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As a boundary of the seashore, the high-water mark (HWM) is relevant to the public, the State, and other rights holders in the coastal zone. Unlike most fixed property boundaries that are surveyed and beaconed, the HWM is subject to dynamic natural coastal processes and moves over time. Its location is difficult to determine, and the precision of this determination is unknown. This paper reports on an experiment to measure the precision (variability/repeatability) of the location of the HWM at a variety of sites near Cape Town, by volunteer participants. Four sites were chosen along stable (non-mobile) shores along the open, high energy oceanic shores south of Cape Town on the Cape Peninsula. One of these sites exhibits large variation in coastal terrain and type – at this site three sets of measurements were undertaken, bringing the total number of experimental sites to six. Surveying was undertaken in the South African national control survey system using network real-time kinematic global navigation satellite systems (GNSS). This experiment shows that the professional land surveyors located the HWM to ±1,6m, coastal engineers to ±4,1m, and the group of ‘others’ to ±4,2m. The professional land surveyors determined the height of the HWM to ±0,4m over all sites, compared to ±0,7m for all participants. The HWM is likely to be about 4 - 5m above the lowest astronomic tide. However, the line is not a contour – it is affected by weather and local variations in the coastline such as slope and seashore composition. The averaged heights of the HWM at each of the sites for all participants showed a range of 1,3m. Since the boundaries of the seashore cannot be determined with precision, property, cadastral and environmental law needs to continue to respect the nature of this environment and the limitations of locating the HWM.

OBJECTIVES: Challenges with patient-reported outcome (PRO) evidence and health state utility values (HSUVs) in rare diseases exist due to small, heterogeneous populations, lack of disease knowledge and early onset. To better incorporate quality of life (QoL) into Health Technology Assessment, a clearer understanding of these challenges is needed.METHODS: NICE appraisals of non-oncology treatments with an EMA orphan designation (n = 24), and corresponding appraisals in the Netherlands, France, and Germany were included. Document analysis of appraisal reports investigated how PROs/HSUVs influenced decision-making and was representative of QoL impact of condition and treatment.RESULTS: PRO evidence was not included in 6/24 NICE appraisals. When included, it either failed to demonstrate change, capture domains important for patients, or was uncertain. In the other countries, little information was reported and evidence largely did not demonstrate change. In NICE appraisals, HSUVs were derived through the collection of EQ-5D data (7/24 cases), mapping (6/24), vignettes (5/24), and published literature or other techniques (6/24). The majority did not use data collected alongside clinical trials. Few measures demonstrated significant change due to lack of sensitivity or face validity, short-term data, or implausible health states. In 8/24 NICE appraisals, patient surveys or input during appraisal committee meetings supported the interpretation of uncertainty or provided evidence about QoL.CONCLUSIONS: This study sheds light on the nature of PRO evidence in rare diseases and associated challenges. Results emphasise the need for improved development and use of PRO/HSUVs. Other forms of evidence and expert input are crucial to support better appraisal of uncertain or missing evidence.

The marine cone snail produces one of the fastest prey strikes in the animal kingdom. It injects highly efficacious venom, often causing prey paralysis and death within seconds. Each snail has hundreds of conotoxins, which serve as a source for discovering and utilizing novel analgesic peptide therapeutics. In this study, we discovered, isolated, and synthesized a novel α3/5-conotoxins derived from the milked venom of

Human rights principles form the foundation for the move towards responsible land administration. They are embedded in such international treatises as the Sustainable Development Goals, New Urban Agenda, and Voluntary Guidelines on the Responsible Governance of Tenure, among others. These treatises provide the backdrop to the development of land policies and administration systems that seek to secure land tenure and land rights for all through adherence to human rights principles such as non-discrimination, equity and justice, gender responsiveness, transparency and accountability. Yet the human rights tradition is built on Western values and biases, and there is some contention as to the universal acceptance of this. In discussing land rights in Africa, assumptions about the universality of human rights should be weighed against such contentions if land reform programmes are to sustainably succeed. In this chapter, the arguments around human rights are presented in the context of African land reform, and a model of democratic land governance is proposed.

Background Effective interventions to enhance adherence to self-care recommendations in patients with heart failure have immense potential to improve health and wellbeing. However, there is substantial inconsistency in the effectiveness of existing self-management interventions, partly because they lack theoretical models underpinning intervention development. Aim To outline how the capability, opportunity and motivation behaviour model has been applied to guide the development of a theory-based intervention aiming to improve adherence to heart failure self-care recommendations. Methods The application of the capability, opportunity and motivation behaviour model involved three steps: (a) identification of barriers and facilitators to heart failure self-care from two comprehensive meta-studies; (b) identification of appropriate behaviour change techniques to improve heart failure self-care; and (c) involvement of experts to reduce and refine potential behaviour change techniques further. Results A total of 119 barriers and facilitators were identified. Fifty-six behaviour change techniques remained after applying three steps of the behaviour model for designing interventions. Expert involvement (n=39, of which 31 were patients (67% men; 45% New York Heart Association II)) further reduced and refined potential behaviour change techniques. Experts disliked some behaviour change techniques such as ‘anticipated regret’ and ‘salience of consequences’. This process resulted in a final comprehensive list consisting of 28 barriers and 49 appropriate behaviour change techniques potentially enhancing self-care that was put forward for further use. Conclusion The application of the capability, opportunity and motivation behaviour model facilitated identifying important factors influencing adherence to heart failure self-care recommendations. The model served as a comprehensive guide for the selection and design of interventions for improving heart failure self-care adherence. The capability, opportunity and motivation behaviour model enabled the connection of heart failure self-care barriers to particular behaviour change techniques to be used in practice.

