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Abstract A first-principle computational method has been used to investigate the effects of Ru dopants on the electronic and optical absorption properties of marcasite FeS2. In addition, we have also revealed a new marcasite phase in RuS2, unlike most studied pyrite structures. The new phase has fulfilled all the necessary criteria of structural stability and its practical existence. The transition pressure of 8 GPa drives the structural change from pyrite to orthorhombic phase in RuS2. From the thermodynamical calculation, we have reported the stability of new-phase under various ranges of applied pressure and temperature. Further, from the results of phonon dispersion calculated at Zero Point Energy, pyrite structure exhibits ground state stability and the marcasite phase has all modes of frequencies positive. The newly proposed phase is a semiconductor with a band gap comparable to its pyrite counterpart but vary in optical absorption by around 106 cm−1. The various Ru doped structures have also shown similar optical absorption spectra in the same order of magnitude. We have used crystal field theory to explain high optical absorption which is due to the involvement of different electronic states in formation of electronic and optical band gaps. Lӧwdin charge analysis is used over the customarily Mulliken charges to predict 89% of covalence in the compound. Our results indicate the importance of new phase to enhance the efficiency of photovoltaic materials for practical applications.

Long-period modulations are shown in aerosol optical depth measured by the Microtops II Sun photometer over a high-altitude site the central Himalayan region (Nainital, 29.4° N, 79.5° E, 1958 m a.m.s.l.) for the first time. Fourier analysis of aerosol optical depth showed dominant 25–45 day oscillations observed in MODerate-resolution Imaging Spectro radiometer data. Further, a Hovmiller diagram showed westward (northward) propagation at a different longitude (latitude), confirming that the modulations are associated with Rossby waves. It is also shown that the Rossby wave amplitude causes an additional warming of 4.16 ± 0.98 W m−2 over the observational site. Hence, the present study illustrates the importance of wave-induced aerosol dynamics and the corresponding radiative effects.

Abstract We propose a complete framework for Bayesian image reconstruction and uncertainty quantification based on a Gaussian process prior (GPP) to overcome limitations of maximum likelihood expectation maximization (ML-EM) image reconstruction algorithm. The prior distribution is constructed with a zero-mean Gaussian process (GP) with a choice of a covariance function, and a link function is used to map the Gaussian process to an image. Unlike many other maximum a posteriori approaches, our method offers highly interpretable hyperparamters that are selected automatically with the empirical Bayes method. Furthermore, the GP covariance function can be modified to incorporate a priori structural priors, enabling multi-modality imaging or contextual data fusion. Lastly, we illustrate that our approach lends itself to Bayesian uncertainty quantification techniques, such as the preconditioned Crank–Nicolson method and the Laplace approximation. The proposed framework is general and can be employed in most radiation image reconstruction problems, and we demonstrate it with simulated free-moving single detector radiation source imaging scenarios. We compare the reconstruction results from GPP and ML-EM, and show that the proposed method can significantly improve the image quality over ML-EM, all the while providing greater understanding of the source distribution via the uncertainty quantification capability. Furthermore, significant improvement of the image quality by incorporating a structural prior is illustrated.

