Phytogenic-Mediated Zinc Oxide Nanoparticles Using the Seed Extract of Citrullus lanatus and Its Integrated Potency against Multidrug Resistant Bacteria.

In the current research study, zinc oxide nanoparticles (ZnO-NPs) were synthesized via a green synthesis technique using the seed extract of Citrullus lanatus. The study further intended to evaluate the potential synergistic effects of ZnO-NPs with antibiotics against multidrug resistant (MDR) bacteria. It was observed that C. lanatus seed extracts obtained by n-hexane and methanolic solvents revealed the presence of constituents, such as tannins, flavonoids, and terpenoids. Furthermore, the extract of n-hexane displayed the strongest antibacterial activity against Yersinia species (17 ± 1.2 mm) and Escherichia coli (17 ± 2.6 mm), while the methanolic extract showed the maximum antibacterial activity against E. coli (17 ± 0.8 mm). Additionally, the ZnO-NP synthesis was confirmed by ultraviolet-visible analysis with a characteristic absorption peak at 280 nm. The Fourier transform infrared spectroscopy analysis suggested the absorption peaks in the 500-3800 cm-1 range, which corresponds to various groups of tertiary alcohol, aldehyde, amine, ester, aromatic compounds, thiol, amine salt, and primary amine. The scanning electron microscopy spectra of ZnO-NPs demonstrated the presence of zero-dimensional spherical particles with well-dispersed character. Moreover, encapsulation with ZnO-NPs improved the antimicrobial activity of antibiotics against the panel of MDR bacteria, and the increases in the effectiveness of particular antibiotics against MDR bacteria were significant (P = 0.0005). In essence, the synthesized ZnO-NPs have the potential as drug carriers with powerful bactericidal properties that work against MDR bacterial strains. These outcomes are an indication of such significance in pharmaceutical science, giving possibilities for further research and development in this field.

Future in the past: paternal reprogramming of offspring phenotype and the epigenetic mechanisms.

That certain preconceptual paternal exposures reprogram the developmental phenotypic plasticity in future generation(s) has conceptualized the "paternal programming of offspring health" hypothesis. This transgenerational effect is transmitted primarily through sperm epigenetic mechanisms-DNA methylation, non-coding RNAs (ncRNAs) and associated RNA modifications, and histone modifications-and potentially through non-sperm-specific mechanisms-seminal plasma and circulating factors-that create 'imprinted' memory of ancestral information. The epigenetic landscape in sperm is highly responsive to environmental cues, due to, in part, the soma-to-germline communication mediated by epididymosomes. While human epidemiological studies and experimental animal studies have provided solid evidences in support of transgenerational epigenetic inheritance, how ancestral information is memorized as epigenetic codes for germline transmission is poorly understood. Particular elusive is what the downstream effector pathways that decode those epigenetic codes into persistent phenotypes. In this review, we discuss the paternal reprogramming of offspring phenotype and the possible underlying epigenetic mechanisms. Cracking these epigenetic mechanisms will lead to a better appreciation of "Paternal Origins of Health and Disease" and guide innovation of intervention algorithms to achieve 'healthier' outcomes in future generations. All this will revolutionize our understanding of human disease etiology.

Predictors and outcomes of withholding and withdrawal of life-sustaining treatments in intensive care units in Singapore: a multicentre observational study.

