This Dead or That Dead: Framing Effects in the Evaluation of Health States.

OBJECTIVES: Current approaches to health state valuation rely on credible classification of states as either "better than dead" or "worse than dead" (WTD). We investigate how such evaluations of health states are affected by the framing in pairwise comparison tasks. METHODS: We conducted an online survey with 361 participants to compare the propensity to evaluate a state as WTD under 6 frames: (A) using a regular time trade-off (TTO) choice task, (B) using a lead-time TTO choice task, (C) excluding the immediacy of death, (D) avoiding reference to the process of dying, (E) focusing on longevity, and (F) focusing on improvements in quality of life. Each participant evaluated 9 EQ-5D-5L health states using 3 frames. The frames were compared using several statistical approaches to confirm robustness to indirect comparisons or respondent heterogeneity and inattentiveness. RESULTS: The odds of a state being evaluated as WTD, compared with frame A, increase 2.7-fold and 1.5-fold in frame B and E, respectively, and decrease >5-fold in frame F. Frames C and D do not differ significantly from frame A. CONCLUSIONS: Different framings for questions about whether a state is WTD or better than dead, even if theoretically equivalent, yield substantially different results. Notably, whether a state is evaluated as WTD differs greatly between the regular TTO and lead-time TTO choice tasks and when either final outcomes or improvements over time are considered.

Using the Online Elicitation of Personal Utility Functions Approach to Derive a Patient-Based 5-Level Version of EQ-5D Value Set: A Study in 122 Patients With Rheumatic Diseases From Germany.

OBJECTIVES: Traditional preference elicitation methods, such as discrete choice experiments or time trade-off, usually require large sample sizes. This can limit their applicability in patient populations, where recruiting enough participants can be challenging. The objective of this study was to test a new method, called the Online elicitation of Personal Utility Functions (OPUF) approach, to derive an EQ-5D-5L value set from a relatively small sample of patients with rheumatic diseases. METHODS: OPUF is a new type of online survey that implements compositional preference elicitation techniques. Central to the method are 3 valuation steps: (1) dimension weighting, (2) level rating, and (3) anchoring. An English demo version of the OPUF survey can be accessed at https://valorem.health/eq5d5l. From the responses, a personal EQ-5D-5L utility function can be constructed for each participant, and a group-level value set can be derived by aggregating model coefficients across participants. RESULTS: A total of 122 patients with rheumatic disease from Germany completed the OPUF survey. The survey was generally well received; most participants completed the survey in less than 20 minutes and were able to derive a full EQ-5D-5L value set. The precision of mean coefficients was high, despite the small sample size. CONCLUSIONS: Our findings demonstrate that OPUF can be used to derive an EQ-5D-5L value set from a relatively small sample of patients. Although the method is still under development, we think that it has the potential to be a valuable preference elicitation tool and to complement traditional methods in several areas.

Exploring health preference heterogeneity in the UK: Using the online elicitation of personal utility functions approach to construct EQ-5D-5L value functions on societal, group and individual level.

A new method has recently been developed for valuing health states, called 'Online elicitation of Personal Utility Functions' (OPUF). In contrast to established methods, such as time trade-off or discrete choice experiments, OPUF does not require hundreds of respondents, but allows estimating utility functions for small groups and even at the individual level. In this study, we used OPUF to elicit EQ-5D-5L health state preferences from a (not representative) sample of the UK general population, and then compared utility functions on the societal-, group-, and individual level. A demo version of the survey is available at: https://eq5d5l.me. Data from 874 respondents were included in the analysis. For each respondent, we constructed a personal EQ-5D-5L value set. These personal value sets predicted respondents' choices in three hold-out discrete choice tasks with an accuracy of 78%. Overall, preferences varied greatly between individuals. However, PERMANOVA analysis showed that demographic characteristics explained only a small proportion of the variability between subgroups. While OPUF is still under development, it has important strengths: it can be used to construct value sets for patient reported outcome instruments such as EQ-5D-5L, while also allowing examination of underlying preferences in an unprecedented level of detail. In the future, OPUF could be used to complement existing methods, allowing valuation studies in smaller samples, and providing more detailed insights into the heterogeneity of preferences across subgroups.

Precise excision of HTLV-1 provirus with a designer-recombinase.

