Development of locally relevant clinical guidelines for procedure-related neonatal analgesic practice in Kenya: a systematic review and meta-analysis.

Background Increasing numbers of neonates are undergoing painful procedures in low-income and middle-income countries, with adequate analgesia seldom used. In collaboration with a multi-disciplinary team in Kenya, we aimed to establish the first evidence-based guidelines for the management of routine procedure-related neonatal pain that consider low-resource hospital settings. METHODS: We did a systematic review by searching MEDLINE, Embase, CINAHL, and CENTRAL databases for studies published from Jan 1, 1953, to March 31, 2019. We included data from randomised controlled trials using heart rate, oxygen saturation (SpO2), premature infant pain profile (PIPP) score, neonatal infant pain scale (NIPS) score, neonatal facial coding system score, and douleur aiguë du nouveau-né scale score as pain outcome measures. We excluded studies in which neonates were undergoing circumcision or were intubated, studies from which data were unextractable, or when pain was scored by non-trained individuals. We did a narrative synthesis of all studies, and meta-analysis when data were available from multiple studies comparing the same analgesics and controls and using the same outcome measures. 17 Kenyan health-care professionals formed our clinical guideline development panel, and we used the Grading of Recommendations, Assessment, Development and Evaluation framework and the panel's knowledge of the local health-care context to guide the guideline development process. This study is registered with PROSPERO, CRD42019126620. FINDINGS: Of 2782 studies assessed for eligibility, data from 149 (5%) were analysed, with 80 (3%) of these further contributing to our meta-analysis. We found a high level of certainty for the superiority of breastfeeding over placebo or no intervention (standardised mean differences [SMDs] were -1·40 [95% CI -1·96 to -0·84] in PIPP score and -2·20 [-2·91 to -1·48] in NIPS score), and the superiority of oral sugar solutions over placebo or no intervention (SMDs were -0·38 [-0·61 to -0·16] in heart rate and 0·23 [0·04 to 0·42] in SpO2). We found a moderate level of certainty for the superiority for expressed breastmilk over placebo or no intervention (SMDs were -0·46 [95% CI -0·87 to -0·05] in heart rate and 0·48 [0·20 to 0·75] in SpO2). Therefore, the panel recommended that breastfeeding should be given as first-line analgesic treatment, initiated at least 2 min pre-procedure. Given contextual factors, for neonates who are unable to breastfeed, 1-2 mL of expressed breastmilk should be given as first-line analgesic, or 1-2 mL of oral sugar (≥10% concentration) as second-line analgesic. The panel also recommended parental presence during procedures with adjunctive provision of skin-to-skin care, or non-nutritive sucking when possible. INTERPRETATION: We have generated Kenya's first neonatal analgesic guidelines for routine procedures, which have been adopted by the Kenyan Ministry of Health, and have shown a framework for clinical guideline development that is applicable to other low-income and middle-income health-care settings. FUNDING: Wellcome Trust Research Programme, and the Africa-Oxford Initiative.

Laser technology in the ART laboratory: a narrative review.

To improve success rates, assisted reproductive technology (ART) procedures continually undergo optimization and enhancement such that the best quality gametes and embryos can be identified and manipulated, thus improving clinical outcomes. Laser technology is now being applied across ART to reduce procedure times and increase the consistency and reproducibility of traditional ART techniques such as assisted hatching, embryo biopsy, intracytoplasmic sperm injection cryopreservation and sperm immobilization/selection. This review examines the current status of cutting-edge laser-assisted reproductive technologies, investigates experimental techniques that are increasingly being applied clinically. It highlights the benefits of lasers as a powerful technology at the forefront of both diagnostic and therapeutic treatments for general subfertility and male-factor infertility. However, it is important to note that although lasers are becoming increasingly commonplace in ART units, there is comparatively little information in the existing literature pertaining to the potential negative effects that laser application might have on the developing human embryo, thus creating the need for further investigative research.

Development of a laser-activated mesoporous silica nanocarrier delivery system for applications in molecular and genetic research.

Nanoparticles have revolutionized medical research over the last decade. One notable emerging area of nanomedicine is research developments in the reproductive sciences. Since increasing evidence indicates links between abnormal gene expression and previously unexplained states of infertility, there is a strong impetus to develop tools, such as nanoparticle platforms, to elucidate the pathophysiological mechanisms underlying such states. Mesoporous silica nanoparticles (MSNPs) represent a powerful and safe delivery tool for molecular and genetic investigations. Nevertheless, ongoing progress is restricted by low efficiency and unpredictable control of cargo delivery. Here, we describe for the first time, the development of a laser-activated MSNP system with heat-responsive cargo. Data derived from human embryonic kidney cells (HEK293T) indicate that when driven by a heat-shock promoter, MSNP cargo exhibits a significantly increased expression following infrared laser stimulus to stimulate a heat-shock response, without adverse cytotoxic effects. This delivery platform, with increased efficiency and the ability to impart spatial and temporal control, is highly useful for molecular and genetic investigations. We envision that this straightforward stimuli-responsive system could play a significant role in developing efficient nanodevices for research applications, for example in reproductive medicine.

