-
The Cochrane Database of Systematic... Nov 2023Postpartum haemorrhage (PPH), defined as blood loss of 500 mL or more after childbirth, is the leading cause of maternal mortality worldwide. It is possible to prevent... (Review)
Review
BACKGROUND
Postpartum haemorrhage (PPH), defined as blood loss of 500 mL or more after childbirth, is the leading cause of maternal mortality worldwide. It is possible to prevent complications of PPH with timely and appropriate detection and management. However, implementing the best methods of PPH prevention, detection and management can be challenging, particularly in low- and middle-income countries.
OBJECTIVES
Our overall objective was to explore the perceptions and experiences of women, community members, lay health workers, and skilled healthcare providers who have experience with PPH or with preventing, detecting, and managing PPH, in community or health facility settings.
SEARCH METHODS
We searched MEDLINE, CINAHL, Scopus, and grey literature on 13 November 2022 with no language restrictions. We then performed reference checking and forward citation searching of the included studies.
SELECTION CRITERIA
We included qualitative studies and mixed-methods studies with an identifiable qualitative component. We included studies that explored perceptions and experiences of PPH prevention, detection, and management among women, community members, traditional birth attendants, healthcare providers, and managers.
DATA COLLECTION AND ANALYSIS
We used three-stage maximum variation sampling to ensure diversity in terms of relevance of the study to the review objectives, richness of data, and coverage of critical contextual elements: setting (region, country income level), perspective (type of participant), and topic (prevention, detection, management). We extracted data using a data extraction form designed for this review. We used thematic synthesis to analyse and synthesise the evidence, and we used the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) approach to assess our confidence in each finding. To identify factors that may influence intervention implementation, we mapped each review finding to the Theoretical Domains Framework (TDF) and the Capability, Motivation, and Opportunity model of Behaviour change (COM-B). We used the Behaviour Change Wheel to explore implications for practice.
MAIN RESULTS
We included 67 studies and sampled 43 studies for our analysis. Most were from low- or middle-income countries (33 studies), and most included the perspectives of women and health workers. We downgraded our confidence in several findings from high confidence to moderate, low, or very-low confidence, mainly due to concerns about how the studies were conducted (methodological limitations) or concerns about missing important perspectives from some types of participants or in some settings (relevance). In many communities, bleeding during and after childbirth is considered "normal" and necessary to expel "impurities" and restore and cleanse the woman's body after pregnancy and birth (moderate confidence). In some communities, people have misconceptions about causes of PPH or believe that PPH is caused by supernatural powers or evil spirits that punish women for ignoring or disobeying social rules or for past mistakes (high confidence). For women who give birth at home or in the community, female family members or traditional birth attendants are the first to recognise excess bleeding after birth (high confidence). Family members typically take the decision of whether and when to seek care if PPH is suspected, and these family members are often influenced by trusted traditional birth attendants or community midwives (high confidence). If PPH is identified for women birthing at home or in the community, decision-making about the subsequent referral and care pathway can be multifaceted and complex (high confidence). First responders to PPH are not always skilled or trained healthcare providers (high confidence). In health facilities, midwives may consider it easy to implement visual estimation of blood loss with a kidney dish or under-pad, but difficult to accurately interpret the amount of blood loss (very low confidence). Quantifying (rather than estimating) blood loss may be a complex and contentious change of practice for health workers (low confidence). Women who gave birth in health facilities and experienced PPH described it as painful, embarrassing, and traumatic. Partners or other family members also found the experience stressful. While some women were dissatisfied with their level of involvement in decision-making for PPH management, others felt health workers were best placed to make decisions (moderate confidence). Inconsistent availability of resources (drugs, medical supplies, blood) causes delays in the timely management of PPH (high confidence). There is limited availability of misoprostol in the community owing to stockouts, poor supply systems, and the difficulty of navigating misoprostol procurement for community health workers (moderate confidence). Health workers described working on the maternity ward as stressful and intense due to short staffing, long shifts, and the unpredictability of emergencies. Exhausted and overwhelmed staff may be unable to appropriately monitor all women, particularly when multiple women are giving birth simultaneously or on the floor of the health facility; this could lead to delays in detecting PPH (moderate confidence). Inadequate staffing, high turnover of skilled health workers, and appointment of lower-level cadres of health workers are key challenges to the provision of quality PPH care (high confidence). Through team-based simulation training, health workers of different cadres (doctors, midwives, lay health workers) can develop a shared mental model to help them work quickly, efficiently, and amicably as a team when managing women with PPH (moderate confidence).