The human T cell leukemia virus type 1 (HTLV-1) is a pathogenic retrovirus that persists as a provirus in the genome of infected cells and can lead to adult T cell leukemia (ATL). Worldwide, more than 10 million people are infected and approximately 5% of these individuals will develop ATL, a highly aggressive cancer that is currently incurable. In the last years, genome editing tools have emerged as promising antiviral agents. In this proof-of-concept study, we use substrate-linked directed evolution (SLiDE) to engineer Cre-derived site-specific recombinases to excise the HTLV-1 proviral genome from infected cells. We identified a conserved loxP-like sequence (loxHTLV) present in the long terminal repeats of the majority of virus isolates. After 181 cycles of SLiDE, we isolated a designer-recombinase (designated RecHTLV), which efficiently recombines the loxHTLV sequence in bacteria and human cells with high specificity. Expression of RecHTLV in human Jurkat T cells resulted in antiviral activity when challenged with an HTLV-1 infection. Moreover, expression of RecHTLV in chronically infected SP cells led to the excision of HTLV-1 proviral DNA. Our data suggest that recombinase-mediated excision of the HTLV-1 provirus represents a promising approach to reduce proviral load in HTLV-1-infected individuals, potentially preventing the development of HTLV-1-associated diseases.

Dual-Action Heteromultivalent Glycopolymers Stringently Block and Arrest Influenza A Virus Infection In Vitro and Ex Vivo.

Here, we demonstrate the concerted inhibition of different influenza A virus (IAV) strains using a low-molecular-weight dual-action linear polymer. The 6'-sialyllactose and zanamivir conjugates of linear polyglycerol are optimized for simultaneous targeting of hemagglutinin and neuraminidase on the IAV surface. Independent of IAV subtypes, hemagglutination inhibition data suggest better adsorption of the heteromultivalent polymer than homomultivalent analogs onto the virus surface. Cryo-TEM images imply heteromultivalent compound-mediated virus aggregation. The optimized polymeric nanomaterial inhibits >99.9% propagation of various IAV strains 24 h postinfection in vitro at low nM concentrations and is up to 10000× more effective than the commercial zanamivir drug. In a human lung ex vivo multicyclic infection setup, the heteromultivalent polymer outperforms the commercial drug zanamivir and homomultivalent analogs or their physical mixtures. This study authenticates the translational potential of the dual-action targeting approach using small polymers for broad and high antiviral efficacy.

The mRNA-Binding Protein KSRP Limits the Inflammatory Response of Macrophages.

KH-type splicing regulatory protein (KSRP) is a single-stranded nucleic acid-binding protein with multiple functions. It is known to bind AU-rich motifs within the 3'-untranslated region of mRNA species, which in many cases encode dynamically regulated proteins like cytokines. In the present study, we investigated the role of KSRP for the immunophenotype of macrophages using bone marrow-derived macrophages (BMDM) from wild-type (WT) and KSRP-/- mice. RNA sequencing revealed that KSRP-/- BMDM displayed significantly higher mRNA expression levels of genes involved in inflammatory and immune responses, particularly type I interferon responses, following LPS stimulation. In line, time kinetics studies revealed increased levels of interferon-γ (IFN-γ), interleukin (IL)-1ß and IL-6 mRNA in KSRP-/- macrophages after 6 h subsequent to LPS stimulation as compared to WT cultures. At the protein level, KSRP-/- BMDM displayed higher levels of these cytokines after overnight stimulation. Matching results were observed for primary peritoneal macrophages of KSRP-/- mice. These showed higher IL-6, tumor necrosis factor-α (TNF-α), C-X-C motif chemokine 1 (CXCL1) and CC-chemokine ligand 5 (CCL5) protein levels in response to LPS stimulation than the WT controls. As macrophages play a key role in sepsis, the in vivo relevance of KSRP deficiency for cytokine/chemokine production was analyzed in an acute inflammation model. In agreement with our in vitro findings, KSRP-deficient animals showed higher cytokine production upon LPS administration in comparison to WT mice. Taken together, these findings demonstrate that KSRP constitutes an important negative regulator of cytokine expression in macrophages.

Textbook Oncological Outcome in European GASTRODATA.

