Predictive factors of the postoperative proptosis recovery in surgery of spheno-orbital meningiomas.

OBJECTIVE: This study aimed to identify factors affecting proptosis recovery in spheno-orbital meningioma (SOM) surgery and assess functional and oncological outcomes. METHODS: Data from 32 consecutive SOM surgery cases (2002-2021) were analyzed. Clinical, radiological, operative, and oncological parameters were examined. Proptosis was assessed using the exophthalmos index (EI) on MRI or CT scans. Statistical analyses were performed to identify predictive factors for proptosis recovery. RESULTS: Proptosis improved in 75% of patients post-surgery (EI decreased from 1.28 ± 0.16 to 1.20 ± 0.13, p = 0.048). Patients with stable or worsened EI had higher body mass index (28.5 ± 7.9 vs. 24.1 ± 4.7, p = 0.18), Simpson grade (IV 75% vs. 65%, p = 0.24), and middle sphenoid wing epicenter involvement (63% vs. 38%, p = 0.12), but no significant factors were associated with unfavorable exophthalmos outcomes. The improvement group had higher en plaque morphology, infratemporal fossa invasion, and radiation treatment for cavernous sinus residual tumor (88% vs. 75%, p = 0.25; 51% vs. 25%, p = 0.42; 41% vs. 25%, p = 0.42, respectively), but without statistical significance. Visual acuity remained stable in 78%, improved in 13%, and worsened in 9% during follow-up. Surgery had a positive impact on preoperative oculomotor nerve dysfunction in 3 of 4 patients (75%). Postoperative oculomotor nerve dysfunction was observed in 25%, of which 75% fully recovered. This occurrence was significantly associated with irradiation of an orbital tumor residue (p = 0.04). New postoperative trigeminal hypoesthesia was observed in 47%, of which 73% recovered. All SOMs were classified as WHO grade 1, and complementary treatments achieved oncological control, requiring gamma-knife radiosurgery in 53% and standard radiotherapy in 6%. CONCLUSIONS: Surgery effectively improves proptosis in SOM, though complete resolution is rare. The absence of predictive factors suggests multifactorial causes, including body mass index and tumor resection grade. Postoperative oculomotor nerve dysfunction and trigeminal hypoesthesia are common but often recover. Gamma-knife radiosurgery maintains long-term oncological control for evolving tumor residue.

An examination of episodic future thinking in the emergency department among youth experiencing suicidal thoughts and behaviors.

Youth experiencing suicidal thoughts and/or behaviors (STBs) frequently present to emergency departments for acute psychiatric care. These settings offer a transitory yet pivotal opportunity to assess, intervene on, and plan continued care for STBs. This study examined a clinically relevant, understudied aspect of psychological functioning among youth experiencing STBs in the emergency department: episodic future thinking, or the ability to imagine discrete autobiographical future events. A sample of 167 youths (10-17 years) presenting to a pediatric psychiatric emergency department for STBs completed a performance-based measure of episodic future thinking assessing richness in detail and subjective characteristics of imagined future events. STB recurrence was assessed 6 months later. Immediately following a suicide-related crisis, youth demonstrated mixed abilities to imagine their future: they generated some concrete future event details but did not subjectively perceive these events as being very detailed or likely to occur. Older adolescents (i.e., 15-17) generated more episodic details than pre-/younger adolescents (i.e., 10-14), particularly those pertaining to actions or sensory perceptions. There was no evidence linking less detailed episodic future thinking and greater likelihood of STBs following the emergency department visit; instead, hopelessness was a more robust risk factor. Findings underscore the importance and clinical utility of better understanding the psychological state of youth during or immediately following a suicide-related crisis. In particular, assessing youths' future thinking abilities in the emergency department may directly inform approaches to acute care delivery.

Association of severe mental illness and septic shock case fatality rate in patients admitted to the intensive care unit: A national population-based cohort study.

