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Protein aggregation is an obstacle for the development of new biopharmaceuticals, presenting challenges in shipping and storage of vital therapies. Though a variety of materials and methods have been explored, the need remains for a simple material that is biodegradable, nontoxic, and highly efficient at stabilizing protein therapeutics. In this work, we investigated zwitterionic polypeptides prepared using a rapid and scalable polymerization technique and conjugated to a supramolecular macrocycle host, cucurbit[7]uril, for the ability to inhibit aggregation of model protein therapeutics insulin and calcitonin. The polypeptides are based on the natural amino acid methionine, and zwitterion sulfonium modifications were compared to analogous cationic and neutral structures. Each polymer was end-modified with a single cucurbit[7]uril macrocycle to afford supramolecular recognition and binding to terminal aromatic amino acids on proteins. Only conjugates prepared from zwitterionic structures of sufficient chain lengths were efficient inhibitors of insulin aggregation and could also inhibit aggregation of calcitonin. This polypeptide exhibited no cytotoxicity in human cells even at concentrations that were five-fold of the intended therapeutic regime. We explored treatment of the zwitterionic polypeptides with a panel of natural proteases and found steady biodegradation as expected, supporting eventual clearance when used as a protein formulation additive. more...

Penile squamous cell carcinoma (PSC) is traditionally treated with surgical resection with significant morbidity. Penile sparing approaches, such as brachytherapy, require expertise, prolonged inpatient stays, poor patient convenience, and heterogenous plans with variable long-term toxicity. In this study, we describe the protocol for novel portable apparatus created for PSC, allowing outpatient hybrid interstitial/surface brachytherapy, improving homogeneity and patient convenience.A portable brachytherapy apparatus was developed utilizing a foley catheter, prostate template, 6F interstitial catheters, 5 mm bolus, and a jock strap. The apparatus allowed for internal and external catheter placement housed in a jock strap to allow mobility and defecation without affecting the implant. High-dose-rate brachytherapy was performed as an outpatient.The apparatus was then used on a 62-year-old male with cT2pN0M0 (stage IIA) PSC with bilateral glans and urethral meatus involvement, who elected for definitive brachytherapy (4000cGy in 10 fractions over 5-days). Given external dwell positions, heterogeneity correction of the template was calculated (AAPM TG186) with2% variation. Patient had minimal impact on his active lifestyle during treatment and had complete clinical response at 3-months. Grade 2 skin desquamation resolved at 2-months, with no necrosis. At 6-months, he was able to resume sexual intercourse, and at 12-months, he remained disease-free with sexual and urinary function intact.Novel portable implant allows for improved patient convenience, reduced inpatient stay, capable of optimizing dosimetry with hybrid brachytherapy. This outpatient treatment allows the opportunity to increase fractionation, offering high local-control and lower toxicity. Future studies utilizing this apparatus for more fractionated regimens with further lower dose-per-fraction (∼3 Gy/fraction) is recommended. more...

A field experiment was conducted at Ludhiana and Amritsar during kharif and rabi 2018–19 and 2019–20 to see the effect of different organic amendments and nitrogen levels on grain quality parameters of rice and wheat. The results revealed that at both locations milling quality such as brown, milled as well as head rice recovery and L:B of rice grain were found significantly higher with treatment in which poultry manure (PM) was applied to rice followed by green manure (GM) and farmyard manure (FYM). N100 recorded better milling quality and L:B which was at par with N75. Residual effects of green manure and organic amendments on physical grain characteristics, viz. grain appearance score, hectolitre weight, grain hardness and chemical grain characteristics, viz. sedimentation value, protein content, gluten content of succeeding wheat crop were recorded higher in PM which was significantly superior than GM and FYM at both locations. Whereas, N100 and N75 found to be superior as compared to N50 and control. The improvement in grain quality may be attributed to the increased availability of nutrients coupled with increased absorption and assimilation by plants on long term basis. more...

