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Magnetic compression has long been proposed a promising method for plasma heating in a field reversed configuration (FRC). However, it remains a challenge to fully understand the physical mechanisms underlying the compression process, due to its highly dynamic nature beyond the one-dimensional (1D) adiabatic theory model (Spencer et al 1983 Phys. Fluids 26 1564). In this work, magnetohydrodynamics simulations on the magnetic compression of FRCs using the NIMROD code (Sovinec et al 2004 J. Comput. Phys. 195 355) and their comparisons with the 1D theory have been performed. The effects of the assumptions of the theory on the compression process have been explored, and the detailed profiles of the FRC during compression have been investigated. The pressure evolution agrees with the theoretical prediction under various initial conditions. The axial contraction of the FRC can be affected by the initial density profile and the ramping rate of the compression magnetic field, but the theoretical predictions on the FRC’s length in general and the relation $r_s = \sqrt{2}r_o$ in particular hold approximately well during the whole compression process, where r _s is the major radius of FRC separatrix and r _o is that of the magnetic axis. The evolutions of the density and temperature can be affected significantly by the initial equilibrium profile and the ramping rate of the compression magnetic field. During the compression, the major radius of the FRC is another parameter that is susceptible to the ramping rate of the compression field. Basically, for the same magnetic compression ratio, the peak density is higher and the FRC’s radius r _s is smaller than the theoretical predictions.

This qualitative study aims to learn about the experiences of first year teachers as they rapidly transitioned to remote teaching during the global COVID-19 crisis in March 2020. Additionally, the murder of George Floyd shortly thereafter exacerbated racial turmoil, impacting communities, students and families simultaneously. As the shift was sudden and drastic, and the first year of teaching is already quite challenging with a large learning curve, we seek to highlight the experiences of beginning teachers during COVID-19, and specifically focus on their strengths, assets and resilience, adding to the literature on asset-based perspectives of beginning teachers. Using data from individual journals and focus groups involving 15 first year urban and suburban teachers, we assert that first year teachers were assets to their school communities due to their technological strengths and their equity-based teacher preparation.

This study uses an interpretive, qualitative research design to highlight beginning teacher perspectives of their experiences teaching during the COVID-19 pandemic. In this study, we share the experiences of 15 K-12 educators who began their teaching careers in the 2019-2020 school year, whose first two years of teaching were marred by frequent changes and a constant unknown. Despite this, and perhaps because of this, they changed as educators--their own beliefs, their expectations for families and students, their pedagogy, and philosophy for the future. Findings from this study help highlight the strengths of beginning teachers (particularly during a pandemic) and ways a pandemic can affect the beliefs and practices of beginning teachers.

Abstract The HIV-1 entry inhibitor temsavir prevents the viral receptor CD4 (cluster of differentiation 4) from interacting with the envelope glycoprotein (Env) and blocks its conformational changes. To do this, temsavir relies on the presence of a residue with small side chain at position 375 in Env and is unable to neutralize viral strains like CRF01_AE carrying His375. Here we investigate the mechanism of temsavir resistance and show that residue 375 is not the sole determinant of resistance. At least six additional residues within the gp120 inner domain layers, including five distant from the drug-binding pocket, contribute to resistance. A detailed structure-function analysis using engineered viruses and soluble trimer variants reveals that the molecular basis of resistance is mediated by crosstalk between His375 and the inner domain layers. Furthermore, our data confirm that temsavir can adjust its binding mode to accommodate changes in Env conformation, a property that likely contributes to its broad antiviral activity.

Providing a definitive diagnostic test in a disease emergency is critical to limit pathogen spread, develop and deploy medical countermeasures, and mitigate the social and economic harms of a serious epidemic. While major accomplishments have accelerated test development, expanded laboratory testing capacity, and established widespread point-of-care testing, the United States does not have a plan to rapidly respond, to develop, manufacture, deploy, and sustain diagnostic testing at a national scale. To address this gap, we are proposing a National Diagnostics Action Plan that describes the steps that are urgently needed to prepare for future infectious disease emergencies, as well as the actions we must take at the first signs of such’ events. These recommendations require substantial collaboration between the US government (USG) and the private sector to solve a series of challenges now, as well as to prepare for the massive and rapid scale-up of laboratory and point-of-care test development and testing capacity in future emergencies. The recommendations include establishing pre-event contracts; ensuring rapid access to clinical samples; creating a permanent public–private testing coordinating body to allow for rapid information sharing and improved cooperation among the USG, test developers, and clinical laboratories; and accelerating testing rollout at the beginning of an event—and thus, the effective public health management of a disease crisis.