AUTHORS' CONCLUSIONS
Our findings highlight how improving PPH prevention, detection, and management is underpinned by a complex system of interacting roles and behaviours (community, women, health workers of different types and with different experiences). Multiple individual, sociocultural, and environmental factors influence the decisions and behaviours of women, families, communities, health workers, and managers. It is crucial to consider the broader health and social systems when designing and implementing PPH interventions to change or influence these behaviours. We have developed a set of prompts that may help programme managers, policymakers, researchers, and other key stakeholders to identify and address factors that affect implementation and scale-up of interventions to improve PPH prevention, detection, and management.
Topics: Pregnancy; Female; Humans; Postpartum Hemorrhage; Misoprostol; Health Personnel; Midwifery; Family
PubMed: 38009552
DOI: 10.1002/14651858.CD013795.pub2 -
BJOG : An International Journal of... Feb 2013Metformin is widely used for treating women with polycystic ovary syndrome (PCOS), and many patients with PCOS who are infertile receive gonadotrophins while being... (Meta-Analysis)
Meta-Analysis Review
Effects of metformin in women with polycystic ovary syndrome treated with gonadotrophins for in vitro fertilisation and intracytoplasmic sperm injection cycles: a systematic review and meta-analysis of randomised controlled trials.
BACKGROUND
Metformin is widely used for treating women with polycystic ovary syndrome (PCOS), and many patients with PCOS who are infertile receive gonadotrophins while being treated with metformin.
OBJECTIVES
To assess the effects of metformin administration in infertile patients with PCOS who receive gonadotrophins for in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) cycles.
SEARCH STRATEGY
We searched international scientific databases, websites for the registration of trials, and bibliographies of retrieved articles, books, and review articles up to August 2012.
SELECTION CRITERIA
Randomised controlled trials (RCTs).
DATA COLLECTION AND ANALYSIS
Authors independently reviewed and extracted the data.
MAIN RESULTS
Ten RCTs (with a total of 845 women with PCOS) were included in the final analysis. Metformin administration in IVF/ICSI cycles had no effect on the rates of pregnancy (OR 1.20, 95% CI 0.90-1.61) and live birth (OR 1.69, 95% CI 0.85-3.34). No effect of metformin dose, metformin pretreatment duration, and stopping time of metformin administration was observed on these reproductive end points. Metformin administration reduced the risk of ovarian hyperstimulation syndrome (OHSS; OR 0.27, 95% CI 0.16-0.46) and of miscarriage (OR 0.50, 95% CI 0.30-0.83), while increased that of implantation (OR 1.42, 95% CI 1.24-2.75).
AUTHOR'S CONCLUSIONS
In infertile patients with PCOS treated with gonadotrophins for IVF/ICSI cycles, metformin exerts no clinical effect on rates of pregnancy or live birth, but it reduces the risk of OHSS, and improves the rates of miscarriage and implantation. Further RCTs are needed to assess the reproductive effect of metformin in young well-selected patients with PCOS and specific phenotypes and features.
Topics: Abortion, Spontaneous; Dinoprostone; Embryo Implantation; Female; Fertility Agents, Female; Fertilization in Vitro; Gonadotropins; Humans; Infertility, Female; Live Birth; Metformin; Oocyte Retrieval; Ovarian Hyperstimulation Syndrome; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Randomized Controlled Trials as Topic; Sperm Injections, Intracytoplasmic
PubMed: 23194199
DOI: 10.1111/1471-0528.12070 -
Prostaglandins, Leukotrienes, and... Apr 2015This paper presents a systematic review of human studies investigating the effect of altering dietary omega-3 polyunsaturated fatty acid (n-3 PUFA) alpha-linolenic acid... (Review)
Review
The effect of modifying dietary LA and ALA intakes on omega-3 long chain polyunsaturated fatty acid (n-3 LCPUFA) status in human adults: a systematic review and commentary.