Technology related to artificial intelligence have the potential to change both the clinical care that is provided to patients and the administrative processes that are followed within healthcare delivery organisations (HDO). The ever-increasing amount and complexity of data relevant to healthcare provides an adequate context for the application of artificial intelligence and machine learning. This setting is supplied by the ever-increasing number of data. It is crucial to keep in mind that artificial intelligence (AI) is not a single technology but rather a group of technologies that can carry out a number of duties. It is important to keep in mind that AI is not a single technology since it is not a singular technology. The following is a summary of some of the applications that artificial intelligence has found in the medical field, however this is by no means a complete list. Because of how rapidly information may become out of date, it has been challenging to attempt to capture knowledge in the form of a book due to the length of time that has passed since the adage "any text is out of date by the time the book is produced." This saying has been around for decades. Nevertheless, in 2019, with what has been determined by some studies to be exponential growth in the field of computer science and AI in particular, change is occurring at a pace that renders sentences in this chapter almost immediately out of date. This is because of the exponential growth in the field of computer science. This is because the discipline of computer science is growing increasingly difficult to understand as time goes on. In order to stay current, we can no longer rely on the monthly updates that we acquired from our previously saved PubMed search. Instead, it is very necessary to sign up for daily news feeds from authoritative websites such as arXiv1 and the Association for the Advancement of Artificial Intelligence (AAAI) (AAAI). As a consequence of this, this chapter contains citations from a wide range of sources, such as historical publications, websites, and articles based on content found on the internet. The accessibility of data pertaining to medical treatment is one of the most important factors that is contributing to the advancement of AI technologies in the field of medicine. The phrase "artificial intelligence" refers not to a single technology but rather to a collection of technologies working together to simulate human intellect. more...

The COVID-19 pandemic has had an unprecedented and disruptive impact on people’s health and lives worldwide. In addition to burdening people’s health in the short-term in the form of infection, illness, and mortality, there has been an enormous negative impact on clinical research. Clinical trials experienced challenges in ensuring patient safety and enrolling new patients throughout the pandemic. Here, we investigate and quantify the negative impact that the COVID-19 pandemic has industry-sponsored clinical trials, both in the USA and worldwide. We find a negative correlation between the severity of the COVID-19 pandemic and clinical trial screening rate, with the relationship being strongest during the first three months of the pandemic compared to the entire duration of the pandemic. This negative statistical relationship holds across therapeutic areas, across states in the USA despite the heterogeneity of responses at the state-level, and across countries. This work has significant implications for the management of clinical trials worldwide in response to the fluctuating severity of COVID-19 moving forward and for future pandemics. more...

Introduction: Newborns exposed to sildenafil citrate (SC) in utero have increased rates of persistent pulmonary hypertension. The mechanism behind this has not yet been fully elucidated. We aimed to utilize a combination of clinically relevant MRI techniques to comprehensively characterize the haemodynamics of the fetal sheep whilst under the influence of SC. We hypothesized that these MRI techniques would detect SC-induced increases in pulmonary blood flow and oxygen delivery prior to birth. Methods: At 116–117 days gestational age (term, 150 days), pregnant Merino ewes (n = 9) underwent fetal catheterization surgery. MRI scans were performed during a basal state and then repeated during a constant umbilical vein infusion of SC to measure blood flow and oxygenation within the major vessels of the fetal circulation using phase-contrast-MRI and T2 oximetry. Results: Right and left ventricular cardiac outputs were not different between states. Pulmonary blood flow increased during the SC state resulting in elevated pulmonary oxygen delivery. Right to left heart shunting through the foramen ovale was reduced without reducing cerebral oxygen delivery. Conclusion: SC induces alterations to pulmonary haemodynamics in utero; a characteristic that if maintained may underlie or act as a precursor towards the elevated rates of poor pulmonary outcomes after birth. These MRI techniques are the first to comprehensively characterize sildenafil’s direct impact on the pulmonary vasculature and its indirect detriment to the flow of oxygen-rich blood through the foramen ovale. more...

