Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. METHODS: Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. RESULTS: Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49-69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI - 0.1% [- 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (- 3.2% [- 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. CONCLUSION: This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 ).

Glucagon-Like Peptide-1 Regulates the Proopiomelanocortin Neurons of the Arcuate Nucleus both Directly and Indirectly via Presynaptic Action.

Glucagon-like peptide-1 (GLP-1) exerts its anorexigenic effect at least partly via the proopiomelanocortin (POMC) neurons of the arcuate (ARC) nucleus. These neurons are known to express GLP-1 receptor (GLP-1R). The aim of the study was to determine whether in addition to its direct effect, GLP-1 also modulates how neuronal inputs can regulate the POMC neurons by acting on presynaptic terminals, ultrastructural and electrophysiological studies were performed on tissues of adult male mice. GLP-1R-immunoreactivity was associated with the cell membrane of POMC neurons and with axon terminals forming synapses on these cells. The GLP-1 analog exendin 4 (Ex4) markedly increased the firing rate of all examined POMC neurons and depolarized these cells. These effects of Ex4 were prevented by intracellular administration of the G-protein blocker guanosine 5'-[ß-thio]diphosphate trilithium salt (GDP-ß-S). Ex4 also influenced the miniature postsynaptic currents (mPSCs) and evoked PSCs of POMC neurons. Ex4 increased the frequency of miniature excitatory PSCs (EPSCs) and the amplitude of the evoked EPSCs in half of the POMC neurons. Ex4 increased the frequency of miniature inhibitory PSCs (IPSCs) and the amplitudes of the evoked IPSCs in one-third of neurons. These effects of Ex4 were not influenced by intracellular GDP-ß-S, indicating that GLP-1 signaling directly stimulates a population of axon terminals innervating the POMC neurons. The different Ex4 responsiveness of their mPSCs indicates the heterogeneity of the POMC neurons of the ARC. In summary, our data demonstrate that in addition to its direct excitatory effect on the POMC neurons, GLP-1 signaling also facilitates the presynaptic input of these cells by acting on presynaptically localized GLP-1R.

Faecal microbiota transplantation for Clostridium difficile infection using a lyophilized inoculum from non-related donors: A case series involving 19 patients.

Faecal microbiota transplantation (FMT) has been reported to be effective in treating relapsing of refractory Clostridium difficile infections, although some practical barriers are limiting its widespread use. In this study, our objective was to evaluate the rate of resolution of diarrhea following administration of lyophilized and resolved FMT via a nasogastric (NG) tube. We recruited 19 patients suffered from laboratory-confirmed C. difficile infection. Each of them was treated by lyophilized and resolved inoculum through a NG tube. One participant succumbed following the procedure due to unrelated diseases. Out of 18 cases, 15 patients reportedly experienced a resolution of the symptoms. One patient was treated with another course of antibiotics, and two of the non-responders were successfully retreated with another course of FMT utilizing a lyophilized inoculum. Notably, no significant adverse activities were observed. In accordance to our clinical experiences, a patient will likely benefit from FMT treatment including lyophilized inoculum.

Experiences with fecal microbiota transplantation in Clostridium difficile infections via upper gastrointestinal tract.

Dramatic changes in the epidemiology of Clostridium difficile infections have been reported from the western world in the past decade. The proportion of severe cases is significantly elevating and clinicians now have to contend with the problem of additional and more frequent episodes of recurrences including an upward trend in the mortality rate. This situation led us to investigate the possibility of the fecal microbiota transplantation (FMT). An amount of 100 ml of fecal microbiota solution was instilled into a nasojejunal (NJ) tube in 16 cases and into a nasogastric (NG) tube in 44 cases. In all of the cases, where the solution was instilled via nasojejunal tubes, the symptoms resolved within 24 h. We did not note any recurrences in this group. When the material was flushed in through nasogastric tubes, the symptoms resolved in 39 (88.64%) cases within 24 h. In this group, we have experienced a recurrent episode of C. difficile infection in five (11.36%) cases. Three of them were cured with a second transplantation. We have found that in our practice the upper gastrointestinal tract methods had the primary cure rate of 91.67%, whereas the secondary cure rate is 96.67%. When we compared the NJ and NG methods, we have found that the differences in the outcomes are not significant statistically (p = 0.3113 using Fisher's exact probability test). In conclusion, FMT proved to be very effective, particularly in recurrent infections and in cases where conventional treatment had failed.