This paper presents a systematic review of human studies investigating the effect of altering dietary omega-3 polyunsaturated fatty acid (n-3 PUFA) alpha-linolenic acid (ALA) and omega-6 polyunsaturated fatty acid (n-6 PUFA) linoleic acid (LA) intakes on n-3 long-chain polyunsaturated fatty acid (LCPUFA) status in adult humans. The results suggest that it is possible to increase n-3 LCPUFA status by reducing LA and/or increasing ALA intake in humans, although decreasing LA intake to below 2.5%E may be required to specifically increase levels of the n-3 LCPUFA docosahexaenoic acid (DHA). The majority of studies in this area to date have been relatively poor in quality, which limits the ability to draw robust conclusions, and we present a series of recommendations to improve the quality of future studies in fatty acid nutrition in humans.
Topics: Adult; Clinical Trials as Topic; Dietary Fats, Unsaturated; Fatty Acids, Omega-3; Female; Humans; Linoleic Acid; MEDLINE; Male; alpha-Linolenic Acid
PubMed: 25687496
DOI: 10.1016/j.plefa.2015.01.001 -
Prostaglandins & Other Lipid Mediators Aug 2024Since the effects of flaxseed supplementation on lipid profile and liver enzymes are still controversial, a meta-analysis of randomized controlled trials was conducted... (Meta-Analysis)
Meta-Analysis Review
Impact of flaxseed supplementation on lipid profile and liver enzymes in patients with non-alcoholic fatty liver disease: Systematic review and meta-analysis of randomized controlled trials.
Since the effects of flaxseed supplementation on lipid profile and liver enzymes are still controversial, a meta-analysis of randomized controlled trials was conducted in the present study to assess the effect of flaxseed supplementation on lipid profile and liver enzymes. The study was designed, conducted, and reported according to the guidelines of the 2020 preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement. A systematic and comprehensive search was performed in several databases from inception up to January 10, 2024. The meta-analysis on the impact of flaxseed supplementation on lipid profile and liver enzymes indicates that the overall effect of flaxseed supplementation on triglycerides, combining different doses, revealed a significant reduction with a WMD of - 230.72 (-53.95, - 27.49) and a P-value of 0.010. High-density lipoprotein (HDL) demonstrated a positive effect, with an overall WMD of 1.82 (0.27, 3.38) and a P-value of 0.021, indicating an increase in HDL levels. The liver enzymes AST and ALT displayed reductions in their levels, with overall WMDs of - 21.18 (-2.95, 0.59) and - 24.83 (-8.74, - 20.91), respectively. Subgroup analysis based on dosage revealed more pronounced reductions in ALT levels for doses below 2000 mg/day. Findings from this study suggest that a flaxseed supplement might be beneficial to modulate the blood lipid profile and liver enzymes.
Topics: Humans; Flax; Randomized Controlled Trials as Topic; Non-alcoholic Fatty Liver Disease; Dietary Supplements; Liver; Lipids; Lipid Metabolism
PubMed: 38663513
DOI: 10.1016/j.prostaglandins.2024.106838 -
The Cochrane Database of Systematic... Jun 2013Supplementary oxygen is routinely administered to low-risk pregnant women during an elective caesarean section under regional anaesthesia; however, maternal and foetal... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Supplementary oxygen is routinely administered to low-risk pregnant women during an elective caesarean section under regional anaesthesia; however, maternal and foetal outcomes have not been well established.
OBJECTIVES
The primary objective was to determine whether supplementary oxygen given to low-risk term pregnant women undergoing elective caesarean section under regional anaesthesia can prevent maternal and neonatal desaturation. The secondary objective was to compare the mean values of maternal and neonatal blood gas levels between mothers who received supplementary oxygen and those who did not (control group).
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 2, 2012), MEDLINE (1948 to February 2012) and EMBASE (1980 to February 2012). We did not apply language restrictions.
SELECTION CRITERIA
We included randomized controlled trials of low-risk pregnant women undergoing an elective caesarean section under regional anaesthesia and compared outcomes with, and without, oxygen supplementation.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data, assessed methodological quality and performed subgroup and sensitivity analyses.