This study describes the design and synthesis of arylboronic acid 2, the first example of a permanently open "frustrated" benzoxaborole, along with an exploration of its application in bioconjugation. An efficient and high yielding seven-step synthesis was optimized. NMR experiments confirmed that compound 2 exists in the open ortho-hydroxyalkyl arylboronic acid structure 2-I, a form that is effectively prevented to undergo a dehydrative cyclization as a result of unfavorable geometry. Compound 2-I conjugates effectively with amines to form stable hemiaminal ether structures, including a highly effective reaction with lysozyme. Complexation with cysteine induces an open structure containing a free hydroxymethyl arm, with the amino and thiol groups reacting preferentially with the formyl group to form a N,S-acetal.

Raw honey contains a diverse microbiota originating from honeybees, plants, and soil. Some gram-positive bacteria isolated from raw honey are known for their ability to produce secondary metabolites that have the potential to be exploited as antimicrobial agents. Currently, there is a high demand for natural, broad-spectrum, and eco-friendly bio-fungicides in the food industry. Naturally occurring antifungal products from food-isolated bacteria are ideal candidates for agricultural applications. To obtain novel antifungals from natural sources, we isolated bacteria from raw clover and orange blossom honey to evaluate their antifungal-producing potential. Two Bacillus velezensis isolates showed strong antifungal activity against food-isolated fungal strains. Antifungal compound production was optimized by adjusting the growth conditions of these bacterial isolates. Extracellular proteinaceous compounds were purified via ammonium sulfate precipitation, solid phase extraction, and RP-HPLC. Antifungal activity of purified products was confirmed by deferred overlay inhibition assay. Mass spectrometry (MS) was performed to determine the molecular weight of the isolated compounds. Whole genome sequencing (WGS) was conducted to predict secondary metabolite gene clusters encoded by the two antifungal-producing strains. Using MS and WGS data, we determined that the main antifungal compound produced by these two Bacillus velezensis isolates was iturin A, a lipopeptide exhibiting broad spectrum antifungal activity.

Intervertebral disc (IVD) degeneration is accompanied by mechanical and gene expression changes to IVDs. SPARC-null mice display accelerated IVD degeneration, and treatment with (toll-like receptor 4 (TLR4) inhibitor) TAK-242 decreases proinflammatory cytokines and pain. This study examined if chronic TAK-242 treatment impacts mechanical properties and gene expression associated with IVD degeneration in SPARC-null mice.Male and female SPARC-null and WT mice aged 7-9 months were given intraperitoneal injections with TAK-242 or an equivalent saline vehicle for 8 weeks (3x/per week, M-W-F). L2-L5 spinal segments were tested in cyclic axial tension and compression. Gene expression analysis (RT-qPCR) was performed on male IVD tissues using Qiagen RT2 PCR arrays.SPARC-null mice had decreased NZ length (p = 0.001) and increased NZ stiffness (p0.001) compared to WT mice. NZ length was not impacted by TAK-242 treatment (p = 0.967) despite increased hysteresis energy (p = 0.024). Tensile stiffness was greater in SPARC-null mice (p = 0.018), and compressive (p0.001) stiffness was reduced from TAK-242 treatment in WT but not SPARC-null mice (p = 0.391). Gene expression analysis found upregulation of 13 ECM and 5 inflammatory genes in SPARC-null mice, and downregulation of 2 inflammatory genes after TAK-242 treatment.TAK-242 had limited impacts on SPARC-null mechanical properties and did not attenuate NZ mechanical changes associated with IVD degeneration. Expression analysis revealed an increase in ECM and inflammatory gene expression in SPARCnull mice with a reduction in inflammatory expression due to TAK-242 treatment. This study provides insight into the role of TLR4 in SPARC-null mediated IVD degeneration.

Although general cognitive behavioural therapy (CBT) can help alleviate distress associated with obsessive-compulsive disorder (OCD), strategies tailored to targeting specific cognitions, feelings, and behaviours associated with OCD such as exposure and ritual prevention (Ex/RP) and cognitive therapy (CT) have been shown to be a significantly more effective form of treatment. Treatment of individuals with unacceptable/taboo obsessions requires its own specific guidelines due to the stigmatizing and often misunderstood nature of accompanying thoughts and behaviours. In this article, OCD expert practitioners describe best practices surrounding two of the longest standing evidence-based treatment paradigms for OCD, CT and Ex/RP, tailored specifically to unacceptable and taboo obsessions, so that clients may experience the best possible outcomes that are sustained once treatment ends. In addition, CT specifically targets obsessions while Ex/RP addresses compulsions, allowing the two to be highly effective when combined together. A wide range of clinical recommendations on clinical competencies is offered, including essential knowledge, psychoeducation, designing fear hierarchies and exposures, instructing the client through behavioural experiments, and relapse prevention skills.Key learning aims(1)To learn about the theoretical underpinnings of specialized approaches to treating taboo/unacceptable thoughts subtype of OCD with gold-standard CBT treatments, cognitive therapy (CT) and exposure and ritual prevention (Ex/RP).(2)To learn about recognizing and identifying commonly missed covert cognitive symptoms in OCD such as rumination and mental compulsions.(3)To learn how to assess commonly unrecognized behavioural symptoms in OCD such as concealment, reassurance seeking, searching on online forums, etc.(4)To gain a nuanced understanding of the phenomenology of the taboo/unacceptable thoughts OCD subtype and the cycles that maintain symptoms and impairment.(5)To learn about in-session techniques such as thought experiments, worksheets, fear hierarchies, and different types of exposures.