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High-risk neuroblastoma remains therapeutically challenging to treat, and the mechanisms promoting disease aggression are poorly understood. Here, we show that elevated expression of dihydrolipoamide S-succinyltransferase (DLST) predicts poor treatment outcome and aggressive disease in patients with neuroblastoma. DLST is an E2 component of the α-ketoglutarate (αKG) dehydrogenase complex, which governs the entry of glutamine into the tricarboxylic acid cycle (TCA) for oxidative decarboxylation. During this irreversible step, αKG is converted into succinyl-CoA, producing NADH for oxidative phosphorylation (OXPHOS). Utilizing a zebrafish model of MYCN-driven neuroblastoma, we demonstrate that even modest increases in DLST expression promote tumor aggression, while monoallelic dlst loss impedes disease initiation and progression. DLST depletion in human MYCN-amplified neuroblastoma cells minimally affected glutamine anaplerosis and did not alter TCA cycle metabolites other than αKG. However, DLST loss significantly suppressed NADH production and impaired OXPHOS, leading to growth arrest and apoptosis of neuroblastoma cells. In addition, multiple inhibitors targeting the electron transport chain, including the potent IACS-010759 that is currently in clinical testing for other cancers, efficiently reduced neuroblastoma proliferation in vitro. IACS-010759 also suppressed tumor growth in zebrafish and mouse xenograft models of high-risk neuroblastoma. Together, these results demonstrate that DLST promotes neuroblastoma aggression and unveils OXPHOS as an essential contributor to high-risk neuroblastoma.Significance:These findings demonstrate a novel role for DLST in neuroblastoma aggression and identify the OXPHOS inhibitor IACS-010759 as a potential therapeutic strategy for this deadly disease. more...

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Introduction: Caesarean Section is the most commonly performed abdominal operation in women all over the world. Caesarean section during the second stage of labor carry higher maternal morbidity due to major haemorrhage, uterine atonia,wound infection and prolonged operation time. Neonatal mortality and morbidity due to hypoxia and fetal trauma, remains to be one of the major issues regarding the caesarean section performed in the second stage of labour. Methods: This observational study was conducted at department of Obstetrics and Gynecology, SMS Medical College, Jaipur from March 2021 to July 2022. 2 groups named group A (stage 1 labor caesarean section) and group B (stage 2 labor caesarean section) each contains 48 subjects, were allocated. Results: A hospital based observational study was conducted with 92 patients to compare caesarean section in first stage and second stage of labour. The maternal complications like uterine atonia and Wound infection higher in second stage of labour. The fetal complications like NICU admission require more and APGAR scoreless in second stage of labour Conclusions: Women undergoing caesarean section in the second stage of labour have increased maternal and fetal morbidity and required special care and should be handled and operated by experienced obstetricians and the neonatologists should be present. &nbsp more...

Aim: To evaluate and compare the clinical outcomes of Cention-N (CN) and stainless steel crowns (SSCs) as restorations for pulpotomised primary molars, and to study clinical and radiographic outcomes of pulpotomies restored with these materials. Methods: The study was conducted on 60 pulpotomised molars with occlusoproximal caries. These were randomly divided into two groups and restored with either stainless steel crowns or Cention-N. Clinical performance of restorations and clinical and radiographic success of pulpotomy was examined at 6, 9 and 12 months. Results: The mean scores for marginal integrity deteriorated significantly at 6, 9 and 12 months in both groups but in comparison were insignificant. The mean for proximal contact deteriorated significantly for the Cention-N group, whereas the mean for gingival health deteriorated remarkably for the stainless steel crown group at successive evaluations. No tooth in either group showed secondary caries or discomfort on biting, except for one tooth in Cention-N group which presented with secondary caries. The clinical success rate for pulpotomised molars was 100% for both groups until nine months, although this had reduced by the end of 12 months. Radiographically, the success rate was 79.3% for Cention-N, while it was 86.6% for stainless steel crowns at 12 months. There was no significant difference in clinical and radiographic success between either group. Conclusion: Cention-N and stainless steel crowns are comparable for marginal integrity. However, crowns maintain significantly better proximal contacts while Cention-N was notably better for gingival health of the restored tooth. Both materials do not show secondary caries and discomfort on biting and are comparable in clinical and radiographic success of pulpotomy at the end of one year. more...

