Ameliorating Child poverty through Connecting Economic Services with child health Services (ACCESS): study protocol for a randomised controlled trial of the healthier wealthier families model in Sweden.

BACKGROUND: Sweden is often held up as an example of a country with low child deprivation; yet, rates of relative deprivation are rising. Every municipality in Sweden is required to provide free, timely and accessible budget and debt counselling under the Social Services Act. The services have been encouraged to perform preventative practice with families; however, this has not been realised. The Healthier Wealthier Families (HWF) model embeds universal screening for economic hardship into child health services and creates a referral pathway to economic support services. Given the universal child health system in Sweden, which is freely available and has excellent coverage of the child population, implementation of the HWF model has potential to support families to access the freely available municipal budget and debt counselling and ultimately improve rates of child deprivation in Sweden. METHODS/DESIGN: We will conduct a two-arm randomised waitlist-control superiority trial to examine the effectiveness and cost-effectiveness of the HWF model in the Sweden. A longitudinal follow-up with the cohort will explore whether any effects are maintained in the longer-term. DISCUSSION: HWF is a collaborative and sustainable model that could maximise the effectiveness of current services to address child deprivation in Sweden. The study outlined in this protocol is the first effectiveness evaluation of the HWF model in Sweden and is a crucial step before HWF can be recommended for national implementation within the child health services. TRIAL REGISTRATION: Clinicaltrials.gov; NCT05511961. Prospectively registered on 23 August 2022. https://clinicaltrials.gov/ct2/show/NCT05511961.

Improving Opioid Stewardship in Pediatric Emergency Medicine.

OBJECTIVES: Poor opioid stewardship contributes to opioid misuse and adverse health outcomes. We sought to decrease opioid prescriptions in children 0 to 18 years treated for pain after fractures and cutaneous abscess drainage from 13.5% to 8%. Our secondary aims were to reduce opioid prescriptions written for >3 days from 41% to 10%, eliminate codeine prescriptions, increase safe opioid storage and disposal discharge instructions from 0% to 70%, and enroll all emergency department (ED) physicians in the state prescription drug monitoring program. METHODS: We implemented an intervention bundle on the basis of 4 key drivers at a pediatric ED: ED-wide education, changes in the electronic medical record, discharge resources, and process standardization. Two plan-do-study-act cycles were performed. Interventions included provider feedback on prescribing, safe opioid storage and disposal instructions, and streamlined electronic medical record functions. Run charts were used to analyze the effect of interventions on outcomes. Our balance measure was return ED or clinic visits for inadequate analgesia within 3 days. RESULTS: During the intervention period, 249 of 3402 (7.3%) patients with fractures and cutaneous abscesses were prescribed opioids. The percentage of opioid prescriptions >3 days decreased from 41% to 13.2% (P < .0001), codeine prescription dropped from 1.1% to 0% (P = .09), opioid discharge instructions increased 0% to 100% (P < .0001), and all physicians enrolled in the prescription drug monitoring program. There was no change in return visits for uncontrolled analgesia compared with the baseline (P = .79). CONCLUSIONS: A comprehensive opioid stewardship program can improve opioid prescribing practices of ED physicians and deliver information on safe storage and disposal of prescription opioids with a negligible effect on return visits for uncontrolled pain.

The Impact of the COVID-19 Pandemic and Societal Infection Control Measures on Children and Adolescents' Mental Health: A Scoping Review.

Background: The COVID-19 pandemic is primarily a crisis that affects people's physical health. However, it is well-known from previous epidemics and pandemics that there are other indirect negative impacts on mental health, among others. The purpose of this scoping review was to explore and summarise primary empirical research evidence on how the COVID-19 pandemic and societal infection control measures have impacted children and adolescents' mental health. Methods: A literature search was conducted in five scientific databases: PubMed, APA PsycINFO, Web of Science, CINHAL, and Social Science Premium Collection. The search string was designed using the Population (0-18 years), Exposure (COVID-19), Outcomes (mental health) framework. Mental health was defined broadly, covering mental well-being to mental disorders and psychiatric conditions. Results: Fifty-nine studies were included in the scoping review. Of these, 44 were cross-sectional and 15 were longitudinal studies. Most studies reported negative impact of the COVID-19 pandemic on child and adolescent mental health outcomes, yet the evidence was mixed. This was also the case for studies investigating societal control measures. Strong resilience, positive emotion regulation, physical activity, parental self-efficacy, family functioning and emotional regulation, and social support were reported as protective factors. On the contrary, emotional reactivity and experiential avoidance, exposure to excessive information, COVID-19 school concerns, presence of COVID-19 cases in the community, parental mental health problems, and high internet, social media and video game use were all identified as potentially harmful factors. Conclusions: Due to the methodological heterogeneity of the studies and geographical variation, it is challenging to draw definitive conclusions about the real impact of the COVID-19 pandemic on the mental health of children and adolescents. However, the existing body of research gives some insight to how parents, clinicians and policy makers can take action to mitigate the effects of COVID-19 and control measures. Interventions to promote physical activity and reduce screen time among children and adolescents are recommended, as well as parenting support programs.

