A Historical Survey of Key Epidemiological Studies of Ionizing Radiation Exposure.

In this article we review the history of key epidemiological studies of populations exposed to ionizing radiation. We highlight historical and recent findings regarding radiation-associated risks for incidence and mortality of cancer and non-cancer outcomes with emphasis on study design and methods of exposure assessment and dose estimation along with brief consideration of sources of bias for a few of the more important studies. We examine the findings from the epidemiological studies of the Japanese atomic bomb survivors, persons exposed to radiation for diagnostic or therapeutic purposes, those exposed to environmental sources including Chornobyl and other reactor accidents, and occupationally exposed cohorts. We also summarize results of pooled studies. These summaries are necessarily brief, but we provide references to more detailed information. We discuss possible future directions of study, to include assessment of susceptible populations, and possible new populations, data sources, study designs and methods of analysis.

Novel approach for tracheal resection in Morquio a syndrome with end-stage critical airway obstruction: a UK case series.

BACKGROUND: Mucopolysaccharidosis (MPS) type IVA is a rare lysosomal storage disorder caused by aberrations of the N-acetyl-galactosamine-6-sulfatase (GALNS) enzyme. MPS IVA is associated with a wide gamut of respiratory and airway disorders that manifest in a continuum of severity. In individuals exhibiting severe phenotypic expression, terminal stages of the disease frequently culminate in life-threatening, critical airway obstruction. These manifestations of end-stage disease are engendered by an insidious progression of multi-level airway pathologies, comprising of tracheomalacia, stenosis, tortuosity and 'buckling'. Historically, the management of end-stage airway disease has predominantly leaned towards palliative modalities. However, contemporary literature has posited that the potential benefits of tracheal resection with aortopexy, performed under cardiopulmonary bypass (CPB), may offer a promising therapeutic option. In this context, we report on outcomes from patients undergoing a novel approach to tracheal resection that is combined with manubrial resection, leading to improved airway calibre, obviating the requisition for CPB. RESULTS: In this study, seven patients with severe MPS IVA exhibited clinical symptoms and radiological evidence indicative of advanced airway obstruction. All patients had a tracheal resection with a partial upper manubriectomy via transcervical approach, which did not require CPB. The surgical cohort consisted of 5 females and 2 males, the median age was 16 years (range 11-19) and the median height was 105.6cm (range 96.4-113.4). Postoperatively, significant improvements were seen in forced expiratory volume in 1 second (FEV1), with a mean increase of 0.68 litres (95% CI: 0.45-0.91; SD: 0.20). Notably, other spirometry variables also showed meaningful improvements, providing evidence of positive treatment effects. Furthermore, there were no major long-term complications, and the procedure resulted in a significant enhancement in patient-reported domains using PedsQL (version 4.0). CONCLUSIONS: This study represents the largest case series to date, on tracheal resection in patients with severe MPS IVA. Our findings demonstrate the effectiveness of the transcervical approach with partial manubriectomy for improving respiratory function and quality of life for individuals with advanced airway obstruction. Tracheal resection presents a promising treatment modality for severe cases of MPS IVA. Successful outcomes rely on meticulous multidisciplinary assessment, judicious decision-making, and appropriate timing of tracheal surgery. Further research and long-term follow-up studies are warranted to validate the long-term efficacy and safety of this approach.

Health-related quality of life following aortopexy for tracheomalacia: a cross-sectional study.

OBJECTIVES: The objective was to measure health-related quality of life (HRQoL) of children following treatment of all-cause tracheomalacia with aortopexy. METHODS: Children ≥5 years and parents of children <18 years who had undergone aortopexy completed the Paediatric Quality of Life Inventory (PedsQL4.0). Scores were compared to published norms. RESULTS: Completed questionnaires were received from 35 parents (65%) and 10 children (38%). Median age at aortopexy was 9.8 months (1 month-12.7 years) and median years of follow-up was 2.6 (4 months-6.9 years). Children who completed questionnaires had a median age of 8.4 (5.7-13.4) years. Parent and child-reported total PedsQL scores were 69.61 (SD : 19.74), and 63.15 (SD : 20.40) respectively. Half of parents and 80% of children reported scores suggesting poor HRQoL outcomes. Parent-reported total, physical and psycho-social scores were lower than those of healthy children and those with acute illness but comparable to children with chronic health conditions and cardiovascular disease. Similarly, children themselves reported comparable total scores to children with chronic illness but child-reported psycho-social scores were lower in the aortopexy group than any other group. There was no association between PedsQL scores and cause of malacia, age or time since aortopexy. The presence of complex congenital comorbidities had a significant (p < 0.05) impact on HRQoL scores. CONCLUSIONS: Following aortopexy children remain at risk of poor HRQoL, especially those with complex comorbidities. HRQoL reported by both parent and child provides important insight into the lives of children following this procedure. Further longitudinal and qualitative study are required to better understand this complex group.

