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BackgroundChronic intestinal pseudo-obstruction (CIPO) is a type of intestinal dysfunction with symptoms of intestinal blockage but without the actual mechanical obstruction. Currently, there are no drugs available to treat this disease. Herein, we report the characterization of the PrP-SCA7-92Q transgenic (Tg) line as a valuable CIPO mouse model and investigated the tolerability and efficacy of the 5-hydroxytryptamine type-4 receptor (5HT4R) agonist velusetrag as a promising pharmacological treatment for CIPO.MethodsTo test the pharmacodynamics of velusetrag, 8-week-old SCA7 Tg mice, which express human mutated Ataxin-7 gene containing 92 CAG repeats under the mouse prion protein promoter, were treated for 5 weeks by oral route with velusetrag at 1 and 3 mg/kg doses or vehicle. Body weight was monitored throughout the treatment. After sacrifice, the small intestine and proximal colon were collected for whole-mount immunostaining. Untreated, age-matched, C57BL/6J mice were also used as controls in comparison with the other experimental groups.ResultsAnalysis of SCA7 Tg mice showed tissue damage and alterations, mucosal abnormalities, and ulcers in the distal small intestine and proximal colon. Morphological changes were associated with significant neuronal loss, as shown by decreased staining of pan-neuronal markers, and with accumulation of ataxin-7-positive inclusions in cholinergic neurons. Administration of velusetrag reversed intestinal abnormalities, by normalizing tissue damage and re-establishing the normal level of glia/neuron’s count in both the small and large intestines.ConclusionWe demonstrated that the PrP-SCA7-92Q Tg line, a model originally developed to mimic spinocerebellar ataxia, is suitable to study CIPO pathology and can be useful in establishing new therapeutic strategies, such as in the case of velusetrag. Our results suggest that velusetrag is a promising compound to treat patients affected by CIPO or intestinal dysmotility disease.

The Response Evaluation in Solid Tumors (RECIST) 1.1 provides key guidance for performing imaging response assessment and defines image-based outcome metrics in oncology clinical trials, including progression free survival. In this framework, tumors identified on imaging are designated as either target lesions, non-target disease or new lesions and a structured categorical response is assigned at each imaging time point. While RECIST provides definitions for these categories, it specifically and objectively defines only the target disease. Predefined thresholds of size change provide unbiased metrics for determining objective response and disease progression of the target lesions. However, worsening of non-target disease or emergence of new lesions is given the same importance in determining disease progression despite these being qualitatively assessed and less rigorously defined. The subjective assessment of non-target and new disease contributes to reader variability, which can impact the quality of image interpretation and even the determination of progression free survival. The RECIST Working Group has made significant efforts in developing RECIST 1.1 beyond its initial publication, particularly in its application to targeted agents and immunotherapy. A review of the literature highlights that the Working Group has occasionally employed or adopted objective measures for assessing non-target and new lesions in their evaluation of RECIST-based outcome measures. Perhaps a prospective evaluation of these more objective definitions for non-target and new lesions within the framework of RECIST 1.1 might improve reader interpretation. Ideally, these changes could also better align with clinically meaningful outcome measures of patient survival or quality of life., Competing Interests: Declarations Ethics approval Not applicable. Consent for publication We consent to publish. Competing interests Jonathan Goldin: Founder of MedQIA LLC., (© 2024. The Author(s).)

Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these bottlenecks. Our drug-repurposing screen, based on gene- and expression-pattern matching and information about the genetic variants influencing onset age among C9orf72 carriers, identified acamprosate, a γ-aminobutyric acid analog, as a potentially repurposable treatment for patients carrying C9orf72 repeat expansions. We validated its neuroprotective effect in cell models and showed comparable efficacy to riluzole, the current standard of care. Our work highlights the potential value of genomics in repurposing drugs in situations where the underlying pathomechanisms are inherently complex. VIDEO ABSTRACT., Competing Interests: Declaration of interests B.J.T. holds patents on clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72., (Published by Elsevier Inc.)

Bifunctional electrocatalysts, capable of efficiently driving both the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER), are crucial for advancing electrochemical processes. While noble-metal-based catalysts are widely recognized for their role in oxygen processes, current state-of-the-art designs are limited to either ORR or OER activity, presenting a notable research gap. In addressing this challenge, we have developed a novel Ni/NiO-C nanocomposite catalyst derived from a nickel-based metal-organic framework ( Ni-SKU-5 ). For the ORR, the Ni/NiO-C catalyst exhibits an onset potential of 0.95 V vs RHE in a 1.0 M KOH solution, coupled with a Tafel slope of -99 mV dec -1 at 1600 rpm. Moreover, the catalyst displays excellent stability, maintaining a performance of over 90% after 10 h of continuous reaction. Furthermore, the catalyst proves effective in the OER, boasting an overpotential of 370 mV (at 10 mA cm -2 ) and a Tafel slope of 114 mV dec -1 , highlighting its bifunctionality. The bifunctional overpotential of the Ni/NiO-C composite is measured at 820 mV, surpassing that of the 20% Pt/C electrocatalyst (860 mV), highlighting its potential for practical applications. Comparative experiments establish the origin of the robust bifunctional reactivity toward the conformal hybrid structure, porous framework, and the synergistic effect operating among the constituents of the nanocomposite.