Tesmilifene modifies brain endothelial functions and opens the blood-brain/blood-glioma barrier.

Tesmilifene, a tamoxifen analog with antihistamine action, has chemopotentiating properties in experimental and clinical cancer studies. In our previous works, tesmilifene increased the permeability of the blood-brain barrier (BBB) in animal and culture models. Our aim was to investigate the effects of tesmilifene on brain microvessel permeability in the rat RG2 glioma model and to reveal its mode of action in brain endothelial cells. Tesmilifene significantly increased fluorescein extravasation in the glioma. Short-term treatment with tesmilifene reduced the resistance and increased the permeability for marker molecules in a rat triple co-culture BBB model. Tesmilifene also affected the barrier integrity in brain endothelial cells co-cultured with RG2 glioblastoma cells. Tesmilifene inhibited the activity of P-glycoprotein and multidrug resistance-associated protein-1 efflux pumps and down-regulated the mRNA expression of tight junction proteins, efflux pumps, solute carriers, and metabolic enzymes important for BBB functions. Among the possible signaling pathways that regulate BBB permeability, tesmilifene activated the early nuclear translocation of NFκB. The MAPK/ERK and PI3K/Akt kinase pathways were also involved. We demonstrate for the first time that tesmilifene increases permeability marker molecule extravasation in glioma and inhibits efflux pump activity in brain endothelial cells, which may have therapeutic relevance. Tesmilifene, a chemopotentiator in experimental and clinical cancer studies increases vascular permeability in RG2 glioma in rats and permeability for marker molecules in a culture model of the blood-brain barrier. Tesmilifene inhibits the activity of efflux pumps and down-regulates the mRNA expression of tight junction proteins, transporters, and metabolic enzymes important for the blood-brain barrier functions, which may have therapeutic relevance.

Structural background for serological cross-reactivity between bacteria of different enterobacterial serotypes.

The structure of the oligosaccharide repeating units of endotoxins from Gram-negative bacteria is characteristic for the different serogroups and serotypes of bacteria. Detailed examination of the cross-reactions of three enterobacterial serotypes, Proteus morganii O34, Escherichia coli O111, and Salmonella enterica sv. Adelaide O35, was performed using sensitive tests (ELISA, immunoblotting). Fine differences between the endotoxins of the bacteria were detected using silver staining of SDS-PAGE gels and chip-technology for the intact lipopolysaccharides (LPSs). The compositions of the O-specific polysaccharides of LPSs extracted from the bacteria were studied, and it was proven that the three cross-reacting bacteria contain O-antigens built from the same monosaccharides, namely colitoses linked to glucose, galactose, and N-acetyl-galactosamine. The NMR and GC-MS studies revealed that the most probable component for the cross-reaction is the rare sugar, colitose.

[Experience with fecal transplantation in the treatment of Clostridium difficile infection]. / Clostridium difficile-fertozések széklettranszplantációval való kezelése során nyert tapasztalataink.

