ASO silencing of a glycosyltransferase, Poglut1 , improves the liver phenotypes in mouse models of Alagille syndrome.

BACKGROUND AND AIMS: Paucity of intrahepatic bile ducts (BDs) is caused by various etiologies and often leads to cholestatic liver disease. For example, in patients with Alagille syndrome (ALGS), which is a genetic disease primarily caused by mutations in jagged 1 ( JAG1) , BD paucity often results in severe cholestasis and liver damage. However, no mechanism-based therapy exists to restore the biliary system in ALGS or other diseases associated with BD paucity. Based on previous genetic observations, we investigated whether postnatal knockdown of the glycosyltransferase gene protein O -glucosyltransferase 1 ( Poglut1) can improve the ALGS liver phenotypes in several mouse models generated by removing one copy of Jag1 in the germline with or without reducing the gene dosage of sex-determining region Y-box 9 in the liver. APPROACH AND RESULTS: Using an ASO established in this study, we show that reducing Poglut1 levels in postnatal livers of ALGS mouse models with moderate to profound biliary abnormalities can significantly improve BD development and biliary tree formation. Importantly, ASO injections prevent liver damage in these models without adverse effects. Furthermore, ASO-mediated Poglut1 knockdown improves biliary tree formation in a different mouse model with no Jag1 mutations. Cell-based signaling assays indicate that reducing POGLUT1 levels or mutating POGLUT1 modification sites on JAG1 increases JAG1 protein level and JAG1-mediated signaling, suggesting a likely mechanism for the observed in vivo rescue. CONCLUSIONS: Our preclinical studies establish ASO-mediated POGLUT1 knockdown as a potential therapeutic strategy for ALGS liver disease and possibly other diseases associated with BD paucity.

Genetics of inborn errors of immunity: Diagnostic strategies and new approaches to CNV detection.

BACKGROUND: Genetic diagnosis of inborn errors of immunity (IEI) is complex due to the large number of genes involved and their molecular features. Missense variants have been reported as the most common cause of IEI. However, the frequency of copy number variants (CNVs) may be underestimated since their detection requires specific quantitative techniques. At this point, the use of Next Generation Sequencing (NGS) is acquiring relevance. METHODS: In this article, we present our experience in the genetic diagnosis of IEI based on three diagnostic algorithms that allowed the detection of single nucleotide variants (SNVs) and CNVs. Following this approximation, 703 index cases were evaluated between 2014 and 2021. Sanger sequencing, MLPA, CGH array, breakpoint spanning PCR or a customized NGS-based multigene-targeted panel were performed. RESULTS: A genetic diagnosis was reached in 142 of the 703 index cases (20%), 19 of them presented deletions as causal variants. Deletions were also detected in 5 affected relatives and 16 healthy carriers during the family studies. Additionally, we compile, characterize and present all the CNVs detected by our diagnostic algorithms, representing the largest cohort of deletions related to IEI to date. Furthermore, three bioinformatic tools (LACONv, XHMM, VarSeq™) based on NGS data were evaluated. VarSeq™ was the most sensitive and specific bioinformatic tool; detecting 21/23 (91%) deletions located in captured regions. CONCLUSION: Based on our results, we propose a strategy to guide the molecular diagnosis that can be followed by expert and non-expert centres in the field of IEI.

A decision support procedure for the bioeconomy transition: A Colombian case study.

An increasing number of countries and regions consider the bioeconomy transition a strategic policy priority. When approached through the lens of a circular economy perspective, investments in bioeconomy have the potential to enhance resource utilisation efficiency, preserve biodiversity and ecosystems, and foster sustainable development with low emissions. At the same time, if requirements and contextual factors of bioeconomy strategies are not formally analysed, bioeconomic investments might lead to unintended negative consequences. This paper proposes a decision support procedure to design, assess, prioritise, and monitor bioeconomy investments and policies. The flexibility and scalability of our decision support procedure is tested in Colombia to foster a regional and local transition to bioeconomy initiatives that consider the local capital assets and the stakeholders' views. The heterogeneous character of the Colombian environment, economy, society and culture represents an ideal condition to test the strength of the decision support procedure to promote bioeconomy in low and middle-income countries. Our empirical results highlight the benefit of adopting a formal assessment framework that includes strategic national indicators, regional features and stakeholders' views. In terms of the Colombian regional bioeconomy ambitions, we highlight the need for expanding knowledge hubs and participatory stakeholder networks and buttressing appropriate financial mechanisms.

