The Past, Present and Future of Sleep Measurement in Mild Cognitive Impairment and Early Dementia – Towards a Core Outcome Set:A Scoping Review

STUDY OBJECTIVES: Sleep abnormalities emerge early in dementia and may accelerate cognitive decline. Their accurate characterization may facilitate earlier clinical identification of dementia and allow for assessment of sleep intervention efficacy. This scoping review determines how sleep is currently measured and reported in Mild Cognitive Impairment (MCI) and early dementia, as a basis for future core outcome alignment. METHODS: This review follows the PRISMA Guidelines for Scoping Reviews. CINAHL, Embase, Medline, Psychinfo, and British Nursing Index databases were searched from inception—March 12, 2021. Included studies had participants diagnosed with MCI and early dementia and reported on sleep as a key objective/ outcome measure. RESULTS: Nineteen thousand five hundred and ninety-six titles were returned following duplicate removal with 188 studies [N] included in final analysis. Sleep data was reported on 17 139 unique, diagnostically diverse participants (n). “Unspecified MCI” was the most common diagnosis amongst patients with MCI (n = 5003, 60.6%). Despite technological advances, sleep was measured most commonly by validated questionnaires (n = 12 586, N = 131). Fewer participants underwent polysomnography (PSG) (n = 3492, N = 88) and actigraphy (n = 3359, N = 38) with little adoption of non-PSG electroencephalograms (EEG) (n = 74, N = 3). Sleep outcome parameters were reported heterogeneously. 62/165 (37.6%) were described only once in the literature (33/60 (60%) in interventional studies). There was underrepresentation of circadian (n = 725, N = 25) and micro-architectural (n = 360, N = 12) sleep parameters. CONCLUSIONS: Alongside under-researched areas, there is a need for more detailed diagnostic characterization. Due to outcome heterogeneity, we advocate for international consensus on core sleep outcome parameters to support causal inference and comparison of therapeutic sleep interventions

Radiotherapy exposure directly damages the uterus and causes pregnancy loss

Female cancer survivors are significantly more likely to experience infertility than the general population. It is well established that chemotherapy and radiotherapy can damage the ovary and compromise fertility, yet the ability of cancer treatments to induce uterine damage, and the underlying mechanisms, have been understudied. Here, we show that in mice total-body γ-irradiation (TBI) induced extensive DNA damage and apoptosis in uterine cells. We then transferred healthy donor embryos into ovariectomized adolescent female mice that were previously exposed to TBI to study the impacts of radiotherapy on the uterus independent from effects to ovarian endocrine function. Following TBI, embryo attachment and implantation were unaffected, but fetal resorption was evident at midgestation in 100% of dams, suggesting failed placental development. Consistent with this hypothesis, TBI impaired the decidual response in mice and primary human endometrial stromal cells. TBI also caused uterine artery endothelial dysfunction, likely preventing adequate blood vessel remodeling in early pregnancy. Notably, when pro-apoptotic protein Puma-deficient (Puma-/-) mice were exposed to TBI, apoptosis within the uterus was prevented, and decidualization, vascular function, and pregnancy were restored, identifying PUMA-mediated apoptosis as a key mechanism. Collectively, these data show that TBI damages the uterus and compromises pregnancy success, suggesting that optimal fertility preservation during radiotherapy may require protection of both the ovaries and uterus. In this regard, inhibition of PUMA may represent a potential fertility preservation strategy.</p

Association of early life factors with prematurity-associated lung disease: prospective cohort study

Introduction Although bronchopulmonary dysplasia (BPD) is associated with lung function deficits in childhood, many who develop BPD have normal lung function in childhood, and many without BPD including those born at 33–34 weeks’ gestation, have lung dysfunction in childhood. Since the predictability of BPD for future lung deficits is increasingly doubted, we prospectively recruited preterm-born children to identify early life factors which are associated with lung function deficits after preterm-birth. Methods From 767 children aged 7–12 years, who had their respiratory symptoms assessed, and had spirometry before and after a bronchodilator in our Respiratory Health Outcomes in Neonates (RHiNO) study, 739 (544 preterm-born at ≤34 weeks’ gestation and 195 term-born) had satisfactory lung function. Data were analysed using multivariable logistic regression and mediation. Results When preterm-born children were classified according to their lung function, low lung function (prematurity-associated lung disease, PLD) was associated with BPD, gestation and intrauterine growth restriction on univariable logistic regression analyses. However, on multivariable logistic regression analyses, gestation (Beta=−0.153, se: 0.051, p=0.003) and intrauterine growth restriction (odds ratio 1.783, 95% confidence interval: 1.06, 3.00, p=0.029) remained significantly associated with later deficits of lung function but BPD (0.99; 0.52, 1.89, p=0.974) did not. Mediation analyses confirmed these results. Conclusions Although traditionally BPD has been associated with low lung function in later life, these data show that gestation and IUGR are significantly associated with PLD in childhood but BPD is not. By identifying children with PLD, we can better understand the underlying mechanisms and develop optimal therapies

