Associations between type 1 diabetes and educational outcomes: an Aotearoa/New Zealand nationwide birth cohort study using the Integrated Data Infrastructure.

AIMS/HYPOTHESIS: Type 1 diabetes is one of the most common chronic diseases of childhood. It is hypothesised that the metabolic and psychosocial consequences of type 1 diabetes may affect educational outcomes; however, existing literature presents conflicting results. This study aimed to assess whether educational outcomes differ for young people with and without type 1 diabetes in Aotearoa/New Zealand (NZ). METHODS: This was a nationwide 9 year birth cohort study of all people born in NZ from 1993 to 2001 using linked administrative data held within the Integrated Data Infrastructure, a national research database containing linked health and non-health data. Educational outcomes of high school attainment, high school attendance and university enrolment were measured from age 13 years until 20 years. Generalised linear regression models with log link and Gaussian distributions were used to compare educational outcomes between those with and those without type 1 diabetes, adjusting for sociodemographic and maternal characteristics. RESULTS: Of the 442,320 children in the birth cohort, type 1 diabetes was identified in 2058 (0.47%) (mean [SD] age of type 1 diabetes diagnosis 7.7 [3.4] years). Educational outcomes were significantly lower for children with type 1 diabetes than for those without type 1 diabetes, including for any high school qualification (RR 0.97 [95% CI 0.95, 0.99]), university entrance-level high school attainment (RR 0.88 [95% CI 0.84, 0.92]), regular high school attendance (RR 0.91 [95% CI 0.85, 0.97]) and university enrolment (RR 0.93 [95% CI 0.88, 0.98]), even after adjusting for sociodemographic and maternal factors. In addition, educational outcomes were substantially lower for those with post type 1 diabetes diagnosis hospitalisations for diabetic ketoacidosis and hypoglycaemia. CONCLUSIONS/INTERPRETATION: In this whole NZ birth cohort study, type 1 diabetes was associated with lower educational outcomes spanning secondary school and into university enrolment. Ongoing efforts to support students with type 1 diabetes are needed, particularly for those with a greater risk profile.

Lenvatinib-Loaded Poly(lactic-co-glycolic acid) Nanoparticles with Epidermal Growth Factor Receptor Antibody Conjugation as a Preclinical Approach to Therapeutically Improve Thyroid Cancer with Aggressive Behavior.

BACKGROUND: Lenvatinib, a tyrosine kinase inhibitor (TKI) approved for the treatment of progressive and radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC), is associated with significant adverse effects that can be partially mitigated through the development of novel drug formulations. The utilization of nanoparticles presents a viable option, as it allows for targeted drug delivery, reducing certain side effects and enhancing the overall quality of life for patients. This study aimed to produce and assess, both in vitro and in vivo, the cytotoxicity, biodistribution, and therapeutic efficacy of lenvatinib-loaded PLGA nanoparticles (NPs), both with and without decoration using antibody conjugation (cetuximab), as a novel therapeutic approach for managing aggressive thyroid tumors. METHODS: Poly(lactic-co-glycolic acid) nanoparticles (NPs), decorated with or without anti-EGFR, were employed as a lenvatinib delivery system. These NPs were characterized for size distribution, surface morphology, surface charge, and drug encapsulation efficiency. Cytotoxicity was evaluated through MTT assays using two cellular models, one representing normal thyroid cells (Nthy-ori 3-1) and the other representing anaplastic thyroid cells (CAL-62). Additionally, an in vivo xenograft mouse model was established to investigate biodistribution and therapeutic efficacy following intragastric administration. RESULTS: The NPs demonstrated success in terms of particle size, polydispersity index (PDI), zeta potential, morphology, encapsulation efficiency, and cetuximab distribution across the surface. In vitro analysis revealed cytotoxicity in both cellular models with both formulations, but only the decorated NPs achieved an ID50 value in CAL-62 cells. Biodistribution analysis following intragastric administration in xenografted thyroid mice demonstrated good stability in terms of intestinal barrier function and tumor accumulation. Both formulations were generally well tolerated without inducing pathological effects in the examined organs. Importantly, both formulations increased tumor necrosis; however, decorated NPs exhibited enhanced parameters related to apoptotic/karyolytic forms, mitotic index, and vascularization compared with NPs without decoration. CONCLUSIONS: These proof-of-concept findings suggest a promising strategy for administering TKIs in a more targeted and effective manner.

Dopamine receptors D1 and D2 show prognostic significance and potential therapeutic applications for endometrial cancer patients.

