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Supplementary data: aa-22-1228-File002_afac284 - docx file available online at https://academic.oup.com/ageing/article/51/12/afac284/6931845?login=false#supplementary-data Copyright © The Author(s) 2022. The minimal important change and analogous terms (MIC) can provide a measure of change in health outcome variables that is associated with a level of importance for participant/patient. This review explores the availability of the MIC for different balance measures used with older adults in research and clinical settings. PubMed, ProQuest and Web of Science search engines were used and based on the inclusion and exclusion criteria, 11 studies were deemed suitable for data extraction and analysis. The results demonstrated that MIC is available for the following balance-associated tests: Berg Balance Scale, Timed Up and Go, Short Physical Performance Battery, BESTest and the Tinetti test. A range of MIC values were shown, reflective of different older adult health conditions, calculation methods and anchors used. It was also evident that the responsiveness of the test was not always available or appropriately determined, questioning the validity of the MIC value published. Greater research is needed to establish MIC for balance measurements for use with older adults with different health conditions, preferably using objective measures such as falls. The calculation of such statistics will improve the evaluation of intervention effectiveness.

Acoustic metamaterials can be designed by inserting along the path of a sound wave periodically spaced side resonators. An example of efficient design was recently proposed consisting of a perforated stacking of flat annular cavities (the pancake resonator), the perforation allowing the propagation of sound waves. The pancake resonator is used in absorber mode and the theoretical description of sound absorption can be achieved with the help of the theory of sound propagation in fluid saturated porous media in which two porosities are considered: the main porosity associated with the perforation and a porosity associated with the flat cavity volumes. Considering a perforation diameter and flat cavity thickness ranging from submillimetric values to a few millimeters allows a wide range of material permeabilities and permeability contrasts between main pore and stacking of cavities. The relatively small values of diameter and cavity thickness also results in the existence of viscous and thermal boundary layers in the main pore (the perforation) and in the flat cavities. This metamaterial makes simultaneous use of viscothermal losses and periodicity in order to achieve low frequency sound absorption for an overall small absorber thickness. Experimental results are also presented for the validation of the model.

Understanding the behavior of complex biochemical networks is the primary goal of systems biology. This task is often addressed through the generation of large data sets such as measurements of biological components like mRNA transcripts, proteins, and metabolites. Although these methods have become increasingly accurate and comprehensive at measuring the state of the system, uncovering the function of the system then becomes a problem of analysis to extract an understanding of the system from the data. A key challenge in analyzing biological data sets is that determining the function of the system depends on a knowledge of the relationship between the components of the system. These relationships can be captured by grouping variables by known associations, such as pathways, or by explicitly modeling their relationships mathematically. Metabolic networks are particularly primed for both of these approaches, because metabolic pathways are well-defined by network topology and the equation governing their function, the mass balance equation, is well understood. In this thesis, the capabilities of metabolic networks to interpret biological data are advanced through the development and application of models of increasing levels of detail. First, pathways systematically derived from a global human metabolic network reconstruction are used to identify metabolic perturbations tied to drug side effects from in vitro drug -treated gene expression data. Second, steady-state flux modeling of a core human metabolic network is used to identify factors underlying two hallmarks of cancer metabolism: the Warburg effect and glutamine addiction. Finally, the concept of a metabolic network reconstruction is extended by the definition of detailed enzyme kinetic mechanisms within E. coli central metabolism, integrating multiple data sets mechanistically to calculate dynamic functional states of enzymes. This work furthers the use of metabolic networks in analyzing complex biological data sets, showcasing the utility of these networks in addressing practical questions in systems biology using methods of increasing mechanistic resolution

Following early retirement from parish work, Edwards undertook a mission to defend and preserve the Church of England. Against those who sought to make optional those doctrines traditionally considered as essential for Christian orthodoxy, such as the Trinity and Incarnation, Edwards was uncompromising. Removing foundational ordinances of Christianity would destroy the church. To counter Arian and Socinian threats, Edwards entered the pamphlet wars, engaging some of the leading heterodox intellectuals of his day, including John Locke, Samuel Clarke, and William Whiston.\ud \ud Edwards was also committed to church unity for those who accepted as essential those doctrines delineated in the Apostles’, Nicene and Athanasian Creeds upon which the XXXIX Articles were based. Though a committed Calvinist, he willingly subordinated his theological preferences on non-essentials to greater principle of unity by respectfully remaining in the church dominated by Latitudinarians and others who did not share his Reformed theology.\ud \ud Leaders on all sides of the seventeenth-century dissension paid lip service to church unity, but failed to act on it. Edwards practiced genuine toleration within the traditional bounds of orthodoxy but he would not extend his tolerance to define the church out of existence. Toleration, after all, is a weak version of Christian love and it was clear to Edwards that lack of love was the basis for division.\ud \ud Most contemporary references to John Edwards describe him very briefly as a rude, extreme, and slandering Calvinist who had a bitter debate with philosopher John Locke, the champion of reasonableness, peace, and toleration. This thesis does more than upend that synopsis. Although Edwards was not always the most diplomatic opponent, a close evaluation of his works demonstrates that he was most often respectful, fairly tolerant, and careful in his accusations. Had others followed his example, Church of England schisms could have been avoided.

