Pathogenesis and progression of anosmia and dysgeusia during the COVID-19 pandemic.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is the causative agent of COVID-19 which was detected in late 2019 in Wuhan, China. As of September 2022, there have been over 612 million confirmed cases of COVID-19 with over 6.5 million associated deaths. In many cases, anosmia and dysgeusia have been identified as primary symptoms of COVID-19 infection in patients. While the loss of smell (anosmia) and loss of taste (dysgeusia) due to COVID-19 infection is transient in most patients, many report that these symptoms persist following recovery. Understanding the pathogenesis of these symptoms is paramount to early treatment of the infection. We conducted a literature review of Google Scholar and PubMed to find and analyze studies discussing anosmia and dysgeusia in the context of COVID-19 to understand the progression and management of these symptoms. The mechanism for dysgeusia is largely unknown; however, pathogenesis of anosmia includes inflammation and cytokine release resulting from the infection that alters neuronal signaling, thus inducing the loss of smell that patients experience. Anosmia may be managed and potentially resolved sooner with a combination therapy of olfactory training and budesonide irrigation of the nasal cavity. It is important to note that the variants of SARS-CoV-2 are genetically distinguished from the original virion due to a mutation in their spike proteins, giving them a different symptom profile regarding anosmia and dysgeusia. This variability in symptomatology is an area of study that needs to be further explored.

Pregnane-Oximino-Alkyl-Amino-Ether Compound as a Novel Class of TGR5 Receptor Agonist Exhibiting Antidiabetic and Anti-Dyslipidemic Activities.

INTRODUCTION: The present study deals with the synthesis of pregnane-oximino-amino-alkyl-ethers and their evaluation for antidiabetic and anti-dyslipidemic activities in validated animal and cell culture models. METHODS: The effect on glucose tolerance was measured in sucrose-loaded rats; antidiabetic activity was evaluated in streptozotocin (STZ)-induced diabetic rats and genetically diabetic db/db mice; the anti-dyslipidemic effect was characterized in high-fructose, high-fat diet (HFD)-fed dyslipidemic hamsters. The effect on glucose production and glucose utilization was analyzed in HepG2 liver and L6 skeletal muscle cells, respectively. RESULTS: From the synthesized molecules, pregnane-oximino-amino-alkyl-ether (compound 14b) improved glucose clearance in sucrose-loaded rats and exerted antihyperglycemic activity on STZ-induced diabetic rats. Further evaluation in genetically diabetic db/db mice showed temporal decrease in blood glucose, and improvement in glucose tolerance and lipid parameters, associated with mild improvement in the serum insulin level. Moreover, compound 14b treatment displayed an anti-dyslipidemic effect characterized by significant improvement in altered lipid parameters of the high-fructose, HFD-fed dyslipidemic hamster model. In vitro analysis in the cellular system suggested that compound 14b decreased glucose production in liver cells and stimulated glucose utilization in skeletal muscle cells. These beneficial effects of compound 14b were associated with the activation of the G-protein-coupled bile acid receptor TGR5. CONCLUSION: Compound 14b exhibits antidiabetic and anti-dyslipidemic activities through activating the TGR5 receptor system and can be developed as a lead for the management of type II diabetes and related metabolic complications.

Disinfestation of stored wheat grain infested with Rhyzopertha dominica by ozone treatment: process optimization and impact on grain properties.

BACKGROUND: Ozone is a highly oxidative gas that has a long history of safe use as a disinfectant and sanitizer from producers of pharmaceuticals and many other organic compounds. In the current work, disinfestation of stored wheat grain infested with a common insect, Rhyzopertha dominica, was attempted through ozone (O3 ) treatment as an alternative to chemical fumigants. RESULTS: The optimized treatment conditions for ozone fumigation of stored wheat grain were 12% (w/w) grain moisture, 2.5 g m-3 ozone concentration and 8 h of treatment. The mortality of R. dominica adults, pupae, larvae and eggs was 97, 100, 99 and 100%, respectively. Moisture and protein content of the ozone-treated wheat was found to be lower as compared to infested wheat. Microstructural changes in the treated samples were clearly visible on scanning electron microscopy images, whereas minimal changes at the molecular level and of rheological parameters were evident based on Fourier transform infrared spectroscopy peak and rheometry data. CONCLUSION: Ozone was found to be an effective reagent for disinfestation, aimed at all life stages of R. dominica in stored wheat grain, that leaves no residue behind. Rotational strategies can be applied to obtain increased mortality while maintaining the usability of the grain for different purposes. © 2019 Society of Chemical Industry.