Abstract Designing artificial viral vectors (AVVs) programmed with biomolecules that can enter human cells and carry out molecular repairs will have broad applications. Here, we describe an assembly-line approach to build AVVs by engineering the well-characterized structural components of bacteriophage T4. Starting with a 120 × 86 nm capsid shell that can accommodate 171-Kbp DNA and thousands of protein copies, various combinations of biomolecules, including DNAs, proteins, RNAs, and ribonucleoproteins, are externally and internally incorporated. The nanoparticles are then coated with cationic lipid to enable efficient entry into human cells. As proof of concept, we assemble a series of AVVs designed to deliver full-length dystrophin gene or perform various molecular operations to remodel human genome, including genome editing, gene recombination, gene replacement, gene expression, and gene silencing. These large capacity, customizable, multiplex, and all-in-one phage-based AVVs represent an additional category of nanomaterial that could potentially transform gene therapies and personalized medicine.

Objective: The objective of this study is to assess the acute toxicities and locoregional response rates in patients with locally advanced head-and-neck squamous cell carcinomas with intensity-modulated radiotherapy (IMRT) and weekly cisplatin versus weekly cisplatin and paclitaxel. Methodology: Fifty-four patients with histologically proven squamous cell carcinoma of the head and neck at the department of radiotherapy, at our hospital, were taken up for this study. Patients were allotted to the study and control arm and results were analyzed. All patients were treated with IMRT 70 Gy along with weekly injection cisplatin 35 mg/m2 (control arm) versus IMRT 70 Gy along with weekly injection paclitaxel 30 mg/m2 and injection cisplatin 20 mg/m2 (study arm). The toxicity profile was assessed weekly during treatment and then monthly for 3 months postchemoradiotherapy with Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The immediate locoregional response rates were assessed clinically postchemoradiotherapy and then monthly for 3 months after concurrent chemoradiotherapy. Results: In this study, oropharyngeal cancer dominated with 52% of patients in the study arm and 47% in the control arm. Most of the patients were in Stage IV a (69%). Toxicities were observed more in the study arm with 59% of patients with Grade 3 mucositis and 52% of patients with Grade 3 dermatitis. Eighty-one percent of patients in the study arm and 70% of patients in the control arm had Grade 3 dysphagia. Grade 2 leukocytopenia was seen in 44% of patients in the study arm and 19% in the control arm. Complete and partial responses at the end of follow-up were 70% and 30% in the study arm and 48% and 52% in the control arm, respectively. Conclusion: Concurrent chemoradiotherapy with injection cisplatin and paclitaxel in locally advanced squamous cell carcinoma of the head and neck has a higher complete response rate with manageable toxicities.

Purpose: The purpose of this study is to assess and compare the acute toxicities between sequential intensity-modulated radiation therapy and simultaneous integrated boost (SIB) intensity-modulated radiation therapy in head-and-neck cancers using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Materials and Methods: Patients with histologically proven squamous cell carcinoma of head and neck at the department of radiotherapy (RT), from December 2018 to July 2020, were taken up for this study. Patients were divided into sequential intensity-modulated RT (IMRT) arm and SIB-IMRT arm. Patients treated with sequential IMRT were treated so as to receive a total dose of 70 Gy in 35 fractions, 2 Gy/fractions, 5 fractions per week – 70 Gy in 35 fractions to the primary tumor, 66 Gy in 33 fractions to high-risk clinical target volume (CTV1), 60 Gy in 30 fractions to high-risk CTV2 and 50 Gy in 25 fractions to elective nodes/low-risk CTV3. Patients treated with SIB-IMRT were treated so as to receive a total dose of 66 Gy in 30 fractions – 2.2 Gy/fraction to gross tumor volume/PTV 66, 60 Gy in 30 fractions – 2.0 Gy/fraction to high-risk nodes (PTV 60), 54 Gy in 30 fractions – 1.8 Gy/fraction to elective nodes (PTV 54), respectively. Patients received concurrent chemotherapy with weekly injections cisplatin (35mg/m2) or injection carboplatin (AUC 2). Toxicities were assessed using CTCAE v 4.03. Results: Higher grades of radiation-induced dermatitis and mucositis were observed in patients in SIB-IMRT. No patients experienced Grade 4 toxicity. The results confirm that irradiation according to our SIB-IMRT protocol is a treatment option with acceptable toxicity. Conclusion: SIB-IMRT is feasible, although associated with increased rates of skin and mucosal toxicity.

