Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds.

Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule IL17 inhibitors have previously been described. Herein, we report the discovery of a novel class of small molecule IL17A inhibitors, identified via a DNA-encoded chemical library screen, and their subsequent optimization to provide in vivo efficacious inhibitors. These new protein-protein interaction (PPI) inhibitors bind in a previously undescribed mode in the IL17A protein with two copies binding symmetrically to the central cavities of the IL17A homodimer.

Dirty Mass sign of abdominal imaging: A case of silent pneumoperitoneum.

Pneumoperitoneum is a common complication after penetrating abdominal trauma, gastric ulcer, or colitis in which free air is present in the peritoneal or retroperitoneal space. Sole pneumoretroperitoneum, which refers to gas in the retroperitoneal space, is a rare entity, and when significant, results in a characteristic radiographic sign known as "Dirty Mass." Common causes include penetrating trauma or perforation of the retroperitoneal portions of the gastrointestinal tract (duodenum, ascending colon, descending colon, and rectum). Our case describes a 59-year-old female admitted for sudden onset RLQ abdominal pain with Dirty Mass sign on abdominal KUB. Early recognition of these key radiographic findings accelerates management and reduces the risk of developing complications.

Subperiosteal Orbital Hematoma: A Rare Clinical Manifestation of Sickle Cell Disease - A Case Report.

Sickle cell disease (SCD), an inherited vaso-occlusive disorder, results in recurrent painful episodes and a variety of serious systemic complications that can lead to severe disabilities and even death. Here, we report a case of a 19-year-old African American patient with homozygous sickle cell trait who presented with right upper lid edema and ptosis, 3 days after his admission to the hospital following a sickle cell crisis. Initially, mistaken as a superinfection in the context of his disease, a diagnosis of orbital abscess was made. Intravenous antibiotics and a proper treatment plan were set accordingly. Only after extensive clinical and radiological examinations, it turned out to be an acute subperiosteal orbital hematoma, a rare clinical manifestation of SCD. The aim of our case report was to highlight the difference in orbital presentation between osteomyelitis and subperiosteal hematoma, as well as spreading awareness among medical professionals and especially ophthalmologists for this rare presentation of orbital wall infarction, as the initial differential diagnosis of SCD patients with ocular involvement.

CT imaging features of bile duct stent complications.

Biliary stents have been widely used to treat both malignant and benign biliary obstruction. Biliary stenting serves as a temporary measure to maintain ductal patency and promote bile drainage. Biliary decompression can help relieve clinical symptoms of pain, obstructive jaundice, pruritis, fat malabsorption, and failure to thrive and prevent disease progression, such as secondary biliary cirrhosis and end-stage liver failure. Endoscopic placement of biliary endoprosthesis is a minimally invasive procedure well tolerated by most patients but is not without problems. Multiple early and late complications have been reported in the literature and Computed Tomography (CT) is the most used modality to assess normal positions and evaluate patients suspected of stent complications. The aim of this article is to provide a review various of biliary stent related complications, as seen on CT. Current literature on risk factors, diagnosis and management is also discussed.

Facile synthesis of a CuSe/PVP nanocomposite for ultrasensitive non-enzymatic glucose biosensing.

