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Abstract Background The recent World Health Organization (WHO) resolution on oral health urges pivoting to a preventive approach and integration of oral health into the non-communicable diseases agenda. This study aimed to: 1) explore the healthcare costs of managing dental caries between the ages of 12 and 65 years across socioeconomic groups in six countries (Brazil, France, Germany, Indonesia, Italy, UK), and 2) estimate the potential reduction in direct costs from non-targeted and targeted oral health-promoting interventions. Methods A cohort simulation model was developed to estimate the direct costs of dental caries over time for different socioeconomic groups. National-level DMFT (dentine threshold) data, the relative likelihood of receiving an intervention (such as a restorative procedure, tooth extraction and replacement), and clinically-guided assumptions were used to populate the model. A hypothetical group of upstream and downstream preventive interventions were applied either uniformly across all deprivation groups to reduce caries progression rates by 30% or in a levelled-up fashion with the greatest gains seen in the most deprived group. Results The population level direct costs of caries from 12 to 65 years of age varied between US10.2 billion in Italy to US$36.2 billion in Brazil. The highest per-person costs were in the UK at US$22,910 and the lowest in Indonesia at US$7,414. The per-person direct costs were highest in the most deprived group across Brazil, France, Italy and the UK. With the uniform application of preventive measures across all deprivation groups, the greatest reduction in per-person costs for caries management was seen in the most deprived group across all countries except Indonesia. With a levelling-up approach, cost reductions in the most deprived group ranged from US$3,948 in Indonesia to US$17,728 in the UK. Conclusion Our exploratory analysis shows the disproportionate economic burden of caries in the most deprived groups and highlights the significant opportunity to reduce direct costs via levelling-up preventive measures. The healthcare burden stems from a higher baseline caries experience and greater annual progression rates in the most deprived. Therefore, preventive measures should be start early, with a focus on lowering early childhood caries and continue through the life course.

Background: Distributing vaccines efficiently during the COVID-19 pandemic presented significant logistical challenges. To address the need for identifying populations at risk of breakthrough infections and those requiring booster shots, Emirates Health Services (EHS) developed a framework utilizing AI-driven digital solutions. Objective: To develop a machine learning (ML) model to identify individuals at risk of breakthrough infections and in need of booster doses, aiming to prioritize booster administration and reduce repeated infections among fully vaccinated individuals in the Northern Emirates of the UAE. Methods: A monitoring dashboard was developed using the EHS Intelligence (PaCE) platform. The study, conducted in three phases, created models to predict infection risk, COVID-19 severity in ICU patients and breakthrough infection risk, using data from the Wareed EMR system. Results: The AI models accurately identified high-risk individuals and predicted ICU mortality, achieving AUCs of 75% and 74% for infection risk, 94% and 91% for ICU mortality in training and validation datasets, observed 79% AUC with 85% accuracy for identifying high-risk groups for booster vaccination. Conclusion: The integration of AI in vaccination prioritization demonstrated its potential to enhance public health initiatives and improve pandemic management in the UAE.

Introduction: Hyperinsulinemic hypoglycaemia (HH) is characterised by unregulated insulin secretion, leading to persistent non-ketotic hypoglycaemia with a lack of alternate fuel that induces a severe risk for brain damage and neurodevelopmental abnormalities. Octreotide, a somatostatin analogue, has been effectively administered as subcutaneous injections or depot preparations in diazoxide-unresponsive HH. Methods: Children and infants with HH receiving short-acting octreotide injections were included. Anthropometric values, hypoglycaemic episodes, HbA1C, and side effects were noted from the records and were followed up for 12 months. Informed written consent was obtained from the parents before administration of a single dose of LAR (long-acting octreotide). Based on home-based glucose monitoring (HBGM), the dosage of LAR was modified, and short-acting octreotide was eventually withdrawn. The patients shared the injection’s cost for cost-effectiveness. HH affects the quality of life (QoL) if not diagnosed and controlled adequately. A QoL questionnaire was given before starting LAR and after 6 months of receiving LAR, and the changes were noted accordingly. Results: Twenty-two patients were diagnosed with HH, of which 11 infants and children were included in the study. Mutations were identified in 7 (63.63%) children. Daily octreotide could be tapered and stopped with the addition of sirolimus in one patient with an increasing dose of LAR to maintain euglycaemia. The hypoglycaemic episodes decreased with increasing dose of LAR with a decrease in the severity. Eight (72.7%) patients showed an improved lifestyle on LAR quantified through a QoL questionnaire. Conclusion: LAR was found effective in reducing hypoglycaemic episodes with no adverse effects. The patient’s parent’s satisfaction was higher. Given its high cost, this trial achieved cost-effectiveness by sharing a single sitting of LAR injection.

