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Background and study aims Endoscopic ultrasound-directed transgastric ERCP (EDGE) is a safe and efficacious procedure to treat pancreaticobiliary diseases in Roux-en-Y gastric bypass (RYGB). This multicenter study aimed to determine the long-term outcomes of EDGE focusing on fistula persistence rates and post-procedure weight change.

Communication between cells in metazoan organisms is mediated by a remarkably small number of highly conserved signaling pathways. Given this small number of signaling pathways, the existence of multiple related ligands for many of these pathways represents a key evolutionary innovation for encoding complexity into cell-cell signaling. Relatedly, crosstalk between pathways is another critical feature which allows a modest number pathways to ultimately generate an enormously diverse range of outcomes. It would thus be useful to have genetic tools to identify and manipulate not only those cells which express a given signaling ligand, but also those cells that specifically co-express pairs of signaling ligands. We present a collection of split-Gal4 knock-in lines targeting many of the ligands for highly conserved signaling pathways in Drosophila (Notch, Hedgehog, FGF, EGF, TGFβ, JAK/STAT, JNK, and PVR). We demonstrate that these lines faithfully recapitulate the endogenous expression pattern of their targets, and that they can be used to identify cells and tissues that co-express pairs of ligands. As a proof of principle, we demonstrate that the 4th chromosome TGFβ ligands myoglianin and maverick are broadly co-expressed in muscles and other tissues of both larva and adults, and that the JAK/STAT ligands upd2 and upd3 are partially co-expressed from cells of the midgut following gut damage. Together with our previously collection of split-Gal4 lines targeting the seven Wnt ligands, this resource allows Drosophila researchers to identify and genetically manipulate cells that specifically express pairs of conserved ligands from nearly all the major intercellular signaling pathways., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

Background/Objective: Bilaterally implanted cochlear implant (CI) users do not consistently have access to interaural time differences (ITDs). ITDs are crucial for restoring the ability to localize sounds and understand speech in noisy environments. Lack of access to ITDs is partly due to lack of communication between clinical processors across the ears and partly because processors must use relatively high rates of stimulation to encode envelope information. Speech understanding is best at higher stimulation rates, but sensitivity to ITDs in the timing of pulses is best at low stimulation rates. Methods: We implemented a practical "mixed rate" strategy that encodes ITD information using a low stimulation rate on some channels and speech information using high rates on the remaining channels. The strategy was tested using a bilaterally synchronized research processor, the CCi-MOBILE. Nine bilaterally implanted CI users were tested on speech understanding and were asked to judge the location of a sound based on ITDs encoded using this strategy. Results: Performance was similar in both tasks between the control strategy and the new strategy. Conclusions: We discuss the benefits and drawbacks of the sound coding strategy and provide guidelines for utilizing synchronized processors for developing strategies.

Background: Due to the progressive decline in β-cell function, it is often necessary to utilize multiple agents with complementary mechanisms of action to address various facets and achieve glycemic control. Thus, this study aimed to evaluate the efficacy and safety of a fixed-dose combination (FDC) of metformin/sitagliptin/pioglitazone (MSP) therapy vs. metformin/sitagliptin (MS) in type 2 diabetes mellitus (T2DM)., Methods: In this phase 3, multicenter, double-blind study, patients with T2DM who exhibited inadequate glycemic control with HbA1c of 8.0-11.0% while taking ≥1500 mg/day metformin for at least 6 weeks were randomized to receive either FDC of MSP (1000/100/15 mg) or MS (1000/100 mg) per day for 24 weeks. The primary outcome measure was the change in HbA1c, and secondary outcomes included changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and body weight from baseline to 24 weeks along with safety and tolerability., Results: Among the 236 patients randomized, 207 (87.71%) successfully completed the study. All baseline characteristics were comparable between the FDC of MSP and MS groups. There was a subsequent significant reduction of HbA1c in FDC of MSP (- 1.64) vs. MS (- 1.32); between groups was [- 0.32% (95% CI, - 0.59, - 0.05)], P = 0.0208. Similar reductions were found in FPG [- 13.2 mg/dL (95% CI, - 22.86, - 3.71)], P = 0.0068, and PPG [- 20.83 mg/dL (95% CI, - 34.11, - 7.55)], P = 0.0023. There were no significant changes in body weight. A total of 27 adverse effects (AEs) and one severe AE were reported, none of which were related to the study drug., Conclusion: The FDC of MSP demonstrated significant efficacy in managing glycemic indices and could serve as a valuable tool for physicians in the management of Indian patients with T2DM., Trial Registration: Clinical Trials Registry of India, CTRI/2021/10/037461., (© 2024. The Author(s).)