Introduction: The prevalence of underweight in women of reproductive age (WRA) in South Asia remains unacceptably high. Underweight women suffer from lowered immunity, infertility, and a risk of developing non-communicable diseases. In pregnancy, undernutrition results in poor neonatal and maternal outcomes. We present the findings and the management strategy of undernutrition in the preconception and pregnancy phase intervention group in the WING study in low- to lower-middle-income neighborhoods of North India., Methods: We analyzed data from the Women and Infants Integrated Interventions for Growth Study (WINGS) intervention group. In this individually randomized factorial design trial, 13,500 women were enrolled from low to middle-income neighborhoods of Delhi: 6,722 women in the preconception group and 2,640 from the pregnancy group. Food supplements in the form of locally prepared snacks were given to provide necessary calories and protein requirements as per the Body mass index (BMI) during the preconception period and each trimester of pregnancy. The snacks (sweet or savory) and milk or egg as a source of high-quality protein were delivered at home, and intakes were observed. Individual tracking and close monthly monitoring were done for compliance, besides screening and treatment of infections., Results: The enrolled women's mean (SD) age was 24.2 (3.1) years. Approximately 35% of women had a height of < 150 cm, and 50% had schooling >12 years. 17% of women in preconception and 14 % in pregnancy intervention groups were Underweight. Approximately two-thirds of underweight women improved 9-12 months after management in the preconception group, and the same proportion improved 4 weeks after management during pregnancy. The proportion of women with inadequate weight gain (IWG) during pregnancy was higher in women who were underweight during preconception., Discussion: A comprehensive approach to managing undernutrition with high-quality energy-dense food supplementation substantially improved weight gain in women during preconception and pregnancy., Clinical Trial Registration: http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=19339%26EncHid=%26userName=societyforappliedstudies, identifier: Clinical Trial Registry India #CTRI/2017/06/008908., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dhabhai, Chowdhury, Taneja, Shekhar, Kaur, Mittal, Dewan and Bhandari.)

Importance: Multidomain interventions in pregnancy and early childhood have improved child neurodevelopment, but little is known about the effects of additional preconception interventions., Objective: To evaluate the effect of a multifaceted approach including health; nutrition; water, sanitation, and hygiene (WASH); and psychosocial support interventions delivered during the preconception period and/or during pregnancy and early childhood on child neurodevelopment., Design, Setting, and Participants: In this randomized trial involving low- and middle-income neighborhoods in Delhi, India, 13 500 participants were assigned to preconception interventions or routine care for the primary outcome of preterm births and childhood growth. Participants who became pregnant were randomized to pregnancy and early childhood interventions or routine care. Neurodevelopmental assessments, the trial's secondary outcome reported herein, were conducted in a subsample of children at age 24 months, including 509 with preconception, pregnancy, and early childhood interventions; 473 with preconception interventions alone; 380 with pregnancy and early childhood interventions alone; and 350 with routine care. This study was conducted from November 1, 2000, through February 25, 2022., Interventions: Health, nutrition, psychosocial care and support, and WASH interventions delivered during preconception, pregnancy, and early childhood periods., Main Outcomes and Measures: Cognitive, motor, language, and socioemotional performance at age 24 months, assessed using the Bayley Scales of Infant and Toddler Development 3 tool., Results: The mean age of participants at enrollment was 23.8 years (SD, 3.0 years). Compared with the controls at age 24 months, children in the preconception intervention groups had higher cognitive scores (mean difference [MD], 1.16; 98.3% CI, 0.18-2.13) but had similar language, motor, and socioemotional scores as controls. Those receiving pregnancy and early childhood interventions had higher cognitive (MD, 1.48; 98.3% CI, 0.49-2.46), language (MD, 2.29; 98.3% CI, 1.07-3.50), motor (MD, 1.53; 98.3% CI, 0.65-2.42), and socioemotional scores (MD, 4.15; 98.3% CI, 2.18-6.13) than did controls. The pregnancy and early childhood group also had lower incidence rate ratios (RRs) of moderate to severe delay in cognitive (incidence RR, 0.62; 98.3% CI, 0.40-0.96), language (incidence RR, 0.73; 98.3% CI, 0.57-0.93), and socioemotional (incidence RR, 0.49; 98.3% CI, 0.24-0.97) development than did those in the control group. Children in the preconception, pregnancy, and early childhood intervention group had higher cognitive (MD, 2.60; 98.3% CI, 1.08-4.12), language (MD, 3.46; 98.3% CI, 1.65-5.27), motor (MD, 2.31; 98.3% CI, 0.93-3.69), and socioemotional (MD, 5.55; 98.3% CI, 2.66-8.43) scores than did those in the control group., Conclusions and Relevance: Multidomain interventions during preconception, pregnancy and early childhood led to modest improvements in child neurodevelopment at 24 months. Such interventions for enhancing children's development warrant further evaluation., Trial Registration: Clinical Trials Registry-India CTRI/2017/06/008908.