Tertiary centre study highlights low inpatient deintensification and risks associated with adverse outcomes in frail people with diabetes.

INTRODUCTION: The community deintensification rates in older people with diabetes are low and hospital admission presents an opportunity for medication review. We audited the inpatient assessment and deintensification rate in people with diabetes and frailty. We also identified factors associated with adverse inpatient outcomes. METHODS: A retrospective review of electronic charts was conducted in all people with diabetes and clinical frailty score ≥6 who were discharged from the medical unit in 2022. Data on demographics, comorbidities and background glucose-lowering medications were collected. RESULTS: Six-hundred-and-sixty-five people with diabetes and moderate/severe frailty were included in our analysis. For people with no HbA1c in the last six months preceding admission, only 9.0% had it assessed during inpatient. Deintensification rates were 19.1%. Factors that were associated with adverse inpatient outcomes included inpatient hypoglycaemia, non-White ethnicity, and being overtreated (HbA1c <7.0% [53 mmol/mol] with any glucose-lowering medication). CONCLUSION: The assessment and deintensification rate in secondary care for people with diabetes and frailty is low. Inpatient hypoglycaemia, non-White ethnicity, and overtreatment are important factors in determining inpatient outcomes highlighting the importance of deintensification and the need for an evidence-based risk stratification tool.

A cross-sectional observation study to evaluate the efficacy and complications of epidural analgesia in paediatric population.

Background and Aims: With advances in pediatric surgery, pediatric epidurals are increasingly being used for analgesia. As there is scarcity of data in India about the pediatric epidurals, we sought to determine the efficacy and complications of epidural analgesia. The aim of this study was to determine the efficacy of pediatric epidural analgesia and the incidence of complications aimed at improving the quality of care. Material and Methods: It was a prospective observational study in tertiary care hospital in the Southern part of India. Newborns to children aged 18 years in whom continuous epidural analgesia was planned were recruited. They were followed up postoperatively at specified intervals wherein pain scores were used to determine analgesic efficacy. Complications were noted in a specified format and the level of satisfaction of patient and surgeon was noted objectively. All the statistical analyses were performed using SPSS 25.0. Results: 100 children were recruited of which 63 received thoracic epidurals and 37 lumbar epidurals. Overall efficacy of epidural in pain management was 90.96% with the highest efficacy for lower abdominal epidurals (94.9%). Kinking of a catheter was the most common complication encountered (11%), followed by migration of catheter, occlusion of pump, and motor block. Conclusion: Continuous epidural analgesia has proven to be a safe and effective method to provide analgesia to the children in a protected environment and experienced hands.

RBM33 directs the nuclear export of transcripts containing GC-rich elements.

Although splicing is a major driver of RNA nuclear export, many intronless RNAs are efficiently exported to the cytoplasm through poorly characterized mechanisms. For example, GC-rich sequences promote nuclear export in a splicing-independent manner, but how GC content is recognized and coupled to nuclear export is unknown. Here, we developed a genome-wide screening strategy to investigate the mechanism of export of NORAD, an intronless cytoplasmic long noncoding RNA (lncRNA). This screen revealed an RNA binding protein, RBM33, that directs the nuclear export of NORAD and numerous other transcripts. RBM33 directly binds substrate transcripts and recruits components of the TREX-NXF1/NXT1 RNA export pathway. Interestingly, high GC content emerged as the feature that specifies RBM33-dependent nuclear export. Accordingly, RBM33 directly binds GC-rich elements in target transcripts. These results provide a broadly applicable strategy for the genetic dissection of nuclear export mechanisms and reveal a long-sought nuclear export pathway for transcripts with GC-rich sequences.

Novel antiviral effects of chloroquine, hydroxychloroquine, and green tea catechins against SARS CoV-2 main protease (Mpro) and 3C-like protease for COVID-19 treatment.

