Metronidazole-modified Au@BSA nanocomposites for dual sensitization of radiotherapy in solid tumors.

The hypoxic microenvironment of solid tumors can lead to reduced therapeutic DNA damage to the tumor cells, thus diminishing tumor sensitivity to radiotherapy. Although hypoxic radiosensitizers can improve radiotherapy efficacy by enhancing the role of oxygen, their effects are limited by the uneven distribution of oxygen within solid tumor tissues. In this study, a novel radiosensitizer via leveraging gold complexes and metronidazole (MN) was synthesized to improve radiotherapeutic efficacy. The gold atoms incorporated in the radiosensitizer enabled efficient deposition of high-energy radiation; the hydrophobic metronidazole was reduced to hydrophilic aminoimidazole under hypoxia conditions and further promoted radiotherapy sensitization. The results of CCK-8 assays, Live/Dead assays, γ-H2AX immunofluorescence indicated that metronidazole-modified Au@BSA nanocomposites (NCs) exhibited excellent antitumor effects. The in vivo antitumor tests further showed an inhibition rate of 100%. These results demonstrated that the NCs successfully enhanced radiotherapy efficacy by the dual sensitization strategy. Overall, we believe this multimodal radiosensitizing nanocomplex can significantly inhibit tumor growth and metastasis, with their hypoxia-oriented characteristics ensuring a higher efficacy and safety.

Evaluation of ImpENSA technology-enabled behaviour change module delivered to healthcare professionals in South Africa to improve micronutrient nutrition during the first 1000 days.

Healthcare professionals (HCPs) have vital roles in providing evidence-based care to promote healthy micronutrient nutrition in early life. Providing such care requires scalable training to strengthen knowledge and confident application of effective behaviour change skills. Among 33 public and private HCPs (primarily dietitians) in South Africa, we evaluated the behaviour change aspects of a technology-enabled National Qualification Sub-Framework level 6 programme, Improving Early Nutrition and Health in South Africa ('ImpENSA'). This programme comprises two self-directed micronutrient and behaviour change knowledge-based eLearning and one facilitated online practical skills modules to improve maternal and infant micronutrient nutrition. Using assessments, questionnaires and interviews, we collected data at baseline, after module completion and at 3-month follow-up after programme completion. Questionnaire and interview data showed major improvements in understanding of and attitudes towards person-centred behaviour change support immediately following the eLearning module on behaviour change. The assessment pass rate increased from 38% at baseline to 88% postmodule, demonstrating significant knowledge gain in behaviour change support. Intention to change practice towards a person-centred approach was high and many had already started implementing changes. Three months postprogramme, support was centred around patients' needs. Open relationships with patients, improved patient outcomes and increased job satisfaction were among reported outcomes. Many reported becoming better change facilitators and reflective practitioners. Additional improvements in understanding and attitudes to behaviour change support were evident, reinforced by making changes and experiencing positive outcomes. The findings suggest that technology-enabled learning can equip HCPs with knowledge and skills to effectively support behaviour change for healthy micronutrient nutrition during pregnancy and infancy.

Correction: A differential-targeting core-shell microneedle patch with coordinated and prolonged release of mangiferin and MSC-derived exosomes for scarless skin regeneration.

Correction for 'A differential-targeting core-shell microneedle patch with coordinated and prolonged release of mangiferin and MSC-derived exosomes for scarless skin regeneration' by Shang Lyu et al., Mater. Horiz., 2024, https://doi.org/10.1039/D3MH01910A.

A differential-targeting core-shell microneedle patch with coordinated and prolonged release of mangiferin and MSC-derived exosomes for scarless skin regeneration.