Web-based testing is an appealing option for expanding psychoacoustics research outside laboratory environments due to its simple logistics. For example, research participants partake in listening tasks using their own computer and audio hardware and can participate in a comfortable environment of their choice at their own pace. However, it is unknown how deviations from conventional in-lab testing affect data quality, particularly in binaural hearing tasks that traditionally require highly precise audio presentation. Here, we used an online platform to replicate two published in-lab experiments: lateralization to interaural time and level differences (ITD and ILD, experiment I) and dichotic and contralateral unmasking of speech (experiment II) in normal-hearing (NH) young adults. Lateralization data collected online were strikingly similar to in-lab results. Likewise, the amount of unmasking measured online and in-lab differed by less than 1 dB, although online participants demonstrated higher speech reception thresholds overall than those tested in-lab by up to ∼7 dB. Results from online participants who completed a hearing screening versus those who self-reported NH did not differ significantly. We conclude that web-based psychoacoustics testing is a viable option for assessing binaural hearing abilities among young NH adults and discuss important considerations for online study design., (© 2023 Acoustical Society of America.)

The split-Gal4 system allows for intersectional genetic labeling of highly specific cell types and tissues in Drosophila . However, the existing split-Gal4 system, unlike the standard Gal4 system, cannot be repressed by Gal80, and therefore cannot be controlled temporally. This lack of temporal control precludes split-Gal4 experiments in which a genetic manipulation must be restricted to specific timepoints. Here, we describe a split-Gal4 system based on a self-excising split-intein, which drives transgene expression as strongly as the current split-Gal4 system and Gal4 reagents, yet which is repressible by Gal80. We demonstrate the potent inducibility of "split-intein Gal4" in vivo using both fluorescent reporters and via reversible tumor induction in the gut. Further, we show that our split-intein Gal4 can be extended to the drug-inducible GeneSwitch system, providing an independent method for intersectional labeling with inducible control. We also show that the split-intein Gal4 system can be used to generate highly cell type-specific genetic drivers based on in silico predictions generated by single-cell RNAseq (scRNAseq) datasets, and we describe an algorithm ("Two Against Background" or TAB) to predict cluster-specific gene pairs across multiple tissue-specific scRNA datasets. We provide a plasmid toolkit to efficiently create split-intein Gal4 drivers based on either CRISPR knock-ins to target genes or using enhancer fragments. Altogether, the split-intein Gal4 system allows for the creation of highly specific intersectional genetic drivers that are inducible/repressible.

Bilateral cochlear implant (BICI) listeners do not have full access to the binaural cues that normal hearing (NH) listeners use for spatial hearing tasks such as localization. When using their unsynchronized everyday processors, BICI listeners demonstrate sensitivity to interaural level differences (ILDs) in the envelopes of sounds, but interaural time differences (ITDs) are less reliably available. It is unclear how BICI listeners use combinations of ILDs and envelope ITDs, and how much each cue contributes to perceived sound location. The CCi-MOBILE is a bilaterally synchronized research processor with the untested potential to provide spatial cues to BICI listeners. In the present study, the CCi-MOBILE was used to measure the ability of BICI listeners to perceive lateralized sound sources when single pairs of electrodes were presented amplitude-modulated stimuli with combinations of ILDs and envelope ITDs. Young NH listeners were also tested using amplitude-modulated high-frequency tones. A cue weighting analysis with six BICI and ten NH listeners revealed that ILDs contributed more than envelope ITDs to lateralization for both groups. Moreover, envelope ITDs contributed to lateralization for NH listeners but had negligible contribution for BICI listeners. These results suggest that the CCi-MOBILE is suitable for binaural testing and developing bilateral processing strategies., (© 2023 Acoustical Society of America.)

While listeners with bilateral cochlear implants (BiCIs) are able to access information in both ears, they still struggle to perform well on spatial hearing tasks when compared to normal hearing listeners. This performance gap could be attributed to the high stimulation rates used for speech representation in clinical processors. Prior work has shown that spatial cues, such as interaural time differences (ITDs), are best conveyed at low rates. Further, BiCI listeners are sensitive to ITDs with a mixture of high and low rates. However, it remains unclear whether mixed-rate stimuli are perceived as unitary percepts and spatially mapped to intracranial locations. Here, electrical pulse trains were presented on five, interaurally pitch-matched electrode pairs using research processors, at either uniformly high rates, low rates, or mixed rates. Eight post-lingually deafened adults were tested on perceived intracranial lateralization of ITDs ranging from 50 to 1600 μs. Extent of lateralization depended on the location of low-rate stimulation along the electrode array: greatest in the low- and mixed-rate configurations, and smallest in the high-rate configuration. All but one listener perceived a unitary auditory object. These findings suggest that a mixed-rate processing strategy can result in good lateralization and convey a unitary auditory object with ITDs.