OBJECTIVES: Coronaviruses are globally emerging viruses that threaten our health care systems and have become a popular pandemic around the world. This causes a sudden rise in positive coronavirus cases and related deaths to occur worldwide, representing a significant health hazard to humans and the economy. METHODS: We examined predominantly catechins of green tea include epigallocatechin-3-gallate (EGCG), epicatechin-3-gallate (ECG), and drugs of chloroquine (CQ), and hydroxychloroquine (HCQ) appearing to reveal anti-viral activities. Data were collected from PubMed, Google Scholar, and Science Direct databases. To investigate the role of antiviral effects (CQ and HCQ), green tea catechins, beneficial use of convalescent plasma; covaxin in COVID-19 patients faced a dangerous healthiness issue. Computational docking analysis has been used for this purpose. RESULTS: The lead compounds are EGCG and ECG act as potential inhibitors bind to the active site region of the HKU4-CoV 3CL protease and M-Pro protease enzymes of coronavirus. Conclusions: SARS-COV-2 is a pathogen of substantial vigour concern and the review unveils the role of catechins associated with many viral diseases. We suggested that the function of green tea catechins, novel drugs of CQ, and HCQ exhibit antiviral activities against positive-sense single-stranded RNA viruses (CoVs).

Intestinal Perforation Secondary to Mucormycosis Associated With Puerperal Sepsis.

Mucormycosis is a rare opportunistic infection, usually seen in diabetics, immunocompromised, or those with coronavirus disease 2019 (COVID-19). Gastrointestinal involvement is uncommon but often deadly. We report a case of gastrointestinal mucormycosis causing intestinal perforation in a non-diabetic, COVID-19 negative, immunocompetent woman, associated with puerperal sepsis. A 22-year-old woman presented to our center on post-natal day five, following delivery with insertion of an intrauterine contraceptive device (IUCD). She had complaints of breathlessness, fatigue, and giddiness. Examination revealed tachycardia, tachypnea, hypotension, and bilateral pedal edema. Following appropriate investigations, she was diagnosed with puerperal sepsis with pre-renal acute kidney injury. Imaging was suggestive of retained products of conception, and she subsequently underwent dilation and evacuation (D&E) on day eight of admission. Following brief symptomatic improvement, on day 10 of admission, she developed vomiting, abdominal distension, and pain, with obstipation. Erect X-ray showed air under the diaphragm, suggestive of perforation. She emergently underwent laparotomy with limited right hemicolectomy, ileostomy with mucous fistula. Intraoperative findings revealed a closed-loop obstruction involving terminal ileum, with two perforations. The biopsy report later revealed colonization of Mucor and hemorrhagic necrosis along the entire length of the resected specimen. She was started on amphotericin B, and after a slow recovery, was discharged. Gastrointestinal mucormycosis is rare and has a mortality rate of 94%. It is usually seen in those with predisposing factors for mucormycosis. This is the first report of mucormycosis associated with puerperal sepsis. It is typically acquired via ingestion and may cause perforation, where mortality is further increased. Diagnosis can only be confirmed by histopathology demonstrating the characteristic morphology of Mucor. Treatment requires resection of necrotic tissues, intensive treatment with amphotericin B, and correction of predisposing factors. Our case highlights the need for a high degree of suspicion for mucormycosis in patients with intestinal perforation, even if immunocompetent, and its potential association with puerperal sepsis.

A True Mimicker to Plasmacytoma Clinically, Radiologically, and Pathologically - A Rare Case Report.

Lympho plasmacytoma is distinct type of diffuse large B cell lymphoma predominantly seen in HIV-positive patients. The diagnosis of lympho plasmacytoma could be a challenge due to its overlapping characterizes with those of myeloma and lymphoma. We report a case of a 50-year-old man who initially presented with a painful solitary destructive lesion at the second lumbar vertebra. Clinico-pathological findings were consistent with a solitary plasmacytoma, and he was treated with definitive radiotherapy. Eight months after completing radiotherapy, he was found to have similar lesions at D4 vertebral body, multiple ribs, and pelvis. Subsequent biopsy confirmed lympho plasmacytoma. Because of its rarity and heterogeneous presentations, lympho plasmacytoma could easily be overlooked clinically and pathologically in immunocompetent patients. The diagnosis of lympho plasmacytoma should be considered when there is coexpression of myeloma and lymphoma immune markers.

Embedding public health advocacy into the role of school-based nurses: addressing the health inequities confronted by vulnerable Australian children and adolescent populations.