High-accuracy machine learning techniques for functional connectome fingerprinting and cognitive state decoding.

The human brain is a complex network comprised of functionally and anatomically interconnected brain regions. A growing number of studies have suggested that empirical estimates of brain networks may be useful for discovery of biomarkers of disease and cognitive state. A prerequisite for realizing this aim, however, is that brain networks also serve as reliable markers of an individual. Here, using Human Connectome Project data, we build upon recent studies examining brain-based fingerprints of individual subjects and cognitive states based on cognitively demanding tasks that assess, for example, working memory, theory of mind, and motor function. Our approach achieves accuracy of up to 99% for both identification of the subject of an fMRI scan, and for classification of the cognitive state of a previously unseen subject in a scan. More broadly, we explore the accuracy and reliability of five different machine learning techniques on subject fingerprinting and cognitive state decoding objectives, using functional connectivity data from fMRI scans of a high number of subjects (865) across a number of cognitive states (8). These results represent an advance on existing techniques for functional connectivity-based brain fingerprinting and state decoding. Additionally, 16 different functional connectome (FC) matrix construction pipelines are compared in order to characterize the effects of different aspects of the production of FCs on the accuracy of subject and task classification, and to identify possible confounds.

A Case of COL1A1-PDGFB Fusion Uterine Sarcoma.

COL1A1-PDGFB gene fusion uterine sarcoma is a recently described entity which shows some overlapping features with dermatofibrosarcoma protuberans. To date, only 4 cases have been reported in the literature. Due to its rarity, succinct clinicopathologic characteristics are yet to be established. We report a fifth case initially mistaken as a uterine fibroid which histologically proved to be a CD34 + high-grade spindle cell proliferation which on fluorescence in situ hybridization analysis displayed COL1A1-PDGFB gene rearrangement. With this case description we hope to raise awareness and aid in the characterization of this emerging entity.

Ovarian activity and reproductive responses of lactating Angus cows due to a mineral supplementation throughout a timed AI protocol.

Two experiments were conducted to evaluate the effect of intramuscular administration of minerals during a TAI program on the reproductive responses of lactating Angus cows. All cows (n=353) were subjected to a 9-day TAI program based on CIDR insertion plus injections of estradiol, cloprostenol, and eCG, and then TAI 48 h later. In experiment 1, two groups were randomly created, one control with a placebo injection (CON, n=109), and the second received 10 mL of Fosfosan® (MIN, n=172) on day 0 of the synchronization. Conception rate (66.9 vs. 55%) and estrus percentage (55.8 vs. 44%) were higher (P≤0.05) in MIN than in CON cows. Given these results, a second experiment was conducted randomly assigning the cows to two treatments (n=36 each): a single injection of 10 mL of Fosfosan® (MIN-O) on day 0 or two injections of 10 mL of Fosfosan® (MIN-T) on synchronization days 0 and 7. Four cows of each treatment were randomly selected to be scanned with transrectal ultrasound before and during the synchronization protocol to assess ovarian structures and cyclicity, and at day 39 post-TAI for pregnancy diagnosis. Also, blood samples were obtained for the determination of serum minerals and progesterone (P4) concentrations. The number of mineral injections did not affect conception rate (P≥0.1229) conception rate, serum mineral and P4 concentrations, number, and size of emerging follicles, or follicle size according to 1 to 4 classifications. The MIN-T promoted (P<0.05) earlier follicular wave emergence than MIN-O. However, MIN-O cows had a dominant follicle of 15.12 mm, which is more significant (P<0.05) than that in MIN-T cows (13.5 mm). In conclusion, providing a single mineral injection of Fosfosan® at the start of a TAI program is an excellent reproductive strategy in lactating Angus cows to improve the dominant follicle growth, estrus response, and conception rate.

Antigenotoxic Effect of Ascorbic Acid and Resveratrol in Erythrocytes of Ambystoma mexicanum, Oreochromis niloticus and Human Lymphocytes Exposed to Glyphosate.