BACKGROUND: Clinical practice guidelines on limitation of life-sustaining treatments (LST) in the intensive care unit (ICU), in the form of withholding or withdrawal of LST, state that there is no ethical difference between the two. Such statements are not uniformly accepted worldwide, and there are few studies on LST limitation in Asia. This study aimed to evaluate the predictors and outcomes of withholding and withdrawal of LST in Singapore, focusing on the similarities and differences between the two approaches. METHODS: This was a multicentre observational study of patients admitted to 21 adult ICUs across 9 public hospitals in Singapore over an average of three months per year from 2014 to 2019. The primary outcome measures were withholding and withdrawal of LST (cardiopulmonary resuscitation, invasive mechanical ventilation, and vasopressors/inotropes). The secondary outcome measure was hospital mortality. Multivariable generalised mixed model analysis was used to identify independent predictors for withdrawal and withholding of LST and if LST limitation predicts hospital mortality. RESULTS: There were 8907 patients and 9723 admissions. Of the former, 80.8% had no limitation of LST, 13.0% had LST withheld, and 6.2% had LST withdrawn. Common independent predictors for withholding and withdrawal were increasing age, absence of chronic kidney dialysis, greater dependence in activities of daily living, cardiopulmonary resuscitation before ICU admission, higher Acute Physiology and Chronic Health Evaluation (APACHE) II score, and higher level of care in the first 24 h of ICU admission. Additional predictors for withholding included being of Chinese race, the religions of Hinduism and Islam, malignancy, and chronic liver failure. The additional predictor for withdrawal was lower hospital paying class (with greater government subsidy for hospital bills). Hospital mortality in patients without LST limitation, with LST withholding, and with LST withdrawal was 10.6%, 82.1%, and 91.8%, respectively (p < 0.001). Withholding (odds ratio 13.822, 95% confidence interval 9.987-19.132) and withdrawal (odds ratio 38.319, 95% confidence interval 24.351-60.298) were both found to be independent predictors of hospital mortality on multivariable analysis. CONCLUSIONS: Differences in the independent predictors of withholding and withdrawal of LST exist. Even after accounting for baseline characteristics, both withholding and withdrawal of LST independently predict hospital mortality. Later mortality in patients who had LST withdrawn compared to withholding suggests that the decision to withdraw may be at the point when medical futility is recognised.

A comprehensive review on signaling attributes of serine and serine metabolism in health and disease.

Serine is a metabolite with ever-expanding metabolic and non-metabolic signaling attributes. By providing one­carbon units for macromolecule biosynthesis and functional modifications, serine and serine metabolism largely impinge on cellular survival and function. Cancer cells frequently have a preference for serine metabolic reprogramming to create a conducive metabolic state for survival and aggressiveness, making intervention of cancer-associated rewiring of serine metabolism a promising therapeutic strategy for cancer treatment. Beyond providing methyl donors for methylation in modulation of innate immunity, serine metabolism generates formyl donors for mitochondrial tRNA formylation which is required for mitochondrial function. Interestingly, fully developed neurons lack the machinery for serine biosynthesis and rely heavily on astrocytic l-serine for production of d-serine to shape synaptic plasticity. Here, we recapitulate recent discoveries that address the medical significance of serine and serine metabolism in malignancies, mitochondrial-associated disorders, and neurodegenerative pathologies. Metabolic control and epigenetic- and posttranslational regulation of serine metabolism are also discussed. Given the metabolic similarities between cancer cells, neurons and germ cells, we further propose the relevance of serine metabolism in testicular homeostasis. Our work provides valuable hints for future investigations that will lead to a deeper understanding of serine and serine metabolism in cellular physiology and pathology.

Retinoic acid signaling in development and differentiation commitment and its regulatory topology.

Retinoic acid (RA), the derivative of vitamin A/retinol, is a signaling molecule with important implications in health and disease. It is a well-known developmental morphogen that functions mainly through the transcriptional activity of nuclear RA receptors (RARs) and, uncommonly, through other nuclear receptors, including peroxisome proliferator-activated receptors. Intracellular RA is under spatiotemporally fine-tuned regulation by synthesis and degradation processes catalyzed by retinaldehyde dehydrogenases and P450 family enzymes, respectively. In addition to dictating the transcription architecture, RA also impinges on cell functioning through non-genomic mechanisms independent of RAR transcriptional activity. Although RA-based differentiation therapy has achieved impressive success in the treatment of hematologic malignancies, RA also has pro-tumor activity. Here, we highlight the relevance of RA signaling in cell-fate determination, neurogenesis, visual function, inflammatory responses and gametogenesis commitment. Genetic and post-translational modifications of RAR are also discussed. A better understanding of RA signaling will foster the development of precision medicine to improve the defects caused by deregulated RA signaling.

Unlocking gut microbiota potential of dairy cows in varied environmental conditions using shotgun metagenomic approach.