OBJECTIVE: To assess the rate of textbook outcome (TO) and textbook oncological outcome (TOO) in the European population based on the GASTRODATA registry. BACKGROUND: TO is a composite parameter assessing surgical quality and strongly correlates with improved overall survival. Following the standard of treatment for locally advanced gastric cancer, TOO was proposed as a quality and optimal multimodal treatment parameter. METHODS: TO was achieved when all the following criteria were met: no intraoperative complications, radical resection according to the surgeon, pR0 resection, retrieval of at least 15 lymph nodes, no severe postoperative complications, no reintervention, no admission to the intensive care unit, no prolonged length of stay, no postoperative mortality and no hospital readmission. TOO was defined as TO with the addition of perioperative chemotherapy compliance. RESULTS: Of the 2558 patients, 1700 were included in the analysis. TO was achieved in 1164 (68.5%) patients. The use of neoadjuvant chemotherapy [odds ratio (OR) = 1.33, 95% CI: 1.04-1.70] and D2 or D2+ lymphadenectomy (OR = 1.55, 95% CI: 1.15-2.10) had a positive impact on TO achievement. Older age (OR = 0.73, 95% CI: 0.54-0.94), pT3/4 (OR = 0.79, 95% CI: 0.63-0.99), ASA 3/4 (OR = 0.68, 95% CI: 0.54-0.86) and total gastrectomy (OR = 0.56, 95% CI: 0.45-0.70), had a negative impact on TO achievement. TOO was achieved in 388 (22.8%) patients. Older age (OR = 0.37, 95% CI: 0.27-0.53), pT3 or pT4 (OR = 0.52, 95% CI: 0.39-0.69), and ASA 3 or 4 (OR = 0.58, 95% CI: 0.43-0.79) had a negative impact on TOO achievement. CONCLUSIONS: Despite successively improved surgical outcomes, stage-appropriate chemotherapy in adherence to the current guidelines for multimodal treatment of gastric cancer remains poor. Further implementation of oncologic quality metrics should include greater emphasis on perioperative chemotherapy and adequate lymphadenectomy.

A machine learning tool to improve prediction of mediastinal lymph node metastases in non-small cell lung cancer using routinely obtainable [18F]FDG-PET/CT parameters.

BACKGROUND: In patients with non-small cell lung cancer (NSCLC), accuracy of [18F]FDG-PET/CT for pretherapeutic lymph node (LN) staging is limited by false positive findings. Our aim was to evaluate machine learning with routinely obtainable variables to improve accuracy over standard visual image assessment. METHODS: Monocentric retrospective analysis of pretherapeutic [18F]FDG-PET/CT in 491 consecutive patients with NSCLC using an analog PET/CT scanner (training + test cohort, n = 385) or digital scanner (validation, n = 106). Forty clinical variables, tumor characteristics, and image variables (e.g., primary tumor and LN SUVmax and size) were collected. Different combinations of machine learning methods for feature selection and classification of N0/1 vs. N2/3 disease were compared. Ten-fold nested cross-validation was used to derive the mean area under the ROC curve of the ten test folds ("test AUC") and AUC in the validation cohort. Reference standard was the final N stage from interdisciplinary consensus (histological results for N2/3 LNs in 96%). RESULTS: N2/3 disease was present in 190 patients (39%; training + test, 37%; validation, 46%; p = 0.09). A gradient boosting classifier (GBM) with 10 features was selected as the final model based on test AUC of 0.91 (95% confidence interval, 0.87-0.94). Validation AUC was 0.94 (0.89-0.98). At a target sensitivity of approx. 90%, test/validation accuracy of the GBM was 0.78/0.87. This was significantly higher than the accuracy based on "mediastinal LN uptake > mediastinum" (0.7/0.75; each p < 0.05) or combined PET/CT criteria (PET positive and/or LN short axis diameter > 10 mm; 0.68/0.75; each p < 0.001). Harmonization of PET images between the two scanners affected SUVmax and visual assessment of the LNs but did not diminish the AUC of the GBM. CONCLUSIONS: A machine learning model based on routinely available variables from [18F]FDG-PET/CT improved accuracy in mediastinal LN staging compared to established visual assessment criteria. A web application implementing this model was made available.

Quality-Adjusted Life Expectancy Norms for the English Population.

