Exploring the association between early childhood caries, malnutrition, and anemia by machine learning algorithm.

OBJECTIVE: The objective of this study was to determine the prevalence of early childhood caries in children with severe acute malnutrition (SAM) and also the hierarchy of association if any with malnutrition, anemia, and other risk factors with ECC using machine learning algorithms. METHODS: A hospital-based preventive and interventional study was conducted on SAM children (age = 2 to <6 years) who were admitted to the malnutrition treatment unit (MTU). An oral examination for early childhood caries status was done using the deft index. The anthropometric measurements and blood examination reports were recorded. Oral health education and preventive dental treatments were given to the admitted children. Three machine learning algorithms (Random Tree, CART, and Neural Network) were applied to assess the relationship between early childhood caries, malnutrition, anemia, and the risk factors. RESULTS: The Random Tree model showed that age was the most significant factor in predicting ECC with predictor importance of 98.75%, followed by maternal education (29.20%), hemoglobin level (16.67%), frequency of snack intake (9.17%), deft score (8.75%), consumption of snacks (7.1%), breastfeeding (6.25%), severe acute malnutrition (5.42%), frequency of sugar intake (3.75%), and religion at the minimum predictor importance of 2.08%. CONCLUSION: Anemia and malnutrition play a significant role in the prediction, hence in the causation of ECC. Pediatricians should also keep in mind that anemia and malnutrition have a negative impact on children's dental health. Hence, Pediatricians and Pediatric dentist should work together in treating this health problem.

How to differentiate induced pluripotent stem cells into sensory neurons for disease modelling: a functional assessment.

BACKGROUND: Human induced pluripotent stem cell (iPSC)-derived peripheral sensory neurons present a valuable tool to model human diseases and are a source for applications in drug discovery and regenerative medicine. Clinically, peripheral sensory neuropathies can result in maladies ranging from a complete loss of pain to severe painful neuropathic disorders. Sensory neurons are located in the dorsal root ganglion and are comprised of functionally diverse neuronal types. Low efficiency, reproducibility concerns, variations arising due to genetic factors and time needed to generate functionally mature neuronal populations from iPSCs remain key challenges to study human nociception in vitro. Here, we report a detailed functional characterization of iPSC-derived sensory neurons with an accelerated differentiation protocol ("Anatomic" protocol) compared to the most commonly used small molecule approach ("Chambers" protocol). Anatomic's commercially available RealDRG™ were further characterized for both functional and expression phenotyping of key nociceptor markers. METHODS: Multiple iPSC clones derived from different reprogramming methods, genetics, age, and somatic cell sources were used to generate sensory neurons. Manual patch clamp was used to functionally characterize both control and patient-derived neurons. High throughput techniques were further used to demonstrate that RealDRGs™ derived from the Anatomic protocol are amenable to high throughput technologies for disease modelling. RESULTS: The Anatomic protocol rendered a purer culture without the use of mitomycin C to suppress non-neuronal outgrowth, while Chambers differentiations yielded a mix of cell types. Chambers protocol results in predominantly tonic firing when compared to Anatomic protocol. Patient-derived nociceptors displayed higher frequency firing compared to control subject with both, Chambers and Anatomic differentiation approaches, underlining their potential use for clinical phenotyping as a disease-in-a-dish model. RealDRG™ sensory neurons show heterogeneity of nociceptive markers indicating that the cells may be useful as a humanized model system for translational studies. CONCLUSIONS: We validated the efficiency of two differentiation protocols and their potential application for functional assessment and thus understanding the disease mechanisms from patients suffering from pain disorders. We propose that both differentiation methods can be further exploited for understanding mechanisms and development of novel treatments in pain disorders.

Multiomic Profiling of Human Clonal Hematopoiesis Reveals Genotype and Cell-Specific Inflammatory Pathway Activation.

