A glucose-sensing mechanism with glucose transporter 1 and pyruvate kinase in the area postrema regulates hepatic glucose production in rats.

The area postrema (AP) of the brain is exposed to circulating metabolites and hormones. However, whether AP detects glucose changes to exert biological responses remains unknown. Its neighboring nuclei, the nucleus tractus solitarius (NTS), responds to acute glucose infusion by inhibiting hepatic glucose production, but the mechanism also remains elusive. Herein, we characterized AP and NTS glucose-sensing mechanisms. Infusion of glucose into the AP, like the NTS, of chow rats suppressed glucose production during the pancreatic (basal insulin)-euglycemic clamps. Glucose transporter 1 or pyruvate kinase lentiviral-mediated knockdown in the AP negated AP glucose infusion to lower glucose production, while the glucoregulatory effect of NTS glucose infusion was also negated by knocking down glucose transporter 1 or pyruvate kinase in the NTS. Furthermore, we determined that high-fat (HF) feeding disrupts glucose infusion to lower glucose production in association with a modest reduction in the expression of glucose transporter 1, but not pyruvate kinase, in the AP and NTS. However, pyruvate dehydrogenase activator dichloroacetate infusion into the AP or NTS that enhanced downstream pyruvate metabolism and recapitulated the glucoregulatory effect of glucose in chow rats still failed to lower glucose production in HF rats. We discovered that a glucose transporter 1- and pyruvate kinase-dependent glucose-sensing mechanism in the AP (as well as the NTS) lowers glucose production in chow rats and that HF disrupts the glucose-sensing mechanism that is downstream of pyruvate metabolism in the AP and NTS. These findings highlight the role of AP and NTS in mediating glucose to regulate hepatic glucose production.

A new physiological medium uncovers biochemical and cellular alterations in Lesch-Nyhan disease fibroblasts.

BACKGROUND: Lesch-Nyhan disease (LND) is a severe neurological disorder caused by the genetic deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGprt), an enzyme involved in the salvage synthesis of purines. To compensate this deficiency, there is an acceleration of the de novo purine biosynthetic pathway. Most studies have failed to find any consistent abnormalities of purine nucleotides in cultured cells obtained from the patients. Recently, it has been shown that 5-aminoimidazole-4-carboxamide riboside 5'-monophosphate (ZMP), an intermediate of the de novo pathway, accumulates in LND fibroblasts maintained with RPMI containing physiological levels (25 nM) of folic acid (FA), which strongly differs from FA levels of regular cell culture media (2200 nM). However, RPMI and other standard media contain non-physiological levels of many nutrients, having a great impact in cell metabolism that does not precisely recapitulate the in vivo behavior of cells. METHODS: We prepared a new culture medium containing physiological levels of all nutrients, including vitamins (Plasmax-PV), to study the potential alterations of LND fibroblasts that may have been masked by the usage of non-physiological media. We quantified ZMP accumulation under different culture conditions and evaluated the activity of two known ZMP-target proteins (AMPK and ADSL), the mRNA expression of the folate carrier SLC19A1, possible mitochondrial alterations and functional consequences in LND fibroblasts. RESULTS: LND fibroblasts maintained with Plasmax-PV show metabolic adaptations such a higher glycolytic capacity, increased expression of the folate carrier SCL19A1, and functional alterations such a decreased mitochondrial potential and reduced cell migration compared to controls. These alterations can be reverted with high levels of folic acid, suggesting that folic acid supplements might be a potential treatment for LND. CONCLUSIONS: A complete physiological cell culture medium reveals new alterations in Lesch-Nyhan disease. This work emphasizes the importance of using physiological cell culture conditions when studying a metabolic disorder.

Neural correlates of context-dependent extinction recall in social anxiety disorder: relevance of intrusions in response to aversive social experiences.