Cholesterol Biosynthesis: A Mechanistic Overview.

Cholesterol is an essential component of cell membranes and the precursor for the synthesis of steroid hormones and bile acids. The synthesis of this molecule occurs partially in a membranous world (especially the last steps), where the enzymes, substrates, and products involved tend to be extremely hydrophobic. The importance of cholesterol has increased in the past half-century because of its association with cardiovascular diseases, which are considered one of the leading causes of death worldwide. In light of the current need for new drugs capable of controlling the levels of cholesterol in the bloodstream, it is important to understand how cholesterol is synthesized in the organism and identify the main enzymes involved in this process. Taking this into account, this review presents a detailed description of several enzymes involved in the biosynthesis of cholesterol. In this regard, the structure and catalytic mechanism of the enzymes involved in cholesterol biosynthesis, from the initial two-carbon acetyl-CoA building block, will be reviewed and their current pharmacological importance discussed. We believe that this review may contribute to a deeper level of understanding of cholesterol metabolism and that it will serve as a useful resource for future studies of the cholesterol biosynthesis pathway.

1-[3-(2-Hydroxyethylsulfanyl)propanoyl]-3,5-bis(benzylidene)-4-piperidones: A novel cluster of P-glycoprotein dependent multidrug resistance modulators.

A series of 1-[3-(2-hydroxyethylsulfanyl)propanoyl]-3,5-bis(benzylidene)-4-piperidones 4a-e display promising P-glycoprotein dependent multidrug resistance (MDR) revertant properties and are significantly more potent than a reference drug verapamil when evaluated against L-5178Y MDR lymphoma cells. These dienones may be referred to as dual agents having both MDR revertant properties and tumour-selective cytotoxicity. In particular, 3,5-bis(4-chlorobenzylidene)-1-[3-(2-hydroxyethylsulfanyl]propanoyl-4-piperidone 4d emerged as a lead molecule for further development based on its MDR revertant properties, cytotoxic potencies and tumour-selective toxicity. The structure-activity relationships reveal important structural requirements for further designing of potent MDR revertants.

Unraveling the mechanism of neuroprotection of curcumin in arsenic induced cholinergic dysfunctions in rats.

Earlier, we found that arsenic induced cholinergic deficits in rat brain could be protected by curcumin. In continuation to this, the present study is focused to unravel the molecular mechanisms associated with the protective efficacy of curcumin in arsenic induced cholinergic deficits. Exposure to arsenic (20mg/kg body weight, p.o) for 28 days in rats resulted to decrease the expression of CHRM2 receptor gene associated with mitochondrial dysfunctions as evident by decrease in the mitochondrial membrane potential, activity of mitochondrial complexes and enhanced apoptosis both in the frontal cortex and hippocampus in comparison to controls. The ultrastructural images of arsenic exposed rats, assessed by transmission electron microscope, exhibited loss of myelin sheath and distorted cristae in the mitochondria both in the frontal cortex and hippocampus as compared to controls. Simultaneous treatment with arsenic (20mg/kg body weight, p.o) and curcumin (100mg/kg body weight, p.o) for 28 days in rats was found to protect arsenic induced changes in the mitochondrial membrane potential and activity of mitochondrial complexes both in frontal cortex and hippocampus. Alterations in the expression of pro- and anti-apoptotic proteins and ultrastructural damage in the frontal cortex and hippocampus following arsenic exposure were also protected in rats simultaneously treated with arsenic and curcumin. The data of the present study reveal that curcumin could protect arsenic induced cholinergic deficits by modulating the expression of pro- and anti-apoptotic proteins in the brain. More interestingly, arsenic induced functional and ultrastructural changes in the brain mitochondria were also protected by curcumin.

Breath-based biosensors and system development for noninvasive detection of diabetes: A review.