INTRODUCTION: During the past years a dramatic change has been observed in the epidemiology of Clostridium difficile infections. AIM: The aim of the authors was to investigate the possibility of the fecal microbiota transplantation and study differences, if any, in the success rate of the two different upper gastrointestinal tract method. METHOD: 100 ml of fecal microbiota solution was instilled via a nasoduodenal tube in 15 cases and a nasogastric tube in 15 cases. The authors defined the primary cure rate as the percentage of cases in which the symptoms disappeared without recurrence within 6 weeks after the first fecal microbiota transplantation, while secondary cure rate was calculated as the percentage of cases in which the symptoms resolved after the second fecal microbiota transplantation. RESULTS: It was found that fecal microbiota transplantation applied via the nasoduodenal tube resulted in a 100% primary cure rate. With the use of the nasogastric tube, the primary and secondary cure rate were 80% and 93.3%, respectively. Fecal microbiota transplantation via the upper gastrointestinal tract was found to have an overall primary cure rate of 90.0% and a secondary cure rate of 96.7%. CONCLUSIONS: Fecal microbiota transplantation proved to be very effective, particularly in recurrent infections and cases where conventional treatment failed.

Encapsulation protocol for fecal microbiota transplantation.

Introduction: Clostridioides difficile infections (CDI) continue to pose a challenge for clinicians. Fecal microbiota transplantation (FMT) is an effective treatment option in CDI. Furthermore, recent and ongoing studies suggest potential benefits of FMT in other diseases as well. Methods: We would like to present a novel protocol for encapsulation of lyophilized fecal material. Our method provides with better compliance as well as improved flexibility, storage and safety. Results: FMT was conducted in 28 patients with an overall success rate of 82,14% using apsules containing lyophilized stool. 16 of patients were given capsules with lessened bacteria counts. The success rate in this group was 93,75%. Discussion: The results highlight the still unanswered questions about the mechanism of action and contribute to a wider use of FMT in the clinical praxis and in research.

GLP-1 Receptor Signaling Has Different Effects on the Perikarya and Axons of the Hypophysiotropic Thyrotropin-Releasing Hormone Synthesizing Neurons in Male Mice.

Background: Glucagon-like peptide 1 (GLP-1) is involved in the regulation of energy and glucose homeostasis. As GLP-1 has similar effects on the energy homeostasis as the hypophysiotropic thyrotropin-releasing hormone (TRH) neurons that regulate the hypothalamic-pituitary-thyroid (HPT) axis, we raised the possibility that the TRH neurons are involved in the mediation of the effects of GLP-1. Therefore, the relationship and interaction of the GLP-1 system and the TRH neurons of the hypothalamic paraventricular nucleus (PVN) were studied. Methods: To examine the anatomical and functional relationship of TRH neurons and the GLP-1 system in the PVN, immunocytochemistry, in situ hybridization, in vitro patch-clamp electrophysiology, metabolic phenotyping, and explant experiments were performed. Results: Our data demonstrate that the TRH neurons of the PVN are innervated by GLP-1 producing neurons and express the GLP-1 receptor (GLP-1R). However, not only do the GLP-1-innervated TRH neurons express GLP-1R but the receptor is also present in the axons of the hypophysiotropic TRH neurons in the blood-brain barrier free median eminence (ME) suggesting that peripherally derived GLP-1 may also influence the TRH neurons. In vitro, GLP-1 increased the firing rate of TRH neurons and depolarized them. In addition, GLP-1 directly stimulated the GABAergic input of a population of TRH neurons. Furthermore, GLP-1 inhibited the release of TRH from the hypophysiotropic axons in the ME. In vivo, peripheral GLP-1R agonist administration markedly inhibited the food intake and the energy expenditure, but had no effect on the TRH expression in the PVN and resulted in lower circulating free T4 levels. Conclusions: Our results indicate that GLP-1R activation has a direct stimulatory effect on TRH neurons in the PVN, but the activation of GLP-1R may also inhibit TRH neurons by facilitating their inhibitory inputs or by inhibiting the axon terminals of these cells in the ME. The innervation of TRH neurons by GLP-1 neurons suggests that TRH neurons might be influenced by both circulating GLP-1 and by GLP-1 neurons of the nucleus tractus solitarii. The lack of GLP-1R agonist-induced regulation of TRH neurons in vivo suggests that the HPT axis does not mediate the GLP-1R agonist-induced weight loss.

Endocannabinoid-mediated long-term depression of afferent excitatory synapses in hippocampal pyramidal cells and GABAergic interneurons.

