Using BCG Vaccine to Enhance Nonspecific Protection of Health Care Workers During the COVID-19 Pandemic: A Randomized Controlled Trial.

BACKGROUND: The BCG (Bacillus Calmette-Guérin) vaccine can induce nonspecific protection against unrelated infections. We aimed to test the effect of BCG on absenteeism and health of Danish health care workers (HCWs) during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A single-blinded randomized controlled trial included 1221 HCWs from 9 Danish hospitals. Participants were randomized 1:1 to standard dose BCG or placebo. Primary outcome was days of unplanned absenteeism. Main secondary outcomes were incidence of COVID-19, all-cause hospitalization, and infectious disease episodes. RESULTS: There was no significant effect of BCG on unplanned absenteeism. Mean number of days absent per 1000 workdays was 20 in the BCG group and 17 in the placebo group (risk ratio, 1.23; 95% credibility interval, 0.98-1.53). BCG had no effect on incidence of COVID-19 or all-cause hospitalization overall. In secondary analyses BCG revaccination was associated with higher COVID-19 incidence (hazard ratio [HR], 2.47; 95% confidence interval [CI], 1.07-5.71), but also reduced risk of hospitalization (HR, 0.28; 95% CI, .09-.86). The incidence of infectious disease episodes was similar between randomization groups (HR, 1.09; 95% CI, .96-1.24). CONCLUSIONS: In this relatively healthy cohort of HCWs, there was no overall effect of BCG on any of the study outcomes. CLINICAL TRIALS REGISTRATION: NCT0437329 and EU Clinical Trials Register (EudraCT number 2020-001888-90).

Dysfunctional breathing and its impact on asthma control in children and adolescents.

BACKGROUND: Dysfunctional breathing (DB) has been shown to negatively affect asthma control in adults, but for children and adolescents, the knowledge is scarce. DB is among others characterized by dyspnea and hyperventilation. The Nijmegen Questionnaire (NQ) is often used as a marker for DB. We conducted a cross-sectional survey to estimate the prevalence of DB in patients with asthma in a pediatric outpatient clinic and to determine the impact of DB on asthma control. METHODS: Patients between 10 and 17 years were invited to complete the NQ and the Asthma Control Questionnaire (ACQ) and report the use of beta2 agonist (ß2). Spirometry data and prescribed asthma medications were noted from the patient record. RESULTS: Three hundred and sixty-three patients (180 boys) completed the survey. Sixty-seven patients (18%) scored ≥23 points in the NQ predicting DB. The DB group was older (median (range)) 15.6 (10.5-17.9) vs. 13.7 (10.0-17.9) years) (p < .01), and girls were overrepresented (84%) (p < .01). FEV1% exp. was higher in the DB group (mean (SD)) (89.4 (9.0) vs. 85.7 (11.8)) (p < .02). ACQ score (median (range)) (2.0 (0-4) vs. 0.6 (0-3.4)) (p < .01) and the use of ß2 (median (range)) (2 (0-56) vs. 0 (0-20) puffs/week) (p < .01) were higher. Inhaled corticosteroid dose (mean (SD) (416 (160) vs. 420 (150) mcg) and the use of a second controller were equal between the groups. CONCLUSION: Dysfunctional breathing was a frequent comorbidity, especially in adolescent girls. DB correlated with poorer asthma control and higher use of ß2 and may be an important cofactor in difficult-to-treat asthma.

Face mask use during the COVID-19 pandemic was associated with breathing difficulties in adolescent patients with asthma.

AIM: Face masks have been used to prevent severe acute respiratory syndrome coronavirus-2 transmission. We investigated the impact of face mask use on paediatric patients with asthma. METHODS: Between February 2021 and January 2022, we surveyed adolescents aged 10-17 attending the paediatric outpatient clinic at the Lillebaelt Hospital, Kolding, Denmark with asthma, other breathing problems or no breathing problems. RESULTS: We recruited 408 participants (53.4% girls) with a median age of 14 years: 312 in the asthma group, 37 in the other breathing problems group and 59 in the no breathing problems group. Most participants experienced mask-related breathing impairment. The relative risk (RR) of experiencing severe breathing problems, compared to no problems, was more than four times as high for adolescents with asthma (RR 4.6, 95% CI 1.3-16.8, p = 0.02) than adolescents with no breathing problems. More than a third (35.9%) of the asthma group experienced mild asthma and 3.9% had severe asthma. Girls experienced more mild (RR 1.9, 95% CI 1.2-3.1, p < 0.01) and severe (RR 6.6, 95% CI 3.1-13.8, p < 0.01) symptoms than boys. Age had no effect. Adequate asthma control minimised negative effects. CONCLUSION: Face masks caused significant breathing impairment in most adolescents, particularly in those with asthma.