BACKGROUND AND AIMS: In recent years, noninvasive techniques are becoming conspicuous for diabetes detection. Sweat, tear, saliva, urine and breath-based methods showing prominent results in breath acetone detection which is considered as a biomarker of diabetes. A concrete relationship between breath acetone and BG helps in the development of devices for diabetes detection. METHODS: The primary source for this study includes scholarly publications that primarily focus on the development of biosensors and systems for diabetes detection using acetone present in breath. Articles were analysed to examine various types of biosensors with their sensing materials to provide acetone detection limits. Recent noninvasive systems and products have been investigated and determine the relationship between breath acetone and BG levels. RESULTS: Breath-based biosensor technologies are capable for diabetes detection. The acetone biosensor detection ranges from 100 ppb to 100 ppm, and it can applicable from room temperature to 400 °C. In healthy volunteers, acetone level ranges from 0.32 to 2.19 ppm, while patients with diabetes exhibit a wider range of 0.22-21 ppm depending on the biosensor, detection method, and clinical circumstances of patients and lab conditions. CONCLUSION: This manuscript presents an extensive analysis of breath-based biosensors and their potential for detection of diabetes. Acetone detection methods are promising but unable to provide concrete correlation between breath acetone and blood glucose levels. The present study motivates the continued research and development of biosensors, and electronic devices to provide linear relationship of breath acetone and BG for noninvasive diabetes detection applications.

Trends in Natural Decannulation in Patients with Robin Sequence: A Twenty-five Year Retrospective Review.

OBJECTIVE: Robin sequence (RS) consists of micrognathia and glossoptosis that result in upper airway obstruction (UAO). In RS patients who undergo tracheostomy, long-term goals include natural decannulation (ND) without further surgical airway intervention. The objective of this study was to identify long-term trends in the rate and length of time to ND. METHODS: Retrospective chart review on 144 patients with RS treated from 1995 to 2020 at a pediatric tertiary care center. Patients were grouped by year of tracheostomy. Demographic data, UAO management, postoperative care, complications, and time to decannulation were recorded. RESULTS: Thirty-six patients met the inclusion criteria. Tracheostomy was performed at a median age of 45.5 days. 19 (53%) patients experienced ND at a median time of 66.1 months. ND rate was higher in non-syndromic patients (93% non-syndromic vs 27% syndromic; P < .0001) and during the first study period (1995-2006: 78%, 2007-2020: 28%; P = .003). Cox proportional-hazard regression demonstrated that white race [aHR 0.15 (0.03-0.8); P = .023] and higher birthweight [aHR 0.9 (0.8-0.98); P = .018] were associated with a higher likelihood of ND while a syndromic diagnosis had a negative association with ND [aHR 12.5 (3.3-50.0); P < .001]. CONCLUSIONS: Our study documented that ND in patients with RS who underwent tracheostomy was significantly associated with ethnicity, birthweight, and syndromic status. The negative impact on successful ND was most observed in patients with syndromic associations. Additionally, ND rates are lower in the 2007 to 2020 subgroup. We suspect this is because alternative management techniques such as tongue lip adhesion and mandibular distraction osteogenesis became primary surgical treatment in severe RS upper airway obstruction at our institution starting in 2007.

Impact of upper airway obstruction management in Robin Sequence on need for myringotomy tubes.

OBJECTIVE: Investigate an association between upper airway obstruction (UAO) management in Robin Sequence (RS) and need for bilateral myringotomy and tubes (BMT). METHODS: Retrospective chart review of RS patients treated at a tertiary free-standing pediatric hospital from 1995 to 2020 was performed. Patients were grouped based on airway management: conservative, tracheostomy, tongue-lip adhesion (TLA), and mandibular distraction osteogenesis (MDO). Demographic data, cleft palate (CP) association, numbers of BMT and ear infections, and audiogram data including tympanograms were collected. One-way ANOVA and Chi-square/Fisher's exact tests were used to compare continuous and categorical data, respectively. Multivariable regression analysis was used to compare BMT rates between treatment groups. RESULTS: One hundred forty-eight patients were included, 70.3 % of which had CP. Most patients (67.6 %) had at least one BMT; 29.1 % required two or more BMT. The rate of BMT was higher in patients with CP compared to those with intact palates (p = 0.003; 95 % CI 1.30-3.57) and those treated with tracheostomy (p = 0.043; 95 % CI 1.01, 2.27). Surgically managed patients were more likely to have hearing loss (67.5 % vs. 35.3 %, p = 0.017) and ear infections (42.1 % vs. 20.0 %, p = 0.014) pre-compared to post-procedure for airway management. CONCLUSION: Most RS patients require at least 1 set of BMT. Those with CP and/or treated with tracheostomy had a higher likelihood of needing BMT. Rate of hearing loss and ear infection was higher in surgically managed RS patients. Patients with RS and overt CP require a statistically higher number of BMTs compared to those with either submucous cleft palate or intact palate.