Abstract Background Excess muscle fat is observed in obesity and associated with greater burden of cardiovascular risk factors and higher risk of mortality. Liraglutide reduces total body weight and visceral fat but its effect on muscle fat and adverse muscle composition is unknown. Methods This is a pre‐specified secondary analysis of a randomized, double‐blind, placebo‐controlled trial that examined the effects of liraglutide plus a lifestyle intervention on visceral adipose tissue and ectopic fat among adults without diabetes with body mass index ≥30 kg/m2 or ≥27 kg/m2 and metabolic syndrome. Participants were randomly assigned to a once‐daily subcutaneous injection of liraglutide (target dose 3.0 mg) or matching placebo for 40 weeks. Body fat distribution and muscle composition was assessed by magnetic resonance imaging at baseline and 40‐week follow‐up. Muscle composition was described by the combination of thigh muscle fat and muscle volume. Treatment difference (95% confidence intervals [CI]) was calculated by least‐square means adjusted for baseline thigh muscle fat. The association between changes in thigh muscle fat and changes in body weight were assessed using Spearman correlation coefficients. The effect of liraglutide versus placebo on adverse muscle composition, denoted by high thigh muscle fat and low thigh muscle volume, was explored. Results Among the 128 participants with follow‐up imaging (92.2% women, 36.7% Black), median muscle fat at baseline was 7.8%. The mean percent change in thigh muscle fat over median follow‐up of 36 weeks was −2.87% among participants randomized to liraglutide (n = 73) and 0.05% in the placebo group (absolute change: −0.23% vs. 0.01%). The estimated treatment difference adjusted for baseline thigh muscle fat was −0.24% (95% CI, −0.41 to −0.06, P‐value 0.009). Longitudinal change in thigh muscle fat was significantly associated with change in body weight in the placebo group but not the liraglutide group. The proportion of participants with adverse muscle composition decreased from 11.0% to 8.2% over follow‐up with liraglutide, but there was no change with placebo. Conclusions In a cohort of predominantly women with overweight or obesity in the absence of diabetes, once‐daily subcutaneous liraglutide was associated with a reduction in thigh muscle fat and adverse muscle composition compared with placebo. The contribution of muscle fat improvement to the cardiometabolic benefits of liraglutide requires further study.

Abstract Background There is a growing population of children with in utero HIV exposure who are at risk of poor neurodevelopmental outcomes despite avoiding HIV infection. However, the underlying neurobiological pathways are not understood and neuroimaging studies are lacking. We aimed to investigate the cortical brain structure of children who are HIV-exposed and uninfected (HEU) compared to HIV-unexposed (HU) children and to examine the relationship with neurodevelopment. Methods The Drakenstein Child Health birth cohort study enrolled pregnant women from a high HIV prevalence area in South Africa with longitudinal follow-up of mother–child pairs. High-resolution magnetic resonance imaging scans from 162 children (70 HEU; 92 HU) were acquired at 2–3 years of age. All HEU children were born to mothers taking antiretroviral therapy. Measures of brain structure (cortical thickness and surface area) in the prefrontal cortex regions were extracted from T1-weighted images and compared between groups using multivariate analysis of variance and linear regression. Child development, assessed using the Bayley Scales of Infant and Toddler Development-III, was correlated with cortical structure, and mediation analyses were performed. Results Analyses demonstrated an association between HIV exposure and cortical thickness across the prefrontal cortex (p = 0.035). Children who were HEU had thicker cortices in prefrontal regions, with significantly greater cortical thickness in the medial orbitofrontal cortex (mOFC) bilaterally compared to HU children (3.21 mm versus 3.14 mm, p = 0.009, adjusted effect size 0.44 [95% CI 0.12 to 0.75]). Estimates held across multiple sensitivity analyses. There were no group differences in cortical surface area. Language scores, which were lower in HEU versus HU children (81.82 versus 86.25, p = 0.011, effect size − 0.44 [95% CI − 0.78 to − 0.09]), negatively correlated with prefrontal cortical thickness in both groups. Cortical thickness in the mOFC mediated the relationship between HIV exposure and poor language outcomes (Sobel test p = 0.032). Conclusions In this cohort study, exposure to HIV during pregnancy was associated with altered cortical structure in early life. Our findings indicate that differences in cortical thickness development in the prefrontal region in children who are HEU may be a pathway leading to language impairment. Longitudinal studies are needed to determine the lasting impact.