Glyphosate is a controversial herbicide. Its genotoxicity and presence in various ecosystems have been reported. The use of ascorbic acid and resveratrol could protect different organisms from glyphosate-induced genetic damage. In the present study, specific genetic damage induced by glyphosate was evaluated in erythrocytes of Oreochromis niloticus, Ambystoma mexicanum and human lymphocytes. Simultaneously, the antigenotoxic capacity of various concentrations of ascorbic acid and resveratrol was evaluated by means of pretreatment and simultaneous treatment protocols. The 0.03, 0.05 and 0.07 mM concentrations of glyphosate induced significant genotoxic activity (p < 0.05) in human lymphocytes and in erythrocytes of the species studied, and could cause genomic instability in these populations. The reduction in genetic damage observed in human lymphocytes exposed to high concentrations of glyphosate is only apparent: excessive genetic damage was associated with undetectable excessive tail migration length. A significant (p < 0.05) antigenotoxic effect of ascorbic acid and resveratrol was observed in all concentrations, organisms and protocols used. Both ascorbic acid and resveratrol play an important role in maintaining the integrity of DNA. Ascorbic acid in Oreochromis niloticus, Ambystoma mexicanum reduced glyphosate-induced genetic damage to a basal level. Therefore, our data indicate that these antioxidants could help preserve the integrity of the DNA of organisms exposed to glyphosate. The consumption of antioxidants is a useful tool against the genotoxicity of glyphosate.

Hereditary spastic paraplegia associated with a novel homozygous intronic noncanonical splice site variant in the AP4B1 gene.

Pathogenic variants in the AP4B1 gene lead to a rare form of hereditary spastic paraplegia (HSP) known as SPG47. We report on a patient with a clinical suspicion of complicated HSP of the lower limbs with intellectual disability, as well as a novel homozygous noncanonical splice site variant in the AP4B1 gene, in which the effect on splicing was validated by RNA analysis. We sequenced 152 genes associated with HSP using Next-Generation Sequencing (NGS). We isolated total RNA from peripheral blood and generated cDNA using reverse transcription-polymerase chain reaction (RT-PCR). A region of AP4B1 mRNA was amplified by PCR and the fragments obtained were purified from the agarose gel and sequenced. We found a homozygous variant of uncertain significance in the AP4B1 gene NM_006594.4: c.1511-6C>G in the proband. Two different AP4B1 mRNA fragments were obtained in the patient and his carrier parents. The shorter fragment was the predominant fragment in the patient and revealed a deletion with skipping of the AP4B1 exon 10. The patient's longer fragment corresponded to an insertion of the last five nucleotides of AP4B1 intron 9. We confirmed that this variant affects the normal splicing of RNA, sustaining the molecular diagnosis of SPG47 in the patient.

Hyperoxemia in postsurgical sepsis/septic shock patients is associated with reduced mortality.

BACKGROUND: Despite growing interest in treatment strategies that limit oxygen exposure in ICU patients, no studies have compared conservative oxygen with standard oxygen in postsurgical patients with sepsis/septic shock, although there are indications that it may improve outcomes. It has been proven that high partial pressure of oxygen in arterial blood (PaO2) reduces the rate of surgical-wound infections and mortality in patients under major surgery. The aim of this study is to examine whether PaO2 is associated with risk of death in adult patients with sepsis/septic shock after major surgery. METHODS: We performed a secondary analysis of a prospective observational study in 454 patients who underwent major surgery admitted into a single ICU. Patients were stratified in two groups whether they had hyperoxemia, defined as PaO2 > 100 mmHg (n = 216), or PaO2 ≤ 100 mmHg (n = 238) at the day of sepsis/septic shock onset according to SEPSIS-3 criteria maintained during 48 h. Primary end-point was 90-day mortality after diagnosis of sepsis. Secondary endpoints were ICU length of stay and time to extubation. RESULTS: In patients with PaO2 ≤ 100 mmHg, we found prolonged mechanical ventilation (2 [8] vs. 1 [4] days, p < 0.001), higher ICU stay (8 [13] vs. 5 [9] days, p < 0.001), higher organ dysfunction as assessed by SOFA score (9 [3] vs. 7 [5], p < 0.001), higher prevalence of septic shock (200/238, 84.0% vs 145/216) 67.1%, p < 0.001), and higher 90-day mortality (37.0% [88] vs. 25.5% [55], p = 0.008). Hyperoxemia was associated with higher probability of 90-day survival in a multivariate analysis (OR 0.61, 95%CI: 0.39-0.95, p = 0.029), independent of age, chronic renal failure, procalcitonin levels, and APACHE II score > 19. These findings were confirmed when patients with severe hypoxemia at the time of study inclusion were excluded. CONCLUSIONS: Oxygenation with a PaO2 above 100 mmHg was independently associated with lower 90-day mortality, shorter ICU stay and intubation time in critically ill postsurgical sepsis/septic shock patients. Our findings open a new venue for designing clinical trials to evaluate the boundaries of PaO2 in postsurgical patients with severe infections.