BACKGROUND: Patients with severe mental illness (SMI) (i.e., schizophrenia, bipolar disorder, or major depressive disorder) have been reported to have excess mortality rates from infection compared to patients without SMI, but whether SMI is associated with higher or lower case fatality rates (CFRs) among infected patients remains unclear. The primary objective was to compare the 90-day CFR in septic shock patients with and without SMI admitted to the intensive care unit (ICU), after adjusting for social disadvantage and physical health comorbidity. METHODS AND FINDINGS: We conducted a nationwide, population-based cohort study of all adult patients with septic shock admitted to the ICU in France between January 1, 2014, and December 31, 2018, using the French national hospital database. We matched (within hospitals) in a ratio of 1:up to 4 patients with and without SMI (matched-controls) for age (5 years range), sex, degree of social deprivation, and year of hospitalization. Cox regression models were conducted with adjustment for smoking, alcohol and other substance addiction, overweight or obesity, Charlson comorbidity index, presence of trauma, surgical intervention, Simplified Acute Physiology Score II score, organ failures, source of hospital admission (home, transfer from other hospital ward), and the length of time between hospital admission and ICU admission. The primary outcome was 90-day CFR. Secondary outcomes were 30- and 365-day CFRs, and clinical profiles of patients. A total of 187,587 adult patients with septic shock admitted to the ICU were identified, including 3,812 with schizophrenia, 2,258 with bipolar disorder, and 5,246 with major depressive disorder. Compared to matched controls, the 90-day CFR was significantly lower in patients with schizophrenia (1,052/3,269 = 32.2% versus 5,000/10,894 = 45.5%; adjusted hazard ratio (aHR) = 0.70, 95% confidence interval (CI) 0.65,0.75, p < 0.001), bipolar disorder (632/1,923 = 32.9% versus 2,854/6,303 = 45.3%; aHR = 0.70, 95% CI = 0.63,0.76, p < 0.001), and major depressive disorder (1,834/4,432 = 41.4% versus 6,798/14,452 = 47.1%; aHR = 0.85, 95% CI = 0.81,0.90, p < 0.001). Study limitations include inability to capture deaths occurring outside hospital, lack of data on processes of care, and problems associated with missing data and miscoding in medico-administrative databases. CONCLUSIONS: Our findings suggest that, after adjusting for social disadvantage and physical health comorbidity, there are improved septic shock outcome in patients with SMI compared to patients without. This finding may be the result of different immunological profiles and exposures to psychotropic medications, which should be further explored.

Clinical relevance of the blanking period on late recurrence after catheter ablation of atrial fibrillation.

INTRODUCTION: Recurrence of atrial fibrillation (AF) within the blanking period after catheter ablation (CA) is traditionally classified as a transient and benign event. However, recent findings suggest that early recurrence (ER) is associated with late recurrence (LR), challenging the predefined "blanking period". We aimed to determine the clinical and procedural predictors of ER and LR after CA and establish the risk of LR in patients who experience ER. METHODS AND RESULTS: Retrospective single-centre study including all patients who underwent a first procedure of AF CA between 2017 and 2019. ER was defined as any recurrence of AF, atrial flutter or atrial tachycardia >30 s within 90 days after CA and LR as any recurrence after 90 days of CA. A total of 399 patients were included, 37% women, median age of 58 years [49-66] and 77% had paroxysmal AF. Median follow-up was 33 months (from 13 to 61). ER after CA was present in 14% of the patients, and LR was reported in 32%. Among patients who experienced ER, 84% also had LR (p < .001). Patients with ER had a higher prevalence of moderate/severe valvular heart disease, persistent AF, previous electrical cardioversion, a larger left atrium, higher coronary artery calcium score, and higher rates of intraprocedural electrical cardioversion and cardiac fibrosis on eletroanatomical mapping compared with patients without ER. After covariate adjustment, ER and female sex were defined as independent predictors of LR (hazard ratio [HR] 4.69; 95% confidence interval [CI], 2.99-7.35; p < .001 and HR 2.73; 95% CI, 1.47-5.10; p = .002, respectively). CONCLUSION: The risk of LR after an index procedure of CA was significantly higher in patients with ER (five-fold increased risk). These results support the imperative need to clarify the clinical role of the blanking period.