Abstract Background Previously, we discovered that human solid tumours, but not normal human tissues, preferentially overexpress interleukin‐13Receptor alpha2, a high binding receptor for IL‐13. To develop novel anti‐cancer approaches, we constructed a chimeric antigen receptor construct using a high binding and codon optimised scFv‐IL‐13Rα2 fragment fused with CD3ζ and co‐stimulatory cytoplasmic domains of CD28 and 4‐1BB. Methods We developed a scFv clone, designated 14‐1, by biopanning the bound scFv phages using huIL‐13Rα2Fc chimeric protein and compared its binding with our previously published clone 4‐1. We performed bioinformatic analyses for complementary determining regions (CDR) framework and residue analyses of the light and heavy chains. This construct was packaged with helper plasmids to produce CAR‐lentivirus and transduced human Jurkat T or activated T cells from peripheral blood mononuclear cells (PBMCs) to produce CAR‐T cells and tested for their quality attributes in vitro and in vivo. Serum enzymes including body weight from non‐tumour bearing mice were tested for assessing general toxicity of CAR‐T cells. Results The binding of 14‐1 clone is to IL‐13Rα2Fc‐chimeric protein is ∼5 times higher than our previous clone 4‐1. The 14‐1‐CAR‐T cells grew exponentially in the presence of cytokines and maintained phenotype and biological attributes such as cell viability, potency, migration and T cell activation. Clone 14‐1 migrated to IL‐13Rα2Fc and cell free supernatants only from IL‐13Rα2+ve confluent glioma tumour cells in a chemotaxis assay. scFv‐IL‐13Rα2‐CAR‐T cells specifically killed IL‐13Rα2+ve but not IL‐13Rα2‐ve tumour cells in vitro and selectively caused significant release of IFN‐γ only from IL‐13Rα2+ve co‐cultures. These CAR‐T cells regressed IL‐13Rα2+ve glioma xenografts in vivo without any general toxicity. In contrast, the IL‐13Rα2 gene knocked‐down U251 and U87 xenografts failed to respond to the CAR‐T therapy. Conclusion Taken together, we conclude that the novel scFv‐IL‐13Rα2 CAR‐T cell therapy may offer an effective therapeutic option after designing a careful pre‐clinical and clinical study.

Abstract Background Chimeric antigen receptor (CAR) T cell therapy is an exciting cell-based cancer immunotherapy. Unfortunately, CAR-T cell therapy is associated with serious toxicities such as cytokine release syndrome (CRS) and neurotoxicity. The mechanism of these serious adverse events (SAEs) and how homing, distribution and retention of CAR-T cells contribute to toxicities is not fully understood. Enabling in vitro methods to allow meaningful, sensitive in vivo biodistribution studies is needed to better understand CAR-T cell disposition and its relationship to both effectiveness and safety of these products. Methods To determine if radiolabelling of CAR-T cells could support positron emission tomography (PET)-based biodistribution studies, we labeled IL-13Rα2 targeting scFv-IL-13Rα2-CAR-T cells (CAR-T cells) with 89Zirconium-oxine (89Zr-oxine) and characterized and compared their product attributes with non-labeled CAR-T cells. The 89Zr-oxine labeling conditions were optimized for incubation time, temperature, and use of serum for labeling. In addition, T cell subtype characterization and product attributes of radiolabeled CAR-T cells were studied to assess their overall quality including cell viability, proliferation, phenotype markers of T-cell activation and exhaustion, cytolytic activity and release of interferon-γ upon co-culture with IL-13Rα2 expressing glioma cells. Results We observed that radiolabeling of CAR-T cells with 89Zr-oxine is quick, efficient, and radioactivity is retained in the cells for at least 8 days with minimal loss. Also, viability of radiolabeled CAR-T cells and subtypes such as CD4 + , CD8 + and scFV-IL-13Rα2 transgene positive T cell population were characterized and found similar to that of unlabeled cells as determined by TUNEL assay, caspase 3/7 enzyme and granzyme B activity assay. Moreover, there were no significant changes in T cell activation (CD24, CD44, CD69 and IFN-γ) or T cell exhaustion (PD-1, LAG-3 and TIM3) markers expression between radiolabeled and unlabeled CAR-T cells. In chemotaxis assays, migratory capability of radiolabeled CAR-T cells to IL-13Rα2Fc was similar to that of non-labeled cells. Conclusions Importantly, radiolabeling has minimal impact on biological product attributes including potency of CAR-T cells towards IL-13Rα2 positive tumor cells but not IL-13Rα2 negative cells as measured by cytolytic activity and release of IFN-γ. Thus, IL-13Rα2 targeting CAR-T cells radiolabeled with 89Zr-oxine retain critical product attributes and suggest 89Zr-oxine radiolabeling of CAR-T cells may facilitate biodistribution and tissue trafficking studies in vivo using PET.