OBJECTIVE: Catecholaminergic signaling has been a target for therapy in different type of cancers. In this work, we characterized the ADRß2, DRD1 and DRD2 expression in healthy tissue and endometrial tumors to evaluate their prognostic significance in endometrial cancer (EC), unraveling their possible application as an antitumor therapy. METHODS: 109 EC patients were included. The expression of the ADRß2, DRD1 and DRD2 proteins was evaluated by immunohistochemistry and univariate and multivariate analysis to assess their association with clinic-pathological and outcome variables. Finally, HEC1A and AN3CA EC cell lines were exposed to different concentrations of selective dopaminergic agents alone or in combination to study their effects on cellular viability. RESULTS: ADRß2 protein expression was not associated with clinico-pathological parameters or prognosis. DRD1 protein expression was reduced in tumors samples but showed a significant inverse association with tumor size and stage. DRD2 protein expression was significantly associated with non-endometrioid EC, high grade tumors, tumor size, worse disease-free survival (HR = 3.47 (95%CI:1.35-8.88)) and overall survival (HR = 2.98 (95%CI:1.40-6.34)). The DRD1 agonist fenoldopam showed a reduction of cellular viability in HEC1A and AN3CA cells. The exposure to domperidone, a DRD2 antagonist, significantly reduced cell viability compared to the control. Finally, DRD1 agonism and DRD2 antagonism combination induced a significant reduction in cell viability of the AN3CA cells compared to monotherapy, close to being an additive response than a synergistic effect (CI of 1.1 at 0.5% Fa). CONCLUSION: DRD1 and DRD2 expression levels showed a significant association with clinico-pathological parameters. Both the combined activation of DRD1 and blockage of DRD2 may form an innovative strategy to inhibit tumor growth in EC.

Diet-induced ketosis in adult patients with subacute acquired brain injury: a feasibility study.

Background: Research in animal models on cerebral metabolism after brain injury highlights the potential benefits of ketosis in reducing secondary brain injury, but studies in humans are lacking. Aim: This study aimed to examine if a 6-week ketogenic diet intervention with added medium-chain triglycerides (MCT) was feasible in adult patients with acquired brain injury in the subacute phase, whether ketosis could be achieved and maintained, and to what extent serious adverse reactions, adverse reactions, serious adverse events, and adverse events occured. Methods: Patients ≥18 years of age diagnosed with subacute acquired brain injury and an expectation of hospitalisation ≥6 weeks were included in the intervention group. Patients not included in the intervention group were included in a standard care reference group. The intervention consisted of a ketogenic diet supplemented with MCT to obtain a plasma concentration of ß-hydroxybutyrate (BHB) ≥0.5 mmol/L. Patients who were enterally fed were given KetoCal® 2.5:1 LQ MCT Multi Fiber (Nutricia A/S, Allerød, Denmark), supplemented with Liquigen® (Nutricia A/S, Allerød, Denmark). Patients consuming oral nutrition were given KetoCal® 2.5:1 LQ MCT Multi Fiber supplemented with Liquigen®, in addition to ketogenic meals. Results: During a 13-week inclusion period, 12 of 13 eligible patients (92% [95% CI: 67% to 99%]) were included in the intervention group, and 17 of 18 excluded patients (94% [95% CI: 74% to 99%]) were included in the reference group. Eight patients (67%) completed the 6-week intervention. It took a median of 1 day to achieve ketosis from starting a 100% MCT ketogenic diet, and it was maintained for 97% of the intervention period after ketosis was obtained. There were no serious adverse reactions to the MCT ketogenic diet, and patients experienced adverse reactions not considered serious in 9.5% of days with the intervention. The MCT ketogenic diet was accepted by patients on all intervention days, and in the two patients transitioning from enteral feeding to oral intake, there were no complications related to transitioning. Conclusion: Intervention with MCT ketogenic diet is feasible and tolerated for 6 weeks in hospitalised adult patients with subacute acquired brain injury. Randomised controlled trials are needed to assess the benefits and harms of the MCT ketogenic diet and the effect on patients' recovery.Clinical trial registration: ClinicalTrials.gov, identifier [NCT04308577].

Sporadic implementation of UK familial mammographic surveillance guidelines 15 years after original publication.

The National Institute of health and Care Excellence issued guidelines on familial breast cancer screening in 2004. Such guidelines should be uniformly implemented to ensure that members of the same family with the same level of risk, but living in different areas, have the same access to screening. We assessed uptake by creating a short, six question online survey designed to assess compliance in each regional area. We used this to conduct a survey of all 22 regional genetics services. There was a 100% response to the survey allowing a complete map to be created. The devolved nations had near complete compliance with the sole exception of SW Scotland, but in England the picture was fragmented with regions representing a combined population of 26.6 million (48%) not implementing the full NICE recommendations. Fifteen years after the publication of the original guidelines, major inequity in provision for screening still occurs and a postcode lottery exists for the management of women from families with a history of breast cancer. We estimate that up to 73 preventable breast cancer deaths occur each year due to the current inequity of access. It may be time to consider alternative funding and implementation models to ensure consistent access across the country.