Although endocannabinoids have emerged as essential retrograde messengers in several forms of synaptic plasticity, it remains controversial whether they mediate long-term depression (LTD) of glutamatergic synapses onto excitatory and inhibitory neurons in the hippocampus. Here, we show that parvalbumin- and somatostatin/metabotropic glutamate receptor 1(a) (mGlu(1a))-positive GABAergic interneurons express diacylglycerol lipase-α (DGL-α), a synthesizing enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), albeit at lower levels than principal cells. Moreover, this lipase accumulates postsynaptically around afferent excitatory synapses in all three cell types. To address the role of retrograde 2-AG signaling in LTD, we investigated two forms: (1) produced by postsynaptic spiking paired with subsequent presynaptic stimulation or (2) induced by group I mGlu activation by (S)-3,5-dihydroxyphenylglycine (DHPG). Neither form of LTD was evoked in the presence of the mGlu(5) antagonist MPEP [2-methyl-6-(phenylethynyl)-pyridine], the DGL inhibitor THL [N-formyl-l-leucine (1S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester], or the intracellularly applied Ca(2+) chelator BAPTA in CA1 pyramidal cells, fast-spiking interneurons (representing parvalbumin-containing cells) and interneurons projecting to stratum lacunosum-moleculare (representing somatostatin/mGlu(1a)-expressing interneurons). Both forms of LTD were completely absent in CB(1) cannabinoid receptor knock-out mice, whereas pharmacological blockade of CB(1) led to inconsistent results. Notably, in accordance with their lower DGL-α level, a higher stimulation frequency or higher DHPG concentration was required for LTD induction in interneurons compared with pyramidal cells. These findings demonstrate that hippocampal principal cells and interneurons produce endocannabinoids to mediate LTD in a qualitatively similar, but quantitatively different manner. The shifted induction threshold implies that endocannabinoid-LTD contributes to cortical information processing during distinct network activity patterns in a cell type-specific manner.

[IL28B CC genotype: a protective factor and predictor of the response to interferon treatment in chronic hepatitis C virus infection]. / IL28B CC genotípus: védo tényezo és az interferonválasz prediktora krónikus hepatitis-C-vírus infekcióban.

INTRODUCTION: In chronic hepatitis C-virus infection the possible role of gene variants encoding cytokines has become the focus of interest. AIM: The aim of the study was to investigate the effect of IL28B polymorphisms on the outcome of chronic hepatitis C-virus genotype 1 infection in the Hungarian population. In addition, the association between IL28B genotypes and the Th1/Th2 cytokine production of activated peripheral blood monocytes and lymphocytes was evaluated. METHOD: Total of 748 chronic hepatitis C-virus genotype 1 positive patients (365 males and 383 females, aged between 18 and 82 years; mean age, 54±10 years) were enrolled, of which 420 patients were treated with pegylated interferon plus ribavirin for 24-72 weeks. Of the 420 patients, 195 patients (46.4%) achieved sustained virological response. The IL28B rs12979860 polymorphism was determined using Custom Taqman SNP Genotyping Assays (Applied Biosystems, Life Technologies, Foster, CA, USA). For cytokine studies, tumour necrosis factor-α, interleukin-2, interferon-γ, interleukin-2 and interleukin-4 production by LPS-stimulated monocytes and PMA-ionomycine activated lymphocytes were measured from the supernatant of the cells obtained from 40 hepatitis C-virus infected patients, using FACS-CBA Becton Dickinson test. The cytokine levels were compared in patients with different (CC, CT, TT) IL28B genotypes. RESULTS: The IL28B rs12979860 CC genotype occurred in lower frequency in hepatitis C-virus infected patients than in healthy controls (26.1% vs 51.4%, OR 0.333, p<0.001). Patients carried the T allele with higher frequency than controls (73.9%, vs 48.6%, OR 3.003, p<0.001). Pegylated interferon plus ribavirin treated patients with the IL28B CC genotype achieved higher sustained virological response rate than those with the CT genotype (58.6% vs 40.8%, OR 2.057, p = 0.002), and those who carried the T allele (41.8%, OR1.976, p = 0.002). LPS-induced TLR-4 activation of monocytes resulted in higher tumour necrosis factor-α production in patients with the IL28B CC genotype compared to non-CC individuals (p<0.01). Similarly, increased tumour necrosis factor-α, interleukin-2 and interferon-γ production by lymphocytes was found in the IL28B CC carriers (p<0.01) CONCLUSIONS: The IL28B CC genotype exerts protective effect against chronic hepatitis C-virus infection and may be a pretreatment predictor of sustained virological response during interferon-based antiviral therapy. The IL28B CC polymorphism is associated with increased Th1 cytokine production of activated peripheral blood monocytes and lymphocytes, which may play a role in interferon-induced rapid immune control and sustained virological response of pegylated interferon plus ribavirin treated patients.