Microneedles for skin regeneration are conventionally restricted by uncontrollable multi-drug release, limited types of drugs, and poor wound adhesion. Here, a novel core-shell microneedle patch is developed for scarless skin repair, where the shell is composed of hydrophilic gelatin methacryloyl (GelMA) loaded with mangiferin, an anti-inflammatory small molecule, and the core is composed of hydrophobic poly (lactide-co-propylene glycol-co-lactide) dimethacrylates (PGLADMA) loaded with bioactive macromolecule and human mesenchymal stromal cell (hMSC)-derived exosomes. This material choice provides several benefits: the GelMA shell provides a swelling interface for tissue interlocking and rapid release of mangiferin at an early wound healing stage for anti-inflammation, whereas the PGLADMA core offers long-term encapsulation and release of exosomes (30% release in 3 weeks), promoting sustained angiogenesis and anti-inflammation. Our results demonstrate that the core-shell microneedle possesses anti-inflammatory properties and can induce angiogenesis both in vitro in terms of macrophage polarization and tube formation of human umbilical vein endothelial cells (HUVECs), and in vivo in terms of anti-inflammation, re-epithelization, and vessel formation. Importantly, we also observe reduced scar formation in vivo. Altogether, the degradation dynamics of our hydrophilic/hydrophobic materials enable the design of a core-shell microneedle for differential and prolonged release, promoting scarless skin regeneration, with potential for other therapies of long-term exosome release.

Role of overnight oximetry in assessing the severity of obstructive sleep apnoea in typically developing children: a multicentre study.

BACKGROUND AND OBJECTIVE: Cardiorespiratory polygraphy (CRP) is the predominant technology used to diagnose obstructive sleep apnoea (OSA) in tertiary centres in the UK. Nocturnal pulse oximetry (NPO) is, however, cheaper and more accessible. This study evaluated the ability of NPO indices to predict OSA in typically developing (TD) children. METHODS: Indices from simultaneous NPO and CRP recordings were compared in TD children (aged 1-16 years) referred to evaluate OSA in three tertiary centres. OSA was defined as an obstructive apnoea-hypopnoea index (OAHI) ≥1 event/hour. Receiver operating characteristic curves assessed the diagnostic accuracy of NPO indices including ODI3 (3% Oxygen Desaturation Index, ODI4 (4% Oxygen Desaturation Index), delta 12 s index and minimum oxygen saturation. Two-by-two tables were generated to determine the sensitivities and specificities of whole number cut-off values for predicting OAHIs ≥1, 5 and 10 events/hour. RESULTS: Recordings from 322 TD children, 197 male (61.2%), median age 4.9 years (range 1.1-15.6), were reviewed. OAHI was ≥1/hour in 144 (44.7%), ≥5/hour in 61 (18.9%) and ≥10/hour in 28 (8.7%) cases. ODI3 and ODI4 had the best diagnostic accuracy. ODI3 ≥7/hour and ODI4 ≥4/hour predicted OSA in TD children with sensitivities/specificities of 57.6%/85.4% and 46.2%/91.6%, respectively. ODI3 ≥8/hour was the best predictor of OAHI ≥5/hour (sensitivity 82.0%, specificity 84.3%). CONCLUSION: Raised ODI3 and ODI4 predict OSA in TD children with high specificity but variable sensitivity. NPO may be an alternative to diagnose moderate-severe OSA if access to CRP is limited. Low sensitivities to detect mild OSA mean that confirmatory CRP is needed if NPO is normal.

The Effect of Glycemic Control on Morbidity and Mortality in Critically Ill COVID-19 Patients.

Background COVID-19 infection has caused a global pandemic affecting a group of patients with chronic conditions including diabetes with exacerbating insulin resistance and hyperglycemia. Investigators noted that pre-existing diabetes and newly diagnosed diabetes are associated with an increased risk of all-cause mortality in hospitalized patients with COVID-19 infection. Aim To evaluate the relationship between ICU patients infected with COVID-19 and mortality among those with high versus low glucose levels. Methods This is a retrospective study of critically ill adult patients infected with COVID-19 who were admitted to the ICU from April 5, 2020, to October 14, 2020. The participants were from San Bernardino County which is a diverse and underserved community. Overall, 84 patients were included in the final analysis. The average age was 59.67 (standard deviation=15.55) with 59.5% being males. Overall mortality was 44.1%. Results Around one-fifth of patients had glucose under control as measured by peak glucose level of <180 mg/dL during hospital stay. A statistically significant association was seen between tighter serum glucose control and mortality (p=0.0354). Patients with serum glucose maintained <180 mg/dL were associated with significantly lower mortality than their counterparts (22.2% vs. 50%). Conclusions This study suggests that maintaining a tighter control of the glycemic index in critically ill COVID-19 patients will improve morbidity and mortality.

