Incidental detection of classical galactosemia through newborn screening for phenylketonuria: a 10-year retrospective audit to determine the efficacy of this approach

In the UK, Classical Galactosaemia (CG) is identified incidentally from the Newborn Screening (NBS) for phenylketonuria (PKU) using an “Other disorder suspected” (ODS) pathway when phenylalanine (Phe) and tyrosine (Tyr) concentrations are increased. We aimed to determine the efficacy of CG detection via NBS and estimate the incidence of CG in live births in the UK. A survey was sent to all UK NBS laboratories to collate CG cases diagnosed in the UK from 2010 to 2020. Cases of CG diagnosed were determined if detected clinically, NBS, or by family screening, as well as age at diagnosis. Cases referred via the ODS pathway were also collated, including the final diagnosis made. Responses were obtained from 13/16 laboratories. Between 2010 and 2020, a total of 6,642,787 babies were screened, and 172 cases of CG were identified. It should be noted that 85/172 presented clinically, 52/172 were identified by NBS, and 17/172 came from family screening. A total of 117 referrals were made via the ODS pathway, and 45/117 were subsequently diagnosed with CG. Median (interquartile range) age at diagnosis by NBS and clinically was 8 days (7–11) and 10 days (7–16), respectively (Mann–Whitney U test, U = 836.5, p-value = 0.082). The incidence of CG is 1:38,621 live births. The incidence of CG in the UK is comparable with that of other European/western countries. No statistical difference was seen in the timing of diagnosis between NBS and clinical presentation based on the current practice of sampling on day 5. Bringing forward the day of NBS sampling to day 3 would increase the proportion diagnosed with CG by NBS from 52/172 (30.2%) to 66/172 (38.4%)

Tutū faʻatasi: A natural disaster relief centre in Poutasi, Sāmoa

RESEARCH QUESTION How can integrating cultural Sāmoan tectonics into a modern disaster relief centre help bring Sāmoan communities together while providing solutions for disaster relief issues? ABSTRACT The South Pacific region is the location of two of the world’s most active cyclone basins. Also located in the South Pacific region is an island nation called Sāmoa. Cyclones are the most common natural disasters to occur on these islands. The situation is worsened by the threat of climate change, which brings with it rising sea levels, rising temperatures, and an increased likelihood of cyclones. This means a climate crisis for our Pacific Island nations, and should be heard as a call for action, since Sāmoa faces a serious gap in its preparedness for natural disasters in terms of education and refuge. Modern technology has brought advancements into the construction industry. There are great techniques and materials available globally that can assist in natural disaster resistant buildings, but they are not being utilized in Sāmoa. At the same time, the influence of westernised architecture has caused a decline in the local knowledge of cultural building techniques. There has been a shift in local buildings from the cultural vernacular architecture to a more westernised take on housing. This means much of the housing that exists in Sāmoan villages today lacks the building standards to withstand natural disasters. There is a need in Sāmoa for housing design that can withstand natural disasters. This is an opportunity to look back on how our ancestors dealt with the climate through architecture and design. It is also an opportunity to educate the people on modern and local building techniques for natural disaster resistance. This research project provides a design for a Natural Disaster Relief Centre. It investigates ways of assisting Sāmoa’s most populated island, Upolu, in natural disaster planning, as well as providing temporary refuge during the recovery period following a natural disaster. The design is aided by studying the culture and the architecture of Sāmoa, as well as natural disaster construction techniques. The design will hopefully influence more contemporary building styles within Sāmoa, that utilize aspects of the cultural architecture

Ferrous iron formation following the co-aggregation of ferric iron and the Alzheimer's disease peptide β-amyloid (1-42)

For decades, a link between increased levels of iron and areas of Alzheimer's disease (AD) pathology has been recognized, including AD lesions comprised of the peptide β-amyloid (Aβ). Despite many observations of this association, the relationship between Aβ and iron is poorly understood. Using X-ray microspectroscopy, X-ray absorption spectroscopy, electron microscopy and spectrophotometric iron(II) quantification techniques, we examine the interaction between Aβ(1–42) and synthetic iron(III), reminiscent of ferric iron stores in the brain. We report Aβ to be capable of accumulating iron(III) within amyloid aggregates, with this process resulting in Aβ-mediated reduction of iron(III) to a redox-active iron(II) phase. Additionally, we show that the presence of aluminium increases the reductive capacity of Aβ, enabling the redox cycling of the iron. These results demonstrate the ability of Aβ to accumulate iron, offering an explanation for previously observed local increases in iron concentration associated with AD lesions. Furthermore, the ability of iron to form redox-active iron phases from ferric precursors provides an origin both for the redox-active iron previously witnessed in AD tissue, and the increased levels of oxidative stress characteristic of AD. These interactions between Aβ and iron deliver valuable insights into the process of AD progression, which may ultimately provide targets for disease therapies