Spatiotemporal patterns of dengue and Zika incidence during the 2015-2018 outbreak of Zika in Mexico.

OBJECTIVE: Evaluate spatially and temporally simultaneous presence of clusters of dengue and Zika clinical cases and their relationship with expected dengue transmission risk. MATERIALS AND METHODS: A classification of dengue risk transmission was carried out for whole country, and spatial autocorrelation analyses to identify clusters of confirmed clinical cases of dengue and Zika from 2015 to 2018 was conducted using Moran's Index statistics. RESULTS: Clusters of both diseases were identified in dengue-high risk munici-palities at the beginning of the outbreak, but, at the end of the outbreak, Zika clusters occurred in dengue low-risk mu-nicipalities. CONCLUSION: This study identified Zika clusters in low-risk dengue areas suggesting participation of several factors that favor virus introduction and dissemination, such as differences in entomological and control interventions, and the possibility of cross-immunity in the population.

Dual-Band CPW Graphene Antenna for Smart Cities and IoT Applications.

In this paper, a dual-band graphene coplanar waveguide antenna is designed for smart cities and internet of things applications. A graphene film is chosen as the conductive material for the radiation patches and ground plane with a thickness of 240 µm and an electric conductivity of 3.5 × 105 S/m. The dielectric is glass with a dielectric permittivity of 6 and a thickness of 2 mm. The implementation of the antenna on glass permits the integration of the antenna in smart cities and IoT applications. This antenna is based on two trapezoidal patches that generate the dual-band behavior. The overall dimensions of the antenna are 30 mm × 30 mm × 2 mm. The reflection coefficient, gain, and radiation patterns were measured and compared with the simulations. The antenna covers two frequency bands; the lower band covers the 2.45 GHz ISM band, and the upper band range covers from 4 to 7 GHz.

Sox9 Is a Modifier of the Liver Disease Severity in a Mouse Model of Alagille Syndrome.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is a multisystem developmental disorder characterized by bile duct (BD) paucity, caused primarily by haploinsufficiency of the Notch ligand jagged1. The course of the liver disease is highly variable in ALGS. However, the genetic basis for ALGS phenotypic variability is unknown. Previous studies have reported decreased expression of the transcription factor SOX9 (sex determining region Y-box 9) in late embryonic and neonatal livers of Jag1-deficient mice. Here, we investigated the effects of altering the Sox9 gene dosage on the severity of liver disease in an ALGS mouse model. APPROACH AND RESULTS: Conditional removal of one copy of Sox9 in Jag1+/- livers impairs the biliary commitment of cholangiocytes and enhances the inflammatory reaction and liver fibrosis. Loss of both copies of Sox9 in Jag1+/- livers further worsens the phenotypes and results in partial lethality. Ink injection experiments reveal impaired biliary tree formation in the periphery of P30 Jag1+/- livers, which is improved by 5 months of age. Sox9 heterozygosity worsens the P30 biliary tree phenotype and impairs the partial recovery in 5-month-old animals. Notably, Sox9 overexpression improves BD paucity and liver phenotypes in Jag1+/- mice without ectopic hepatocyte-to-cholangiocyte transdifferentiation or long-term liver abnormalities. Notch2 expression in the liver is increased following Sox9 overexpression, and SOX9 binds the Notch2 regulatory region in the liver. Histological analysis shows a correlation between the level and pattern of SOX9 expression in the liver and outcome of the liver disease in patients with ALGS. CONCLUSIONS: Our results establish Sox9 as a dosage-sensitive modifier of Jag1+/- liver phenotypes with a permissive role in biliary development. Our data further suggest that liver-specific increase in SOX9 levels is a potential therapeutic approach for BD paucity in ALGS.

