ERCP using balloon-assisted endoscopes versus EUS-guided treatment for common bile duct stones in Roux-en-Y gastrectomy.

BACKGROUND AND AIMS: We compared ERCP using a balloon-assisted endoscope (BE-ERCP) with EUS-guided antegrade treatment (EUS-AG) for removal of common bile duct (CBD) stones in patients with Roux-en-Y (R-Y) gastrectomy. METHODS: Consecutive patients who had previous R-Y gastrectomy undergoing BE-ERCP or EUS-AG for CBD stones in 16 centers were retrospectively analyzed. RESULTS: BE-ERCP and EUS-AG were performed in 588 and 59 patients, respectively. Baseline characteristics were similar, except for CBD diameter and angle. The technical success rate was 83.7% versus 83.1% (P = .956), complete stone removal rate was 78.1% versus 67.8% (P = .102), and early adverse event rate was 10.2% versus 18.6% (P = .076) in BE-ERCP and EUS-AG, respectively. The mean number of endoscopic sessions was smaller in BE-ERCP (1.5 ± .8 vs 1.9 ± 1.0 sessions, P = .01), whereas the median total treatment time was longer (90 vs 61.5 minutes, P = .001). Among patients with biliary access, the complete stone removal rate was significantly higher in BE-ERCP (93.3% vs 81.6%, P = .009). Negative predictive factors were CBD diameter ≥15 mm (odds ratio [OR], .41) and an angle of CBD <90 degrees (OR, .39) in BE-ERCP and a stone size ≥10 mm (OR, .07) and an angle of CBD <90 degrees (OR, .07) in EUS-AG. The 1-year recurrence rate was 8.3% in both groups. CONCLUSIONS: Effectiveness and safety of BE-ERCP and EUS-AG were comparable in CBD stone removal for patients after R-Y gastrectomy, but complete stone removal after technical success was superior in BE-ERCP.

Corticocortical innervation subtypes of layer 5 intratelencephalic cells in the murine secondary motor cortex.

Feedback projections from the secondary motor cortex (M2) to the primary motor and sensory cortices are essential for behavior selection and sensory perception. Intratelencephalic (IT) cells in layer 5 (L5) contribute feedback projections to diverse cortical areas. Here we show that L5 IT cells participating in feedback connections to layer 1 (L1) exhibit distinct projection patterns, genetic profiles, and electrophysiological properties relative to other L5 IT cells. An analysis of the MouseLight database found that L5 IT cells preferentially targeting L1 project broadly to more cortical regions, including the perirhinal and auditory cortices, and innervate a larger volume of striatum than the other L5 IT cells. We found experimentally that in upper L5 (L5a), ER81 (ETV1) was found more often in L1-preferring IT cells, and in IT cells projecting to perirhinal/auditory regions than those projecting to primary motor or somatosensory regions. The perirhinal region-projecting L5a IT cells were synaptically connected to each other and displayed lower input resistance than contra-M2 projecting IT cells including L1-preferring and nonpreferring cells. Our findings suggest that M2-L5a IT L1-preferring cells exhibit stronger ER81 expression and broader cortical/striatal projection fields than do cells that do not preferentially target L1.

Suppression of joint destruction with subcutaneous tocilizumab for Japanese patients with rheumatoid arthritis in clinical practice.

Objectives: To investigate the efficacy of suppressing joint destruction with subcutaneous tocilizumab (TCZ-SC) for Japanese rheumatoid arthritis (RA) patients in the real-world clinical setting.Methods: This 1-year prospective, multicenter study included 110 RA patients in whom TCZ-SC was newly initiated. Primary endpoint was the change from baseline in vdH-modified total Sharp score (mTSS) at week 52. Structural remission was defined as yearly mTSS of 0.5 or less. Disease activity was evaluated using the disease activity score (DAS28-ESR) and clinical disease activity index (CDAI).Results: At baseline, the patients' mean age was 58.6 years, and the mean disease duration was 10.6 years. The proportion of patients who were naïve for biologics was 44.5%, and 64.5% concomitantly received methotrexate. The yearly mTSS showed significant improvement from 9.41 before TCZ-SC initiation to -0.15 after 52 weeks. The structural remission rate was 76.1%. After 52 weeks, the DAS28-ESR and CDAI remission rates were 52% and 21%, respectively. Although the previous usage of biologics and baseline disease activity significantly affected the clinical remission, no factors with significant effects on structural remission were identified.Conclusion: These findings support the efficacy of TCZ-SC in suppressing disease activity as well as joint destruction over a 1-year period.