Migraine as a Disease Associated with Dysbiosis and Possible Therapy with Fecal Microbiota Transplantation.

Migraine is a painful neurological condition characterized by severe pain on one or both sides of the head. It may be linked to changes in the gut microbiota, which are influenced by antibiotic use and other factors. Dysbiosis, which develops and persists as a result of earlier antibiotic therapy, changes the composition of the intestinal flora, and can lead to the development of various diseases such as metabolic disorders, obesity, hematological malignancies, neurological or behavioral disorders, and migraine. Metabolites produced by the gut microbiome have been shown to influence the gut-brain axis. The use of probiotics as a dietary supplement may reduce the number and severity of migraine episodes. Dietary strategies can affect the course of migraines and are a valuable tool for improving migraine management. With fecal microbiota transplantation, gut microbial restoration is more effective and more durable. Changes after fecal microbiota transplantation were studied in detail, and many data help us to interpret the successful interventions. The microbiological alteration of the gut microflora can lead to normalization of the inflammatory mediators, the serotonin pathway, and influence the frequency and intensity of migraine pain.

The Role of the Intestinal Microbiome in Multiple Sclerosis-Lessons to Be Learned from Hippocrates.

Based on recent advances in research of chronic inflammatory conditions, there is a growing body of evidence that suggests a close correlation between the microbiota of the gastrointestinal tract and the physiologic activity of the immune system. This raises the idea that disturbances of the GI ecosystem contribute to the unfolding of chronic diseases including neurodegenerative pathologies. Here, we overview our current understanding on the putative interaction between the gut microbiota and the immune system from the aspect of multiple sclerosis, one of the autoimmune conditions accompanied by severe chronic neuroinflammation that affects millions of people worldwide.

Adverse Reactions after Booster SARS-CoV-2 Vaccination Have Less Impact on Antibody Response than after Basic Vaccination Scheme.

BACKGROUND: It is known that adverse reactions following SARS-CoV-2 vaccinations show a positive correlation with the subsequent antibody titer. However, it is not clear how the adverse reactions following the booster vaccination are related to the antibody levels that can be measured after a 3rd dose. The primary goal of this study was to investigate whether the adverse reactions following the booster vaccination show a correlation with subsequent antibody levels. METHODS: Adverse reactions occurring within 7 days after the 3rd vaccination were recorded and the anti-SARS-CoV-2 spike protein immunoglobulin (Ig) level in the venous blood was measured on post-vaccination 14th, 60th and 120th days. RESULTS: A total of 218 volunteers were included in the study. MAIN FINDINGS: (i) The adverse reactions that appeared after the booster dose did not show a positive correlation with the subsequent antibody level, except a correlation in the case of fever; (ii) there were more symptomatic patients in the group receiving heterologous booster vaccine, (iii) fever after the 2nd dose was independently associated with a reduction in the likelihood of COVID-19 positivity after the booster dose. CONCLUSION: No adverse reactions, but fever showed a correlation with the antibody level after the booster SARS-CoV-2 vaccine.