BACKGROUND: There are phenomenological similarities between social anxiety disorder (SAD) and posttraumatic stress disorder, such as a provoking aversive event, posttraumatic stress symptoms (e.g. intrusions) in response to these events and deficient (context-dependent) fear conditioning processes. This study investigated the neural correlates of context-dependent extinction recall and fear renewal in SAD, specifically in patients with intrusions in response to an etiologically relevant aversive social event. METHODS: During functional magnetic resonance imaging a two-day context-dependent fear conditioning paradigm was conducted in 54 patients with SAD and 54 healthy controls (HC). This included fear acquisition (context A) and extinction learning (context B) on one day, and extinction recall (context B) as well as fear renewal (contexts C and A) one day later. The main outcome measures were blood oxygen level-dependent responses in regions of interest and skin conductance responses. RESULTS: Patients with SAD showed reduced differential conditioned amygdala activation during extinction recall in the safe extinction context and during fear renewal in the acquisition context compared to HC. Patients with clinically relevant intrusions moreover exhibited hypoactivation of the ventromedial prefrontal cortex (vmPFC) during extinction learning, extinction recall, and fear renewal in a novel context, while amygdala activation more strongly decreased during extinction learning and increased during fear renewal in the acquisition context compared with patients without intrusions. CONCLUSIONS: Our study provides first evidence that intrusions in SAD are associated with similar deficits in context-dependent regulation of conditioned fear via the vmPFC as previously demonstrated in posttraumatic stress disorder.

Decontextualized fear memories? Stronger conditioned fear responses during extinction learning and extinction recall in a safe context predict the development of long-term analog intrusions.

BACKGROUND: Difficulties in the context-dependent modulation of conditioned fear are known for posttraumatic stress disorder and may explain the occurrence of intrusive memories in safe contexts. The current study therefore investigated if reduced context-dependent modulation of conditioned fear and its underlying neural circuitry constitute risk factors for the development of analog intrusions in response to an experimental trauma. METHODS: Eighty-five healthy women participated in the trauma film paradigm to investigate the development of analog intrusions as well as explicit memory for an experimental trauma after one week and three months, respectively. Before, participants underwent a context-dependent fear conditioning paradigm during functional magnetic resonance imaging with fear acquisition in context A and extinction training in context B on a first day, as well as extinction recall in context B and fear renewal in a novel context C one day later. Skin conductance responses (SCRs) and blood oxygen level dependent responses were main outcome measures. RESULTS: In addition to stronger fear acquisition in context A, stronger conditioned fear responses in the safe context B, as indicated by stronger conditioned SCRs or stronger activation of fear expressing regions during extinction learning and recall, predicted the development of long-term analog intrusions. CONCLUSIONS: Stronger fear responses in safe and danger contexts were risk factors for the development of long-term analog intrusions and point to decontextualized fear memories and difficulties in the context-dependent modulation of conditioned fear. Altered fear conditioning processes and reduced storage of contextual information may cause the occurrence of fear independent of context.

The chemokine XCL1 functions as a pregnancy hormone to program offspring innate anxiety.

Elevated levels of cytokines in maternal circulation increase the offspring's risk for neuropsychiatric disease. Because of their low homeostatic levels, circulating maternal cytokines during normal pregnancies have not been considered to play a role in fetal brain development and offspring behavior. Here we report that the T/NK cell chemotactic cytokine XCL1, a local paracrine immune signal, can function as a pregnancy hormone and is required for the proper development of placenta and male offspring approach-avoidance behavior. We found that circulating XCL1 levels were at a low pregestational level throughout pregnancy except for a midgestational rise and fall. Blunted elevation in maternal plasma XCL1 in dams with a genetic 5HT1A receptor deficit or following neutralization by anti-XCL1 antibodies increased the expression of tissue damage associated factors in WT fetal placenta and led to increased innate anxiety and stress reactivity in the WT male offspring. Therefore, chemokines like XCL1 may act as pregnancy hormones to regulate placenta development and offspring emotional behavior.

Emotional Changes during Imagery Rescripting of Aversive Social Memories in Social Anxiety Disorder: A Randomized Controlled Trial.