Developing and Implementing a Father-Friendly Neonatal Intensive Care Unit Improved Nurses' Self-Efficacy.

BACKGROUND: The need for paternal support is rarely addressed in neonatal intensive care units (NICUs). Neonatal nurses often primarily focus on the needs of the mother and infant and may not be trained in support of fathers. PURPOSE: To investigate nurses' self-efficacy (SE) in guiding and supporting fathers after implementing a father-friendly NICU. METHODS: Nurses from the intervention NICU and 13 control NICUs were included in a before-and-after intervention study. Questionnaires measuring nurses' SE regarding support of fathers and mothers were obtained when starting the development process, before and 18 months after the implementation. The primary outcome was the difference between nurses' SE scores for father and mother questions in the intervention group compared with the control group. RESULTS: In total, 294, 330, and 288 nurses responded to the first, second, and third questionnaires, respectively. From the first to third questionnaires, the intervention group showed a significantly higher increase in SE scores for father questions compared with the control group (0.53 vs 0.20, P = .005) and a nonsignificantly higher increase for mother questions (0.30 vs 0.09, P = .13). In the third questionnaire, the intervention group showed a higher SE score for father questions compared with the control group (9.02 vs 8.45, P = .002) and the first questionnaire (9.02 vs 8.49, P = .02). IMPLICATIONS FOR PRACTICE AND RESEARCH: By implementing a father-friendly NICU, nurses' SE for providing support to fathers increased significantly. Training in a father-friendly approach increases nurses' ability to support both parents.

Warming Prior to Heel Stick: Blood Sample Quality and Infant Comfort-A Randomized Controlled Trial.

BACKGROUND: Capillary blood sampling (heel stick) in infants is commonly performed in neonatal care units. Before the procedure, warming the infant's heel is often a customary practice, but no consensus exists on the most effective heel-warming method. PURPOSE: To compare the effects of routinely used warming methods (glove, gel pack, or blanket) applied prior to heel stick on blood sample quality and infant's comfort. METHODS: This prospective, double-blind, randomized controlled trial conducted in the neonatal intensive care unit included infants (postmenstrual age of ≥28 + 0 weeks and ≤43 + 6 weeks) who were computer-randomized to 1 of 3 warming methods.The primary outcome was blood flow velocity at sampling. Secondary outcomes were hemolysis index, infant COMFORTneo score, and frequency of postprocedure skin injuries. In addition, irrespective of the warming method used, the correlation between heel skin temperature and postprocedure heel skin injury was analyzed. RESULTS: A total of 176 heel warmings were successfully randomized, and 173 were analyzed. Despite a significant difference in obtained heel skin temperature after warming between the 3 warming methods ( P = .001), no difference in blood flow velocity ( P = .91), hemolysis index ( P = .99), or COMFORTneo score ( P = .76) was found. Baseline skin temperatures above 37.0°C were associated with higher incidences of skin injury, and skin temperatures after warming were significantly higher in skin-injured heels ( P = .038). IMPLICATIONS FOR PRACTICE AND RESEARCH: All 3 warming methods had similar effects on blood sample quality and infant's comfort. However, excessive warming of the heel should be avoided to prevent skin injuries.

Parents' comfort and staffs' working-environment when infants are sitting skin-to-skin: a randomised controlled trial comparing a recliner and a hospital bed.

Skin-to-skin contact between parents and preterm infants is recommended because it has proven to be valuable for the infants' development and healing. However, it can be difficult to comply with this guideline and still ensure a good working environment for the staff.This randomised controlled trial compared a new recliner developed in collaboration with parents and staff with a hospital bed for use in neonatal and maternity care using parents' rating of own comfort/discomfort, self-reliance, and felt security, and the chair's/bed's functionality at two different days (Q1 and Q2) of hospitalisation. The physical work-environment was evaluated through a questionnaire to the staff.Ninety-seven parents and 53 health professionals participated. Parents had significantly lower discomfort, in the recliner at Q1 compared to the hospital bed. The staff had to twist and/or bend their back significantly less often when working at the recliner as compared to the hospital bed. Practitioner summary: Due to poor working environment, a participatory design project developed a new recliner that improved the possibility of infants having skin-to-skin contact with their parents. The recliner provided a better working-environment for the staff while focussing on improving comfort and self-reliance of the parents, as compared to a hospital bed. Abbreviations: NICU: Neonatal Intensive Care Unit; VELA: Vermund Larsen.

