Dyrk1a is required for craniofacial development in Xenopus laevis.

Loss of function variations in the dual specificity tyrosine-phosphorylation-regulated kinase 1 A (DYRK1A) gene are associated with craniofacial malformations in humans. Here we characterized the effects of deficient DYRK1A in craniofacial development using a developmental model, Xenopus laevis. Dyrk1a mRNA and protein were expressed throughout the developing head and both were enriched in the branchial arches which contribute to the face and jaw. Consistently, reduced Dyrk1a function, using dyrk1a morpholinos and pharmacological inhibitors, resulted in orofacial malformations including hypotelorism, altered mouth shape, slanted eyes, and narrower face accompanied by smaller jaw cartilage and muscle. Inhibition of Dyrk1a function resulted in misexpression of key craniofacial regulators including transcription factors and members of the retinoic acid signaling pathway. Two such regulators, sox9 and pax3 are required for neural crest development and their decreased expression corresponds with smaller neural crest domains within the branchial arches. Finally, we determined that the smaller size of the faces, jaw elements and neural crest domains in embryos deficient in Dyrk1a could be explained by increased cell death and decreased proliferation. This study is the first to provide insight into why craniofacial birth defects might arise in humans with variants of DYRK1A.

Peritoneal Dialysis Technique Survival: A Cohort Study.

RATIONALE & OBJECTIVE: Reasons for transfer from peritoneal dialysis (PD) to hemodialysis (HD) remain incompletely understood. Among incident and prevalent patients receiving PD, we evaluated the association of clinical factors, including prior treatment with HD, with PD technique survival. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adults who initiated PD at a Dialysis Clinic, Inc (DCI) outpatient facility between January 1, 2010, and September 30, 2019. EXPOSURE: The primary exposure of interest was timing of PD start, categorized as PD-first, PD-early, or PD-late. Other covariates included demographics, clinical characteristics, and routine laboratory results. OUTCOME: Modality switch from PD to HD sustained for more than 90 days. ANALYTICAL APPROACH: Multivariable Fine-Gray models with competing risks and time-varying covariates, stratified at 9 months to account for lack of proportionality. RESULTS: Among 5,224 patients who initiated PD at a DCI facility, 3,174 initiated dialysis with PD ("PD-first"), 942 transitioned from HD to PD within 90 days ("PD-early"), and 1,108 transitioned beyond 90 days ("PD-late"); 1,472 (28%) subsequently transferred from PD to HD. The PD-early and PD-late patients had a higher risk of transfer to HD as compared with PD-first patients (in the first 9 months: adjusted hazard ratio [AHR], 1.51 [95% CI, 1.17-1.96] and 2.41 [95% CI, 1.94-3.00], respectively; and after 9 months: AHR, 1.16 [95% CI, 0.99-1.35] and AHR, 1.43 [95% CI, 1.24-1.65], respectively). More peritonitis episodes, fewer home visits, lower serum albumin levels, lower residual kidney function, and lower peritoneal clearance calculated with weekly Kt/V were additional risk factors for PD-to-HD transfer. LIMITATIONS: Missing data on dialysis adequacy and residual kidney function, confounded by short PD technique survival. CONCLUSIONS: Initiating dialysis with PD is associated with greater PD technique survival, though many of those who initiate PD-late in their dialysis course still experience substantial time on PD. Peritonitis, lower serum albumin, and lower Kt/V are risk factors for PD-to-HD transfer that may be amenable to intervention. PLAIN-LANGUAGE SUMMARY: Peritoneal dialysis (PD) is an important kidney replacement modality with several potential advantages compared with in-center hemodialysis (HD). However, a substantial number of patients transfer to in-center HD early on, without having experienced the quality-of-life and other benefits that come with sustained maintenance of PD. Using retrospective data from a midsize national dialysis provider, we found that initiating dialysis with PD is associated with longer maintenance of PD, compared with initiating dialysis with HD and a later switch to PD. However, many of those who initiate PD-late in their dialysis course still experience substantial time on PD. Peritonitis, lower serum albumin, and lower small protein removal are other risk factors for PD-to-HD transfer that may be amenable to intervention.