OLFM4 polymorphisms predict septic shock survival after major surgery.

BACKGROUND: Higher expression of olfactomedin-4 (OLFM4), a gene regulated by nuclear factor-kappa B (NF-κB), has been related to a higher risk of organ failure and death in patients with septic shock. We aimed to evaluate the association between OLFM4 single nucleotide polymorphisms (SNPs) and septic shock-related death in 175 patients who underwent major surgery, as well as its performance in predicting mortality. MATERIALS AND METHODS: We carried out a retrospective study. A total of seven OLFM4 SNPs were genotyped by Agena Bioscience's MassARRAY platform. Statistical analysis was performed by Kaplan-Meier and Cox regression tests. The diagnostic performance for predicting septic shock-related death was evaluated by the area under the receiver-operating characteristic (AUROC) curve. RESULTS: Patients with rs17552047 A allele and rs1891944 TT genotype had higher survival than patients with rs17552047 G allele (P-value = .024) and patients with rs1891944 CC/CT genotype (P-value = .038). However, only rs17552047 was associated with a lower risk of death under an additive inheritance model (adjusted hazard ratio [aHR] = 0.44, 95% CI = 0.27-0.71). The multivariate model with the most significant clinical variables (lactate, chronic kidney disease, peritonitis, heart disease and elective surgery) showed an AUROC of 0.776 for predicting septic shock-related death. When we added the OLFM4 rs17552047 SNP to the previous model, the AUROC was 0.811 and was close to reaching significant differences with the previous model (P-value = .065). CONCLUSION: OLFM4 rs17552047 A allele predicts septic shock survival in patients who underwent major surgery. Furthermore, rs17552047, together with clinical variables, could be useful to predict the outcome of septic shock.

Repetitions in Reserve and Rate of Perceived Exertion Increase the Prediction Capabilities of the Load-Velocity Relationship.

ABSTRACT: Balsalobre-Fernández, C, Muñoz-López, M, Marchante, D, and García-Ramos, A. Repetitions in reserve and rate of perceived exertion increase the prediction capabilities of the load-velocity relationship. J Strength Cond Res 35(3): 724-730, 2021-This study aimed to (a) analyze the relationships between relative load (i.e., %1 repetition maximum; 1RM) and movement velocity, repetitions in reserve (RIR) and rate of perceived exertion (RPE) in competitive powerlifters and (b) examine whether a multiple linear regression model with the movement velocity, RIR, and RPE as predictor variables could improve the goodness of fit of the load-velocity relationship. Ten competitive powerlifters performed an incremental loading test (from 50 to 100% 1RM) on the full-squat, hip-thrust, and bench press exercises. Barbell velocity was measured using a linear position transducer, while RIR and RPE were registered immediately after each set. Velocity (r2: 0.747-0.887), RIR (r2: 0.857-0.928), and RPE (r2: 0.908-0.933) were moderately to highly related to relative load. A higher amount of variance of the relative load was explained when the RIR and RPE were added to velocity in a multiple regression model in comparison with the load-velocity relationship (r2: 0.924-0.947). Moreover, it was observed that, in all cases, individual load-velocity, load-RIR, and load-RPE relationships had higher r2 scores than the generalized load-velocity relationship. Incorporating the RIR and RPE as predictors of the relative load along with movement velocity into a multiple linear regression was shown to provide better estimations of the %1RM than using a linear load-velocity relationship.

The city turned off: Urban dynamics during the COVID-19 pandemic based on mobile phone data.

Due to the rapid expansion of the COVID-19 pandemic, many countries ordained lockdowns, establishing different restrictions on people's mobility. Exploring to what extent these measures have been effective is critical in order to better respond to similar future scenarios. This article uses anonymous mobile phone data to study the impact of the Spanish lockdown on the daily dynamics of the Madrid metropolitan area (Spain). The analysis has been carried out for a reference week prior to the lockdown and during several weeks of the lockdown in which different restrictions were in place. During these weeks, population distribution is compared during the day and at night and presence profiles are obtained throughout the day for each type of land use. In addition, a spatial multiple regression analysis is carried out to determine the impact of the different land uses on the local population. The results in the reference week, pre-COVID-19, show how the population in activity areas increases in each time slot on a specific day and how in residential areas it decreases. However, during the lockdown, activity areas cease to attract population during the day and the residential areas therefore no longer show a decrease. Only basic essential commercial activities, or others that require the presence of workers (industrial or logistics) maintain some activity during lockdown.