Synthetic α-(aminomethyl)-γ-butyrolactones and their anti-pancreatic cancer activities.

Aminated α-methylene-γ-butyrolactones, which are readily synthesized with facile control of the diastereoisomerism, provide an economical and commercially-viable alternative to the use of aminated natural products. These aminoloactones, which exhibit excellent activity against three pancreatic cancer cell lines when measured at 10 µM-Panc-1, MIA PaCa-2, and BxPC-3-and are comparable to or better than parthenolide and dimethylaminoparthenolide (DMAPT, LC-1). It has also been shown that there is an effect on the biological activity depending on the identity of the amine.

Forced inspiratory suction and swallow tool (FISST): an automation of Valsalva maneuver variants for therapeutic interventions.

INTRODUCTION: The Valsalva maneuver and its modifications have been utilized across several conditions in medicine; however, there have been difficulties in its application. Thus, at the University of Texas Health Science Center in San Antonio, we designed and patented an affordable and accessible device that mimics Valsalva called "Forced Inspiratory Suction and Swallow Tool (FISST). AREAS COVERED: In this review, we discuss the premise for the design of FISST, based on applications of the law of conservation energy, the continuity equation, and Bernoulli's principle. We then detail the mechanism by which FISST stimulates hiccup cessation by increasing negative inspiratory pressure when drinking through the apparatus, causing diaphragmatic contraction and disruption of the hiccup reflex. We then detail the efficacy and future applications of FISST in addressing other pathologies. EXPERT OPINION: FISST has been used to address hiccups by utilizing its reverse-Valsalva effect to increase parasympathetic stimulation by increasing vagal tone. In a prospective study that we conducted on a cohort of 249 hiccup subjects worldwide, this tool achieved 92% effectiveness. Additionally, several cases, including a published case report, have found FISST successful in terminating supraventricular tachycardias (SVT). FISST may be further utilized in diagnosing or addressing various upper airway pathologies and should be explored further.

Socioeconomic Status Affects Postoperative Time to Union in Pediatric Patients with a Surgically Treated Fracture.

Fractures account for 10% to 25% of all pediatric injuries, and surgical treatment is common. In such cases, postoperative healing can be affected by a number of factors, including those related to socioeconomic status (SES). The purpose of this study was to investigate the relationship between time to fracture union and SES, which was measured with use of the median household income (MHI) and Child Opportunity Index (COI). Methods: A retrospective review was conducted of pediatric patients with a long-bone fracture that had been surgically treated at a Level-I pediatric trauma center between January 2010 and June 2020. Demographic and relevant medical data were collected. Patients were sorted into union and nonunion groups. The ZIP code of each patient was collected and the MHI and COI of that ZIP code were identified. Income brackets were created in increments of $10,000 ranging from $20,000 to $100,000, with an additional category of >$100,000, and patients were sorted into these groups according to MHI. Comparisons among the income groups and among the union status groups were conducted for each of the collected variables. A multiple regression analysis was utilized to determine the independent effect of each variable on time to union. Results: A total of 395 patients were included in the final sample, of whom 51% identified as Hispanic. Patients in the union group had a higher mean COI and MHI. Nonunion occurred in only 8 patients. Patients who achieved fracture union in ≤4 months had a significantly higher mean COI and MHI. When controlling for other demographic variables, the time to union increased by a mean of 9.6 days for every $10,000 decrease in MHI and increased by a mean of 6.8 days for every 10-unit decrease in the COI. Conclusions: The present study is the first, to our knowledge, to investigate the relationship between SES and time to fracture union in pediatric patients. When controlling for other demographic factors, we found a significant relationship between SES and time to union in pediatric patients with a surgically treated fracture. Further investigations of the relationship between SES and time to union in pediatric patients are needed to determine potential mechanisms for this relationship. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Malabaricone C, a constituent of spice Myristica malabarica, exhibits anti-inflammatory effects via modulation of cellular redox.

