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Premkumar Jayaraman,1,2 Kishore R Sakharkar,3 ChuSing Lim,1,2 Mohammad Imran Siddiqi,4 Sarinder K Dhillon,5 Meena K Sakharkar1,61Biomedical Engineering Research Centre, Nanyang Technological University, Singapore; 2Advanced Design and Modeling Lab, Nanyang Technological University, Singapore; 3OmicsVista, Singapore; 4Molecular and Structural Biology Division, Central Drug Research Institute, India; 5Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia; 6School of Life and Environmental Sciences, University of Tsukuba, Ibaraki, JapanBackground: There is a dearth of treatment options for community-acquired and nosocomial Pseudomonas infections due to several rapidly emerging multidrug resistant phenotypes, which show resistance even to combination therapy. As an alternative, developing selective promiscuous hybrid compounds for simultaneous modulation of multiple targets is highly appreciated because it is difficult for the pathogen to develop resistance when an inhibitor has activity against multiple targets.Methods: In line with our previous work on phytochemical–antibiotic combination assays and knowledge-based methods, using a fragment combination approach we here report a novel drug design strategy of conjugating synergistic phytochemical–antibiotic combinations into a single hybrid entity for multi-inhibition of P. aeruginosa DNA gyrase subunit B (GyrB)/topoisomerase IV subunit B (ParE) and dihydrofolate reductase (DHFR) enzymes. The designed conjugates were evaluated for their multitarget specificity using various computational methods including docking and dynamic simulations, drug-likeness using molecular properties calculations, and pharmacophoric features by stereoelectronic property predictions.Results: Evaluation of the designed hybrid compounds based on their physicochemical properties has indicated that they are promising drug candidates with drug-like pharmacotherapeutic profiles. In addition, the stereoelectronic properties such as HOMO (highest occupied molecular orbital), LUMO (lowest unoccupied molecular orbital), and MEP (molecular electrostatic potential) maps calculated by quantum chemical methods gave a good correlation with the common pharmacophoric features required for multitarget inhibition. Furthermore, docking and dynamics simulations revealed that the designed compounds have favorable binding affinity and stability in both the ATP-binding sites of GyrB/ParE and the folate-binding site of DHFR, by forming strong hydrogen bonds and hydrophobic interactions with key active site residues.Conclusion: This new design concept of hybrid “phyto-drug” scaffolds, and their simultaneous perturbation of well-established antibacterial targets from two unrelated pathways, appears to be very promising and could serve as a prospective lead in multitarget drug discovery.Keywords: hybrid compounds, multi-target inhibition, drug resistance, dihydrofolate reductase, DNA gyrase subunit B, topoisomerase IV subunit B, rational drug design

Currently, global annual CO 2 emissions from fossil fuel consumption are extremely high, surpassing tens of billions of tons, yet our capacity to capture and utilize CO 2 remains below a small fraction of the amount generated. Microbial electrosynthesis (MES) systems, an integration of microbial metabolism with electrochemistry, have emerged as a highly efficient and promising bio-based carbon-capture-and-utilization technology over other conventional techniques. MES is a unique technology for lowering the atmospheric CO 2 as well as CO 2 in the biogas, and also simultaneously convert them to renewable bioenergy, such as biomethane. As such, MES techniques could be applied for biogas upgrading to generate high purity biomethane, which has the potential to meet natural gas standards. This article offers a detailed overview and assessment of the latest advancements in MES for biomethane production and biogas upgrading, in terms of selecting optimal methane production pathways and associated electron transfer processes, different electrode materials and types, inoculum sources and microbial communities, ion-exchange membrane, externally applied energy level, operating temperature and pH, mode of operation, CO 2 delivery method, selection of inorganic carbon source and its concentration, start-up time, and system pressure. It also highlights the current MES challenges associated with upscaling, design and configuration, long-term stability, energy demand, techno-economics, achieving net negative carbon emission, and other operational issues. Moreover, we provide a summary of current and future opportunities to integrate MES with other unique biosystems, such as methanotrophic bioreactors, and incorporate quorum sensing, 3D printing, and machine learning to further develop MES as a better biomethane-producer and biogas upgrading technique., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Neonatal encephalopathy remains a major contributor to death and disability around the world. Acute hypoxia-ischaemia before, during or after birth creates a series of events that can lead to neonatal brain injury. Understanding the evolution of injury underpinned the development of therapeutic hypothermia. This review discusses the determinants of injury, including maturity, the pattern of exposure to HI, impaired placental function, often associated with fetal growth restriction and in the long-term, socio-economic deprivation. Chorioamnionitis has been associated with the presence of NE, but it is important to note that experimentally, inflammation can either sensitize to greater neural injury after HI or alleviate injury, depending on its precise timing. As fetal surveillance tools improve it is likely that improved detection of specific pathways will offer future opportunities for preventive and reparative interventions in utero and after birth., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Fetal hypoxemia is ubiquitous during labor and, when severe, is associated with perinatal death and long-term neurodevelopmental disability. Adverse outcomes are highly associated with barriers to care, such that developing countries have a disproportionate burden of perinatal injury. The prevalence of hypoxemia and its link to injury can be obscure, simply because the healthy fetus has robust coordinated defense mechanisms, spearheaded by the peripheral chemoreflex, such that hypoxemia only becomes apparent in the minority of cases associated with stillbirth, severe metabolic acidemia or adverse neurodevelopmental outcomes. This represents only the extreme end of the spectrum, when defense mechanisms have failed due to severe/prolonged hypoxemia, or the fetal defenses are compromised by additional risk factors. Understanding the fetal defenses to hypoxemia and when the fetus begins to decompensate is crucial to understanding perinatal health and disease, by linking antenatal health, intrapartum events, the neonatal trajectory and ultimately life-long neurodevelopmental health., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cervical cancer screening is a cornerstone of cervical cancer elimination. Detection of high-risk human papillomavirus (hrHPV) is recommended as the first step in screening provided that the assay used has been adequately validated. The Sansure® Human Papillomavirus DNA Diagnostic Kit is a new assay designed to detect HPV16, HPV18 and 13 other HPV in aggregate. The study aimed to evaluate the intra- and interlaboratory reproducibility of the assay according to international guidelines. Five hundred and fifty cervical residual cell samples from women attending cervical cancer screening were selected from the biobank of the HPV National Reference Centre in Belgium and used in this study. After DNA extraction, HPV was tested using the Sansure® Human Papillomavirus DNA Diagnostic Kit. The lower 95% confidence limit around the general reproducibility of this assay should be greater than or equal to 87%, with κ ≥ 0.50. Five hundred and thirty-three samples had valid results. The Sansure® Human Papillomavirus DNA Diagnostic Kit demonstrated an excellent intra-laboratory reproducibility of 93.8% (95% confidence interval [CI]: 91.4-95.7, κ = 0.85). The interlaboratory reproducibility was 93.4 (95% CI: 91.0-95.4, κ = 0.84). Intra and interlaboratory reproducibility were also excellent at the genotype level. Excluding HPV53 single infection samples from the analyses also resulted in excellent agreement. These data show that the Sansure® Human Papillomavirus DNA Diagnostic Kit is highly reproducible., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