Abstract The study of muscle mass as an imaging-derived phenotype (IDP) may yield new insights into determining the normal and pathologic variations in muscle mass in the population. This can be done by determining 3D abdominal muscle mass from 12 distinct abdominal muscle regions and groups using computed tomography (CT) in a racially diverse medical biobank. To develop a fully automatic technique for assessment of CT abdominal muscle IDPs and preliminarily determine abdominal muscle IDP variations with age and sex in a clinically and racially diverse medical biobank. This retrospective study was conducted using the Penn Medicine BioBank (PMBB), a research protocol that recruits adult participants during outpatient visits at hospitals in the Penn Medicine network. We developed a deep residual U-Net (ResUNet) to segment 12 abdominal muscle groups including the left and right psoas, quadratus lumborum, erector spinae, gluteus medius, rectus abdominis, and lateral abdominals. 110 CT studies were randomly selected for training, validation, and testing. 44 of the 110 CT studies were selected to enrich the dataset with representative cases of intra-abdominal and abdominal wall pathology. The studies were divided into non-overlapping training, validation and testing sets. Model performance was evaluated using the Sørensen–Dice coefficient. Volumes of individual muscle groups were plotted to distribution curves. To investigate associations between muscle IDPs, age, and sex, deep learning model segmentations were performed on a larger abdominal CT dataset from PMBB consisting of 295 studies. Multivariable models were used to determine relationships between muscle mass, age and sex. The model's performance (Dice scores) on the test data was the following: psoas: 0.85 ± 0.12, quadratus lumborum: 0.72 ± 0.14, erector spinae: 0.92 ± 0.07, gluteus medius: 0.90 ± 0.08, rectus abdominis: 0.85 ± 0.08, lateral abdominals: 0.85 ± 0.09. The average Dice score across all muscle groups was 0.86 ± 0.11. Average total muscle mass for females was 2041 ± 560.7 g with a high of 2256 ± 560.1 g (41–50 year old cohort) and a change of − 0.96 g/year, declining to an average mass of 1579 ± 408.8 g (81–100 year old cohort). Average total muscle mass for males was 3086 ± 769.1 g with a high of 3385 ± 819.3 g (51–60 year old cohort) and a change of − 1.73 g/year, declining to an average mass of 2629 ± 536.7 g (81–100 year old cohort). Quadratus lumborum was most highly correlated with age for both sexes (correlation coefficient of − 0.5). Gluteus medius mass in females was positively correlated with age with a coefficient of 0.22. These preliminary findings show that our CNN can automate detailed abdominal muscle volume measurement. Unlike prior efforts, this technique provides 3D muscle segmentations of individual muscles. This technique will dramatically impact sarcopenia diagnosis and research, elucidating its clinical and public health implications. Our results suggest a peak age range for muscle mass and an expected rate of decline, both of which vary between genders. Future goals are to investigate genetic variants for sarcopenia and malnutrition, while describing genotype–phenotype associations of muscle mass in healthy humans using imaging-derived phenotypes. It is feasible to obtain 3D abdominal muscle IDPs with high accuracy from patients in a medical biobank using fully automated machine learning methods. Abdominal muscle IDPs showed significant variations in lean mass by age and sex. In the future, this tool can be leveraged to perform a genome-wide association study across the medical biobank and determine genetic variants associated with early or accelerated muscle wasting.

Nonessential heavy metals are toxic to human health. In this study, mercury, a hazardous metal, was detected by colorimetric analysis using Murraya koenigii. The eco-friendliness of this method was also emphasized. UV spectrum is a broad peak observed at 200–250 nm in P. guajava leaf extracts. The UV spectrum of green synthesized P. guajava exhibited an absorption band of 418 nm, which confirms the nanoparticle synthesis. FTIR analysis of the vibrational peak around 3307 cm−1 is assigned to ν(O–H) stretching that could possibly emanate from carbohydrates or phenolics. The peaks found around 2917 and 2849 cm−1 are ascribed to the –C-H stretch of the alkyl group, and the peak around 1625 cm−1 is due to the enolic β-diketones or -C = O stretch of carboxylic acids, while the corresponding -C-O stretch is observed around 1375 and 1029 cm−1. The assignment of peaks is similar. It is clear from the SEM image that the constituent parts were non-uniform sphere-shaped, agglomerated, and of an average size of 30.9 nm. XRD analysis was utilized to determine the structural characteristics and crystalline nature of P. guajava. The observed intensity peaks at 32.35°, 36.69°, 39.24°, 44.76°, 59.42°, and 67.35° represent the 2θ values for P. guajava in the diffraction pattern, aligning with the values in the standard database. The synthesized AgNPs tested antibacterial properties against various strains of microorganisms, including Escherichia coli, 25 μg/mL 6.02 ± 0.17 and 100 μg/mL 7.3 ± 0.05, Staphylococcus aureus, 25 μg/mL 05.02 ± 0.07 and 100 μg/mL 11.3 ± 1.12, Streptococcus mutans, 25 μg/mL 04.02 ± 0.19 and 100 μg/mL 11.1 ± 0.11, Enterococcus faecalis, 25 µg/mL 0.8.05 ± 0.11 and 100 µg/mL 11.7 ± 0.02. The short novelty of Psidium guajava (guava) lies in its potential relevance to human health, as it has been found to possess bioactive compounds with various medicinal properties, such as antimicrobial, antioxidant, and anti-inflammatory activities, making it a promising natural resource for therapeutic applications.