Control of excitatory hierarchical circuits by parvalbumin-FS basket cells in layer 5 of the frontal cortex: insights for cortical oscillations.

The cortex contains multiple neuron types with specific connectivity and functions. Recent progress has provided a better understanding of the interactions of these neuron types as well as their output organization particularly for the frontal cortex, with implications for the circuit mechanisms underlying cortical oscillations that have cognitive functions. Layer 5 pyramidal cells (PCs) in the frontal cortex comprise two major subtypes: crossed-corticostriatal (CCS) and corticopontine (CPn) cells. Functionally, CCS and CPn cells exhibit similar phase-dependent firing during gamma waves but participate in two distinct subnetworks that are linked unidirectionally from CCS to CPn cells. GABAergic parvalbumin-expressing fast-spiking (PV-FS) cells, necessary for gamma oscillation, innervate PCs, with stronger and global inhibition to somata and weaker and localized inhibitions to dendritic shafts/spines. While PV-FS cells form reciprocal connections with both CCS and CPn cells, the excitation from CPn to PV-FS cells exhibits short-term synaptic dynamics conducive for oscillation induction. The electrical coupling between PV-FS cells facilitates spike synchronization among PV-FS cells receiving common excitatory inputs from local PCs and inhibits other PV-FS cells via electrically communicated spike afterhyperpolarizations. These connectivity characteristics can promote synchronous firing in the local networks of CPn cells and firing of some CCS cells by anode-break excitation. Thus subsets of L5 CCS and CPn cells within different levels of connection hierarchy exhibit coordinated activity via their common connections with PV-FS cells, and the resulting PC output drives diverse neuronal targets in cortical layer 1 and the striatum with specific temporal precision, expanding the computational power of the cortical network.

Multiple layer 5 pyramidal cell subtypes relay cortical feedback from secondary to primary motor areas in rats.

Higher-order motor cortices, such as the secondary motor area (M2) in rodents, select future action patterns and transmit them to the primary motor cortex (M1). To better understand motor processing, we characterized "top-down" and "bottom-up" connectivities between M1 and M2 in the rat cortex. Somata of pyramidal cells (PCs) in M2 projecting to M1 were distributed in lower layer 2/3 (L2/3) and upper layer 5 (L5), whereas PCs projecting from M1 to M2 had somata distributed throughout L2/3 and L5. M2 afferents terminated preferentially in upper layer 1 of M1, which also receives indirect basal ganglia output through afferents from the ventral anterior and ventromedial thalamic nuclei. On the other hand, M1 afferents terminated preferentially in L2/3 of M2, a zone receiving indirect cerebellar output through thalamic afferents from the ventrolateral nucleus. While L5 corticopontine (CPn) cells with collaterals to the spinal cord did not participate in corticocortical projections, CPn cells with collaterals to the thalamus contributed preferentially to connections from M2 to M1. L5 callosal projection (commissural) cells participated in connectivity between M1 and M2 bidirectionally. We conclude that the connectivity between M1 and M2 is directionally specialized, involving specific PC subtypes that selectively target lamina receiving distinct thalamocortical inputs.

Remission in patients with active rheumatoid arthritis by tocilizumab treatment in routine clinical practice: results from 3 years of prospectively registered data.