The etiology of perinatal brain injury is multifactorial, but exposure to perinatal hypoxiaischemia (HI) is a major underlying factor. This review discusses the role of exposure to infection/inflammation in the evolution of HI brain injury, changes in immune responsiveness to subsequent inflammatory challenges after HI and modulation of neural outcomes with interaction between perinatal HI and inflammatory insults. The authors critically assess the clinical and preclinical evidence for the neuroprotective efficacy of therapeutic hypothermia and other anti-inflammatory treatments for inflammation-sensitized HI injury., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: In people with lower limb amputation (LLA), the loss of limb structures and peripheral motor and sensory systems result in significant mobility challenges, including impaired postural stability., Objective: The primary objective of this study was to evaluate the dual-task interference (DTI) on postural control and dual-task interference on cognition during static and dynamic balance in people with LLA and compare the same with controls. The secondary objective of this study was to compare the DTI on postural control and DTI on cognition between LLA of different etiology., Design: Cross-sectional observational study METHODOLOGY: Fifteen people with unilateral LLA and 15 age and gender-matched controls participated in this study at a tertiary care hospital. The outcome measures used were anterior-posterior stability index (APSI), medial-lateral stability index, and overall stability index (OSI) using Biodex Balance System and a cognitive task parameter, namely correct response rate in serial seven subtraction test. Quantitative variables were compared using a Wilcoxon rank-sum test. Spearman's correlation test was used to establish the correlation between the DTI on cognition and the DTI on postural control., Results: DTI on postural control during static balance was significantly higher in people with LLA than controls (APSI, OSI). No significant difference was observed in DTI on postural control during dynamic balance. No significant difference was observed in DTI on cognition during static and dynamic balance. A significant negative correlation was observed between DTI on cognition and DTI on postural control (APSI) during static balance people with LLA., Significance: In people with unilateral LLA, the addition of a cognitive task results in significant deterioration of sagittal plane postural control during static balance but not during dynamic balance due to the over-allocation of resources to a cognitive task., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Clinically validated human papillomavirus (HPV) assays are crucial in cervical cancer screening. In this study, we evaluated the Allplex HPV HR Detection assay (Seegene, SouthKorea) for its clinical accuracy and reproducibility according to the international criteria, using the RealTime High Risk HPV m2000 assay (Abbott, USA) as standard comparator. The Allplex HPV HR assay exhibits significant non-inferior sensitivity to detect cervical intraepithelial neoplasia grade (CIN) 2 or worse (CIN2+) with a ratio of 1.00 (95% CI: 0.97-1.03, P = 0.006), insignificant non-inferior sensitivity to detect CIN3+ with a ratio of 1.00 (95% CI: 0.88-1.13, P = 0.098), and non-inferior specificity to exclude CIN2+ with a ratio of 0.99 (95% CI: 0.99-1.00, P < 0.001) compared to the standard comparator. In addition, the assay shows an excellent reproducibility within the same laboratory [96.5% (95% CI: 94.6-97.9) with a kappa value of 0.91 (95% CI: 0.87-0.95)] and between laboratories [96.7% (95% CI: 94.8-98.0) with a kappa value of 0.91 (95% CI: 0.87-0.95)] for overall high-risk HPV positivity as well as for each individual HPV type. Pooling our study data with those of another independent study supports the consistency of our findings. We conclude that both the clinical accuracy to detect cervical precancer and the reproducibility of Allplex HPV HR Detection assay fulfill the international validation criteria of use in cervical cancer screening.IMPORTANCEThe clinical validation of human papillomavirus (HPV) assays in accordance with well-established international guidelines is crucial to ensure that only validated assays are used in the context of screening (Meijer et al., Int J Cancer, 2009). The guidelines, developed by an international consortium, require that a novel HPV assay has non-inferior accuracy against a standard comparator test for the detection of cervical intraepithelial neoplasia grade (CIN) 2 or worse (CIN2+). Additionally, a new HPV assay should meet specific criteria for both intra- and inter-laboratory reproducibility to ensure the assay consistently exhibits technical precision and robust performance. Pooling our study data with those of another independent study supports the consistency of our findings. In conclusion, both the clinical accuracy to detect cervical precancer and the reproducibility of Allplex HPV HR Detection assay fulfill the international validation criteria of use in cervical cancer screening., Competing Interests: The authors declare no conflict of interest.

Therapeutic hypothermia is now standard of care for neonates with hypoxic-ischemic encephalopathy (HIE) in high income countries (HIC). Conversely, compelling trial evidence suggests that hypothermia is ineffective, and may be deleterious, in low- and middle-income countries (LMIC), likely reflecting the lower proportion of infants who had sentinel events at birth, suggesting that injury had advanced to a stage when hypothermia is no longer effective. Although hypothermia significantly reduced the risk of death and disability in HICs, many infants survived with disability and in principle may benefit from targeted add-on neuroprotective or neurorestorative therapies. The present review will assess biomarkers that could be used to personalize treatment for babies with HIE - to determine first whether an individual infant is likely to respond to hypothermia, and second, whether additional treatments may be beneficial., (Copyright © 2024. Published by Elsevier Inc.)