Non-enzymatic glucose biosensors show high sensitivity, lower response time, wide linear range and low cost. Copper based composites show excellent electrocatalytic tunability and lead to a better charge transfer in electrochemical non-enzymatic glucose biosensors. In this work, a nanocomposite of polyvinylpyrrolidone (PVP) and copper selenide was synthesized by a facile one pot sol gel method. Synthesized nanomaterials were characterized by XRD, FTIR, UV-visible spectroscopy, SEM, EDS and XPS techniques. Electrochemical behavior was analyzed by cyclic voltammetry (CV), electrochemical impendence (EIS) and chronoamperometry techniques. XRD analysis revealed a hexagonal structure and crystalline nature of CuSe/PVP. FTIR spectra depicted C-N bonding at 1284 cm-1 and C[double bond, length as m-dash]O stretching at 1634 cm-1, which indicated the presence of PVP in the nanocomposite. Stretching at 823 cm-1 was attributed to the presence of copper selenide. UV-visible absorption indicated the bandgap of copper selenide/PVP at 2.7 eV. SEM analysis revealed a flake like morphology of CuSe/PVP. EDS and XPS analysis confirmed the presence of copper and selenium in the prepared nanocomposite. Prior to employing for biosensing applications, it is important to evaluate the antibacterial activity of nanomaterials for long term use in biological in vitro testing. These materials have shown an efficient inhibition zone of 26 mm against Gram negative Pseudomonas at 50 µg ml-1 and MIC value of 10 µg ml-1. Cyclic voltammetry shows that CuSe/PVP is a promising biosensor for monitoring glucose levels in a wide linear range of 0.5 mM to 3 mM at an excellent sensitivity of 13 450 µA mM-1 cm-2 with an LOD of 0.223 µM. Chronoamperometry measurements revealed a selective behavior of CuSe/PVP for glucose biosensing amongst ascorbic acid and dopamine as common interfering molecules. The nanocomposite was stable after 8 repeated cycles with 92% retention for glucose sensing capacity. This is attributed to the stable nature of the CuSe/PVP nanocomposite as well as higher surface area of available active sites. Herein the CuSe/PVP nanocomposite offered reasonable selectivity, high sensitivity wide linear range with very low LOD, as well as being abundant in nature, this Cu based biosensor has promising applications for future point of care tests (POCT).

Fracture Surface Evolution During Acidized Brine Injection in Calcareous Mudrocks.

During hydraulic fracturing, the oxic hydraulic fracturing fluid physically and chemically alters the fracture surface and creates a "reaction-altered zone". Recent work has shown that most of the physicochemical changes occur on the shale fracture surface, and the depth of reaction penetration is small over the course of shut-in time. In this work, we investigate the physicochemical evolution of a calcite-rich fracture surface during acidized brine injection in the presence of applied compressive stress. A calcite-rich Wolfcamp shale sample is selected, and a smooth fracture is generated. An acidized equilibrated brine is then injected for 16 h, and the pressure change is measured. A series of experimental measurements are done before and after the flood to note the change in physicochemical properties of the fracture. High resolution computed tomography scanning is conducted to observe the fracture aperture growth, which shows an increase of ∼8.3 µm during the course of injection. The fracture topography, observed using a surface roughness analyzer, is shown to be smoother after the injection. The calcite dissolution signature, i.e., surface stripping of calcite, is observed by X-ray fluorescence, and mass spectrometry of the timer-series of the effluent also points in the same direction. We conclude that mineral dissolution is the primary mechanism through which the fracture aperture is growing. The weakening of the fracture surface, along with the applied compressive stresses, promotes erosion of the surface generating fines which reduce the fracture conductivity during the course of injection. In this work, we also highlight the importance of rock mineralogy on the fracture evolution mechanism and determine the thickness of the "reaction altered" zone.

One-pot hydrothermal synthesis of a carbon quantum dot/CaFe2O4 hybrid nanocomposite for carcinogenic Congo red dye degradation.

Semiconductor materials show a restricted degradation response to organic pollutants due to limited photocatalytic activity under visible light. Therefore, researchers have devoted much attention to novel and effective nanocomposite materials. For the first time, herein, a novel nano-sized semiconductor calcium ferrite modified by carbon quantum dots (CaFe2O4/CQDs) photocatalyst is fabricated via simple hydrothermal treatment for the degradation of aromatic dye using a visible light source. The crystalline nature, structure, morphology, and optical parameters of each of the synthesized materials were investigated using X-ray diffraction spectroscopy (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and UV-visible spectroscopy. The nanocomposite exhibits excellent photocatalytic performance (90% degradation) against Congo red (CR) dye. In addition, a mechanism for CaFe2O4/CQDs improving photocatalytic performance has been proposed. The CQDs in the CaFe2O4/CQD nanocomposite are considered to act as an electron pool and transporter, as well as a strong energy transfer material, during photocatalysis. CaFe2O4/CQDs appear to be a promising and cost-effective nanocomposite for dye-contaminated water purification, according to the findings of this study.