DNA double-strand breaks (DSBs) are deleterious lesions, which must be repaired precisely to maintain genomic stability. During meiosis, programmed DSBs are repaired via homologous recombination (HR) while repair using the nonhomologous end joining (NHEJ) pathway is inhibited, thereby ensuring crossover formation and accurate chromosome segregation. 1 , 2 How DSB repair pathway choice is implemented during meiosis is unknown. In C. elegans, meiotic DSB repair takes place in the context of the fully formed, highly dynamic zipper-like structure present between homologous chromosomes called the synaptonemal complex (SC). 3 , 4 , 5 , 6 , 7 , 8 , 9 The SC consists of a pair of lateral elements bridged by a central region composed of the SYP proteins in C. elegans. How the structural components of the SC are regulated to maintain the architectural integrity of the assembled SC around DSB repair sites remained unclear. Here, we show that SYP-4, a central region component of the SC, is phosphorylated at Serine 447 in a manner dependent on DSBs and the ATM/ATR DNA damage response kinases. We show that this SYP-4 phosphorylation is critical for preserving the SC structure following exogenous (γ-IR-induced) DSB formation and for promoting normal DSB repair progression and crossover patterning following SPO-11-dependent and exogenous DSBs. We propose a model in which ATM/ATR-dependent phosphorylation of SYP-4 at the S447 site plays important roles both in maintaining the architectural integrity of the SC following DSB formation and in warding off repair via the NHEJ repair pathway, thereby preventing aneuploidy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The measurement of pupil dilation has become a common way to assess listening effort. Pupillometry data are subject to artifacts, requiring highly contaminated data to be discarded from analysis. It is unknown how trial exclusion criteria impact experimental results. The present study examined the effect of a common exclusion criterion, percentage of blinks, on speech intelligibility and pupil dilation measures in 9 participants with single-sided deafness (SSD) and 20 participants with normal hearing. Participants listened to and repeated sentences in quiet or with speech maskers. Pupillometry trials were processed using three levels of blink exclusion criteria: 15%, 30%, and 45%. These percentages reflect a threshold for missing data points in a trial, where trials that exceed the threshold are excluded from analysis. Results indicated that pupil dilation was significantly greater and intelligibility was significantly lower in the masker compared with the quiet condition for both groups. Across-group comparisons revealed that speech intelligibility in the SSD group decreased significantly more than the normal hearing group from quiet to masker conditions, but the change in pupil dilation was similar for both groups. There was no effect of blink criteria on speech intelligibility or pupil dilation results for either group. However, the total percentage of blinks in the masker condition was significantly greater than in the quiet condition for the SSD group, which is consistent with previous studies that have found a relationship between blinking and task difficulty. This association should be carefully considered in future experiments using pupillometry to gauge listening effort.

Deafness in both ears is highly disruptive to communication in everyday listening situations. Many individuals with profound deafness receive bilateral cochlear implants (CIs) to gain access to spatial cues used in localization and speech understanding in noise. However, the benefit of bilateral CIs, in particular sensitivity to interaural time and level differences (ITD and ILDs), varies among patients. We measured binaural sensitivity in 46 adult bilateral CI patients to explore the relationship between binaural sensitivity and three classes of patient-related factors: age, acoustic exposure, and electric hearing experience. Results show that ILD sensitivity increased with shorter years of acoustic exposure, younger age at testing, or an interaction between these factors, moderated by the duration of bilateral hearing impairment. ITD sensitivity was impacted by a moderating effect between years of bilateral hearing impairment and CI experience. When age at onset of deafness was treated as two categories (<18 vs. >18 years of age), there was no clear effect for ILD sensitivity, but some differences were observed for ITD sensitivity. Our findings imply that maximal binaural sensitivity is obtained by listeners with a shorter bilateral hearing impairment, a longer duration of CI experience, and potentially a younger age at testing. 198/200.