OBJECTIVES: This study aimed to evaluate the remission in rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ), based on prospectively registered data in clinical practice. METHODS: We studied 114 consecutive RA patients treated with TCZ for an average of 3.5 years. Remission was evaluated by using the EULAR criteria and the new ACR/EULAR Boolean-based criteria. RESULTS: Among 114 patients (average age 52.2 years; average disease duration 10.6 years), 76 (67 %) had previously received anti-TNF biologics. Mean baseline DAS28-ESR of 5.4 and improved to 2.4 at 36 months. Overall, DAS28-ESR <2.6 was attained by 66.7 %, while ACR/EULAR remission was attained by 35.1 %. ACR/EULAR remission rate was significantly higher in the patients who were biologics-naïve and had good response at the first month. Among 23 patients who completed the treatment for 3 years and had ACR/EULAR remission at 1 year, 15 (65 %) remained in the remission and 16 (70 %) had a DAS28-ESR <2.6 at the final follow-up. The retention rate at 36 months was 68.2 %. CONCLUSIONS: In patients with RA, TCZ is highly effective for both biologics-naïve patients and patients previously exposed to biologics, achieving a high remission rate and drug continuation rate (68.2 %) in clinical practice.

Oligodendrocyte-derived LGI3 and its receptor ADAM23 organize juxtaparanodal Kv1 channel clustering for short-term synaptic plasticity.

Neurodevelopmental disorders, such as intellectual disability (ID), epilepsy, and autism, involve altered synaptic transmission and plasticity. Functional characterization of their associated genes is vital for understanding physio-pathological brain functions. LGI3 is a recently recognized ID-associated gene encoding a secretory protein related to an epilepsy-gene product, LGI1. Here, we find that LGI3 is uniquely secreted from oligodendrocytes in the brain and enriched at juxtaparanodes of myelinated axons, forming nanoscale subclusters. Proteomic analysis using epitope-tagged Lgi3 knockin mice shows that LGI3 uses ADAM23 as a receptor and selectively co-assembles with Kv1 channels. A lack of Lgi3 in mice disrupts juxtaparanodal clustering of ADAM23 and Kv1 channels and suppresses Kv1-channel-mediated short-term synaptic plasticity. Collectively, this study identifies an extracellular organizer of juxtaparanodal Kv1 channel clustering for finely tuned synaptic transmission. Given the defective secretion of the LGI3 missense variant, we propose a molecular pathway, the juxtaparanodal LGI3-ADAM23-Kv1 channel, for understanding neurodevelopmental disorders.

Common excitatory synaptic inputs to electrically connected cortical fast-spiking cell networks.

Cortical fast-spiking (FS) interneurons are electrically interconnected through gap junctions and form dendritic net structures extending over different functional columns. Here we investigated how pyramidal cells regulate FS cell network activity. Using paired recordings and glutamate puff stimulations, we found that FS cell pairs connected by electrical synapses shared common inputs from surrounding pyramidal cells more frequently than those unconnected or connected only by chemical synapses. Experimental and simulation results suggest that activity spread evoked by common inputs to electrically connected FS cells depends on network state. When cells were in the depolarized state, common inputs to electrically connected cells enhanced spike induction and induced inhibitory effects in surrounding FS cells. By contrast, in the hyperpolarized state, either sub- or suprathreshold inputs produced depolarizing potentials in nearby cells. Our results suggest that globally connected FS cell networks are locally regulated by pyramidal cells in an electrical connection- and network state-dependent manner.

Remission in patients with active rheumatoid arthritis by tocilizumab treatment in routine clinical practice: results from 3 years of prospectively registered data.