Nanotechnology has become a wide range in pharmaceutical sciences, which has an effect on various drug delivery research from the last 10 years. The developed technology is being explored for the better therapeutic performance of drugs by enhancing the solubility of water-hating drugs (hydrophobic drugs), increasing permeability, regulating drug disposition and biodistribution, and permitting the targeted delivery of drugs. Nanotechnology is broadly categorized into drug nanoparticles or nanosuspension, nanocarriers like lipids, polymeric, and inorganic nanocarriers, as these nanocarriers involve liposomes and microemulsions nanoemulsions, lipid core micelles, solid lipid nanoparticles which are used for the targeted drug delivery systems.2 Based on this technology, the drug components that have poor aqueous solubility, permeability, bioavailability, and instability in physiological medium, the nanoemulsions are selected to enhance the properties. Nanoemulsions are group of heterogeneous with two immiscible liquids as o/w or w/o with droplet size ranges between 20 to 200 nm after the method preparation, before the term nanoemulsions, these are termed as mini-emulsions, micro-emulsions, submicron emulsions, and ultrafine emulsion due to unclear emulsions based on their size of the particles present. Therefore, to overcome the confusion in identifying the actual term, the particles size is within limits or in range, and the main factor is the emulsion, which is indicating transparent, are termed as nanoemulsions and slightly different called microemulsions. more...

OBJECTIVES To characterize, using magnetic resonance imaging (MRI), the distribution of blood flow and oxygen transport in human fetuses with subtypes of congenital heart disease (CHD) that present with neonatal cyanosis. METHODS Blood flow was measured in the major vessels of 152 late-gestation human fetuses with CHD and 40 gestational-age-matched normal fetuses, using cine phase-contrast MRI. Oxygen saturation (SaO2 ) was measured in the major vessels of 57 fetuses with CHD and 40 controls. RESULTS Compared with controls, we found lower combined ventricular output in fetuses with single-ventricle physiology, with the lowest being observed in fetuses with severe forms of Ebstein's anomaly. Obstructive lesions of the left or right heart were associated with increased flow across the contralateral side. Pulmonary blood flow was reduced in fetuses with Ebstein's anomaly, while those with Ebstein's anomaly and tricuspid atresia had reduced umbilical flow. Flow in the superior vena cava was elevated in fetuses with transposition of the great arteries, normal in fetuses with hypoplastic left heart, tetralogy of Fallot or tricuspid atresia and reduced in fetuses with Ebstein's anomaly. Umbilical vein SaO2 was reduced in fetuses with hypoplastic left heart or tetralogy of Fallot. Ascending aorta and superior vena cava SaO2 were reduced in nearly all CHD subtypes. CONCLUSIONS Fetuses with cyanotic CHD exhibit profound changes in the distribution of blood flow and oxygen transport, which result in changes in cerebral, pulmonary and placental blood flow and oxygenation. These alterations of fetal circulatory physiology may influence the neonatal course and help account for abnormalities of prenatal growth and development that have been described in newborns with cyanotic CHD. © 2021 International Society of Ultrasound in Obstetrics and Gynecology. more...