Objectives An increasing number of innovative therapies (e.g., gene- and cell-based treatments) have been developed in the past 20 years. Despite the significant clinical potential of these therapies, access delays may arise because of differing perspectives of manufacturers and payers regarding issues such as the value of the product, clinical and financial uncertainties, and sustainability. Managed entry agreements (MEAs) can enable access to treatments that would not be reimbursed by conventional methods because of such concerns. However, although MEA typologies exist, there is currently no structured process to come to agreements on MEAs, which can be difficult to decide upon and implement. To facilitate more structured MEA negotiations, we propose a conceptual “value-based negotiation framework” with corresponding application tools. Methods The framework was developed based on an iterative process of scientific literature review and expert input. Results The framework aims to (i) systematically identify and prioritize manufacturer and payer concerns about a new treatment, and (ii) select a mutually acceptable combination of MEA terms that can best address priority concerns, with the lowest possible implementation burden. Conclusions The proposed framework will be tested in practice, and is a step toward supporting payers and manufacturers to engage in more structured, transparent negotiations to balance the needs of both sides, and enabling quicker, more transparent MEA negotiations and patient access to innovative products.

The Delphi technique is an important tool for structuring a group communication process among key stakeholders to inform the development of an intervention. However, when designing a Delphi study the scarcity of information on different voting schemes to analyse key stakeholders’ responses became evident, despite the fact that selecting the voting scheme a priori is paramount, since the selected method can influence the outcome. To fill that gap in literature, this article introduces key concepts derived from social choice theory to inform Delphi design. This includes optimising collective decisions by gaining deeper understandings of key stakeholders’ preferences, reducing avoidable unhappiness and minimising possibilities of insincere voting strategies. Four voting schemes (majority, approval, Borda, range) are presented and their implications are discussed. Since the purpose of each Delphi study is unique, we aim to increase awareness of the differential utility of voting schemes and encourage researchers to make an informed choice.

Estradiol is essential for the development of female sex characteristics and fertility. Postmenopausal women and breast cancer patients have high levels of estradiol. Aromatase catalyzes estradiol synthesis; however, the factors regulating aromatase activity are unknown. We identified a new 22-kDa protein, aromatase interacting partner in breast (AIPB), from the endoplasmic reticulum of human breast tissue. AIPB expression is reduced in tumorigenic breast and further reduced in triple-negative tumors. Like that of aromatase, AIPB expression is induced by nonsteroidal estrogen. We found that AIPB and aromatase interact in nontumorigenic and tumorigenic breast tissues and cells. In tumorigenic cells, conditional AIPB overexpression decreased estradiol, and blocking AIPB availability with an AIPB-binding antibody increased estradiol. Estradiol synthesis is highly increased in AIPB knockdown cells, suggesting that the newly identified AIPB protein is important for aromatase activity and a key modulator of estradiol synthesis. Thus, a change in AIPB protein expression may represent an early event in tumorigenesis and be predictive of an increased risk of developing breast cancer.

There is a rising recognition of the crucial role self-care plays in managing heart failure (HF). Yet patients often have difficulties implementing ongoing self-care recommendations into their daily lives. There is also recognition of the importance of theory for successful intervention design, and understanding of key factors for implementation so interventions fit a given context. Local key stakeholders can provide valuable insights to help understand relevant context-specific factors for intervention implementation. This study sought to engage stakeholders to explore and determine relevant contextual factors needed to design and facilitate successful implementation of an HF self-care intervention in the German health care system. A ranking-type Delphi approach was used to establish consensus from stakeholders (i.e., clinicians, patients, policymakers/potential funders) regarding eight factors (content, interventionist, target group, location, mode of delivery, intensity, duration, and format) to adequately define the components and implementation strategy of the intervention. Seventeen participants were invited to participate in the first Delphi round. A response rate of 94% (16/17) was achieved and maintained for all three Delphi rounds. Stakeholder consensus determined that nurses specializing in HF are the most appropriate interventionists, target groups should include patients and carers, and the intervention should occur in an outpatient HF clinic, be a mixture of group and individual training sessions, and last for 30 minutes. Sessions should take place more frequently in the beginning and less often over time. Local stakeholders can help determine contextual factors that must be taken into account for successful delivery of an intervention. This enables the intervention to be developed and applied based on these factors, to make it suitable for the target context and to enhance participation to achieve the desired outcomes.