Co-culture of chondrocytes and stem cells: a review of head and neck cell lines for cartilage regeneration.

INTRODUCTION: Bioprinting, using "bio-inks" consisting of living cells, supporting structures and biological motifs to create customized constructs, is an emerging technique that aims to overcome the challenges of cartilaginous reconstruction of head and neck structures. Several living cell lines and culturing methods have been explored as bio-inks with varying efficacy. Co-culture of primary chondrocytes and stem cells (SCs) is one technique, well established for degenerative joint disease treatment, with potential for use in expanding chondrocyte populations for bio-inks. This study aims to evaluate the techniques for co-culture of primary chondrocytes and SCs for head and neck cartilage regeneration. METHODS: A literature review was performed through OVID/Web of Science/MEDLINE/BIOSIS Previews/Embase. Studies reporting on chondrocytes and SCs in conjunction with co-culture or cartilage regeneration were included. Studies not reporting on findings from chondrocytes/SCs of the head and neck were excluded. Extracted data included cell sources, co-culture ratios and histological, biochemical and clinical outcomes. RESULTS: 15 studies met inclusion criteria. Auricular cartilage was the most common chondrocyte source (n=10), then nasal septum (n=5), articular (n=1) and tracheal cartilage (n=1). Bone marrow was the most common SC source (n=9) then adipose tissue (n=7). Techniques varied, with co-culture ratios ranging from 1:1 to 1:10. All studies reported co-culture to be superior to SC mono-culture by all outcomes. Most studies reported superiority or equivalence of co-culture to chondrocyte mono-culture by all outcomes. When comparing clinical outcomes, co-culture constructs were equivalent to chondrocyte mono-culture in diameter, and equivalent or inferior in wet weight and height. CONCLUSION: Co-culture of primary chondrocytes and SCs is a promising technique for expanding chondrocyte populations, with at least equivalence to chondrocyte mono-culture and superior to SC mono-culture when seeded at the same chondrocyte densities. However, there remains a lack of consensus regarding the optimal cell sources and co-culture ratios.

Enhancing Cementitious Composites with Functionalized Graphene Oxide-Based Materials: Surface Chemistry and Mechanisms.

Graphene oxide-based materials (GOBMs) have been widely explored as nano-reinforcements in cementitious composites due to their unique properties. Oxygen-containing functional groups in GOBMs are crucial for enhancing the microstructure of cementitious composites. A better comprehension of their surface chemistry and mechanisms is required to advance the potential applications in cementitious composites of functionalized GOBMs. However, the mechanism by which the oxygen-containing functional groups enhance the response of cementitious composites is still unclear, and controlling the surface chemistry of GOBMs is currently constrained. This review aims to investigate the reactions and mechanisms for functionalized GOBMs as additives incorporated in cement composites. A variety of GOBMs, including graphene oxide (GO), hydroxylated graphene (HO-G), edge-carboxylated graphene (ECG), edge-oxidized graphene oxide (EOGO), reduced graphene oxide (rGO), and GO/silane composite, are discussed with regard to their oxygen functional groups and interactions with the cement microstructure. This review provides insight into the potential benefits of using GOBMs as nano-reinforcements in cementitious composites. A better understanding of the surface chemistry and mechanisms of GOBMs will enable the development of more effective functionalization strategies and open up new possibilities for the design of high-performance cementitious composites.

Technology-enabled multidisciplinary team in-reach for oral corticosteroid stewardship and optimizing care of suspected airways disease exacerbations.

Overuse of corticosteroids is an important problem not only in asthma but also the management of other airways diseases including bronchiectasis and COPD and results in associated risks of serious side effects and irreversible harm. We report a pilot using an in-reach solution to review patients, optimise their care and facilitate early discharge. We discharged >20% of our patients immediately, which is potentially a significant reduction in hospital bed use and, most importantly, through this approach we were able to establish early diagnosis and reduce inappropriate oral corticosteroid use.