Food security and environmental pollution are major concerns for the expanding world population, where farm animals are the largest source of dietary proteins and are responsible for producing anthropogenic gases, including methane, especially by cows. We sampled the fecal microbiomes of cows from varying environmental regions of Pakistan to determine the better-performing microbiomes for higher yields and lower methane emissions by applying the shotgun metagenomic approach. We selected managed dairy farms in the Chakwal, Salt Range, and Patoki regions of Pakistan, and also incorporated animals from local farmers. Milk yield and milk fat, and protein contents were measured and correlated with microbiome diversity and function. The average milk protein content from the Salt Range farms was 2.68%, with an average peak milk yield of 45 litters/head/day, compared to 3.68% in Patoki farms with an average peak milk yield of 18 litters/head/day. Salt-range dairy cows prefer S-adenosyl-L-methionine (SAMe) to S-adenosyl-L-homocysteine (SAH) conversion reactions and are responsible for low milk protein content. It is linked to Bacteroides fragilles which account for 10% of the total Bacteroides, compared to 3% in the Patoki region. The solid Non-Fat in the salt range was 8.29%, whereas that in patoki was 6.34%. Moreover, Lactobacillus plantarum high abundance in Salt Range provided propionate as alternate sink to [H], and overcoming a Methanobrevibacter ruminantium high methane emissions in the Salt Range. Furthermore, our results identified ruminant fecal microbiomes that can be used as fecal microbiota transplants (FMT) to high-methane emitters and low-performing herds to increase farm output and reduce the environmental damage caused by anthropogenic gases emitted by dairy cows.

Genetic characteristics of complete mtDNA genome sequence of Indonesian local rabbit (Oryctolagus cuniculus).

BACKGROUND: Indonesian local rabbit (Oryctolagus cuniculus) is a local breed in Indonesia. We reveal the mitochondrial genome sequence of the Indonesian local Rabbit for the first time. A better understanding of the mechanisms underlying these beneficial aspects of local breeds over imported ones requires detailed genetic investigations, of which mtDNA genome sequencing is of particular importance. Such an investigation will solve the major issues of misidentification with Javanese hares (Lepus nigricollis) and maternal lineage. In addition, this information will guide better statistics on the Indonesian local rabbit breed population and strategies for its conservation and breeding plans. This study aimed to identify and explore the characteristics of the mtDNA genomes of Indonesian local rabbits. RESULT: This study observed that the length of the mtDNA genome is 17,469 bp, consisting of two ribosomal RNA (12S rRNA, 16S rRNA), 22 transfer RNA genes (trnR, trnG, trnK, trnD, trnS, trnY, trnC, trnN, trnA, trnW, trnM, trnQ, trnl, trnL, trnV, trnF, trnP, trnT, trnE, trnL, trnS, trnH), 13 protein-coding genes (PCGs) (ND4l, ND3, COX3, ATP6, ATP8, COX2, COX1, ND2, ND1, CYTB, ND6, ND5, ND4), a replication origin, and a noncoding control region (D-loop). CONCLUSIONS: mtDNA genome of Indonesian local rabbit was the longest and had the most extended D-loop sequence among the other references of Oryctolagus cuniculus. Other specific differences were also found in the percentage of nucleotides and variation in most of the PCGs when they were aligned with Oryctolagus cuniculus references from GenBank. Indonesian local Rabbits strongly suspected brought from Europe during the colonial period in Indonesia.

The emerging era of lactate: A rising star in cellular signaling and its regulatory mechanisms.

Cellular metabolites are ancient molecules with pleiotropic implications in health and disease. Beyond their cognate roles, they have signaling functions as the ligands for specific receptors and the precursors for epigenetic or posttranslational modifications. Lactate has long been recognized as a metabolic waste and fatigue product mainly produced from glycolytic metabolism. Recent evidence however suggests lactate is an unique molecule with diverse signaling attributes in orchestration of numerous biological processes, including tumor immunity and neuronal survival. The copious metabolic and non-metabolic functions of lactate mediated by its bidirectional shuttle between cells or intracellular organelles lead to a phenotype called "lactormone." Importantly, the mechanisms of lactate signaling, via acting as a molecular sensor and a regulator of NAD+ metabolism and AMP-activated protein kinase signaling, and via the newly identified lactate-driven lactylation, have been discovered. Further, we include a brief discussion about the autocrine regulation of efferocytosis by lactate in Sertoli cells which favoraerobic glycolysis. By emphasizing a repertoire of the most recent discovered mechanisms of lactate signaling, this review will open tantalizing avenues for future investigations cracking the regulatory topology of lactate signaling covered in the veil of mystery.

