Global, regional and national availability of essential medicines for children, 2009-2020: a systematic review and meta-analysis.

BACKGROUND: Access to essential medicines is a vital component of universal health coverage. The low availability of essential medicines for children (EMC) has led the World Health Organization (WHO) to issue a number of resolutions calling on member states on its improvement. But its global progress has been unclear. We aimed to systematically evaluate the progress of availability of EMC over the past decade across economic regions and countries. METHODS: We searched eight databases from inception to December 2021 and reference lists to identify included studies. Two reviewers independently conducted literature screening, data extraction and quality evaluation. This study was registered with PROSPERO, CRD42022314003. RESULTS: Overall, 22 cross-sectional studies covering 17 countries, 4 income groups were included. Globally, the average availability rates of EMC were 39.0% (95%CI: 35.5-42.5%) in 2009-2015 and 43.1% (95%CI: 40.1-46.2%) in 2016-2020. Based on the World Bank classification of economic regions, income was not proportional to availability. Nationally, the availability rate of EMC was reasonable and high (> 50%) in only 4 countries, and low or very low for the rest 13 countries. The availability rates of EMC in primary healthcare centers had increased, while that for other levels of hospitals slightly declined. The availability of original medicines decreased while that of generic medicines was stable. All drug categories had not achieved the high availability rate. CONCLUSION: The availability rate of EMC was low globally, with slight increase in the last decade. Continuous monitoring and timely reporting of the availability of EMC are also needed to facilitate targets setting and inform relevant policy making.

Drug utilisation in neonatal units in England and Wales: a national cohort study.

PURPOSE: To describe drug utilisation patterns in neonatal units. METHODS: Retrospective observational cohort study using data held in the National Neonatal Research Database (NNRD) for neonatal units in England and Wales including infants born at 23 to 44 weeks' gestational age (GA) from 01 January 2010 to 31 December 2017. RESULTS: The cohort included 17,501 (3%) extremely preterm infants; 40,607 (7%) very preterm infants; 193,536 (31%) moderate-to-late preterm infants; and 371,606 (59%) term infants. The number of unique drugs received by an infant (median (IQR)) increased with decreasing GA: 17 (11-24) in extremely preterm, 7 (5-11) in very preterm, 3 (0-4) in moderate-to-late preterm, and 3 (0-3) in term infants. The two most frequently prescribed drugs were benzylpenicillin and gentamicin in all GA groups, and caffeine in extremely preterm. Other frequently used drugs among preterm infants were electrolytes, diuretics and anti-reflux medications. Among infants <32 weeks' GA, the largest increase in use was for surfactant (given on the neonatal unit), caffeine and probiotics, while domperidone and ranitidine had the largest decline. CONCLUSION: Antibiotics, for all GAs and caffeine, among preterm infants, are the most frequently used drugs in neonatal medicine. Preterm infants are exposed to a high burden of drugs, particularly antibiotics. Changing patterns in use reflect the emergence of evidence in some areas but several non-evidence-based drugs continue to be used widely. Improvements are needed to ensure rational drug use on neonatal units. REGISTRATION: ClinicalTrials.gov (NCT03773289). Date of registration 21 Dec 2018.

Safety of azithromycin in pediatrics: a systematic review and meta-analysis.

PURPOSE: To evaluate the toxicity of azithromycin in neonates, infants, and children. METHODS: A systematic review was performed for relevant studies using Medline (Ovid), PubMed, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, and International Pharmaceutical Abstracts. We calculated the pooled incidence of adverse drug reactions (ADRs) associated with azithromycin based on prospective studies (RCTs and prospective cohort studies) and analyzed the risk difference (RD) of ADRs between azithromycin and placebo or other antibiotics using meta-analysis of RCTs. RESULTS: We included 133 studies with 4243 ADRs reported in 197,675 neonates, infants, and children who received azithromycin. The safety of azithromycin as MDA in pediatrics was poorly monitored. The main ADRs were diarrhea and vomiting. In prospective non-MDA studies, the most common toxicity was gastrointestinal ADRs (938/1967; 47.7%). The most serious toxicities were cardiac (prolonged QT or irregular heart beat) and idiopathic hypertrophic pyloric stenosis (IHPS). Compared with placebo, azithromycin did not show increased risk ADRs based on RCTs (risk difference - 0.17 to 0.07). The incidence of QT prolonged was higher in the medium-dosage group (10-30 mg/kg/day) than that of low-dosage group (≤ 10 mg/kg/day) (82.0% vs 1.2%). CONCLUSION: The safety of azithromycin as MDA needs further evaluation. The most common ADRs are diarrhea and vomiting. The risk of the most serious uncommon ADRs (cardiac-prolonged QT and IHPS) is unknown.