A comprehensive review of transvenous obliteration techniques in the management of gastric varices.

Bleeding gastric varices (GVs) is a life-threatening complication of portal hypertension, with higher morbidity and mortality rates compared with bleeding esophageal varices (EVs). The endovascular techniques for the management of GVs are mainly transjugular intrahepatic portosystemic shunt (TIPS) and transvenous obliteration of the GVs. Transvenous obliteration techniques can be an alternative or an adjunct to TIPS for treatment of GVs, depending on the clinical scenario, and are less invasive than TIPS. However, these procedures are associated with increased portal pressure and related complications, mainly worsening of the EVs. In this article, the different techniques of transvenous obliteration of GVs, their indications, contraindications, and outcomes are discussed.

Localized nasopharyngeal amyloidosis: A case report.

Amyloidosis is a rare condition on its own but finding localized amyloidosis of a site such as the nasopharynx is an extremely rare condition with very few cases described in the literature. The condition occurs due to the accumulation of misfolded proteins in the extracellular space disrupting the cell architecture and causing eventual dysfunction. In this case report we discuss the pathophysiology, symptoms, and imaging findings of a patient initially thought to have giant cell arteritis, but who was found on CT to have a mass later determined to be localized nasopharyngeal amyloidosis. Evaluation will require biopsy as it is the gold standard, but there are many other tests and even reasons to consider the use of interventional radiology to sample other tissues rather than the primary target site for amyloid deposition in conjunction with nuclear imaging.

Peritoneal vaginal fistula and contrast extravasation during MRI.

Gynecological malignancies including primary cervical cancers are frequently treated with chemotherapy and radiation. Fistulas affecting the gynecological organs and surrounding cavities are a known consequence of radiotherapy due to focal necrosis of the regional mucosa. In this report, we will demonstrate a rare case of a posterior vaginal wall rupture with resulting fistulization into the peritoneal cavity in a 50-year-old female patient with squamous cell carcinoma of the cervix status postchemoradiotherapy. Magnetic resonance imaging (MRI) showed a discontinuity in the posterior vaginal wall near the fornix with extravasation of ultrasound gel used as contrast into the intraperitoneal compartment. Patient later presented with peritonitis like signs and symptoms and was treated successfully with antibiotics. Vaginal gel should be used with caution in patients with prior history of radiation due to the possibility of vaginal rupture which may lead to peritoneal vaginal fistula and contrast extravasation.

Perception of Dietary Influences on Renal Stone Formation Among the General Population.

Introduction Urolithiasis is a common disorder worldwide with an increasing prevalence and high recurrence rate. This makes preventive measures like dietary modification an essential part of patient care. This study focuses on gauging the perception of dietary habits favoring kidney stone formation. Materials and methods A cross-sectional questionnaire-based study was conducted at Aga Khan University, Karachi, Pakistan. For nine food items and 14 beverages, respondents chose one of four options with regards to their relationship with stone formation, i.e. "increasing", "decreasing", "no effect", and "do not know". Responses were matched against evidence from the literature to generate correct and incorrect responses, thereby gauging perception for individual items.  Results Seven hundred and three participants including 69 (9.6%) with a prior history of kidney stones, were recruited for the study. Participants with a personal history of kidney stone disease were older (odds ratio {OR}: 1.042 CI 1.020-1.064) with a significantly higher family history of stones (OR: 2.151 CI: 1.472-3.144). The majority were managed medically (87%) but never received dietary counseling (57%). Water, soft drinks, and tomatoes were the only three items out of 23 that were correctly identified by >50% of the participants with regards to their effect on stone formation. Responses did not differ significantly between those with stone disease and those without. Conclusion There is a lack of awareness among the general population, including individuals with a prior history of kidney stones regarding dietary prevention of kidney stone disease. This demonstrates a lack of existing dietary counseling thus necessitating the need for incorporating it at a mass level.