Efficacy of lyophilised bacteria-rich faecal sediment and supernatant with reduced bacterial count for treating patients with Clostridioides difficile Infection - A novel method for capsule faecal microbiota transfer.

Background and aims: Faecal microbiota transfer (FMT) has managed to earn its place in the Clostridioides difficile infection (CDI) guidelines by having comparable efficacy and recurrence rate of fidaxomicin. After more than 100 successful FMT administration through nasogastric tube, we started using hard gelatine capsules filled with lyophilised faecal sediment and supernatant. Our main question was whether uncoated capsules (containing faecal sediment or supernatant) are comparable to the widely used nasogastric tubes in CDI. We also investigated the effect of storage and time on the survival rate of bacteria in the samples. Methods: We compared the efficacy of our capsules to other treatment options of CDI at the Department of Infectology at the University of Pécs (Hungary). For our study, stool was collected from a single donor. We treated 10 patients with relapsing CDI, 5 of them received supernatant, 5 received sediment. Donor samples were stored on 4 different temperatures and tested to determine the survival rates of bacteria. As pilot projects, we also assessed the changes of bacterial taxa, protein- and lipid compositions. Moreover, we selected 4 patients to compare their samples prior and after FMT by using microbiome (16S amplicon sequencing), protein, and lipid analyses. Results: 4 out of the 5 patients who received supernatant became symptomless within 2 days after FMT. In the sediment group 3 out of 5 patients were cured from CDI. Comparing the supernatant to the sediment, we found significantly lower number of colony-forming units in the supernatant. We found that -80°C is the most suitable temperature to store the samples. The stool lipid profiles of recipients showed a more diverse composition after FMT, and changes in the stool protein profiles were observed as well. In the microbiome analysis, we observed an increase in the alpha diversity after FMT. Conclusions: Our study of 10 patients showed good efficacy of lyophilised faecal supernatant using capsules. The single donor approach proved to be effective in our investigation. A significantly lower CFU number was sufficient for the effect, the separation can be achieved by widely available instruments. For storage temperature, -20°C was sufficient in our clinical practice.

[Cholangitis and cholecystitis: diagnostic criteria and management]. / Epeút- és epehólyag-gyulladás: diagnosztikus kritériumok és terápia.

In developed countries, diseases of the gallbladder and the biliary tract count as some of the most frequent gastrointestinal disorders. The inflammation of the gallbladder/biliary tree is a potentially severe, even lethal condition that requires rapid diagnosis and early multidisciplinary approach to be treated. Although the frequency of these diseases is high, the treatment is not unified in Hungary yet. The aim of the evidence-based recommendation is to clarify the diagnostic criteria and severity grading of these diseases and to highlight the indications and rules of proper application of the numerous available therapeutic interventions. The recent guideline is based on the consensus of the Board members of the Endoscopic Section of the Hungarian Gastroenterology Society in contribution with renown experts of surgery, infectology as well as interventional radiology and it counts as a clear and easy applicable guide during the all-day healthcare practice. Our guidelines are based on Tokyo guidelines established on the basis of the consensus reached in the International Consensus Meeting held in Tokyo which were revised in 2013 (TG13) and in 2018 (TG18). Orv Hetil. 2023; 164(20): 770-787.

Morphoelectric and transcriptomic divergence of the layer 1 interneuron repertoire in human versus mouse neocortex.

Neocortical layer 1 (L1) is a site of convergence between pyramidal-neuron dendrites and feedback axons where local inhibitory signaling can profoundly shape cortical processing. Evolutionary expansion of human neocortex is marked by distinctive pyramidal neurons with extensive L1 branching, but whether L1 interneurons are similarly diverse is underexplored. Using Patch-seq recordings from human neurosurgical tissue, we identified four transcriptomic subclasses with mouse L1 homologs, along with distinct subtypes and types unmatched in mouse L1. Subclass and subtype comparisons showed stronger transcriptomic differences in human L1 and were correlated with strong morphoelectric variability along dimensions distinct from mouse L1 variability. Accompanied by greater layer thickness and other cytoarchitecture changes, these findings suggest that L1 has diverged in evolution, reflecting the demands of regulating the expanded human neocortical circuit.