Social workers' perspectives on a medical home model for children and adolescents in out of home care - an interview study.

BACKGROUND: This study seeks to explore how social workers have perceived and experienced a medical home model for children and adolescents in out-of-home care in Uppsala County, Sweden. METHOD: A qualitative explorative study was conducted, which involved ten semi-structured individual telephone interviews with social workers. The study sample included employees within the social service, working in a specialised case unit who had experience of referring children and/or adolescents to the medical home model called Hälsofam. Data were analysed inductively using thematic analysis. RESULTS: The findings of the current study indicated that working with Hälsofam has offered social workers a way into the health care sector and an active collaborative working situation, with focus on organised work across the 'silos' of care services. However, the findings raised the question of whether or not all children and adolescents have the same possibility to receive care from Hälsofam. CONCLUSION: The findings indicated that the Hälsofam model had a positive impact on the interrelations between the social service and the health care sector. Yet, findings showed that personal views of the social worker and the societal situation in which they operate create limitations for providing care for every child and adolescent. This study adds to the extant literature for it addresses the limitations within the work of children and adolescents in out-of-home care.

Bisphosphonate Therapy and Tooth Development in Children and Adolescents with Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous connective tissue disorder characterized by repeated fractures and skeletal disorders. At present, bisphosphonate (BP) therapy is the gold standard for OI treatment. The present retrospective study evaluated the effect of BP therapy on tooth development and eruption of permanent teeth in a cohort of children receiving pamidronate. Three groups were studied: patients with OI who were treated with BPs (n = 45), patients with OI who were not treated with BPs (n = 117), and age- and gender-matched healthy controls (n = 121). Dental age, dental maturity, and tooth eruption were assessed on panoramic radiographs using the methods of Demirjian et al. (Hum Biol 45(2):211-227, 1973) and Haavikko (Suom Hammaslaak Toim 66(3):103-170, 1970) and were evaluated using the t-test, Chi-square test, and the Mann-Whitney U test. Dental age in the study group was significantly (p < 0.05) lower than chronological age compared with both control groups. Dental maturity and the eruption of permanent teeth were also significantly (p < 0.05) delayed in the study group in relation to the two control groups. The dental age was significantly lower (p < 0.001) in patients with OI type III treated with BPs compared with healthy controls and the dental maturation was significantly delayed in patients with OI type IV treated with BPs compared with those not treated. In conclusion, BP therapy in OI patients seems to lower the dental age, delay the dental maturity, and tooth eruption. BP administration before 2 years of age might be a contributing factor.

Comparative sequence analysis and mutagenesis of ethylene forming enzyme (EFE) 2-oxoglutarate/Fe(II)-dependent dioxygenase homologs.

BACKGROUND: Ethylene is one of the most used chemical monomers derived from non-renewable sources and we are investigating the possibility of producing it in yeast via the ethylene forming enzyme (EFE) from Pseudomonas syringae. To enable engineering strategies to improve the enzyme, it is necessary to identify the regions and amino acid residues involved in ethylene formation. RESULTS: We identified the open reading frame for the EFE homolog in Penicillium digitatum and also showed its capability of mediating ethylene production in yeast. The sequence of the EFE homologs from P.digitatum and P. syringae was compared to that of the non-functional EFE-homolog from Penicillium chrysogenum and ten amino acids were found to correlate with ethylene production. Several of these amino acid residues were found to be important for ethylene production via point mutations in P. syringae EFE. The EFE homolog from P. chrysogenum was engineered at 10 amino acid residues to mimic the P. syringae EFE, but this did not confer ethylene producing capability.Furthermore, we predicted the structure of EFE by homology to known structures of 2-oxoglutarate/Fe(II) dependent dioxygenases. Three of the amino acids correlating with ethylene production are located in the predicted 2-oxoglutarate binding domain. A protein domain specific for the EFE-class was shown to be essential for activity. Based on the structure and alanine substitutions, it is likely that amino acids (H189, D191 and H268) are responsible for binding the Fe(II) ligand. CONCLUSION: We provide further insight into the structure and function of the ethylene forming (EFE) - subclass of 2-oxoglutarate/Fe(II) dependent dioxygenases. We conclude that residues in addition to the 10 identified positions implicated in ethylene production by sequence comparison, are important for determining ethylene formation. We also demonstrate the use of an alternative EFE gene. The data from this study will provide the basis for directed protein engineering to enhance the ethylene production capability and properties of EFE.