Breast cancer is the most common invasive cancer in females worldwide and accounts for 16% of all female cancers, 22.9% of invasive cancers in women, and 18.2% of all cancer-related deaths worldwide. About 80% of these cancers, once established, depend on available estrogens (i.e., estradiol) to grow. The production of estrogens occurs via a catalytic process governed by the enzyme Aromatase. This process occurs primarily in the ovaries in pre-menopause, while in post-menopause, this occurs in peripheral tissues, including the breast. In patients whose cancers have specific hormone receptors, such as Estrogen Receptor positive (ER+), Progesterone Receptor positive (PR+), and Human Epidermal Growth Factor 2 Receptor positive (HER2+), these tumors can continue receiving nutrients and signals to grow, which provides targets for therapy. Although many of the currently available drugs for breast cancer seek to suppress this process and thus reduce available estrogens, they have numerous harmful side effects and have high rates of therapy failure due to the development of resistance. Therefore, new therapies and targets for this devastating disease are needed. We observed that breast tumors had increased estrogen production in postmenopausal women, leading us to question the cause of this increase. Further, the complete mechanism of aromatase action and the possibility of targetable cofactors remained previously unknown. Thus, we set out to identify the mechanism of Aromatase action to provide prognostic and therapeutic insight into this distressing disease. As Aromatase is an endoplasmic reticulum (ER) resident protein, we purified ER fractions from breast tissues, separated through 1D, and then each ten kDa fractions were further separated and analyzed through Mass-spectrometry to determine the cofactors associated with aromatase activity. We observed an 11 mer peptide LEVVVDQPMER, which on cloning resulted in a 207 amino acid protein not present in the database. This previously undiscovered protein is colocalized with Aromatase in the ER. We saw that knocking down its expression by siRNA in wild-type breast cells (MCF-12A) or tumorigenic MCF-7 or T47-D cells increased estradiol synthesis significantly without affecting aromatase expression. Further biochemical experiments showed that Aromatase and the 207 amino acid protein interacted directly without affecting the expression of other ER-resident proteins. Additionally, our experiments showed that the new protein is not hormonally stimulated or transcriptionally inhibited and thus, regulates the aromatase catalytic activity of estradiol synthesis. Therefore, we have termed this new protein "Aromatase Interacting Partner in Breast" (AIPB). Presentation: Tuesday, June 14, 2022 9:45 a.m. - 10:00 a.m.

The marine cone snail produces one of the fastest prey strikes in the animal kingdom. It injects highly efficacious venom, often causing prey paralysis and death within seconds. Each snail has hundreds of conotoxins, which serve as a source for discovering and utilizing novel analgesic peptide therapeutics. In this study, we discovered, isolated, and synthesized a novel α3/5-conotoxins derived from the milked venom of Conus obscurus (α-conotoxin OI) and identified the presence of α-conotoxin SI-like sequence previously found in the venom of Conus striatus. Five synthetic analogs of the native α-conotoxin OI were generated. These analogs incorporated single residue or double residue mutations. Three synthetic post-translational modifications (PTMs) were synthetically incorporated into these analogs: N-terminal truncation, proline hydroxylation, and tryptophan bromination. The native α-conotoxin OI demonstrated nanomolar potency in Poecilia reticulata and Homosapiens muscle-type nicotinic acetylcholine receptor (nAChR) isoforms. Moreover, the synthetic α-[P9K] conotoxin OI displayed enhanced potency in both bioassays, ranging from a 2.85 (LD50) to 18.4 (IC50) fold increase in comparative bioactivity. The successful incorporation of PTMs, with retention of both potency and nAChR isoform selectivity, ultimately pushes new boundaries of peptide bioengineering and the generation of novel α-conotoxin-like sequences. ispartof: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES vol:23 issue:20 ispartof: location:Switzerland status: published

Edaravone is considered to be a potent antioxidant drug known to scavenge free radical species and prevent free radical-induced lipid peroxidation. In this study, we investigated the effect of edaravone on the myeloperoxidase (MPO) activity, an enzyme responsible for the production of an array of neutrophil-derived oxidants that can cause cellular damage. The addition of edaravone to the reaction of MPO and hydrogen peroxide (H2O2) significantly enhanced the reduction of MPO Compound II back to native MPO. Interestingly, the MPO-mediated production of toxic hypochlorous acid exhibited a concentration-dependent biphasic effect, with the apparent optimal edaravone concentration at 10 μM. Oxidation of edaravone by MPO was examined by various analytical methods. An MPO-catalyzed product(s) of edaravone was identified at 350 nm by kinetic analysis of UV–Vis spectroscopy. Several MPO-catalyzed metabolites of edaravone were proposed from the LC-MS analyses, including oxidized dimers from edaravone radicals. Electron spin resonance (ESR) spin trapping detected a carbon-centred radical metabolite of edaravone. NMR studies revealed that there are two exchangeable hydrogens, one of which is on the α-carbon, justifying the carbon-centred edaravone radical produced from MPO. Despite the formation of an edaravone carbon-radical metabolite, it did not appear to effectively oxidize GSH (in comparison with phenoxyl radicals). Viability (ATP) and cytotoxicity (LDH release) assays showed a concentration-dependent effect of edaravone on HL-60 cells treated with either a bolus concentration of 30 μM H2O2 or a flux of H2O2 generated by 5 mM glucose and 10 mU/mL glucose oxidase. The H2O2-induced toxicity was ameliorated at high edaravone concentrations (100–200 μM). In contrast, low concentrations of edaravone (1–10 μM) exacerbated the H2O2-induced toxicity. However, the effect of edaravone at low concentration (0–10 μM) appeared more prominent with the LDH assay only. The cellular findings correlated with the biochemical studies with respect to hypochlorous acid formation. These findings provide interesting perspectives regarding the duality of edaravone as an antioxidant drug.