Background: The microbiota in the intestine is made up of trillions of living bacteria that coexist with the host. Administration of antibiotics during neonatal infection causes depletion of gut flora resulting in gut dysbiosis. Over the last few decades, probiotics have been created and promoted as microbiota management agents to enrich gut flora. Probiotics decrease the overgrowth of pathogenic bacteria in the gut of preterm neonates, reducing the frequency of nosocomial infections in the Neonatal Intensive Care Unit (NICUs). Methods: The systematic review will include randomized control trials (RCTs) of premier neonates with sepsis. Studies will be retrieved from global databases like Cochrane CENTRAL, CINAHL Plus via EBSCO host, MEDLINE via PubMed, EMBASE, SCOPUS, Ovid, Web of Science, ProQuest Medical Library, Microsoft academic, and DOAJ by utilizing database-specific keywords. Screening, data extraction, and critical appraisal of included research will be carried out separately by two review writers. Findings will be reported in accordance with the PRISMS-P 2020 guidelines. Conclusions: The findings of this systematic review will help to translate the evidence-based information needed to encourage the implementation of potential research output in the field of neonatal intensive care, guide best clinical practise, assist policy making and implementation to prevent gut dysbiosis in neonates with sepsis by summarising and communicating the evidence on the topic. PROSPERO registration number: This systematic review protocol has been registered in PROSPERO (Prospective Register of Systematic Reviews) on 10th March 2022. The registration number is CRD42022315980.

Abstract The objective of this study is to define CT imaging derived phenotypes for patients with hepatic steatosis, a common metabolic liver condition, and determine its association with patient data from a medical biobank. There is a need to further characterize hepatic steatosis in lean patients, as its epidemiology may differ from that in overweight patients. A deep learning method determined the spleen-hepatic attenuation difference (SHAD) in Hounsfield Units (HU) on abdominal CT scans as a quantitative measure of hepatic steatosis. The patient cohort was stratified by BMI with a threshold of 25 kg/m2 and hepatic steatosis with threshold SHAD ≥ − 1 HU or liver mean attenuation ≤ 40 HU. Patient characteristics, diagnoses, and laboratory results representing metabolism and liver function were investigated. A phenome-wide association study (PheWAS) was performed for the statistical interaction between SHAD and the binary characteristic LEAN. The cohort contained 8914 patients—lean patients with (N = 278, 3.1%) and without (N = 1867, 20.9%) steatosis, and overweight patients with (N = 1863, 20.9%) and without (N = 4906, 55.0%) steatosis. Among all lean patients, those with steatosis had increased rates of cardiovascular disease (41.7 vs 27.8%), hypertension (86.7 vs 49.8%), and type 2 diabetes mellitus (29.1 vs 15.7%) (all p

Purpose: The psychosocial aspects of type 1 diabetes mellitus (T1DM) are still a neglected area, especially among children in India. This study was planned to evaluate and screen the children with T1DM for family support, symptoms of anxiety and depression, and to assess the role of these psychosocial aspects in glycemic control. Methods: This cross-sectional observational questionnaire-based study conducted over a year included 70 children aged 8–18 years diagnosed with T1DM for at least a year. The child and caregiver answered pre-validated standard questionnaires and the children underwent HbA1C testing once every 3 months. The methods used for inferential statistical analysis were reliability analysis, correlation analysis, χ2 test, and factor analysis. Results: Poorer glycemic control was noted by children raised by single parents (mean HbA1C 14.4, p < 0.001). It was also noted that children whose mothers had formal education beyond 10th standard had better glycemic control. 14 children (20%) had anxiety/depression of medium to high severity. The relationship between family conflict and glycemic control was not significant in either the parent or the child scoring. Conclusion: Children with T1DM experience considerable stress related to the diagnosis and management. Many families experience significant depression and anxiety which leads to increase in family conflicts which have a negative effect on parenting, the child’s quality of life, and their glycemic control.

Background: Turner syndrome (TS) is the commonest chromosomal abnormality in females with an incidence of 25–50 per 100,000 females. Girls with TS universally have short stature (95%), along with gonadal failure (>90%) and infertility (99%); however, the ethnic differences are not well elaborated. Objectives: This study has been planned to evaluate the presentation and course of Indian girls with TS. Methods: Patients with TS presenting to our referral endocrinology clinic were included in this study. Diagnosis of TS was done by karyotyping. A retrospective chart review of these patients formed the basis of this study. Results: A total of 55 patients with TS karyotype were seen, and the mean age at diagnosis was 12.3 years. The commonest presenting features were short stature alone seen in 37 (65.45%) and short stature with delayed puberty in 18 (32.72%). The earliest age at presentation was 4.5 years who presented with short stature. The mean height was 124.17 cm and mean BMI 17.54 kg/m2. The most common karyotype was 45, XO found in 34 (61.6%) of the cases. 15 (27.27%) the cases were started on growth hormone therapy. 26 cases (47.27%) required pubertal induction. Conclusion: A vast number of cases with TS in India remain undiagnosed until puberty or present very late. A high degree of clinical suspicion can help us diagnose these children earlier. If TS is diagnosed earlier, growth can be achieved up to their maximum potential. Early identification and management will help us provide multidisciplinary care and hence prevent complications.