There has been a growth in Australian school-based nurses to address the inequities confronted by vulnerable students and school populations. Failure to address inequities can be evidenced in intergenerational poverty, poorer health and educational attainment and diminished life opportunities. School-based nurses are ideally located to advocate for public health policies and programs that address social determinants that detrimentally affect the health of school populations. However, school-based nurses can confront professional and speciality challenges in extending their efforts beyond individual student advocacy to effect change at the school population level. Guidance is required to redress this situation. This paper describes public health advocacy, the professional and speciality advocacy roles of school-based nurses and the barriers they confront in advocating for the health of school populations and strategies that can be used by key stakeholders to enhance school-based nursing public health advocacy efforts. School-based nurses who are competent, enabled and supported public health advocates are required if we are to achieve substantial and sustained health equity and social justice outcomes for vulnerable school populations.

Antigenicity, stability, and reproducibility of Zika reporter virus particles for long-term applications.

The development of vaccines against flaviviruses, including Zika virus (ZIKV) and dengue virus (DENV), continues to be a major challenge, hindered by the lack of efficient and reliable methods for screening neutralizing activity of sera or antibodies. To address this need, we previously developed a plasmid-based, replication-incompetent DENV reporter virus particle (RVP) production system as an efficient and safe alternative to the Plaque Reduction Neutralization Test (PRNT). As part of the response to the 2015-2016 ZIKV outbreak, we developed pseudo-infectious ZIKV RVPs by modifying our DENV RVP system. The use of ZIKV RVPs as critical reagents in human clinical trials requires their further validation using stability and reproducibility metrics for large-scale applications. In the current study, we validated ZIKV RVPs using infectivity, neutralization, and enhancement assays with monoclonal antibodies (MAbs) and human ZIKV-positive patient serum. ZIKV RVPs are antigenically equivalent to live virus based on binding ELISA and neutralization results and are nonreplicating based on the results of live virus replication assays. We demonstrate reproducible neutralization titer data (NT50 values) across different RVP production lots, volumes, time frames, and laboratories. We also show RVP stability across experimentally relevant time intervals and temperatures. Our results demonstrate that ZIKV RVPs provide a safe, high-throughput, and reproducible reagent for large-scale, long-term studies of neutralizing antibodies and sera, which can facilitate large-scale screening and epidemiological studies to help expedite ZIKV vaccine development.

Fate and impact of pharmaceuticals and personal care products during septage co-composting using an in-vessel composter.

The present study aimed at understanding the impact of pharmaceutical and personal care product (PPCP) load on compost dynamics and fate of PPCPs during the composting. In addition, the compost dynamics during single PPCP degradation and multiple PPCPs degradation were investigated. Results revealed that co-composting could degrade the pharmaceutical, carbamazepine (CBZ) up to 83% during single pollutant degradation while it was 66% during multiple pollutant system, at an initial concentration (IC) of 5 mg/kg dw. In case of personal care product, namely triclosan (TCS), single pollutant degradation resulted in 86% removal whereas the removal efficiency was 83% in multiple pollutant system. Relatively high concentration of CBZ showed a negative impact on compost dynamics compared to that of TCS. Higher IC resulted in lower temperature development and relatively lower pollutant removal. The study on pollutant transfer in compost solid surface and in leachate revealed that TCS was not leached out while the leaching of CBZ was significant during composting process. The various transformation products formed during composting were identified and tentative pathways for CBZ and TCS degradation were proposed.

PUMILIO, but not RBMX, binding is required for regulation of genomic stability by noncoding RNA NORAD.

NORAD is a conserved long noncoding RNA (lncRNA) that is required for genome stability in mammals. NORAD acts as a negative regulator of PUMILIO (PUM) proteins in the cytoplasm, and we previously showed that loss of NORAD or PUM hyperactivity results in genome instability and premature aging in mice (Kopp et al., 2019). Recently, however, it was reported that NORAD regulates genome stability through an interaction with the RNA binding protein RBMX in the nucleus. Here, we addressed the contributions of NORAD:PUM and NORAD:RBMX interactions to genome maintenance by this lncRNA in human cells. Extensive RNA FISH and fractionation experiments established that NORAD localizes predominantly to the cytoplasm with or without DNA damage. Moreover, genetic rescue experiments demonstrated that PUM binding is required for maintenance of genomic stability by NORAD whereas binding of RBMX is dispensable for this function. These data provide an important foundation for further mechanistic dissection of the NORAD-PUMILIO axis in genome maintenance.

lncRNA H19 prevents endothelial-mesenchymal transition in diabetic retinopathy.