Background/Aims: The management of extracerebral collections of fluid in patients with hydrocephalus can be problematic for either their simultaneous separate management or sequential management, each of which may require multiple surgeries and the management of external drains. The object of this report is to review the experience with a shunt configuration that simultaneously diverts ventricular fluid and extracerebral fluid, whether subdural or subarachnoid in location, through different outflow resistances. Methods: The medical records, including neuroimaging of patients with hydrocephalus and clinically significant extracerebral collections of low density who were managed by implanting a differential pressure type shunt, were retrospectively reviewed. Results: Four patients, 3 children and 1 adult, met inclusion criteria. Three had the entire differential pressure shunt implanted under 1 anesthetic, and 1 had a catheter inserted into the subdural space and connected into an existing ventriculoperitoneal shunt system. The extracerebral fluid collections cleared in all 4 patients, and the CSF shunt continued to function normally. Conclusion: A single surgical procedure to implant a differential pressure shunt can simultaneously drain and obliterate an extracerebral fluid collection while managing the hydrocephalus. Compared to routines that include external drainage, differential pressure shunting requires fewer surgeries, shorter hospitalization, with expected less expense.

Background: Systemic immunoglobulin light chain-associated amyloidosis (AL) is a rare disorder associated with plasma cell dyscrasias and the production of monoclonal free light chain proteins. Pathology results from the extracellular deposition of proteinaceous (amyloid) fibrils in association with proteoglycans and other serum derived proteins. The amyloid accumulates in abdominothoracic organs, notably the heart, liver, spleen, kidneys, as well as peripheral nerves leading to organ dysfunction and significant morbidity. At present, there are no radiotracers approved in the US for the non-invasive quantitative measurement of systemic AL amyloid disease. We have developed a synthetic polybasic peptide radiotracer, designated 124I-p5+14, which has been shown, in preclinical assays, to bind many forms of amyloid, including AL, ATTR, and ALECT2 (Wall, J.S. et al. (2015) Molecules, 20, 7657). The peptide binds, through multivalent electrostatic interactions, to the hypersulfated heparan sulfate glycosaminoglycans and potentially to the fibrillar constituents of amyloid deposits. Using SPECT and PET imaging of murine systemic amyloidosis, we have demonstrated the specific interaction of radioiodinated peptide p5+14 with amyloid in abdominothoracic organs and tissues. No detectable binding of p5+14 with amyloid-free tissues was observed. In light of these data, p5+14 was prepared for a first-in-human PET imaging study using iodine-124-labeled peptide (NCT 03678259). Methods: Patients >18 years of age with biopsy proven amyloidosis with adequate renal function and not requiring heparin therapy are eligible. Subjects receive Results: To date, 10 patients have been dosed and evaluated. No serious adverse events of any grade were noted. Organ-specific and whole body effective dosimetry were calculated using time activity curves generated from the initial cohort. The gender-averaged mean whole body effective dose attributed to 124I-p5+14 injection was estimated to be ~0.5 mSv/MBq. Blood pool clearance of the 124I-p5+14 was analyzed using a two phase exponential equation which yielded an excellent fit to the data (R2 > 0.99 for all data), with estimated fast half-life values of 11.8 min - 22.4 min, and a corresponding elimination half-life of between 667.8 min and 746.7 min. Analysis of PET images indicated retention of 124I-p5+14 in the heart, kidneys, liver, spleen, pancreas, bone marrow, lung, and adrenal gland of AL patients (Fig. 1 (A) Cardio-renal AL, and (B) Hepatosplenic AL amyloidosis). Cardiac uptake of the radiotracer was observed in 80% of AL patients (n = 5) who received ≥ 1 mCi 124I-p5+14, with a mean myocardium:blood pool ratio of 2.3 ± 0.5 in positive images. Additionally, liver, spleen and kidney retention of 124I-p5+14 was observed in 20%, 40%, and 60% of AL patients, respectively. Furthermore, retention of the radiotracer has been indicated in the heart, spleen and kidney in patients with ATTR and ALECT2--associated amyloidoses. Conclusion: Initial PET/CT image data indicate that 124I-p5+14 can provide quantitative detection of systemic AL amyloidosis in multiple organ systems and may have general utility in detecting and monitoring amyloid burden in many forms of amyloidosis. Acknowledgments: This study was supported in part by the National Heart Lung and Blood Institute, National Institutes of Health, through the Science Moving TowArds Research Translation and Therapy (SMARTT) program via the following contracts: HHSN268201600011C, HHSN268201600012C, and HHSN268201600014C, as well as by contributions from Gerdau to the ACTP Gift Fund at the UTGSM and support from UHS. In addition, we thank Michael Stabin, PhD, Brett Hines, Carmella Moody, PhD and Derry Ridgway, MD and the many patients for their support. Figure 1 Disclosures Wall: Solex LLC: Equity Ownership; University of Tennessee Research Foundation: Patents & Royalties. Stuckey:Solex LLC: Equity Ownership. Martin:Solex LLC: Equity Ownership. Richey:Solex LLC: Equity Ownership. Ramchandren:Sandoz-Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Pharmacyclics LLC, an Abbvie company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding. Kennel:University of Tennessee Research Foundation: Patents & Royalties; Solex LLC: Equity Ownership.