The present study primarily focuses on the efficacy of Malabaricone C (Mal C) as an anti-inflammatory agent. Mal C inhibited mitogen-induced T-cell proliferation and cytokine secretion. Mal C significantly reduced cellular thiols in lymphocytes. N-acetyl cysteine (NAC) restored cellular thiol levels and abrogated Mal C-mediated inhibition of T-cell proliferation and cytokine secretion. Physical interaction between Mal C and NAC was evinced from HPLC and spectral analysis. Mal C treatment significantly inhibited concanavalin A-induced phosphorylation of ERK/JNK and DNA binding of NF-κB. Administration of Mal C to mice suppressed T-cell proliferation and effector functions ex vivo. Mal C treatment did not alter the homeostatic proliferation of T-cells in vivo but completely abrogated acute graft-versus-host disease (GvHD)-associated morbidity and mortality. Our studies indicate probable use of Mal C for prophylaxis and treatment of immunological disorders caused due to hyper-activation of T-cells.

One-pot asymmetric synthesis of 2- and 2,3-disubstituted tetrahydrofuran derivatives.

A novel and convenient one-pot asymmetric synthesis of 2- and 2,3-disubstituted tetrahydrofurans has been achieved in 56-81% yields and 86-99% ee from aliphatic and aromatic aldehydes via an allyl/crotyl/alkoxyallylboration-hydroboration-iodination-cyclization reaction sequence.

The potential value of the neutral comet assay and the expression of genes associated with DNA damage in assessing the radiosensitivity of tumor cells.

The assessment of tumor radiosensitivity would be particularly useful in optimizing the radiation dose during radiotherapy. Therefore, the degree of correlation between radiation-induced DNA damage, as measured by the alkaline and the neutral comet assays, and the clonogenic survival of different human tumor cells was studied. Further, tumor radiosensitivity was compared with the expression of genes associated with the cellular response to radiation damage. Five different human tumor cell lines were chosen and the radiosensitivity of these cells was established by clonogenic assay. Alkaline and neutral comet assays were performed in γ-irradiated cells (2-8Gy; either acute or fractionated). Quantitative PCR was performed to evaluate the expression of DNA damage response genes in control and irradiated cells. The relative radiosensitivity of the cell lines assessed by the extent of DNA damage (neutral comet assay) immediately after irradiation (4Gy or 6Gy) was in agreement with radiosensitivity pattern obtained by the clonogenic assay. The survival fraction of irradiated cells showed a better correlation with the magnitude of DNA damage measured by the neutral comet assay (r=-0.9; P<0.05; 6Gy) than evaluated by alkaline comet assay (r=-0.73; P<0.05; 6Gy). Further, a significant correlation between the clonogenic survival and DNA damage was observed in cells exposed to fractionated doses of radiation. Of 15 genes investigated in the gene expression study, HSP70, KU80 and RAD51 all showed significant positive correlations (r=0.9; P<0.05) with tumor radiosensitivity. Our study clearly demonstrated that the neutral comet assay was better than alkaline comet assay for assessment of radiosensitivities of tumor cells after acute or fractionated doses of irradiation.

Delayed cerebral pseudoaneurysm following surgical and combined-modality therapy for glioblastoma multiforme: illustrative case.