The impact of integrase inhibitors on steatosis and fibrosis biomarkers in persons with HIV naïve to antiretroviral therapy.

BACKGROUND: Non-alcoholic Fatty Liver Disease (NAFLD) has a high prevalence among persons with HIV infection. Since Integrase Strand Transfer Inhibitors (INSTIs) are used worldwide and have been associated with weight gain, we must determine their effect in the development of NAFLD and Non-alcoholic Steatohepatitis (NASH) in these patients. The aim of this study was to explore the impact of INSTIs on variation of liver steatosis and fibrosis in the ART-naïve person with HIV, using Hepatic Steatosis Index (HSI), Fibrosis-4 Index (FIB-4), BARD score and NAFLD Fibrosis Score (NFS). METHODS: We performed a monocentric, retrospective cohort study in ART-naïve persons with HIV that initiated INSTI based regimens between December 2019 and January 2022. Data was collected at baseline, 6 and 12 months after initiation. Demographic, clinical and laboratory characteristics, hepatic steatosis, and fibrosis scores were compared between baseline and last visit at 12 months. Linear regression models were performed to analyse the associations between analytical data at baseline and hepatic scores variation during the 12 months of treatment. Models were performed unadjusted and adjusted for age and sex. RESULTS: 99 patients were included in our study. 82% were male and median age was 36 years. We observed a significant increase in body mass index (BMI), HDL, platelet count, albumin, and creatinine and a significant decrease in AST levels. HSI showed no statistically significant differences during follow-up (p = 0.114). We observed a significant decrease in FIB-4 (p = 0.007) and NFS (p = 0.002). BARD score showed a significant increase (p = 0.006). The linear regression model demonstrated a significant negative association between baseline HIV RNA and FIB-4 change (ß= -0.08, 95% CI [-0.16 to -0.00], p = 0.045), suggesting that higher HIV RNA loads at baseline were associated with a greater decrease in FIB-4. CONCLUSION: INSTIs seem to have no impact on hepatic steatosis, even though they were associated with a significant increase in BMI. This might be explained by the direct effect of a dolutegravir-containing regimen and/or by the "return-to-health effect" observed with ART initiation. Furthermore, INSTIs were associated with a reduction in risk of liver fibrosis in ART-naïve persons with HIV, possibly due to their effect on viral suppression.

Impact of Coronary Artery Calcium Score Screening on Cardiovascular Risk Stratification of Patients with Atrial Fibrillation Undergoing Ablation.

INTRODUCTION: There is a well-established association between atrial fibrillation (AF) and coronary artery disease. Coronary artery calcium score (CACS) is a helpful tool to refine cardiovascular (CV) risk stratification and inform on the best strategies for primary CV prevention. This study aims to evaluate the impact of opportunistic screening with CACS on risk stratification and decision of preventive therapies, in patients with AF. METHODS: Cross-sectional study including patients with AF or atrial flutter undergoing cardiac computed tomography for ablation procedure planning, from 2017 to 2019. Baseline clinical and demographical data were collected. CACS was assessed in patients without coronary artery disease using the Agatston method. RESULTS: A total of 474 patients were included (93% with AF, mean age of 58 ± 10 years, 62% male). CACS >0 was present in 254 (54%) patients. According to CACS and the Society of Cardiovascular Computed Tomography recommendations, 25% of the patients would be candidates for statin therapy and 17% would be candidates for changes in the current statin intensity; in 11 patients (8%), acetylsalicylic acid would be recommended. CONCLUSION: In our study, more than half of the patients undergoing cardiac computed tomography before AF catheter ablation had CACS above zero. Our findings suggest that an opportunistic evaluation of CACS at the time of ablation can be an important tool to improve CV risk stratification, with important clinical and therapeutic implications.