Analysis of low birth weight first-born babies by geography and deprivation as an aid to policy and service targeting.

BACKGROUND: Low birth weight (LBW), which is defined as a birth weight of <2500 g, is considered to be an indicator of a range of negative health outcomes. METHODS: The feasibility of using child health data at small area (SA) level to explore patterns of LBW in an Irish region comprising the counties of Dublin, Kildare and Wicklow (DKW) for the 2006-2015 period was assessed. A logistic regression model was created using R software. RESULTS: LBW occurred in 5% of births to first time mothers and was associated with living in more deprived areas (OR: 1.5) and a maternal age of over 40 years (OR: 1.8). CONCLUSION: The potential of geocoding routinely collected data to explore the relationship between child health indicators and areas of deprivation, and inform the targeting of resources to reduce health inequalities is demonstrated.

Graphene Oxide-Based Nanomaterials: An Insight into Retinal Prosthesis.

Retinal prosthesis has recently emerged as a treatment strategy for retinopathies, providing excellent assistance in the treatment of age-related macular degeneration (AMD) and retinitis pigmentosa. The potential application of graphene oxide (GO), a highly biocompatible nanomaterial with superior physicochemical properties, in the fabrication of electrodes for retinal prosthesis, is reviewed in this article. This review integrates insights from biological medicine and nanotechnology, with electronic and electrical engineering technological breakthroughs, and aims to highlight innovative objectives in developing biomedical applications of retinal prosthesis.

The effects of monoclonal anti-CD47 on RBCs, compatibility testing, and transfusion requirements in refractory acute myeloid leukemia.

BACKGROUND: CD47 is a novel therapeutic target in the treatment of solid-organ and hematologic malignancies. CD47 is also expressed on RBCs. Here, we report our experience of the RBC effects and the impact on blood bank testing and transfusion management in a Phase 1 trial of the humanized anti-CD47 monoclonal antibody Hu5F9-G4 in relapsed or primary refractory acute myeloid leukemia (AML) (NCT02678338). STUDY DESIGN AND METHODS: Nineteen patients with relapsed or primary refractory AML treated across five UK centers were included for analysis. Patients received escalating doses of Hu5F9-G4. Serial laboratory data were collected to evaluate impact on hemoglobin (Hb), markers of hemolysis (bilirubin, lactate dehydrogenase, reticulocyte count), transfusion requirements, and blood compatibility testing. RESULTS: A decline in Hb was observed with drug administration (median Hb change, -1.0 g/dL; range, 0.4-1.6) with associated increase in transfusion requirements. Patients responded to transfusion with a median Hb increment per unit of 1.0 g/dL. RBC agglutination was seen in all cases without associated change in Hb, lactate dehydrogenase, bilirubin, or reticulocyte count. Nine of 19 (47%) patients developed a newly positive antibody screen with a pan-agglutinin identified in plasma. Invalid ABO blood grouping occurred in 4 of 12 (33%) non-group O patients due to anomalous reactivity in the reverse ABO-type results. CONCLUSIONS: Treatment with Hu5F9-G4 in patients with AML resulted in an Hb decline and increased transfusion requirements. Problems with ABO blood typing and compatibility testing were widely observed and should be expected by centers treating recipients of Hu5F9-G4.

A Comparison of Summer and Winter Emergency Hospitalisations in Ireland

There is increasing demand on the Irish health service, particularly in winter months. This study described and compared acute hospitals admissions across summer and winter periods from 2015 to 2018. The analysis used Hospital In-Patient Enquiry data accessed through the National Quality Assurance Information System ­ NQAIS Clinical. There were 84 additional emergency hospitalisations in winter per week compared with summer (1.2% increase). Across diagnostic categories, emergency hospitalisations reduced in winter, except respiratory conditions which increased by 379 per week representing a 40.5% increase. The profile of emergency respiratory admissions were similar in summer and winter in terms of age, length of stay, day of week and medical card status. Length of stay was approximately one day longer for weekend admissions in both seasons. This research highlights the importance of taking a whole-population approach to winter resilience planning, focussing on prevention and optimal management of respiratory conditions.