Living prosthetic breast for promoting tissue regeneration and inhibiting tumor recurrence.

Developing a living prosthetic breast to inhibit potential breast cancer recurrence and simultaneously promote breast reconstruction would be a promising strategy for clinical treatment of breast cancer after mastectomy. Here, a living prosthetic breast in the form of injectable gelatin methacryloyl microspheres is prepared, where they encapsulated zeolitic imidazolate framework (ZIF) nanoparticles loaded with small molecules urolithin C (Uro-C) and adipose-derived stem cells (ADSCs). Taking advantage of the acidic tumor microenvironment, the ZIF triggered a pH-sensitive drug release in situ so that Uro-C can induce tumor cell apoptosis via reactive oxygen species (ROS) generation. Meanwhile, the ADSCs proliferate in situ to promote tissue regeneration. Using such a design, our data showed that the ADSCs maintained viable and proliferate under the inhibitory effect of Uro-C in vitro. Through ROS generation, Uro-C also activated a suppressive tumor microenvironment in mice by both re-polarizing M2 macrophages to M1 macrophages for elevated inflammatory responses, and increasing the ratio between CD8 and CD4 T cells for tumor recurrence inhibition, significantly promoting new adipose tissue formation. Altogether, our results demonstrate that the prepared living prosthetic breast with bifunctional properties can be a promising candidate in clinic involving tumor treatment and tissue engineering in synergy.

Structural Origins of Viscosity in Imidazolium and Pyrrolidinium Ionic Liquids Coupled with the NTf2- Anion.

Ionic liquid viscosity is one of the most important properties to consider for practical applications. Yet, the connection between local structure and viscosity remains an open question. This article explores the structural origin of differences in the viscosity and viscoelastic relaxation across several ionic liquids, including cations with alkyl, ether, and thioether tails, of the imidazolium and pyrrolidinium families coupled with the NTf2- anion. In all cases, for the systems studied here, we find that pyrrolidinium-based ions are "harder" than their imidazolium-based counterparts. We make a connection between the chemical concept of hardness vs softness and specific structural and structural dynamic quantities that can be derived from scattering experiments and simulations.

Knowledge, attitudes and intention on fertility preservation among breast cancer patients.

Breast cancer is the most common cancer in reproductive age women. The aim of this study is to assess the knowledge, attitude and intention on fertility preservation among women diagnosed to have breast cancer. This is a multi-centre cross-sectional questionnaire study. Reproductive age women diagnosed with breast cancer attending Oncology, Breast Surgery and Gynaecology Clinics and support groups were invited to participate. Women filled in paper or electronic form of the questionnaire. 461 women were recruited and 421 women returned the questionnaire. Overall, 181/410 (44.1%) women had heard of fertility preservation. Younger age and higher education level were significantly associated with increased awareness of fertility preservation. Awareness and acceptance of the different fertility preservation methods in reproductive age women with breast cancer was suboptimal. However, 46.1% women felt that their fertility concerns affected their decision for cancer treatment in some way.

Going below and beyond the surface: Microneedle structure, materials, drugs, fabrication, and applications for wound healing and tissue regeneration.