Clonal hematopoiesis (CH) is an age-associated phenomenon that increases risk for hematologic malignancy and cardiovascular disease. CH is thought to enhance disease risk through inflammation in the peripheral blood1. Here, we profile peripheral blood gene expression in 66,968 single cells from a cohort of 17 CH patients and 7 controls. Using a novel mitochondrial DNA barcoding approach, we were able to identify and separately compare mutant TET2 and DNMT3A cells to non-mutant counterparts. We discovered the vast majority of mutated cells were in the myeloid compartment. Additionally, patients harboring DNMT3A and TET2 CH mutations possessed a pro-inflammatory profile in CD14+ monocytes through previously unrecognized pathways such as galectin and macrophage Inhibitory Factor (MIF). We also found that T cells from CH patients, though mostly un-mutated, had decreased expression of GTPase of the immunity associated protein (GIMAP) genes, which are critical to T cell development, suggesting that CH impairs T cell function.

Rhythmic motor behavior explains individual differences in grammar skills in adults.

A growing body of literature has reported the relationship between music and language, particularly between individual differences in perceptual rhythm skill and grammar competency in children. Here, we investigated whether motoric aspects of rhythm processing-as measured by rhythmic finger tapping tasks-also explain the rhythm-grammar connection in 150 healthy young adults. We found that all expressive rhythm skills (spontaneous, synchronized, and continued tapping) along with rhythm discrimination skill significantly predicted receptive grammar skills on either auditory sentence comprehension or grammaticality well-formedness judgment (e.g., singular/plural, past/present), even after controlling for verbal working memory and music experience. Among these, synchronized tapping and rhythm discrimination explained unique variance of sentence comprehension and grammaticality judgment, respectively, indicating differential associations between different rhythm and grammar skills. Together, we demonstrate that even simple and repetitive motor behavior can account for seemingly high-order grammar skills in the adult population, suggesting that the sensorimotor system continue to support syntactic operations.

IgA Vasculitis following AstraZeneca/Oxford COVID-19, case report.

Immunoglobulin A (IgA) vasculitis, also known as Henoch-Schönlein purpura, is an immune-mediated vasculitis that affects small vessels. IgA vasculitis could be triggered by numerous conditions including infectious and non-infectious conditions. So far, few reported cases of Covid-19 vaccines related vasculitis. We report a case of IgA vasculitis after AstraZeneca/Oxford COVID-19 vaccine. A 29-year-old healthy man who developed purpuric skin lesions one week after his second AstraZeneca/Oxford COVID-19 vaccine which complicated by glomerulonephritis and gastrointestinal involvement. Skin biopsy revealed fibrinoid necrosis and leukocytoclasia consistent with small vessel vasculitis. Due to the temporal association, AstraZeneca/Oxford COVID-19 vaccine-related IgA vasculitis would be the most likely explanation.

Highly specific σ2R/TMEM97 ligand FEM-1689 alleviates neuropathic pain and inhibits the integrated stress response.

The sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal antinociceptive effect is approximately 24 h following dosing. We sought to understand this unique antineuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout mice for Tmem97, we find that a σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce antinociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain.

How to differentiate induced pluripotent stem cells into sensory neurons for disease modelling: a comparison of two protocols.

Background: Human induced pluripotent stem cell (iPSC)-derived peripheral sensory neurons present a valuable tool to model human diseases and are a source for applications in drug discovery and regenerative medicine. Clinically, peripheral sensory neuropathies can result in maladies ranging from a complete loss of pain to severe painful neuropathic symptoms. Sensory neurons are located in the dorsal root ganglion and are comprised of functionally diverse neuronal types. Low efficiency, reproducibility concerns, variations arising due to genetic factors and time needed to generate functionally mature neuronal populations from iPSCs for disease modelling remain key challenges to study human nociception in vitro. Here, we report a detailed characterization of iPSC-derived sensory neurons with an accelerated differentiation protocol ("Anatomic" protocol) compared to the most commonly used small molecule approach ("Chambers" protocol). Methods: Multiple iPSC clones derived from different reprogramming methods, genetics, age, and somatic cell sources were used to generate sensory neurons. Expression profiling of sensory neurons was performed with Immunocytochemistry and in situ hybridization techniques. Manual patch clamp and high throughput cellular screening systems (Fluorescence imaging plate reader, automated patch clamp and multi-well microelectrode arrays recordings) were applied to functionally characterize the generated sensory neurons. Results: The Anatomic protocol rendered a purer culture without the use of mitomycin C to suppress non-neuronal outgrowth, while Chambers differentiations yielded a mix of cell types. High throughput systems confirmed functional expression of Na+ and K+ ion channels. Multi-well microelectrode recordings display spontaneously active neurons with sensitivity to increased temperature indicating expression of heat sensitive ion channels. Patient-derived nociceptors displayed higher frequency firing compared to control subject with both, Chambers and Anatomic differentiation approaches, underlining their potential use for clinical phenotyping as a disease-in-a-dish model. Conclusions: We validated the efficiency of two differentiation protocols and their potential application for understanding the disease mechanisms from patients suffering from pain disorders. We propose that both differentiation methods can be further exploited for understanding mechanisms and development of novel treatments in pain disorders.