Chloroquine-susceptible and -resistant Plasmodium falciparum strains survive high chloroquine concentrations by becoming dormant but are eliminated by prolonged exposure.

BACKGROUND: Plasmodium falciparum strains that are resistant to standard-dose chloroquine can be treated by higher chloroquine concentrations maintained for a longer time in vivo. OBJECTIVES: To determine the relative importance of chloroquine concentrations versus exposure time for elimination of chloroquine-susceptible and -resistant P. falciparum in vitro. METHODS: Chloroquine-susceptible (3D7) and -resistant (FCR3) strains were exposed in vitro to 1, 2, 4, 8, 16 or 32 times their respective 90% inhibitory chloroquine concentrations for 3, 5, 7 or 14 days and then followed until recrudescence, or not, by 42 days after the end of exposure. RESULTS: Exposure to chloroquine appeared to eliminate susceptible and resistant parasites, leaving small pyknotic apparently dead parasites. Chloroquine-susceptible and -resistant parasites recrudesced after 3 and 5 days of chloroquine exposure. Recrudescence occurred in one out of four 7 day exposure series but not after 14 days exposure. The median time to recrudescence was 13 to 28 days with a range of 8 to 41 days after the end of exposure. Time to recrudescence after the end of exposure increased with duration of exposure for susceptible and resistant strains (P < 0.001). Time to recrudescence did not correlate with concentrations greater than 1× IC90. CONCLUSIONS: Chloroquine-susceptible and -resistant P. falciparum probably become dormant. Elimination of dormant parasites is primarily dependent upon the duration of chloroquine exposure. Exposure to effective drug concentrations for 7 days eliminates most parasites in vitro. The results support in vivo data indicating that elimination of chloroquine-resistant P. falciparum correlates with Day 7 chloroquine concentrations.

The impact of COVID-19 lockdown on glycaemic control and use of health services among children followed at a Danish diabetes clinic.

AIM: During COVID-19 restrictions, the paediatric clinic only accepted essential outpatient visits, schools closed, sports activities and social life were limited. Most employees worked at home. This quasi-experiment evaluates how this affected glycaemic control and use of health services among children with diabetes. METHODS: Paired t-tests were used to compare HbA1c-values before, during and after lockdown. Sub-analyses were stratified by pre-lockdown HbA1c-values. RESULTS: Overall mean HbA1c decreased from 58.3 to 56.9 mmol/mol (p = 0.025) from pre- to post-lockdown, a decrease also seen during the same season the previous year. HbA1c decreased by -4.2 mmol/mol (p = 0.002) for patients with pre-lockdown HbA1c > 59 mmol/mol, but increased slightly by 0.8 mmol/mol (p = 0.176) for patients with HbA1c < 52 mmol/mol. HbA1c measured 8 months post-lockdown increased again, most pronounced for patients with lowest HbA1c. During lockdown, virtual contacts increased from 0.1 to 0.5 contacts/patient/month and stayed post-lockdown at 0.3 contacts/patient/month. CONCLUSION: Compared to 2019, overall the COVID-19 restrictions did not influence the glycaemic control negatively. However, patients with pre-lockdown HbA1c < 52 mmol/mol experienced a deterioration, whereas those with HbA1c > 59 mmol/mol experienced an improvement. Less stress and more contact with parents may contribute to the last-mentioned finding. The lockdown enforced more virtual contacts between patients and the clinic.

Reactivation of BCG vaccination scars after vaccination with mRNA-Covid-vaccines: two case reports.