Background High‐density lipoprotein (HDL) particle concentration likely outperforms HDL cholesterol in predicting atherosclerotic cardiovascular events. Whether size‐based HDL subspecies explain the atheroprotective associations of HDL particle concentration remains unknown. Our objective was to assess whether levels of specific size‐based HDL subspecies associate with atherosclerotic cardiovascular disease in a multiethnic pooled cohort and improve risk prediction beyond traditional atherosclerotic cardiovascular disease risk factors. Methods and Results Seven HDL size‐based subspecies were quantified by nuclear magnetic resonance (LP4 algorithm; H1=smallest; H7=largest) among participants without prior atherosclerotic cardiovascular disease in ARIC (Atherosclerosis Risk in Communities), MESA (Multi‐Ethnic Study of Atherosclerosis), PREVEND (Prevention of Renal and Vascular Endstage Disease), and DHS (Dallas Heart Study) cohorts (n=15 371 people). Multivariable Cox proportional hazards models were used to evaluate the association between HDL subspecies and incident myocardial infarction (MI) or ischemic stroke at follow‐up (average 8–10 years) adjusting for HDL cholesterol and risk factors. Improvement in risk prediction was assessed via discrimination and reclassification analysis. Within the pooled cohort (median age 57 years; female 54%; Black 22%) higher H1 (small) and H4 (medium) concentrations were inversely associated with incident MI (hazard ratio [HR]/SD, H1 0.88 [95% CI, 0.81–0.94]; H4 0.89 [95% CI, 0.82–0.97]). H4 but not H1 improved risk prediction indices for incident MI. Increasing H2 and H4 were inversely associated with improved risk prediction indices for composite end point of stroke, MI, and cardiovascular death (HR/SD, H2 0.94 [95% CI, 0.88–0.99]; H4 0.91 [95% CI, 0.85–0.98]). Levels of the large subspecies (H6 and H7) were not associated with any vascular end point. Conclusions Two of 7 HDL size‐based subspecies modestly improved risk prediction for MI and composite vascular end points in a large multiethnic pooled cohort. These findings support assessment of precise HDL subspecies for future studies regarding clinical utility.

Introduction: It is thought that oral hygiene can be influenced by socioeconomic status to some extent. People with higher socioeconomic status often have better access to resources and opportunities, which can impact their oral hygiene practices and overall dental health. Hence, this study assessed knowledge, attitude and behaviour regarding oral health amongst the adult population in urban and rural populations of Ahmedabad city. Materials and Methods: This cross-sectional study was carried out amongst the urban and rural segments of Ahmedabad district. The zones of the district and participants were selected by systematic random sampling method. The participants in the Ahmedabad district were selected, and those 204 who fulfilled the inclusion criteria were considered. A validated questionnaire was designed in our study so as to satisfy the quality, attain the objective of our study and make the study effective. Results: About 70.42% of the rural population and 77.30% of the urban population has good knowledge, while only 36.1% of the rural population and 47.16% of the urban population had a positive attitude towards oral hygiene practices. 61.27% of the rural population and 64.81% of the urban population showed positive behaviour. The absence of correlation was identified between knowledge-attitude and attitude-behaviour. Conclusion: It has been found that a massive number of the urban population possess a higher level of knowledge and attitude towards oral health than the rural population. No linear positive correlation was seen in knowledge, attitude and behaviour towards oral health.