Association between antibody responses post-vaccination and severe COVID-19 outcomes in Scotland.

Several population-level studies have described individual clinical risk factors associated with suboptimal antibody responses following COVID-19 vaccination, but none have examined multimorbidity. Others have shown that suboptimal post-vaccination responses offer reduced protection to subsequent SARS-CoV-2 infection; however, the level of protection from COVID-19 hospitalisation/death remains unconfirmed. We use national Scottish datasets to investigate the association between multimorbidity and testing antibody-negative, examining the correlation between antibody levels and subsequent COVID-19 hospitalisation/death among double-vaccinated individuals. We found that individuals with multimorbidity ( ≥ five conditions) were more likely to test antibody-negative post-vaccination and 13.37 [6.05-29.53] times more likely to be hospitalised/die from COVID-19 than individuals without conditions. We also show a dose-dependent association between post-vaccination antibody levels and COVID-19 hospitalisation or death, with those with undetectable antibody levels at a significantly higher risk (HR 9.21 [95% CI 4.63-18.29]) of these serious outcomes compared to those with high antibody levels.

Conformational rigidity of cytochrome c'-α from a thermophile is associated with slow NO binding.

Cytochromes c'-α are nitric oxide (NO)-binding heme proteins derived from bacteria that can thrive in a wide range of temperature environments. Studies of mesophilic Alcaligenes xylosoxidans cytochrome c'-α (AxCP-α) have revealed an unusual NO-binding mechanism involving both heme faces, in which NO first binds to form a distal hexa-coordinate Fe(II)-NO (6cNO) intermediate and then displaces the proximal His to form a proximal penta-coordinate Fe(II)-NO (5cNO) final product. Here, we characterize a thermally stable cytochrome c'-α from thermophilic Hydrogenophilus thermoluteolus (PhCP-α) to understand how protein thermal stability affects NO binding. Electron paramagnetic and resonance Raman spectroscopies reveal the formation of a PhCP-α 5cNO product, with time-resolved (stopped-flow) UV-vis absorbance indicating the involvement of a 6cNO intermediate. Relative to AxCP-α, the rates of 6cNO and 5cNO formation in PhCP-α are ∼11- and ∼13-fold lower, respectively. Notably, x-ray crystal structures of PhCP-α in the presence and absence of NO suggest that the sluggish formation of the proximal 5cNO product results from conformational rigidity: the Arg-132 residue (adjacent to the proximal His ligand) is held in place by a salt bridge between Arg-75 and Glu-135 (an interaction not present in AxCP-α or a psychrophilic counterpart). Overall, our data provide fresh insights into structural factors controlling NO binding in heme proteins, including 5cNO complexes relevant to eukaryotic NO sensors.

Haspin kinase binds to a nucleosomal DNA supergroove.

Phosphorylation of histone H3 threonine 3 (H3T3) by Haspin recruits the chromosomal passenger complex to the inner centromere and ensures proper cell cycle progression through mitosis. The mechanism by which Haspin binds to nucleosomes to phosphorylate H3T3 is not known. We report here cryo-EM structures of the Haspin kinase domain bound to a nucleosome. In contrast with previous structures of histone-modifying enzymes, Haspin solely contacts the nucleosomal DNA, inserting into a supergroove formed by apposing major grooves of two DNA gyres. This unique binding mode provides a plausible mechanism by which Haspin can bind to nucleosomes in a condensed chromatin environment to phosphorylate H3T3. We identify key basic residues in the Haspin kinase domain that are essential for phosphorylation of nucleosomal histone H3 and binding to mitotic chromatin. Our structure is the first of a kinase domain bound to a nucleosome and is the first example of a histone-modifying enzyme that binds to nucleosomes solely through DNA contacts.