Rapid and sustainable HPLC method for the determination of uremic toxins in human plasma samples.

Protein-bound uremic toxins, mainly indoxyl sulfate (3-INDS), p-cresol sulfate (pCS), and indole-3-acetic acid (3-IAA) but also phenol (Pol) and p-cresol (pC), are progressively accumulated during chronic kidney disease (CKD). Their accurate measurement in biomatrices is demanded for timely diagnosis and adoption of appropriate therapeutic measures. Multianalyte methods allowing the establishment of a uremic metabolite profile are still missing. Hence, the aim of this work was to develop a rapid and sensitive method based on high-performance liquid chromatography with fluorescence detection for the simultaneous quantification of Pol, 3-IAA, pC, 3-INDS, and pCS in human plasma. Separation was attained in 12 min, using a monolithic C18 column and isocratic elution with acetonitrile and phosphate buffer containing an ion-pairing reagent, at a flow rate of 2 mL min-1. Standards were prepared in plasma and quantification was performed using the background subtraction approach. LOQ values were ≤ 0.2 µg mL-1 for all analytes except for pCS (LOQ of 2 µg mL-1). The method proved to be accurate (93.5-112%) and precise (CV ≤ 14.3%). The multianalyte application of the method, associated to a reduced sample volume (50 µL), a less toxic internal standard (eugenol) in comparison to the previously applied 2,6-dimethylphenol and 4-ethylphenol, and a green extraction solvent (ethanol), resulted in the AGREE score of 0.62 which is in line with the recent trend of green and sustainable analytical chemistry. The validated method was successfully applied to the analysis of plasma samples from control subjects exhibiting normal levels of uremic toxins and CKD patients presenting significantly higher levels of 3-IAA, pC, 3-INDS, and pCS that can be further investigated as biomarkers of disease progression.

Gahvora cradling in Tajikistan: Cultural practices and associations with motor development.

In Tajikistan, infants are bound supine in a "gahvora" cradle that severely restricts movement. Does cradling affect motor development and body growth? In three studies (2013-2018), we investigated associations between time in the gahvora (within days and across age) and motor skills and flattened head dimensions in 8-24-month-old Tajik infants (N = 269, 133 girls, 136 boys)) and 4.3-5.1-year-old children (N = 91, 53 girls, 38 boys). Infants had later motor onset ages relative to World Health Organization standards and pronounced brachycephaly; cradling predicted walk onset age and the proficiency of sitting, crawling, and walking. By 4-5 years, children's motor skills were comparable with US norms. Cultural differences in early experiences offer a unique lens onto developmental processes and equifinality in development.

Assessing of the Italian version of the Memory Strategy Test (TMS) in people with Parkinson disease: a preliminary descriptive psychometric study.

BACKGROUND: Previous literature has shown that executive functions (EF) are related to performance in memory (M) tasks. The Test of Memory strategies (TMS) is a psychometric test that examines EF and M simultaneously and it was recently validated on an Italian healthy cohort. The first aim of the study was to apply TMS, for the first time, on a sample of patients with Parkinson's disease (PD), who are characterized by mild cognitive impairment. The second aim is to investigate whether TMS scores can discriminate PD patients from healthy controls. METHOD: Ninety-eight subjects were enrolled, including 68 patients with PD, and 30 Italian healthy controls (HC), who also underwent a memory evaluation through well-known tests. RESULTS: Confirmatory factor analysis (CFA) demonstrated that TMS of PD patients had a bi-dimensional structure as previously found in healthy cohort. In detail, The TMS-1 and TMS-2 lists require greater involvement of the EF factor, while TMS-3, TMS-4 and TMS-5 the M factor. Receiver operating characteristic (ROC) curves and precision-recall (PR) curves showed that the M subscale can distinguish between HC and PD, while EF had poor discrimination power. CONCLUSION: The hypothesized prediction model of TMS test seems to have adequate ability to discriminate PD from HC especially for the M function.