Abstract Background The epidemiology and treatment of acute promyelocytic leukaemia (APL) are changing. We have incorporated oral arsenic trioxide (oral-ATO) into induction/maintenance. Methods Newly-diagnosed APL from 1991 to 2021 divided into three 10-year periods were studied to define its epidemiology and how oral-ATO impacted on its outcome. Primary endpoints included APL incidence, early deaths (ED, first 30 days), and overall survival (OS). Secondary endpoints included post-30-day OS, relapse-free survival (RFS), and incidence of second cancers. Results APL occurred in 374 males and 387 females at a median age of 44 (1–97) years. Annual incidences increased progressively, averaging 0.32 per 100,000 people. All-trans retinoic acid (ATRA)-based and oral-ATO-based regimens were used in 469 and 282 patients. There were 144 EDs, occurring almost exclusively in ATRA-based inductions (N = 139), being more with males, age > 50 years, leucocyte > 10 × 109/L, diagnosis during 1991–2009 and fewer with oral-ATO-based regimens. After a median of 75 (interquartile range: 14–161) months, 5-year and 10-year OS were 68.1% and 63.3%, inferior with males, age > 50 years, leucocyte > 10 × 109/L, high-risk Sanz score and superior with oral-ATO-based regimens. Factoring out EDs, 5-year and 10-year post-30-day OS were 84.0% and 78.1%, inferior with males and superior with oral-ATO-based regimens. In 607 CR1 patients, the 5-year RFS was 83.8%, superior with diagnosis in 2010–2021 and oral-ATO-based regimens. Second cancers developed in 21 patients, unrelated to oral-ATO-based regimens. Conclusions There was an increasing incidence of APL, and all survivals were superior with the use of oral-ATO-based regimens. This study formed part of the Acute Promyelocytic Leukaemia Asian Consortium Project (ClinicalTrials.gov identifier: NCT04251754).

Introduction: For individuals with end-stage organ disease, organ transplantation is the most preferred therapeutic option. There is an insufficient supply of organs to meet the demand. Students in the health sciences are an important link in raising public awareness about organ donation (OD). Their attitudes and views have the potential to influence public opinion. The purpose of this research was to better understand the knowledge, attitudes, and practices regarding OD among health science students at the Symbiosis Institute of Health Sciences, Pune. Subjects and Methods: A web-based, cross-sectional institution-based study of students pursuing different health sciences courses was conducted. A specially designed questionnaire was used to survey the students. A total of 680 students were sent the Google questionnaire, out of which 219 participants responded, for a response rate of 32.20%. Results: Out of 219 respondents, 60.3% did not have any knowledge regarding the process of registering for OD. Moreover, 78.1% and 72.1% had no idea about the brain-dead donor ventilation support protocol or the law regarding OD in India, respectively. However, around 4/5th of the study participants were willing to sign a donor card, and only around 12% of participants have pledged or registered for OD. Conclusion: Students have a good attitude regarding OD; however, there is a dearth of understanding and practice on the subject. Improving their understanding by integrating the issue of OD into their curriculum may help close this gap.

Background: India has the highest number of prevalent type-1 diabetes (T1D) cases in the under-20-year age population. Data on the anthropometry of underprivileged Indian children with T1D are scarce. In economically disadvantaged countries like India, poor growth in patients with T1D is a major concern due to limited accessibility and affordability. Besides, due to the double burden of malnutrition, the prevalence of obesity is increasing mirroring the global trends, which may lead to the development of insulin resistance. Objectives: This study aims to assess the prevalence of malnutrition in Indian children and youth with T1D and to identify the determinants of short stature. Methods: A registry-based cross-sectional analysis of data collected from various centres across India enrolled in the Changing Diabetes in Children (CDiC) programme. Results: We observed that 6.4% were undernourished (3.4% severe undernutrition) and 17.7% (overweight 13.2%) had combined overweight/obesity. 21.2% of participants had short stature (adjusted for mid-parental height) with 7.4% cases of familial short stature. Longer duration of illness and insulin requirement were significant positive predictors of short stature while glycaemic control, insulin regimen and mid-parental height did not have a significant relationship with short stature. Participants on basal-bolus regimen had significantly higher insulin requirements and better glycaemic control than the ones on mixed-split regimen. Conclusion: We report that around one-fifth of children and youth with T1D were overweight/obese and around a fourth were stunted, especially those with longer duration of diabetes and higher insulin requirements. Close monitoring of anthropometric parameters is necessary for all children with T1D to optimize growth and nutrition.

Background: Regular self-monitoring of blood glucose (SMBG) remains the mainstay method for diabetes monitoring. The major limitation of SMBG is poor compliance and it only provides a snapshot of glucose values at that point of time. Continuous glucose monitors (CGMs) are non-invasive devices which measure subcutaneous interstitial glucose for every five minutes and provide glucose variability throughout the day. Aim and Objective: To assess the effectiveness of intermittent continuous blood glucose monitoring in comparison with SMBG on the percentage reduction in HbA1c level in children with type 1 diabetes mellitus (DM). Methods: Children diagnosed with type 1 DM of age group 3–18 years were enlisted into the study. Participants were randomised to the study arm (CGMs+SMBG) or the control arm (SMBG alone). Subjects in the study group were given CGM along with regular SMBG for 14 days. The control group was asked to perform SMBG. HbA1c levels were measured in both groups after three months of intervention. Results: There were 62 children in each group. After three months, in the intervention group HbA1c level dropped from 11.23% ± 1.53% (Mean ± SD) to 10.14% ± 1.99%, in control group HbA1c level dropped from 11.62% ± 1.62% to 11.32% ± 1.57%. The fall in HbA1c level in intervention group is significant (p value –0.01). Conclusion: In a resource-limited setting, intermittent use of CGMs atleast once every two to three months will help in understanding the factors influencing glucose variation throughout the day and, with appropriate therapeutic modifications, will aid in achieving optimal glycaemic control.