The cellular glycocalyx and extracellular matrix are rich in glycoproteins and proteoglycans that play essential physical and biochemical roles in all life. Synthetic mimics of these natural bottlebrush polymers have wide applications in biomedicine, yet preparation has been challenged by their high grafting and glycosylation densities. Using one-pot dual-catalysis polymerization of glycan-bearing α-amino acid N-carboxyanhydrides, we report grafting-from glycopolypeptide brushes. The materials are chemically and conformationally tunable where backbone and sidechain lengths were precisely altered, grafting density modulated up to 100%, and glycan density and identity tuned by monomer feed ratios. The glycobrushes are composed entirely of sugars and amino acids, are non-toxic to cells, and are degradable by natural proteases. Inspired by native lipid-anchored proteoglycans, cholesterol-modified glycobrushes were displayed on the surface of live human cells. Our materials overcome long-standing challenges in glycobrush polymer synthesis and offer new opportunities to examine glycan presentation and multivalency from chemically defined scaffolds., Synthetic mimics of glycoproteins and proteoglycans have wide applications in biomedicine, yet preparation has been challenged by their high grafting and glycosylation densities. Here the authors show one-pot dual-catalysis polymerization of glycan-bearing α-amino acid N-carboxyanhydrides to form glycopolypeptide brushes. more...

Range side-lobes suppression which is responsible for detection ambiguity is a challenging task in pulse compression (PC) radar. Targets generating weak signals tend to hide in undesired side-lobes creating ambiguity. In general, the side-lobes behaviour performance of received signals is observed by their correlation with other contemporary signals. In this paper, a new polyphase code is proposed that exhibits good auto-correlation and cross-correlation properties to reduce peak side-lobe level (PSL) and integrated side-lobe level (ISL). The proposed polyphase code named P43code is produced by combining left and right shifted versions of $$P4$$ code. The amount of rotation depends upon the overall code length. The optimum rotation combination is the one that produces maximum side-lobes reduction. The proposed design is also applied to multiple-input multiple-output (MIMO) radar, where for the proposed $$P4_{3}$$ code, orthogonal waveforms are used to minimize cross-interference. Using ambiguity function (AF), the impact of proposed code on the delay-Doppler plane is investigated. Simulation results demonstrate the superiority of the proposed $$P4_{3}$$ code compared to existing alternatives. more...

The COVID-19 pandemic has had an unprecedented and disruptive impact on people’s health and lives worldwide. In addition to burdening people’s health in the short-term in the form of infection, illness, and mortality, there has been an enormous negative impact on clinical research. Clinical trials experienced challenges in ensuring patient safety and enrolling new patients throughout the pandemic. Here, we investigate and quantify the negative impact that the COVID-19 pandemic has industry-sponsored clinical trials, both in the United States and worldwide. We find a negative correlation between the severity of the COVID-19 pandemic and clinical trial enrollment rate, with the relationship being strongest during the first three months of the pandemic compared to the entire duration of the pandemic. This negative statistical relationship holds across therapeutic areas, across states in the US despite the heterogeneity of responses at the state-level, and across countries. This work has significant implications for the management of clinical trials worldwide in response to the fluctuating severity of COVID-19 moving forward, and for future pandemics. more...

Background: This study sought to determine whether range of motion (ROM) of the ankle and subtalar joint complex (STJ) is correlated with ankle injuries in National Basketball Association (NBA) G-league and collegiate basketball players to identify an at-risk population that may benefit from participation in an ankle injury prevention program. Methods: This prospective cohort study encompassed 103 player-seasons (68 collegiate, 35 NBA G-League). Patient demographics, passive ankle and STJ range of motion measurements, anterior drawer, and talar tilt tests were collected at preseason physicals along with plain radiographs. Subtalar eversion and inversion measurements were added to assess the Combination Motion (CM) of the STJ and subtracted to calculate the Subtalar Difference (SD). We defined the ratio of CM to SD as Subtalar Mobility Index (SMI=CM/SD). Results: Twenty-one ankle injuries occurred with 10 405 player exposures yielding an incidence of 2.11/1000 exposures, resulting in 113 days of missed playing time. No direct measures of ankle, subtalar, or combined motion were associated with risk of injury, rejecting our original hypothesis that increased STJ ROM would predispose to ankle injuries. However, we did find that athletes with CM >16 degrees in combination with either SD 3.75 ( P = .032) were nearly 3 times more likely to have an ankle injury (3.14 vs 2.97, respectively). Conclusion: Using the predictive subtalar mobility thresholds found in this study may help identify at-risk players that may benefit from targeted ankle injury prevention programs. Level of Evidence: Level II, prospective cohort study. more...