Background: Radiotherapy is an important treatment modality for locally advanced breast cancer and includes irradiation of the chest wall and supraclavicular nodes, with or without the axilla. Since the esophagus is close to the supraclavicular nodes, patients may experience acute radiation esophagitis during treatment which decreases their quality of life. Objective: To identify the dosimetric parameters of the esophagus which may affect the occurrence of esophagitis in patients with breast cancer who received supraclavicular nodal irradiation. Materials and Methods: This was a single-center retrospective observational study carried out from January 2021 to June 2022 at Father Muller Medical College Hospital, Mangalore, India. We enrolled patients with histologically proven breast cancer, who had received post-mastectomy radiation to the chest wall and supraclavicular nodes to a dose of 50 Gy in 25 fractions, 2 Gy per fraction, 5 fractions per week with 6 MV photon linear accelerator by intensity modulated radiation therapy. Toxicities were recorded every week. The parameters documented included the mean esophageal dose, maximum dose to the esophagus, and length of the esophagus within the treatment area. Results: We enrolled 25 patients with infiltrating ductal carcinoma of the breast who had undergone mastectomy and received neoadjuvant or adjuvant chemotherapy. The median age was 53 years (IQR, 44.5-63.5). Esophagitis (any grade) was noted in 18 of the 25 patients (72%). Grade 2 esophagitis developed in all 6 patients (100%) who had received a mean esophageal dose >20 Gy, and in none of the 19 (0%) who received a dose

Abstract The oceanic South Atlantic Convergence Zone (SACZ) has played a major role during South America’s 2021/2022 summer extreme rainy season, being responsible for more than 90% of the precipitation in some regions of Southeast Brazil and in some regions of the Southwestern Atlantic Ocean (SWA). The summer of 2021/2022 was unique and rare and considered an abnormally humid season as verified by official Brazilian Institutes. First, the unusual number of cases of SACZ episodes (seven), was the highest recorded in the last decade. Second, all the cases that occurred were oceanic SACZ that assumed characteristics of an Atmospheric River and produced an excessively anomalous amount of precipitation during this period. Excess precipitation along with the regions located in mountainous and very uneven relief, which by orographic effects favors high precipitation volumes, were responsible for amplifying the observed impacts, such as landslides and floods that caused several losses to society. We also showed the main effects of coupling and interaction between the waters of the surface layer of the SWA and the atmosphere. Our learning from this study ends with the unprecedented results of how the marine atmospheric boundary layer (MABL) is locally modulated by the sea surface temperature (SST) that lies just below it. Until the present moment, we emphasize that this important mechanism has not been widely highlighted in the literature, showing that even though the ocean is colder than before oceanic SACZ is established, it is still warmer than the overlying air, thus, the ocean continues to be an active source of heat and moisture for the atmosphere and enhances the MABL instability process.

Periventricular-intraventricular hemorrhage (PIVH) is common in extremely low gestational age neonates (ELGAN) and leads to motor and behavioral impairments. Currently there is no effective treatment for PIVH. Whether human nonhematopoietic umbilical cord blood-derived stem cell (nh-UCBSC) administration reduces the severity of brain injury and improves long-term motor and behavioral function was tested in an ELGAN-equivalent neonatal rat model of PIVH. In a collagenase-induced unilateral PIVH on postnatal day (P) 2 model, rat pups received a single dose of nh-UCBSCs at a dose of 1 × 10 6 cells i.p. on P6 (PIVH + UCBSC group) or were left untreated (Untreated PIVH group). Motor deficit was determined using forelimb placement, edge-push, and elevated body swing tests at 2 months ( N = 5–8). Behavior was evaluated using open field exploration and rearing tests at 4 months ( N =10–12). Cavity volume and hemispheric volume loss on the PIVH side were determined at 7 months ( N = 6–7). Outcomes were compared between the Untreated PIVH and PIVH + UCBSC groups and a Control group. Unilateral motor deficits were present in 60%–100% of rats in the Untreated PIVH group and 12.5% rats in the PIVH + UCBSC group ( P = 0.02). Untreated PIVH group exhibited a higher number of quadrant crossings in open field exploration, indicating low emotionality and poor habituation, and had a cavitary lesion and hemispheric volume loss on the PIVH side. Performance in open field exploration correlated with cavity volume ( r 2 = 0.25; P < 0.05). Compared with the Untreated PIVH group, performance in open field exploration was better ( P = 0.0025) and hemispheric volume loss was lower (19.9 ± 4.4% vs 6.1 ± 2.6%, P = 0.018) in the PIVH + UCBSC group. These results suggest that a single dose of nh-UCBSCs administered in the subacute period after PIVH reduces the severity of injury and improves neurodevelopment in neonatal rats.