Paediatric safety signals identified in VigiBase: Methods and results from Uppsala Monitoring Centre.

PURPOSE: The purpose of this study is to uncover previously unrecognised risks of medicines in paediatric pharmacovigilance reports and thereby advance a safer use of medicines in paediatrics. METHODS: Individual case safety reports (ICSRs) with ages less than 18 years were retrieved from VigiBase, the World Health Organization (WHO) global database of ICSRs, in September 2014. The reports were grouped according to the following age spans: 0 to 27 days; 28 days to 23 months; 2 to 11 years; and 12 to 17 years. vigiRank, a data-driven predictive model for emerging safety signals, was used to prioritise the list of drug events by age groups. The list was manually assessed, and potential signals were identified to undergo in-depth assessment to determine whether a signal should be communicated. RESULTS: A total of 472 drug-event pairs by paediatric age groups were the subject of an initial manual assessment. Twenty-seven drug events from the two older age groups were classified as potential signals. An in-depth assessment resulted in eight signals, of which one concerned harm in connection with off-label use of dextromethorphan and another with accidental overdose of olanzapine by young children, and the remaining signals referred to potentially new causal associations for atomoxetine (two signals), temozolamide, deferasirox, levetiracetam, and desloratadine that could be relevant also for adults. CONCLUSIONS: Clinically relevant signals were uncovered in VigiBase by using vigiRank applied to paediatric age groups. Further refinement of the methodology is needed to identify signals in reports with ages under 2 years and to capture signals specific to the paediatric population as a risk group.

Effectiveness of prothrombin complex concentrate (PCC) in neonates and infants with bleeding or risk of bleeding: a systematic review and meta-analysis.

To systematically evaluate the effectiveness of prothrombin complex concentrate (PCC) in neonates and infants, we performed a systematic review and meta-analysis based on current evidence. Quality of studies was assessed by Cochrane Collaboration's risk of bias tool and Newcastle-Ottawa quality assessment scale. For dichotomous data, we obtained the number of events and total number and calculated the relative risk (RR) with 95% confidence intervals (CI). For continuous variables, we obtained mean and standard deviation (SD) values and calculated mean difference (MD) with 95% CI. We identified six trials and two cohort studies. For trials, selection bias and performance bias were high, while detection bias, attrition bias, and reporting bias were relatively low. For cohort studies, selection bias was low. Both individual studies and meta-analysis failed to find any benefit of PCC on mortality. Meta-analysis also failed to show any benefit in reducing intracranial hemorrhage. The effectiveness of PCC on the correction of hemostatic defects was inconsistent among studies. In addition, PCC was not more effective than fresh frozen plasma (FFP) in correcting hemostatic defects. CONCLUSION: There is insufficient evidence to allow a recommendation for use of PCC in neonates and infants. What is Known: • Prothrombin Complex Concentrate is becoming increasingly used off-label for treatment of neonates and infants with severe bleeding or risk of severe bleeding. • Some case reports showed PCC seemed to be effective for infants and children with coagulation factor deficiency, but evidence about the effectiveness of PCC to reverse serious Vitamin K Deficiency Bleeding is limited. What is New: • As far as we know, this is the first systematic review that evaluates the effectiveness of PPC in neonates with bleeding or risk of bleeding. • There is insufficient evidence to allow a recommendation for use of PCCs in neonates and infants.

Inter-individual variation in morphine clearance in children.