MAIN RESULTS
We included 10 trials with a total of 683 participants. Supplementary oxygen administration varied widely in dose and duration between trials. No cases of maternal desaturation were reported, although none of the 10 trials focused on maternal desaturation. Significant differences were noted in maternal oxygen saturation (higher with oxygen, N = three trials; mean difference (MD) 1.6%, 95% confidence interval (CI) 0.8 to 2.3, P < 0.0001), maternal PaO2 (oxygen pressure in the blood; higher with oxygen, N = six trials; MD 141.8 mm Hg, 95% CI 109.3 to 174.3, P < 0.00001), neonatal UaPO2 (foetal umbilical arterial blood; higher with oxygen, N = eight trials; MD 3.3 mm Hg, 95% CI 1.8 to 4.9, P < 0.0001) and UvPO2 (foetal umbilical venous blood; higher with oxygen, N = 10 trials; MD 5.9 mm Hg, 95% CI 3.2 to 8.5, P < 0.0001). No significant differences were reported in neonatal UapH (N = eight trials; MD 0.00, 95% CI -0.01 to 0.00, P = 0.26) and in average Apgar scores at one minute (N = five trials; MD 0.07, 95% CI -0.20 to 0.34, P = 0.6) and at five minutes (N = five trials; MD 0.00, 95% CI -0.06 to 0.05, P = 0.91).Only two out of 10 trials had a low risk of bias in all categories. When we separated the studies into low risk and high risk for bias, we found substantial statistical heterogeneity. None of the low-risk studies showed a significant difference in neonatal UaPO2 between the two intervention groups, whereas the high-risk studies showed a benefit for the neonatal oxygen group.The level of oxygen free radicals (malondialdehyde (MDA) and 8-isoprostane) was higher in participants who received supplementary oxygen (N = two trials; MD 0.2 µmol/L, 95% CI 0.1 to 0.4, P = 0.0002; MD 64.3 pg/mL, 95% CI 51.7 to 76.8, P < 0.00001, respectively).
AUTHORS' CONCLUSIONS
Current evidence suggests that supplementary oxygen given to healthy term pregnant women during elective caesarean section under regional anaesthesia is associated with higher maternal and neonatal oxygen levels (maternal SpO2, PaO2, UaPO2 and UvPO2) and higher levels of oxygen free radicals. However, the intervention was neither beneficial nor harmful to the neonate's short-term clinical outcome as assessed by Apgar scores.
Topics: Anesthesia, Conduction; Anesthesia, Obstetrical; Apgar Score; Cesarean Section; Dinoprost; Elective Surgical Procedures; Female; Humans; Malondialdehyde; Oxygen; Pregnancy; Randomized Controlled Trials as Topic
PubMed: 23813306
DOI: 10.1002/14651858.CD006161.pub2 -
PloS One 2016Marine-derived n-3 polyunsaturated fatty acids (PUFA) may have a beneficial effect on inflammation via lowering pro-inflammatory eicosanoid concentrations. We aimed to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Marine-derived n-3 polyunsaturated fatty acids (PUFA) may have a beneficial effect on inflammation via lowering pro-inflammatory eicosanoid concentrations. We aimed to assess the effect of marine-derived n-3 PUFA on prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and leukotriene B4 (LTB4) through systematic review and meta-analysis of randomized controlled trials.
METHOD AND FINDINGS
A structured search strategy on PubMed, Web of Science and Cochrane up to November 2015 was undertaken in this meta-analysis. Standard mean difference was used to calculate the effect size of marine-derived n-3 PUFA on PGE2, TXB2 and LTB4 in a random-effect model. A total of 18 RCTs with 826 subjects were included in this systematic review and meta-analysis. Supplementation of marine-derived n-3 PUFA significantly decreased concentrations of TXB2 in serum/plasma in subjects with high risk of cardiovascular diseases (SMD:-1.26; 95% CI: -1.65, -0.86) and LTB4 in neutrophils in unhealthy subjects (subjects with non-autoimmune chronic diseases or auto-immune diseases) (SMD:-0.59: 95% CI: -1.02, -0.16). Subgroup analyses showed a significant reduction of LTB4 in subjects with rheumatoid arthritis (SMD: -0.83; 95% CI: -1.37, -0.29), but not in non-autoimmune chronic disease patients (SMD: -0.33; 95% CI: -0.97, 0.31). No significant publication bias was shown in the meta-analysis.