Context: Dose received to each pelvic group of lymph nodes, namely obturator (OB), internal iliac (II), and external iliac (EI), is less certain. This study is conducted to evaluate the dose delivered to these nodal groups so that this can be considered while planning external beam radiotherapy external beam radiation therapy (EBRT) boost in patients with gross pelvic lymph nodes. Aims: This study aimed to estimate the dose contribution to pelvic lymph nodes in three-dimensional high-dose-rate intracavitary radiotherapy (HDR-ICRT) of cervical cancer patients. Settings and Design: This was a single-arm retrospective observational study among 25 locally advanced carcinoma cervix patients treated with definitive chemoradiation. Materials and Methods: EI, II, and OB groups of lymph nodes were delineated on computed tomography data sets of selected 25 patients, and D100, D50, and D2cc to each lymph node were analyzed. The dose received by each pelvic lymph node group from all the 3 fractions of HDR-ICRT, corresponding equivalent 2 Gy dose, and percentage of brachytherapy (BT) contribution to each pelvic lymph node were calculated. Results: Mean D100 received by EI, II, and OB lymph node groups after summation across 3 fractions was 1.1 Gy, 2.34 Gy, and 3.11 Gy, respectively. Mean 2 Gy equivalent doses (D100) were 1.66 Gy, 3.41 Gy, and 4.53 Gy, respectively. Corresponding percentage of the dose received by EI, II, and OB was 4.89%, 10.43%, and 13.83% when 7.5 Gy per fraction for 3 fractions was prescribed to Point A. Conclusions: There is a significant contribution from HDR intracavitary BT to the pelvic lymph nodes in the radical treatment of cervical cancer. The dosimetric results given in this work can be used by a radiation oncologist to estimate BT doses to affected lymph nodes and integrate them into the preceding EBRT planning phase.

Background: Despite the advances in breast cancer treatment, it has a higher rate of mortality. The response of treatment varies significantly; this could be due to the various subtypes that determine the course of the disease. In this study, we evaluated patients who were treated definitively and had developed organ-specific metastasis and local recurrence according to biological subtype. Materials and Methods: Out of 856 patients who were diagnosed to have carcinoma breast from the year January 2015 to January 2020, 468 patients were treated definitively, out of which 55 patients developed recurrent or metastatic disease after completion of treatment. Results: The most frequent subgroup for relapse was triple-negative breast cancer (TNBC) 23 (41.8%). Twenty-two (40%) had multiple metastases at the time of first distant recurrence. The most common site of distant recurrence was bone 28 patients (50.9%) with maximum incidence in Luminal B subgroup (23.6%), followed by liver metastasis 23 patients (41.81%) with the highest incidence seen among TNBC (18%), followed by lung 19 (34.5%) patients with maximum incidence in TNBC (16.3%) followed by brain 5 (9%) patients. Locoregional recurrence was observed in 13 patients, out of which 8 (61.5%) patients had TNBC molecular subgroup. Conclusion: Our results demonstrate an association between molecular subtype and pattern of recurrence.

The 5-hydroxytrptamine 3 (5-HT3) receptor is a member of the ’Cys-loop’ family and the only pentameric ligand gated ion channel among the serotonin receptors. 5-HT3 receptors play an important role in controlling growth, development, and behaviour in animals. Several 5-HT3 receptor antagonists are used to treat diseases (e.g., irritable bowel syndrome, nausea and emesis). Humans express five different subunits (A-E) enabling a variety of heteromeric receptors to form but all contain 5HT3A subunits. However, the information available about the 5-HT3 receptor subunit occurrence among the metazoan lineages is minimal. In the present article we searched for 5-HT3 receptor subunit homologs from different phyla in Metazoa. We identified more than 1000 5-HT3 receptor subunits in Metazoa in different phyla and undertook simultaneous phylogenetic analysis of 526 5HT3A, 358 5HT3B, 239 5HT3C, 70 5HT3D, and 173 5HT3E sequences. 5-HT3 receptor subunits were present in species belonging to 11 phyla: Annelida, Arthropoda, Chordata, Cnidaria, Echinodermata, Mollusca, Nematoda, Orthonectida, Platyhelminthes, Rotifera and Tardigrada. All subunits were most often identified in Chordata phylum which was strongly represented in searches. Using multiple sequence alignment, we investigated variations in the ligand binding region of the 5HT3A subunit protein sequences in the metazoan lineage. Several critical amino acid residues important for ligand binding (common structural features) are commonly present in species from Nematoda and Platyhelminth gut parasites through to Chordata. Collectively, this better understanding of the 5-HT3 receptor evolutionary patterns raises possibilities of future pharmacological challenges facing Metazoa including effects on parasitic and other species in ecosystems that contain 5-HT3 receptor ligands.