Ethylene production in relation to nitrogen metabolism in Saccharomyces cerevisiae.

We have previously shown that ethylene production in Saccharomyces cerevisiae expressing the ethylene-forming enzyme (EFE) from Pseudomonas syringae is strongly influenced by variations in the mode of cultivation as well as the choice of nitrogen source. Here, we have studied the influence of nitrogen metabolism on the production of ethylene further. Using ammonium, glutamate, glutamate/arginine, and arginine as nitrogen sources, it was found that glutamate (with or without arginine) correlates with a high ethylene production, most likely linked to an observed increase in 2-oxoglutarate levels. Arginine as a sole nitrogen source caused a reduced ethylene production. A reduction of arginine levels, accomplished using an arginine auxotrophic ARG4-deletion strain in the presence of limiting amounts of arginine or through CAR1 overexpression, did however not correlate with an increased ethylene production. As expected, arginine was necessary for ethylene production as ethylene production in the ARG4-deletion strain ceased at the time when arginine was depleted. In conclusion, our data suggest that high levels of 2-oxoglutarate and a limited amount of arginine are required for successful ethylene production in yeast.

Identification of factors for improved ethylene production via the ethylene forming enzyme in chemostat cultures of Saccharomyces cerevisiae.

BACKGROUND: Biotechnological production of the traditional petrochemical ethylene is presently being explored using yeasts as well as bacteria. In this study we quantify the specific ethylene production levels at different conditions in continuous (chemostat) cultivation of Saccharomyces cerevisae expressing the ethylene forming enzyme (EFE) from Pseudomonas syringae. RESULTS: Our study shows that oxygen availability is an important factor for the ethylene formation. Maintaining a high percentage dissolved oxygen in the cultivation was found to be necessary to achieve maximal ethylene productivity. Even at oxygen levels high enough to sustain respiratory metabolism the ethylene formation was restricted. Oxygen was also important for sustaining a high respiratory rate and to re-oxidize the surplus of NADH that accompanies ethylene formation. By employing three different nitrogen sources we further found that the nitrogen source available can both improve and impair the ethylene productivity. Contrary to findings in batch cultures, using glutamate did not give a significant increase in specific ethylene production levels compared to the reference condition with ammonia, whereas a combination of glutamate and arginine resulted in a strongly diminished specific ethylene production. Furthermore, from cultivations at different dilution rates the ethylene formation was found to be coupled to growth rate. CONCLUSION: To optimize the ethylene productivity in S. cerevisiae expressing a bacterial ethylene forming enzyme, controlling the oxygen availability and growth rate as well as employing an ideal nitrogen source is of importance. The effects of these factors as studied here provide a basis for an optimized process for ethylene production in S. cerevisiae.

Synthesis and biological evaluation of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitors based on a thieno[2,3-d]pyrimidin-4(3H)-one core.

Many breast tumors are hormone-dependent, and estrogens, especially estradiol (E2), have a pivotal role in their growth and development. 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is a key enzyme in the biosynthesis of female sex steroids, catalyzing the NADPH-dependent reduction of estrone into biologically active estradiol. In this study, a library of fused (di)cycloalkeno thieno[2,3-d]pyrimidin-4(3H)-one based compounds was synthesized, and the biological activities against 17beta-HSD1 in a cell-free and in a cell-based assay were evaluated. Several thieno[2,3-d]pyrimidin-4(3H)-one based compounds, at 0.1 and 1 muM test concentrations, were found to be potent 17beta-HSD1 inhibitors. For example, 4-(3-hydroxyphenylthio)-1,2,7,8,9,10,11,13-octahydro-13-oxo-[1]benzothieno[2',3':4,5]-pyrimido[1,2-a]azepine-3-carboxaldehyde (7f) is one of the most potent nonsteroidal 17beta-HSD1 inhibitors reported to date with 94% inhibition of the recombinant enzyme at 0.1 muM test concentration. Importantly, the majority of these compounds exhibited excellent selectivity over the oxidative isoform 17beta-HSD2 and lacked estrogenic effects in an estrogen receptor (ER) binding assay.

Plasmid CpG depletion improves degree and duration of tumor gene expression after intravenous administration of polyplexes.