Is Increasing Life Expectancy Leading To More Complexity?

Life expectancy is increasing in Ireland, but whether this has resulted in healthier life years among the elderly and its impact (if any) on hospital services is unknown. The purpose of the study was to use routinely available data to explore the relationship of age and indicators of clinical complexity in acute hospitals over ten years. The study included all in-patients aged 65+ years from the Hospital In-Patient Enquiry (HIPE) discharged between 2005 and 2014. Indicators of complexity included the Charlson index, overall length of stay (LOS), intensive care unit LOS and deaths in hospital, analysed by the major clinical classification software (CCS). Over the period, the number and rate of admissions increased, especially among those aged 85+. Indicators of patient complexity increased and LOS decreased. In-hospital mortality decreased from 5.9% to 4.7%. Hospitals appear to be managing the emergency care of the older and more complex patient more efficiently and with better outcomes.

Inpatient Children and Adolescent Mental Health Services (CAMHS): outcomes of young people with and without intellectual disability.

BACKGROUND: Little is known about the effectiveness of inpatient care for young people with co-morbid mental illness and intellectual disability (ID). This study aims to compare the demographics and outcome of young people with mental illness with or without ID admitted to psychiatric hospital. A secondary aim is to look into the outcome of those with ID admitted to general mental health young people's units. METHOD: Data were collected on the outcome of young people's admissions to specialist ID and general adolescent mental health units as part of a larger quality improvement project run by the College Centre for Quality Improvement. Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) scores were completed by local clinical staff at admission and discharge on 38 young people with and 113 people without ID from 14 units. RESULTS: Young people with mental disorders significantly improved clinically over the admission whether or not they had ID. There were no differences between the groups in age or use of the Mental Health Act but people admitted with ID were more likely to be male and had longer lengths of stay. Admission to a general adolescent unit was associated with clinical improvement for people with ID. CONCLUSIONS: This study needs replication because of the small sample and incomplete data but it suggests that young people with ID and mental disorders significantly improve clinically when admitted to hospital as do their non-disabled peers.

Who mixes with whom among men who have sex with men? Implications for modelling the HIV epidemic in southern India.

In India, the identity of men who have sex with men (MSM) is closely related to the role taken in anal sex (insertive, receptive or both), but little is known about sexual mixing between identity groups. Both role segregation (taking only the insertive or receptive role) and the extent of assortative (within-group) mixing are known to affect HIV epidemic size in other settings and populations. This study explores how different possible mixing scenarios, consistent with behavioural data collected in Bangalore, south India, affect both the HIV epidemic, and the impact of a targeted intervention. Deterministic models describing HIV transmission between three MSM identity groups (mostly insertive Panthis/Bisexuals, mostly receptive Kothis/Hijras and versatile Double Deckers), were parameterised with behavioural data from Bangalore. We extended previous models of MSM role segregation to allow each of the identity groups to have both insertive and receptive acts, in differing ratios, in line with field data. The models were used to explore four different mixing scenarios ranging from assortative (maximising within-group mixing) to disassortative (minimising within-group mixing). A simple model was used to obtain insights into the relationship between the degree of within-group mixing, R0 and equilibrium HIV prevalence under different mixing scenarios. A more complex, extended version of the model was used to compare the predicted HIV prevalence trends and impact of an HIV intervention when fitted to data from Bangalore. With the simple model, mixing scenarios with increased amounts of assortative (within-group) mixing tended to give rise to a higher R0 and increased the likelihood that an epidemic would occur. When the complex model was fit to HIV prevalence data, large differences in the level of assortative mixing were seen between the fits identified using different mixing scenarios, but little difference was projected in future HIV prevalence trends. An oral pre-exposure prophylaxis (PrEP) intervention was modelled, targeted at the different identity groups. For intervention strategies targeting the receptive or receptive and versatile MSM together, the overall impact was very similar for different mixing patterns. However, for PrEP scenarios targeting insertive or versatile MSM alone, the overall impact varied considerably for different mixing scenarios; more impact was achieved with greater levels of disassortative mixing.