CA19-9 capability as predictor of pancreatic cancer resectability in a Spanish cohort.

CA19-9 serum has been suggested as a marker of unresectability but different cut-off levels have been published. A cut-off of 500 U/ml is currently considered in an international consensus as biological criteria of borderline resectable pancreatic adenocarcinoma. To evaluate whether serum CA19-9 threshold of 500 U/ml could be adequate predictor of resectability in pancreatic adenocarcinoma. Multicenter, observational, prospective study performed in Spain including 203 patients diagnosed with pancreatic adenocarcinoma. 43 (21.2%) cases were resectable and 160 (78.8%) unresectable. Among the 176 preoperative CA19-9 available values, 98 (58.3%) were ≤ 500 U/ml and 73 (42.7%) > 500 U/ml. Resectability rate in those patients with CA19-9 ≤ 500 U/ml was 60% while it was found to be 18% when CA19-9 > 500 U/ml. Statistical model to predict resectability based on CA19-9 provide an AUC of 0.6618 (95% CI 0.53-0.83) when only CA19-9 values > 500 U/ml are studied. Serum levels of CA19-9 higher than 500 U/ml are indicative of unresectable disease, however reduced sensitivity and specificity lead to a limited clinical applicability for resectability.

A Study of the Psychometric Properties of the "Stanford Proxy Test for Delirium" (S-PTD): A New Screening Tool for the Detection of Delirium.

BACKGROUND: Delirium is a prevalent neuropsychiatric disorder associated with increased morbidity and mortality. Half the cases remain misdiagnosed. OBJECTIVE: Assess the effectiveness of the Stanford Proxy Test for Delirium (S-PTD) in detecting delirium in an inpatient setting. METHODS: This is a comparison study. Daily assessment with S-PTD, by the patient's nurse, and a neuropsychiatric assessment by a psychiatrist. Assessments were blinded. Inclusion criteria included 18 years or older. Exclusion criteria included patient's or surrogate's unwillingness to participate, inability to consent if a surrogate was not available, and inability to communicate in English or Spanish. A total of 309 patients were approached: 27 declined participation, 4 were excluded, and 278 subjects were followed up throughout their hospital stay. In the end, 78 were excluded for lack of neuropsychiatric assessment, S-PTD, or both. One was excluded for lack of demographic data. The sensitivity and specificity of the S-PTD in detecting delirium when compared with a neuropsychiatric assessment. RESULTS: Participants were on average 60.8 years old and 54.3% were male. Patients who developed delirium were, on average, older (15.12 y, confidence interval: 8.94-21.32). A total of 199 patients were analyzed; 43 patients (21.6%) met criteria for delirium. S-PTD detected 67 days with delirium (16.5%) of 405 hospital days, while neuropsychiatric evaluation identified 83 (20.5%). S-PTD had a sensitivity of 80.72% and a specificity of 90.37%. CONCLUSION: S-PTD is an effective, comprehensive, and simple screening tool for delirium, which is robust despite fluctuating symptoms and lack of cooperation. The use of S-PTD may enhance early diagnosis of delirium.

Impaired immune reaction and increased lactate and C-reactive protein for early prediction of severe morbidity and pancreatic fistula after pancreatoduodenectomy.