Microneedle, as a novel drug delivery system, has attracted widespread attention due to its non-invasiveness, painless and simple administration, controllable drug delivery, and diverse cargo loading capacity. Although microneedles are initially designed to penetrate stratum corneum of skin for transdermal drug delivery, they, recently, have been used to promote wound healing and regeneration of diverse tissues and organs and the results are promising. Despite there are reviews about microneedles, few of them focus on wound healing and tissue regeneration. Here, we review the recent advances of microneedles in this field. We first give an overview of microneedle system in terms of its potential cargos (e.g., small molecules, macromolecules, nucleic acids, nanoparticles, extracellular vesicle, cells), structural designs (e.g., multidrug structures, adhesive structures), material selection, and drug release mechanisms. Then we briefly summarize different microneedle fabrication methods, including their advantages and limitations. We finally summarize the recent progress of microneedle-assisted wound healing and tissue regeneration (e.g., skin, cardiac, bone, tendon, ocular, vascular, oral, hair, spinal cord, and uterine tissues). We expect that our article would serve as a guideline for readers to design their microneedle systems according to different applications, including material selection, drug selection, and structure design, for achieving better healing and regeneration efficacy.

Normalized L3-based link prediction in protein-protein interaction networks.

BACKGROUND: Protein-protein interaction (PPI) data is an important type of data used in functional genomics. However, high-throughput experiments are often insufficient to complete the PPI interactome of different organisms. Computational techniques are thus used to infer missing data, with link prediction being one such approach that uses the structure of the network of PPIs known so far to identify non-edges whose addition to the network would make it more sound, according to some underlying assumptions. Recently, a new idea called the L3 principle introduced biological motivation into PPI link predictions, yielding predictors that are superior to general-purpose link predictors for complex networks. Interestingly, the L3 principle can be interpreted in another way, so that other signatures of PPI networks can also be characterized for PPI predictions. This alternative interpretation uncovers candidate PPIs that the current L3-based link predictors may not be able to fully capture, underutilizing the L3 principle. RESULTS: In this article, we propose a formulation of link predictors that we call NormalizedL3 (L3N) which addresses certain missing elements within L3 predictors in the perspective of network modeling. Our computational validations show that the L3N predictors are able to find missing PPIs more accurately (in terms of true positives among the predicted PPIs) than the previously proposed methods on several datasets from the literature, including BioGRID, STRING, MINT, and HuRI, at the cost of using more computation time in some of the cases. In addition, we found that L3-based link predictors (including L3N) ranked a different pool of PPIs higher than the general-purpose link predictors did. This suggests that different types of PPIs can be predicted based on different topological assumptions, and that even better PPI link predictors may be obtained in the future by improved network modeling.

Role of foetal kidney size on kidney function in childhood: the born in bradford cohort renal study.

BACKGROUND: Foetal and early childhood development contributes to the risk of adult non-communicable diseases such as hypertension and cardiovascular disease. We aimed to investigate whether kidney size at birth is associated with markers of kidney function at 7-11 years. METHODS: Foetal kidney dimensions were measured using ultrasound scans at 34 weeks gestation and used to derive kidney volume (cm3) in 1802 participants in the Born in Bradford (BiB) birth cohort. Blood and urine samples were taken from those who participated in the BiB follow-up at 7-11 years (n = 630) and analysed for serum creatinine, cystatin C, urea, and urinary albumin to creatinine ratio (ACR), protein to creatinine ratio (PCR) and retinol binding protein (RBP). Estimated glomerular filtration rate (eGFR) was calculated using Schwartz creatinine only and combined with cystatin C, and cystatin C only Zappitelli and Filler equations. Linear regression was used to examine the association between foetal kidney volume and eGFR, ACR, PCR and blood pressure, unadjusted and adjusted for confounders. RESULTS: Kidney volume was positively associated in adjusted models with eGFR calculated using Schwartz combined (0.64 ml/min diff per unit increase in volume, 95% CI 0.25 to 1.02), Zappitelli (0.79, 95% CI 0.38 to 1.20) and Filler (2.84, 95% CI 1.40 to 4.28). There was an association with the presence of albuminuria but not with its level, or with other urinary markers or with blood pressure. CONCLUSION: Foetal kidney volume was associated with small increases in eGFR in mid-childhood. Longitudinal follow-up to investigate the relationship between kidney volume and markers of kidney function as children go through puberty is required.