Background and Purpose: Cerebral venous thrombosis (CVT) presenting as vision loss is uncommon. Raised intracranial tension in CVT is proposed as one of the mechanisms (13.2%). There are still unknown underlying mechanisms to explain vision loss in CVT. The safety and outcome of the surgery (optic nerve sheath fenestration [ONSF] or theco-peritoneal shunt [TPS]) to reduce intracranial hypertension and prevent vision loss has not been studied. Methods: A retrospective case record review of CVT patients with impending vision loss who underwent ONSF/TPS from 2007 to 2019 was performed from the stroke registry. All patients had formal neuro-ophthalmological evaluation and documentation of visual acuity, supplemented by visual field assessments by perimetry in a subset of patients. Safety and outcomes were assessed based on vision improvement and adverse effects after the surgery. Results: Among approximately 1400 patients with CVT admitted in the stroke ward over 12 years, surgery for rescuing vision was done in 18. Among these, the males were 6, and the females were 12. The mean age of presentation was 24 (range 18–52 years). All of them had headaches and progressive blurring of vision with papilledema. The number of patients who underwent TPS was 13, ONSF was 1, and both were 4. In the TPS group (26 eyes), vision improved in 15 eyes (57.7%), remained status-quo in 8 eyes (30.7%), and worsened in 3 eyes (11.5%). Four patients underwent both surgeries; three eyes improved, two remained status quo, and three worsened. One patient underwent ONSF, and his vision remained status quo (no perception of light). Three patients (17.6%) of the TPS group had minor complications (low-pressure headache, subdural hygroma), and five (29.4%) had major complications like subdural hemorrhage, abdominal wound infection, and meningitis. Conclusion and Implications: In patients with CVT, adequate vision monitoring is mandatory. Shunt surgeries (especially TPS) may help in stabilizing/improving vision in CVT patients with impending vision loss, despite adequate anti-edema measures (53.8% improved). Early diagnosis and precise decisions in referring for surgery are crucial.

IntroductionSubanesthetic ketamine is a rapidly acting antidepressant that has also been found to improve neurocognitive performance in adult patients with treatment resistant depression (TRD). Provisional evidence suggests that ketamine may induce change in hippocampal volume and that larger pre-treatment volumes might be related to positive clinical outcomes. Here, we examine the effects of serial ketamine treatment on hippocampal subfield volumes and relationships between pre-treatment subfield volumes and changes in depressive symptoms and neurocognitive performance.MethodsPatients with TRD (N = 66; 31M/35F; age = 39.5 ± 11.1 years) received four ketamine infusions (0.5 mg/kg) over 2 weeks. Structural MRI scans, the National Institutes of Health Toolbox (NIHT) Cognition Battery, and Hamilton Depression Rating Scale (HDRS) were collected at baseline, 24 h after the first and fourth ketamine infusion, and 5 weeks post-treatment. The same data was collected for 32 age and sex matched healthy controls (HC; 17M/15F; age = 35.03 ± 12.2 years) at one timepoint. Subfield (CA1/CA3/CA4/subiculum/molecular layer/GC-ML-DG) volumes corrected for whole hippocampal volume were compared across time, between treatment remitters/non-remitters, and patients and HCs using linear regression models. Relationships between pre-treatment subfield volumes and clinical and cognitive outcomes were also tested. All analyses included Bonferroni correction.ResultsPatients had smaller pre-treatment left CA4 (p = 0.004) and GC.ML.DG (p = 0.004) volumes compared to HC, but subfield volumes remained stable following ketamine treatment (all p > 0.05). Pre-treatment or change in hippocampal subfield volumes over time showed no variation by remission status nor correlated with depressive symptoms (p > 0.05). Pre-treatment left CA4 was negatively correlated with improved processing speed after single (p = 0.0003) and serial ketamine infusion (p = 0.005). Left GC.ML.DG also negatively correlated with improved processing speed after single infusion (p = 0.001). Right pre-treatment CA3 positively correlated with changes in list sorting working memory at follow-up (p = 0.0007).DiscussionThese results provide new evidence to suggest that hippocampal subfield volumes at baseline may present a biomarker for neurocognitive improvement following ketamine treatment in TRD. In contrast, pre-treatment subfield volumes and changes in subfield volumes showed negligible relationships with ketamine-related improvements in depressive symptoms.