AIMS/HYPOTHESIS: The pathophysiology of diabetic retinopathy is linked to hyperglycaemia and its effect on retinal microvascular tissues. The resulting endothelial injury changes the endothelial cell phenotype to acquire mesenchymal properties (i.e. endothelial-mesenchymal transition [EndMT]). Such changes can be regulated by epigenetic mechanisms, including long non-coding RNAs (lncRNAs). lncRNA H19 may influence EndMT through TGF-ß. We investigated the role of H19 in regulating EndMT during diabetic retinopathy. METHODS: H19 was overexpressed or silenced in human retinal endothelial cells exposed to various glucose levels. The cells were examined for H19, endothelial and mesenchymal markers. We then expanded the study to retinal tissues in a mouse model of diabetic retinopathy and also examined vitreous humour samples from individuals with proliferative diabetic retinopathy. RESULTS: Expression of H19 was downregulated in high glucose conditions (25 mmol/l). H19 overexpression prevented glucose-induced EndMT. Such changes appear to involve TGF-ß through a Smad-independent mechanism. Diabetes caused downregulation of retinal H19. Using H19 knockout mice, we demonstrated similar EndMT in the retina. Examination of vitreous humour from individuals with proliferative diabetic retinopathy also reinforced the downregulation of H19 in diabetes. CONCLUSIONS/INTERPRETATION: We therefore concluded that H19 regulates EndMT in diabetic retinopathy through specific mechanisms. DATA AVAILABILITY: The results from our previous microarray can be found online using the GEO accession number GSE122189.

A community engaged primary healthcare strategy to address rural school student inequities: a descriptive paper.

AIM: This descriptive paper aims to describe the design and implementation of a community engaged primary healthcare strategy in rural Australia, the Primary Healthcare Registered Nurse: Schools-Based strategy. This strategy seeks to address the health, education and social inequities confronting children and adolescents through community engaged service provision and nursing practice. BACKGROUND: There have been increasing calls for primary healthcare approaches to address rural health inequities, including contextualised healthcare, enhanced healthcare access, community engagement in needs and solutions identification and local-level collaborations. However, rural healthcare can be poorly aligned to community contexts and needs and be firmly entrenched in health systems, marginalising community participation. METHODS: This strategy has been designed to enhance nursing service and practice responsiveness to the rural context, primary healthcare principles, and community experiences and expectations of healthcare. The strategy is underpinned by a cross-sector collaboration between a local health district, school education and a university department of rural health. A research framework is being developed to explore strategy impacts for service recipients, cross-sector systems, and the establishment and maintenance of a primary healthcare nursing workforce. FINDINGS: Although in the early stages of implementation, key learnings have been acquired and strategic, relationship, resource and workforce gains achieved.

A Rare Case of Dumbbell-shaped Primary Intraspinal Peripheral Primitive Neuroectodermal Tumor Involving Thoracic Spinal Epidural Space.

Primary intraspinal primitive neuroectodermal tumor (PNET) is a type of round cell malignant tumor which is reported only above 100 in literature. We report a case of epidural thoracic peripheral PNET, discuss its pathological features, radiology, and treatment options.

LncRNAs: Proverbial Genomic "Junk" or Key Epigenetic Regulators During Cardiac Fibrosis in Diabetes?

Long non-coding RNAs (lncRNAs) are critical regulators in a multitude of biological processes. Recent evidences demonstrate potential pathogenetic implications of lncRNAs in diabetic cardiomyopathy (DCM); however, the majority of lncRNAs have not been comprehensively characterized. While the precise molecular mechanisms underlying the functions of lncRNAs remain to be deciphered in DCM, emerging data in other pathophysiological conditions suggests that lncRNAs can have versatile features such as genomic imprinting, acting as guides for certain histone-modifying complexes, serving as scaffolds for specific molecules, or acting as molecular sponges. In an effort to better understand these features of lncRNAs in the context of DCM, our review will first summarize some of the key molecular alterations that occur during fibrosis in the diabetic heart (extracellular proteins and endothelial-to-mesenchymal transitioning), followed by a review of the current knowledge on the crosstalk between lncRNAs and major epigenetic mechanisms (histone methylation, histone acetylation, DNA methylation, and microRNAs) within this fibrotic process.