OBJECTIVES: This study aimed to evaluate the remission in rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ), based on prospectively registered data in clinical practice. METHODS: We studied 114 consecutive RA patients treated with TCZ for an average of 3.5 years. Remission was evaluated by using the EULAR criteria and the new ACR/EULAR Boolean-based criteria. RESULTS: Among 114 patients (average age 52.2 years; average disease duration 10.6 years), 76 (67 %) had previously received anti-TNF biologics. Mean baseline DAS28-ESR of 5.4 and improved to 2.4 at 36 months. Overall, DAS28-ESR <2.6 was attained by 66.7 %, while ACR/EULAR remission was attained by 35.1 %. ACR/EULAR remission rate was significantly higher in the patients who were biologics-naïve and had good response at the first month. Among 23 patients who completed the treatment for 3 years and had ACR/EULAR remission at 1 year, 15 (65 %) remained in the remission and 16 (70 %) had a DAS28-ESR <2.6 at the final follow-up. The retention rate at 36 months was 68.2 %. CONCLUSIONS: In patients with RA, TCZ is highly effective for both biologics-naïve patients and patients previously exposed to biologics, achieving a high remission rate and drug continuation rate (68.2 %) in clinical practice.

Usefulness of Intraductal Placement of a Dumbbell-Shaped Fully Covered Self-Expandable Metal Stent for Post-Cholecystectomy Bile Leaks.

Background and aims: In the treatment of post-cholecystectomy bile leaks, endoscopic naso-biliary drainage (ENBD) or biliary stenting using plastic stents is the standard of care. Fully covered self-expandable metal stent (FCSEMS) placement across the sphincter of Oddi is considered a salvage therapy for refractory cases, but pancreatitis and migration are the major concerns. Intraductal placement of a dumbbell-shaped FCSEMS (D-SEMS) could avoid these drawbacks of FCMSESs. In this retrospective study, we investigated the usefulness of intraductal placement of the D-SEMS for post-cholecystectomy bile leaks. Methods: Six patients who underwent intraductal placement of the D-SEMS for post-cholecystectomy bile leaks were enrolled. This method was performed as initial treatment in three patients and as salvage treatment in three ENBD refractory cases. Results: Technical and clinical successes were obtained in 6 (100%) patients and 5 (83%) patients, respectively. One clinically unsuccessful patient required laparoscopic peritoneal lavage. The early adverse event was one case of mild pancreatitis (17%). The median duration of the D-SEMS indwelling was 61 days (42-606 days) with no migration cases, all of which were successfully removed. The median follow-up after index ERCP was 761 (range: 161-1392) days with no cases of recurrent bile leaks. Conclusions: Intraductal placement of the D-SEMS for post-cholecystectomy bile leaks might be safe and effective even in refractory cases.

Endoscopic Ultrasound-Guided Gastrojejunostomy for Malignant Afferent Loop Syndrome Using a Fully Covered Metal Stent: A Multicenter Experience.

BACKGROUND: Endoscopic-ultrasound-guided gastrojejunostomy (EUS-GJ) can be a new alternative for patients with malignant afferent loop syndrome (MALS). However, a fully covered self-expandable metal stent (FCSEMS) has not been well investigated in this setting. METHODS: This is a multicenter retrospective cohort study. Consecutive patients that underwent EUS-GJ using a FCSEMS for MALS between April 2017 and November 2022 were enrolled. Primary outcomes were technical and clinical success rates. Secondary outcomes were adverse events, recurrent symptoms, and overall survival. RESULTS: Twelve patients (median age: 67.5 years (interquartile range: 58-74.8); 50% male) were included. The most common primary disease and type of previous surgery were pancreatic cancer (67%) and pancreatoduodenectomy (75%), respectively. Technical success and clinical success were achieved in all patients. Procedure-related adverse events occurred in one patient (8%) with mild peritonitis. During a median follow-up of 96.5 days, one patient (8%) had recurrent symptoms due to the EUS-GJ stent dysfunction; including biliary events unrelated to the EUS-GJ stent, five patients (42%) had recurrent events. The median overall survival was 137 days. Nine patients (75%) died due to disease progression. CONCLUSIONS: EUS-GJ with a FCSEMS seems safe and effective for MALS with high technical and clinical success rates and an acceptable recurrence rate.

A pilot study of Spring Stopper Stents: Novel partially covered self-expandable metallic stents with anti-migration properties for EUS-guided hepaticogastrostomy.