Background Adherence to heart failure (HF) self-care behaviours has been found to be effective for alleviating illness symptoms, increasing quality of life and reducing hospital re-admissions and mortality. However, many patients fail to implement on-going self-care into their daily lives. It is therefore crucial to improve the behaviour of HF patients to increase self-care adherence. The aim of this study is to identify relevant factors to successfully implement a complex, theory-based HF self-care intervention into routine practice. Methods We conducted semi-structured interviews to obtain key stakeholders’ opinions on previously developed behaviour change techniques for enhancing HF patients’ self-care behaviours, in order to optimise implementation of these techniques in an intervention. The interview topic guide was developed based on the Normalisation Process Theory (NPT), a tool that takes into account the feasibility of implementation and the acceptability to stakeholders. Interviews were analysed using thematic analysis and supported by MAXQDA 2020, a software for qualitative research. Results Interview participants included 18 key stakeholders consisting of three crucial groups: clinical experts (n = 7), patients (n = 3) and high calibre policy makers/potential funders (n = 8). The interviews revealed numerous factors to consider for successful implementation of an intervention into routine practice. The findings are presented according to two major categories: (1) themes within the NPT framework and (2) themes beyond the NPT framework. Themes within the NPT component ‘Coherence’ include three sub-themes: ‘understandability’, ‘value beyond existing interventions’ and ‘perceived benefits’. The NPT component ‘Cognitive participation’ revealed two sub-themes: ‘time resources’ and ‘financial sustainability’. Finally, the NPT component ‘Collective action’ uncovered three sub-themes: ‘need for training’, ‘compatibility with existing practice’ and ‘influence on roles’. A further two themes were identified beyond the NPT framework, namely: ‘structural challenges’ and (2) ‘role of carers’. Conclusions Factors identified previously by NPT were validated, but stakeholders further identified relevant aspects beyond NPT. Based on these findings, we suggest the existing NPT framework could be expanded to include a fifth component: questions considering specific environmental factors (contextual considerations). Sensitising researchers to these issues at an early stage when designing an intervention can facilitate its later success. Supplementary Information The online version contains supplementary material available at 10.1186/s12913-021-06596-w.

Supplemental material, sj-docx-1-heb-10.1177_10901981211043116 for Determining Contextual Factors for a Heart Failure Self-Care Intervention: A Consensus Delphi Study (ACHIEVE) by Amanda Whittal, Isabell Ehringfeld, Paula Steinhoff and Oliver Rudolf Herber in Health Education & Behavior

Background Patient-reported outcome measures (PROMs) are used in health technology assessment (HTA) to measure patient experiences with disease and treatment, allowing a deeper understanding of treatment impact beyond clinical endpoints. Developing and administering PROMs for rare diseases poses unique challenges because of small patient populations, disease heterogeneity, lack of natural history knowledge, and short-term studies. Objective This research aims to identify key factors to consider when using different types of PROMs in HTA for rare disease treatments (RDTs). Methods A scoping review of scientific and grey literature was conducted, with no date or publication type restrictions. Information on the advantages of and the challenges and potential solutions when using different types of PROMs for RDTs, including psychometric properties, was extracted and synthesized. Results Of 79 records from PubMed, 32 were included, plus 12 records from the grey literature. PROMs for rare diseases face potential data collection and psychometric challenges resulting from small patient populations and disease heterogeneity. Generic PROMs are comparable across diseases but not sensitive to disease specificities. Disease-specific instruments are sensitive but do not exist for many rare diseases and rarely provide the utility values required by some HTA bodies. Creating new PROMs is time and resource intensive. Potential solutions include pooling data (multi-site/international data collection), using computer-assisted technology, or using generic and disease-specific PROMs in a complementary way. Conclusions PROMs are relevant in HTA for RDTs but pose a number of difficulties. A deeper understanding of the potential advantages of and the challenges and potential solutions for each can help manage these difficulties. Supplementary Information The online version contains supplementary material available at 10.1007/s40271-020-00493-w.

Additional file 1: Appendix: Interview topic guide.