BACKGROUND: From May 2020 to January 2021, we enrolled 1233 health care workers (HCW) from Danish Hospitals in a randomized trial evaluating whether Bacille Calmette-Guérin (BCG) provides protection against COVID-19. Participants were randomized 1:1 to BCG vs saline and followed for 6 months. From December 2020, Covid-19 vaccines were offered to the HCW. In most cases, BCG vaccination results in a characteristic scar. Reactivation of the BCG scar has been described in children during viral infections and following influenza vaccination, but is mostly associated to Kawasaki's disease, a disease entity with pathogenesis likely similar to the child Covid-19 complication MIS-C: Multi-System Inflammatory Syndrome. Reactivation of scars after neonatal BCG vaccination has recently been described in four women after Covid-19 mRNA vaccination. Two of our trial participants experienced reactivation of their novel BCG scars after receiving mRNA Covid-19 vaccination 6 to 8 months post-BCG. CASE PRESENTATIONS: Two female HCW participants that had been randomly allocated to BCG in the BCG-DENMARK-COVID trial, spontaneously reported itching and secretion at the BCG scar site after having received mRNA Covid-19 vaccination (Moderna and Pfizer-BioNTech) 6 to 8 months following inclusion and BCG vaccination. One participant, who had a larger BCG skin reaction, noticed re-appearing symptoms after both the first and the second COVID-vaccine dose, while the other participant only noted symptoms after the second dose. Both had been BCG vaccinated during childhood, and no reactivation was noted in the older scars. No treatment was needed or provided. CONCLUSIONS: The reactivation of the BCG scar after receiving mRNA vaccine might have been caused by cross-reactivity between BCG and SARS-CoV-2. In both cases, the symptoms were bothersome, but self-limiting and left no sequelae. The risk of reactivation at the scar site is thus not a reason to avoid vaccination with either vaccine.

High-Dose Chloroquine for Uncomplicated Plasmodium falciparum Malaria Is Well Tolerated and Causes Similar QT Interval Prolongation as Standard-Dose Chloroquine in Children.

Higher chloroquine doses can effectively treat up to 93 to 96% of malaria infections caused by Plasmodium falciparum carrying the resistance-conferring chloroquine resistance transporter (pfcrt) 76T allele. The tolerability of 50 (double the standard dose) and 70 mg/kg total chloroquine doses were assessed in this study. Fifteen 4- to 8-year-old children with uncomplicated malaria were given 10 mg/kg of chloroquine twice daily for 2 days and 5 mg/kg twice daily on the third day. Fifteen additional children were given 5 mg/kg twice daily for 2 more days. Chloroquine concentrations, blood pressure, electrocardiograms (ECGs), parasite density, and adverse events were assessed until day 28. Both dosages were well tolerated, and symptoms resolved by day 3 in parallel with increasing chloroquine concentrations. The median corrected QT (QTc) interval was 12 to 26 ms higher at expected peak concentrations than at day 0 (P < 0.001). Pfcrt 76T was associated with delayed parasite clearance. Day 28 clinical and parasitological responses against P. falciparum with pfcrt 76T were 57% (4/7) and 67% (4/6) after treatment with 50 and 70 mg/kg, respectively. Dosages were well tolerated, and no severe cardiac adverse events occurred. The QTc interval increase was similar to that found in adults taking 25 mg/kg of chloroquine. (This study has been registered at ClinicalTrials.gov under identifier NCT01814423.).

Leaving the responsibility of booking appointments to parents in a paediatric diabetes outpatient clinic resulted in a deterioration of metabolic control.

It is recommended that children and adolescents with diabetes are seen at paediatric diabetes clinics at least four times a year. This study examined whether an increased involvement of parents in planning the contacts would help them take more responsibility and thus lead to better metabolic control. METHODS: Patients with type 1 diabetes at the paediatric outpatient clinic at Lillebaelt Hospital were included in a before-after study. During the intervention, the parents were asked to contact the clinic whenever they needed help or wanted to book a consultation. HbA1c levels 1 year before, at the start of, and 1 year after the intervention were compared, as were the number of consultations and telephone contacts during the year prior to and during the intervention. RESULTS: 139 patients were included in the analyses. The mean HbA1c levels were 1 year before the start of the intervention (HbA1c-1) 61.8 mmol/mol (7.8%), and at the start of the intervention (HbA1c-2) 59.9 mmol/mol (7.6%) (P = .01), and after the end of the intervention (HbA1c-3) 63.1 mmol/mol (7.9%) (HbA1c-2 vs HbA1c-3: P = .0002). During the year prior to the intervention, the mean number of consultations was 5.8, and during the intervention period, the mean was 4.4 (P = .0001); the mean number of telephone calls was 1.8 and 3.8 (P < .0001), respectively. CONCLUSION: Children were seen less often when parents were responsible for booking appointments, leading to higher HbA1c levels indicating that frequent consultations are essential for good metabolic control and cannot be replaced by frequent telephone contacts.