Tuning energetic properties through co-crystallisation - a high-pressure experimental and computational study of nitrotriazolone: 4,4'-bipyridine.

We report the preparation of a co-crystal formed between the energetic molecule 3-nitro-1,2,4-triazol-5-one (NTO) and 4,4'-bipyridine (BIPY), that has been structurally characterised by high-pressure single crystal and neutron powder diffraction data up to 5.93 GPa. No phase transitions or proton transfer were observed up to this pressure. At higher pressures the crystal quality degraded and the X-ray diffraction patterns showed severe twinning, with the appearance of multiple crystalline domains. Computational modelling indicates that the colour changes observed on application of pressure can be attributed to compression of the unit cell that cause heightened band dispersion and band gap narrowing that coincides with a shortening of the BIPY π⋯π stacking distance. Modelling also suggests that the application of pressure induces proton migration along an N-H⋯N intermolecular hydrogen bond. Impact-sensitivity measurements show that the co-crystal is less sensitive to initiation than NTO, whereas computational modelling suggests that the impact sensitivities of NTO and the co-crystal are broadly similar.

Introducing the portable AttentionTrip: An engaging tool for measuring the networks of attention.

BACKGROUND: Measurement of the efficacy of the networks of attention is a frequent component of research in cognitive and clinical neuroscience. Developed in 2002, the Attention Network Test (ANT), has become the most widely used tool for this purpose. NEW METHOD: In 2017 a more engaging, game-like tool based on the ANT, called the AttentionTrip was described. The network scores from five studies which used AttentionTrip are shown to be robust. NEWER METHOD: That version of AttentionTrip required a steering wheel and desk-top computer. Here we describe a new, portable version of the AttentionTrip that is administered using a hand-held tablet (iPad) RESULTS: Three samples of participants (total = 44) completed the portable version of AttentionTrip. The network scores generated using the portable AttentionTrip were also robust. Effect sizes compare favourably with those generated by the ANT and the desktop version. CONCLUSIONS: The findings support the use of the portable AttentionTrip as an alternative to the ANT when user engagement is important, such as when participants are prone to boredom, and when repeated administrations are required.

Evidence for the differential efficacy of yaw and pitch gaze stabilization mechanisms in people with multiple sclerosis.

People with multiple sclerosis (PwMS) who report dizziness often have gaze instability due to vestibulo-ocular reflex (VOR) deficiencies and compensatory saccade (CS) abnormalities. Herein, we aimed to describe and compare the gaze stabilization mechanisms for yaw and pitch head movements in PwMS. Thirty-seven PwMS (27 female, mean ± SD age = 53.4 ± 12.4 years old, median [IQR] Expanded Disability Status Scale Score = 3.5, [1.0]. We analyzed video head impulse test results for VOR gain, CS frequency, CS latency, gaze position error (GPE) at impulse end, and GPE at 400 ms after impulse start. Discrepancies were found for median [IQR] VOR gain in yaw (0.92 [0.14]) versus pitch-up (0.71 [0.44], p < 0.001) and pitch-down (0.81 [0.44], p = 0.014]), CS latency in yaw (258.13 [76.8]) ms versus pitch-up (208.78 [65.97]) ms, p = 0.001] and pitch-down (132.17 [97.56] ms, p = 0.006), GPE at impulse end in yaw (1.15 [1.85] degs versus pitch-up (2.71 [3.9] degs, p < 0.001), and GPE at 400 ms in yaw (-0.25 [0.98] degs) versus pitch-up (1.53 [1.07] degs, p < 0.001) and pitch-down (1.12 [1.82] degs, p = 0.001). Compared with yaw (0.91 [0.75]), CS frequency was similar for pitch-up (1.03 [0.93], p = 0.999) but lower for pitch-down (0.65 [0.64], p = 0.023). GPE at 400 ms was similar for yaw and pitch-down (1.88 [2.76] degs, p = 0.400). We postulate that MS may have preferentially damaged the vertical VOR and saccade pathways in this cohort.

Aging represses lung tumorigenesis and alters tumor suppression.