INTRODUCTION: Imagery rescripting (ImRs) is a psychotherapeutic intervention targeting aversive memories. During the three-phase intervention, patients reexperience their aversive memory (phase 1), observe the scene from their adult perspective, and intervene to help their former selves (phase 2), and reexperience it again with the positive changes (phase 3). Previous studies have rarely investigated emotional and regulatory processes taking place during the intervention. OBJECTIVE: This randomized controlled trial investigated self-reported affective and physiological responses during ImRs. METHODS: Seventy-seven patients with social anxiety disorder (SAD) were randomly assigned to a single session of ImRs or a control intervention (recall and discussion of the memory) targeting an aversive social memory. Heart rate (HR) and heart rate variability (HRV) were assessed during and post hoc ratings of positive and negative feelings after baseline and the intervention phases. RESULTS: Relative to the control intervention, ImRs resulted in an initial increase in negative feelings from baseline to phase 1 and a following larger (phase 1 to phase 2) and more stable (phase 2 to phase 3) decrease in negative feelings/increase in positive feelings. On the physiological level, during ImRs compared to the control intervention, mean HR was significantly higher during phase 1 and HRV during phase 3, each compared to baseline. CONCLUSIONS: These results provide further information about the specific sequence of emotional responses on different response levels during ImRs, being consistent with known theories of emotional processing and supposed mechanisms of ImRs.

Cation leak through the ATP1A3 pump causes spasticity and intellectual disability.

ATP1A3 encodes the α3 subunit of the sodium-potassium ATPase, one of two isoforms responsible for powering electrochemical gradients in neurons. Heterozygous pathogenic ATP1A3 variants produce several distinct neurological syndromes, yet the molecular basis for phenotypic variability is unclear. We report a novel recurrent variant, ATP1A3(NM_152296.5):c.2324C>T; p.(Pro775Leu), in nine individuals associated with the primary clinical features of progressive or non-progressive spasticity and developmental delay/intellectual disability. No patients fulfil diagnostic criteria for ATP1A3-associated syndromes, including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism or cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss (CAPOS), and none were suspected of having an ATP1A3-related disorder. Uniquely among known ATP1A3 variants, P775L causes leakage of sodium ions and protons into the cell, associated with impaired sodium binding/occlusion kinetics favouring states with fewer bound ions. These phenotypic and electrophysiologic studies demonstrate that ATP1A3:c.2324C>T; p.(Pro775Leu) results in mild ATP1A3-related phenotypes resembling complex hereditary spastic paraplegia or idiopathic spastic cerebral palsy. Cation leak provides a molecular explanation for this genotype-phenotype correlation, adding another mechanism to further explain phenotypic variability and highlighting the importance of biophysical properties beyond ion transport rate in ion transport diseases.

Requirements for Accessing New Dermatology Drugs in Spain: Results of the EQUIDAD Study. / Condicionantes de acceso a nuevos medicamentos dermatológicos en España: resultados del proyecto EQUIDAD.

BACKGROUND: Although the Spanish Ministry of Health prepares national therapeutic positioning reports (TPRs) and drug reimbursement policies, each of the country's 17 autonomous communities (ACs) is responsible for health care services and prescription requirements in its territory. The aim of the EQUIDAD study was to describe and explore potential differences in prescription requirements for new dermatology drugs across the autonomous communities. MATERIAL AND METHODS: Cross-sectional study conducted in April and May, 2023. Two dermatologists with management responsibilities from each autonomous community reported on territorial and more local prescription requirements for drugs covered by national TPRs issued between 2016 and 2022. RESULTS: Thirty-three researchers from 17 autonomous communities participated. The data submitted revealed between-community inequities in access to new drugs. Overall, 64.7% of the regions imposed additional prescription requirements to those mentioned in the TPRs for psoriasis. This percentage was lower for atopic dermatitis (35.3%) and melanoma (11.8%). The most common requirement for accessing a new drug was a previous prescription for another drug. Differences and additional requirements were also detected at the local level (i.e., differences between hospitals within the same autonomous community). CONCLUSIONS: Spain's autonomous communities have multiple regional and local prescription requirements that are not aligned with national TPR recommendations. These differences result in inequitable access to new drugs for both patients and practitioners across Spain.

[Translated article] Requirements for Accessing New Dermatology Drugs in Spain: Results of the EQUIDAD Study.