Home Groups: Integrating Peer Support and Clinical Care in a Community Mental Health Center.

With peer supporters now comprising one of the most rapidly growing components of the mental health workforce, group interventions that combine their expertise with those of more traditional mental health providers are needed. An example of one such intervention, developed and implemented at a large community mental health center for individuals with serious mental illnesses, is presented. Called a "Home Group" and co-led by peers and clinical psychology interns, this intervention provides unique learning opportunities for peers and trainees and many potential benefits to group members. Vignettes to illustrate the model are presented and the potential therapeutic and empowering aspects of this innovative and promising approach are identified and discussed.

In vitro assessment of the Lenz effect on heart valve prostheses at 1.5 T.

PURPOSE: Increasing numbers of patients with cardiac valve prostheses are being referred for magnetic resonance imaging (MRI) despite concerns about the potential for functional valve impedance due to Lenz forces. This study aims to determine, in vitro, the occurrence of Lenz forces on 9 heart valve prostheses at 1.5 T and assess the risk of impedance of valve function. MATERIALS AND METHODS: A specially designed hydro-pneumatic system was used to record pressure changes across the valve indicative of any MR induced alteration in leaflet performance. Nine cardiac valve prostheses were exposed to the B0 field at 1.5 T. Each valve was advanced through the B0 field and continuous signals from high frequency pressure transducers were recorded and pressure drops across the valve were assessed using time correction superimposition. The delta p across the valve was assessed as a marker of any MRI induced alteration in leaflet performance. RESULTS: All prostheses produced sinusoidal waveforms. Profiles were asymmetrical and there was no consistency in complex shape and valve type/sub-group. Irregularities in pressure profiles of 4 prostheses were detected indicating resistance of the occluder to the B0 field. CONCLUSION: This study provides empirical evidence of the Lenz Effect on cardiac valve prostheses exposed to the MR B0 field causing functional valve impedance and increasing the risk of valvular regurgitation and reduced cardiac output. Thus, it is essential to consider the potential for the Lenz Effect when scanning cardiac valve implant patients in order to safeguard their wellbeing.

'Being a presence': The ways in which family support workers encompass, embrace, befriend, accompany and endure with families of life-limited children.

Children with life-limiting and disabling conditions are surviving longer than previously, and many require palliative and supportive care, usually at home. Home-based care can put family life under considerable strain, as parents care for their child's complex, often unpredictable, continuing care needs. Rainbow Trust Children's Charity aims to bridge gaps in services for children with life-threatening or terminal conditions by providing family support workers (FSWs). The study used a range of methods (surveys, interviews and ethnographic observation) approach to explore key aspects of the work of the FSWs. The target population for the surveys was families with a child having complex, life-threatening or terminal conditions receiving care from FSWs. The participants included 55 families (12 bereaved) and 39 children aged 2-18 years. Thematic analysis revealed how the FSWs became a presence in families' lives in three main ways: (1) encompassing and embracing families through supporting needs and promoting resilience; (2) befriending and bonding through developing knowledge, trusting relationships and a sense of closeness; and (3) accompanying and enduring by 'being with' families in different settings, situations and crises and by enduring alongside the families. The study demonstrated the fundamental importance of workers who are able to provide aspects of support that is usually not provided by other services.

Anticoagulant management of pregnancy following heart valve replacement in the United Kingdom, 1986-2002.