MALAT1: An Epigenetic Regulator of Inflammation in Diabetic Retinopathy.

Despite possessing limited protein-coding potential, long non-coding RNAs (lncRNAs) have been implicated in a myriad of pathologic conditions. Most well documented in cancer, one prominent intergenic lncRNA known as MALAT1 is notorious for its role in impacting epigenetic mechanisms. In this study, we established a novel epigenetic paradigm for MALAT in diabetic retinopathy (DR) by employing siRNA-mediated MALAT1 knockdown in human retinal endothelial cells (HRECs), a Malat1 knockout animal model, vitreous humor from diabetic patients, pharmacological inhibitors for histone and DNA methylation, RNA immunoprecipitation, western blotting, and a unique DNA methylation array to determine glucose-related alterations in MALAT1. Our findings indicated that MALAT1 is capable of impacting the expressions of inflammatory transcripts through its association with components of the PRC2 complex in diabetes. Furthermore, the vitreous humors from diabetic patients revealed increased expressions of MALAT1, TNF-α, and IL-6. Intriguingly, our DNA methylation array demonstrated that transient high glucose exposure in HRECs does not contribute to significant methylation alterations at CpG sites across the MALAT1 gene. However, global inhibition of DNA methyltransferases induced significant increases in MALAT1 and associated inflammatory transcripts in HRECs. Our findings collectively demonstrate the importance of MALAT1 in inflammation and epigenetic regulation in DR.

Penetrating Injury to Cauda Equina from a Missile Fragment, Completely Recovered after Delayed Surgical Removal of Ballistic Fragment.

Penetrating injuries to cauda equina due to missile fragment are rare. The mechanism of injury may be more complex due to thermal effect of missile fragment, apart from mechanisms described in penetrating gunshot injuries or stab injuries. We report a case of a 42-year-old male with penetrating missile injury to cauda equina, improved completely after delayed surgical exploration and removal of ballistic fragment. Furthermore, his bowel and bladder dysfunction improved completely within 1 week of neurosurgical exploration. Although early neurosurgical intervention is recommended for penetrating injuries of the cauda equina, delayed intervention may also be beneficial in selected patients. Computed tomography (CT) scan and CT myelogram are extremely useful in surgical planning when magnetic resonance imaging contraindicated due to impregnated metal fragments.

ANRIL regulates production of extracellular matrix proteins and vasoactive factors in diabetic complications.

noncoding RNAs (lncRNAs) have gained widespread interest due to their prevailing presence in various diseases. lncRNA ANRIL (a. k. a. CDKN2B-AS1) is located on human chromosome 9 (p21.3) and transcribed in opposite direction to the INK4b-ARF-INK4a gene cluster. It has been identified as a highly susceptible region for diseases such as coronary artery diseases and type 2 diabetes. Here, we explored its regulatory role in diabetic nephropathy (DN) and diabetic cardiomyopathy (DCM) in association with epigenetic modifiers p300 and polycomb repressive complex 2 (PRC2) complex. We used an ANRIL-knockout (ANRILKO) mouse model for this study. The wild-type and ANRILKO animals with or without streptozotocin-induced diabetes were monitored for 2 min. At the end of the time point, urine and tissues were collected. The tissues were measured for fibronectin (FN), type IV collagen (Col1α4), and VEGF mRNA and protein expressions. Renal function was determined by the measurement of 24-h urine volume and albumin/creatinine ratio at euthanasia. Renal and cardiac structures were investigated using periodic acid-Schiff stain and/or immunohistochemical analysis. Elevated expressions of extracellular matrix (ECM) proteins were prevented in ANRILKO diabetic animals. Furthermore, ANRILKO had a protective effect on diabetic mouse kidneys, as evidenced by lowering of urine volume and urine albumin levels in comparison with the wild-type diabetic animals. These alterations regulated by ANRIL may be mediated by p300 and enhancer of zeste 2 (EZH2) of the PRC2 complex. Our study concludes that ANRIL regulates functional and structural alterations in the kidneys and hearts in diabetes through controlling the expressions of ECM proteins and VEGF.

The Bitter Taste Receptor TAS2R16 Achieves High Specificity and Accommodates Diverse Glycoside Ligands by using a Two-faced Binding Pocket.