OBJECTIVES: The aim of the study was to determine the extent of inter-individual variation in clearance of intravenous morphine in children and to establish which factors are responsible for this variation. METHODS: A systematic literature review was performed to identify papers describing the clearance of morphine in children. The following databases were searched: Medline, Embase, International Pharmaceutical Abstracts, CINAHL, and Cochrane library. From the papers, the range in plasma clearance and the coefficient of variation (CV) in plasma clearance were determined. RESULTS: Twenty-eight studies were identified. After quality assessment, 20 studies were included. Only 10 studies gave clearance values for individual patients. The majority of the studies were in critically ill patients. Inter-individual variability of morphine clearance was observed in all age groups, but greatest in critically ill neonates (both preterm and term) and infants. In critically ill patients, the CV was 16-97% in preterm neonates, 24-87% in term neonates, 35 and 134% in infants, 39 and 55% in children, and 74% in adolescents. The CV was 37 and 44% respectively in non-critically ill neonates and infants. The mean clearance was higher in children (32 and 52 ml min(-1) kg(-1)) than in neonates (2 to 16 ml min(-1) kg(-1)). CONCLUSIONS: Large inter-individual variation was seen in morphine clearance values in critically ill neonates and infants.

Paediatric nurses' adherence to the double-checking process during medication administration in a children's hospital: an observational study.

AIM: To evaluate how closely double-checking policies are followed by nurses in paediatric areas and also to identify the types, frequency and rates of medication administration errors that occur despite the double-checking process. BACKGROUND: Double-checking by two nurses is an intervention used in many UK hospitals to prevent or reduce medication administration errors. There is, however, insufficient evidence to either support or refute the practice of double-checking in terms of medication error risk reduction. DESIGN: Prospective observational study. METHODS: This was a prospective observational study of paediatric nurses' adherence to the double-checking process for medication administration from April-July 2012. RESULTS: Drug dose administration events (n = 2000) were observed. Independent drug dose calculation, rate of administering intravenous bolus drugs and labelling of flush syringes were the steps with lowest adherence rates. Drug dose calculation was only double-checked independently in 591 (30%) drug administrations. There was a statistically significant difference in nurses' adherence rate to the double-checking steps between weekdays and weekends in nine of the 15 evaluated steps. Medication administration errors (n = 191) or deviations from policy were observed, at a rate of 9·6% of drug administrations. These included 64 drug doses, which were left for parents to administer without nurse observation. CONCLUSION: There was variation between paediatric nurses' adherence to double-checking steps during medication administration. The most frequent type of administration errors or deviation from policy involved the medicine being given to the parents to administer to the child when the nurse was not present.

Randomized controlled trials of antibiotics for neonatal infections: a systematic review.

AIMS: Antibiotics are a key resource for the management of infectious diseases in neonatology and their evaluation is particularly challenging. We reviewed medical literature to assess the characteristics and quality of randomized controlled trials on antibiotics in neonatal infections. METHODS: We performed a systematic search of PubMed, Embase and the Cochrane Library from January 1995 to March 2010. Bibliographies of relevant articles were also hand-searched. We included all randomized controlled trials that involved neonates and evaluated the use of an antibiotic agent in the context of a neonatal infectious disease. Methodological quality was evaluated using the Jadad scale and the Cochrane Risk of Bias Tool. Two reviewers independently assessed studies for inclusion and evaluated methodological quality. RESULTS: A total of 35 randomized controlled trials were evaluated. The majority were conducted in a single hospital institution, without funding. Median sample size was 63 (34-103) participants. The most frequently evaluated antibiotic was gentamicin. Respectively, 18 (51%) and 17 (49%) trials evaluated the therapeutic or prophylactic use of antibiotics in various neonatal infections. Overall, the methodological quality was poor and did not improve over the years. Risk of bias was high in 66% of the trials. CONCLUSIONS: Design and reporting of randomized controlled trials of antibacterial agents in neonates should be improved. Nevertheless, the necessity of implementing such trials when antibacterial efficacy has already been established in other age groups may be questioned and different methods of evaluation should be further developed.