BACKGROUND AND AIM OF THE STUDY: Patients with mechanical heart valves require anticoagulation which is associated with significant maternal mortality (1-4%) and fetal complications (31%) in pregnancy. The study aim was to identify anticoagulant protocols and outcomes for pregnant women undergoing heart valve replacement (HVR) in the United Kingdom. METHODS: Women aged between 18 and 45 years and registered with the United Kingdom Heart Valve Registry (UKHVR) each completed a questionnaire, and their obstetric notes were reviewed. The data analyzed included valve type (mechanical, bioprosthetic, homograft), valve site (mitral, aortic, tricuspid, pulmonary), anticoagulation at confirmation of pregnancy, between 6-12 weeks and from 12 weeks to term, delivery, maternal and fetal outcomes, and cause of death. The summary statistics and a descriptive review of the findings are reported. RESULTS: Of 2,532 women eligible for the study, 922 responded. Among these women, 72 became pregnant, with 60 pregnancies in the mechanical valve (MV) group and 45 in the tissue valve (TV) group. Three anticoagulation regimes were used during early pregnancy: unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) or warfarin. All women received warfarin in the second trimester and heparin for delivery. Live births were recorded in 30% of MV pregnancies and in 60% of TV pregnancies. Miscarriage rates differed markedly (37% MV versus 2% TV). Fetal outcome was poorest in the warfarin-only group, with embryopathy occurring at a dose level of 6 mg. The maternal outcomes did not differ significantly among groups. High-dose heparin during the first trimester and for delivery was effective for the majority of mechanical valves. CONCLUSION: The study results illustrate the diverse and uncertain manner in which UKHVR patients are managed during pregnancy. A national notification system would record much-needed prospective information on anticoagulation and pregnancy outcomes, thus aiding evidence-based management.

Composite aortic valve graft replacement: mortality outcomes in a national registry.

BACKGROUND: Composite aortic valve and root replacement (CVG) is a complex surgical procedure, but excellent center-specific outcomes are reported. We sought to report outcomes in a national cohort. METHODS AND RESULTS: The United Kingdom Heart Valve Registry was interrogated for 1962 first-time CVG (and 37,102 aortic valve replacements [AVR] as a reference group) procedures from 1986 to 2004. We analyzed 30-day mortality, long-term survival (97.2% complete follow-up), and examined available risk factors for mortality using univariate and multivariate logistic regression analysis and causes of death. CVG patients were younger, received larger valve sizes and were more likely to be emergent than AVR patients. Overall 30-day mortality was 10.7% (CVG) and 3.6% (AVR). For CVG, multivariate analysis identified advanced age (> 70 years), concomitant coronary artery surgery, impaired left ventricular function, urgent or emergency status, prosthetic valve size < or = 23 mm and hospital activity volume < or = 8 procedures per annum as significant factors for 30-day mortality. Kaplan-Meier, 1-year, 5-year, 10-year and 20-year survival were 85.2%, 77.1%, 70% and 59.3%, respectively. The conditional (post-30-day) survival was similar to the AVR cohort. CONCLUSIONS: These Registry data provide a unique national insight into CVG outcomes. After a higher initial mortality risk, CVG has equivalent conditional longer-term survival to AVR.

Mechanical testing of human cardiac tissue: some implications for MRI safety.

PURPOSE: The effects of aging on tissue strength and its ability to withstand forces associated with MRI have not been investigated. This study aimed to determine the forces required to cause partial or total detachment of a heart valve prosthesis in patients with age-related degenerative diseases exposed to MRI. METHODS: Eighteen tissue samples excised during routine heart valve replacement surgery were subjected to a suture pull-out test using a tensile materials testing machine. Five preconditioning cycles were applied before commencing the final destructive test. The test was complete when the sample ruptured and the suture was pulled completely free from the tissue. Results were compared with previously calculated magnetically induced forces at 4.7 T. RESULTS: All tissue samples displayed a basic failure pattern. Mean forces required to cause initial yield and total rupture were 4.0 N (+/- 3.3 N) and 4.9 N (+/- 3.6 N), respectively. Significant factors determining initial yield were stenosed calcific tissue (p < .01), calcific degeneration (single pathology) (p < .04) and tissue stiffness (p < .01). Calcific degeneration (p < .03) and tissue stiffness (p < .03) were also significant in determining maximum force required to cause total rupture. CONCLUSION: Specific age-related degenerative cardiac diseases stiffen and strengthen tissue resulting in significant forces being required to pull a suture through valve annulus tissue. These forces are significantly greater than magnetically induced < 4.7 T. Therefore, patients with degenerative valvular diseases are unlikely to be at risk of valve dehiscence during exposure to static magnetic field < or = 4.7 T.

Assessment of magnetic field (4.7 T) induced forces on prosthetic heart valves and annuloplasty rings.

PURPOSE: To assess the magnetic field interactions on 11 heart valve prostheses and 12 annuloplasty rings subjected to a 4.7 T MR system. MATERIALS AND METHODS: Ex vivo testing was performed to evaluate translational and rotational forces using previously described techniques. RESULTS: Seventeen out of 23 prostheses showed zero interaction with the magnetic field. Translational forces with deflection angles of 2-20 degrees were demonstrated in six prostheses. Only two heart valves and two annuloplasty rings demonstrated rotational forces. The Carpentier Edwards (CE) Physio Ring, which contains Elgiloy, demonstrated deflection angles three times greater than those previously measured at 1.5 T. Furthermore, there was a direct relationship between increasing prosthesis size and increasing translational force. All heart valve prostheses attracted to the magnetic field were slightly paramagnetic/weakly ferromagnetic. CONCLUSION: Twenty-three heart valve prostheses evaluated for MRI are considered safe in static fields up to 4.7 T based on current safety criteria. However, the CE Physio Ring appeared to develop an increasing magnetism upon re-entry into the MR system. We conclude that prostheses made from Elgiloy may not be acceptable for patients in an MR environment of > or =4.7 T. Further investigations are required to confirm the safety of Elgiloy.