Antenatal hypoxia-ischaemia (HI) in preterm fetal sheep can trigger delayed evolution of severe, cystic white matter injury (WMI), in a similar timecourse to WMI in preterm infants. We therefore examined how severe hypoxia-ischaemia affects recovery of electroencephalographic (EEG) activity. Chronically instrumented preterm fetal sheep (0.7 gestation) received 25 min of complete umbilical cord occlusion (UCO, n = 9) or sham occlusion (controls, n = 9), and recovered for 21 days. HI was associated with a shift to lower frequency EEG activity for the first 5 days with persisting loss of EEG power in the delta and theta bands, and initial loss of power in the alpha and beta bands in the first 14 days of recovery. In the final 3 days of recovery, there was a marked rhythmic shift towards higher frequency EEG activity after UCO. The UCO group spent less time in high-voltage sleep, and in the early evening (7:02 pm ± 47 min) abruptly stopped cycling between sleep states, with a shift to a high frequency state for 2 h 48 min ± 40 min, with tonic electromyographic activity. These findings demonstrate persisting EEG and sleep state dysmaturation after severe hypoxia-ischaemia. Loss of fetal or neonatal sleep state cycling in the early evening may be a useful biomarker for evolving cystic WMI., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

To meet the screening goal of WHO's 90-70-90 strategy aimed at eliminating cervical cancer (CC) by 2030, clinical validation of human papillomavirus (HPV) assays is essential to provide accurate and valid results through fulfilling three criteria of the international validation guidelines (IVGs). Previously, the clinical accuracy of the AmpFire® HPV Screening 16/18/HR assay (AmpFire assay) was reported but reproducibility data are lacking. Here, we aim to evaluate the intra- and inter-laboratory reproducibility of the AmpFire assay. The reproducibility of the isothermal AmpFire assay was assessed using 556 cervical cell samples collected from women attending CC screening and biobanked in a Belgian HPV national reference center. This assay detects HPV16, HPV18, and 12 other high-risk HPV (hrHPV) types (31/33/35/39/45/51/52/56/58/59/66/68) in aggregate. Lower 95% confidence interval bound around the assay's reproducibility should exceed 87%, with κ ≥ 0.50. Additionally, a literature review of the assay's clinical performance was performed. The AmpFire assay showed an excellent intralaboratory (96.4%, 95% CI:94.5-97.8%, κ = 0.920) and interlaboratory (95.3%, 95% CI:93.2-96.9%, κ = 0.897) reproducibility. One study demonstrated noninferior sensitivity of a prototype AmpFire assay targeting 15 hrHPV types (including HPV53) to detect CIN2+. However, clinical specificity became similar to the comparator after removing HPV53 from analyses. The low-cost and easy-to-use AmpFire assay presents excellent reproducibility and-after removing HPV53 from the targeted types-fulfills also clinical accuracy requirements. Inclusion of HPV53, which is not recognized as carcinogenic, comprises clinical specificity of screening assays., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Perinatal infection or inflammation are associated with adverse neurodevelopmental effects and cardiovascular impairments in preterm infants. Most preclinical studies have examined the effects of gram-negative bacterial inflammation on the developing brain, although gram-positive bacterial infections are a major contributor to adverse outcomes. Killed Su-strain group 3 A streptococcus pyogenes (Picibanil, OK-432) is being used for pleurodesis in fetal hydrothorax/chylothorax. We therefore examined the neural and cardiovascular effects of clinically relevant intra-plural infusions of Picibanil. Chronically instrumented preterm (0.7 gestation) fetal sheep received an intra-pleural injection of low-dose (0.1 mg, n = 8) or high-dose (1 mg, n = 8) Picibanil or saline-vehicle (n = 8). Fetal brains were collected for histology one-week after injection. Picibanil exposure was associated with sustained diffuse white matter inflammation and loss of immature and mature oligodendrocytes and subcortical neurons, and associated loss of EEG power. These neural effects were not dose-dependent. Picibanil was also associated with acute changes in heart rate and attenuation of the maturational increase in mean arterial pressure. Even a single exposure to a low-dose gram-positive bacterial-mediated inflammation during the antenatal period is associated with prolonged changes in vascular and neural function., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background. Fieldwork is an essential part of experiential learning in occupational therapy education. Fieldwork educators identify limits on reasonable accommodation and difficulty implementing disability-related accommodations. Student occupational therapists with disabilities report discrimination from within the profession, including inflexible fieldwork environments. Purpose. To understand the experiences of occupational therapy fieldwork educators in Canada in accommodating students with disabilities and to develop action-oriented practice recommendations. Method. In this interpretive description study, we interviewed 11 fieldwork educators about their experiences accommodating students with disabilities. Interviews were recorded, transcribed, and analyzed using a constant comparative approach. Findings. Educators emphasized a meta-theme of "Learning" when asked about disability-related accommodations. Three subthemes about student learning emerged: 1. Educators focused on "Student Learning in Preparation for Professional Practice" rather than their fieldwork setting only; 2. Educators were "Using Occupational Therapy Skills for Student Learning" in fieldwork; and 3. Educators recognized that their professional and personal "Context Influences Student Learning." Conclusion. Fieldwork educators can work with students to align their accommodations with required learning outcomes for professional practice and use their occupational therapy skills to assist with implementation. Fieldwork educators require time and other supports to work effectively with all students.

Brain maturity and many clinical treatments such as therapeutic hypothermia (TH) can significantly influence the morphology of neonatal EEG seizures after hypoxia-ischemia (HI), and so there is a need for generalized automatic seizure identification. This study validates efficacy of advanced deep-learning pattern classifiers based on a convolutional neural network (CNN) for seizure detection after HI in fetal sheep and determines the effects of maturation and brain cooling on their accuracy. The cohorts included HI-normothermia term ( n = 7), HI-hypothermia term ( n = 14), sham-normothermia term ( n = 5), and HI-normothermia preterm ( n = 14) groups, with a total of >17,300 h of recordings. Algorithms were trained and tested using leave-one-out cross-validation and k -fold cross-validation approaches. The accuracy of the term-trained seizure detectors was consistently excellent for HI-normothermia preterm data (accuracy = 99.5%, area under curve (AUC) = 99.2%). Conversely, when the HI-normothermia preterm data were used in training, the performance on HI-normothermia term and HI-hypothermia term data fell (accuracy = 98.6%, AUC = 96.5% and accuracy = 96.9%, AUC = 89.6%, respectively). Findings suggest that HI-normothermia preterm seizures do not contain all the spectral features seen at term. Nevertheless, an average 5-fold cross-validated accuracy of 99.7% (AUC = 99.4%) was achieved from all seizure detectors. This significant advancement highlights the reliability of the proposed deep-learning algorithms in identifying clinically translatable post-HI stereotypic seizures in 256Hz recordings, regardless of maturity and with minimal impact from hypothermia.