A FIB induced boiling mechanism for rapid nanopore formation.

Focused ion beam (FIB) technology is widely used to fabricate nanopores in solid-state membranes. These nanopores have desirable thermomechanical properties for applications such as high-throughput DNA sequencing. Using large scale molecular dynamics simulations of the FIB nanopore formation process, we show that there is a threshold ion delivery rate above which the mechanism underlying nanopore formation changes. At low rates nanopore formation is slow, with the rate proportional to the ion flux and therefore limited by the sputter rate of the target material. However, at higher fluxes nanopores form via a thermally dominated process, consistent with an explosive boiling mechanism. In this case, mass is rapidly rearranged via bubble growth and coalescence, much more quickly than would occur during sputtering. This mechanism has the potential to greatly speed up nanopore formation.

Investigation of an association between onset of narcolepsy and vaccination with pandemic influenza vaccine, Ireland April 2009-December 2010.

In 2011, the Irish Medicines Board received reports of onset of narcolepsy following vaccination against influenza A(H1N1)pdm09 with Pandemrix. A national steering committee was convened to examine the association between narcolepsy and pandemic vaccination. We conducted a retrospective population-based cohort study. Narcolepsy cases with onset from 1 April 2009 to 31 December 2010 were identified through active case finding. Narcolepsy history was gathered from medical records. Pandemic vaccination status was obtained from vaccination databases. Two independent experts classified cases using the Brighton case definition. Date of onset was defined as date of first healthcare contact for narcolepsy symptoms. Incidence of narcolepsy in vaccinated and non-vaccinated individuals was compared. Of 32 narcolepsy cases identified, 28 occurred in children/adolescents and for 24 first healthcare contact was between April 2009 and December 2010. Narcolepsy incidence was 5.7 (95% confidence interval (CI): 3.4­8.9) per 100,000 children/adolescents vaccinated with Pandemrix and 0.4 (95% CI: 0.1­1.0) per 100,000 unvaccinated children/adolescents (relative risk: 13.9; absolute attributable risk: 5.3 cases per 100,000 vaccinated children/adolescents). This study confirms the crude association between Pandemrix vaccination and narcolepsy as observed in Finland and Sweden. The vaccine is no longer in use in Ireland. Further studies are needed to explore the immunogenetic mechanism of narcolepsy.

Dyrk1a is required for craniofacial development in Xenopus laevis.

Loss of function mutations in the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene are associated with craniofacial malformations in humans. Here we characterized the effects of deficient DYRK1A in craniofacial development using a developmental model, Xenopus laevis . Dyrk1a mRNA and protein was expressed throughout the developing head and was enriched in the branchial arches which contribute to the face and jaw. Consistently, reduced Dyrk1a function, using dyrk1a morpholinos and pharmacological inhibitors, resulted in orofacial malformations including hypotelorism, altered mouth shape, slanted eyes, and narrower face accompanied by smaller jaw cartilage and muscle. Inhibition of Dyrk1a function resulted in misexpression of key craniofacial regulators including transcription factors and members of the retinoic acid signaling pathway. Two such regulators, sox9 and pax3 are required for neural crest development and their decreased expression corresponds with smaller neural crest domains within the branchial arches. Finally, we determined that the smaller size of the faces, jaw elements and neural crest domains in embryos deficient in Dyrk1a could be explained by increased cell death and decreased proliferation. This study is the first to provide insight into why craniofacial birth defects might arise in humans with DYRK1A mutations.

Patterned graphene oxide via one-step thermal annealing for controlling collective cell migration.