Is 30-day mortality an adequate outcome statistic for patients considering heart valve replacement?

BACKGROUND: In-hospital mortality is widely used by clinicians as a benchmark measure of outcome for determining risks/benefits of cardiac surgery. Patients, however, may wish to have information on estimated longer-term outcomes. Mortality risk by 1 year after the operation may be a more meaningful outcome statistic. We therefore undertook to determine 30-day and 365-day postoperative mortality rates in a large series of consecutive patients who have undergone heart valve replacement (HVR) surgery in the United Kingdom since 1986. METHODS: Data on 80,757 patients registered on the UK Heart Valve Registry were analyzed. Kaplan-Meier actuarial survival analysis was calculated to determine 30-day (group 1) and 365-day (group 2) mortality. Cox proportional hazards were calculated for each group to identify significant risk factors for mortality less than 1 year. RESULTS: Thirty-day mortality represents around half (56%) of the 365-day mortality. This ratio was robust for most subdivisions of the total population. Cox proportional hazards demonstrated female sex, age older than 70 years, single tricuspid valve replacement, multiple valve replacement regardless of type of valve, and subsequent valve operation as significant risk factors of early mortality (group 1). However, men were at significantly greater risk of late mortality (group 2). All other factors remained significant with the exception of subsequent valve operation, which was dropped from the model (group 2). CONCLUSIONS: The robustness of these data would allow cardiologists and cardiac surgeons to provide preoperative patients with a reasonably accurate estimate of survival rates at 1 year after valve replacement surgery in addition to the customary short-term 30-day outcome.

Outcomes in nonagenarians after heart valve replacement operation.

BACKGROUND: Changes in the age profile of the United Kingdom population and improvements in preoperative and postoperative care have resulted in increasing numbers of very elderly patients undergoing heart valve replacement (HVR) operations. Although HVR operations in nonagenarians are relatively uncommon, the demand for cardiac operations in this age group may increase over time. Outcomes after HVR operations in nonagenarians have not been well described yet. Therefore, the aim of this study was to determine outcomes in terms of early mortality and long-term survival in 35 nonagenarians after HVR operation. METHODS: Data from the United Kingdom Heart Valve Registry were analyzed and nonagenarian patients were identified. Additional analyzed data include gender, valve position, valve type, valve size, operative priority, follow-up time, and date and cause of death. Kaplan-Meier actuarial curves were calculated to determine accurate 30-day mortality and long-term survival. RESULTS: On average five HVR operations are performed annually in the United Kingdom in nonagenarians with equal numbers of males and females. Aortic valve replacement with a bioprosthetic valve was the most common operation and 86% were elective admissions. Fourteen patients died within the review period; mean time to death was 402 days. Overall 30-day mortality was 17%, which was higher for males compared with females; females also displayed better long-term survival. CONCLUSIONS: HVR operations in nonagenarians carry a significantly higher risk of early mortality and reduced long-term survival. Despite increases in the age profile of the population, elective HVR operation with patients aged 90 years or older is likely to remain an infrequent surgical procedure reserved for very carefully selected patients.

Translational and rotational forces on heart valve prostheses subjected ex vivo to a 4.7-T MR system.

PURPOSE: To assess the magnetic field interactions on 60 heart valve prostheses subjected to a 4.7 T MR system. It addresses the question of whether heart valves deemed safe at 1.5 T may pose safety hazards as patients are exposed to increased static magnetic fields. MATERIALS AND METHODS: Ex vivo testing was performed to evaluate translational and rotational forces on 60 heart valves using previously described techniques. RESULTS: Translational forces were detected on 58 heart valves ranging from 0.5 degrees to 7.5 degrees. Seven valves exhibited paramagnetic/weakly ferromagnetic behavior, and 51 valves exhibited diamagnetic behavior. Rotational forces were observed for 46 valves. CONCLUSIONS: Criteria previously used for safety assessment of heart valve prostheses and expressed in terms of magnetic forces suggest the forces observed in this study are compatible with the safe use of these valves in magnetic resonance (MR) systems with static fields up to 4.7 T.