The coronavirus disease 2019 (COVID-19) pandemic demonstrated the need for accurate diagnostic testing for the early detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the pandemic has ended, accurate assays are still needed to monitor viral spread at national levels and beyond through population and wastewater surveillance. To enhance early detection, SARS-CoV-2 assays should have high diagnostic accuracy and should be validated to assure accurate results. Three distinct SARS-CoV-2 assays were evaluated with clinical samples using the VALCOR (VALidation of SARS-CORona Virus-2 assays) framework, with the TaqPath COVID-19 assay (ThermoFisher Scientific, USA) as a comparator. We evaluated clinical sensitivity, specificity, limit of detection (LOD), and overall concordance between comparator and three index Allplex SARS-CoV-2 assays (Seegene, South Korea): Allplex-SC2, Allplex-SC2Fast (Fast PCR), and Allplex-SC2FabR (SARS-CoV-2/FluA/FluB/respiratory syncytial virus). Analytical performance and LOD of index assays were assessed using a dilution series of three synthetic SARS-CoV-2 sequence reference materials (RMs). Ninety SARS-CoV-2 positives and 90 SARS-CoV-2 negatives were tested. All Allplex assays had 100.0% sensitivity (95%CI = 95.9%-100.0%). Allplex-SC2 and Allplex-SC2Fast assays had 97.8% specificity (95%CI = 92.3%-99.7%) and 98.9% overall concordance [ κ = 0.978 (95%CI = 0.947-1.000)]. Allplex-SC2FabR assay showed 100.0% specificity (95%CI = 95.9%-100.0%) and 100.0% overall concordance [ κ = 1.000 (95%CI = 1.000-1.000)]. LOD assessment of index assays revealed detection down to 2.61 × 10 2 copies/mL in clinical samples, while the analytical LOD was 9.00 × 10 2 copies/mL. In conclusion, the evaluation of the three Seegene Allplex SARS-CoV-2 assays showed high sensitivity and specificity and an overall good assay concordance with the comparator. The assays showed low analytical LOD using RM and even a slightly lower LOD in clinical samples. Non-overlapping target gene sequences between SARS-CoV-2 assays and RMs emphasize the need for aligning targeted sequences of diagnostic assays and RMs.IMPORTANCEThe coronavirus disease 2019 pandemic has a significant impact on global public health, economies, and societies. As shown through the first phases of the pandemic, accurate and timely diagnosis is crucial for disease control, prevention, and monitoring. Though the pandemic phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has concluded, diagnostic assays remain in demand to monitor SARS-CoV-2 at the individual patient level, regionally, and nationally, as well as to remain an infectious disease preparedness instrument to monitor any new SARS-CoV-2 dissemination across borders using population and wastewater surveillance. The anticipation by WHO and central health care policy entities such as the Center for Disease Control, EMA, and multiple national health authorities is that SARS-CoV-2 will reside as an endemic respiratory disease for years to come. The key strategic consideration is hence shifting from combating a pandemic situation with a high number of patients to instead allowing precise diagnostics of suspected patients with the intention of correct management in a low-prevalence setting., Competing Interests: The authors declare no conflict of interest.

Clinical validation of human papillomavirus (HPV) assays according to international criteria is prerequisite for their implementation in cervical cancer screening. OncoPredict HPV Quantitative Typing (QT) assay (Hiantis Srl, Milan, Italy) is a novel full-genotyping multiplex real-time PCR quantitative assay targeting E6/E7 genes, allowing individual viral load determination of 12 high-risk (HR) HPV types. Quality controls for sample adequacy, efficiency of nucleic acid extraction and PCR inhibition are included in the assay. Clinical performance of OncoPredict HPV QT test was assessed as part of the "Validation of HPV Genotyping Tests" (VALGENT-2) framework, consisting of 1300 cervical liquid-based cytology (LBC) samples of women aged between 20 and 60 years who had originally attended for routine cervical screening in Scotland. The clinical accuracy of the OncoPredict HPV QT (index test) for the detection of CIN2+ was assessed relative to the GP5+/6+ Enzyme ImmunoAssay (GP5+/6+ EIA) (comparator test), using noninferiority criteria. Intra- and interlaboratory reproducibility of the assay was assessed on a subpopulation, comprising 526 samples. The relative sensitivity and specificity for OncoPredict HPV QT vs GP5+/6+-PCR-EIA were 1.01 (95% CI: 0.99-1.03) and 1.03 (95% CI: 1.0-1.06) respectively. The P-values for noninferiority were ≤0.001. The intra- and inter-laboratory reproducibility demonstrated a high concordance (>98.7%) with kappas for individual types ranging from 0.66 to 1.00. OncoPredict HPV QT fulfills the international validation criteria for the use of HPV tests in cervical cancer screening., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Seizures are common in preterm newborns and are associated with poor neurodevelopmental outcomes. Current anticonvulsants have poor efficacy, and many have been associated with upregulation of apoptosis in the developing brain. Apigenin, a natural bioactive flavonoid, is a potent inhibitor of hyaluronidase and reduces seizures in adult animal models. However, its impact on perinatal seizures is unclear. In the present study, we examined the effect of apigenin and S3, a synthetic, selective hyaluronidase inhibitor, on seizures after cerebral ischemia in preterm fetal sheep at 0.7 gestation (98-99 days, term ~147 days). Fetuses received sham ischemia ( n = 9) or ischemia induced by bilateral carotid occlusion for 25 min. Immediately after ischemia, fetuses received either a continuous infusion of vehicle (0.036% dimethyl sulfoxide, n = 8) or apigenin (50 µM, n = 6). In a pilot study, we also tested infusion of S3 (2 µM, n = 3). Fetuses were monitored continuously for 72 h after ischemia. Infusion of apigenin or S3 were both associated with reduced numbers of animals with seizures, total seizure time, and mean seizure burden. S3 was also associated with a reduction in the total number of seizures over the 72 h recovery period. In animals that developed seizures, apigenin was associated with earlier cessation of seizures. However, apigenin or S3 treatment did not alter recovery of electroencephalographic power or spectral edge frequency. These data support that targeting brain hyaluronidase activity with apigenin or S3 may be an effective strategy to reduce perinatal seizures following ischemia. Further studies are required to determine their effects on neurohistological outcomes.

The implementation of cervical screening based on human papillomavirus (HPV) continues to progress rapidly across countries. Evidence has shown that assays detecting high-risk human papillomavirus (hrHPV) deoxyribonucleic acid (DNA) are more effective than cytology-based screening. Validation of new hrHPV DNA assays requires both noninferior clinical accuracy compared to a standard comparator for cervical precancer and good reproducibility. This study builds upon previous diagnostic accuracy assessments of the RIATOL HPV genotyping qPCR assay and aims to evaluate the international validation criteria for reproducibility. The intra- and interreproducibility of the RIATOL-qPCR assay were assessed using 550 remnant cervical cell material from the cytology archive of the National Reference Center for HPV in Belgium. Specimens were collected in the context of cervical cancer screening and tested in two different laboratories. The international reproducibility criteria include the lower bound of 95% confidence interval of the intra- and interlaboratory agreement regarding the detection of hrHPV DNA exceeding 87% with kappa ≥0.50. The RIATOL-qPCR assay demonstrated excellent intralaboratory reproducibility, achieving an overall agreement of 98.2 (95% CI 96.6-99.1%) and a kappa of 0.96. Interlaboratory testing showed an overall agreement of 98.5 (95% CI 97.1-99.4%) with a kappa of 0.97. The RIATOL-qPCR assay fulfills the third criterion for HPV test reproducibility requirement for use in cervical cancer screening., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article.