Bacterial conjunctivitis (BC) entails inflammation of the ocular mucous membrane. Early effective treatment of BC can prevent the spread of the infection to the intraocular tissues, which could lead to bacterial endophthalmitis or serious visual disability. In 2003, gatifloxacin (GTX) eyedrops were introduced as a new broad-spectrum fluoroquinolone to treat BC. Subsequently, GTX use was extended to other ocular bacterial infections. However, due to precorneal loss and poor ocular bioavailability, frequent administration of the commercial eyedrops is necessary, leading to poor patient compliance. Thus, the goal of the current investigation was to formulate GTX in a lipid-based drug delivery system to overcome the challenges with the existing marketed eyedrops and, thus, improve the management of bacterial conjunctivitis. GTX-NLCs and SLNs were formulated with a hot homogenization–probe sonication method. The lead GTX-NLC formulation was characterized and assessed for in vitro drug release, antimicrobial efficacy (against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa), and ex vivo permeation. The lead formulation exhibited desired physicochemical characteristics, an extended release of GTX over a 12 h period, and was stable over three months at the three storage conditions (refrigerated, room temperature, and accelerated). The transcorneal flux and permeability of GTX from the GTX-NLC formulation were 5.5- and 6.0-fold higher in comparison to the commercial eyedrops and exhibited a similar in vitro antibacterial activity. Therefore, GTX-NLCs could serve as an alternative drug delivery platform to improve treatment outcomes in BC.

Ocular bacterial infections can lead to serious visual disability without proper treatment. Moxifloxacin (MOX) has been approved by the US Food and Drug Administration as a monotherapy for ocular bacterial infections and is available commercially as an ophthalmic solution (0.5% w/v). However, precorneal retention, drainage, and low bioavailability remain the foremost challenges associated with current commercial eyedrops. With this study, we aimed to design a MOX-loaded nanoemulsion (NE; MOX-NE) with mucoadhesive agents (MOX-NEM) to sustain MOX release, as well as to overcome the potential drawbacks of the current commercial ophthalmic formulation. MOX-NE and MOX-NEM formulations were prepared by hot homogenization coupled with probe sonication technique and subsequently characterized. The lead formulations were further evaluated for in vitro release, ex vivo transcorneal permeation, sterilization, and antimicrobial efficacy studies. Commercial MOX ophthalmic solution was used as a control. The lead formulations showed the desired physicochemical properties and viscosity. All lead formulations showed sustained release profiles a period of more than 12 h. Filtered and autoclaved lead formulations were stable for one month (the last time point tested) under refrigeration and at room temperature. Ex vivo transcorneal permeation studies revealed a 2.1-fold improvement in MOX permeation of the lead MOX-NE formulation compared with Vigamox® eyedrops. However, MOX-NEM formulations showed similar flux and permeability coefficients to those of Vigamox® eyedrops. The lead formulations showed similar in vitro antibacterial activity as the commercial eyedrops and crude drug solution. Therefore, MOX-NE and MOX-NEM formulations could serve as effective delivery vehicles for MOX and could improve treatment outcomes in different ocular bacterial infections.

IL-13Rα2 is a high-affinity binding protein for its ligand IL-13 and a cancer-testis antigen as it is expressed in the testis. IL-13Rα2 is highly expressed in various cancers, including pancreatic cancer, and consists of three domains: extracellular, transmembrane, and cytoplasmic. The extracellular domain binds to the ligand to form a biologically active complex, which initiates signaling through AP-1 and other pathways. IL-13Rα2 is also expressed in diseased cells such as fibroblasts that are involved in various inflammatory diseases, including cancer. We have reported that IL-13Rα2 is a prognostic biomarker for malignant glioma, adrenocortical cancer, and pancreatic cancer. In pancreatic cancer, a small sample of tissue could be examined for the expression of IL-13Rα2 by using the endoscopic ultrasound-fine needle aspiration technique (EUS-FNA). In addition, a peptide-based targeted approach using Pep-1L peptide could be used to study the biodistribution and whole-body cancer imaging for the screening of pancreatic cancer in suspected subjects.