CONCLUSIONS
Marine-derived n-3 PUFA had a beneficial effect on reducing the concentration of TXB2 in blood of subjects with high risk of CVD as well as LTB4 in neutrophils in unhealthy subjects, and that subjects with RA showed lower LTB4 content with supplementation of marine-derived n-3 PUFA.
Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Chronic Disease; Dietary Supplements; Dinoprostone; Dose-Response Relationship, Drug; Eicosanoids; Fatty Acids, Omega-3; Fish Oils; Humans; Leukotriene B4; Randomized Controlled Trials as Topic; Research Design; Thromboxane B2; Treatment Outcome
PubMed: 26808318
DOI: 10.1371/journal.pone.0147351 -
Inflammation Research : Official... Mar 2016A systematic review of all literature was done to assess the ability of the progestin dienogest (DNG) to influence the inflammatory response of endometriotic cells. (Review)
Review
OBJECTIVE AND DESIGN
A systematic review of all literature was done to assess the ability of the progestin dienogest (DNG) to influence the inflammatory response of endometriotic cells.
MAIN OUTCOME MEASURES
In vitro and in vivo studies report an influence of DNG on the inflammatory response in eutopic or ectopic endometrial tissue (animal or human).
RESULTS
After strict inclusion criteria were satisfied, 15 studies were identified that reported a DNG influence on the inflammatory response in endometrial tissue. These studies identified a modulation of prostaglandin (PG) production and metabolism (PGE2, PGE2 synthase, cyclo-oxygenase-2 and microsomal PGE synthase-1), pro-inflammatory cytokine and chemokine production [interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, monocyte chemoattractant protein-1 and stromal cell-derived factor-1], growth factor biosynthesis (vascular endothelial growth factor and nerve growth factor) and signaling kinases, responsible for the control of inflammation. Evidence supports a progesterone receptor-mediated inhibition of the inflammatory response in PR-expressing epithelial cells. It also indicated that DNG inhibited the inflammatory response in stromal cells, however, whether this was via a PR-mediated mechanism is not clear.
CONCLUSIONS
DNG has a significant effect on the inflammatory microenvironment of endometriotic lesions that may contribute to its clinical efficacy. A better understanding of the specific anti-inflammatory activity of DNG and whether this contributes to its clinical efficacy can help develop treatments that focus on the inhibition of inflammation while minimizing hormonal modulation.
Topics: Animals; Cytokines; Endometriosis; Epithelial Cells; Female; Hormone Antagonists; Humans; Immunologic Factors; Intercellular Signaling Peptides and Proteins; Nandrolone; Prostaglandins; Stromal Cells
PubMed: 26650031
DOI: 10.1007/s00011-015-0909-7 -
Artificial Organs Nov 2022Understanding kidney metabolism during perfusion is vital to further develop the technology as a preservation, viability assessment, and resuscitation platform. We... (Review)
Review
BACKGROUND
Understanding kidney metabolism during perfusion is vital to further develop the technology as a preservation, viability assessment, and resuscitation platform. We reviewed the evidence on the use of labeled metabolites (tracers) to understand "on-pump" kidney behavior.
METHODS
PubMed, Embase, Web of Science, and Cochrane databases were systematically searched for studies evaluating metabolism of (non)radioactively labeled endogenous compounds during kidney perfusion.
RESULTS
Of 5899 articles, 30 were included. All were animal studies [rat (70%), dog (13%), pig (10%), rabbit (7%)] perfusing but not transplanting kidneys. Perfusion took place at hypothermic (4-12°C) (20%), normothermic (35-40°C) (77%), or undefined temperatures (3%). Hypothermic perfusion used albumin or a clinical kidney preservation solution, mostly in the presence of oxygen. Normothermic perfusion was mostly performed with oxygenated crystalloids often containing glucose and amino acids with unclear partial oxygen tensions. Active metabolism of carbohydrate, amino acid, lipids, and large molecules was shown in hypothermic and normothermic perfusion. Production of macromolecules, such as prostaglandin, thromboxane, and vitamin D, takes place during normothermic perfusion. No experiments compared differences in metabolic activity between hypothermic and normothermic perfusion. One conference abstract showed increased anaerobic metabolism in kidneys donated after circulatory death by adding labeled glucose to hypothermically perfused human kidneys.