BACKGROUND: Although the Spanish Ministry of Health prepares national therapeutic positioning reports (TPRs) and drug reimbursement policies, each of the country's 17 autonomous communities (ACs) is responsible for health care services and prescription requirements in its territory. The aim of the EQUIDAD study was to describe and explore potential differences in prescription requirements for new dermatology drugs across the autonomous communities. MATERIAL AND METHODS: Cross-sectional study conducted in April and May, 2023. Two dermatologists with management responsibilities from each autonomous community reported on territorial and more local prescription requirements for drugs covered by national TPRs issued between 2016 and 2022. RESULTS: Thirty-three researchers from 17 autonomous communities participated. The data submitted revealed between-community inequities in access to new drugs. Overall, 64.7% of the regions imposed additional prescription requirements to those mentioned in the TPRs for psoriasis. This percentage was lower for atopic dermatitis (35.3%) and melanoma (11.8%). The most common requirement for accessing a new drug was a previous prescription for another drug. Differences and additional requirements were also detected at the local level (i.e., differences between hospitals within the same autonomous community). CONCLUSIONS: Spain's autonomous communities have multiple regional and local prescription requirements that are not aligned with national TPR recommendations. These differences result in inequitable access to new drugs for both patients and practitioners across Spain.

The role of multiparametric magnetic resonance in active surveillance of a low-risk prostate cancer cohort from clinical practice.

INTRODUCTION: Active surveillance (AS) is considered a suitable management practice for those patients with low-risk prostate cancer (PCa). At present, however, the role of multiparametric magnetic resonance imaging (mpMRI) in AS protocols has not yet been clearly established. OUTCOMES: To determine the role of mpMRI and its ability to detect significant prostate cancer (SigPCa) in PCa patients enrolled in AS protocols. MATERIALS AND METHODS: There were 229 patients enrolled in an AS protocol between 2011 and 2020 at Reina Sofía University Hospital. MRI interpretation was based on PIRADS v.1 or v.2/2.1 classification. Demographics, clinical, and analytical data were collected and analyzed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for mpMRI in different scenarios. We defined SigPCa and reclassification/progression as a Gleason score (GS) ≥ 3 + 4, a clinical stage ≥T2b, or an increase in PCa volume. Kaplan-Meier and log-rank tests were used to estimate progression-free survival time. RESULTS: Median age was 69.02 (±7.73) at diagnosis, with a 0.15 (±0.08) PSA density (PSAD). Eighty-six patients were reclassified after confirmatory biopsy, with a suspicious mpMRI an indication for a clear reclassification and risk-predictor factor in disease progression (p < 0.05). During follow-up, 46 patients were changed from AS to active treatment mainly due to disease progression. Ninety patients underwent ≥2mpMRI during follow-up, with a median follow-up of 29 (15-49) months. Thirty-four patients had a baseline suspicious mpMRI (at diagnostic or confirmatory biopsy): 14 patients with a PIRADS 3 and 20 patients with ≥PIRADS 4. From 14 patients with a PIRADS 3 baseline mpMRI, 29% progressed radiologically, with a 50% progression rate versus 10% (1/10 patients) for those with similar or decreased mpMRI risk. Of the 56 patients with a non-suspicious baseline mpMRI (PIRADS < 2), 14 patients (25%) had an increased degree of radiological suspicion, with a detection rate of SigPCa of 29%. The mpMRI NPV during follow-up was 0.91. CONCLUSION: A suspicious mpMRI increases the reclassification and disease progression risk during follow-up and plays an important role in monitoring biopsies. In addition, a high NPV at mpMRI follow-up can help to decrease the need to monitor biopsies during AS.

Weathering the storm of emotions: immediate and lasting effects of reinterpretation and distancing on event-related potentials and their association with habitual use of cognitive reappraisal.