Abstract Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. Methods This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. Results In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology. Trial registration ClinicalTrials.gov, NCT03706885.

Ameloblastoma is a benign, locally invasive epithelial odontogenic tumour occuring in the jaw. Among all types, multicystic ameloblastoma is a locally aggressive lesion and prone to recurrence. Hereby, the authors present a case report of a 23-yearold female with a chief complaint of painful swelling on the right lower third of the face for the past one month. History revealed a gradual increase in size of the swelling, along with intermittent and non radiating pain that worsened during mastication and improved with rest. Patient past history revealed similar swelling in the same region twice, with the first occurring five-yearsago and a recurrence after two years of treatment. Both the episodes were treated with laser ablative surgery and extraction of the affected tooth. The patient presented with recurrent swelling one month ago and underwent an incisional biopsy, which revealed a histopathological diagnosis of unicystic ameloblastoma. Additional investigations, including an occlusal radiograph, orthopantomogram, and Computed Tomography (CT), were performed. Based on the recurrence, clinical examination, and investigations, the present case was diagnosed as unicystic ameloblastoma. It was treated with segmental resection followed by reconstruction of the mandible using a free fibula graft was planned. The prognosis was good, and regular follow-up has been maintained for the last four months, with the patient still under review. The uniqueness of present case lies in the patient’s second decade of life, three episodes of recurrence within five years, and the treatment approach of segmental mandibulectomy with immediate free fibula graft reconstruction. This procedure reduces the risk of recurrence, allows for full rehabilitation within a short period, and minimises the number of surgical procedures.

Lithium-based electrolytes are, at least from a thermodynamic standpoint, the most suitable ion-transport materials for energy storage systems. However, lithium-based ionic conductors suffer from safety concerns, and the limited availability of lithium in the Earth’s crust is at the root of the need to consider alternative metal ions. Notably, sodium stands out as the sixth most-prevalent element; therefore, when considering mineral reserves, it as a very attractive candidate as an alternative to the status quo. Even if the specific energy and energy density of sodium are indeed inferior with respect to those of lithium, there is substantial economic appeal in promoting the use of the former metal in stationary energy storage applications. For these reasons, the promise of sodium is likely to extend to other commercial applications, including portable electronics, as well as hybrid and electric vehicles. Widely used organic liquid electrolytes, regardless of their chosen metal cation, are disadvantageous due to leakage, evaporation, and high flammability. Polymer electrolytes are acknowledged as the most effective candidates to overcome these obstacles and facilitate the advancement of next-generation energy storage applications. In this contribution, an in-depth and comprehensive review of sodium polymer electrolytes for primary and secondary batteries is proposed. The overarching goal was to gain insight into successful synthetic strategies and their implications for conduction parameters and conductivity mechanisms. The focus lies on solid, gel, and composite polymer electrolytes. Our hope is that the proposed discussion will be helpful to all operators in the field, whether in tackling fundamental research problems or resolving issues of practical significance.

Abstract Background A pro-oxidant enzyme, NADPH oxidase 4 (Nox4) has been reported to be a critical downstream effector of TGFβ-induced myofibroblast transformation during fibrosis. While there are a small number of studies suggesting an oncogenic role of Nox4 derived from activated fibroblasts, direct evidence linking this pro-oxidant to the tumor-supporting CAF phenotype and the mechanisms involved are lacking, particularly in breast cancer. Methods We targeted Nox4 in breast patient-derived CAFs via siRNA-mediated knockdown or administration of a pharmaceutical inhibitor (GKT137831). We also determine primary tumor growth and metastasis of implanted tumor cells using a stable Nox4-/- syngeneic mouse model. Autophagic flux of CAFs was assessed using a tandem fluorescent-tagged ptfl-LC3 plasmid via confocal microscopy analysis and determination of the expression level of autophagy markers (beclin-1 and LC3B). Nox4 overexpressing CAFs depend on the Nrf2 (nuclear factor-erythroid factor 2-related factor 2) pathway for survival. We then determined the dependency of Nox4-overexpressing CAFs on the Nrf2-mediated adaptive stress response pathway for survival. Furthermore, we investigated the involvement of Birc5 on CAF phenotype (viability and collagen contraction activity) as well as the expression level of CAF markers, FAP and αSMA. Conclusions We found that deletion of stroma Nox4 and pharmaceutically targeting its activity with GKT137831 significantly inhibited orthotopic tumor growth and metastasis of implanted E0771 and 4T1 murine mammary carcinoma cell lines in mice. More importantly, we found a significant upregulation of Nox4 expression in CAFs isolated from human breast tumors versus normal mammary fibroblasts (RMFs). Our in situ RNA hybridization analysis for Nox4 transcription on a human breast tumor microarray further support a role of this pro-oxidant in the stroma of breast carcinomas. In addition, we found that Nox4 promotes autophagy in CAFs. Moreover, we found that Nox4 promoted survival of CAFs via activation of Nrf2, a master regulator of oxidative stress response. We have further shown Birc5 is involved as a downstream modulator of Nrf2-mediated pro-survival phenotype. Together these studies indicate a role of redox signaling via the Nox4-Nrf2 pathway in tumorigenesis and metastasis of breast cancer cells by promoting autophagy and survival of CAFs.