Background: A limited number of studies have explored the association between health literacy (HL) and health outcomes. Effectively managing HIV infection expects from the patients the ability to seek medical help, understand the instructions provided by the healthcare professionals, and adhere to the treatment plans. This study aimed to evaluate the HL and medication regimen complexity index (MRCI) among people living with HIV and determine the associated factors. Methods: This was a prospective, cross-sectional study. Each study participant was assessed using the HIV literacy test (HIV-LT). The complexity of the prescribed drug regimen was measured using MRCI. Changes in HL and MRCI with age, gender, and educational status of the individual were assessed. The presence of any correlation between HL and MRCI scores was assessed using Spearman's correlation coefficient test. Results: Of the 285 patients with HIV infection studied, 51.6% were males and 48.4% were females. The median HIV-LT score was 3 (out of 10) (interquartile range [IQR], 0–6), and the median MRCI score was 8 (6–12). A statistically significant increase in the HL scores based on the educational status of the participants was seen (x2 = 87.324, p

The effects of early-life iron deficiency anemia (IDA) extend past the blood and include both short- and long-term adverse effects on many tissues including the brain. Prior to IDA, iron deficiency (ID) can cause similar tissue effects, but a sensitive biomarker of iron-dependent brain health is lacking. To determine serum and CSF biomarkers of ID-induced metabolic dysfunction we performed proteomic and metabolomic analysis of serum and CSF at 4- and 6- months from a nonhuman primate model of infantile IDA. LC/MS/MS analyses identified a total of 227 metabolites and 205 proteins in serum. In CSF, we measured 210 metabolites and 1,560 proteins. Data were either processed from a Q-Exactive (Thermo Scientific, Waltham, MA) through Progenesis QI with accurate mass and retention time comparisons to a proprietary small molecule database and Metlin or with raw files imported directly from a Fusion Orbitrap (Thermo Scientific, Waltham, MA) through Sequest in Proteome Discoverer 2.4.0.305 (Thermo Scientific, Waltham, MA) with peptide matches through the latest Rhesus Macaque HMDB database. Metabolite and protein identifiers, p-values, and q-values were utilized for molecular pathway analysis with Ingenuity Pathways Analysis (IPA). We applied multiway distance weighted discrimination (DWD) to identify a weighted sum of the features (proteins or metabolites) that distinguish ID from IS at 4-months (pre-anemic period) and 6-months of age (anemic).

Colorectal Cancer (CRC) has seen a dramatic increase in incidence globally. In 2019, colorectal cancer accounted for 1.15 million deaths and 24.28 million disability-adjusted life-years (DALYs) worldwide. In India, the annual incidence rates (AARs) for colon cancer was 4.4 per 100,000. There has been a steady rise in the prevalence of CRC in India which may be attributed to urbanization, mass migration of population, westernization of diet and lifestyle practices and a rise of obesity and metabolic risk factors that place the population at a higher risk of CRC. Moreoever, CRC in India differs from that described in the Western countries, with a higher proportion of young patients and more patients presenting with an advanced stage. This may be due to poor access to specialized healthcare and socio-economic factors. Early identification of adenomatous colonic polyps, which are well-recognized pre-cancerous lesions, at the time of screening colonoscopy has been shown to be the most effective measure used for CRC prevention. However, colonic polyps are frequently missed during colonoscopy and moreover, these screening programs necessitate man-power, time and resources for processing resected polyps, that may hamper penetration and efficacy in mid- to low-income countries. In the last decade, there has been significant progress made in the automatic detection of colonic polyps by multiple AI-based systems. With the advent of better AI methodology, the focus has shifted from mere detection to accurate discrimination and diagnosis of colonic polyps. These systems, once validated, could usher in a new era in Colorectal Cancer (CRC) prevention programs which would center around “Leave in-situ” and “Resect and discard” strategies. These new strategies hinge around the specificity and accuracy of AI based systems in correctly identifying the pathological diagnosis of the polyps, thereby providing the endoscopist with real-time information in order to make a clinical decision of either leaving the lesion in-situ (mucosal polyps) or resecting and discarding the polyp (hyperplastic polyps). The major advantage of employing these strategies would be in cost optimization of CRC prevention programs while ensuring good clinical outcomes. The adoption of these AI-based systems in the national cancer prevention program of India in accordance with the mandate to increase technology integration could prove to be cost-effective and enable implementation of CRC prevention programs at the population level. This level of penetration could potentially reduce the incidence of CRC and improve patient survival by enabling early diagnosis and treatment. In this review, we will highlight key advancements made in the field of AI in the identification of polyps during colonoscopy and explore the role of AI based systems in cost optimization during the universal implementation of CRC prevention programs in the context of mid-income countries like India.