OBJECTIVES: The National Institute for Health and Care Excellence in England has implemented severity-of-disease modifiers that give greater weight to health benefits accruing to patients who experience a larger shortfall in quality-adjusted life-years (QALYs) under current standard of care than healthy individuals. This requires an estimate of quality-adjusted life expectancy (QALE) of the general population based on age and sex. Previous QALE population norms are based on nearly 30-year-old assessments of health-related quality of life in the general population. This study provides updated QALE estimates for the English population based on age and sex. METHODS: 5-level version of EQ-5D data for 14 412 participants from the Health Survey for England (waves 2017 and 2018) were pooled, and health-related quality of life population norms were calculated. These norms were combined with official life tables from the Office for National Statistics for 2017 to 2019 using the Sullivan method to derive QALE estimates based on age and sex. Values were discounted using 0%, 1.5%, and 3.5% discount rates. RESULTS: QALE at birth is 68.24 QALYs for men and 68.21 QALYs for women. These values are significantly lower than previously published QALE population norms based on the older 3-level version of EQ-5D data. CONCLUSION: This study provides new QALE population norms for England that serve to establish absolute and relative QALY shortfalls for the purpose of health technology assessments.

Liver Cell Type-Specific Targeting by Nanoformulations for Therapeutic Applications.

Hepatocytes exert pivotal roles in metabolism, protein synthesis and detoxification. Non-parenchymal liver cells (NPCs), largely comprising macrophages, dendritic cells, hepatic stellate cells and liver sinusoidal cells (LSECs), serve to induce immunological tolerance. Therefore, the liver is an important target for therapeutic approaches, in case of both (inflammatory) metabolic diseases and immunological disorders. This review aims to summarize current preclinical nanodrug-based approaches for the treatment of liver disorders. So far, nano-vaccines that aim to induce hepatitis virus-specific immune responses and nanoformulated adjuvants to overcome the default tolerogenic state of liver NPCs for the treatment of chronic hepatitis have been tested. Moreover, liver cancer may be treated using nanodrugs which specifically target and kill tumor cells. Alternatively, nanodrugs may target and reprogram or deplete immunosuppressive cells of the tumor microenvironment, such as tumor-associated macrophages. Here, combination therapies have been demonstrated to yield synergistic effects. In the case of autoimmune hepatitis and other inflammatory liver diseases, anti-inflammatory agents can be encapsulated into nanoparticles to dampen inflammatory processes specifically in the liver. Finally, the tolerance-promoting activity especially of LSECs has been exploited to induce antigen-specific tolerance for the treatment of allergic and autoimmune diseases.

Natural reference structures for three-dimensional maxillary regional superimposition in growing patients.

BACKGROUND: Assessment of growth-related or treatment-related changes in the maxilla requires a reliable method of superimposition. Such methods are well established for two-dimensional (2D) cephalometric images but not yet for three-dimensions (3D). The aims of this study were to identify natural reference structures (NRS) for the maxilla in growing patients in 3D, opportunistically using orthodontic mini-screws as reference; and to test the applicability of the proposed NRS for maxillary superimposition by assessing the concordance of this approach with Björk's 'stable reference structures' in lateral projection. METHODS: The stability of the mini-screws was tested on longitudinal pairs of pre- and post-orthodontic cone-beam computed tomography (CBCT) images by measuring the distance changes between screws. After verifying the stability of the mini-screws, rigid registration was performed for aligning the stable mini-screws. Then, non-rigid registration was used to establish the dense voxel-correspondence among CBCT images and calculate the displacement of each voxel belonging to the maxilla relative to the mini-screws. The displacement vectors were transformed to a standardized maxillary template to categorize the stability of the internal structures statistically. Those voxels that displaced less relative to the mini-screws were considered as the natural reference structures (NRS) for the maxilla. Test samples included another dataset of longitudinal CBCT scans. They were used to evaluate the applicability of the proposed NRS for maxillary superimposition. We assessed whether aligning the maxilla with proposed NRS is in concordance with the maxillary internal reference structures superimposition in the traditional 2D lateral view as suggested by Björk. This was quantitively assessed by comparing the mean sagittal and vertical tooth movements for both superimposition methods. RESULTS: The stability of the mini-screws was tested on 10 pairs of pre- and post-orthodontic cone-beam computed tomography (CBCT) images (T1: 12.9 ± 0.8 yrs, T2: 14.8 ± 0.7 yrs). Both the loaded and the unloaded mini-screws were shown to be stable during orthodontic treatment, which indicates that they can be used as reference points. By analyzing the deformation map of the maxilla, we confirmed that the infraorbital rims, maxilla around the piriform foramen, the infrazygomatic crest and the hard palate (palatal vault more than  1 cm distal to incisor foramen except the palatal suture) were stable during growth. Another dataset of longitudinal CBCT scans (T1: 12.2 ± 0.63 yrs, T2: 15.2 ± 0.96 yrs) was used to assess the concordance of this approach with Björk's 'stable reference structures'. The movement of the maxillary first molar and central incisor showed no statistically significant difference when superimposing the test images with the proposed NRS or with the classic Björk maxillary superimposition in the lateral view. CONCLUSIONS: The infraorbital rims, maxilla around the piriform foramen, the infrazygomatic crest and the hard palate (palatal vault more than 1 cm posterior to incisal foramen except the palatal suture) were identified as stable regions in the maxilla. These stable structures can be used for maxillary superimposition in 3D and generate comparable results to Björk superimposition in the lateral view.

Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme 2 (ACE2) transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in the alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis is still elusive. METHODS: Spectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 "gain-of-function" experiments were applied to infected human lung explants and adult stem cell derived human lung organoids to correlate ACE2 and related host factors with SARS-CoV-2 tropism, propagation, virulence and immune activation compared to SARS-CoV, influenza and Middle East respiratory syndrome coronavirus (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used to validate ex vivo results. RESULTS: We provide evidence that alveolar ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation and virus-induced tissue damage in the human alveolus. Instead, ex vivo infected human lungs and COVID-19 autopsy samples showed that alveolar macrophages were frequently positive for SARS-CoV-2. Single-cell/-nucleus transcriptomics further revealed nonproductive virus uptake and a related inflammatory and anti-viral activation, especially in "inflammatory alveolar macrophages", comparable to those induced by SARS-CoV and MERS-CoV, but different from NL63 or influenza virus infection. CONCLUSIONS: Collectively, our findings indicate that severe lung injury in COVID-19 probably results from a macrophage-triggered immune activation rather than direct viral damage of the alveolar compartment.

Socioeconomic inequalities in HRQoL in England: an age-sex stratified analysis.

BACKGROUND: Socioeconomic status is a key predictor of lifetime health: poorer people can expect to live shorter lives with lower average health-related quality-of-life (HRQoL) than richer people. In this study, we aimed to improve understanding of the socioeconomic gradient in HRQoL by exploring how inequalities in different dimensions of HRQoL differ by age. METHODS: Data were derived from the Health Survey for England for 2017 and 2018 (14,412 participants). HRQoL was measured using the EQ-5D-5L instrument. We estimated mean EQ-5D utility scores and reported problems on five HRQoL dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) for ages 16 to 90+ and stratified by neighbourhood deprivation quintiles. Relative and absolute measures of inequality were assessed. RESULTS: Mean EQ-5D utility scores declined with age and followed a socioeconomic gradient, with the lowest scores in the most deprived areas. Gaps between the most and least deprived quintiles emerged around the age of 35, reached their greatest extent at age 60 to 64 (relative HRQoL of most deprived compared to least deprived quintile: females = 0.77 (95% CI: 0.68-0.85); males = 0.78 (95% CI: 0.69-0.87)) before closing again in older age groups. Gaps were apparent for all five EQ-5D dimensions but were greatest for mobility and self-care. CONCLUSION: There are stark socioeconomic inequalities in all dimensions of HRQoL in England. These inequalities start to develop from early adulthood and increase with age but reduce again around retirement age.

The QALY is ableist: on the unethical implications of health states worse than dead.

INTRODUCTION: A long-standing criticism of the QALY has been that it would discriminate against people in poor health: extending the lives of individuals with underlying health conditions gains fewer QALYs than extending the lives of 'more healthy' individuals. Proponents of the QALY counter that this only reflects the general public's preferences and constitutes an efficient allocation of resources. A pivotal issue that has thus far been overlooked is that there can also be negative QALYs. METHODS AND RESULTS: Negative QALYs are assigned to the times spent in any health state that is considered to be worse than dead. In a health economic evaluation, extending the lives of people who live in such states reduces the overall population health; it counts as a loss. The problem with this assessment is that the QALY is not based on the perspectives of individual patients-who usually consider their lives to be well worth living-but it reflects the preferences of the general public. While it may be generally legitimate to use those preferences to inform decisions about the allocation of health care resources, when it comes to states worse than dead, the implications are deeply problematic. In this paper, I discuss the (un)ethical aspects of states worse than dead and demonstrate how their use in economic evaluation leads to a systematic underestimation of the value of life-extending treatments. CONCLUSION: States worse than dead should thus no longer be used, and a non-negative value should be placed on all human lives.