CT-P39 is being developed as a biosimilar of reference omalizumab. This study aimed to assess the pharmacokinetic equivalence of CT-P39 to European Union-approved and United States-licensed reference omalizumab (EU- and US-omalizumab, respectively).This two-part, randomised, parallel-group, double-blind Phase 1 trial (NCT04018313) was conducted in healthy individuals with a total immunoglobulin E (IgE) level ≤100 international units (IU)/ml at screening. In part 2, described herein, participants were randomised (1:1:1) to receive a single 150 mg subcutaneous dose of CT-P39, EU-omalizumab, or US-omalizumab. The primary endpoint was pharmacokinetic equivalence in terms of area under the concentration-time curve (AUC) from time zero to the last quantifiable concentration (AUCOverall, 146 participants were randomised (CT-P39, N = 47; EU-omalizumab, N = 49; US-omalizumab, N = 50). For all primary pharmacokinetic parameters, 90% CIs for pairwise treatment comparisons were within the 80%-125% equivalence margin, demonstrating pharmacokinetic equivalence. Decreases in free IgE and increases in total IgE serum concentrations were comparable across groups. CT-P39 was well tolerated. Safety endpoints were comparable across groups: there were no treatment-related serious adverse events, deaths, or discontinuations due to treatment-emergent adverse events.CT-P39 was well tolerated and demonstrated pharmacokinetic equivalence with EU-omalizumab and US-omalizumab following administration of a single dose in healthy individuals. more...

Peritoneal-mediastinal communication is a rare complication of peritoneal dialysis (PD). We report the first case of peritoneal-mediastinal communication complication in a 36-year-old Caucasian man on continuous cycler peritoneal dialysis (CCPD) after undergoing cardiac surgery. He developed end-stage kidney disease (ESKD) due to calcineurin inhibitor nephrotoxicity and BK virus nephropathy in the setting of prior heart transplantation. He was initially started on intermittent hemodialysis (iHD) and was switched to CCPD 1 year later. He presented with increased drainage from his sternal incision site and reduced ultrafiltration. A contrast-enhanced chest computed tomography scan revealed an anterior chest wall subcutaneous fluid collection. He was found to have a peritoneal-mediastinal communication intraoperatively. He was successfully managed with "low-volume" PD by using reduced fill volumes for all his exchanges and did not require transition to iHD. He also had no vascular access options because of multiple prior thromboses, which would have made transitioning to iHD not feasible. This case further highlights the complex management of an ESKD patient who cannot do iHD and only do low-volume PD because of a surgical complication and the need for a multidisciplinary approach to ensure appropriate patient care. more...