BACKGROUND: Prediction of complications after pancreatoduodenectomy (PD) remains of interest. Blood parameters and biomarkers during first and second postoperative days (POD1, POD2) may be early indicators of complications. METHODS: This case-control study included 50 patients. Baseline, POD1 and POD2 values of leukocytes, neutrophils, lymphocytes, platelets, hemoglobin, C-reactive protein (CRP), procalcitonin and arterial lactate were compared between individuals presenting Clavien ≥ III morbidity, pancreatic fistula (PF) or clinically relevant PF (CRPF) and those without these morbidities. Common variables reaching significance were further analyzed in order to calculate a predictive score. RESULTS: Severe morbidity, PF and CRPF rates were 28.0%, 26.0% and 14.0%, respectively. Patients with severe morbidity had lower leukocytes on POD2 (P = 0.04). Patients with PF presented higher CRP on POD2 (P = 0.001), higher lactate on POD1 (P = 0.007) and POD2 (P = 0.008), and lower lymphocytes on POD1 (P = 0.007) and POD2 (P = 0.008). Patients with CRPF had lower leukocytes and neutrophils on POD1 (P = 0.048, P = 0.038), lower lymphocytes on POD1 (P = 0.001) and POD2 (P = 0.003), and higher CRP on POD2 (P = 0.001). Baseline parameters and procalcitonin obtained no statistical associations. Score was defined according to lymphocytes on POD1 < 650/µL and CRP on POD2 ≥ 250 mg/L allocating patients in 3 risk categories. PF and CRPF rates were statistically higher as risk category increased (P<0.001). Receiver operating characteristic curves and Hosmer-Lemeshow tests showed a good accuracy. CONCLUSIONS: Impaired immunological reaction during early postoperative period (lower leukocytes and, particularly, lymphocytes) in response to surgical aggression would favor complications after PD. Likewise, acidosis (higher arterial lactate) could behave as risk factor of PF. An elevated CRP on POD2 is also an early biomarker of PF. Our novel score based on postoperative lymphocyte count and CRP seems reliable for early prediction of PF.

Cerebral Oxygen Saturation and Negative Postoperative Behavioral Changes in Pediatric Surgery: A Prospective Observational Study.

OBJECTIVE: To evaluate if an intraoperative cerebral regional oxygen saturation (crSO2) decrease, less pronounced than 20% below baseline (the current threshold believed to be associated with cognitive dysfunction in adults), is associated with negative postoperative behavioral changes (NPOBC) in the pediatric population after noncardiac surgeries. STUDY DESIGN: A prospective observational study was conducted with 198 children aged 2-12 years old scheduled for noncardiac procedures under general anesthesia. Intraoperatively, crSO2 was monitored with a cerebral oximeter. On postoperative day 7, the Post-Hospital Behavior Questionnaire was used to diagnose NPOBC. RESULTS: The incidence of NPOBC was 38.8%. Logistic regression analysis revealed that with every 1% reduction of crSO2 from the baseline value, the odds of developing NPOBC were 1.199 higher. Likewise, preoperative anxiety (OR 2.832, P = .006), duration of surgery (OR 1.026, P < .0001), and being between the ages of 2 and 3 years (OR 2.604, P = .048) were associated with NPOBC incidence. The multivariable logistic regression model receiver operating characteristic curve showed an area under the curve (95% CI) = 0.820 (0.759-0.881). CONCLUSIONS: During noncardiac surgeries in the pediatric population, an intraoperative decrease in crSO2 less pronounced than 20% from the baseline value is associated with negative postoperative behavior changes on postoperative day 7. The long-term implications remain to be determined, but this supports attention to crSO2 during noncardiac surgeries.

Loss of function BMP4 mutation supports the implication of the BMP/TGF-ß pathway in the etiology of combined pituitary hormone deficiency.

Despite BMP4 signaling being critical to Rathke's pouch induction and maintenance during early stages of pituitary development, its implication in the etiology of combined pituitary hormone deficiency (CPHD) and other clinical presentations of congenital hypopituitarism has not yet been definitely demonstrated. We report here the first CPHD patient with a de novo pathogenic loss-of-function variant in BMP4. A 6-year-old boy, with macrocephaly, myopia/astigmatism, mild psychomotor retardation, anterior pituitary hypoplasia and ectopic posterior pituitary, clinically diagnosed with growth hormone deficiency, and central hypothyroidism, was referred for genetic analysis of CPHD. Targeted NGS analysis with a custom panel (n = 310 genes) identified a novel heterozygous de novo nonsense variant, NM_001202.5:c.794G > A, p.(Trp265*) in BMP4, which introduces a premature stop codon in the BMP4 pro-domain, impairing the transcription of the TGF-ß mature peptide domain. Additional relevant variants in other genes implicated in pituitary development signaling pathways such as SMAD4 and E2F4 (BMP/TGF-pathway), ALMS1 (NOTCH-pathway), and TSHZ1 (Prokineticin-pathway), were also identified. Our results support the implication of the BMP/TGF-ß signaling pathway in the etiology of CPHD and suggest that oligogenic contribution of additional inherited variants may modify the phenotypic expressivity of BMP4 pathogenic variants.