Background: Breast cancer (BC) is the most common cancer in Malaysia, with many diagnosed at late stages. The "Know Your Lemons" (KYL) visual educational tools were developed by KYL Foundation. This study aimed to evaluate participants' confidence levels and perceived knowledge in identifying BC symptoms before and after exposure to KYL tools., Materials and Methods: A cross-sectional study was carried out among 788 participants in three KYL health campaigns from 2017 to 2020. Perceived knowledge (a 5-item Likert scale was used, zero means "very poor" and 4 means "excellent knowledge") and confidence in identifying BC symptoms were studied. A Wilcoxon Matched-Paired Signed-Rank Test was performed to assess the perceived knowledge., Results: There was a significant improvement in the perceived knowledge Mean (±SD) score (2.84 ± 1.02) versus (4.31 ± 0.66) before and after the campaign ( P < 0.01). About 95.6% agreed that the language used in KYL materials was clear and understandable, 89.8% agreed it is acceptable in Malaysian culture, and 80% felt more confident in identifying BC symptoms. Therefore, 90.8% had the intention of breast self-examination and 90.8% would consult a doctor if symptomatic. The majority (92.7%) agreed that the KYL tools clarified the BC tests needed., Conclusion: The KYL tools enhanced perceived BC symptom recognition knowledge and confidence levels., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Education and Health Promotion.)

Hypoxia-ischaemia (HI) before birth is a key risk factor for stillbirth and severe neurodevelopmental disability in survivors, including cerebral palsy, although there are no reliable biomarkers to detect at risk fetuses that may have suffered a transient period of severe HI. We investigated time and frequency domain measures of fetal heart rate variability (FHRV) for 3 weeks after HI in preterm fetal sheep at 0.7 gestation (equivalent to preterm humans) until 0.8 gestation (equivalent to term humans). We have previously shown that this is associated with delayed development of severe white and grey matter injury, including cystic white matter injury (WMI) resembling that observed in human preterm infants. HI was associated with suppression of time and frequency domain measures of FHRV and reduced their circadian rhythmicity during the first 3 days of recovery. By contrast, circadian rhythms of multiple measures of FHRV were exaggerated over the final 2 weeks of recovery, mediated by a greater reduction in FHRV during the morning nadir, but no change in the evening peak. These data suggest that the time of day at which FHRV measurements are taken affects their diagnostic utility. We further propose that circadian changes in FHRV may be a low-cost, easily applied biomarker of antenatal HI and evolving brain injury. KEY POINTS: Hypoxia-ischaemia (HI) before birth is a key risk factor for stillbirth and probably for disability in survivors, although there are no reliable biomarkers for antenatal brain injury. In preterm fetal sheep, acute HI that is known to lead to delayed development of severe white and grey matter injury over 3 weeks, was associated with early suppression of multiple time and frequency domain measures of fetal heart rate variability (FHRV) and loss of their circadian rhythms during the first 3 days after HI. Over the final 2 weeks of recovery after HI, exaggerated circadian rhythms of frequency domain FHRV measures were observed. The morning nadirs were lower with no change in the evening peak of FHRV. Circadian changes in FHRV may be a low-cost, easily applied biomarker of antenatal HI and evolving brain injury., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Neonatal seizures after an hypoxic-ischemic (HI) event in preterm newborns can contribute to neural injury and cause impaired brain development. Preterm neonatal seizures are often not detected or their occurrence underestimated. Therefore, there is a need to improve knowledge about preterm seizures that can help establish diagnostic tools for accurate identification of seizures and for determining morphological differences. We have previously shown the superior utility of deep-learning algorithms for the accurate identification and quantification of post-HI microscale epileptiform transients (e.g., gamma spikes and sharp waves) in preterm fetal sheep models; before the irreversible secondary phase of cerebral energy failure starts by the bursts of high-amplitude stereotypic evolving seizures (HAS) in the signal. We have previously developed successful deep-learning algorithms that accurately identify and quantify the micro-scale transients, during the latent phase. Building up on our deep-learning strategies, this work introduces a real-time deep-learning-based pattern fusion approach to identify HAS in the 256Hz sampled post-HI data from our preterm fetuses. Here, for the first time, we propose a 17-layer deep convolutional neural network (CNN) classifier fed with 2D wavelet-scalogram (WS) images of the EEG patterns for accurate seizure identification. The WS-CNN classifier was cross-validated over 1812 manually annotated EEG segments during ~6 to 48 hours post-HI recordings. The classifier accurately recognized HAS patterns with 97.19% overall accuracy (AUC = 0.96).Clinical relevance-The promising results from this preliminary work indicate the ability of the proposed WS-CNN pattern classifier to identify HI-related seizures in the neonatal preterm brain using 256Hz EEG; the frequency commonly used clinically for data collection.

Radiology reporting is narrative, and its content depends on the clinician's ability to interpret the images accurately. A tertiary hospital, such as anonymous institute, focuses on writing reports narratively as part of training for medical personnel. Nevertheless, free-text reports make it inconvenient to extract information for clinical audits and data mining. Therefore, we aim to convert unstructured breast radiology reports into structured formats using natural language processing (NLP) algorithm. This study used 327 de-identified breast radiology reports from the anonymous institute. The radiologist identified the significant data elements to be extracted. Our NLP algorithm achieved 97% and 94.9% accuracy in training and testing data, respectively. Henceforth, the structured information was used to build the predictive model for predicting the value of the BIRADS category. The model based on random forest generated the highest accuracy of 92%. Our study not only fulfilled the demands of clinicians by enhancing communication between medical personnel, but it also demonstrated the usefulness of mineable structured data in yielding significant insights.