Reinterpretation and distancing, two cognitive reappraisal tactics, are known to effectively reduce negative feelings and event-related potentials (ERPs), such as the P300 and the late positive potential (LPP), in the short-term. Less is known about differential and lasting effects on ERPs as well as their association with habitual reappraisal. Fifty-seven participants were instructed to passively view or reappraise (reinterpretation, distancing) pictures that were repeatedly presented with the same instruction (active regulation phase). Thirty minutes later, these pictures were shown again without instruction for the assessment of lasting effects (re-exposure phase). ERPs were recorded and participants rated the intensity of negative feelings following picture presentation. Reappraisal led to an attenuation of the LPP, and both tactics decreased negative feelings during active regulation, whereby reinterpretation had a stronger impact on the subjective level. Passive re-exposure resulted in reduced negative feelings for previously reappraised pictures but had no lasting effects on ERPs. Higher habitual reappraisal was associated with higher P300 and early LPP amplitudes for emotional reactivity during the active regulation phase. During the re-exposure phase, higher habitual reappraisal was not related to ERPs. The current findings emphasize the effectiveness of both tactics in the short-term and lasting effects on the subjective experience of negative feelings. Enhanced emotional reactivity on the electrocortical level in individuals with a more frequent habitual use of reappraisal might indicate a higher preparedness to regulate.

The integrated curriculum and student empathy: a longitudinal multi-cohort analysis.

Research has demonstrated erosion of empathy in students during medical education. Particularly, U.S. studies have demonstrated empathy declines during clinical training in the third and fourth year of traditional medical programs. Yet, studies conducted outside the U.S. have not confirmed this trend. Timing and extent of patient interactions have been identified as empathy-protective factors. The need to examine empathy within different learning contexts has been noted, as has the need for longitudinal and time-series research designs to analyze trajectories. Between fall 2010 and spring 2019, we assessed empathy longitudinally among six student cohorts (N = 493) at a U.S. medical school, where patient interaction occurs early and throughout an integrated curriculum. Empathy levels of students in each cohort were assessed at five time points utilizing the Jefferson Scale of Physician Empathy-Student version. We hypothesized empathy levels will not degrade by program end, and trajectories will not show patterns of decline in Years Three and Four. Analysis of Variance (ANOVA) and Linear Mixed Model (LMM) analyses were used to analyze differences at baseline and changes in empathy trajectories. ANOVA analyses revealed statistically significant differences at baseline by class cohort (F(5, 487) = [23.28], p < 0.001). LMM analyses indicated empathy was either significantly higher or not different at the end of the program (F(19, 1676) = [13.97], p < 0.001). Empathy trajectories varied among cohorts; yet, none resulted in an overall empathy decline by the end of the program. Findings demonstrate empathy in U.S. medical students can be unchanged or higher by the end of medical education. Outcomes are consistent with reports of non-declining medical student empathy outside the U.S. and support the notion of context-specificity. Results further support recent research, suggesting decreases in empathy during training can stabilize or increase by program end. These findings have important implications for future empathy research context and design considerations, as well as program planning.

Physiological levels of folic acid reveal purine alterations in Lesch-Nyhan disease.

Lesch-Nyhan disease (LND), caused by a deficient salvage purine pathway, is characterized by severe neurological manifestations and uric acid overproduction. However, uric acid is not responsible for brain dysfunction, and it has been suggested that purine nucleotide depletion, or accumulation of other toxic purine intermediates, could be more relevant. Here we show that purine alterations in LND fibroblasts depend on the level of folic acid in the culture media. Thus, physiological levels of folic acid induce accumulation of 5-aminoimidazole-4-carboxamide riboside 5'-monophosphate (ZMP), an intermediary of de novo purine biosynthetic pathway, and depletion of ATP. Additionally, Z-nucleotide derivatives (AICAr, AICA) are detected at high levels in the urine of patients with LND and its variants (hypoxanthine-guanine phosphoribosyltransferase [HGprt]-related neurological dysfunction and HGprt-related hyperuricemia), and the ratio of AICAr/AICA is significantly increased in patients with neurological problems (LND and HGprt-related neurological dysfunction). Moreover, AICAr is present in the cerebrospinal fluid of patients with LND, but not in control individuals. We hypothesize that purine alterations detected in LND fibroblasts may also occur in the brain of patients with LND.

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.

Pyridostigmine reduces mortality of patients with severe SARS-CoV-2 infection: A phase 2/3 randomized controlled trial.