High flow nasal cannula and continuous positive airway pressure therapy in treatment of viral bronchiolitis: a randomized clinical trial.

Continuous positive airway pressure (CPAP) has been used in infants with bronchiolitis for decades. Recently, high flow nasal cannula (HFNC) therapy was introduced. We conducted a trial of 50 children with bronchiolitis who were randomized to treatment with CPAP or HFNC. Objectives were to compare the development in respiratory rate, pCO2, and Modified Woods Clinical Asthma Score (M-WCAS) in young children with bronchiolitis, treated with CPAP or HFNC. Secondarily, to compare Neonatal Infant Pain Score (NIPS), treatment duration, treatment failure, and hospitalization length. Median age at inclusion was 2.8 (CPAP group) vs 2.1 months (HFNC group). Mean baseline pCO2 was 6.7 in both groups and mean respiratory rate was 60 vs 56 in the CPAP and HFNC group respectively. No differences were observed in development of respiratory rate, pCO2, or M-WCAS. NIPS was higher in the CPAP group. Treatment failure was scarce in both groups. No significant differences in treatment duration or length of hospitalization were observed.Conclusion: In infants and young children with bronchiolitis, HFNC may be an effective and pleasant alternative to CPAP. Larger multicenter studies are needed to further explore differences in treatment failure and treatment duration.Trial registration: www.clinicaltrial.gov. id NCT02618213, registration date December 1, 2015.What is Known:• CPAP has been used for many years for respiratory support in infant bronchiolitis. The method requires special staff skills and may be stressful to the child.• HFNC has been introduced as a newer tool.What is New:• In infants with bronchiolitis, HFNC and CPAP were comparable in decreasing respiratory rate, pCO2, and need for oxygen supply.• Pain score during therapy was lower in the HFNC group.

Cerebral disorders in the first 7 years of life in children born post-term: a cohort study.

BACKGROUND: To estimate the association between post-term delivery and risk of physical disabilities, mental disabilities, and seizures during the first 7 years of life. METHODS: Data from 57,884 singleton infants born alive in week 39-45 by mothers included in the Danish National Birth Cohort (1997 to 2004) were analyzed, of these 51,268 were born at term (39-41 + 6) and 6616 post-term (42 + 0-44 + 6). Information on clinical endpoints was obtained from an interview at 18 months of gestational age, from a 7-year questionnaire, and from the Danish National Patient Register. Logistic regression and Cox regression were used to estimate odds ratios and hazard rate ratios for the outcome obtained from the interview/questionnaire data and from the register-based data, respectively. RESULTS: We found no statistically significant increased risk of physical disabilities, mental disabilities, and epilepsy among children born post-term, though for most outcomes studied a tendency towards more adverse outcomes was seen. When children born late term (week 41) were compared to children born in week 42 or later the same tendency was found. CONCLUSION: Post-term born children had a tendency to an excess risk of neurological disabilities as followed for up to 7 years of age.

Codebook for rating clinical communication skills based on the Calgary-Cambridge Guide.

BACKGROUND: The aim of the study was to confirm the validity and reliability of the Observation Scheme-12, a measurement tool for rating clinical communication skills. METHODS: The study is a sub-study of an intervention study using audio recordings to assess the outcome of communication skills training. This paper describes the methods used to validate the assessment tool Observation Scheme-12 by operationalizing the crude 5-point scale into specific elements described in a codebook. Reliability was tested by calculating the intraclass correlation coefficients for interrater and intrarater reliability. RESULTS: The validation of the Observation Scheme-12 produced a rating tool with 12 items. Each item has 0 to 5 described micro-skills. For each item, the codebook described the criteria for delivering a rating from 0 to 4 depending on how successful the different micro-skills (or number of used jargon words) was accomplished. Testing reliability for the overall score intraclass correlation coefficients was 0.74 for interrater reliability and 0.86 for intrarater reliability. An intraclass correlation coefficient greater than 0.5 was observed for 10 of 12 items. CONCLUSION: The development of a codebook as a supplement to the assessment tool Observation Scheme-12 enables an objective rating of audiotaped clinical communication with acceptable reliability. The Observation Scheme-12 can be used to assess communication skills based on the Calgary-Cambridge Guide.