Supplemental material, sj-docx-1-heb-10.1177_10901981211043116 for Determining Contextual Factors for a Heart Failure Self-Care Intervention: A Consensus Delphi Study (ACHIEVE) by Amanda Whittal, Isabell Ehringfeld, Paula Steinhoff and Oliver Rudolf Herber in Health Education & Behavior

Substantial inconsistency exists in the effectiveness of existing interventions to improve heart failure (HF) self-care, which can be partially explained by the fact that self-management interventions often lack theoretical models that underpin intervention development. The COM-B behavior model is a comprehensive theoretical framework that can be used to develop effective, theory-based interventions. The aim of this article is to highlight the challenges and practical solutions when applying the COM-B model to HF self-care, in order to provide useful support for researchers intending to use the model for designing behavior change interventions. “The Behaviour Change Wheel” handbook provides a step-by-step guide to understand and change behavior. When following the guide, some practical and methodological challenges were encountered. Lessons learnt to overcome these challenges are reported. Although the handbook is a comprehensive guide for designing behavior change interventions, a number of challenges arose. For example, the descriptions provided in the guide were not always sufficient to make solid judgments on how to categorize determinants; narrowing down intervention possibilities to a manageable number and prioritizing potential behavior change techniques over others involved a certain amount of subjectivity in an otherwise highly systematic and structured approach. For the encountered challenges, solutions are provided to illustrate how the model was applied practically to design theory-based behavior change interventions. This article provides a useful reference for researchers’ use of the COM-B behavior model, as it outlines challenges that may occur and potential solutions to overcome them.

Aldosterone, which regulates renal salt retention, is synthesized in adrenocortical mitochondria in response to angiotensin II. Excess aldosterone causes myocardial injury and heart failure, but potential intracardiac aldosterone synthesis has been controversial. We hypothesized that the stressed heart might produce aldosterone. We used blue native gel electrophoresis, immunoblotting, protein crosslinking, coimmunoprecipitations, and mass spectrometry to assess rat cardiac aldosterone synthesis. Chronic infusion of angiotensin II increased circulating corticosterone levels 350-fold and induced cardiac fibrosis. Angiotensin II doubled and telmisartan inhibited aldosterone synthesis by heart mitochondria and cardiac production of aldosterone synthase (P450c11AS). Heart aldosterone synthesis required P450c11AS, Tom22 (a mitochondrial translocase receptor), and the intramitochondrial form of the steroidogenic acute regulatory protein (StAR); protein crosslinking and coimmunoprecipitation studies showed that these three proteins form a 110-kDa complex. In steroidogenic cells, extramitochondrial (37-kDa) StAR promotes cholesterol movement from the outer to inner mitochondrial membrane where cholesterol side-chain cleavage enzyme (P450scc) converts cholesterol to pregnenolone, thus initiating steroidogenesis, but no function has previously been ascribed to intramitochondrial (30-kDa) StAR; our data indicate that intramitochondrial 30-kDa StAR is required for aldosterone synthesis in the heart, forming a trimolecular complex with Tom22 and P450c11AS. This is the first activity ascribed to intramitochondrial StAR, but how this promotes P450c11AS activity is unclear. The stressed heart did not express P450scc, suggesting that circulating corticosterone (rather than intracellular cholesterol) is the substrate for cardiac aldosterone synthesis. Thus, the stressed heart produced aldosterone using a previously undescribed intramitochondrial mechanism that involves P450c11AS, Tom22, and 30-kDa StAR. SIGNIFICANCE STATEMENT: Prior studies of potential cardiac aldosterone synthesis have been inconsistent. This study shows that the stressed rat heart produces aldosterone by a novel mechanism involving aldosterone synthase, Tom22, and intramitochondrial steroidogenic acute regulatory protein (StAR) apparently using circulating corticosterone as substrate. This study establishes that the stressed rat heart produces aldosterone and for the first time identifies a biological role for intramitochondrial 30-kDa StAR.

Health psychology sheds light on the process of returning to work after sick leave and subsequent medical rehabilitation. A 15-month longitudinal study with N = 201 orthopedic rehabilitation patients is reported. It examined whether and how both physiological health (e.g. body mass index and oxygen reabsorption) and psychological/social-cognitive factors (e.g. self-efficacy and social support) are related to returning to work. It was found that social-cognitive and physiological variables, such as oxygen consumption at anaerobic threshold, are important for returning to work. While physical activity was significantly correlated with social-cognitive variables, it was not significantly correlated directly with returning to work. Results suggest that self-efficacy and oxygen consumption at anaerobic threshold should be improved during medical rehabilitation.

The SAE G-27 committee was tasked by ICAO to develop a performance-based packaging standard for lithium batteries transported as cargo on aircraft. The standard details test criteria to qualify packages of lithium batteries & cells for transportation as cargo on-board passenger aircraft. Lithium batteries and cells have been prohibited from shipment as cargo on passenger aircraft since 2016. This paper summarizes the results of the tests conducted by Transport Canada and National Research Council Canada to support the development of this standard with evidence-based recommendations. It includes a description of the test specimens, the test set up, instrumentation used, and test procedures following the standard as drafted to date. The study considered several lithium-ion battery and cell chemistries that were tested under various proposed testing scenarios in the draft standard. The aim was to assess the feasibility of proposed tests, and to determine whether the tests are able to accurately capture hazards which may arise from a catastrophic battery or a cell failure within the package. Laboratory results were also simulated with Computational Fluid Dynamics software for confirmation. A comprehensive study involved validating several areas of the draft standard: i) the baseline test method consisting of a package of lithium cells; ii) an oversized battery (i.e. electric vehicle battery) to large to be tested within the proposed test chamber; iii) stratification of evolved gases within the test chamber; iv) control thermocouple placement location on the test cell for compliant measurement; and, v) test chamber leak rate effect on vented gas ignition. The main findings of the experiments are presented in this paper for each test scenario as prescribed in the draft standard; results for proposed recommendations to improve the standard to identify a hazard with higher accuracy are presented. A discussion on each of the recommendations is included., AeroTech, March 17-20, 2020