Most cancers are diagnosed in persons over the age of sixty, but little is known about how age impacts tumorigenesis. While aging is accompanied by mutation accumulation - widely understood to contribute to cancer risk - it is also associated with numerous other cellular and molecular changes likely to impact tumorigenesis. Moreover, cancer incidence decreases in the oldest part of the population, suggesting that very old age may reduce carcinogenesis. Here we show that aging represses tumor initiation and growth in genetically engineered mouse models of human lung cancer. Moreover, aging dampens the impact of inactivating many, but not all, tumor suppressor genes with the impact of inactivating PTEN, a negative regulator of the PI3K/AKT pathway, weakened to a disproportionate extent. Single-cell transcriptomic analysis revealed that neoplastic cells from tumors in old mice retain many age-related transcriptomic changes, showing that age has an enduring impact that persists through oncogenic transformation. Furthermore, the consequences of PTEN inactivation were strikingly age-dependent, with PTEN deficiency reducing signatures of aging in cancer cells and the tumor microenvironment. Our findings suggest that the relationship between age and lung cancer incidence may reflect an integration of the competing effects of driver mutation accumulation and tumor suppressive effects of aging.

Lysyl Oxidase Production by Murine C3H10T1/2 Mesenchymal Stem Cells Is Increased by TGFßs and Differentially Modulated by Mechanical Stimuli.

Tendons are frequently injured and have limited regenerative capacity. This motivates tissue engineering efforts aimed at restoring tendon function through strategies to direct functional tendon formation. Generation of a crosslinked collagen matrix is paramount to forming mechanically functional tendon. However, it is unknown how lysyl oxidase (LOX), the primary mediator of enzymatic collagen crosslinking, is regulated by stem cells. This study investigates how multiple factors previously identified to promote tendon formation and healing (transforming growth factor [TGF]ß1 and TGFß2, mechanical stimuli, and hypoxia-inducible factor [HIF]-1α) regulate LOX production in the murine C3H10T1/2 mesenchymal stem cell (MSC) line. We hypothesized that TGFß signaling promotes LOX activity in C3H10T1/2 MSCs, which is regulated by both mechanical stimuli and HIF-1α activation. TGFß1 and TGFß2 increased LOX levels as a function of concentration and time. Inhibiting the TGFß type I receptor (TGFßRI) decreased TGFß2-induced LOX production by C3H10T1/2 MSCs. Low (5 mPa) and high (150 mPa) magnitudes of fluid shear stress were applied to test impacts of mechanical stimuli, but without TGFß2, loading alone did not alter LOX levels. Low loading (5 mPa) with TGFß2 increased LOX at 7 days greater than TGFß2 treatment alone. Neither HIF-1α knockdown (siRNA) nor activation (CoCl2) affected LOX levels. Ultimately, results suggest that TGFß2 and appropriate loading magnitudes contribute to LOX production by C3H10T1/2 MSCs. Potential application of these findings includes treatment with TGFß2 and appropriate mechanical stimuli to modulate LOX production by stem cells to ultimately control collagen matrix stiffening and support functional tendon formation.

Reliability and validity of the force intersection point in the assessment of human quiet standing balance.

BACKGROUND: This study evaluated psychometric properties of the Intersection Point Height, derived from ground-on-feet force characteristics, as a tool for assessing balance control. We compare this metric with traditional center of pressure (CP) measurements. METHODS: Data from a public dataset of 146 participants, divided into younger (<60 years old) and older (≥60 years old) adults, were analyzed. Clinical tests included the Short Falls Efficacy Scale-International, International Physical Activity Questionnaire-Short Form, Trail Making Tests A and B, and the Mini-Balance Evaluation Systems Test. Reliability and validity were assessed through the intra-class correlation coefficient (ICC[3,1]) for mean Intersection Point Height in each test condition and Spearman's rho between summative Intersection Point Height (the sum of intra-condition mean values across all test conditions within one subject) and other variables of interest, respectively. FINDINGS: Mean Intersection Point Height showed good to excellent reliability (ICC = 0.712-0.901), similar to that of CP velocity (ICC = 0.733-0.922) and greater than that of variance CPx (0.475-0.768). Summative Intersection Point Height exhibited strong convergent validity with Trail Making Tests A and B (rho = 0.49, p < 0.001) and the Mini-Balance Evaluation Systems Test (rho = -0.47, p < 0.001). At most, a weak to moderate association (rho = 0.39-0.49, p < 0.001) was found between intra-condition mean Intersection Point Height with CP metrics. Intra-condition mean Intersection Point Height demonstrated weak to moderate convergent validity with several clinical measures (rho = 0.32-0.52, p < 0.001). In contrast, at most, a weak to moderate association (rho = 0.39-0.49, p < 0.001) was found between intra-condition mean Intersection Point Height with CP metrics. INTERPRETATION: The Intersection Point Height is a reliable and valid balance measure. Further, we believe that it is a more comprehensive evaluation than CP metrics.