Recent advances in chromosome capture techniques unraveling 3D genome architecture in germ cells, health, and disease.

In eukaryotes, the genome does not emerge in a specific shape but rather as a hierarchial bundle within the nucleus. This multifaceted genome organization consists of multiresolution cellular structures, such as chromosome territories, compartments, and topologically associating domains, which are frequently defined by architecture, design proteins including CTCF and cohesin, and chromatin loops. This review briefly discusses the advances in understanding the basic rules of control, chromatin folding, and functional areas in early embryogenesis. With the use of chromosome capture techniques, the latest advancements in technologies for visualizing chromatin interactions come close to revealing 3D genome formation frameworks with incredible detail throughout all genomic levels, including at single-cell resolution. The possibility of detecting variations in chromatin architecture might open up new opportunities for disease diagnosis and prevention, infertility treatments, therapeutic approaches, desired exploration, and many other application scenarios.

Automated rapid response system activation-Impact on nurses' attitudes and perceptions towards recognising and responding to clinical deterioration: Mixed-methods study.

AIM: To explore general ward nurses' attitudes and perceptions towards recognising and responding to clinical deterioration in a hospital with automated rapid response system activation. BACKGROUND: There is growing interest in deploying automated clinical deterioration notification systems to reduce delayed or failed recognition and response to clinical deterioration of ward patients. However, little is known about its impact on ward nurses' perspectives and work patterns. DESIGN: A mixed-methods study. METHODS: Online survey of 168 registered nurses and individual interviews with 10 registered nurses in one acute hospital in Singapore. The study adhered to the STROBE checklist for cross-sectional studies and the COREQ guidelines for qualitative studies. RESULTS: Many nurses (38.1%) rarely performed patient assessments or observations other than vital signs assessment to assess for early signs of clinical deterioration. About 30% were worried about being criticised for calling the primary team doctors. Four themes emerged from the qualitative analysis: automated rapid response system activation as a safety net, being more cautious with vital signs monitoring, the NEWS2 alone is inadequate, and ward nurses as the 'middleman' between the intensive care unit outreach nurse and primary team doctors. CONCLUSIONS: Although nurses value the automated rapid response system activation as a safety net to minimise delays in accessing urgent critical care resources, it does not address the sociocultural barriers inherent in escalation of care. Although the automated system led nurses to be more cautious with vital signs monitoring, it does not encourage them to perform comprehensive patient assessments to detect early signs of deterioration. RELEVANCE TO CLINICAL PRACTICE: Nurse education on assessing for clinical deterioration should focus on the use of broader patient assessment skills other than vital signs. Sociocultural barriers to escalation of care remain a key issue that needs to be addressed by hospital management. NO PATIENT OR PUBLIC CONTRIBUTION: No patients, service users, care-givers or members of the public were involved in the study.

Phantosmia: A neglected symptom after Dacryocystorhinostomy with intubation (A case report).

A 62-year-old female presented with complaints of persistent phantosmia (foul smell) for the last 4 months. She has a past history of right-sided dacryocystorhinostomy (DCR) 18 months back and left-sided DCR 12 months back. In the initial follow-up period, the patient had frequent visits to her otolaryngologist and ophthalmologist. She experienced phantosmia often but was reassured. The patient presented to us and was examined in an operation theater. It was discovered that the foul-smelling foreign body was present in her right nasal cavity above the middle turbinate. It was removed. A retained gauze piece was revealed to be a cause of phantosmia. The purpose of reporting is to create awareness among ophthalmologists and otolaryngologists. Retained gauze piece following DCR surgery presenting as phantosmia is a new symptom after DCR surgery previously not reported in the literature. Repeated complaints of a postoperative patient, should be dealt with vigilantly and timely.

Inhaled volatile anesthetic gas for severe bronchospasm in the emergency department.