Jonathan Corren,1 Sarbjit S Saini,2 Remi Gagnon,3 Mark H Moss,4 Gordon Sussman,5 Joshua Jacobs,6 Elizabeth Laws,7 Elinore S Chung,8 Tatiana Constant,8 Yiping Sun,8 Jennifer Maloney,8 Jennifer D Hamilton,8 Marcella Ruddy,8 Claire Q Wang,8 Meagan P O’Brien8 1Departments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; 2Department of Internal Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins Asthma and Allergy Center, Baltimore, MD, USA; 3Clinique Spécialisée en Allergie de la Capitale, Québec, QC, Canada; 4Departments of Medicine and Pediatrics, Division of Allergy, Pulmonary and Critical Care, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 5Department of Medicine, University of Toronto, Toronto, ON, Canada; 6Allergy and Asthma Clinical Research, Inc, Walnut Creek, CA, USA; 7Sanofi, Bridgewater, NJ, USA; 8Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USACorrespondence: Meagan P O’BrienRegeneron Pharmaceuticals, Inc, 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USATel +1 914 826-5271Email meagan.obrien@regeneron.comJonathan CorrenDepartments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Ave, Los Angeles, CA, 90095, USATel +1 310 312-5050, ext 250Email jcorren@ucla.eduBackground: Subcutaneous immunotherapy (SCIT) has been proven as an effective therapy against some allergens for seasonal allergic rhinitis (SAR) patients unresponsive to intranasal corticosteroids and/or antihistamines but carries risk of systemic allergic reactions. Dupilumab blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation in multiple diseases.Objective: To evaluate the efficacy and safety of SCIT+dupilumab vs SCIT alone.Methods: This phase 2a, multicenter, double-blind, placebo-controlled parallel-group study conducted in 103 adults with grass pollen-induced SAR (NCT03558997) randomized patients 1:1:1:1 to SCIT, dupilumab (300 mg every 2 weeks), SCIT+dupilumab, or placebo. SCIT was administered using an 8-week cluster protocol followed by 8 weeks of maintenance injections. Primary endpoint was change from pre-treatment baseline in area under the curve (AUC) in total nasal symptom score (TNSS) 0– 1 h following nasal allergen challenge (NAC) with timothy grass extract at Week 17.Results: Although 16 weeks of treatment with SCIT+dupilumab did not significantly improve TNSS AUC (0– 1 h) following NAC at Week 17 vs SCIT (least squares mean − 56.76% vs − 52.03%), a higher proportion of SCIT+dupilumab-treated patients (61.5%) achieved SCIT maintenance dose vs SCIT (46.2%). A lower proportion of SCIT+dupilumab-treated patients (7.7%) required epinephrine rescue treatment vs SCIT (19.2%). There were significantly fewer withdrawals in the SCIT+dupilumab group than in the SCIT group (n = 2 [7.7%] vs n = 8 [30.8%]; P = 0.0216); the majority of SCIT group withdrawals were due to SCIT-related intolerability, compared with no discontinuations from the SCIT+dupilumab group.Conclusion: In SAR patients, 16 weeks of SCIT+dupilumab may improve SCIT tolerability but did not incrementally reduce post-allergen challenge nasal symptoms compared with SCIT alone.Clinical Study Number: NCT03558997.Keywords: dupilumab, seasonal allergic rhinitis, subcutaneous immunotherapy, nasal allergen responses more...

This paper presents the detailed study of parameter’s effect on Nusselt number (Nu), friction factor (f), and thermohydraulic performance parameter (η) of a rectangular duct through experiments usi... more...

High-risk neuroblastoma remains therapeutically challenging to treat, and the mechanisms promoting disease aggression are poorly understood. Here, we show that elevated expression of dihydrolipoamide S-succinyltransferase (DLST) predicts poor treatment outcome and aggressive disease in patients with neuroblastoma. DLST is an E2 component of the α-ketoglutarate (αKG) dehydrogenase complex, which governs the entry of glutamine into the tricarboxylic acid cycle (TCA) for oxidative decarboxylation. During this irreversible step, αKG is converted into succinyl-CoA, producing NADH for oxidative phosphorylation (OXPHOS). Utilizing a zebrafish model of MYCN-driven neuroblastoma, we demonstrate that even modest increases in DLST expression promote tumor aggression, while monoallelic dlst loss impedes disease initiation and progression. DLST depletion in human MYCN-amplified neuroblastoma cells minimally affected glutamine anaplerosis and did not alter TCA cycle metabolites other than αKG. However, DLST loss significantly suppressed NADH production and impaired OXPHOS, leading to growth arrest and apoptosis of neuroblastoma cells. In addition, multiple inhibitors targeting the electron transport chain, including the potent IACS-010759 that is currently in clinical testing for other cancers, efficiently reduced neuroblastoma proliferation in vitro. IACS-010759 also suppressed tumor growth in zebrafish and mouse xenograft models of high-risk neuroblastoma. Together, these results demonstrate that DLST promotes neuroblastoma aggression and unveils OXPHOS as an essential contributor to high-risk neuroblastoma. Significance: These findings demonstrate a novel role for DLST in neuroblastoma aggression and identify the OXPHOS inhibitor IACS-010759 as a potential therapeutic strategy for this deadly disease. more...