Life-course neighbourhood deprivation and brain structure in older adults: the Lothian Birth Cohort 1936.

Neighbourhood disadvantage may be associated with brain health but the importance of exposure at different stages of the life course is poorly understood. Utilising the Lothian Birth Cohort 1936, we explored the relationship between residential neighbourhood deprivation from birth to late adulthood, and global and local neuroimaging measures at age 73. A total of 689 participants had at least one valid brain measures (53% male); to maximise the sample size structural equation models with full information maximum likelihood were conducted. Residing in disadvantaged neighbourhoods in mid- to late adulthood was associated with smaller total brain (ß = -0.06; SE = 0.02; sample size[N] = 658; number of pairwise complete observations[n]=390), grey matter (ß = -0.11; SE = 0.03; N = 658; n = 390), and normal-appearing white matter volumes (ß = -0.07; SE = 0.03; N = 658; n = 390), thinner cortex (ß = -0.14; SE = 0.06; N = 636; n = 379), and lower general white matter fractional anisotropy (ß = -0.19; SE = 0.06; N = 665; n = 388). We also found some evidence on the accumulating impact of neighbourhood deprivation from birth to late adulthood on age 73 total brain (ß = -0.06; SE = 0.02; N = 658; n = 276) and grey matter volumes (ß = -0.10; SE = 0.04; N = 658; n = 276). Local analysis identified affected focal cortical areas and specific white matter tracts. Among individuals belonging to lower social classes, the brain-neighbourhood associations were particularly strong, with the impact of neighbourhood deprivation on total brain and grey matter volumes, and general white matter fractional anisotropy accumulating across the life course. Our findings suggest that living in deprived neighbourhoods across the life course, but especially in mid- to late adulthood, is associated with adverse brain morphologies, with lower social class amplifying the vulnerability.

Simulation of chloropicrin emissions in response to soil conditions and applicator practices.

HYDRUS 2D was used to simulate chloropicrin (CP) emissions across a range of expected application and environmental conditions present within California, where CP is widely used in the pre-plant treatment of soils for high-value specialty crops. Simulations were developed based on field calibration work and physicochemical parameters from literature with additional consideration of application rate-dependent degradation and applicator practices including application depth, application mode, and tarp material. Model output was compared to the distribution of indirect whole-field flux estimates derived from field monitoring studies using measures of maximum 8-h, maximum 24-h, and cumulative emissions due to their relevance to public health. We observed a strong linear relationship (R2 ≥ 0.80, p < 0.001) between HYDRUS-simulated and field-based maximum flux estimates and no evidence of statistical difference depending on the estimation source for maximum 24-h flux. A linear relationship of similar strength (R2 = 0.82, p < 0.001) was observed between simulated and field-based cumulative emission estimates, although mean HYDRUS estimates were lower than field-estimated values for some high-emission application methods. Analysis of simulation output demonstrated large differences in CP emissions in response to application method and a non-linear increase in CP emissions with increasing application rate, with considerable interaction between application variables including application depth, tarp types, and field layout. The findings generally support the use of simulated CP emission estimates as a tool to address gaps in field-based flux estimates, particularly where characterization of short-term peak emissions is needed.

Bortezomib Inhibits Open Configurations of the 20S Proteasome.

Bortezomib, a small dipeptide-like molecule, is a proteasome inhibitor used widely in the treatment of myeloma and lymphoma. This molecule reacts with threonine side chains near the center of the 20S proteasome and disrupts proteostasis by blocking enzymatic sites that are responsible for protein degradation. In this work, we use novel mass-spectrometry-based techniques to examine the influence of bortezomib on the structures and stabilities of the 20S core particle. These studies indicate that bortezomib binding dramatically favors compact 20S structures (in which the axial gate is closed) over larger structures (in which the axial gate is open)─suppressing gate opening by factors of at least ∼400 to 1300 over the temperature range that is studied. Thus, bortezomib may also restrict degradation in the 20S proteasome by preventing substrates from entering the catalytic pore. That bortezomib influences structures at the entrance region of the pore at such a long distance (∼65 to 75 Å) from its binding sites raises a number of interesting biophysical issues.