Coexistence of superior mesenteric artery syndrome and nutcracker phenomenon.

Superior mesenteric artery (SMA) syndrome is a rare cause of upper gastrointestinal obstruction. Nutcracker syndrome occurs as the result of external compression of the left renal vein. Although they share a similar pathophysiology, SMA and nutcracker syndrome occurring simultaneously is rare. In this case report, we discuss the pathophysiology and unique computed tomography findings in a 25-year-old female patient diagnosed with SMA syndrome who was also incidentally found to have a coexisting nutcracker phenomenon. Due to similar pathogenesis, radiologists should consider the possibility of coexistence of these rare syndromes in appropriate patients.

Hemosuccus Pancreaticus: A Comprehensive Review of Presentation Patterns, Diagnostic Approaches, Therapeutic Strategies, and Clinical Outcomes.

Hemosuccus pancreaticus is a rare but potentially torrential and life-threatening cause of acute upper gastrointestinal bleeding. It is described as an intermittent hemorrhage from the major duodenal papilla via the main pancreatic duct. Peripancreatic pseudoaneurysm following chronic pancreatitis is a common underlying etiology. However, gastroduodenal artery pseudoaneurysm-related hemosuccus pancreaticus remains exceedingly rare in the etiological spectrum of upper gastrointestinal bleeding. We hereby delineate a rare case of hemosuccus pancreaticus associated with gastroduodenal artery pseudoaneurysm in a patient who initially presented with abdominal pain and hematochezia. He was successfully managed with coil embolization without recurrence or sequelae. Furthermore, we conducted a search of the MEDLINE (PubMed and Ovid) database for relevant studies on hemosuccus pancreaticus published between inception and September 15, 2021. The available clinical evidence on causes, presentation patterns, diagnosis, and management was analyzed and summarized. This article highlights the rarity, the intermittent nature of hemorrhage, and the lack of a standardized diagnostic approach for this elusive disease. Clinicians should remain cognizant of hemosuccus pancreaticus, especially in patients presenting with symptoms and signs of intermittent gastrointestinal bleeding and abdominal pain. Prompt diagnosis carries paramount importance in saving patients from repeat hospital admissions and disease-associated morbidity and mortality. Conventional angiography with coil embolization may constitute an effective treatment strategy.

Bioengineering bacterial encapsulin nanocompartments as targeted drug delivery system.

The development of Drug Delivery Systems (DDS) has led to increasingly efficient therapies for the treatment and detection of various diseases. DDS use a range of nanoscale delivery platforms produced from polymeric of inorganic materials, such as micelles, and metal and polymeric nanoparticles, but their variant chemical composition make alterations to their size, shape, or structures inherently complex. Genetically encoded protein nanocages are highly promising DDS candidates because of their modular composition, ease of recombinant production in a range of hosts, control over assembly and loading of cargo molecules and biodegradability. One example of naturally occurring nanocompartments are encapsulins, recently discovered bacterial organelles that have been shown to be reprogrammable as nanobioreactors and vaccine candidates. Here we report the design and application of a targeted DDS platform based on the Thermotoga maritima encapsulin reprogrammed to display an antibody mimic protein called Designed Ankyrin repeat protein (DARPin) on the outer surface and to encapsulate a cytotoxic payload. The DARPin9.29 chosen in this study specifically binds to human epidermal growth factor receptor 2 (HER2) on breast cancer cells, as demonstrated in an in vitro cell culture model. The encapsulin-based DDS is assembled in one step in vivo by co-expressing the encapsulin-DARPin9.29 fusion protein with an engineered flavin-binding protein mini-singlet oxygen generator (MiniSOG), from a single plasmid in Escherichia coli. Purified encapsulin-DARPin_miniSOG nanocompartments bind specifically to HER2 positive breast cancer cells and trigger apoptosis, indicating that the system is functional and specific. The DDS is modular and has the potential to form the basis of a multi-receptor targeted system by utilising the DARPin screening libraries, allowing use of new DARPins of known specificities, and through the proven flexibility of the encapsulin cargo loading mechanism, allowing selection of cargo proteins of choice.