Characterisation and long-term follow-up of children with Brugada syndrome: experience from a tertiary paediatric referral centre.

AIMS: Brugada syndrome is an inherited condition, which typically presents in young adults. It can also be diagnosed in children, but data in this group remain scarce. This study aims to describe the clinical features, management, and follow-up of children with personal or family history of Brugada syndrome. METHODS: Retrospective study of consecutive patients with Brugada history followed up in a tertiary paediatric referral centre between 2009 and 2021. Patients were assessed according to the phenotype: positive (with variable genotype) or negative (with positive genotype). RESULTS: Thirty patients were included (mean age at diagnosis 7 ± 6 years, 53% male). Within the positive phenotype (n = 16), 81% were male, and 88% had spontaneous type 1 ECG pattern. A genetic test was performed in 88% and was positive in 57%. Fourteen patients had a negative phenotype-positive genotype, 79% female, all diagnosed during family screening; 43% mentioned family history of sudden cardiac death. Although most of the patients were asymptomatic, the prevalence of rhythm/conduction disturbances was not negligible, particularly if a positive phenotype. No clinically significant events were reported in the negative phenotype patients. Three patients were hospitalised due to an arrhythmic cause, all in patients with a positive phenotype. CONCLUSION: In our study, the documentation of rhythm and conduction disturbances was not infrequent, especially in patients with a positive phenotype. Despite the significant family history, phenotype negative patients had no relevant events during follow-up. Nevertheless, the management of these patients is not clear cut, and a personalised therapeutic strategy with close follow-up is essential.

The Central Nervous System Source Modulates Microglia Function and Morphology In Vitro.

The regional heterogeneity of microglia was first described a century ago by Pio del Rio Hortega. Currently, new information on microglia heterogeneity throughout central nervous system (CNS) regions is being revealed by high-throughput techniques. It remains unclear whether these spatial specificities translate into different microglial behaviors in vitro. We cultured microglia isolated from the cortex and spinal cord and analyzed the effect of the CNS spatial source on behavior in vitro by applying the same experimental protocol and culture conditions. We analyzed the microglial cell numbers, function, and morphology and found a distinctive in vitro phenotype. We found that microglia were present in higher numbers in the spinal-cord-derived glial cultures, presenting different expressions of inflammatory genes and a lower phagocytosis rate under basal conditions or after activation with LPS and IFN-γ. Morphologically, the cortical microglial cells were more complex and presented longer ramifications, which were also observed in vivo in CX3CR1+/GFP transgenic reporter mice. Collectively, our data demonstrated that microglial behavior in vitro is defined according to specific spatial characteristics acquired by the tissue. Thus, our study highlights the importance of microglia as a source of CNS for in vitro studies.

The teaching of headache medicine in France: A questionnaire-based study.

BACKGROUND: The treatment of patients with headache represents an important part of a neurologist's activity. It requires sufficient training for neurology residents. In France, residents in neurology can complete this training by attending specialized consultations or by participating in a postgraduate training program called "Diplôme Inter-Universitaire Migraine et Céphalées" (DIUMC). OBJECTIVE: The objective of this cross-sectional study was to investigate the French residents' knowledge in headache medicine and the impact of different types of training in headache medicine that are available in France. METHODS: An anonymous survey was carried out among 548 French residents in neurology. RESULTS: The questionnaires of 121 residents (22.1%) were analyzed. Among them, 54.5% (66/121) had no complementary training apart from the internship (Group 1), 21.5% (26/121) had attended only specialized consultations (Group 2), and 24% (29/121) had participated in the DIUMC (Group 3). There was no difference between all groups regarding the knowledge of the prevalence of primary or chronic headaches. There was almost no difference between the groups in the management of episodic migraine. In contrast, the management of tension-type headache and chronic headache was better known by residents of Group 3 than residents of Group 1. In these two diseases, residents of Group 3 offered prophylactic treatment more often. Almost 29% of the residents (35/121) had read the French guidelines for the diagnosis and management of migraine. In Group 3, residents had read them significantly more often (1.6% in Group 1, 38.5% in Group 2 and 62.1% in Group 3, p < 0.001). CONCLUSION: This study shows the lack of knowledge among French neurology residents regarding headache medicine. It highlights the interest of specific training programs that could improve the practical and theoretical knowledge of future neurologists.