“There is many a slip twist the cup and the lip” is a proverb that dates back to the 3rd century. This proverb comes to mind while writing a review on pregnancy loss; so many complications can occur between fertilization and development of the embryo through the long period of gestation until successful delivery of the baby. These include failure of implantation of the embryo, spontaneous miscarriage in the first trimester, pre-eclampsia in the second trimester, premature rupture of fetal membranes, pre-term labour, and pre-term delivery. The maternal immune system which does a phenomenal job of protecting the host from a daunting variety of infections, sometimes also mounts adverse reactions that complicate pregnancy and endanger the fetus. Maternal immune reactions that can adversely affect pregnancy have been shown to be mediated by lymphocytes, macrophages and natural killer cells, and by cytokines secreted by these cellular effectors. This review summarizes the deleterious effects of cytokines leading to recurrent spontaneous miscarriage, pre-eclampsia and pre-term delivery, which are the major complications of pregnancy. It then goes on to discuss the potential use of progesterone and dydrogesterone, an orally-administered progestogen, as immunomodulatory molecules that can be considered for the prevention and/or treatment of these complications.

Photocatalytic CO _2 reduction is a sustainable pathway to produce syngas (H _2 + CO), which is a key feedstock for the production of several important liquid fuels on the industrial scale. However, achieving an appropriate tunable ratio of H _2 :CO in syngas for commercial purposes is a challenging task. In this work, we present a low-cost and non-noble metal, phosphide-based co-catalyst—Ni _2 P-loaded cadmium sulfide (CdS) photocatalyst system, for photocatalytic CO _2 reduction. As a co-catalyst, Ni _2 P fosters an efficient charge separation of photoexcited charges generated in the CdS production of syngas. In total, 3 wt.% Ni _2 P/CdS exhibited exceptional performance of 50.6 µ mol g ^−1 h ^−1 in the CO evolution rate and 115 µ mol g ^−1 h ^−1 in the H _2 evolution rate, with a syngas composition varying from 2 to 4 in the H _2 :CO ratio. Furthermore, first-principles density functional theory calculations were performed to study the surface energetics of the catalyst system and the results are found to be consistent with our experimental findings. Indeed, they establish that the composite favors CO _2 photoreduction into syngas more efficiently than pure surfaces.

Fungal diseases, including downy mildew (caused by Plasmopara viticola) and gray mold (caused by Botrytis cinerea), significantly impact the marketable yield of grapes produced worldwide. Cytochrome b of the mitochondrial respiratory chain of these two fungi is a key target for Quinone outside inhibitor (QoI)-based fungicide development. Since the mode of action (MOA) of QoI fungicides is restricted to a single site, the extensive usage of these fungicides has resulted in fungicide resistance. The use of fungicide combinations with multiple targets is an effective way to counter and slow down the development of fungicide resistance. Due to the high cost of in planta trials, in silico techniques can be used for the rapid screening of potential fungicides. In this study, a combination of in silico simulations that include Schrödinger Glide docking, molecular dynamics, and Molecular Mechanism-Generalized Born Surface Area calculation were used to screen the most potent QoI and non-QoI-based fungicide combinations to wild-type, G143A-mutated, F129L-mutated, and double-mutated versions that had both G143A and F129L mutations of fungal cytochrome b. In silico docking studies indicated that mandestrobin, famoxadone, captan, and thiram have a high affinity toward WT cytochrome b of Botrytis cinerea. Although the QoIs mandestrobin and famoxadone were effective for WT based on in vitro results, they were not broadly effective against G143A-mutated isolates. Famoxadone was only effective against one isolate with G143A-mutated cytochrome b. The non-QoI fungicides thiram and captan were effective against both WT and isolates with G143A-mutated cytochrome b. Follow-up in silico docking and molecular dynamics studies suggested that fungicide combinations consisting of famoxadone, mandestrobin, fenamidone, and thiram should be considered in field testing targeting Plasmopara viticola and Botrytis cinerea fungicide resistance.

Insulin is the cornerstone of type 1 diabetes mellitus (T1DM) treatment. Insulin allergy in patients with T1DM on insulin is an uncommon problem that might manifest itself as immediate or delayed symptoms after injections. We present 2 cases: the first is a 17-year-old girl who was diagnosed with T1DM at the age of 14 and has had several skin lesions at injection sites over the past 2 months that have not responded to antibiotics. The second case involves a 4-year-old boy who was diagnosed with T1DM at the age of 15 months and had non-tender, erythematous, and indurated lesions. Insulin hypersensitivity was detected in both cases, thus newer analogues were administered instead of regular and isophane insulin, and the lesions dramatically reduced.