Bronchospasm is caused by reversible constriction of the smooth muscles of the bronchial tree. This causes obstruction of the lower airways, which is commonly seen at the emergency department (ED) in patients with acute exacerbation of asthma or chronic obstructive pulmonary disease. Ventilation may be difficult in mechanically intubated patients with severe bronchospasm due to airflow limitation, air trapping, and high airway resistance. The beneficial effects of volatile inhaled anesthetic gas had been reported due to its bronchodilation properties. In this case series, we would like to share our experience delivering inhaled volatile anesthetic gas via a conserving device for three patients with refractory bronchospasm at the ED. Inhaled anesthetic gas is safe, feasible and should be considered as an alternative rescue therapy for ventilated patients with severe lower airway obstruction.

Cytoskeletal orchestration of glucose uptake in Sertoli cell to support efferocytosis of apoptotic germ cells.

Efferocytosis of non-viable germ cells by Sertoli cells (SCs) constitutes a sentinel for testis homeostasis, yet how SCs signal for the metabolic and cytoskeletal adaption to this energetically costly process remains unexplored. Spectrin is membrane-associated periodic skeleton assembled into an actin-spectrin-based cytoskeletal structure with an interaction with glucose transporter Glut1. The contribution of spectrin to glucose uptake and efferocytosis is unknown. In this study, we identified a cross-regulation between glucose metabolism and efferocytosis in SCs. Pharmacological or genetic inhibition of glucose uptake or glycolysis compromises efferocytosis activity. We further found that ßII-spectrin is a hitherto unappreciated regulator of glucose metabolism and cytoskeletal architecture. ßII-spectrin deficiency impairs glucose uptake and lactate production in SCs. Moreover, a defective assembly of cytoskeleton and a loss of blood-testis barrier integrity are also featured by SCs deficient in ßII-spectrin. The disruption in glucose metabolism and cytoskeletal organization synergistically lead to a defective efferocytosis. In vivo siRNA-mediated targeting of ßII-spectrin in testis causes an obvious morphological aberration in seminiferous epithelium with the presence of exfoliated germ cells and multinucleated giant cells. Importantly, a decrease in expression of αII/ßII-spectrin was observed in testes of Adjudin-induced infertility model. By exploring the functional relevance of ßII-spectrin to the metabolic and cytoskeletal regulation of efferocytosis, our study proposes a potential link between ßII-spectrin deregulation and male infertility.

Comparison of ROX index (SpO2/FIO2 ratio/respiratory rate) with a modified dynamic index incorporating PaO2/FIO2 ratio and heart rate to predict high flow nasal cannula outcomes among patients with acute respiratory failure: a single centre retrospective study.

BACKGROUND: High flow nasal cannula (HFNC) is increasingly being used to support patients with acute respiratory failure (ARF) and to avoid need for intubation. However, almost one third of the patients do not respond and require escalation of respiratory support. Previously, ROX index (SpO2/FIO2 [SF] ratio/respiratory rate) has been validated among pneumonia patients to facilitate early recognition of patients likely to fail HFNC and therefore, benefit from timely interventions. However, it has been postulated that incorporation of PaO2/FIO2 (PF) ratio from arterial blood gas (ABG) analysis may better predict the outcome of HFNC compared to indices that utilizes SF ratio. Similarly, heart rate increase after HFNC therapy initiation has been found to be associated with HFNC failure. Therefore, we aimed to compare ROX index with a new modified index to predict HFNC outcomes among ARF patients. MATERIALS AND METHODS: This single centre 2-year retrospective study included ARF patients of varying etiologies treated with HFNC. The modified index incorporated heart rate and substituted PF ratio for SF ratio in addition to respiratory rate. We named the index POX-HR and calculated Delta POX-HR index as the difference pre- and post-HFNC initiation POX-HR. We also recorded ROX index at the time when post-HFNC initiation ABG was done ('post-HFNC initiation ROX') and calculated Delta ROX. HFNC success was defined as no need of escalation of respiratory support or discharged to ward within 48 h of HFNC initiation, or successful wean off HFNC for at least 12 h. Evaluation was performed using area under the receiver operating characteristic curve (AUROC) and cut-offs assessed for prediction of HFNC outcomes. RESULTS: One hundred eleven patients were initiated on HFNC for ARF, of whom 72 patients (64.9%) had HFNC success. Patients with HFNC failure had significantly lower values for all the indices. At median of 3.33 h (IQR 1.48-7.24 h), Delta POX-HR demonstrated the best prediction accuracy (AUROC 0.813, 95% CI 0.726-0.900). A Delta POX-HR > 0.1 was significantly associated with a lower risk of HFNC failure. CONCLUSIONS: Our proposed modified dynamic index (Delta POX-HR) may facilitate early and accurate prediction of HFNC outcomes compared to ROX index among ARF patients of varied etiologies.