Background and Objectives: EUS-guided hepaticogastrostomy (EUS-HGS) is an effective salvage procedure when conventional endoscopic transpapillary biliary drainage is difficult or fails. However, the risk of stent migration into the abdominal cavity has not been resolved completely. In this study, we evaluated a newly developed partially covered self-expandable metallic stent (PC-SEMS) that has a spring-like anchoring function on the gastric side. Methods: This retrospective pilot study took place at four referral centers in Japan between October 2019 and November 2020. We enrolled 37 cases consecutively who underwent EUS-HGS for unresectable malignant biliary obstruction. Results: The rates of technical and clinical success were 97.3% and 89.2%, respectively. Technical failures included one case in which the stent was dislocated during the removal of the delivery system, requiring additional EUS-HGS on another branch. Early adverse events (AEs) were observed in four patients (10.8%): two with mild peritonitis (5.4%) and one each (2.7%) with fever and bleeding. No late AEs were observed during the mean follow-up period of 5.1 months. All recurrent biliary obstructions (RBOs) were stent occlusions (29.7%). The median cumulative time to RBO was 7.1 months (95% confidence interval, 4.3 to not available). Although stent migration in which the stopper was in contact with the gastric wall on follow-up computed tomography was observed in six patients (16.2%), no migration was observed. Conclusions: The newly developed PC-SEMS is feasible and safe for the EUS-HGS procedure. The spring-like anchoring function on the gastric side is an effective anchor preventing migration.

Suicidality in civilian women with PTSD: Possible link to childhood maltreatment, proinflammatory molecules, and their genetic variations.

Background: Posttraumatic stress disorder (PTSD) is a robust risk factor for suicide. Studies have suggested an association between suicide and elevated inflammatory markers, although such evidence in PTSD is scarce. Suicide risk, PTSD, and inflammatory molecules are all shown to be associated with childhood maltreatment and genetic factors. Methods: We examined the association between suicidal ideation/risk and inflammatory markers in 83 civilian women with PTSD, and explored the possible influence of childhood maltreatment and inflammatory genes. Suicidal ideation and risk were assessed using the Beck Depression Inventory-II and the Mini-International Neuropsychiatric Interview. Childhood maltreatment history was assessed with the Childhood Trauma Questionnaire (CTQ). Blood levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and high-sensitivity tumor necrosis factor-α were measured. Genetic polymorphisms of CRP rs2794520 and IL6 rs1800796 were genotyped. Results: Suicidal ideation was significantly positively correlated with hsCRP (p = 0.002) and IL-6 (p = 0.015) levels. Suicide risk weighted score was significantly positively correlated with hsCRP (p = 0.016) levels. The risk alleles of CRP rs2794520 and IL6 rs1800796 leading to increased respective protein levels were dose-dependently associated with higher risk of suicide (p = 0.007 and p = 0.029, respectively). The CTQ total score was significantly correlated with suicidal ideation and risk, but not with inflammatory marker levels. Furthermore, a multivariate regression analysis controlling for PTSD severity and potential confounders revealed that rs2794520 and rs1800796, but not hsCRP or IL-6 levels, significantly predicted suicidal ideation (p < 0.001) and risk (p = 0.007), respectively. Conclusion: Genetic variations within inflammatory genes might be useful in detecting PTSD patients at high risk of suicide.

Cell diversity and connection specificity between callosal projection neurons in the frontal cortex.