Validation of blood gas analysis in arteriovenous fistula for hemodialysis.

INTRODUCTION: Arterial blood gas analysis is a minimally invasive technique used in our daily practice but is not a complication free technique. The aim of this study was to validate results from blood gas analysis obtained from the arteriovenous fistula (AVF)/graft as a surrogate marker of the arterial blood gas analysis. METHODS: A prospective observational study was made in 45 patients. We performed arterial and AVF/graft blood gas analysis and results were compared by a paired sample t Student test. RESULTS: Most of our subjects was male (68.9%) and the mean age was 67 years (±14). Hemodialysis vintage was 63 months (±66), and vascular access age was 62 months (±56). The more prevalent vascular access was left radiocephalic AVF (n = 16; 35.6%) and the main puncture artery was right radial artery (n = 27; 60.0%). There were no statistically significant differences between the samples collected. CONCLUSIONS: Our results suggest a possible alternative of arterial blood gas analysis in AVF/graft for hemodialysis patients. This could result in making an uncomfortable procedure almost painless and reducing complications. Future research should take place to include anatomical characteristics of the AVF or the circulation of recirculation.

Automatic and renewable micro-solid-phase extraction based on bead injection lab-on-valve system for determination of tranexamic acid in urine by UHPLC coupled with tandem mass spectrometry.

An automatic micro-solid-phase extraction (µSPE) method using on-line renewable sorbent beads followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was established for the determination of tranexamic acid (TXA) in urine. The µSPE method was based on the bead injection (BI) concept combined with the mesofluidic lab-on-valve (LOV) platform. All steps of the µSPE-BI-LOV were implemented by computer programming, rendering enhanced precision on time and flow events. Several parameters, including the type of sorbent, volume and composition of the conditioning solution, washing solution, and eluent composition, were evaluated to improve the extraction efficiency. The best results were obtained with a hydrophilic-lipophilic balanced mixed-mode sorbent, decorated with sulfonic acid groups (Oasis MCX), and 99% acetonitrile-water (50:50, v/v)-1% ammonium hydroxide as eluent. Chromatographic separation was performed using a BEH amide column coupled to MS/MS detection in positive ionization mode. Good linearity was achieved (R2 > 0.998) for TXA concentrations in urine ranging from 300 to 3000 ng mL-1, with LOD and LOQ of 30 and 65 ng mL-1, respectively. Dilution integrity was observed for dilution factors up to 20,000 times, providing the extension of the upper limit of quantification to 12 mg mL-1. The method was validated according to international guidelines and successfully applied to urine samples collected during scoliosis surgery of pediatric patients treated with TXA.

Self-Injurious Thoughts and Behaviors Interview-Revised (SITBI-R): Reliability, Validity, and Inter-Informant Agreement in an Adolescent Sample.