Medication errors in the Middle East countries: a systematic review of the literature.

BACKGROUND: Medication errors are a significant global concern and can cause serious medical consequences for patients. Little is known about medication errors in Middle Eastern countries. The objectives of this systematic review were to review studies of the incidence and types of medication errors in Middle Eastern countries and to identify the main contributory factors involved. METHODS: A systematic review of the literature related to medication errors in Middle Eastern countries was conducted in October 2011 using the following databases: Embase, Medline, Pubmed, the British Nursing Index and the Cumulative Index to Nursing & Allied Health Literature. The search strategy included all ages and languages. Inclusion criteria were that the studies assessed or discussed the incidence of medication errors and contributory factors to medication errors during the medication treatment process in adults or in children. RESULTS: Forty-five studies from 10 of the 15 Middle Eastern countries met the inclusion criteria. Nine (20 %) studies focused on medication errors in paediatric patients. Twenty-one focused on prescribing errors, 11 measured administration errors, 12 were interventional studies and one assessed transcribing errors. Dispensing and documentation errors were inadequately evaluated. Error rates varied from 7.1 % to 90.5 % for prescribing and from 9.4 % to 80 % for administration. The most common types of prescribing errors reported were incorrect dose (with an incidence rate from 0.15 % to 34.8 % of prescriptions), wrong frequency and wrong strength. Computerised physician rder entry and clinical pharmacist input were the main interventions evaluated. Poor knowledge of medicines was identified as a contributory factor for errors by both doctors (prescribers) and nurses (when administering drugs). Most studies did not assess the clinical severity of the medication errors. CONCLUSION: Studies related to medication errors in the Middle Eastern countries were relatively few in number and of poor quality. Educational programmes on drug therapy for doctors and nurses are urgently needed.

Safety of fluconazole in paediatrics: a systematic review.

PURPOSE: To determine the safety of fluconazole in neonates and other paediatric age groups by identifying adverse events (AEs) and drug interactions associated with treatment. METHODS: A search of EMBASE (1950-January 2012), MEDLINE (1946-January 2012), the Cochrane database for systematic reviews and the Cumulative Index to Nursing and Allied Health Literature (1982-2012) for any clinical study about fluconazole use that involved at least one paediatric patient (≤17 years) was performed. Only articles with sufficient quality of safety reporting after patients' exposure to fluconazole were included. RESULTS: We identified 90 articles, reporting on 4,209 patients, which met our inclusion criteria. In total, 794 AEs from 35 studies were recorded, with hepatotoxicity accounting for 378 (47.6 %) of all AEs. When fluconazole was compared with placebo and other antifungals, the relative risk (RR) of hepatotoxicity was not statistically different [RR 1.36, 95 % confidence interval (CI) 0.87-2.14, P = 0.175 and RR 1.43, 95 % CI 0.67-3.03, P = 0.352, respectively]. Complete resolution of hepatoxicity was achieved by 84 % of patients with follow-up available. There was no statistical difference in the risk of gastrointestinal events of fluconazole compared with placebo and other antifungals (RR 0.81, 95 % CI 0.12-5.60, P = 0.831 and RR 1.23, 95 %CI 0.87-1.71, P = 0.235, respectively). There were 41 drug withdrawals, 17 (42 %) of which were due to elevated liver enzymes. Five reports of drug interactions occurred in children. CONCLUSION: Fluconazole is relatively safe for paediatric patients. Hepatotoxicity and gastrointestinal toxicity are the most common adverse events. It is important to be aware that drug interactions with fluconazole can result in significant toxicity.

Wide intra- and inter-country variability in drug use and dosage in very-low-birth-weight newborns with severe infections.