Quantitative microfluidic analysis of S- and R-type endotoxin components with chip capillary electrophoresis.

A novel, fast, and sensitive ME method was developed to analyze and differentiate the smooth (S) and rough (R) type bacterial endotoxin components labeled covalently with a fluorescent dye. The quantitative analysis of purified lipopolysaccharides, or partially purified samples from whole-cell lysates becomes possible with this method. Two groups with three sub-groups in the first group of S-type lipopolysaccharides can be classified based on the electrophoretic profiles. The LOD of the endotoxins from S- and R-type Gram-negative bacteria was found to be 2.6 ng and 6.9 ng, respectively. This method is capable to replace the commonly used SDS-PAGE combined with silver staining.

Hepatitis C Screening and Treatment Program in Hungarian Prisons in the Era of Direct Acting Antiviral Agents.

A hepatitis C virus (HCV) screening and treatment program was conducted in Hungarian prisons on a voluntary basis. After HCV-RNA testing and genotyping for anti-HCV positives, treatments with direct-acting antiviral agents were commenced by hepatologists who visited the institutions monthly. Patients were supervised by the prisons' medical staff. Data were retrospectively collected from the Hungarian Hepatitis Treatment Registry, from the Health Registry of Prisons, and from participating hepatologists. Eighty-four percent of Hungarian prisons participated, meaning a total of 5779 individuals (28% of the inmate population) underwent screening. HCV-RNA positivity was confirmed in 317/5779 cases (5.49%); 261/317 (82.3%) started treatment. Ninety-nine percent of them admitted previous intravenous drug use. So far, 220 patients received full treatment and 41 patients are still on treatment. Based on the available end of treatment (EOT) + 24 weeks timepoint data, per protocol sustained virologic response rate was 96.8%. In conclusion, the Hungarian prison screening and treatment program, with the active participation of hepatologists and the prisons' medical staff, is a well-functioning model. Through the Hungarian experience, we emphasize that the "test-and-treat" principle is feasible and effective at micro-eliminating HCV in prisons, where infection rate, as well as history of intravenous drug usage, are high.

Screening and treatment of hepatitis C virus in prisons: 10 years of experience / A hepatitis C-vírus szurésének és kezelésének 10 éves tapasztalata a börtönökben

Introduction and objective: Two-thirds of patients with hepatitis C virus (HCV) infection are unaware of their infection in the European Union. The WHO aims to reduce the number of new cases of chronic hepatitis by 90% by 2030. The proportion of people infected with HCV in prisons can be up to ten times higher compared to the general population. This article is a summary of the results of the HCV screening carried out in the Hungarian prisons between 2007 and 2017. Method: Screening of anti-HCV antibodies has been performed on a voluntary basis followed by HCV PCR and genotyping in positive cases. After obtaining written informed consent from the patients, treatment was started. Treatments were performed under the guidance of hepatologists in collaboration with prison medical staff. Results: HCV screening programs and treatments are in place in 84% of Hungarian prisons. A total of 25 384 patients underwent anti-HCV screening. Anti-HCV positive result was detected in 6.6% and HCV PCR positivity was confirmed in 3.8% of the screened inmates. 55.2% patients from the HCV PCR positive population were put on treatment. Only 143 patients received full treatment, while 162 (42.6%) treatments were terminated prematurely, and the duration of treatment was unknown in 75 patients. Based on the results available on the 24th week after the end of treatment, sustained virologic response rate was 88%. Discussion: Education of patients and collaboration between hepatologists and prison medical staff play an important role in the successful result of treatment. Conclusion: Our experience demonstrates that the test and treat principle is feasible and effective at microeliminating HCV in prisons.