Graphene oxide (GO) is a two-dimensional metastable nanomaterial. Interestingly, GO formed oxygen clusterings in addition to oxidized and graphitic phases during the low-temperature thermal annealing process, which could be further used for biomolecule bonding. By harnessing this property of GO, we created a bio-interface with patterned structures with a common laboratory hot plate that could tune cellular behavior by physical contact. Due to the regional distribution of oxygen clustering at the interface, we refer to it as patterned annealed graphene oxide (paGO). In addition, since the paGO was a heterogeneous interface and bonded biomolecules to varying degrees, arginine-glycine-aspartic acid (RGD) was modified on it and successfully regulated cellular-directed growth and migration. Finally, we investigated the FRET phenomenon of this heterogeneous interface and found that it has potential as a biosensor. The paGO interface has the advantages of easy regulation and fabrication, and the one-step thermal reduction method is suitable for biological applications. We believe that this low-temperature thermal annealing method would make GO interfaces more accessible, especially for the development of nano-interfacial modifications for biological applications, revealing its potential for biomedical applications.

Situational, interpersonal, and intrapersonal characteristic associations with adolescent conflict forgiveness.

ABSTRACT. Given the voluntary nature of adolescent friendships, forgiveness of interpersonal transgressions has been identified as a critical aspect of maintaining these relationships. However, transgression forgiveness is related to a range of situational (e.g., transgression severity), interpersonal (e.g., friendship commitment), and intrapersonal (e.g., victim's empathy) factors. Data from 161 adolescents were used to examine the nature of the relationships between these factors and forgiveness and to examine the differential association patterns for adolescent boys and girls. Results for the overall adolescent sample indicated both situational and interpersonal factor associations with forgiveness (R2 = .52, p < .001). Examination of separate female and male forgiveness reports indicated similar interpersonal factor associations and differential situational factor associations with female (R2 = .46, p < .001), and male (R2 = .60, p < .001) forgiveness. Findings suggest the likelihood of forgiving may be contextually dependent, and that researchers should consider transgression, relationship, and intrapersonal characteristics when examining forgiveness. Further, the present study suggests the contextual factors associated with forgiveness may be further differentiated by gender.

Use of a geographic information system to map cases of measles in real-time during an outbreak in Dublin, Ireland, 2011.

In 2011, there was a large measles outbreak in Dublin. Nationally 285 cases were notified to the end of December 2011, and 250 (88%) were located in the Dublin region. After the first case was notified in week 6, numbers gradually increased, with 25 notified in June and a peak of 53 cases in August. Following public health intervention including a measles-mumps-rubella (MMR) vaccination campaign, no cases were reported in the Dublin region in December 2011. Most cases (82%) were children aged between 6 months and 14 years, and 46 cases (18%) were under 12 months-old. This is the first outbreak in Dublin to utilise a geographic information system for plotting measles cases on a digital map in real time. This approach, in combination with the analysis of case notifications, assisted the department of public health in demonstrating the extent of the outbreak. The digital mapping documented the evolution of two distinct clusters of 87 (35%) cases. These measles cases were infected with genotype D4-Manchester recently associated with large outbreaks across Europe. The two clusters occurred in socio-economically disadvantaged areas and were attributable to inadequate measles vaccination coverage due in part to the interruption of a school-based MMR2 vaccination programme.

Relationship duration moderation of identity status differences in emerging adults' same-sex friendship intimacy.

Previous research has not yielded consistent identity and intimacy associations for female and male emerging adults. Intimacy varies with time spent in a relationship, and relationship duration may explain variations in the identity process association with intimacy. Data from 278 female and 156 male emerging adults revealed relationship duration moderated the identity commitment and exploration associations with intimacy. Findings indicated longer relationship duration was associated with lower intimacy levels for high identity commitment/high exploration females, and longer relationship duration was associated with higher intimacy levels for high commitment/low exploration females. Findings also indicated longer relationship duration was associated with higher intimacy levels for high commitment/high exploration males, and longer relationship duration was associated with lower intimacy levels for low commitment/high exploration males. Findings are discussed with regards to the empirical importance of considering relationship characteristics when examining emerging adult identity process associations with friendship intimacy.