Pulmonary embolism (PE) is the third most common vascular disease in the US, a frequently underdiagnosed and potentially fatal condition where embolic material blocks one or more pulmonary arteries impairing blood flow. In this study, we aim to describe the prevalence, outcomes, and predictors of mortality of PE patients treated with mechanical (MT) and surgical thrombectomy (ST). This is a retrospective study using the Agency for Healthcare Research and Quality’s HCUP NIS data from 2010–2018. We used the ninth and tenth revisions of the International Classification of Diseases clinical modification codes (ICD-9-CM and ICD-10-CM) to identify patients admitted with a primary diagnosis of PE (ICD-10-CM codes I26.02, I26.09, I26.92, I26.93, I26.94, and I26.99; ICD-9-CM codes 415.11, 415.13, and 415.19). We extracted demographics, hospital-level, and patient-level characteristics, and defined the severity of comorbid conditions using Deyo modification of the Elixhauser Comorbidity Index. The primary outcomes of interest were the utilization trends of PE (treated with MT and ST); the secondary outcomes were mortality, discharge to facility, peri-procedural complications, and length of hospital (LOS) stay; the tertiary outcome was to identify the predictors of in-hospital mortality. From 2010–2018, there were 1,627,718 hospitalizations for PE, of which 6531 (0.39%) underwent MT and 3465 (0.21%) underwent ST. The utilization trend of MT increased from 336 (0.20%) in 2010 to 1655 (0.87%) in 2018; the utilization trend of ST was 260 (0.15%) in 2010 and 430 (0.23%) in 2018. The unadjusted in-hospital mortality for MT was 9.1% with the mean LOS being 7(±0.3) days; for ST, mortality was 13.9% with a mean LOS of 13(±0.4) days. The occurrences of periprocedural complications for MT and ST were as follows: invasive mechanical ventilation was 13.8% and 32%; cardiopulmonary bypass was 3.3% and 68.3%; pulmonary embolectomy surgery was 1.7%; and bleeding complications were 1.4% and 3.4%. Predictors associated with in-hospital mortality for MT were: increasing age (OR 1.2, 95% CI 1.0–1.3, p < 0.026), female sex (OR 1.9, 95% CI 1.2–2.8, p < 0.004), large hospitals (OR 2.2, 95% 1.4–3.5, p < 0.001), and teaching hospitals (OR 1.8, 95% CI 1.1–3.1, p < 0.023). The predictor of in-hospital mortality for ST was increasing age (OR 1.2, 95% CI 1.0–1.4, p < 0.046). The number of MT procedures performed has rapidly increased over the past decade. Further studies are warranted to determine their rise and therapeutic use.

Among head and neck malignancies salivary gland malignancies constitutes less than 5%. This case presents a malignant neoplasm of parotid gland. A 64 year old male patient came with a painless, hard, mobile swelling present over the left side pre-auricular region was presented. Fine needle aspiration cytology showed benign and premalignant features. Magnetic resonance imaging and biopsy of the tumour showed PT2 PN0 Mucoepidermoid carcinoma – Parotid, low grade, margins focally involved by the tumour. Superficial parotidectomy was done without injuring the facial nerve. Post-operative period was uneventful. Facial nerve functions were intact. Histopathology report confirmed malignancy of the parotid gland. Most of the parotid swellings are benign but it also includes some of the malignant tumours. Early detection of such tumours through multidisciplinary team approach and good clinical history will give favourable disease outcomes.

Summary: Cisplatin- and gemcitabine-based chemotherapeutics represent a mainstay of cancer therapy for most solid tumors; however, resistance limits their curative potential. Here, we identify RNA polymerase II-associated factor 1 (PAF1) as a common driver of cisplatin and gemcitabine resistance in human cancers (ovarian, lung, and pancreas). Mechanistically, cisplatin- and gemcitabine-resistant cells show enhanced DNA repair, which is inhibited by PAF1 silencing. We demonstrate an increased interaction of PAF1 with RAD52 in resistant cells. Targeting the PAF1 and RAD52 axis combined with cisplatin or gemcitabine strongly diminishes the survival potential of resistant cells. Overall, this study shows clinical evidence that the expression of PAF1 contributes to chemotherapy resistance and worse clinical outcome for lethal cancers.

Abstract Bone metastases occur in patients with advanced-stage prostate cancer (PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases bone deformities, and drives tumor growth in the bone. However, the molecular mechanisms of PCa-mediated modulation of the bone microenvironment are complex and remain poorly defined. Here, we evaluated growth differentiation factor-15 (GDF15) function using in vivo preclinical PCa-bone metastasis mouse models and an in vitro bone cell coculture system. Our results suggest that PCa-secreted GDF15 promotes bone metastases and induces bone microarchitectural alterations in a preclinical xenograft model. Mechanistic studies revealed that GDF15 increases osteoblast function and facilitates the growth of PCa in bone by activating osteoclastogenesis through osteoblastic production of CCL2 and RANKL and recruitment of osteomacs. Altogether, our findings demonstrate the critical role of GDF15 in the modulation of the bone microenvironment and subsequent development of PCa bone metastasis.

Abstract Haploinsufficiency of chromosome 17p and c-Myc amplification distinguish group 3 medulloblastomas which are associated with early metastasis, rapid recurrence, and swift mortality. Tumor suppressor genes on this locus have not been adequately characterized. We elucidated the role of miR-212-3p in the pathophysiology of group 3 tumors. First, we learned that miR-212-3p undergoes epigenetic silencing by histone modifications in group 3 tumors. Restoring its expression reduced cancer cell proliferation, migration, colony formation, and wound healing in vitro and attenuated tumor burden and improved survival in vivo. MiR-212-3p also triggered c-Myc destabilization and degradation, leading to elevated apoptosis. We then isolated an oncogenic target of miR-212-3p, i.e. NFIB, a nuclear transcription factor implicated in metastasis and recurrence in various cancers. Increased expression of NFIB was confirmed in group 3 tumors and associated with poor survival. NFIB silencing reduced cancer cell proliferation, migration, and invasion. Concurrently, reduced medullosphere formation and stem cell markers (Nanog, Oct4, Sox2, CD133) were noted. These results substantiate the tumor-suppressive role of miR-212-3p in group 3 MB and identify a novel oncogenic target implicated in metastasis and tumor recurrence.

