alteplase enhances brain reperfusion, which results in reduced expansion of the infarction and improved neuronal integrity. ANN NEUROL 2022;92:860-870.

Fundamental limits on radiative χ(2) second harmonic generation.

Recent advances in fundamental performance limits for power quantities based on Lagrange duality are proving to be a powerful theoretical tool for understanding electromagnetic wave phenomena. To date, however, in any approach seeking to enforce a high degree of physical reality, the linearity of the wave equation plays a critical role. In this manuscript, we generalize the current quadratically constrained quadratic program framework for evaluating linear photonics limits to incorporate nonlinear processes under the undepleted pump approximation. Via the exemplary objective of enhancing second harmonic generation in a (free-form) wavelength-scale structure, we illustrate a model constraint scheme that can be used in conjunction with standard convex relaxations to bound performance in the presence of nonlinear dynamics. Representative bounds are found to anticipate features observed in optimized structures discovered via computational inverse design. The formulation can be straightforwardly modified to treat other frequency-conversion processes, including Raman scattering and four-wave mixing.

Polymorphisms indicating risk of inflammatory bowel disease or antigenicity to anti-TNF drugs as biomarkers of response in children.

Few genetic polymorphisms predict early response to anti-TNF drugs in inflammatory bowel disease (IBD), and even fewer have been identified in the pediatric population. However, it would be of considerable clinical interest to identify and validate genetic biomarkers of long-term response. Therefore, the aim of the study was to analyze the usefulness of biomarkers of response to anti-TNFs in pediatric IBD (pIBD) as long-term biomarkers and to find differences by type of IBD and type of anti-TNF drug. The study population comprised 340 children diagnosed with IBD who were treated with infliximab or adalimumab. Genotyping of 9 selected SNPs for their association with early response and/or immunogenicity to anti-TNFs was performed using real-time PCR. Variants C rs10508884 (CXCL12), A rs2241880 (ATG16L1), and T rs6100556 (PHACTR3) (p value 0.049; p value 0.03; p value 0.031) were associated with worse long-term response to anti-TNFs in pIBD. DNA variants specific to disease type and anti-TNF type were identified in the pediatric population. Genotyping of these genetic variants before initiation of anti-TNFs would enable, if validated in a prospective cohort, the identification of pediatric patients who are long-term responders to this therapy.

Biological action at a distance: Correlated pattern formation in adjacent tessellation domains without communication.

Tessellations emerge in many natural systems, and the constituent domains often contain regular patterns, raising the intriguing possibility that pattern formation within adjacent domains might be correlated by the geometry, without the direct exchange of information between parts comprising either domain. We confirm this paradoxical effect, by simulating pattern formation via reaction-diffusion in domains whose boundary shapes tessellate, and showing that correlations between adjacent patterns are strong compared to controls that self-organize in domains with equivalent sizes but unrelated shapes. The effect holds in systems with linear and non-linear diffusive terms, and for boundary shapes derived from regular and irregular tessellations. Based on the prediction that correlations between adjacent patterns should be bimodally distributed, we develop methods for testing whether a given set of domain boundaries constrained pattern formation within those domains. We then confirm such a prediction by analysing the development of 'subbarrel' patterns, which are thought to emerge via reaction-diffusion, and whose enclosing borders form a Voronoi tessellation on the surface of the rodent somatosensory cortex. In more general terms, this result demonstrates how causal links can be established between the dynamical processes through which biological patterns emerge and the constraints that shape them.

Environmental filtering drives the assembly of mammal communities in a heterogeneous Mediterranean region.

Agricultural expansion and intensification are major drivers of global change. Quantifying the importance of different processes governing the assembly of local communities in agroecosystems is essential to guide the conservation effort allocated to enhancing habitat connectivity, improving habitat quality or managing species interactions. We used multiple detection methods to record the occurrence of medium-sized and large-sized mammals in three managed landscapes of a heterogeneous Mediterranean region. Then we used a joint species distribution model to evaluate the relative influence of dispersal limitation, environmental filtering, and interspecific interactions on the local assembly of mammal communities in 4-km2 plots. The partitioning of the explained variation in species occurrence was attributed on average 99% to environmental filters and 1% to dispersal filters. No role was attributed to biotic filters, in agreement with the scarce support for strong competition or other negative interactions found after a literature review. Four principal environmental factors explained on average 63% of variance in species occurrence and operated mainly at the landscape scale. The amount of shrub cover in the neighboring landscape was the most influential factor favoring mammal occurrence and accounted for nearly one-third of the total variance. The proportion of intensively managed croplands and proxies of human activity within landscape samples limited mammal presence. At the microhabitat scale (~80 m2 plots) the mean percentage area deprived of woody vegetation also had a negative effect. Functional traits such as body mass or social behavior accounted for a substantial fraction of the variation attributed to environmental factors. We concluded that multiscale environmental filtering governed local community assembly, whereas the role of dispersal limitation and interspecific interactions was negligible. Our results suggest that further removal of shrubland, the expansion of intensive agriculture, and the increase of human activity are expected to result in species losses. The fact that community integrity responds to a single type of ecological process simplifies practical recommendations. Management strategies should focus on the conservation and restoration of shrubland, adopting alternatives to intensive schemes of agricultural production, and minimizing recreational and other human activities in remnant natural habitats within agroecosystems or mosaic landscapes.