Intervertebral disc (IVD) degeneration is associated with low back pain (LBP) and accompanied by mechanical changes to the spine. Secreted protein acidic and rich in cysteine (SPARC) is a protein that contributes to the functioning and maintenance of the extracellular matrix. SPARC-null mice display accelerated IVD degeneration and pain-associated behaviors. This study examined if SPARC-null mice also display altered spine mechanics as compared to wild-type (WT) mice. Lumbar spines from SPARC-null (n = 36) and WT (n = 18) mice aged 14–25 months were subjected to cyclic axial tension and compression to determine neutral zone (NZ) length and stiffness. Three separate mechanical tests were completed for each spine to determine the effect of the number of IVDs tested in series (one versus two versus three IVDs). SPARC-null spine NZs were both stiffer (p

BACKGROUND There is increasing recognition that conventional appraisal approaches may be unsuitable for assessing the value for money of rare disease treatments (RDTs). This research examines whether supplemental appraisal processes for RDTs are needed, and if so, what form should these take. A qualitative research design was used that included (1) documentation of country appraisal/reimbursement processes for RDTs via questionnaires, desk research and iterative interactions with country experts to produce country vignettes, and (2) a cross-country analysis of these processes to identify and characterise countries with supplemental processes for RDTs, and compare them to countries without supplemental processes. RESULTS Thirty-two of the 37 invited countries participated in this research. Forty-one percent (13/32) use supplemental processes for RDTs. Their level of integration within standard processes ranged from low to high, characterised by whether they are separate or partially separate from the standard process, adapted or accelerated standard processes, or standard processes that account for rarity. They are characterised by features implemented throughout the appraisal process. These features are mechanisms that allow application of different standards to assess the value of the medicine, support to the appraisal/decision-making process, overcome the issues of lack of cost-effectiveness, or exempt from part of/the full HTA process. They apply to ultra-RDTs and/or RDTs, and are often combined. They increase the likelihood of reimbursement by adjusting and/or foregoing part of the assessment process, or accepting to pay more for the same added benefit as for common conditions, which is likely to lead to accepting high prices. A large proportion of countries with standard processes include one or more of these features (formally or informally) or are discussing potential changes in their systems. CONCLUSIONS Results suggest revealed preferences to treat RDTs differently than conventional medicines. Some of the challenges around uncertainty and high price remain, but supplemental process features allow for more adapted and consistent decision-making. Many of these processes are new and countries continue to adjust as they gain experience. These results do not outline what an ideal process for RDTs looks like, but identify some key features that can be implemented to facilitate this process.

Land reform in South Africa has failed to meet its objectives. The intended beneficiaries often do not have their land reform needs met. Failures may be attributed to multiple sources. We propose a conceptual framework to assist governments conducting land reform projects. It draws on aspects of human rights, good governance, and pro-poor policy. Existing frameworks are combined with these aspects to derive the conceptual framework. By using the framework, development projects in South Africa and similar contexts may become more Successful, Sustainable, and Significant. The paper holds interest for land tenure and cadastral systems researchers and developers.

This article investigates the concept of using cell-phone technology for obtaining informationabout unofficial (off-register) transfers in land as are commonly undertaken by the urban poor inSouth Africa. Since the introduction of social housing programmes in South Africa after the democratic elections in 1994, mass land distribution and housing projects have been undertaken. Formal transfer of these properties has been discouraged by policy (such as a moratorium on transfers for a period of years), and the inaccessibility of land professionals and formal processes to the poor. From the disuse of formal transfer mechanisms one can conclude that these fail, at least in part, to meet the needs of this segment of society. Cell- (mobile) phone technology penetrates urban poverty more than other interactive technologies such as the internet, largely due to the lack of access to computers and the 'digital divide'. The aim of this article is exploratory. It investigates the potential use of cell-phone technology as a means to inform authorities that a transfer of property has taken place informally or semi-formally. Such information could pave the way for a process of formal registration and hence aid the upkeep of the deeds registration system. Research into the potential use of the cell-phone as an information and communication technology (ICT) tool of land administration, particularly in the developing world, is undertaken. It is envisaged that a more detailed investigation will follow, which will include an analysis of organisational and legislative capacity. Further study in which the use of cell-phone technology in land administration is tested, taking into consideration structural/organisational factors as well as socio-economic and cultural factors and motivating factors for use, may be required.KEYWORDS: Land registration, land tenure, cadastral systems, e-registration, m-registration, e-governance.