OBJECTIVE: The present study sought to evaluate the psychometric properties and inter-informant agreement of the Self-Injurious Thoughts and Behaviors Interview-Revised (SITBI-R) in adolescents and their parents. METHOD: Suicidal and nonsuicidal adolescents from the community (N = 206), ages 12-19 years, were administered the SITBI-R during a lab visit. Approximately half of the adolescents' parents opted to complete a parent assessment, including the SITBI-R, on behalf of their child. Inter-rater reliability, convergent validity, and inter-informant agreement were assessed. RESULTS: The SITBI-R exhibited overall excellent inter-rater reliability and good convergent validity in adolescents. Parent-adolescent agreement ranged from fair to poor across most outcomes, with parents tending not to report past self-injurious thoughts and behaviors endorsed by their children. CONCLUSIONS: The present study suggests that the SITBI-R can be extended for use with adolescents. Future research should evaluate moderators and implications of parent-adolescent disagreement, particularly with regard to suicide risk.

Genotype-phenotype correlation in French patients with myelin protein zero gene-related inherited neuropathy.

BACKGROUND AND PURPOSE: Preparations for clinical trials of unfolded protein response (UPR) inhibitors (such as Sephin1) that target the upregulated UPR in patients with Charcot-Marie-Tooth disease (CMT) carrying MPZ mutations are currently underway. The inclusion criteria for these trials are still being formulated. Our objective was to characterize the relation between genotypes and phenotypes in patients with CMT caused by MPZ mutations, and to refine the inclusion criteria for future trials. METHODS: Clinical and neurophysiological data of CMT patients with MPZ mutations were retrospectively collected at 11 French reference centers. RESULTS: Forty-four mutations in MPZ were identified in 91 patients from 61 families. There was considerable heterogeneity. The same mutation was found to cause either axonal or demyelinating neuropathy. Three groups were identified according to the age at disease onset. CMT Examination Score (CMTES) tended to be higher in the early (≤22 years) and adult (23-47 years) onset groups (mean CMTESv2 = 10.4 and 10.0, respectively) than in the late onset group (>47 years, mean CMTESv2 = 8.6, p = 0.47). There was a significant positive correlation between CMTESv2 and the age of patients in Groups I (p = 0.027) and II (p = 0.023), indicating that clinical severity progressed with age in these patients. CONCLUSIONS: To optimize the selection of CMT patients carrying MPZ mutations for the upcoming trials, inclusion criteria should take into account the pathophysiology of the disease (upregulated UPR). Recruited patients should have a mild to moderate disease severity and a disease onset at between 18 and 50 years, as these patients exhibit significant disease progression over time.

Glucocorticoid receptor signaling in leukocytes after early life adversity.

Early life adversity (ELA) has been associated with inflammation and immunosenescence, as well as hyporeactivity of the HPA axis. Because the immune system and the HPA axis are tightly intertwined around the glucocorticoid receptor (GR), we examined peripheral GR functionality in the EpiPath cohort among participants who either had been exposed to ELA (separation from parents and/or institutionalization followed by adoption; n = 40) or had been reared by their biological parents (n = 72).Expression of the strict GR target genes FKBP5 and GILZ as well as total and 1F and 1H GR transcripts were similar between groups. Furthermore, there were no differences in GR sensitivity, examined by the effects of dexamethasone on IL6 production in LPS-stimulated whole blood. Although we did not find differences in methylation at the GR 1F exon or promoter region, we identified a region of the GR 1H promoter (CpG 1-9) that showed lower methylation levels in ELA.Our results suggest that peripheral GR signaling was unperturbed in our cohort and the observed immune phenotype does not appear to be secondary to an altered GR response to the perturbed HPA axis and glucocorticoid (GC) profile, although we are limited in our measures of GR activity and time points.

The COVID-19 Pandemic: Does Our Early Life Environment, Life Trajectory and Socioeconomic Status Determine Disease Susceptibility and Severity?