BACKGROUND: Respiratory failure in severe coronavirus disease 2019 (COVID-19) is associated with a severe inflammatory response. Acetylcholine (ACh) reduces systemic inflammation in experimental bacterial and viral infections. Pyridostigmine increases the half-life of endogenous ACh, potentially reducing systemic inflammation. We aimed to determine if pyridostigmine decreases a composite outcome of invasive mechanical ventilation (IMV) and death in adult patients with severe COVID-19. METHODS: We performed a double-blinded, placebo-controlled, phase 2/3 randomized controlled trial of oral pyridostigmine (60 mg/day) or placebo as add-on therapy in adult patients admitted due to confirmed severe COVID-19 not requiring IMV at enrollment. The primary outcome was a composite of IMV or death by day 28. Secondary outcomes included reduction of inflammatory markers and circulating cytokines, and 90-day mortality. Adverse events (AEs) related to study treatment were documented and described. RESULTS: We recruited 188 participants (94 per group); 112 (59.6%) were men; the median (IQR) age was 52 (44-64) years. The study was terminated early due to a significant reduction in the primary outcome in the treatment arm and increased difficulty with recruitment. The primary outcome occurred in 22 (23.4%) participants in the placebo group vs. 11 (11.7%) in the pyridostigmine group (hazard ratio, 0.47, 95% confidence interval 0.24-0.9; P = 0.03). This effect was driven by a reduction in mortality (19 vs. 8 deaths, respectively). CONCLUSION: Our data indicate that adding pyridostigmine to standard care reduces mortality among patients hospitalized for severe COVID-19.

High chromosomal mobility of rDNA clusters in holocentric chromosomes of Triatominae, vectors of Chagas disease (Hemiptera-Reduviidae).

The subfamily Triatominae (Hemiptera-Reduviidae) includes more than 150 blood-sucking species, potential vectors of the protozoan Trypanosoma cruzi, causative agent of Chagas disease. A distinctive cytogenetic characteristic of this group is the presence of extremely stable chromosome numbers. Unexpectedly, the analyses of the chromosomal location of ribosomal gene clusters and other repetitive sequences place Triatominae as a significantly diverse hemipteran subfamily. Here, we advance the understanding of Triatominae chromosomal evolution through the analysis of the 45S rDNA cluster chromosomal location in 92 Triatominae species. We found the 45S rDNA clusters in one to four loci per haploid genome with different chromosomal patterns: On one or two autosomes, on one, two or three sex chromosomes, on the X chromosome plus one to three autosomes. The movement of 45S rDNA clusters is discussed in an evolutionary context. Our results illustrate that rDNA mobility has been relatively common in the past and in recent evolutionary history of the group. The high frequency of rDNA patterns involving autosomes and sex chromosomes among closely related species could affect genetic recombination and the viability of hybrid populations, which suggests that the mobility of rDNA clusters could be a driver of species diversification.

Blood pressure nomograms for children undergoing general anesthesia, stratified by age and anesthetic type, using data from a retrospective cohort at a tertiary pediatric center.

Reference values for non-invasive blood pressure (NIBP) are available for children undergoing general anesthesia, but have not been analyzed by type of anesthetic. This study establishes age-specific pediatric NIBP reference values, stratified by anesthetic type: inhalational anesthesia (IHA), total intravenous anesthesia (TIVA), and mostly intravenous anesthesia (MIVA, an inhalational induction followed by intravenous maintenance of anesthesia). NIBP measurements were extracted from a de-identified vital signs database for children < 19 years undergoing anesthesia between Jan/2013-Dec/2016, excluding cardiac surgery. We automatically rejected artifacts and randomly sampled 20 NIBP values per case. Anesthetic phase (induction/maintenance) was identified using operating room booking times for procedure start, and anesthetic types were identified based on intraoperative minimum alveolar concentration values in the different phases of the anesthetic. From 36,347 cases in our operating room booking system, we matched 24,457 cases with available vital signs. Of these, 20,613 (84%) had valid NIBP data and could be assigned to one anesthetic type: TIVA 11,819 [57%], IHA 4,752 [23%], and MIVA 4,042 [20%]. Mean NIBP during anesthesia increased with age, from median values of 48 mmHg (TIVA), 45 mmHg (IHA), and 41 mmHg (MIVA) in neonates, to 70 mmHg (TIVA), 68 mmHg (IHA), and 64 mmHg (MIVA) in 18-year-olds, respectively. In children < 1 year, mean NIBP values were 4 mmHg higher with TIVA than IHA (p < 0.001). These pediatric NIBP reference values contribute to ongoing debate about alarm limits based on age and anesthetic type, and may motivate prospective studies into the effects of different anesthesia regimes on vital signs.