Baseline and peak cortisol response to the low dose short Synacthen test relates to indication for testing, age and sex

Objective To review the outcomes of a simplified low dose Synacthen test (LDSST) performed in a tertiary endocrine service over seven years, and to examine for relationships between cortisol measurements and indication for testing, age and sex. Design Retrospective, observational study of LDSST performed in 2008 – 2014 (N=335) and 2016-2020 (N=160). Methods LDSST were performed by endocrine nurses. Synacthen 500ng/1.73m 2 administered as IV bolus, sampling at 0, 15, 25 and 35 minutes. Results Mean (± 1SD) baseline cortisol was 221 ± 120 nmol/L, peak 510 ± 166nmol/L and increment 210 ± 116 nmol/L. 336 (70%) of patients had a normal response (baseline cortisol >100nmol/L, peak >450nmol/L), 78 (16%) a suboptimal response (peak cortisol 350-450nmol/L) and were prescribed hydrocortisone to during periods of stress only, 67 (14%) an abnormal response (baseline <100nmol/L or peak <350nmol/L) and were prescribed daily hydrocortisone. Basal, peak and incremental increases in cortisol were higher in females (p=0.03, p<0.001, p=0.03 respectively). Abnormal results occurred most frequently in patients treated previously with pharmacological doses of glucocorticoids or structural brain abnormalities (p<0.0001). Discussion There are concerns that the specificity of the LDSST is poor. The low prevalence and strong association of abnormal results with indication for testing, suggests that over diagnosis occurred infrequently in this clinical setting

Development and community-based validation of the IDEA study Instrumental Activities of Daily Living (IDEA-IADL) questionnaire

Background: The dementia diagnosis gap in sub-Saharan Africa (SSA) is large, partly due to difficulties in assessing function, an essential step in diagnosis. Objectives: As part of the Identification and Intervention for Dementia in Elderly Africans (IDEA) study, to develop, pilot, and validate an Instrumental Activities of Daily Living (IADL) questionnaire for use in a rural Tanzanian population to assist in the identification of people with dementia alongside cognitive screening. Design: The questionnaire was developed at a workshop for rural primary healthcare workers, based on culturally appropriate roles and usual activities of elderly people in this community. It was piloted in 52 individuals under follow-up from a dementia prevalence study. Validation subsequently took place during a community dementia-screening programme. Construct validation against gold standard clinical dementia diagnosis using DSM-IV criteria was carried out on a stratified sample of the cohort and validity assessed using area under the receiver operating characteristic (AUROC) curve analysis. Results: An 11-item questionnaire (IDEA-IADL) was developed after pilot testing. During formal validation on 130 community-dwelling elderly people who presented for screening, the AUROC curve was 0.896 for DSM-IV dementia when used in isolation and 0.937 when used in conjunction with the IDEA cognitive screen, previously validated in Tanzania. The internal consistency was 0.959. Performance on the IDEA-IADL was not biased with regard to age, gender or education level. Conclusions: The IDEA-IADL questionnaire appears to be a useful aid to dementia screening in this setting. Further validation in other healthcare settings in SSA is required

Evidence of redox-active iron formation following aggregation of ferrihydrite and the Alzheimer's disease peptide β-amyloid

Synopsis: Here, we demonstrate that the peptide β-amyloid, which forms the senile plaques characteristic of the Alzheimer’s disease (AD) brain, has a remarkable efficiency to chemically change the benign natural iron mineral ferrihydrite to a redox-active and potentially neurotoxic form. These findings indicate that both amyloid and iron could contribute to AD pathology, and they also suggest an origin for the reactive iron minerals magnetite and wüstite, which have been found previously in Alzheimer’s tissue. Recent work has demonstrated increased levels of redox-active iron biominerals in Alzheimer’s disease (AD) tissue. However, the origin, nature, and role of iron in AD pathology remains unclear. Using X-ray absorption, X-ray microspectroscopy, and electron microscopy techniques, we examined interactions between the AD peptide β-amyloid (Aβ) and ferrihydrite, which is the ferric form taken when iron is stored in humans. We report that Aβ is capable of reducing ferrihydrite to a pure iron(II) mineral where antiferromagnetically ordered Fe2+ cations occupy two nonequivalent crystal symmetry sites. Examination of these iron(II) phases following air exposure revealed a material consistent with the iron(II)-rich mineral magnetite. These results demonstrate the capability of Aβ to induce the redox-active biominerals reported in AD tissue from natural iron precursors. Such interactions between Aβ and ferrihydrite shed light upon the processes of AD pathogenesis, while providing potential targets for future therapies