Smtnl2 regulates apoptotic germ cell clearance and lactate metabolism in mouse Sertoli cells.

Smtnl2 is an epithelial Smoothelin that binds to actin filaments and is crucial for epithelial morphogenesis. We examined the role of Smtnl2 in Sertoli cells, which undergo dynamic cytoskeleton reorganization to phagocytose apoptotic germ cells, a process known as efferocytosis. We observed Smtnl2 expression in primary mouse Sertoli cells and the 15P1 Sertoli cell line. Smtnl2 expression increased in 15P1 cells committing efferocytosis. Smtnl2-deficient Sertoli cells exhibited defective ability to engulf apoptotic germ cells and importantly, the phenomenon occurred in the setting of an unaffected maturation of phagosome. We demonstrated that Smtnl2 regulates the engulfment process through the function of branched actin nucleation protein ARP3, an actin assembly dictator. Intriguingly, a shift in glucose metabolism that restricts lactate production in Sertoli cells was induced upon Smtnl2 depletion, leading to the activation of downstream AMPK and AKT signaling. Using an in vivo RNAi approach, we found that silencing of Smtnl2 in testis triggers an obvious disruption in cytoskeleton architecture and blood-testis barrier integrity across seminiferous epithelium, causing the detachment of massive germ cells from their nest, as evidenced by their exfoliation into the lumen. Overall, our study identifies Smtnl2 as a determinant for Sertoli cells' functioning in supporting spermatogenesis.

Sepsis in a Combined Medical and Surgical High Dependency/Intensive Care Unit in Singapore: A Cohort Study and Survival Analysis.

Background: Sepsis is a common indication for intensive care unit (ICU) admission and is associated with significant mortality and morbidity. The aim of our study was to first assess the incidence, severity, short-term and long-term mortality of sepsis in a combined medical and surgical high dependency/ ICU in Singapore, and to identify factors associated with increasing short-term and long-term mortality. Methods: All admissions from July 1 to December 31, 2017 were retrospectively screened and clinical data were collected. Patients were followed up until 3 years post ICU admission. Results: Of a total 1526 admissions, 281 had infection at ICU admission, and 254 (16.6%) fulfilled sepsis-3 criteria for sepsis. A total of 141 (9.2%) had septic shock. The 30-day, 1-year, 2-year and 3-year mortality of sepsis patients were 19.3%, 25.2%, 30.3% and 32.3%, respectively. Lung was the most common site of infection. Compared with 30-day sepsis survivors, non-survivors were older (median age 70 vs 63, P <0.001), had higher percentage of lung infection (65.3% vs 36.1%, P <0.05), higher admission Sequential Organ Failure Assessment (SOFA) score (median 9 vs 5, P <0.001), and longer ICU stay (median days: 4 vs 3, P = 0.037). In stepwise Cox regression analysis, lung infection was an independent risk factor for both increasing 30-day and 3-year mortality. Immunocompromised host, increasing age and SOFA score were associated with higher 30-day mortality. Diabetes, admission quick Sequential Organ Failure Assessment (qSOFA) score >1 and unplanned ICU re-admission were associated with increasing 3-year mortality in 30-day survivors. Conclusion: Our retrospective cohort single center study first reported sepsis admission incidence of 16.6% in a combined medical and surgical high dependency/ICU in Singapore, with significant short-term and long-term mortality. Lung infection was an independent risk factor for both 30-day and 3-year mortality.

Pre- and apnoeic high-flow oxygenation for rapid sequence intubation in the emergency department (the Pre-AeRATE trial): A multicentre randomised controlled trial.