Introducing Birth Companion in Labour: A Quality Improvement Initiative.

Background: Birth companion (BC) has been globally recognised as an essential component of childbirth care. As our institution did not allow BC in labour, this study was planned as a quality improvement (QI) project to introduce the concept. We aimed to achieve birth companionship from existing 0 to 100% over a period of six months. Intervention: QI team was constituted, and an initial brainstorming session conducted. A fishbone diagram was drawn to analyse issues that need addressal before implementation of the initiative. The framework was defined, and team members assigned their roles and responsibilities. A series of five successive Plan-Do-Study-Act (PDSA) cycles were carried out over a period of six months, which included introduction of the concept, dissemination of information, infrastructural changes in labour room and introducing column for documentation in birth register. To achieve sustainability, comprehensive group counselling sessions were started for women during antenatal period, and sensitisation classes were regularly conducted for newly inducted trainees and faculty. Result: Birth companionship was achieved in 98% of cases. Conclusion: The QI tools helped in preparation and planning of changes by breaking down a large problem into smaller sections and covering all aspects of challenges in a systematic manner using team-based approach. National directives and recommendations, sensitisation of leadership and training of stakeholders were found to be important facilitators. Robust systems of monitoring and successive PDSA cycles were needed for continuous improvement and sustainability of the idea.

Assessment of Acute Side Effects Among 3D-Concurrent Radiotherapy With Cisplatin-Treated Head and Neck Cancer Patients.

INTRODUCTION: Three-dimensional conformal radiation therapy has become one of the basic components of multidisciplinary treatment for head and neck cancer. Generally, patients with squamous-cell carcinoma of the head and neck receive cisplatin-based chemoradiation. AIMS: In the current project, the goal was to assess 3D-CRT with cisplatin-induced acute side effects (dermatitis plus xerostomia) among head and neck cancer patients. METHODOLOGY: This descriptive case series was held at the Institute of Nuclear Medicine and Oncology, Lahore, Pakistan, with an enrollment of 106 head and neck cancer patients following the hospital's ethical approval. All patients received 3D-CRT with concurrent cisplatin chemotherapy according to the oncology treatment protocol at the Institute of Nuclear Medicine and Oncology. The evaluation of enrolled patients was done during treatment at a weekly interval and at one-month post-radiation. Stage 3 patients (17.9%) received chemo-radiation therapy with 40 mg/m2 cisplatin once weekly for seven weeks. All patients received 70 grays in 35 fractions with two grays per fraction over the course of seven weeks following a standard protocol. All enrolled cases had biopsy-proven squamous cell carcinoma of the head and neck. IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. analyzed the data. Chi-square and Fisher's exact tests were applied, while a p-value ≤ 0.05 was taken as statistically significant. RESULTS: All patients developed acute skin changes (dermatitis plus xerostomia) as a side effect of radiation therapy, with cisplatin having different grades during treatment until seven weeks. However, these changes improved and became less severe in terms of grade after one month of post-treatment among all patients. CONCLUSION: It was concluded that 3D-CRT was associated with dermatitis and xerostomia during and immediately after follow-up, even though the treatment response was good. However, clinical signs and symptoms improved, indicating that radiation therapy is a relatively safe treatment modality among cancer patients. Moreover, 40 mg/m2 cisplatin once weekly for seven weeks resulted in better loco-regional control and survival among advanced-stage head and neck cancer patients as a part of treatment. Although, higher doses of cisplatin (100 mg/m2 ) every three weeks have more harmful acute side effects and delay treatment for patients due to poor compliance.