A poor socioeconomic environment and social adversity are fundamental determinants of human life span, well-being and health. Previous influenza pandemics showed that socioeconomic factors may determine both disease detection rates and overall outcomes, and preliminary data from the ongoing coronavirus disease (COVID-19) pandemic suggests that this is still true. Over the past years it has become clear that early-life adversity (ELA) plays a critical role biasing the immune system towards a pro-inflammatory and senescent phenotype many years later. Cytotoxic T-lymphocytes (CTL) appear to be particularly sensitive to the early life social environment. As we understand more about the immune response to SARS-CoV-2 it appears that a functional CTL (CD8+) response is required to clear the infection and COVID-19 severity is increased as the CD8+ response becomes somehow diminished or exhausted. This raises the hypothesis that the ELA-induced pro-inflammatory and senescent phenotype may play a role in determining the clinical course of COVID-19, and the convergence of ELA-induced senescence and COVID-19 induced exhaustion represents the worst-case scenario with the least effective T-cell response. If the correct data is collected, it may be possible to separate the early life elements that have made people particularly vulnerable to COVID-19 many years later. This will, naturally, then help us identify those that are most at risk from developing the severest forms of COVID-19. In order to do this, we need to recognize socioeconomic and early-life factors as genuine medically and clinically relevant data that urgently need to be collected. Finally, many biological samples have been collected in the ongoing studies. The mechanisms linking the early life environment with a defined later-life phenotype are starting to be elucidated, and perhaps hold the key to understanding inequalities and differences in the severity of COVID-19.

[Progressive muscle relaxation in postoperative pain therapy]. / Progressive Muskelrelaxation in der postoperativen Schmerztherapie.

BACKGROUND: Early and optimal treatment of postoperative pain based on a multimodal treatment concept is very important so that subsequent chronification can be avoided. OBJECTIVES: This study investigated the influence of progressive muscle relaxation on the sensation of pain and the need for analgesics after orthopedic interventions. MATERIALS AND METHODS: This nonrandomized pilot study tested 104 patients in the Clinic of Orthopedics at the Saarland University Medical Center in Homburg, Germany. The patients underwent total endoprosthesis (TEP) of the or the knee or spine surgery (laminectomy), and they had the option of choosing to use the technique of progressive muscle relaxation. All patients completed a questionnaire on the first, fourth, and ninth postoperative day. Data were collected on the maximum and minimum intensity of pain, duration of strong pain, length of hospital stay, and use of pain medication. These were compared by means of t tests for the group with progressive muscle relaxation and the group without progressive muscle relaxation. RESULTS: No significant difference was observed between the two groups regarding pain sensation analgesic dosage. There was a tendency for the length of hospital stay to be shorter in the group with progressive muscle relaxation. CONCLUSION: The positive effect of progressive muscle relaxation cannot be confirmed on the basis of the study data. Owing to the varying study design and implementation as well as the inclusion of heterogeneous patient groups, no conclusion can be drawn at present regarding the effectiveness of progressive muscle relaxation in common practice; therefore, further research is necessary.

Insights on Ultrafiltration-Based Separation for the Purification and Quantification of Methotrexate in Nanocarriers.

The evaluation of encapsulation efficiency is a regulatory requirement for the characterization of drug delivery systems. However, the difficulties in efficiently separating nanomedicines from the free drug may compromise the achievement of accurate determinations. Herein, ultrafiltration was exploited as a separative strategy towards the evaluation of methotrexate (MTX) encapsulation efficiency in nanostructured lipid carriers and polymeric nanoparticles. The effect of experimental conditions such as pH and the amount of surfactant present in the ultrafiltration media was addressed aiming at the selection of suitable conditions for the effective purification of nanocarriers. MTX-loaded nanoparticles were then submitted to ultrafiltration and the portions remaining in the upper compartment of the filtering device and in the ultrafiltrate were collected and analyzed by HPLC-UV using a reversed-phase (C18) monolithic column. A short centrifugation time (5 min) was suitable for establishing the amount of encapsulated MTX in nanostructured lipid carriers, based on the assumption that the free MTX concentration was the same in the upper compartment and in the ultrafiltrate. The defined conditions allowed the efficient separation of nanocarriers from the free drug, with recoveries of >85% even when nanoparticles were present in cell culture media and in pig skin surrogate from permeation assays.