Objective: Deceleration area (DA) and capacity (DC) of the fetal heart rate can help predict risk of intrapartum fetal compromise. However, their predictive value in higher risk pregnancies is unclear. We investigated whether they can predict the onset of hypotension during brief hypoxaemia repeated at a rate consistent with early labour in fetal sheep with pre-existing hypoxaemia., Design: Prospective, controlled study., Setting: Laboratory., Sample: Chronically instrumented, unanaesthetised near-term fetal sheep., Methods: One-minute complete umbilical cord occlusions (UCOs) were performed every 5 minutes in fetal sheep with baseline p a O 2 <17 mmHg (hypoxaemic, n = 8) and >17 mmHg (normoxic, n = 11) for 4 hours or until arterial pressure fell <20 mmHg., Main Outcome Measures: DA, DC and arterial pressure., Results: Normoxic fetuses showed effective cardiovascular adaptation without hypotension and mild acidaemia (lowest arterial pressure 40.7 ± 2.8 mmHg, pH 7.35 ± 0.03). Hypoxaemic fetuses developed hypotension (lowest arterial pressure 20.8 ± 1.9 mmHg, P < 0.001) and acidaemia (final pH 7.07 ± 0.05). In hypoxaemic fetuses, decelerations showed faster falls in FHR over the first 40 seconds of UCOs but the final deceleration depth was not different to normoxic fetuses. DC was modestly higher in hypoxaemic fetuses during the penultimate (P = 0.04) and final (P = 0.012) 20 minutes of UCOs. DA was not different between groups., Conclusion: Chronically hypoxaemic fetuses had early onset of cardiovascular compromise during labour-like brief repeated UCOs. DA was unable to identify developing hypotension in this setting, while DC only showed modest differences between groups. These findings highlight that DA and DC thresholds need to be adjusted for antenatal risk factors, potentially limiting their clinical utility., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Exposure to hypoxic-ischaemia (HI) is consistently followed by a delayed fall in cerebral perfusion. In preterm fetal sheep this is associated with impaired cerebral oxygenation, consistent with mismatch between perfusion and metabolism. In the present study we tested the hypothesis that alpha-adrenergic inhibition after HI would improve cerebral perfusion, and so attenuate mismatch and reduce neural injury. Chronically instrumented preterm (0.7 gestation) fetal sheep received sham-HI (n = 10) or HI induced by complete umbilical cord occlusion for 25 minutes. From 15 minutes to 8 hours after HI, fetuses received either an intravenous infusion of a non-selective alpha-adrenergic antagonist, phentolamine (10 mg bolus, 10 mg/h infusion, n = 10), or saline (n = 10). Fetal brains were processed for histology 72 hours post-HI. Phentolamine infusion was associated with increased epileptiform transient activity and a greater fall in cerebral oxygenation in the early post-HI recovery phase. Histologically, phentolamine was associated with greater loss of oligodendrocytes and hippocampal neurons. In summary, contrary to our hypothesis, alpha-adrenergic inhibition increased epileptiform transient activity with an exaggerated fall in cerebral oxygenation, and increased neural injury, suggesting that alpha-adrenergic receptor activation after HI is an important endogenous neuroprotective mechanism.