Although bitter taste receptors (TAS2Rs) are important for human health, little is known of the determinants of ligand specificity. TAS2Rs such as TAS2R16 help define gustatory perception and dietary preferences that ultimately influence human health and disease. Each TAS2R must accommodate a broad diversity of chemical structures while simultaneously achieving high specificity so that diverse bitter toxins can be detected without all foods tasting bitter. However, how these G protein-coupled receptors achieve this balance is poorly understood. Here we used a comprehensive mutation library of human TAS2R16 to map its interactions with existing and novel agonists. We identified 13 TAS2R16 residues that contribute to ligand specificity and 38 residues whose mutation eliminated signal transduction by all ligands, providing a comprehensive assessment of how this GPCR binds and signals. Our data suggest a model in which hydrophobic residues on TM3 and TM7 form a broad ligand-binding pocket that can accommodate the diverse structural features of ß-glycoside ligands while still achieving high specificity.

PSIP1/p75 promotes tumorigenicity in breast cancer cells by promoting the transcription of cell cycle genes.

Breast cancer (BC) is a highly heterogeneous disease, both at the pathological and molecular level, and several chromatin-associated proteins play crucial roles in BC initiation and progression. Here, we demonstrate the role of PSIP1 (PC4 and SF2 interacting protein)/p75 (LEDGF) in BC progression. PSIP1/p75, previously identified as a chromatin-adaptor protein, is found to be upregulated in basal-like/triple negative breast cancer (TNBC) patient samples and cell lines. Immunohistochemistry in tissue arrays showed elevated levels of PSIP1 in metastatic invasive ductal carcinoma. Survival data analyses revealed that the levels of PSIP1 showed a negative association with TNBC patient survival. Depletion of PSIP1/p75 significantly reduced the tumorigenicity and metastatic properties of TNBC cell lines while its over-expression promoted tumorigenicity. Further, gene expression studies revealed that PSIP1 regulates the expression of genes controlling cell-cycle progression, cell migration and invasion. Finally, by interacting with RNA polymerase II, PSIP1/p75 facilitates the association of RNA pol II to the promoter of cell cycle genes and thereby regulates their transcription. Our findings demonstrate an important role of PSIP1/p75 in TNBC tumorigenicity by promoting the expression of genes that control the cell cycle and tumor metastasis.

miR-146a regulates glucose induced upregulation of inflammatory cytokines extracellular matrix proteins in the retina and kidney in diabetes.

Hyperglycemic damage to the endothelial cells (ECs) leads to increased synthesis of inflammatory cytokines. We have previously shown miR-146a downregulation in ECs and in the tissues of diabetic mice. Here we investigated the role of miR-146a, in the production of specific inflammatory cytokines and extracellular matrix (ECM) proteins in retina and kidneys in diabetes. We generated an endothelial specific miR-146a overexpressing transgenic mice (TG). We investigated these mice and wild type (WT) controls with or without streptozotocin (STZ) induced diabetes. Retinal and renal cortical tissues from the mice were examined for mRNAs for specific inflammatory markers, (ECM) proteins and inflammation inducible transcription factor by real time RT-PCR. Corresponding proteins, where possible, were examined using immunofluorescence or ELISA. In parallel, we examined ECs following incubation with various levels of glucose with or without miR-146a mimic transfection. In the retina and kidneys of WT mice with diabetes, increased expression of inflammatory markers (IL-6, TNFα, IL1ß) in association augmented expression of ECM proteins (collagen 1αIV, fibronectin) and NF κB-P65 were observed, compared to WT non-diabetic controls. These changes were prevented in diabetic miR-146a TG mice along with retinal and renal functional and structural changes. In vitro studies showed similar changes in the ECs exposed to high glucose. Such changes were corrected in the cells following miR-146a mimic transfection. Further analyses of renal cortical tissues showed diabetes induced significant upregulation of two regulators of NFκB, namely Interleukin-1 associated Kinase 1 and tumour necrosis factor receptor associated factor. Such changes were prevented in diabetic TG animals. These data indicate that augmented production of inflammatory cytokines and ECM proteins in the retina and kidneys in diabetes are regulated through endothelium derived miR-146a. Identification of such novel mechanisms may potentially lead to the development of novel therapies.