Bacteriophage T4 is decorated with 155 180 Å-long fibers of the highly antigenic outer capsid protein (Hoc). In this study, we describe a near-atomic structural model of Hoc by combining cryo-electron microscopy and AlphaFold structure predictions. It consists of a conserved C-terminal capsid-binding domain attached to a string of three variable immunoglobulin (Ig)-like domains, an architecture well-preserved in hundreds of Hoc molecules found in phage genomes. Each T4-Hoc fiber attaches randomly to the center of gp23* hexameric capsomers in one of the six possible orientations, though at the vertex-proximal hexamers that deviate from 6-fold symmetry, Hoc binds in two preferred orientations related by 180° rotation. Remarkably, each Hoc fiber binds to all six subunits of the capsomer, though the interactions are greatest with three of the subunits, resulting in the off-centered attachment of the C-domain. Biochemical analyses suggest that the acidic Hoc fiber (pI, ~4–5) allows for the clustering of virions in acidic pH and dispersion in neutral/alkaline pH. Hoc appears to have evolved as a sensing device that allows the phage to navigate its movements through reversible clustering–dispersion transitions so that it reaches its destination, the host bacterium, and persists in various ecological niches such as the human/mammalian gut.

Abstract Background Sex‐specific mechanisms explaining the association between mothers with obesity and the development of obesity in children are poorly characterized. Permanent changes in fetal brain glucocorticoid receptor (GR) expression caused by exposure to overnutrition in utero may program aberrant energy homeostasis, thereby predisposing the offspring to obesity. This study explores sex differences in brain GR expression using an established mouse model of overnutrition during pregnancy. Methods Female C57Bl/6J mice were fed control (CON) or high‐fat–high‐sucrose (HFHS) diets. Dam cholesterol, insulin, and triglycerides were measured by colorimetric assays. Fetal corticosterone exposure was measured by placental Abca1, Hsd11β1, Hsd11β2, and brain Nr3c1 (GR); Pomc expression measured by RT‐qPCR. Results Female, but not male, HFHS fetuses had 46% decreased brain GR and twofold increased Pomc expression. There was decreased Abca1 and Hsd11β1 but not Hsd11β2 expression in HFHS placentas. Caloric and sucrose intake, but not fat intake, in dams inversely correlated with fetal GR expression in both sexes. Excess sucrose consumption by dams inversely correlated with female fetal GR and directly correlated with female fetal Pomc expression. Conclusions Excess sucrose consumption in pregnant dams caused lower GR and higher Pomc expression in the female fetal brain. Clinical investigation of excess sucrose intake during pregnancy and its subsequent effect on hypothalamic‐pituitary‐adrenal axis activity and appetite in offspring may lead to novel, sex‐specific obesity prevention strategies in the development of obesity in children.

ABSTRACT The U.S. Food and Drug Administration-authorized mRNA- and adenovirus-based SARS-CoV-2 vaccines are intramuscularly injected in two doses and effective in preventing COVID-19, but they do not induce efficient mucosal immunity or prevent viral transmission. Here, we report the first noninfectious, bacteriophage T4-based, multicomponent, needle- and adjuvant-free, mucosal vaccine harboring engineered Spike trimers on capsid exterior and nucleocapsid protein in the interior. Intranasal administration of two doses of this T4 SARS-CoV-2 vaccine 21 days apart induced robust mucosal immunity, in addition to strong systemic humoral and cellular immune responses. The intranasal vaccine induced broad virus neutralization antibody titers against multiple variants, Th1-biased cytokine responses, strong CD4+ and CD8+ T cell immunity, and high secretory IgA titers in sera and bronchoalveolar lavage specimens from vaccinated mice. All of these responses were much stronger in intranasally vaccinated mice than those induced by the injected vaccine. Furthermore, the nasal vaccine provided complete protection and sterilizing immunity against the mouse-adapted SARS-CoV-2 MA10 strain, the ancestral WA-1/2020 strain, and the most lethal Delta variant in both BALB/c and human angiotensin converting enzyme (hACE2) knock-in transgenic mouse models. In addition, the vaccine elicited virus-neutralizing antibodies against SARS-CoV-2 variants in bronchoalveolar lavage specimens, did not affect the gut microbiota, exhibited minimal lung lesions in vaccinated and challenged mice, and is completely stable at ambient temperature. This modular, needle-free, phage T4 mucosal vaccine delivery platform is therefore an excellent candidate for designing efficacious mucosal vaccines against other respiratory infections and for emergency preparedness against emerging epidemic and pandemic pathogens. IMPORTANCE According to the World Health Organization, COVID-19 may have caused ~15-million deaths across the globe and is still ravaging the world. Another wave of ~100 million infections is predicted in the United States due to the emergence of highly transmissible immune-escaped Omicron variants. The authorized vaccines would not prevent these transmissions since they do not trigger mucosal immunity. We circumvented this limitation by developing a needle-free, bacteriophage T4-based, mucosal vaccine. This intranasally administered vaccine generates superior mucosal immunity in mice, in addition to inducing robust humoral and cell-mediated immune responses, and provides complete protection and sterilizing immunity against SARS-CoV-2 variants. The vaccine is stable, adjuvant-free, and cost-effectively manufactured and distributed, making it a strategically important next-generation COVID vaccine for ending this pandemic.