An Exploratory Study Provides Insights into MMP9 and Aß Levels in the Vitreous and Blood across Different Ages and in a Subset of AMD Patients.

Matrix metalloproteinase-9 (MMP9) and total amyloid-beta (Aß) are prospective biomarkers of ocular ageing and retinopathy. These were quantified by ELISA in the vitreous and blood from controls (n = 55) and in a subset of age-related macular degeneration (AMD) patients (n = 12) for insights and possible additional links between the ocular and systemic compartments. Vitreous MMP9 levels in control and AMD groups were 932.5 ± 240.9 pg/mL and 813.7 ± 157.6 pg/mL, whilst serum levels were 2228 ± 193 pg/mL and 2386.8 ± 449.4 pg/mL, respectively. Vitreous Aß in control and AMD groups were 1173.5 ± 117.1 pg/mL and 1275.6 ± 332.9 pg/mL, whilst plasma Aß were 574.3 ± 104.8 pg/mL and 542.2 ± 139.9 pg/mL, respectively. MMP9 and Aß showed variable levels across the lifecourse, indicating no correlation to each other or with age nor AMD status, though the smaller AMD cohort was a limiting factor. Aß and MMP9 levels in the vitreous and blood were unrelated to mean arterial pressure. Smoking, another modifiable risk, showed no association with vitreous Aß. However, smoking may be linked with vitreous (p = 0.004) and serum (p = 0.005) MMP9 levels in control and AMD groups, though this did not reach our elevated (p = 0.001) significance. A bioinformatics analysis revealed promising MMP9 and APP/Aß partners for further scrutiny, many of which are already linked with retinopathy.

The effects of SARS-CoV-2 infection on modulating innate immunity and strategies of combating inflammatory response for COVID-19 therapy.

The global pandemic of COVID-19 has caused huge causality and unquantifiable loss of social wealth. The innate immune response is the first line of defense against SARS-CoV-2 infection. However, strong inflammatory response associated with dysregulation of innate immunity causes severe acute respiratory syndrome (SARS) and death. In this review, we update the current knowledge on how SARS-CoV-2 modulates the host innate immune response for its evasion from host defense and its corresponding pathogenesis caused by cytokine storm. We emphasize Type I interferon response and the strategies of evading innate immune defense used by SARS-CoV-2. We also extensively discuss the cells and their function involved in the innate immune response and inflammatory response, as well as the promises and challenges of drugs targeting excessive inflammation for antiviral treatment. This review would help us to figure out the current challenge questions of SARS-CoV-2 infection on innate immunity and directions for future studies.

Ethnic differences in kidney function in childhood: the Born in Bradford Cohort Renal Study.

Background: Endstage kidney failure rates are higher in South Asians than in White Europeans. Low birth weight is associated with adult chronic kidney disease and is more common in South Asians. Foetal kidney size was smaller in South Asians in the Born in Bradford (BiB) birth cohort. As part of BiB follow up, we aimed to investigate if there were ethnic differences in kidney function and blood pressure in early childhood and whether this was different by foetal kidney size. Methods: Serum creatinine, cystatin C, urea, and urinary albumin to creatinine ratio (ACR), protein to creatinine ratio (PCR) and retinol binding protein (RBP) were analysed in blood and urine samples from those who participated in the BiB follow-up at 7-11 years. Ethnicity was categorised by parental self-report as White European and South Asian. Estimated glomerular filtration rate (eGFR) was calculated using Schwartz, and cystatin C Zappitelli and Filler equations. Linear regression was used to examine the association between ethnicity and eGFR, PCR and blood pressure. Results: 1591 children provided blood (n=1403) or urine (n=625) samples. Mean eGFR was 92 ml/min/1.73m 2 (standard deviation (SD) 9) using Schwartz (n=1156) and 94 (SD 11) using Zappitelli (n=1257). CKD prevalence was rare (1 with eGFR <60 ml/min/1.73m 2, 14 (2.4%) had raised ACR (>2.5 mg/mmol in boys/3.5 mg/mmol in girls). Diastolic blood pressure was higher in South Asian children (difference 2.04 mmHg, 95% CI 0.99 to 3.10) but was not significant in adjusted analysis. There was no evidence of association in adjusted models between ethnicity and any eGFR or urinary measure at this age. Conclusions: There was no evidence of significant ethnic differences in kidney function at pre-pubertal age despite differences in kidney volume at birth. Longitudinal follow-up is required to track ethnic patterns in kidney function and blood pressure as children develop through puberty.