Maternal magnesium sulphate (MgSO 4 ) treatment is widely recommended before preterm birth for neuroprotection. However, this is controversial because there is limited evidence that MgSO 4 provides long-term neuroprotection. Preterm fetal sheep (104 days gestation; term is 147 days) were assigned randomly to receive sham occlusion with saline infusion (n = 6) or i.v. infusion with MgSO 4 (n = 7) or vehicle (saline, n = 6) from 24 h before hypoxia-ischaemia induced by umbilical cord occlusion until 24 h after occlusion. Sheep were killed after 21 days of recovery, for fetal brain histology. Functionally, MgSO 4 did not improve long-term EEG recovery. Histologically, in the premotor cortex and striatum, MgSO 4 infusion attenuated post-occlusion astrocytosis (GFAP + ) and microgliosis but did not affect numbers of amoeboid microglia or improve neuronal survival. In the periventricular and intragyral white matter, MgSO 4 was associated with fewer total (Olig-2 + ) oligodendrocytes compared with vehicle + occlusion. Numbers of mature (CC1 + ) oligodendrocytes were reduced to a similar extent in both occlusion groups compared with sham occlusion. In contrast, MgSO 4 was associated with an intermediate improvement in myelin density in the intragyral and periventricular white matter tracts. In conclusion, a clinically comparable dose of MgSO 4 was associated with moderate improvements in white and grey matter gliosis and myelin density but did not improve EEG maturation or neuronal or oligodendrocyte survival. KEY POINTS: Magnesium sulphate is widely recommended before preterm birth for neuroprotection; however, there is limited evidence that magnesium sulphate provides long-term neuroprotection. In preterm fetal sheep exposed to hypoxia-ischaemia (HI), MgSO 4 was associated with attenuated astrocytosis and microgliosis in the premotor cortex and striatum but did not improve neuronal survival after recovery to term-equivalent age, 21 days after HI. Magnesium sulphate was associated with loss of total oligodendrocytes in the periventricular and intragyral white matter tracts, whereas mature, myelinating oligodendrocytes were reduced to a similar extent in both occlusion groups. In the same regions, MgSO 4 was associated with an intermediate improvement in myelin density. Functionally, MgSO 4 did not improve long-term recovery of EEG power, frequency or sleep stage cycling. A clinically comparable dose of MgSO 4 was associated with moderate improvements in white and grey matter gliosis and myelin density but did not improve EEG maturation or neuronal or oligodendrocyte survival., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Reduced grey matter volume in preterm infants is associated with later disability, but its time course and relationship with white matter injury are not well understood. We recently showed that moderate-severe hypoxia-ischaemia (HI) in preterm fetal sheep led to severe cystic injury 2-3 weeks later. In the same cohort we now show profound hippocampal neuronal loss from 3 days after HI. By contrast, reduction in cortical area and perimeter developed much more slowly, with maximum reduction at day 21. There was transient upregulation of cleaved caspase-3-positive apoptosis in the cortex at day 3 but no change in neuronal density or macroscopic injury of the cortex. Both microglia and astrocytes were transiently upregulated in the grey matter. EEG power was initially profoundly suppressed but partially recovered by 21 days of recovery, and final power was correlated with white matter area (p < 0.001, r 2  = 0.75, F = 24.19), cortical area (p = 0.004, r 2  = 0.44, F = 11.90) and hippocampi area (p = 0.049, r 2  = 0.23, F = 4.58). In conclusion, the present study suggests that in preterm fetal sheep, hippocampal injury is established within a few days of acute HI, but impaired cortical growth develops slowly, in a similar time course to severe white matter injury., Competing Interests: Declaration of Competing Interest The authors report no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Brief repeated fetal hypoxaemia during labour can trigger intrapartum decelerations of the fetal heart rate (FHR) via the peripheral chemoreflex or the direct effects of myocardial hypoxia, but the relative contribution of these two mechanisms and how this balance changes with evolving fetal compromise remain unknown. In the present study, chronically instrumented near-term fetal sheep received surgical vagotomy (n = 8) or sham vagotomy (control, n = 11) to disable the peripheral chemoreflex and unmask myocardial hypoxia. One-minute complete umbilical cord occlusions (UCOs) were performed every 2.5 min for 4 h or until arterial pressure fell below 20 mmHg. Hypotension and severe acidaemia developed progressively after 65.7 ± 7.2 UCOs in control fetuses and 49.5 ± 7.8 UCOs after vagotomy. Vagotomy was associated with faster development of metabolic acidaemia and faster impairment of arterial pressure during UCOs without impairing centralization of blood flow or neurophysiological adaptation to UCOs. During the first half of the UCO series, before severe hypotension developed, vagotomy was associated with a marked increase in FHR during UCOs. After the onset of evolving severe hypotension, FHR fell faster in control fetuses during the first 20 s of UCOs, but FHR during the final 40 s of UCOs became progressively more similar between groups, with no difference in the nadir of decelerations. In conclusion, FHR decelerations were initiated and sustained by the peripheral chemoreflex at a time when fetuses were able to maintain arterial pressure. After the onset of evolving hypotension and acidaemia, the peripheral chemoreflex continued to initiate decelerations, but myocardial hypoxia became progressively more important in sustaining and deepening decelerations. KEY POINTS: Brief repeated hypoxaemia during labour can trigger fetal heart rate decelerations by either the peripheral chemoreflex or myocardial hypoxia, but how this balance changes with fetal compromise is unknown. Reflex control of fetal heart rate was disabled by vagotomy to unmask the effects of myocardial hypoxia in chronically instrumented fetal sheep. Fetuses were then subjected to repeated brief hypoxaemia consistent with the rates of uterine contractions during labour. We show that the peripheral chemoreflex controls brief decelerations in their entirety at a time when fetuses were able to maintain normal or increased arterial pressure. The peripheral chemoreflex still initiated decelerations even after the onset of evolving hypotension and acidaemia, but myocardial hypoxia made an increasing contribution to sustain and deepen decelerations., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Cystic white matter injury is highly associated with severe neurodevelopmental disability and cerebral palsy in preterm infants, yet its pathogenesis remains poorly understood and there is no established treatment. In the present study, we tested the hypothesis that slowly evolving cystic white matter injury after hypoxia-ischaemia is mediated by programmed necrosis initiated by tumour necrosis factor. Tumour necrosis factor blockade was begun 3 days after hypoxia-ischaemia to target the tertiary phase of injury, when most secondary cell death is thought to be complete. Chronically instrumented preterm foetal sheep (0.7 gestation) received 25 min of hypoxia-ischaemia induced by complete umbilical cord occlusion or sham-umbilical cord occlusion (controls, n = 10), followed by intracerebroventricular infusion of the soluble TNF inhibitor, Etanercept, at 3, 8 and 13 days after umbilical cord occlusion (n = 9) or vehicle (n = 9). Foetal brains were processed for histology at 21 days after umbilical cord occlusion. Umbilical cord occlusion with vehicle was associated with a spectrum of macroscopic white matter degeneration, including white matter atrophy, ventriculomegaly and overt temporal lobe cystic white matter injury. Oligodendrocyte maturational arrest and impaired labelling of myelin proteins, characteristic of diffuse white matter injury, was observed in the parietal lobe and surrounding the cystic lesions in the temporal lobe. Etanercept markedly attenuated cystic white matter injury on the side of the intracerebroventricular infusion, with partial contralateral protection. Further, Etanercept improved oligodendrocyte maturation and labelling of myelin proteins in the temporal and parietal lobes. The present study shows that cystic white matter injury reflects late-onset tertiary cell death mediated by delayed neuroinflammation through the tumour necrosis factor pathway. Delayed tumour necrosis factor blockade markedly attenuated cystic white matter injury and restored oligodendrocyte maturation and deficits in myelin protein expression. These data suggest that delayed tumour necrosis factor blockade may represent a viable therapeutic strategy to reduce the risk of cystic and diffuse white matter injury and potentially cerebral palsy after preterm birth, with a surprisingly wide therapeutic window., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: The COVID-19 pandemic highlighted the importance of diagnostic testing against curbing the spread of SARS-CoV-2. The urgent need and scale for diagnostic tools resulted in manufacturers of SARS-CoV-2 assays receiving emergency authorization that lacked robust analytical or clinical evaluation. As it is highly likely that testing for SARS-CoV-2 will continue to play a central role in public health, the performance characteristics of assays should be evaluated to ensure reliable diagnostic outcomes are achieved., Methods: VALCOR or "VALidation of SARS-CORona Virus-2 assays" is a study protocol designed to set up a framework for test validation of SARS-CoV-2 virus assays. Using clinical samples collated from VALCOR, the performance of Aptima SARS-CoV-2 assay was assessed against a standard comparator assay. Diagnostic test parameters such as sensitivity, specificity and overall per cent agreement were calculated for the clinical performance of Aptima SARS-CoV-2 assay., Results: A total of 180 clinical samples were tested with an addition of 40 diluted clinical specimens to determine the limit of detection. When compared to the standard comparator assay Aptima had a sensitivity of 100.0% [95% CI 95.9-100.0] and specificity of 96.7% [95% CI 90.8-99.3]. The overall percent agreement was 98.3% with an excellent Cohen's coefficient of κ = 0.967 [95% CI 0.929-1.000]. For the limit of detection, Aptima was able to detect all of the diluted clinical samples., Conclusion: In conclusion. validation of Aptima SARS-CoV-2 assay using clinical samples collated through the VALCOR protocol showed excellent test performance. Additionally, Aptima demonstrated high analytical sensitivity by detecting all diluted clinical samples corresponding to a low limit of detection., (© 2023. The Author(s).)

Context: The protean mucocutaneous manifestations of HIV and the resultant opportunistic infections are well documented. Genital dermatoses can be either venereal or nonvenereal in origin. As the presence of HIV infection greatly increases the chances of acquiring another sexually transmitted pathogen, these are often presumed to be venereal in origin., Aims: The aims of the study were to record the different morphologies of genital skin lesions in seropositive patients and to classify them as venereal or nonvenereal in origin., Settings and Design: This was an observational study undertaken in seropositive patients with genital skin lesions attending the outpatient department of dermatology at a tertiary health-care center., Subjects and Methods: One hundred and seventy-seven seropositive patients with genital lesions were enrolled. A detailed history was taken; the genital and dermatological examination was performed., Statistical Analysis Used: None., Results: Males predominated the study population with the majority (79.1%) falling into the reproductive age group of 15-49 years. Nonvenereal genital dermatoses (59%) outnumbered sexually transmitted infections (STIs) (41%) out of which the most frequently encountered were dermatophytosis, scabies, and intertrigo. Other entities recorded were inflammatory dermatoses, cutaneous adverse drug reactions, and tumors. The most common STIs were herpes genitalis (55.4%) and anogenital warts (32.5%)., Conclusion: This study showed that nonvenereal genital dermatoses are more common than STIs in people living with HIV. Our findings reiterate the fact that genital lesions should be approached with caution as a presumptive and hasty diagnosis of STI adds greatly to the morbidity of the patient in terms of guilt and shame, and adversely affects the quality of life., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Indian Journal of Sexually Transmitted Diseases and AIDS.)