PURPOSE: To describe the use of ciprofloxacin and fluconazole for the treatment of sepsis in European neonatal intensive care units (NICUs) in order to better orient research aimed at acquiring essential knowledge in this critical area. METHODS: The survey consisted of an online questionnaire for all participating NICUs on treatment schemes employed, rationales behind drug choices and interest in participation in research involving the two drugs. RESULTS: A total of 189 level II and III NICUs participated in the survey, representing 25 countries, with Italy, UK and France providing the greatest number of centres (54 % of total). Ciprofloxacin is used in 25 % of NICUs that responded, although the indications for administering it vary between centres and the dosage ranges vary considerably, with 25 % of NICUs giving ≤10 mg/kg/day and another 25 % giving ≥21 mg/kg/day. Factors given as affecting the decision to use ciprofloxacin are uncertainty about its safety and pharmacokinetics and level of penetration in the cerebrospinal fluid. Among the 70 % of responding units that use fluconazole to treat fungal infection, 45 % administer 6 mg/kg unit doses while 33 % administer 12 mg/kg; 41 % of NICUs use a 24-h interval between administrations while 20 % wait 72 h. Among the responding NICUs, 57 % were willing to participate in a project on ciprofloxacin and 59 % would consider participating in a randomized controlled trial evaluating fluconazole versus micafungin. CONCLUSIONS: Great variability in therapies exists within and between countries. Numerous centres are interested in participating in research on these drugs, highlighting the need for further knowledge on sepsis treatment and European centres' interest in off-patent medicine research.

Educational Paper: Aspects of clinical pharmacology in children--pharmacovigilance and safety.

Adverse drug reactions (ADRs) are a significant problem in children, affecting one in ten children in hospital. Within the community, one in 500 children will experience an adverse drug reaction each year. Pharmacovigilance has been useful in detecting suspected ADRs. However, most ADRs are unreported and often not suspected. Education of health professionals in relation to drug toxicity improves the reporting rate of suspected ADRs. Clinical trials are useful to evaluate the efficacy of drugs. They are, however, not the best way of looking at ADRs where surveillance following the widespread use of a drug is more appropriate. Alongside work by the regulatory agencies, independent investigators have helped collate data. This information has been useful in developing guidelines to prevent further cases of drug toxicity. Greater awareness and understanding of drug toxicity in children should result in more rational prescribing.

Availability of essential medicines, progress and regional distribution in China: a systematic review and meta-analysis.

Background: Essential medicines are the backbone of healthcare and meet the priority healthcare needs of the population. However, approximately one-third of the global population does not have access to essential medicines. Although China formulated essential medicine policies in 2009, the progress of availability of essential medicines and regional variations remains unknown. Therefore, this study was conducted to evaluate the availability of essential medicines, their progress, and regional distribution in China in the last decade. Methods: We searched eight databases from their inception to February 2022, relevant websites, and reference lists of included studies. Two reviewers selected studies, extracted data, and evaluated the risk of bias independently. Meta-analyses were performed to quantify the availability of essential medicines, their progress, and regional distribution. Results: Overall 36 cross-sectional studies conducted from 2009 to 2019 were included, with regional data for 14 provinces. The availability of essential medicines in 2015-2019 [28.1%, 95% confidence interval (CI): 26.4-29.9%] was similar to that in 2009-2014 (29.4%, 95% CI: 27.5-31.3%); lower in the Western region (19.8%, 95% CI: 18.1-21.5%) than Eastern (33.8%, 95% CI: 31.6-36.1%) and Central region (34.5%, 95% CI: 30.6-38.5%); very low for 8 Anatomical Therapeutic Chemical (ATC) categories (57.1%), and low for 5 categories (35.7%) among all ATC groups. Conclusion: The availability of essential medicines in China is low compared with the World Health Organization goal, has not changed much in the last decade, is unequal across regions, and lacks data for half of provinces. For policy-making, the monitoring system of the availability of essential medicines is to be strengthened to enable long-term surveillance, especially in provinces where the data has been missing. Meanwhile, Joint efforts from all stakeholders are warranted to improve the availability of essential medicines in China toward the universal health coverage target. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=315267, identifier: PROSPERO CRD42022315267.

The price and affordability of essential medicines, progress and regional distribution in China: a systematic review.