Protease-Activated Receptor 2 (PAR2) Expressed in Sensory Neurons Contributes to Signs of Pain and Neuropathy in Paclitaxel Treated Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting side effect of cancer therapy. Protease-activated receptor 2 (PAR2) is implicated in a variety of pathologies, including CIPN. In this study, we demonstrate the role of PAR2 expressed in sensory neurons in a paclitaxel (PTX)-induced model of CIPN in mice. PAR2 knockout/wildtype (WT) mice and mice with PAR2 ablated in sensory neurons were treated with PTX administered via intraperitoneal injection. In vivo behavioral studies were done in mice using von Frey filaments and the Mouse Grimace Scale. We then examined immunohistochemical staining of dorsal root ganglion (DRG) and hind paw skin samples from CIPN mice to measure satellite cell gliosis and intra-epidermal nerve fiber (IENF) density. The pharmacological reversal of CIPN pain was tested with the PAR2 antagonist C781. Mechanical allodynia caused by PTX treatment was alleviated in PAR2 knockout mice of both sexes. In the PAR2 sensory neuronal conditional knockout (cKO) mice, both mechanical allodynia and facial grimacing were attenuated in mice of both sexes. In the DRG of the PTX-treated PAR2 cKO mice, satellite glial cell activation was reduced compared to control mice. IENF density analysis of the skin showed that the PTX-treated control mice had a reduction in nerve fiber density while the PAR2 cKO mice had a comparable skin innervation as the vehicle-treated animals. Similar results were seen with satellite cell gliosis in the DRG, where gliosis induced by PTX was absent in PAR cKO mice. Finally, C781 was able to transiently reverse established PTX-evoked mechanical allodynia. PERSPECTIVE: Our work demonstrates that PAR2 expressed in sensory neurons plays a key role in PTX-induced mechanical allodynia, spontaneous pain, and signs of neuropathy, suggesting PAR2 as a possible therapeutic target in multiple aspects of PTX CIPN.

Highly specific σ2R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response.

The Sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal anti-nociceptive effect is approximately 24 hours following dosing. We sought to understand this unique anti-neuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout (KO) mice for Tmem97, we find that a new σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce anti-nociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion (DRG) neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain.

Decreasing the Rate of Surgical Site Infection in Patients Operated by Cesarean Section in a Tertiary Care Hospital in India: A Quality Improvement Initiative.

Background Surgical site infections (SSIs) are a substantial cause of maternal morbidity and are associated with a significant increase in hospital stay and cost. The prevention of SSI is complex and requires the integration of a range of measures before, during, and after surgery. Jawaharlal Nehru Medical College (JNMC), Aligarh Muslim University (AMU) is one of the referral centers of India with a huge influx of patients. Methods The project was undertaken by the Department of Obstetrics and Gynaecology, JNMC, AMU, Aligarh. Our department was sensitized to the need for quality improvement (QI) through Laqshya, a Government of India initiative for labor rooms in 2018. We were facing problems like a high surgical site infection rate, poor documentation and records, no standard protocols, overcrowding, and no admission discharge policy. There was a high rate of surgical site infections, leading to maternal morbidity, increased days of hospitalization, more usage of antibiotics, and increased financial burden. A multidisciplinary quality improvement (QI) team was formed comprising obstetricians and gynecologists, the hospital infection control team, the head of the neonatology unit, staff nurses, and multitasking staff (MTS) workers. Results The baseline data were collected for a period of one month and it was found that the rate of SSI was around 30%. Our aim was to decrease the rate of SSI from 30% to less than 5% over a period of six months. The QI team worked meticulously, implemented evidence-based measures, regularly analyzed the results, and devised measures to overcome the obstacles. The point-of-care improvement (POCQI) model was adopted for the project. The rate of SSI decreased significantly in our patients and the rates are around 5% persistently. Conclusion The project not only helped in decreasing the infection rates but also led to vast improvements in the department with the formulation of an antibiotic policy, surgical safety checklist, and admission-discharge policy.