Pathophysiology of Demineralization, Part I: Attrition, Erosion, Abfraction, and Noncarious Cervical Lesions.

PURPOSE OF THE REVIEW: Compare pathophysiology for infectious and noninfectious demineralization disease relative to mineral maintenance, physiologic fluoride levels, and mechanical degradation. RECENT FINDINGS: Environmental acidity, biomechanics, and intercrystalline percolation of endemic fluoride regulate resistance to demineralization relative to osteopenia, noncarious cervical lesions, and dental caries. Demineralization is the most prevalent chronic disease in the world: osteoporosis (OP) >10%, dental caries ~100%. OP is severely debilitating while caries is potentially fatal. Mineralized tissues have a common physiology: cell-mediated apposition, protein matrix, fluid logistics (blood, saliva), intercrystalline ion percolation, cyclic demineralization/remineralization, and acid-based degradation (microbes, clastic cells). Etiology of demineralization involves fluid percolation, metabolism, homeostasis, biomechanics, mechanical wear (attrition or abrasion), and biofilm-related infections. Bone mineral density measurement assesses skeletal mass. Attrition, abrasion, erosion, and abfraction are diagnosed visually, but invisible subsurface caries <400µm cannot be detected. Controlling demineralization at all levels is an important horizon for cost-effective wellness worldwide.

Pathophysiology of Demineralization, Part II: Enamel White Spots, Cavitated Caries, and Bone Infection.

PURPOSE OF REVIEW: Compare noninfectious (part I) to infectious (part II) demineralization of bones and teeth. Evaluate similarities and differences in the expression of hard tissue degradation for the two most common chronic demineralization diseases: osteoporosis and dental caries. RECENT FINDINGS: The physiology of demineralization is similar for the sterile skeleton compared to the septic dentition. Superimposing the pathologic variable of infection reveals a unique pathophysiology for dental caries. Mineralized tissues are compromised by microdamage, demineralization, and infection. Osseous tissues remodel (turnover) to maintain structural integrity, but the heavily loaded dentition does not turnover so it is ultimately at risk of collapse. A carious tooth is a potential vector for periapical infection that may be life-threatening. Insipient caries is initiated as a subsurface decalcification in enamel that is not detectable until a depth of ~400µm when it becomes visible as a white spot. Reliable detection and remineralization of invisible caries would advance cost-effective wellness worldwide.

Endoscopic Lung Volume Reduction with One-Way Valves in Patients with Severe Chronic Obstructive Pulmonary Disease with Hypercapnia.

BACKGROUND: Robust clinical evidence on the efficacy and safety of endoscopic lung volume reduction (ELVR) with one-way valves in patients with severe lung emphysema with chronic hypercapnic respiratory failure is lacking. OBJECTIVE: The aim of this study was to compare patient characteristics, clinical outcome measures, and incidences of adverse events between patients with severe COPD undergoing ELVR with one-way valves and with either a partial pressure of carbon dioxide (pCO2) of ≤45 mm Hg or with pCO2 >45 mm Hg. METHODS: This was a multicentre prospective study of patients with severe lung disease who were evaluated based on lung function, exercise capacity (6-min walk test [6-MWT]), and quality-of-life tests. RESULTS: Patients with pCO2 ≤45 mm Hg (n = 157) and pCO2 >45 mm Hg (n = 40) showed similar baseline characteristics. Patients with pCO2 ≤45 mm Hg demonstrated a significant increase in forced expiratory volume in 1 s (p < 0.001), a significant decrease in residual volume (RV) (p < 0.001), and significant improvements in the quality of life and 6-MWT at the 3-month follow-up. Patients with pCO2 >45 mm Hg had significant improvements in RV only (p < 0.05). There was a significant decrease in pCO2 between baseline and follow-up in hypercapnic patients, relative to the decrease in patients with pCO2 ≤45 mm Hg (p = 0.008). Patients who were more hypercapnic at baseline showed a greater reduction in pCO2 after valve placement (r = -0.38, p < 0.001). Pneumothorax was the most common adverse event in both groups. CONCLUSIONS: ELVR with one-way valves seems clinically beneficial with a remarkably good safety profile for patients with chronic hypercapnic respiratory failure.