Impact of ambient air pollution on lung function in preterm-born school-aged children

Rationale Increased outdoor air pollution worsens lung function in children. However, these associations are less well studied in preterm-born individuals. Objectives We assessed associations between ambient air pollutants and spirometry measures in preterm-born children. Methods The Respiratory Health Outcomes in Neonates study recruited preterm-born children aged 7–12 years who were born at ≤34 week's gestation. We associated four ambient air pollutants (particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5), PM10, nitrogen dioxide (NO2) and sulfur dioxide) at time of birth and spirometry assessment and averaged exposure between these two time points with spirometry measures, using linear regression analyses. Gestational age was banded into 23–28, 29–31 and 32–34 week's. Regression models estimated spirometry values against pollutant levels at birth and at the time of spirometry. Measurements and main results From 565 preterm-born children, 542 (96%) had satisfactory data. After adjustments for early and current life factors, significant detrimental associations were noted between PM10 at birth and per cent predicted forced vital capacity (%FVC) for the 23–28 and 29–31 week's gestation groups and between current PM2.5 and NO2 exposure and %FVC for the 23–28 week's gestation group. No associations with spirometry were noted for the averaged pollution exposure between birth and spirometry. Predictive models showed 5.9% and 7.4% differences in %FVC between the highest and lowest current pollution exposures for PM2.5 and NO2, respectively, in the 23–28 week group. Conclusions Birth and current exposures to road-traffic-associated pollutants detrimentally affected %FVC in preterm-born school-aged children, who already have compromised lung function

Characterising airway obstructive, dysanaptic and PRISm phenotypes of prematurity-associated lung disease

Introduction Although obstructive airway disease has been shown to be associated with prematurity, other spirometry phenotypes are less well described. Objectives We characterised abnormal spirometry phenotypes in preterm-born children, including prematurity-associated obstructive lung disease (POLD, forced expiratory volume in 1 s (FEV1

Association of gestation and fetal growth restriction on cardiovascular health in preterm-born children

Objectives TO prospectively evaluate the associations of early and current life factors, including gestational age, and fetal growth restriction (FGR) in preterm-born subjects, on cardiovascular health including measures of central and peripheral blood pressure and arterial stiffness and assesscardiovascular changes before and after acute exercise in preterm- and term-born school-aged children. Study Design From 240 children, aged 7-12 years, 204 (141 preterm-born and 63 term-born) had satisfactory data. An oscillometric device recorded cardiovascular measures before and after cycle ergometer exercise testing. Data were analysed with multivariable linear regression and mediation. Results Central systolic blood pressure (SBP) was 6.4mmHg (95%CI 1.2,11.6) higher in preterm-born children with FGR and 3.4mmHg (0.02,6.8) higher in those without FGR when compared with term controls. Augmentation index (AIx) was 4.1% (0.7,7.4) higher in the preterm FGR group when compared with those without FGR but was similar between the latter group and term controls. Regression modelling showed gestational age, female sex, and antenatal smoking, but not FGR, were significantly associated with SBP. In contrast, FGR and fat mass index, but not gestation, were significantly associated with AIx. Cardiovascular exercise responses were similar between all three groups studied. Conclusions Our data show the differential associations of prematurity and FGR on central SBP and AIx. Cardiovascular responses to exercise were similar in all three groups. Preterm-born children with and without FGR are at increased risk of cardiovascular disease in adult life

Spectrally tailored 'hyperpixel' filter arrays for imaging of chemical compositions

We present a method for designing and fabricating 'HyperPixels': pixel filter arrays with custom spectral transmission properties that enable efficient imaging of specific chromophores or fluorophores. Multispectral imaging typically targets particular spectral bands to uncover the spectral properties of tissue in combination with spatial resolution. Unmixing spectral properties can uncover the type and quantity of chromophores or fluorophores due to their unique spectral absorption or emission. Pixelated filter arrays atop imaging sensors are low-cost techniques used to achieve multispectral imaging. Typically, the filter pixels exhibit bandpass spectral behaviour, allowing only a fraction of the incident light to reach the sensor. As a result, narrowband filter pixels trade off high spectral resolution with optical power loss. A way to avoid this issue and improve the signal to noise ratio (SNR) for individual targets is to use a filter array where individual pixels are matched to a target chemical compound's reflectance or emission spectrum. Simulations show a > 5-fold improvement in SNR under realistic noise conditions. These matched optical filters can also reduce the complexity of software or hardware spectral unmixing algorithms, offering the potential for real-time imaging of target compounds. We present a method for tailoring spectral transmission of individual pixels by building HyperPixels comprising multiple Fabry-Perot resonator subpixels with varying bandpass properties (FWHM = approximately 50-60 nm, thicknesses 75-150 nm) that collectively have the desired transmission spectrum. We used a numerical optimization process to design filter arrays for simultaneous detection of methylene blue and indocyanine green, commonly used in cancer diagnostics by clinicians. We then fabricated filters for indocyanine green detection using grayscale lithography with pixel sizes down to 5 µm and individual subpixels down to 0.5 µm and characterized them for their spectral properties