Normal hearing listeners extract small interaural time differences (ITDs) and interaural level differences (ILDs) to locate sounds and segregate targets from noise. Bilateral cochlear implant listeners show poor sensitivity to ITDs when using clinical processors. This is because common clinical stimulation approaches use high rates [∼1000 pulses per-second (pps)] for each electrode in order to provide good speech representation, but sensitivity to ITDs is best at low rates of stimulation (∼100-300 pps). Mixing rates of stimulation across the array is a potential solution. Here, ITD sensitivity for a number of mixed-rate configurations that were designed to preserve speech envelope cues using high-rate stimulation and spatial hearing using low rate stimulation was examined. Results showed that ITD sensitivity in mixed-rate configurations when only one low rate electrode was included generally yielded ITD thresholds comparable to a configuration with low rates only. Low rate stimulation at basal or middle regions on the electrode array yielded the best sensitivity to ITDs. This work provides critical evidence that supports the use of mixed-rate strategies for improving ITD sensitivity in bilateral cochlear implant users.

Normal-hearing human listeners and a variety of studied animal species localize sound sources accurately in reverberant environments by responding to the directional cues carried by the first-arriving sound rather than spurious cues carried by later-arriving reflections, which are not perceived discretely. This phenomenon is known as the precedence effect (PE) in sound localization. Despite decades of study, the biological basis of the PE remains unclear. Though the PE was once widely attributed to central processes such as synaptic inhibition in the auditory midbrain, a more recent hypothesis holds that the PE may arise essentially as a by-product of normal cochlear function. Here we evaluated the PE in a unique human patient population with demonstrated sensitivity to binaural information but without functional cochleae. Users of bilateral cochlear implants (CIs) were tested in a psychophysical task that assessed the number and location(s) of auditory images perceived for simulated source-echo (lead-lag) stimuli. A parallel experiment was conducted in a group of normal-hearing (NH) listeners. Key findings were as follows: 1) Subjects in both groups exhibited lead-lag fusion. 2) Fusion was marginally weaker in CI users than in NH listeners but could be augmented by systematically attenuating the amplitude of the lag stimulus to coarsely simulate adaptation observed in acoustically stimulated auditory nerve fibers. 3) Dominance of the lead in localization varied substantially among both NH and CI subjects but was evident in both groups. Taken together, data suggest that aspects of the PE can be elicited in CI users, who lack functional cochleae, thus suggesting that neural mechanisms are sufficient to produce the PE., (Copyright © 2015 the American Physiological Society.)

Aims: This study was undertaken to assess the effectiveness and safety of insulin aspart in patients with gestational and pregestational diabetes., Settings and Design: An open-label, prospective, nonrandomized, comparative, and observational study conducted at single center in India., Subjects and Methods: A total of 276 patients were in gestational diabetes mellitus (GDM) group, 79 were in the pre-GDM group. Patients were started on insulin therapy (insulin aspart ± neutral protamine hagedorn) once medical nutrition therapy for 2 weeks failed to achieve control, that is., fasting plasma glucose ≥90 mg/dL and/or 1.0 h postprandial plasma glucose ≥130 mg/dL. Insulin dose was titrated to keep the blood glucose values between 90 and 130 mg/dL. Patients were followed once every 4 weeks until the 28(th) week, then once every 2 weeks until 32(nd) week, then once every week until delivery, and the final visit was on 60 ± 7 days. The final outcome was assessed in terms of incidence of macrosomia (>3.5 kg body weight) between the two groups and episodes of confirmed (blood glucose <56 mg/dL) minor or major maternal hypoglycemia., Results: There was no statistically significant difference among the two groups in terms of incidence of macrosomia that is., it was 5.1%, 8.9% in GDM, pre-GDM group, respectively., Conclusions: Insulin aspart was found safe in pregnancy, however, more studies with double-blind, standard controlled studies are required to confirm the findings of this study.

Astroblastomas are extremely rare neuroepithelial tumors of uncertain histogenesis, affecting children and young adults, and constitute a new addition to the WHO 2000 classification of CNS tumors. We report the largest series of nine cases diagnosed in a single institute over the last 13 years and review published literature. Mean age at presentation was 12.8 years (range: 22 months to 27years). Seven out of nine cases were supratentorial (frontal/frontoparietal - three, parieto-occipital - three, parafalcine - one), one was intraventricular and another was optochaismatic/suprasellar. Five cases were high grade (anaplastic) astroblastomas with Ki-67 labeling index of 8-10%. Immunohistochemical and ultrastructural evidence suggesting origin from cells intermediate between ependymocytes and astrocytes is presented. The histogenetic origin of these tumors remains speculative. But the lack of Isocitrate dehydrogenase 1 (IDH1) mutation as detected by immunohistochemistry in this study, which is similar to ependymomas supports putative origin from ependymoglial cells. Out of the nine cases, recurrence was noted in one case, 12 months after gross total resection with progression to high grade in the recurrent tumor. There is no recommended treatment protocol due to the rarity of this entity and prognostic factors are yet to be established., (© 2015 Japanese Society of Neuropathology.)