CONCLUSIONS
Tracer studies during kidney perfusion contribute to unraveling kidney metabolic behavior in pre-clinical models. Whether findings are truly translational needs further investigation in large animal models of human kidneys. Furthermore, it is essential to better understand how ischemia changes this metabolic behavior.
Topics: Swine; Humans; Rats; Animals; Rabbits; Dogs; Organ Preservation; Kidney Transplantation; Perfusion; Kidney; Oxygen; Glucose
PubMed: 35848397
DOI: 10.1111/aor.14355 -
Human Reproduction Update 2009Adaptation of the maternal immune response to accommodate the semi-allogeneic fetus is necessary for pregnancy success, and disturbances in maternal tolerance are... (Review)
Review
BACKGROUND
Adaptation of the maternal immune response to accommodate the semi-allogeneic fetus is necessary for pregnancy success, and disturbances in maternal tolerance are implicated in infertility and reproductive pathologies. T regulatory (Treg) cells are a recently discovered subset of T-lymphocytes with potent suppressive activity and pivotal roles in curtailing destructive immune responses and preventing autoimmune disease.
METHODS
A systematic review was undertaken of the published literature on Treg cells in the ovary, testes, uterus and gestational tissues in pregnancy, and their link with infertility, miscarriage and pathologies of pregnancy. An overview of current knowledge on the generation, activation and modes of action of Treg cells in controlling immune responses is provided, and strategies for manipulating regulatory T-cells for potential applications in reproductive medicine are discussed.
RESULTS
Studies in mouse models show that Treg cells are essential for maternal tolerance of the conceptus, and that expansion of the Treg cell pool through antigen-specific and antigen non-specific pathways allows their suppressive actions to be exerted in the critical peri-implantation phase of pregnancy. In women, Treg cells accumulate in the decidua and are elevated in maternal blood from early in the first trimester. Inadequate numbers of Treg cells or their functional deficiency are linked with infertility, miscarriage and pre-eclampsia.
CONCLUSIONS
The potency and wide-ranging involvement of Treg cells in immune homeostasis and disease pathology indicates the considerable potential of these cells as therapeutic agents, raising the prospect of their utility in novel treatments for reproductive pathologies.
Topics: Abortion, Spontaneous; Animals; Cytokines; Dendritic Cells; Female; Humans; Immune Tolerance; Indoleamine-Pyrrole 2,3,-Dioxygenase; Infertility; Male; Mice; Models, Immunological; Ovary; Pregnancy; Pregnancy Complications; Prostaglandins; Semen; Signal Transduction; T-Lymphocytes, Regulatory; Testis; Toll-Like Receptors
PubMed: 19279047
DOI: 10.1093/humupd/dmp004 -
Clinical Obstetrics and Gynecology Sep 2006Using oral agents for induction of labor would reduce the need for repeated vaginal examinations; this is more acceptable to women and could reduce infection rates. A... (Review)
Review
Using oral agents for induction of labor would reduce the need for repeated vaginal examinations; this is more acceptable to women and could reduce infection rates. A systematic review was conducted of 41 randomized trials comparing oral misoprostol to other induction agents. Oral misoprostol is effective at achieving vaginal delivery, and may have benefits over both vaginal and intracervical dinoprostone. Although it does not achieve vaginal delivery as quickly as vaginal misoprostol, the rates of hyperstimulation are lower when using comparable doses. As the primary consideration should be safety rather than speed, an oral regimen using a maximum of 50 mcg 4 hourly is recommended.
Topics: Administration, Oral; Female; Humans; Labor, Induced; Misoprostol; Oxytocics; Pregnancy
PubMed: 16885670
DOI: 10.1097/00003081-200609000-00023