Molecular mechanisms of membrane interaction at implantation.

Successful pregnancy is dependent upon the implantation of a competent embryo into a receptive endometrium. Despite major advancement in our understanding of reproductive medicine over the last few decades, implantation failure still occurs in both normal pregnancies and those created artificially by assisted reproductive technology (ART). Consequently, there is significant interest in elucidating the etiology of implantation failure. The complex multistep process of implantation begins when the developing embryo first makes contact with the plasma membrane of epithelial cells within the uterine environment. However, although this biological interaction marks the beginning of a fundamental developmental process, our knowledge of the intricate physiological and molecular processes involved remains sparse. In this synopsis, we aim to provide an overview of our current understanding of the morphological changes which occur to the plasma membrane of the uterine endothelium, and the molecular mechanisms that control communication between the early embryo and the endometrium during implantation. A multitude of molecular factors have been implicated in this complex process, including endometrial integrins, extracellular matrix molecules, adhesion molecules, growth factors, and ion channels. We also explore the development of in vitro models for embryo implantation to help researchers investigate mechanisms which may underlie implantation failure. Understanding the precise molecular pathways associated with implantation failure could help us to generate new prognostic/diagnostic biomarkers, and may identify novel therapeutic targets.

Deleterious effects of obesity upon the hormonal and molecular mechanisms controlling spermatogenesis and male fertility.

Worldwide obesity rates have nearly doubled since 1980 and currently over 10% of the population is obese. In 2008, over 1.4 billion adults aged 20 years and older had a body mass index or BMI above a healthy weight and of these, over 200 million men and nearly 300 million women were obese. While obesity can have many ramifications upon adult life, one growing area of concern is that of reproductive capacity. Obesity affects male infertility by influencing the hypothalamic-pituitary-gonadal axis, thus causing detrimental effects upon spermatogenesis and subsequent fertility. In particular, evidence indicates that excess adipose tissue can alter the relative ratio of testosterone and oestrogen. Additional effects involve the homeostatic disruption of insulin, sex-hormone-binding-globulin, leptin and inhibin B, leading to diminished testosterone production and impairment to spermatogenesis. Aberrant spermatogenesis arising from obesity is associated with downstream changes in key semen parameters, defective sperm capacitation and binding, and deleterious effects on sperm chromatin structure. More recent investigations into trans-generational epigenetic inheritance further suggest that molecular changes in sperm that arise from obesity-related impaired spermatogenesis, such as modified sperm RNA levels, DNA methylation, protamination and histone acetylation, can impact upon the development of offspring. Here, we summarise our current understanding of how obesity exerts influence over spermatogenesis and subsequent fertility status, and make recommendations for future investigative research.

Characterization of a degradable polar hydrophobic ionic polyurethane with circulating angiogenic cells in vitro.

This study investigated the interaction of human circulating angiogenic cells (CACs) with a degradable polar hydrophobic ionic polyurethane (D-PHI) which has been previously shown to exhibit anti-inflammatory character and favorable interactions with human endothelial cells (ECs). Given the implication of the CACs in microvessel development it was of intrinsic interest to expand our knowledge of D-PHI biocompatibility with this relevant primary cell involved in angiogenesis. The findings will be compared to a well-established benchmark substrate for CACs, fibronectin-coated tissue culture polystyrene (TCPS). Immunoblotting analysis showed that CACs were a heterogeneous population of cells composed mostly of monocytic cells expressing the CD14 marker. Assessment of the cytokine release profile, using ELISA, showed that D-PHI supported a higher concentration of interleukin-10 (IL-10) when compared to the concentration of tumor necrosis factor alpha, which is indicative of an anti-inflammatory phenotype, and was different from the response with TCPS. It was found that the CACs were attached to D-PHI and remained viable and functional (nitric oxide production) during the seven days of culture. However, there did not appear to be any significant proliferation on D-PHI, contrary to the CAC growth on fibronectin-coated TCPS. It was concluded that D-PHI displayed some of the qualities suitable to enable the retention of CACs onto this substrate, as well as maintaining an anti-inflammatory phenotype, characteristics which have been reported to be important for angiogenesis in vivo.