In normal-hearing (NH) listeners, elevation perception is produced by the spectral cues imposed by the pinna, head, and torso. Elevation perception in cochlear-implant (CI) listeners appears to be non-existent; this may be a result of poorly encoded spectral cues. In this study, an analog of elevation perception was investigated by having 15 CI and 8 NH listeners report the intracranial location of spectrally simple signals (single-electrode or bandlimited acoustic stimuli, respectively) in both horizontal and vertical dimensions. Thirteen CI listeners and all of the NH listeners showed an association between place of stimulation (i.e., stimulus frequency) and perceived elevation, generally responding with higher elevations for more basal stimulation. This association persisted in the presence of a randomized temporal pitch, suggesting that listeners were not associating pitch with elevation. These data provide evidence that CI listeners might perceive changes in elevation if they were presented stimuli with sufficiently salient elevation cues.

Background: The purpose of this study is to review the cases of total colonic aganglionosis seen in the span of ten years at a pediatric surgery unit of a tertiary care public hospital in New Delhi., Methods: Medical records of twelve patients with total colonic aganglionosis were retrieved., Results: Ten out of the twelve patients were males; seven were of the Muslim community. Average recorded birth weight was 2.2 kg. Ten patients presented with features of intestinal obstruction, while two presented with perforation peritonitis. Among the cases of obstruction, Hirschsprung's disease was suspected in eight cases (one was associated with Shah-Waardenburg syndrome), one case each was preoperatively diagnosed as ileal atresia and meconium ileus. Abdominal X-rays at presentation of all the neonates except in one with Shah-Waardenburg syndrome showed multiple air fluid levels. Contrast enema was done in five patients. It showed micro-colon in two patients, and typical question mark sign, dilated small bowel with transition zone in hepatic flexure and normal caliber colon in one each. All the patients underwent exploratory laparotomy. Intra-operatively, the transition zone was seen at distal ileum in ten cases and at hepatic flexure and transverse colon in one each. Biopsies of all the twelve patients eventually showed absence of ganglion cells in entire colon. Ileostomy was done in nine cases, colostomy in two and primary Kimura's procedure in one (this patient was discharged and lost to follow up). Left colonic patch with Swenson's pull through with ileostomy was done for one patient on colostomy. His stoma was closed; he was eventually discharged and lost to follow up. In the other patient with colostomy, the stoma was closed and an ileostomy was created. Of all the patients on ileostomy, three expired in the immediate postoperative period. Four were lost to follow up. Two underwent Kimura's procedure; and expired few months later. One patient on ileostomy is awaiting further treatment., Conclusion: The outcomes for total colonic aganglionosis in those presenting in neonatal age tend to be unsatisfactory in the developing countries.

Mucoadhesive drug delivery systems are those that provide intimate contact of the drug with the mucosa for an extended period of time. In present work, mucoadhesive chitosan microspheres of Levosalbutamol sulphate were prepared by Spray drying method. Formulations were characterized for various physicochemical attributes size, encapsulation efficiency, swelling ability, in vitro release study and mucoadhesion study by rat ileum. Through these parameters we conclude that the batch B(2) was found to be best mainly by mucoadhesion study and in vitro drug release. Mucoadhesion was found to be increased with incresed concentration of polymer and visa versa in case of drug release. Batch B(3) had also similar results with that of Batch B(2). That's why here Batch B(2) was said to be the best batch with less polymeric content as compare to Batch B(3).

The influence of preparation methodology of silymarin solid dispersions using a hydrophilic polymer on the dissolution performance of silymarin was investigated. Silymarin solid dispersions were prepared using HPMC E 15LV by kneading, spray drying and co-precipitation methods and characterized by FTIR, DSC, XRPD and SEM. Dissolution profiles were compared by statistical and model independent methods. The FTIR and DSC studies revealed weak hydrogen bond formation between the drug and polymer, while XRPD and SEM confirmed the amorphous nature of the drug in co-precipitated solid dispersion. Enhanced dissolution compared to pure drug was found in the following order: co-precipitation > spray drying > kneading methodology (p < 0.05). All preparation methods enhanced silymarin dissolution from solid dispersions of different characteristics. The co-precipitation method proved to be best and provided a stable amorphous solid dispersion with 2.5 improved dissolution compared to the pure drug.