A Critical Review of the Physicochemical Impacts of Water Chemistry on Shale in Hydraulic Fracturing Systems.

Hydraulic fracturing of unconventional hydrocarbon resources involves the sequential injection of a high-pressure, particle-laden fluid with varying pH's to make commercial production viable in low permeability rocks. This process both requires and produces extraordinary volumes of water. The water used for hydraulic fracturing is typically fresh, whereas "flowback" water is typically saline with a variety of additives which complicate safe disposal. As production operations continue to expand, there is an increasing interest in treating and reusing this high-salinity produced water for further fracturing. Here we review the relevant transport and geochemical properties of shales, and critically analyze the impact of water chemistry (including produced water) on these properties. We discuss five major geochemical mechanisms that are prominently involved in the temporal and spatial evolution of fractures during the stimulation and production phase: shale softening, mineral dissolution, mineral precipitation, fines migration, and wettability alteration. A higher salinity fluid creates both benefits and complications in controlling these mechanisms. For example, higher salinity fluid inhibits clay dispersion, but simultaneously requires more additives to achieve appropriate viscosity for proppant emplacement. In total this review highlights the nuances of enhanced hydrogeochemical shale stimulation in relation to the choice of fracturing fluid chemistry.

Degradation of highly chlorinated pesticide, lindane, in water using UV/persulfate: kinetics and mechanism, toxicity evaluation, and synergism by H2O2.

Sulfate radical-advanced oxidation processes (SR-AOPs) are emerging technologies for decomposing organic pollutants in water. This study investigated the efficiency of UV/persulfate (UV/S2O82-) process to degrade lindane in water, showing 93.2% lindane removal ([lindane]0 = 3.43 µM, [S2O82-]0 = 100 µM) at a UV fluence of 720 mJ/cm2. The lindane degradation followed first order kinetics and mechanistic studies suggested H-abstraction by SO4•- and Cl removal via C-Cl bond cleavage by UV-C light. Toxicity assessment using ECOSAR program showed toxicity gradually decreased and eventually no significant toxicity remained when all by-products vanished at high UV dose. Removal efficiency of lindane decreased from 93.2% to 38.4, 45.5, 56.0, 84.3 and 88.6%, by adding 1.0 mg/L humic acid or 1.0 mM CO32-, HCO3-, Cl- or SO42-, respectively. Coupling of H2O2 with UV/S2O82- showed a significant synergistic effect with 99.0% lindane removal at a UV fluence of 600 mJ/cm2, using [S2O82-]0 = [H2O2]0 = 50 µM while UV/H2O2 resulted in only 36.6% lindane removal ([lindane]0 = 3.43 µM, [H2O2]0 = 100 µM) at a UV fluence of 720 mJ/cm2. The results indicate that SR-AOP has potential for consideration as a remedial technology to treat persistent chlorinated pesticides such as lindane in contaminated water.

Replicating carbonaceous vug in synthetic porous media.

This paper presents an alternative method of creating vuggy glass-bead core proxies, which can be used to investigate the effects of pore-scale features on carbonate petrophysical properties. Carbonates are complex rocks having a widespread variation in pore type, size, distribution, and porosity. With this method we can control vug shape, size, and position. Homogeneous glass bead core proxies are sintered using 1.0 mm diameter glass beads in a muffle furnace. Vugs are 3D-printed in plastic and used to make a mold in Play-Doh®; which is cast in gypsum cement and used as a placeholder during the sintering process. The gypsum vug dissolves during acid flood, leaving an empty space inside the glass matrix. Computed tomography (CT) scans are made of the acid washed vug space and compared to the 3D model.