Dynamic seals are one of the critical components of Absorber Rod Drive Mechanism of Fast Breeder Reactors, requiring separate experimental development. Their significance can't be overemphasized considering that the availability and re-usability of Control Rod Drive Mechanisms of Fast Breeder Test Reactor is governed by the failure rate of dynamic seals (bellows). For prototype and subsequent Fast Breeder Reactors in India, choice of the dynamic seal is changed to an in-house designed & developed labyrinth type V-ring seal. The present work is related to the numerical investigations carried out to gain insights into the sealing mechanism and the thermal behaviour of these seals. The results indicate that the seal geometry is very important for obtaining optimum performance. By changing the geometry of the present seal, performance enhancement by more than 50% in important indices is obtained. Further, the results point out that caution shall be exercised when the seal material & its operating temperature are changed. Also, the numerical model developed in this study will be useful for developing more robust dynamic seals in future.

Abstract Background Glioblastoma (GBM) has a devastating median survival of only one year. Treatment includes resection, radiation therapy, and temozolomide (TMZ); however, the latter increased median survival by only 2.5 months in the pivotal study. A desperate need remains to find an effective treatment. Methods We used the Connectivity Map (CMap) bioinformatic tool to identify candidates for repurposing based on GBM’s specific genetic profile. CMap identified histone deacetylase (HDAC) inhibitors as top candidates. In addition, Gene Expression Profiling Interactive Analysis (GEPIA) identified HDAC1 and HDAC2 as the most upregulated and HDAC11 as the most downregulated HDACs. We selected PCI-24781/abexinostat due to its specificity against HDAC1 and HDAC2, but not HDAC11, and blood-brain barrier permeability. Results We tested PCI-24781 using in vitro human and mouse GBM syngeneic cell lines, an in vivo murine orthograft, and a genetically engineered mouse model for GBM (PEPG - PTENflox/+; EGFRvIII+; p16Flox/− & GFAP Cre +). PCI-24781 significantly inhibited tumor growth and downregulated DNA repair machinery (BRCA1, CHK1, RAD51, and O6-methylguanine-DNA- methyltransferase (MGMT)), increasing DNA double-strand breaks and causing apoptosis in the GBM cell lines, including an MGMT expressing cell line in vitro. Further, PCI-24781 decreased tumor burden in a PEPG GBM mouse model. Notably, TMZ + PCI increased survival in orthotopic murine models compared to TMZ + vorinostat, a pan-HDAC inhibitor that proved unsuccessful in clinical trials. Conclusion PCI-24781 is a novel GBM-signature specific HDAC inhibitor that works synergistically with TMZ to enhance TMZ efficacy and improve GBM survival. These promising MGMT-agnostic results warrant clinical evaluation.

Lung cancer (LC) is the leading cause of cancer‐related mortality. However, the molecular mechanisms associated with the development of metastasis are poorly understood. Understanding the biology of LC metastasis is critical to unveil the molecular mechanisms for designing targeted therapies. We developed two genetically engineered LC mouse models KrasG12D/+; Trp53R172H/+; Ad‐Cre (KPA) and KrasG12D/+; Ad‐Cre (KA). Survival analysis showed significantly (P = 0.0049) shorter survival in KPA tumor‐bearing mice as compared to KA, suggesting the aggressiveness of the model. Our transcriptomic data showed high expression of N‐acetylgalactosaminide alpha‐2, 6‐sialyltransferase 1 (St6galnac‐I) in KPA compared to KA tumors. ST6GalNAc‐I is an O‐glycosyltransferase, which catalyzes the addition of sialic acid to the initiating GalNAc residues forming sialyl Tn (STn) on glycoproteins, such as mucins. Ectopic expression of species‐specific p53 mutants in the syngeneic mouse and human LC cells led to increased cell migration and high expression of ST6GalNAc‐I, STn, and MUC5AC. Immunoprecipitation of MUC5AC in the ectopically expressing p53R175H cells exhibited higher affinity toward STn. In addition, ST6GalNAc‐I knockout (KO) cells also showed decreased migration, possibly due to reduced glycosylation of MUC5AC as observed by low STn on the glycoprotein. Interestingly, ST6GalNAc‐I KO cells injected mice developed less liver metastasis (P = 0.01) compared to controls, while colocalization of MUC5AC and STn was observed in the liver metastatic tissues of control mice. Collectively, our findings support the hypothesis that mutant p53R175H mediates ST6GalNAc‐I expression, leading to the sialyation of MUC5AC, and thus contribute to LC liver metastasis.

Pachydermoperiostosis is an inherited osseocutaneous disorder. The unusual increased levels of prostaglandin E2 due to mutations in either HPGD gene or SLCO2A1 gene are regarded as the causative factor. Our case report is about a 16-year-old boy who presented with cutis verticis gyrata, clubbing of digits, arthralgia, seborrhea, acne vulgaris, blepharoptosis, macrocheilia, column-like legs, and periosteal thickening in all long bones of the extremities characteristic of complete form of pachydermoperiostosis. No effective treatment has been proposed for this condition. Hence, counseling the child and parents about the disease progression, detecting the complications, and efficaciously managing them will be the mainstay of the treatment.