C781, a ß-Arrestin Biased Antagonist at Protease-Activated Receptor-2 (PAR2), Displays in vivo Efficacy Against Protease-Induced Pain in Mice.

Given the limited options and often harmful side effects of current analgesics and the suffering caused by the opioid crisis, new classes of pain therapeutics are needed. Protease-activated receptors (PARs), particularly PAR2, are implicated in a variety of pathologies, including pain. Since the discovery of the role of PAR2 in pain, development of potent and specific antagonists has been slow. In this study, we describe the in vivo characterization of a novel small molecule/peptidomimetic hybrid compound, C781, as a ß-arrestin-biased PAR2 antagonist. In vivo behavioral studies were done in mice using von Frey filaments and the Mouse Grimace Scale. Pharmacokinetic studies were done to assess pharmacokinetic/pharmacodynamic relationship in vivo. We used both prevention and reversal paradigms with protease treatment to determine whether C781 could attenuate protease-evoked pain. C781 effectively prevented and reversed mechanical and spontaneous nociceptive behaviors in response to small molecule PAR2 agonists, mast cell activators, and neutrophil elastase. The ED50 of C781 (intraperitoneal dosing) for inhibition of PAR2 agonist (20.9 ng 2-AT)-evoked nociception was 6.3 mg/kg. C781 was not efficacious in the carrageenan inflammation model. Pharmacokinetic studies indicated limited long-term systemic bioavailability for C781 suggesting that optimizing pharmacokinetic properties could improve in vivo efficacy. Our work demonstrates in vivo efficacy of a biased PAR2 antagonist that selectively inhibits ß-arrestin/MAPK signaling downstream of PAR2. Given the importance of this signaling pathway in PAR2-evoked nociception, C781 exemplifies a key pharmacophore for PAR2 that can be optimized for clinical development. PERSPECTIVE: Our work provides evidence that PAR2 antagonists that only block certain aspects of signaling by the receptor can be effective for blocking protease-evoked pain in mice. This is important because it creates a rationale for developing safer PAR2-targeting approaches for pain treatment.

Use of social media platforms by migrant and ethnic minority populations during the COVID-19 pandemic: a systematic review.

OBJECTIVE: Migrants and ethnic minority groups have been disproportionately impacted by COVID-19 and have lower levels of vaccine uptake in some contexts. We aimed to determine the extent and nature of social media use in migrant and ethnic minority communities for COVID-19 information, and implications for preventative health measures including vaccination intent and uptake. DESIGN: A systematic review of published and grey literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched databases including Embase, Web of Science, PubMed NIH, CINAHL, facilitated through the WHO Global Research on COVID-19 database from 31 December 2019 to 9 June 2021. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Research reporting the use of social media by migrants and/or ethnic minority groups in relation to COVID-19. DATA EXTRACTION: We extracted data on key outcomes, study design, country, population under study and sample size. RESULTS: 1849 unique records were screened, and 21 data sources were included, including populations in the UK, USA, China, Jordan, Qatar and Turkey. We found evidence of consistent use of a range of social media platforms for COVID-19 information in some migrant and ethnic minority populations (including WeChat, Facebook, WhatsApp, Instagram, Twitter, YouTube), which may stem from difficulty in accessing COVID-19 information in their native languages or from trusted sources. Some evidence suggested circulating misinformation and social media use may be associated with lower participation in preventative health measures, including vaccine intent and uptake, findings which are likely relevant to multiple population groups. CONCLUSIONS: Social media platforms are an important source of information about COVID-19 for some migrant and ethnic minority populations. Urgent actions and further research are now needed to better understand effective approaches to tackling circulating misinformation, and to seize on opportunities to better use social media platforms to support public health communication and improve vaccine uptake. REGISTRATION: This study has been registered with PROSPERO (CRD42021259190).