BACKGROUND: Post-radiation therapy and chemotherapy cerebral pseudoaneurysms are rare entities. Within previous tumor treatment areas on nonvascular imaging, they are potentially confused as recurrent tumor. OBSERVATIONS: A 61-year-old man was a long-term survivor of glioblastoma multiforme whose treatment consisted of open biopsy followed by radiotherapy to 60 Gy and systemic carmustine. On surveillance imaging, enlargement of a posttreatment cyst and new enhancing lateral "mural nodule" was first noticed approximately 16 years after initial treatment. Over 12 months, both continued to enlarge. Initially referred to as recurrence, subsequent angiography showed the mural nodule to be an unruptured distal middle cerebral artery pseudoaneurysm within the previous tumor bed. The patient underwent repeat craniotomy for clipping of the aneurysm and biopsy of the cyst wall, which was negative for malignancy. LESSONS: Delayed pseudoaneurysms following radiation therapy and chemotherapy for malignant brain tumors are rare but have been previously reported. Their appearance on cross-sectional imaging can mimic recurrence, and they should be kept in the differential of new, circumscribed enhancement within such treatment areas.

Current and Future Biomarkers for Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma.

With the introduction of immunotherapy, significant improvement has been made in the treatment of head and neck squamous cell carcinoma (HNSCC). However, only a small subset of patients with HNSCC benefit from immunotherapy. The current biomarker, a programmed cell death protein ligand 1 (PD-L1) expression that is widely used in treatment decision making for advanced HNSCC, has only a moderate predictive value. Additionally, PD-L1-based assay has critical inherent limitations due to its highly dynamic nature and lack of standardization. With the advance in molecular techniques and our understanding of biology, more reliable, reproducible, and practical novel biomarkers are being developed. These include but are not limited to neoantigen/mutation characteristics, immune transcriptomes, tumor-infiltrating immune cell composition, cancer epigenomic, proteomics and metabolic characteristics, and plasma-based and organoid assays.

There should always be a free lunch: the impact of COVID-19 lockdown suspension of the mid-day meal on nutriture of primary school children in Karnataka, India.

Background: The COVID-19 pandemic lockdown in 2020 resulted in school closures with eventual suspension of the mid-day meal programme, biannual deworming and iron-folic acid supplements. One year into the lockdown, we evaluated the impact of the withdrawal of these programmes on the nutritional status of rural primary-school children, aged 6-12 years, in Karnataka, India. Methods: Anthropometry, haemoglobin, serum ferritin and C reactive protein were measured in 290 children at two time points, 1 year apart, starting from just before the lockdown (February 2020 to February 2021). Results: The prevalence of anaemia doubled from 21% to 40% (p<0.0001) with more pronounced changes in older girls (10%-53%); however, the prevalence of iron deficiency did not change (48.8%-51.9%), despite cessation of deworming and iron/folic acid supplements. Conclusion: The increase in anaemia was due to limiting intakes of other erythropoietic nutrients, possibly due to a lower dietary diversity. The mid-day lunch meal at school (MDM) is an important part of daily food intake in rural school children, and it is important to maintain dietary diversity through the delivery of MDM for such vulnerable groups.

Understanding and Addressing COVID-19 Vaccine Hesitancy Among Healthcare Providers in Bexar County, Texas.

Introduction: COVID-19 challenged our healthcare systems and unsurprisingly, so did its vaccine. Chief among these were the uniquely politicized nature and logistical difficulties surrounding its deployment. Understanding provider attitudes toward the COVID-19 vaccines and their willingness/ability to deliver them is essential to developing an ideal vaccine distribution plan for Bexar County, Texas. Methods: An electronic survey was sent to providers serving adult patients across Bexar County. Membership includes representation from local hospitals, Bexar County Medical Society, and the San Antonio Metropolitan Health District's vaccination program. The survey measured provider attitudes toward the vaccines and asked logistical questions regarding patient hesitancy and clinic infrastructure. Results: Responses were collected from 66 ZIP codes (90% of ZIP codes in the county), and 377 providers answered the survey. Respondents who were unlikely to recommend the vaccine (3%) shared concerns involving distrust of the vaccine manufacturing process. Recommendations made by physicians to support their vaccine administration efforts included broadening the reporting timeframe (n=35), providing trained support staff (n=18), and improving logistical support (n=14). Furthermore, responses showed that only 14.44% of provider facilities were able to meet originally published refrigeration requirements to store Pfizer's vaccines compared with 87.47% for Moderna's vaccines. Conclusions: Survey results were used to improve the efficiency of vaccination programs and address vaccine hesitancy through various avenues of information delivery. It is recommended to replicate the outcomes and applications of this study in other populations to improve the efficiency of vaccination programs and reduce vaccine hesitancy.