A heterodimer of evolved designer-recombinases precisely excises a human genomic DNA locus.

Site-specific recombinases (SSRs) such as the Cre/loxP system are useful genome engineering tools that can be repurposed by altering their DNA-binding specificity. However, SSRs that delete a natural sequence from the human genome have not been reported thus far. Here, we describe the generation of an SSR system that precisely excises a 1.4 kb fragment from the human genome. Through a streamlined process of substrate-linked directed evolution we generated two separate recombinases that, when expressed together, act as a heterodimer to delete a human genomic sequence from chromosome 7. Our data indicates that designer-recombinases can be generated in a manageable timeframe for precision genome editing. A large-scale bioinformatics analysis suggests that around 13% of all human protein-coding genes could be targetable by dual designer-recombinase induced genomic deletion (dDRiGD). We propose that heterospecific designer-recombinases, which work independently of the host DNA repair machinery, represent an efficient and safe alternative to nuclease-based genome editing technologies.

The influence of neighbourhood equity on parkrunners in a British city.

Physical activity benefits both physical and mental health. Specific events may augment participation in physical activity at a population level. Parkrun is a popular, free, weekly, timed 5 km run or walk in public spaces located in five continents. However, these events may be distributed inequitably, possibly reinforcing inequities in health. As a prelude to a comprehensive analysis of a larger dataset, we explore a hypothesis that participation in parkrun is influenced by the socio-economic characteristics of both parkrunners and their park. Two parkruns, 4.5 km apart, were selected in the city of Sheffield in the United Kingdom. Defined by indices of multiple deprivation, Castle parkrun is located in an economically deprived neighbourhood and Hallam parkrun is in a prosperous area of the city. Parkrunners were defined by applying these same indices to the neighbourhood of home registration. Results: (i) the prosperous Hallam catchment area produced over five times more parkrun participants than Castle; (ii) compared with Castle, Hallam parkrun attracted more participants from both catchment areas; (iii) consequently, Hallam parkrun had seven times more participants than Castle parkrun. Conclusion: establishing parkruns in deprived areas is a necessary but not sufficient prerequisite for equity of participation in this heath promoting activity.

Parkruns are popular, free, weekly, timed 5 km runs or walks in public places across the world. They contribute to both mental and physical health. But they could also increase health inequality. Participants may already have the better health generally associated with above average incomes and home life in attractive neighbourhoods. Our pilot study compares two parkruns in the British city of Sheffield; one located in the city's poorer East End, the other in the richer West End.

Automated assessment of mandibular shape asymmetry in 3-dimensions.

INTRODUCTION: This study aimed to develop an automatic pipeline for analyzing mandibular shape asymmetry in 3-dimensions. METHODS: Forty patients with skeletal Class I pattern and 80 patients with skeletal Class III pattern were used. The mandible was automatically segmented from the cone-beam computed tomography images using a U-net deep learning network. A total of 17,415 uniformly sampled quasi-landmarks were automatically identified on the mandibular surface via a template mapping technique. After alignment with the robust Procrustes superimposition, the pointwise surface-to-surface distance between original and reflected mandibles was visualized in a color-coded map, indicating the location of asymmetry. The degree of overall mandibular asymmetry and the asymmetry of subskeletal units were scored using the root-mean-squared-error between the left and right sides. These asymmetry parameters were compared between the skeletal Class I and skeletal Class III groups. RESULTS: The mandible shape was significantly more asymmetrical in patients with skeletal Class III pattern with positional asymmetry. The condyles were identified as the most asymmetric region in all groups, followed by the coronoid process and the ramus. CONCLUSIONS: This automated approach to quantify mandibular shape asymmetry will facilitate high-throughput image processing for big data analysis. The spatially-dense landmarks allow for evaluating mandibular asymmetry over the entire surface, which overcomes the information loss inherent in conventional linear distance or angular measurements. Precise quantification of the asymmetry can provide important information for individualized diagnosis and treatment planning in orthodontics and orthognathic surgery.