Recent advances have established that intralaminar and interlaminar excitatory networks between neocortical pyramidal cells are specialized into subnetworks. Here, we have investigated how the commissural system organizes the intracortical excitatory subnetworks to communicate between cortical hemispheres. Whole-cell recordings were obtained from callosal projection neurons [commissural (COM) cells], identified by in vivo injection of retrograde fluorescent tracer into one hemisphere, in rat frontal cortical slices. We found that layer V (L5) COM cells were heterogeneous in physiological and morphological properties that correlated with projection patterns to contralateral and ipsilateral cortical areas. The probability of synaptically connected pairs of L5 COM cells was higher in cell pairs of the same firing subtypes than that in different cell subtype pairs. In interlaminar connections, layer II/III (L2/3) COM cells preferentially innervated L5 COM cells. Moreover, pairs of the same L5 COM subtypes were more likely to share inputs from L2/3 COM cells than were different COM subtype cell pairs. In addition, common inputs from L2/3 COM cells were frequently observed in L5 pairs of corticopontine cells and given firing subtypes of COM cells. Our results suggest that callosal communications are achieved via several distinct COM cell subnetworks differentiated according to the ipsilateral corticocortical and subcortical projection patterns.

[Successful resuscitation in a life-threatening obstetric hemorrhagic patient with hematocrit 3%: a case report].

We report a postpartum woman who suffered from obstetric bleeding after caesarean section. Her lowest hematocrit was 3% when a large amount of blood was lost. "Guidelines for management of critical bleeding in obstetrics" published by the Japanese Society of Anesthesiologists and four related academic societies was helpful for the resuscitation of the parturient. A systematic approach was effective for the care of women with major obstetric hemorrhage.

Practical Tips for Safe and Successful Endoscopic Ultrasound-Guided Hepaticogastrostomy: A State-of-the-Art Technical Review.

Currently, endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) is widely performed worldwide for various benign and malignant biliary diseases in cases of difficult or unsuccessful endoscopic transpapillary cholangiopancreatography (ERCP). Furthermore, its applicability as primary drainage has also been reported. Although recent advances in EUS systems and equipment have made EUS-HGS easier and safer, the risk of serious adverse events such as bile leak and stent migration still exists. Physicians and assistants need not only sufficient skills and experience in ERCP-related procedures and basic EUS-related procedures such as fine needle aspiration and pancreatic fluid collection drainage, but also knowledge and techniques specific to EUS-HGS. This technical review mainly focuses on EUS-HGS with self-expandable metal stents for unresectable malignant biliary obstruction and presents the latest and detailed tips for safe and successful performance of the technique.

The Feasibility of Whole-Liver Drainage with a Novel 8 mm Fully Covered Self-Expandable Metal Stent Possessing an Ultra-Slim Introducer for Malignant Hilar Biliary Obstructions.

BACKGROUND: In the case of an unresectable malignant hilar biliary obstruction (MHBO), the optimal drainage method has not yet been established. Recently, an 8 mm, fully covered, self-expandable metal stent (FCSEMS) with an ultra-slim introducer has become available. In this article, the results of whole-liver drainage tests using this novel FCSEMS for MHBO are reported. METHODS: Unresectable MHBOs up to Bismuth IIIa with strictures limited to the secondary branches were eligible. The proximal end of the stent was placed in such a way as to avoid blocking the side branches, and the distal end was placed above the papilla when possible. Consecutive patients treated between April 2017 and January 2021 were retrospectively analyzed. The technical and functional success rates, rates and causes of recurrent biliary obstruction (RBO), time to RBO (TRBO), revision for RBO, and adverse events (AEs) were evaluated. RESULTS: Eleven patients (Bismuth I/II/IIIa: 1/7/3) were enrolled. Two stents were placed in nine patients and three were placed in two patients. Both the technical and functional success rates were 100%. RBO occurred in four (36%) patients due to sludge formation. Revision was performed for three patients, with the successful removal of all stents. The median TRBO was 187 days, and no late AEs other than the RBO occurred. Regarding the distal position of the stent, the RBO rate was significantly lower (14.3% vs. 75%, p = 0.041) and the cumulative TRBO was significantly longer (median TRBO: not reached vs. 80 days, p = 0.031) in the case of the placement above the papilla than the placement across the papilla. CONCLUSION: For unresectable MHBOs of Bismuth I, II, and IIIa, whole-liver drainage with a novel 8 mm FCSEMS possessing an ultra-slim introducer was feasible and potentially safe, with favorable stent patency. Placement above the papilla might be preferrable to placement across the papilla.