Aerosolization of micro- and nanoplastics via sea spray: Investigating the role of polymer type, size, and concentration, and potential implications for human exposure.

Micro- and nanoplastics (MNPs) can enter the atmosphere via sea spray aerosols (SSAs), but the effects of plastic characteristics on the aerosolization process are unclear. Furthermore, the importance of the transport of MNPs via these SSAs as a possible new exposure route for human health remains unknown. The aim of this study was two-fold: (1) to examine if a selection of factors affects aerosolization processes of MNPs, and (2) to estimate human exposure to MNPs via aerosols inhalation. A laboratory-based bubble bursting mechanism, simulating the aerosolization process at sea, was used to investigate the influence of MNP as well as seawater characteristics. To determine the potential human exposure to microplastics via inhalation of SSAs, the results of the laboratory experiments were extrapolated to the field based on sea surface microplastic concentrations and the volume of inhaled aerosols. Enrichment seemed to be influenced by MNP size, concentration and polymer type. With higher enrichment for smaller particles and denser polymers. Experiments with different concentrations showed a larger range of variability but nonetheless lower concentrations seemed to result in higher enrichment, presumably due to lower aggregation. In addition to the MNP characteristics, the type of seawater used seemed to influence the aerosolization process. Our human exposure estimate to microplastic via inhalation of sea spray aerosols shows that in comparison with reported inhaled concentrations in urban and indoor environments, this exposure route seems negligible for microplastics. Following the business-as-usual scenario on plastic production, the daily plastic inhalation in coastal areas in 2100 is estimated to increase but remain far below 1 particle per day. This study shows that aerosolization of MNPs is a new plastic transport pathway to be considered, but in terms of human exposure it seems negligible compared to other more important sources of MNPs, based on current reported environmental concentrations.

Phase II Study to Determine the Antitumor Activity and Safety of Simlukafusp Alfa (FAP-IL2v) Combined with Atezolizumab in Esophageal Cancer.

PURPOSE: In this study, we report the results from the esophageal squamous cell carcinoma (SCC) cohort of a phase II, noncomparative, basket study evaluating the antitumor activity and safety of fibroblast activation protein-IL2 variant (FAP-IL2v) plus atezolizumab in patients with advanced/metastatic solid tumors (NCT03386721). PATIENTS AND METHODS: Eligible patients had an Eastern Cooperative Oncology Group performance status of 0 to 1; measurable metastatic, persistent, or recurrent esophageal SCC; progression on ≥1 prior therapy; and were checkpoint inhibitor-naïve. Patients received FAP-IL2v 10 mg plus atezolizumab 1,200 mg intravenously every 3 weeks, or FAP-IL2v weekly for 4 weeks and then every 2 weeks plus atezolizumab 840 mg intravenously every 2 weeks. The primary endpoint was investigator-assessed objective response rate (ORR). RESULTS: In the response-evaluable population (N = 34), the best confirmed ORR was 20.6% [95% confidence interval (CI), 10.4-36.8], with a complete response seen in 1 patient and partial responses in 6 patients. The disease control rate was 44.1% (complete response = 2.9%; partial response = 17.6%; stable disease = 23.5%), and the median duration of response was 10.1 mon/ths (95% CI, 5.6-26.7). The median progression-free survival was 1.9 months (95% CI, 1.8-3.7). Analysis of response by PDL1 expression (Ventana SP263) resulted in an ORR of 26.7% for patients with PDL1-positive tumors (tumor area positivity cutoff ≥1%; n = 15) and 7.1% for patients with PDL1-negative tumors (tumor area positivity cutoff <1%; n = 14). Overall, the treatment combination was tolerable, and adverse events were consistent with the known safety profiles of each drug. CONCLUSIONS: FAP-IL2v plus atezolizumab demonstrated clinical activity and was tolerable in patients with previously treated esophageal SCC.