Increased astrocytic Ca2+ signaling has been shown in Alzheimer’s disease mouse models, but to date no reports have characterized behaviorally induced astrocytic Ca2+ signaling in such mice. Here, we employ an event-based algorithm to assess astrocytic Ca2+ signals in the neocortex of awake-behaving tg-ArcSwe mice and non-transgenic wildtype littermates while monitoring pupil responses and behavior. We demonstrate an attenuated astrocytic Ca2+ response to locomotion and an uncoupling of pupil responses and astrocytic Ca2+ signaling in 15-month-old plaque-bearing mice. Using the genetically encoded fluorescent norepinephrine sensor GRABNE, we demonstrate a reduced norepinephrine signaling during spontaneous running and startle responses in the transgenic mice, providing a possible mechanistic underpinning of the observed reduced astrocytic Ca2+ responses. Our data points to a dysfunction in the norepinephrine–astrocyte Ca2+ activity axis, which may account for some of the cognitive deficits observed in Alzheimer’s disease.

The 5-hydroxytryptamine 3 (5-HT3) receptor belongs to the pentameric ligand-gated cation channel superfamily. Humans have five different 5-HT3 receptor subunits: A to E. The 5-HT3 receptors are located on the cell membrane, but a previous study suggested that mitochondria could also contain A subunits. In this article, we explored the distribution of 5-HT3 receptor subunits in intracellular and cell-free mitochondria. Organelle prediction software supported the localization of the A and E subunits on the inner membrane of the mitochondria. We transiently transfected HEK293T cells that do not natively express the 5-HT3 receptor with an epitope and fluorescent protein-tagged 5HT3A and 5HT3E subunits. Fluorescence microscopy and cell fractionation indicated that both subunits, A and E, localized to the mitochondria, while transmission electron microscopy revealed the location of the subunits on the mitochondrial inner membrane, where they could form heteromeric complexes. Cell-free mitochondria isolated from cell culture media colocalized with the fluorescent signal for A subunits. The presence of A and E subunits influenced changes in the membrane potential and mitochondrial oxygen consumption rates upon exposure to serotonin; this was inhibited by pre-treatment with ondansetron. Therefore, it is likely that the 5-HT3 receptors present on mitochondria directly impact mitochondrial function and that this may have therapeutic implications.

Background and Aims: Regional anaesthesia techniques are a part of perioperative medicine that affects both perioperative and long-term outcomes. We have a paucity of the data on the usage and practices of plexus and peripheral nerve blocks (PNBs). To the best of our knowledge, this is the first effort to validate a survey for plexus and PNBs. Subsequently, this questionnaire could be used for the survey to look for the trends and disparities in PNB practices and further to develop a national registry in the future. Methods: Thirty questions were prepared after evidence-based search and reviewed by experts for suggestions. Changes were done and the questionnaire with the grading sheet was sent to 19 experts. The responses were analysed to calculate the content validity index (CVI) item-wise (I-CVI), scale-wise (S-CVI), and modified kappa statistics. The I-CVI of 0.78 and an S-CVI/average of 0.90 was taken as acceptable with more than six experts. Results: Fourteen experts out of 19 assessed and graded the questions as per the provided sheet and submitted suggestions through the mail. Question reframing, option reconsideration, and change from single to multiple choices were incorporated as per the suggestions of the experts. Mean I-CVI for relevance, simplicity, clarity, and ambiguity was 0.99, 0.98, 0.98, and 0.99, respectively. S-CVI/average was 0.98, 0.97, 0.98, and 0.99 for relevance, simplicity, clarity, and ambiguity, respectively. Conclusion: We conclude that this questionnaire has met the content validity criteria and can be used to study plexus and PNBs practices.

Background: Molecular confirmation of histologic diagnosis has become mandatory for the diagnosis of Ewing sarcoma family of tumors (ESFT). Aim: To validate the diagnosis made by morphology and immunohistochemistry (IHC) by fluorescence in-situ hybridization (FISH) for EWSR1 rearrangement on formalin fixed paraffin embedded (FFPE) tissues. Settings and design: A retrospective and prospective observational study. Material and methods: All patients who had FISH studies for EWSR1 rearrangement for small round cell tumors during 10 years period were included. Demographic, clinical and radiological details were obtained from medical records. Morphology was reviewed with IHC by CD99, FLI1 and others. FISH studies were performed using the break apart probe. Additional molecular studies and IHC were done to resolve the diagnosis in EWSR1 rearranged tumors. Final diagnosis was made by integrating clinical, morphology, IHC and molecular features. Results: There were 81 patients (M: F 45:36, median age 21 years) with 32 skeletal and 49 extra skeletal tumors. CD 99 was positive in 94.52%. FISH for EWSR1 were positive in 59, negative in 13 and failed in 9. The final diagnosis was made as ESFT in 67, angiomatoid fibrous histiocytoma in 3, desmoplastic small round cell tumor in 3, myxoid chondrosarcoma in 2, unclassified in one, synovial sarcoma in 3, and one each of lymphoma and small cell neuroendocrine carcinoma. FISH was positive for ESFT in 89.83% of EWSR1 rearranged tumors. FISH validated the diagnosis made on IHC in 79.10%. FISH resolved the diagnosis in 1.49% CD99 negative tumors. Conclusion: FISH is a reliable ancillary technique for the diagnosis of ESFT on FFPE tissues.