Human papillomavirus (HPV) assays used in cervical cancer screening should be clinically validated according to international criteria. OncoPredict HPV® Screening (SCR) is a partial genotyping multiplex real-time PCR assay targeting E6/E7 genes of 13 high-risk (hr) HPVs. OncoPredict HPV® SCR (index assay) identifies HPV-16 and HPV-18 separately, 11 other hrHPV in aggregate and includes quality controls for sample adequacy, DNA extraction efficiency and PCR inhibition. 1300 VALGENT-2 study samples (from women aged 20-60 attending the Scottish cervical cancer screening program) were tested with the index assay and the GP5+/6+ PCR enzyme immunoassay (standard comparator assay). Non-inferior accuracy detecting cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) of the index versus comparator was verified. Intra- and interlaboratory reproducibility of the index was evaluated by overall concordance and Cohen's kappa, using a sub-population (n = 526). Relative sensitivity and specificity for CIN2+ of the index versus comparator were 1.01 (95% confidence interval [CI]: 0.99-1.03) and 1.02 (95% CI: 1.0-1.04), respectively. Noninferiority p values were all ≤0.05, except for CIN3+ in patients ≥30 years. Excellent intra- and interlaboratory reproducibility was shown with concordance >98% and kappas >0.95. OncoPredict HPV® SCR fulfills the three international validation criteria for hrHPV DNA tests in cervical cancer screening., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Microbial fuel cells (SC-MFCs) have emerged as green energy devices to resolve the growing energy and environmental crisis. However, the technology's application depends on the sluggish oxygen reduction reaction (ORR) kinetics. Among the electrocatalysts explored, transition metal-nitrogen-carbon composites exhibit satisfactory ORR activity. Herein, we investigate the performance of copper-nitrogen-carbon (Cu/NC) electrocatalysts for ORR, highlighting the effect of temperature, role of nitrogen functionalities, and Cu-N x sites in catalyst performance. Cu/NC-700 demonstrated satisfactory ORR activity with an onset potential of 0.7 V (vs. RHE) and a limiting current density of 3.4 mA cm -2 . Cu/NC-700 modified MFC exhibited a maximum power density of 489.2 mW m -2 , higher than NC-700 (107.3 mW m -2 ). These observations could result from synergistic interaction between copper and nitrogen atoms, high density of Cu-N x sites, and high pyridinic-N content. Moreover, the catalyst exhibited superior stability, implying its use in long-term operations. The electrocatalytic performance of the catalyst suggests that copper-doped carbon catalysts could be potential metal-nitrogen-carbon material for scaled-up MFC applications., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Microbial fuel cells (MFCs) have drawn attention among renewable energy devices. High capital cost, poor durability, and slow oxygen reduction reaction (ORR) kinetics are the major hindrances in the commercialization of the technology. In this work, an environmentally benign approach is followed to synthesize a composite of magnesium cobaltite (MgCo 2 O 4 ) embedded in nitrogen-doped carbon to optimize the performance of MFCs. Detailed characterization confirms the formation of MgCo 2 O 4 nanostructures in the catalyst treated at 700 °C. Electrochemical studies suggest the superior performance of the MgCo 2 O 4 /NC-700 catalyst with a peak reduction current of -0.068 mA and a charge transfer resistance ( R ct ) of 40.5 Ω. The performance of the air cathodes is evaluated using activated sludge as inoculum in the anode chamber in single-chamber MFCs. The power output of MFC with MgCo 2 O 4 /NC-700 as an air cathode reaching 873.81 mW m -2 is 59.56 and 216.05% higher than those of MFCs with Pt/C (547.65 mW m -2 ) and Co/NC-700 (276.48 mW m -2 ) cathodes, respectively. These findings suggest that substituting magnesium in transition metal-nitrogen-carbon composites could help realize long-term application as air cathodes for power generation and wastewater treatment in MFCs.

The practice of medical decision making is changing rapidly with the development of innovative computing technologies. The growing interest of data analysis with improvements in big data computer processing methods raises the question of whether machine learning can be integrated with conventional statistics in health research. To help address this knowledge gap, this paper presents a review on the conceptual integration between conventional statistics and machine learning, focusing on the health research. The similarities and differences between the two are compared using mathematical concepts and algorithms. The comparison between conventional statistics and machine learning methods indicates that conventional statistics are the fundamental basis of machine learning, where the black box algorithms are derived from basic mathematics, but are advanced in terms of automated analysis, handling big data and providing interactive visualizations. While the nature of both these methods are different, they are conceptually similar. Based on our review, we conclude that conventional statistics and machine learning are best to be integrated to develop automated data analysis tools. We also strongly believe that machine learning could be explored by health researchers to enhance conventional statistics in decision making for added reliable validation measures.

Competing Interests: None disclosed.

Hypoxic-ischemic encephalopathy is brain injury resulting from the loss of oxygen and blood supply around the time of birth. It is associated with a high risk of death or disability. The only approved treatment is therapeutic hypothermia. Therapeutic hypothermia has consistently been shown to significantly reduce the risk of death and disability in infants with hypoxic-ischemic encephalopathy. However, approximately 29% of infants treated with therapeutic hypothermia still develop disability. Recent preclinical and clinical studies have shown that there is still persistent neuroinflammation even after treating with therapeutic hypothermia, which may contribute to the deficits seen in infants despite treatment. This suggests that potentially targeting this persistent neuroinflammation would have an additive benefit in addition to therapeutic hypothermia. A potential additive treatment is Exendin-4, which is a glucagon-like peptide 1 receptor agonist. Preclinical data from various in vitro and in vivo disease models have shown that Exendin-4 has anti-inflammatory, mitochondrial protective, anti-apoptotic, anti-oxidative and neurotrophic effects. Although preclinical studies of the effect of Exendin-4 in perinatal hypoxic-ischemic brain injury are limited, a seminal study in neonatal mice showed that Exendin-4 had promising neuroprotective effects. Further studies on Exendin-4 neuroprotection for perinatal hypoxic-ischemic brain injury, including in large animal translational models are warranted to better understand its safety, window of opportunity and effectiveness as an adjunct with therapeutic hypothermia.