Proof of concept: used malaria rapid diagnostic tests applied for parallel sequencing for surveillance of molecular markers of anti-malarial resistance in Bissau, Guinea-Bissau during 2014-2017.

BACKGROUND: Large-scale surveillance of molecular markers of anti-malarial drug resistance is an attractive method of resistance monitoring, to complement therapeutic efficacy studies in settings where the latter are logistically challenging. METHODS: Between 2014 and 2017, this study sampled malaria rapid diagnostic tests (RDTs), used in routine clinical care, from two health centres in Bissau, Guinea-Bissau. In order to obtain epidemiological insights, RDTs were collected together with patient data on age and sex. A subset of positive RDTs from one of the two sites (n = 2184) were tested for Plasmodium DNA content. Those testing positive for Plasmodium DNA by PCR (n = 1390) were used for library preparation, custom designed dual indexing and next generation Miseq targeted sequencing of Plasmodium falciparum genes pfcrt, pfmdr1, pfdhfr, pfdhps and pfk13. RESULTS: The study found a high frequency of the pfmdr1 codon 86N at 88-97%, a significant decrease of the pfcrt wildtype CVMNK haplotype and elevated levels of the pfdhfr/pfdhps quadruple mutant ranging from 33 to 51% between 2014 and 2017. No polymorphisms indicating artemisinin tolerance were discovered. The demographic data indicate a large proportion of young adults (66%, interquartile range 11-28 years) presenting with P. falciparum infections. While a total of 5532 gene fragments were successfully analysed on a single Illumina Miseq flow cell, PCR-positivity from the library preparation varied considerably from 13 to 87% for different amplicons. Furthermore, pre-screening of samples for Plasmodium DNA content proved necessary prior to library preparation. CONCLUSIONS: This study serves as a proof of concept for using leftover clinical material (used RDTs) for large-scale molecular surveillance, encompassing the inherent complications regarding to methodology and analysis when doing so. Factors such as RDT storage prior to DNA extraction and parasitaemia of the infection are likely to have an effect on whether or not parasite DNA can be successfully analysed, and are considered part of the reason the data yield is suboptimal. However, given the necessity of molecular surveillance of anti-malarial resistance in settings where poor infrastructure, poor economy, lack of educated staff and even surges of political instability remain major obstacles to performing clinical studies, obtaining the necessary data from used RDTs, despite suboptimal output, becomes a feasible, affordable and hence a justifiable method.

Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis.

BACKGROUND: The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. METHODS AND FINDINGS: A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. CONCLUSIONS: Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

Direct whole-genome sequencing of Plasmodium falciparum specimens from dried erythrocyte spots.

BACKGROUND: Plasmodium falciparum malaria remains a major health burden and genomic research represents one of the necessary approaches for continued progress towards malaria control and elimination. Sample acquisition for this purpose is troublesome, with the majority of malaria-infected individuals living in rural areas, away from main infrastructure and the electrical grid. The aim of this study was to describe a low-tech procedure to sample P. falciparum specimens for direct whole genome sequencing (WGS), without use of electricity and cold-chain. METHODS: Venous blood samples were collected from malaria patients in Bandim, Guinea-Bissau and leukocyte-depleted using Plasmodipur filters, the enriched parasite sample was spotted on Whatman paper and dried. The samples were stored at ambient temperatures and subsequently used for DNA-extraction. Ratios of parasite:human content of the extracted DNA was assessed by qPCR, and five samples with varying parasitaemia, were sequenced. Sequencing data were used to analyse the sample content, as well as sample coverage and depth as compared to the 3d7 reference genome. RESULTS: qPCR revealed that 73% of the 199 samples were applicable for WGS, as defined by a minimum ratio of parasite:human DNA of 2:1. WGS revealed an even distribution of sequence data across the 3d7 reference genome, regardless of parasitaemia. The acquired read depths varied from 16 to 99×, and coverage varied from 87.5 to 98.9% of the 3d7 reference genome. SNP-analysis of six genes, for which amplicon sequencing has been performed previously, confirmed the reliability of the WGS-data. CONCLUSION: This study describes a simple filter paper based protocol for sampling P. falciparum from malaria patients for subsequent direct WGS, enabling acquisition of samples in remote settings with no access to electricity.