Purpose: Carcinoma cervix forms a major burden among malignancies in women in India. Anemia is very common among Indian women and a high proportion of carcinoma cervix patients present with anemia. Previous studies show that hemoglobin level may be considered as a prognostic factor in carcinoma cervix. It has been observed that anemia is associated with diminished radiocurability in patients with carcinoma of the cervix. However, the therapeutic benefit of the measures to correct anemia remains debatable. The objective of this study was to evaluate the association of hemoglobin concentrations and its correction by blood transfusions before and during treatment and the response to chemoradiation. Materials and Methods: Fifty patients with histologically proven squamous cell carcinoma of the cervix (Stage II to IV) from December 2018 to May 2020 were taken up for this study. Patients received definitive chemoradiation of 50 Gy in 25 fractions, 2 Gy/fraction, 5 fractions per week, along with-weekly injection cisplatin/carboplatin, followed by brachytherapy. All patients had their pretreatment hemoglobin levels measured at the first consultation. The effects of hemoglobin concentrations at presentation and during therapy on the clinical response to radiotherapy were studied. Blood transfusions and the time point when transfusions were given were recorded. Results: Eighteen patients received packed red blood cell transfusion before the start of radiation therapy and 9 patients received packed cell transfusion during radiation therapy. Out of the 18 patients who received transfusion before RT, 3 patients had complete response. Out of the 9 patients who received transfusion during radiation, 4 had complete response. The presence of anemia had a significant impact on the response rate. Pretreatment anemia was associated with poor response and local control among patients who underwent chemoradiotherapy for cervical cancer. Conclusion: Pretreatment hemoglobin and hemoglobin levels during radiation therapy were prognostic factors for local control, in addition to stage and histology, which might have independently predicted the outcome.

Background: In locally advanced head-and-neck cancers (HNCs), definitive chemoradiation therapy has emerged as the treatment of choice due to the benefit of organ preservation. Radiation therapy is known to cause significant acute and late toxicities when it is used at radical doses. Studies have shown that more severe toxicities such as mucositis were observed in patients who received radiation therapy with concurrent chemotherapy. Incidental radiation exposure to buccal mucosa during radiation therapy for HNCs contributed to acute radiation-induced oral mucositis (RIOM). Objective: The objective of the study was to dosimetrically evaluate the dose received by buccal mucosa in patients with HNC patients undergoing sequential intensity-modulated radiotherapy technique (SEQ-IMRT) and simultaneous integrated boost intensity-modulated radiotherapy technique (SIB-IMRT). Materials and Methods: Forty patients with histologically proven squamous cell carcinoma of head and neck excluding nasopharyngeal and oral cavity cancers, who received radical chemoradiation therapy by SEQ-IMRT or SIB-IMRT were retrospectively analyzed. The total prescribed dose to the planning target volume was 70 Gy delivered in 2 Gy daily fractions in SEQ-IMRT and 66 Gy in 30 fractions in SIB-IMRT. All patients received concurrent weekly injection cisplatin (35 mg/m2). Dosimetric parameters of right and left buccal mucosa (V 15 Gy, V 30 Gy, and V 45 Gy) were recorded and correlated with grades of RIOM and weight loss as per CTCAE v5.0. Results: Mucositis and weight loss were accessed from week 1 to 7 in the SEQ-IMRT arm and week 1–6 for SIB-IMRT arm. Grade 3 mucositis was observed among 2 patients (10%) and 3 (15%) patients in the SIB-IMRT and none in SEQ-IMRT arm. Grade 2 Weight loss was observed among 35% of patients in SIB-IMRT arm and 5% patients in SEQ-IMRT arm. Conclusion: This study assessed the occurrence of several RIOM as predictive factor with respect to dose received to buccal mucosa in HNC patients, except nasopharyngeal and oral cavity cancer. Our data demonstrated relationship between V30 Gy of buccal mucosa and oral mucosal toxicity with associated weight loss in patients with HNCs undergoing radical chemoradiation therapy.