INTRODUCTION: Evidence regarding the efficacy of high-flow nasal cannula (HFNC) oxygenation for preoxygenation and apnoeic oxygenation is conflicting. Our objective is to evaluate whether HFNC oxygenation for preoxygenation and apnoeic oxygenation maintains higher oxygen saturation (SpO2) during rapid sequence intubation (RSI) in ED patients compared to usual care. METHODS: This was a multicentre, open-label, randomised controlled trial in adult ED patients requiring RSI. Patients were randomly assigned 1:1 to either intervention (HFNC oxygenation at 60L/min) group or control (non-rebreather mask for preoxygenation and nasal prongs of at least 15L/min oxygen flow for apnoeic oxygenation) group. Primary outcome was lowest SpO2 during the first intubation attempt. Secondary outcomes included incidence of SpO2 falling below 90% and safe apnoea time. RESULTS: One hundred and ninety patients were included, with 97 in the intervention and 93 in the control group. Median lowest SpO2 during the first intubation attempt was 100% in both groups. Incidence of SpO2 falling below 90% was lower in the intervention group (15.5%) compared to the control group (22.6%) (adjusted relative risk=0.68, 95% confidence interval [CI] 0.37-1.25). Post hoc quantile regression analysis showed that the first quartile of lowest SpO2 during the first intubation attempt was greater by 5.46% (95% CI 1.48-9.45%, P=0.007) in the intervention group. CONCLUSION: Use of HFNC for preoxygenation and apnoeic oxygenation, when compared to usual care, did not improve lowest SpO2 during the first intubation attempt but may prolong safe apnoea time.

Perfluorooctanoic acid alters the developmental trajectory of female germ cells and embryos in rodents and its potential mechanism.

The epidemiological studies regarding perfluorooctanoic acid (PFOA) suggests that its exposure causes reproductive health issues, the underlying mechanisms of which are still in its infancy. Here, we report that PFOA deteriorates female reproduction at multiple development stages. Oocyte meiosis and preimplantation development are severely impaired by PFOA with oxidative stress being a contributor. Supplementing with antioxidant melatonin partially rescues oocyte meiotic maturation and non-apoptotic demise. The attenuation in ovarian follicle development however can be improved by metformin but not melatonin. Importantly, metformin blunts PFOA-induced fetal growth retardation (FGR) and such protective effect could be recapitulated by transplantation of fecal material and pharmacological activation of AMPK. Mechanistically, PFOA causes gut microbiota dysbiosis, which might thereby rewire host metabolism of L-phenylalanine, histamine and L-palmitoylcarnitine that triggers hyperphenylalaninaemia, inflammation and ferroptosis to initiate FGR. Deregulated serine metabolism by the gut microbe constitutes an alternative mechanism underlying PFOA-induced FGR in that modulation of serine in dam's diet phenocopied the FGR. Our study expands the understanding of risk factors that impair human reproductive health, and proposes restoration of gut microbiota diversity and intervention of metabolism as therapeutics mitigating health risks predisposed by environmental perturbation.

Alternative splicing and MicroRNA: epigenetic mystique in male reproduction.

Infertility is rarely life threatening, however, it poses a serious global health issue posing far-reaching socio-economic impacts affecting 12-15% of couples worldwide where male factor accounts for 70%. Functional spermatogenesis which is the result of several concerted coordinated events to produce sperms is at the core of male fertility, Alternative splicing and microRNA (miRNA) mediated RNA silencing (RNAi) constitute two conserved post-transcriptional gene (re)programming machinery across species. The former by diversifying transcriptome signature and the latter by repressing target mRNA activity orchestrate a spectrum of testicular events, and their dysfunctions has several implications in male infertility. This review recapitulates the knowledge of these mechanistic events in regulation of spermatogenesis and testicular homoeostasis. In addition, miRNA payload in sperm, vulnerable to paternal inputs, including unhealthy diet, infection and trauma, creates epigenetic memory to initiate intergenerational phenotype. Naive zygote injection of sperm miRNAs from stressed father recapitulates phenotypes of offspring of stressed father. The epigenetic inheritance of paternal pathologies through miRNA could be a tantalizing avenue to better appreciate 'Paternal Origins of Health and Disease' and the power of tiny sperm.