Social phobic beliefs mediate the relationship between post-event processing regarding the worst socially aversive experience and fear of negative evaluation.

The experience of socially aversive events is proposed to be a critical etiological factor in the development of social anxiety symptoms even though the experience itself is also common among healthy individuals. Rather than the event itself, accompanying factors such as maladaptive processing might be associated with higher levels of social anxiety symptoms. One-hundred-seventy-four individuals participated in this online-survey comprising questionnaires regarding social anxiety symptoms and retrospective reports concerning maladaptive processing of the worst socially aversive event. Structural equation modelling was used to analyze the hypothesized mediation of maladaptive processing and fear of negative evaluation by intrusive re-experiencing and social phobic beliefs. The positive association between retrospectively evaluated maladaptive processing after the worst socially aversive event and fear of negative evaluation was mediated by social phobic beliefs but not by intrusive re-experiencing. These results point towards the relevance of further investigating processing strategies after socially aversive events as a potential influencing factor for SAD development. Trial registration. The trial was registered at the German Clinical Trial Register (DRKS00021502) on June 3rd, 2020. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12144-022-02805-9.

FXR in the dorsal vagal complex is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats.

OBJECTIVE: Conjugated bile acids are metabolised by upper small intestinal microbiota, and serum levels of taurine-conjugated bile acids are elevated and correlated with insulin resistance in people with type 2 diabetes. However, whether changes in taurine-conjugated bile acids are necessary for small intestinal microbiome to alter insulin action remain unknown. DESIGN: We evaluated circulating and specifically brain insulin action using the pancreatic-euglycaemic clamps in high-fat (HF) versus chow fed rats with or without upper small intestinal healthy microbiome transplant. Chemical and molecular gain/loss-of-function experiments targeting specific taurine-conjugated bile acid-induced changes of farnesoid X receptor (FXR) in the brain were performed in parallel. RESULTS: We found that short-term HF feeding increased the levels of taurochenodeoxycholic acid (TCDCA, an FXR ligand) in the upper small intestine, ileum, plasma and dorsal vagal complex (DVC) of the brain. Transplantation of upper small intestinal healthy microbiome into the upper small intestine of HF rats not only reversed the rise of TCDCA in all reported tissues but also enhanced the ability of either circulating hyperinsulinaemia or DVC insulin action to lower glucose production. Further, DVC infusion of TCDCA or FXR agonist negated the enhancement of insulin action, while genetic knockdown or chemical inhibition of FXR in the DVC of HF rats reversed insulin resistance. CONCLUSION: Our findings indicate that FXR in the DVC is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats, and highlight a previously unappreciated TCDCA-FXR axis linking gut microbiome and host insulin action.

Normal head and neck lymph nodes in the paediatric population.

AIM: To determine the normal range of head and neck lymph nodes in a paediatric population. MATERIALS AND METHODS: A retrospective review was undertaken of 200 brain magnetic resonance imaging (MRI) examinations in patients aged between 5 months to 16 years. Exclusion criteria included possible causes for lymphadenopathy. Studies were reported previously as normal. Eight regions were assessed for the presence of nodes, short and long axis of the largest node measured, and the ratio was calculated. RESULTS: Most commonly identifiable nodes were the deep cervical, submandibular, and posterior cervical in 100%, 99.5%, and 92.5% of studies. In the long axis, the three largest were the submandibular, deep, and posterior cervical with mean values of 19.7, 18.1, and 15.4 mm, respectively. For the S/L ratio, the three with the most oval shape were the pre-auricular, occipital, and submental with ratios of 0.64, 0.63, and 0.6, respectively. A positive correlation between the occipital and deep cervical lymph node groups with age was found to be stronger than the rest of localisations. CONCLUSION: This study characterises the normal distribution, size, and shape of head and neck lymph nodes in a healthy paediatric population, demonstrating that rounder and larger lymph nodes may be a normal finding, depending on their location and patient age.