Petite miracles: insight into the nano-management of scarless wound healing.

Scars affect millions of patients worldwide, yet their treatment efficacy and options clinically remain limited. In recent years, increased understanding of scar formation pathways leading to developments in nanotechnology have opened many opportunities for scar detection, prevention, and treatment due to the nanoscale features and therapeutic delivery capabilities of such technologies. Led by nanoparticles (NPs) and nanofibers, these novel strategies can aid in reducing scar contracture, improving wound-healing efficacy, and advancing progress towards scarless wound healing.

Miller-Fisher Syndrome Presenting as Facial Diplegia With COVID-19 Co-Infection.

Coronavirus disease 2019 (COVID-19) has reportedly been associated with various neurological manifestations, including unilateral facial palsy and, very rarely, facial diplegia. We present a unique case of Miller-Fisher Syndrome (MFS), a variant of Guillain-Barré Syndrome (GBS) that was noted in conjunction with a COVID-19 infection. In this case, a patient presented with bilateral facial palsy, dysarthria, right-sided hemiparesis, ataxia, and the confirmation of SARS-CoV-2 infection. His computed tomography (CT) scan of the brain and serology test results did not support alternate etiologies for facial palsy. His cerebrospinal fluid (CSF) studies demonstrated albuminocytologic dissociation, which was consistent with the diagnosis of MFS and further supported by his ataxia and ophthalmoplegia. A five-day course of intravenous immunoglobulin (IVIG) therapy combined with physical, occupational, and speech therapy improved his recovery.

The impact of post-operative atrial fibrillation on outcomes in coronary artery bypass graft and combined procedures.

BACKGROUND: Post-operative atrial fibrillation (POAF) is a common yet understudied clinical issue after coronary artery bypass graft (CABG) leading to higher mortality rates and stroke. This systematic review and meta-analysis evaluated the rates of adverse outcomes between patients with and without POAF in patients treated with CABG or combined procedures. METHODS: The search period was from the beginning of PubMed and Embase to May 18th, 2020 with no language restrictions. The inclusion criteria were: (1) studies comparing new onset atrial fibrillation before or after revascularization vs. no new onset AF before or after revascularization. The outcomes assessed included all-cause mortality, cardiac death, cerebral vascular accident (CVA), myocardial infarction (MI), repeated revascularization, major adverse cardiac event (MACE), and major adverse cardiac and cerebrovascular events (MACCEs). RESULTS: Of the 7,279 entries screened, 11 studies comprising of 57,384 patients were included. Compared to non-POAF, POAF was significantly associated with higher risk of all-cause mortality (Risk Ratio (RR) = 1.58; 95% Confidence Interval (CI): 1.42-1.76, P < 0.00001) with accompanying high level of heterogeneity ( I 2 = 62%). CONCLUSIONS: Patients with POAF after CABG or combined procedures are at an increased risk of all-cause mortality or CVAs. Therefore, POAF after such procedures should be closely monitored and treated judiciously to minimize risk of further complications. While there are studies on POAF versus no POAF on outcomes, the heterogeneity suggests that further studies are needed.