PURPOSE: Tumor gene expression after the intravenous (i.v.) administration of current polymer-based gene delivery systems is generally low and short-lived. Immune stimulatory CpG dinucleotides, present within the plasmid DNA of the polyplexes are likely to contribute to this. The effect of CpG replacement on the levels of transgene expression was studied, after the i.v. administration of polyethylenimine (PEI) polyplexes. METHODS: Tumor transfection and immune stimulation of PEI polyplexes containing plasmid DNA encoding for luciferase and rich in CpG motifs was monitored and compared to polyplexes containing the same gene but devoid of CpG motifs. Lipoplexes based on 1,2-dioleyl-3-trimethylammonium-propane/dioleoylphosphatidylethanolamine liposomes were included as a control. RESULTS: The replacement of CpGrich DNA by CpGfree DNA did neither affect the physical properties of the DNA complexes nor did it affect their in vitro transfection activity or cytotoxicity. The immune stimulation (interleukin-12) after i.v. administration of the PEI DNA complexes was low and unaffected by the presence of CpG motifs. The absence of CpG motifs within the different DNA complexes improved the degree and the duration of organ and tumor gene expression. CONCLUSION: The depletion of CpG dinucleotides within the plasmid DNA of polyplexes enhances the degree and duration of in vivo transgene expression.

Enzyme inhibitor screening using a homogeneous proximity-based immunoassay for estradiol.

The authors have previously reported a homogeneous time-resolved fluorescence proximity immunoassay for estradiol. The assay was based on luminescence resonance energy transfer between a long lifetime fluorescent europium(III) chelate-dyed nanoparticle donor and a short lifetime, near-infrared fluorescent acceptor. The energy transfer prolonged the lifetime of the sensitized acceptor emission, and the fluorescence of the acceptor was measured using a time-resolved detection. The developed immunoassay was employed to screen inhibitors for enzyme 17beta-hydroxysteroid dehydrogenase type 1. The enzyme overexpressed in MCF-7 cells catalyzed a reversible conversion of estroneto17beta-estradiol. The inhibition efficiency of the tested molecule was obtained by comparing the final concentration of converted estradiol after 60 min of conversion reaction in a sample and in a conversion control not containing an inhibitor. The Zbeta factor calculated using the E2 concentrations of the homogeneous assay was 0.64, demonstrating a relatively good performance of the assay. The results from the homogeneous assay were comparable with the results obtained using radioactively labeled estrone as a substrate and high-performance liquid chromatography (HPLC) separation of estrone and converted estradiol after the enzyme reaction. Thus, this homogeneous assay can simplify the primary screening of potential new drug molecules by replacing a tedious radiometric HPLC method.

Relationship between mercury concentration in blood, cognitive performance, and blood pressure, in an elderly urban population.

Concentration of mercury (Hg) in whole blood in an elderly urban population with a mean age of 87 years was studied in relation to cognitive function, arterial blood pressure (arterial BP), age, gender, body mass index (BMI) and smoking habits. This population-based study consisted of 106 subjects both males and females. Clinical assessment of the subjects included medical and social history, physical and neurologic examination and assessment of cognitive functions with Mini-Mental State Examination (MMSE). Information on use of all potentially antihypertensive drugs was collected. Whole blood from 106 subjects were collected and analysed for mercury by Cold Vapour Atomic Absorption Spectrometry (Milton Ray ASS-CV) with Seronorm Trace Element as matrix matched quality control. Males and females did not differ in blood-mercury (B-Hg) concentrations or in any of the other studied variables. B-Hg concentrations did not differ between smokers and non-smokers. Females were treated more often than males with antihypertensive drugs. There was no relation found between B-Hg concentration and cognitive function, arterial BP, age, gender or BMI. In conclusion, no relations were found between B-Hg concentrations and the studied variables.

Expression of collagenase-3 (MMP-13) enhances invasion of human fibrosarcoma HT-1080 cells.

Collagenase-3 (MMP-13) is characterized by an exceptionally wide substrate specificity and restricted expression. MMP-13 is 1 of the few MMPs primarily expressed by tumor cells in malignant tumors, e.g., squamous cell carcinomas and its expression correlates with their invasion capacity. In this work, we have constructed an expression vector and a recombinant adenovirus harboring human MMP-13 cDNA to investigate the role of MMP-13 in cancer cell invasion. Our results show that constitutive expression of MMP-13 by HT-1080 cells stably transfected with MMP-13 expression vector or transduced with MMP-13 adenovirus markedly increased their invasion both through type I collagen and reconstituted basement membrane (Matrigel) with no alterations in expression or activation of collagenase-1 (MMP-1), gelatinase-A (MMP-2), or gelatinase-B (MMP-9). The enhanced invasion capacity of MMP-13 expressing HT-1080 cells was dependent on MMP activity, as it was blocked by MMP inhibitor Batimastat (BB-94) and tissue inhibitor of metalloproteinases-3 (TIMP-3). Our data provide direct evidence for the role of MMP-13 as a potent invasion proteinase, which alone can enhance the ability of malignant cells to penetrate through both basement membrane and fibrillar collagen.