This case is a 15-year-old male, presenting with headaches, right face, and arm numbness, and ataxia. MRI (magnetic resonance imaging) revealed a large right sided dumbbell shaped lesion, extending into the middle and posterior fossa with compression of the brainstem consistent with a trigeminal schwannoma. Treatment options here would be a retrosigmoid suprameatal approach or a lateral presigmoid approach. Given the tumor extension into multiple compartments, a presigmoid craniotomy, combining a middle fossa approach with anterior petrosectomy, and retrolabyrinthine approach with posterior petrosectomy were used to maximize the direct access corridor for resection. The petrous apex was already expanded and remodeled by the tumor. Nerve fascicles preservation technique is paramount to the functional preservation of the trigeminal nerve. The extent of resection should be weighed against the anatomical functional integrity of the nerve. Near total resection is considered if that means more nerve preservation. Postoperatively, the patient had a slight (House–Brackman grade II) facial droop, which resolved over days and developed right trigeminal hypesthesia at several weeks. This case is presented to demonstrate a combined petrosectomy technique for resection of lesions extending into both the middle and posterior cranial fossa with near total resection and trigeminal nerve preservation.The link to the video can be found at: https://youtu.be/kA9GyFhL1dg.

Tropospheric ozone (O3) adversely affects human health, reduces crop yields, and contributes to climate forcing. To limit these effects, the processes controlling O3 abundance as well as that of its precursor molecules must be fully characterized. Here, I examine three facets of O3 production, both in heavily polluted and remote environments. First, using in situ observations from the DISCOVER-AQ field campaign in the Baltimore/Washington region, I evaluate the emissions of the O3 precursors CO and NOx (NOx = NO + NO2) in the National Emissions Inventory (NEI). I find that CO/NOx emissions ratios derived from observations are 21% higher than those predicted by the NEI. Comparisons to output from the CMAQ model suggest that CO in the NEI is accurate within 15 ± 11%, while NOx emissions are overestimated by 51-70%, likely due to errors in mobile sources. These results imply that ambient ozone concentrations will respond more efficiently to NOx controls than current models suggest. I then investigate the source of high O3 and low H2O structures in the Tropical Western Pacific (TWP). A combination of in situ observations, satellite data, and models show that the high O3 results from photochemical production in biomass burning plumes from fires in tropical Southeast Asia and Central Africa; the low relative humidity results from large-scale descent in the tropics. Because these structures have frequently been attributed to mid-latitude pollution, biomass burning in the tropics likely contributes more to the radiative forcing of climate than previously believed. Finally, I evaluate the processes controlling formaldehyde (HCHO) in the TWP. Convective transport of near surface HCHO leads to a 33% increase in upper tropospheric HCHO mixing ratios; convection also likely increases upper tropospheric CH3OOH to ~230 pptv, enough to maintain background HCHO at ~75 pptv. The long-range transport of polluted air, with NO four times the convectively controlled background, intensifies the conversion of HO2 to OH, increasing OH by a factor of 1.4. Comparisons between the global chemistry model CAM-Chem and observations show that consistent underestimates of HCHO by CAM-Chem throughout the troposphere result from underestimates in both NO and acetaldehyde.

As torso flexion and repetitive lifting are known risk factors for low back pain and injury, it is important to investigate lifting techniques that might reduce injury during repetitive lifting. By normalizing lumbar posture to a subject's range of motion (ROM), as a function of torso flexion, this research examined when subjects approached their range of motion limits during dynamic lifting tasks. For this study, it was hypothesized that experienced lifters would maintain a more neutral lumbar angle relative to their range of motion, while novice lifters would approach the limits of their lumbar ROM during the extension phase of a straight-leg lift. The results show a statistically significant difference in lifting patterns for these two groups supporting this hypothesis. The novice group maintained a much more kyphotic lumbar angle for both the flexion (74% of the lumbar angle ROM) and extension phases (86% of the lumbar angle ROM) of the lifting cycle, while the experienced group retained a more neutral curvature throughout the entire lifting cycle (37% of lumbar angle ROM in flexion and 48% of lumbar angle ROM in extension). By approaching the limits of their range of motion, the novice lifters could be at greater risk of injury by placing greater loads on the supporting soft tissues of the spine. Future research should examine whether training subjects to assume more neutral postures during lifting could indeed lower injury risks.