Fathers' Stress in a Neonatal Intensive Care Unit.

BACKGROUND: Healthcare professionals in neonatal intensive care units (NICUs) tend to focus attention on the mothers and the newborn infants. Thus, fathers may find it difficult to establish an optimal father-child relationship and their stress may increase and persist during hospitalization. PURPOSE: To investigate the impact of a more father-friendly NICU on paternal stress and their participation in childcare. METHODS: A quasiexperimental design was conducted on Danish-speaking fathers of newborn infants 28 or more weeks' gestational age. The Parental Stressor Scale: Neonatal Intensive Care Unit (PSS:NICU) was used to measure paternal perceptions of stressors. Paternal participation in childcare was measured using 7 additional items. The questionnaires were distributed on admission to the NICU, at the 14th day of hospitalization, and at the time of discharge. The primary outcome was the difference in the PSS:NICU overall stress score on admission to the NICU and at the time of discharge in the control group compared with the intervention group. RESULTS: A total of 109 fathers were included. The overall PSS:NICU stress score increased after the intervention. Paternal involvement, staff expectations, and the social expectation to fulfill the traditional role of a breadwinner and additionally of a caregiver may have caused increased stress. IMPLICATIONS FOR PRACTICE: Healthcare professionals must be aware of the father's need to be an equal coparent. Nurses, as key persons, should motivate and expect fathers to be involved, and support them to establish a father-child relationship, although they might become more stressed. IMPLICATIONS FOR RESEARCH: More adequate outcome measures are needed to determine the effect of interventions on paternal stress.

Neonatal BCG vaccination has no effect on recurrent wheeze in the first year of life: A randomized clinical trial.

BACKGROUND: Recurrent wheeze (RW) is frequent in childhood. Studies have suggested that BCG vaccination can have nonspecific effects, reducing general nontuberculosis morbidity, including respiratory tract infections and atopic diseases. The mechanisms behind these nonspecific effects of BCG are not fully understood, but a shift from a TH2 to a TH1 response has been suggested as a possible explanation. OBJECTIVE: We hypothesized that BCG at birth would reduce the cumulative incidence of RW during the first year of life. METHODS: The Danish Calmette Study is a multicenter randomized trial conducted from 2012-2015 at 3 Danish hospitals. The 4262 newborns of 4184 included mothers were randomized 1:1 to BCG (SSI strain 1331) or to a no-intervention control group within 7 days of birth; siblings were randomized together as one randomization unit. Exclusion criteria were gestational age of less than 32 weeks, birth weight of less than 1000 g, known immunodeficiency, or no Danish-speaking parent. Information was collected through telephone interviews and clinical examinations at 3 and 13 months of age; data collectors were blind to randomization group. RW was defined in several ways, with the main definition being physician-diagnosed and medically treated RW up to 13 months of age. RESULTS: By 13 months, 211 (10.0%) of 2100 children in the BCG group and 195 (9.4%) of 2071 children in the control group had received a diagnosis of RW from a medical doctor and received antiasthma treatment (relative risk, 1.07; 95% CI, 0.89-1.28). Supplementary analyses were made, including an analysis of baseline risk factors for development of RW. CONCLUSION: Neonatal BCG had no effect on the development of RW before 13 months of age.

Mothers' informational needs when deciding to have their newborn infant vaccinated with BCG. A Mixed-methods design.

OBJECTIVE: To explore the informational needs of mothers with different levels of education in order to improve counselling about vaccination. METHODS: In the setting of a large vaccination trial, mothers' assessments and yield of written information in combination with telephone consultations were evaluated in a survey. Furthermore, searching strategies for additional information were investigated. Mothers' perspectives on informational needs were explored in focus group discussions. RESULTS: Out of 2025 mothers, 95% felt well-informed. Of the 4% not feeling well-informed, there were significantly more mothers with basic schooling and nontheoretical education. There was no correlation between searching for additional information and feeling well-informed. The telephone consultation was found to be very supportive for the decision. CONCLUSION: The written information was digestible over time. The telephone consultation ensured the mothers' understanding by tailoring and deriving meaning from the information to her special needs. Moreover, it helped the mothers gain an overview of risks and benefits and inspired confidence. These findings indicate that the telephone consultation improved health literacy. PRACTICE IMPLICATIONS: Individual counselling about vaccines is required in addition to information about side effects and accurate instructions on how to react upon them.