Critical appraisal beyond clinical guidelines for intraabdominal candidiasis.

BACKGROUND: Regardless of the available antifungals, intraabdominal candidiasis (IAC) mortality continues to be high and represents a challenge for clinicians. MAIN BODY: This opinion paper discusses alternative antifungal options for treating IAC. This clinical entity should be addressed separately from candidemia due to the peculiarity of the required penetration of antifungals into the peritoneal cavity. Intraabdominal concentrations may be further restricted in critically ill patients where pathophysiological facts alter normal drug distribution. Echinocandins are recommended as first-line treatment in guidelines for invasive candidiasis. However, considering published data, our pharmacodynamic analysis suggests the required increase of doses, postulated by some authors, to attain adequate pharmacokinetic (PK) levels in peritoneal fluid. Given the limited evidence in the literature on PK/PD-based treatments of IAC, an algorithm is proposed to guide antifungal treatment. Liposomal amphotericin B is advocated as first-line therapy in patients with sepsis/septic shock presenting candidemia or endophthalmitis, or with prior exposure to echinocandins and/or fluconazole, or with infections by Candida glabrata. Other situations and alternatives, such as new compounds or combination therapy, are also analysed. CONCLUSION: There is a critical need for more robust clinical trials, studies examining patient heterogeneity and surveillance of antifungal resistance to enhance patient care and optimise treatment outcomes. Such evidence will help refine the existing guidelines and contribute to a more personalised and effective approach to treating this serious medical condition. Meanwhile, it is suggested to broaden the consideration of other options, such as liposomal amphotericin B, as first-line treatment until the results of the fungogram are available and antifungal stewardship could be implemented to prevent the development of resistance.

Impact of macrolide treatment on long-term mortality in patients admitted to the ICU due to CAP: a targeted maximum likelihood estimation and survival analysis.

INTRODUCTION: Patients with community-acquired pneumonia (CAP) admitted to the intensive care unit (ICU) have high mortality rates during the acute infection and up to ten years thereafter. Recommendations from international CAP guidelines include macrolide-based treatment. However, there is no data on the long-term outcomes of this recommendation. Therefore, we aimed to determine the impact of macrolide-based therapy on long-term mortality in this population. METHODS: Registered patients in the MIMIC-IV database 16 years or older and admitted to the ICU due to CAP were included. Multivariate analysis, targeted maximum likelihood estimation (TMLE) to simulate a randomised controlled trial, and survival analyses were conducted to test the effect of macrolide-based treatment on mortality six-month (6 m) and twelve-month (12 m) after hospital admission. A sensitivity analysis was performed excluding patients with Pseudomonas aeruginosa or MRSA pneumonia to control for Healthcare-Associated Pneumonia (HCAP). RESULTS: 3775 patients were included, and 1154 were treated with a macrolide-based treatment. The non-macrolide-based group had worse long-term clinical outcomes, represented by 6 m [31.5 (363/1154) vs 39.5 (1035/2621), p < 0.001] and 12 m mortality [39.0 (450/1154) vs 45.7 (1198/2621), p < 0.001]. The main risk factors associated with long-term mortality were Charlson comorbidity index, SAPS II, septic shock, and respiratory failure. Macrolide-based treatment reduced the risk of dying at 6 m [HR (95% CI) 0.69 (0.60, 0.78), p < 0.001] and 12 m [0.72 (0.64, 0.81), p < 0.001]. After TMLE, the protective effect continued with an additive effect estimate of - 0.069. CONCLUSION: Macrolide-based treatment reduced the hazard risk of long-term mortality by almost one-third. This effect remains after simulating an RCT with TMLE and the sensitivity analysis for the HCAP classification.

Effect of diet on cardiovascular health-related circulating parameters in men and women athletes participating in a marathon race: A cross-sectional study.

OBJECTIVES: The main objective of this study is to understand how diet affects performance and cardiovascular health in a group of women participating in a demanding aerobic race such as marathon, compared to men. METHODS: Fifteen women participating in the Barcelona Marathon-2016 were recruited to participate in the study. A group of men (n = 15) that performed the same marathon race was selected. Anthropometric parameters and diet records were collected before the race. Circulating parameters were analyzed 24 h-pre-race, immediately after the race and 48 h-post-race. These included certain minerals, lipid profile, muscle damage, inflammatory and cardiovascular health markers. RESULTS: Diets were very similar in the men and women, with inadequate amounts of carbohydrates and proteins for endurance events. Creatine kinase (CK; a muscle damage marker) and C-reactive protein (CRP; a marker of inflammation) remained elevated 48 h post-race in all participants, but was significant in women (641 vs. 143 U/L for CK and 5.8 vs. 0.7 mg/dL for CRP). Cardiac markers (high sensitivity troponin T (Hs-TnT), suppression of tumorigenicity and N-terminal pro B-type natriuretic peptide) increased post-race and returned to pre-race values after 48 h in men and women. In particular, Hs-TnT (marker of myocyte stress) increased from 2.2 to 62.5 ng/L post-race in women and from 3.1 to 52.9 ng/L in men. Finally, circulating lipid parameters were at borderline unhealthy levels in both sexes. CONCLUSION: Structural and functional cardiac advantages that women display compared to men in aerobic efforts are not manifested when diet is not adequately designed.