Hydrogenation catalyst generates cyclic peptide stereocentres in sequence.

Molecular recognition plays a key role in enzyme-substrate specificity, the regulation of genes, and the treatment of diseases. Inspired by the power of molecular recognition in enzymatic processes, we sought to exploit its use in organic synthesis. Here we demonstrate how a synthetic rhodium-based catalyst can selectively bind a dehydroamino acid residue to initiate a sequential and stereoselective synthesis of cyclic peptides. Our combined experimental and theoretical study reveals the underpinnings of a cascade reduction that occurs with high stereocontrol and in one direction around a macrocyclic ring. As the catalyst can dissociate from the peptide, the C to N directionality of the hydrogenation reactions is controlled by catalyst-substrate recognition rather than a processive mechanism in which the catalyst remains bound to the macrocycle. This mechanistic insight provides a foundation for the use of cascade hydrogenations.

Oxidative removal of brilliant green by UV/S2O82‒, UV/HSO5‒ and UV/H2O2 processes in aqueous media: A comparative study.

The removal of brilliant green (BG), a toxic organic and cationic dye, has been examined by UV/S2O82- (PS), UV/HSO5- (PMS) and UV/H2O2 processes. BG showed insignificant direct photolysis at 254 nm (i.e., 8.6% after 30 min). However, enhanced BG degradation was observed in UV/PS, UV/PMS and UV/H2O2 systems as revealed from 63.1, 47.0 and 34.8% BG degradation, respectively, at 30 min of reaction time, using 0.05 mM BG and 1.0 mM oxidant initial concentration. The bimolecular rate constants of OH and SO4- with BG were determined to be 2.35 × 109 and 2.21 × 109 M-1 s-1, respectively. Electrical energy per order (EE/O) values for UV/PS, UV/PMS and UV/H2O2 processes were calculated to be 5.4, 6.8, and 7.8 KWh/m3/order, respectively. The addition of humic acid (HA) and inorganic anions inhibited the degradation of BG by UV/PS in the order of NO2- > HA > HCO3- > Cl-  > NO3- ≈ SO42-. The results of frontier electron densities (FEDs) showed that C-atom holding the three rings (C7), and C-atoms at para positions to N-alkyl groups of the two rings (C4 and C14) are the predominant sites for radical addition. Furthermore, nine degradation products (DPs) of BG were detected experimentally using LC/MS/MS.

Seroprevalence of anti-polio antibodies in children from polio high risk area of Afghanistan: A cross sectional survey 2017.

BACKGROUND: Afghanistan is one of the remaining wild-poliovirus (WPV) endemic countries. We conducted a seroprevalence survey of anti-poliovirus antibodies in Kandahar Province. METHODS: Children in two age groups (6-11 months and 36-48 months) visiting Mirwais hospital in Kandahar for minor ailments unrelated to polio were enrolled. After obtaining informed consent, we collected venous blood and conducted neutralization assay to detect poliovirus neutralizing antibodies. RESULTS: A total of 420 children were enrolled and 409/420 (97%) were analysed. Seroprevalence to poliovirus type 1 (PV1) was 97% and 100% in the younger and older age groups respectively; it was 71% and 91% for PV2; 93% and 98% for PV3. Age group (RR = 3.6, CI 95% = 2.2-5.6) and place of residence outside of Kandahar city (RR = 1.8, CI 95% = 1.2-2.6) were found to be significant risk factors for seronegativity. CONCLUSIONS: The polio eradication program in Kandahar achieved high serological protection, especially against PV1 and PV3. Lower PV2 seroprevalence in the younger age group is a result of a withdrawal of live type 2 vaccine in 2016 and is expected. Ability to reach all children with poliovirus vaccines is a pre-requisite for achieving poliovirus eradication.