Evidence of abnormality in glutathione metabolism in the airways of preterm born children with a history of bronchopulmonary dysplasia

Preterm-born children are at risk of long-term pulmonary deficits, including those who developed bronchopulmonary dysplasia (BPD) in infancy, however the underlying mechanisms remain poorly understood. We characterised the exhaled breath condensate (EBC) metabolome from preterm-born children, both with and without BPD. Following spirometry, EBC from children aged 7–12 years, from the Respiratory Health Outcomes in Neonates study, were analysed using Time-of-Flight Mass Spectrometry. Metabolite Set Enrichment Analysis (MSEA) linked significantly altered metabolites to biological processes. Linear regression models examined relationships between metabolites of interest and participant demographics. EBC was analysed from 214 children, 144 were born preterm, including 34 with BPD. 235 metabolites were detected, with 38 above the detection limit in every sample. Alanine and pyroglutamic acid were significantly reduced in the BPD group when compared to preterm controls. MSEA demonstrated a reduction in glutathione metabolism. Reduced quantities of alanine, ornithine and urea in the BPD group were linked with alteration of the urea cycle. Linear regression revealed significant associations with BPD when other characteristics were considered, but not with current lung function parameters. In this exploratory study of the airway metabolome, preterm-born children with a history of BPD had changes consistent with reduced antioxidant mechanisms suggesting oxidative stress

Similarities of metabolomic disturbances in prematurity-associated obstructive lung disease to chronic obstructive pulmonary disease

Prematurity-associated lung disease (PLD) is a long-term consequence of preterm-birth. Since the underlying mechanisms of PLD remain poorly characterised, we compared the urinary metabolome between recently described spirometry phenotypes of PLD. Preterm- and term-born children aged 7–12 years, from the Respiratory Health Outcomes in Neonates (RHiNO) cohort, underwent spirometry and urine collection. The urinary metabolome was analysed by gas chromatography time-of-flight mass spectrometry. Preterm-born children were classified into phenotypes of prematurity-associated obstructive lung disease (POLD, Forced expiratory volume in 1 s (FEV1) < lower limit of normal (LLN), FEV1/Forced Vital Capacity (FVC) < LLN), prematurity-associated preserved ratio impaired spirometry (pPRISm, FEV1 < LLN, FEV1/FVC ≥ LLN) and Preterm/Term controls (FEV1 ≥ LLN). Metabolite set enrichment analysis was used to link significantly altered metabolites between the groups with metabolic pathways. Univariable and multivariable linear regression models examined associations between early and current life factors and significantly altered metabolites of interest. Urine from 197 preterm- and 94 term-born children was analysed. 23 and 25 were classified into POLD and pPRISm groups respectively. Of 242 identified metabolites, 49 metabolites were significantly altered in the POLD group compared with Preterm controls. Decreased capric acid (log2 fold change − 0.23; p = 0.003), caprylic acid (− 0.18; 0.003) and ceratinic acid (− 0.64; 0.014) in the POLD group, when compared to preterm controls, were linked with reduced β-oxidation of very long chain fatty acids (p = 0.004). Reduced alanine (log2 fold change − 0.21; p = 0.046), glutamic acid (− 0.24; 0.023), and pyroglutamic acid (− 0.17; 0.035) were linked with decreased glutathione metabolism (p = 0.008). These metabolites remained significantly associated with POLD in multivariable models adjusting for early/current life factors. The pPRISm urinary metabolome was minimally changed when compared with preterm-born controls. When compared to term-born subjects, alterations in tryptophan metabolism were implicated (p = 0.01). The urinary metabolome in POLD showed significantly altered β-oxidation of fatty acids and glutathione metabolism, implying alterations in cellular metabolism and oxidative stress. Similar findings have been noted in adults with chronic obstructive pulmonary disease. Given the similarity of findings between the POLD group and those reported for COPD, the POLD group should be considered at future risk of developing COPD