Background: Essential medicine is a vital component to assure universal access to quality healthcare. However, the trend of affordability to essential medicines in China and its regional differences were not yet fully understood. This study aimed to systematically evaluate the price and affordability of essential medicines, their progress, and regional distribution in China in the last decades. Methods: We searched seven databases and three websites for potentially eligible studies from inception until March 2022. Studies on the price and affordability of essential medicines investigated in China were included. Median and interquartile range (IQR) was used to describe the price and affordability of essential medicines, and compared in three periods, before 2009, from 2009 to 2014, and from 2015 to 2019. Subgroup analysis was performed to examine the price and affordability by regions, health facilities, and ATC categories of medicines. The study was registered with PROSPERO (CRD42022310173). Results: A total of 65 studies including 11,639 health facilities investigated between 2006 and 2019 were included in this review. Median price ratios (MPR) and affordability of essential medicines were reported in 44 studies and 50 studies, respectively. The median MPRs of essential medicines in China was 1.59 (IQR: 5.39), with a tendency to rise first and then fall from 2006 to 2019. And the median affordability was equal to 0.88 (IQR: 2.58) days' wage of the lowest paid unskilled government worker, but steadily rose from 2006 to 2019. Subgroup analysis showed that the affordability in the western region (1.40, IQR: 2.88), urban area (0.95, IQR: 2.80), private sector (0.90, IQR: 2.30), of originator brands (OB) (2.90, IQR: 6.68), and antineoplastic and immunomodulating agents (5.68, IQR: 56.47) were worse than their counterparts. Conclusion: The prices of essential medicine were higher than international level, the overall affordability of essential medicines in China is acceptable but poor in the western region, for OB drugs and anti-cancer medicines. Further national essential medicine policies are needed to reduce regional disparities and improve the affordability of expensive drugs. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails.

Systematic review of safety in paediatric drug trials published in 2007.

BACKGROUND: There is now greater involvement of children in drug trials to ensure that paediatric medicines are supported by sound scientific evidence. The safety of the participating children is of paramount importance. Previous research shows that these children can suffer moderate and severe adverse drug reactions (ADRs) in clinical trials, yet very few of the trials designated a data safety monitoring board (DSMB) to oversee the trial. METHODS: Safety data from a systematic review of paediatric drug randomised controlled trials (RCTs) published in 2007 were analysed. All reported adverse events (AEs) were classified and assessed to determine whether an ADR had been experienced. ADRs were then categorised according to severity. Each trial report was examined as to whether an independent DSMB was in place. RESULTS: Of the 582 paediatric drug RCTs analysed, 210 (36%) reported that a serious AE had occurred, and in 15% mortality was reported. ADRs were detected in more than half of the RCTs (305); 66 (11%) were severe, and 79 (14%) were moderate. Severe ADRs involved a wide range of organ systems and were frequently associated with cytotoxic drugs, antiparasitics, anticonvulsants and psychotropic drugs. Two RCTs reported significantly higher mortality rates in the treatment group. Only 69 (12%) of the RCTs stated there was a DSMB. DSMBs terminated five RCTs and changed the protocol in one. CONCLUSIONS: Children participating in drug RCTs experience a significant amount and a wide range of ADRs. DSMBs are needed to ensure the safety of paediatric participants in clinical drug trials.

Pharmacokinetics of buccal and intranasal lorazepam in healthy adult volunteers.

PURPOSE: To investigate the plasma-concentration profile of lorazepam when administered by the intranasal and buccal routes to determine their utility for the treatment of prolonged seizures. METHODS: On two occasions separated by at least 7 days washout, 12 healthy adult male volunteers received 2 mg of lorazepam via the intranasal or buccal route. Blood samples were collected at time periods from 0 to 48 h, and pharmacokinetic parameters were determined. RESULTS: Lorazepam was well absorbed from both administration routes; however, there was a more pronounced lag phase with the buccal route and absorption was more rapid from the intranasal route. CONCLUSIONS: Intranasal lorazepam has more favourable pharmacokinetics than buccal lorazepam when considering the need for the rapid blood concentrations required for seizure termination. Further clinical evaluation of this route is required.

European survey on the use of prophylactic fluconazole in neonatal intensive care units.

UNLABELLED: Neonatal fungal infections are associated with substantial mortality and morbidity. Although prophylactic use of several antifungals has been proposed, this practice remains controversial. In order to evaluate the use of fluconazole prophylaxis in European NICUs, we conducted a cross-sectional survey by means of a structured questionnaire that was sent to European level II and III neonatal intensive care units, over a 9-month period, as part of a neonatal research FP7 European project. A total of 193 questionnaires from 28 countries were analysed. Use of antifungal prophylaxis was reported by 55% of the responders, and the most frequently used antifungal agent was fluconazole (92%). Main indications for prophylaxis were low gestational age (<28 weeks) and birth weight (<1,000 g). A dose of 3 mg/kg was used in 66% of NICUs using fluconazole, with an administration interval of 72 h in 52% of them. All responders acknowledged the need for additional trials on the efficacy of prophylactic fluconazole. Non-users of fluconazole prophylaxis were more likely to be influenced by the local incidence of candidiasis, the risk of increasing antifungal resistance and the absence of specific recommendations by paediatric societies. CONCLUSIONS: Major concerns about the use of fluconazole prophylaxis include its efficacy, the risk of emergence of resistant species and the absence of clear consensus to support routine use. Future studies that address these issues will contribute to a more rational use of fluconazole prophylaxis.

Lessons from Building a Sustainable Healthcare Exchange between the Netherlands and Cuba.

Over the past ten years, seven Dutch Universities have built a sustainable exchange with seven institutes in Cuban healthcare. The exchange was initiated by the Leiden University Medical Centre and the University of Medical Sciences of Havana. Cooperation with Cuba was chosen as Cuba has excellent primary healthcare and has a strong focus on prevention and public health. These were considered important due to the major contribution of non-communicable diseases to morbidity and mortality in the Netherlands. Exchanges have occurred with Dutch health professionals and students visiting Cuban healthcare institutions and Cuban postgraduate students studying in the Netherlands. There has been an increased awareness of the importance of public health and prevention in Dutch professional organizations following the exchange. The exchange has also helped to break the scientific and economic US blockade of Cuba and resulted in joint publications. In this review we described the process, key aspects, results and lessons learned in this process. Collaboration between Cuba (a middle income) and the Netherlands (a high-income country) is possible.

Management of patent ductus arteriosus in very preterm infants in England and Wales: a retrospective cohort study.

OBJECTIVE: To describe the diagnosis and treatment of patent ductus arteriosus (PDA) in infants born at <32 weeks' gestational age (GA) in England and Wales between 2010 and 2017. STUDY DESIGN: Retrospective cohort study using routinely recorded data from the National Neonatal Research Database of infants born at <32 weeks admitted to neonatal units in England and Wales from 2010 to 2017. RESULTS: Among 58 108 infants born at <32 weeks' GA, 28.3% (n=16 440) had a PDA diagnosed clinically or with echocardiographic confirmation. Of these, 34.8% (n=5721; 9.8% of total <32 weeks' infants included) had PDA treatment including 7.6% (n=1255) with indomethacin, 23.5% (n=3857) with ibuprofen and 5.6% (n=916) with surgical closure. The highest incidence of PDA was among infants born at 24 and 25 weeks' GA (70.2% and 70.8%, respectively), decreasing to 6.1% among infants born at 31 weeks' GA. The percentage of infants with a PDA increased over the study period (25.5% in 2010 to 28.5% in 2017). The percentage of infants who received ibuprofen or indomethacin or had PDA surgery decreased from 41.3% in 2010 to 33.7% in 2017, with an increase in use of ibuprofen from 20.2% to 27.3% while use of indomethacin decreased from 20.0% to 8.8%. Surgical closure of PDA decreased from 9.1% to 3.0%. Indomethacin was used for median (IQR) 3 (2-5) days while ibuprofen was given for 3 (2-4) days, at a median of 8 and 10 days after birth, respectively; surgical treatment was used later at 33 (24-45) days after birth. CONCLUSIONS: Ibuprofen is the preferred drug and surgical interventions are becoming less frequent for PDA closure among very preterm infants in England and Wales. TRIAL REGISTRATION NUMBER: NCT03773289.