The acute response to stress consists of a series of physiological programs to promote survival by generating glucocorticoids and activating stress response genes that increase the synthesis of many chaperone proteins specific to individual organelles. In the endoplasmic reticulum (ER), short-term stress triggers activation of the unfolded protein response (UPR) module that either leads to neutralization of the initial stress or adaptation to it; chronic stress favors cell death. UPR induces expression of the transcription factor, C/EBP homology protein (CHOP), and its deletion protects against the lethal consequences of prolonged UPR. Here, we show that stress-induced CHOP expression coincides with increased metabolic activity. During stress, the ER and mitochondria come close to each other, resulting in the formation of a complex consisting of the mitochondrial translocase, translocase of outer mitochondrial membrane 22 (Tom22), steroidogenic acute regulatory protein (StAR), and 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2) via its intermembrane space (IMS)-exposed charged unstructured loop region. Stress increased the circulation of phosphates, which elevated pregnenolone synthesis by 2-fold by increasing the stability of 3βHSD2 and its association with the mitochondrion-associated ER membrane (MAM) and mitochondrial proteins. In summary, cytoplasmic CHOP plays a central role in coordinating the interaction of MAM proteins with the outer mitochondrial membrane translocase, Tom22, to activate metabolic activity in the IMS by enhanced phosphate circulation.

BACKGROUND Work-life balance is associated with health behaviors. In the face of digitalization, understanding this link requires a theory-based investigation of problematic internet use and perceived stress, which are so far unknown. OBJECTIVE On the basis of the compensatory carry-over action model, this study aimed to determine whether problematic internet use and perceived stress mediate the relationship between health behaviors and work-life balance in two groups of internet users from different environments (residents in Germany and China). We also investigated whether the place of residence was a moderator. METHODS An online questionnaire (N=877) was administered to residents from Germany (n=374) and China (n=503) in 3 languages (German, English, and Chinese). Moderated mediation analyses were run with health behaviors as the independent variable, work-life balance as the dependent variable, problematic internet use and perceived stress as the mediator variables, and place of residence as a potential moderator. RESULTS On a mean level, individuals in Germany reported less problematic internet use and more health behaviors than individuals in China; however, they also had lower work-life balance and higher perceived stress. Results showed that health behaviors seem to be directly related to work-life balance in both groups. Among the residents of Germany, a partial mediation was revealed (β=.13; P=.01), whereas among the residents of China, a full mediation was found (β=.02; P=.61). The mediator role of perceived stress was compared with problematic internet use in all the serial models and the parallel model. Residence moderated the relationship between health behaviors and work-life balance: The interrelation between health behaviors and work-life balance was stronger in Germany (β=.19; PP=.01) when controlling for other variables. CONCLUSIONS The findings of this study are in line with the compensatory carry-over action model. To promote work-life balance, individuals should perform health behaviors to help overcome problematic internet use and perceived stress. Both problematic internet use and perceived stress mediated health behaviors and work-life balance partially in German study participants and fully in Chinese study participants.

We evaluated a novel, empirically-based cognitive therapy for compulsive checking - a common form of obsessive-compulsive disorder. Twelve adults completed 12 sessions of the therapy. Significant reductions in checking-related symptoms were found pre- to post-treatment, and pre-treatment to 6-month follow-up (moderate to large effect sizes). Participants reported high treatment acceptability after the third session, which was maintained at post-treatment. This pilot trial provides preliminary support for treating compulsive checking using this novel cognitive approach.

The movement and distribution of mitochondria is essential for cellular function in response to physiological demand. Thus, coordinated mitochondrial action is necessary in cell development. The molecular basis of mitochondrial redistribution depends on the different steps of protein folding as the rapid burst of movements is interrupted by variables, including environmental and hormonal stressors, such as adrenocorticotropic hormone (ACTH). In adrenal and gonads, CYP11A1, catalyzes cholesterol to pregnenolone conversion. During stress, the ER and mitochondria comes close to each other, resulting in the formation of a complex consisting of the translocase of outer mitochondrial membrane 22, steroidogenic acute regulatory protein and 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2) via its intermembrane space exposed charged unstructured loop region. An excess of ACTH inhibits organelle organization and fiber formation as visualized by transmission electron microscopy. We created stress in cells by depriving serum. Next isolation of mitochondrial complex with digitonin and analysis through a native-gradient PAGE formed a 400-kDa complex in the absence of serum. However an additional complex of 650 kDa was observed with serum. Western staining of the stressed cells with Tom22, 3βHSD2 and Tim23 antibodies independently showed several fold increase in expression of Tim23 and 3βHSD2 after 8 hour and a three fold increase Tom 22 after 2 hour. The expression of mitochondrial VDAC2 or cytoplasmic calnexin was unchanged. We conclude that an increase in Tim23 expression possibly opens the TIM23 complex resulting rapid interaction with the MAM and ER proteins for faster metabolic activity.

Mitochondrial protein import and sorting are mediated by translocases. Precursor proteins with amino-terminal presequences transition from the translocase of the outer membrane (TOM) complex to the translocase of the inner membrane (TIM) complex. In adrenal and gonadal cells, the molecular mechanism of mitochondrial complex formation and electron transport to initiate and maintain steroid metabolic activity has remained unclear. On the mitochondrial surface, Tom22 or Tom20 directs precursor import through the pore-forming subunit, Tom40. After emerging from the Tom40 channel, presequence-containing precursors engage with the presequence translocase of the inner membrane or reach the matrix directly as a permanent resident or are integrated into the membrane. Thus, the activity of the inner membrane translocase is tightly regulated by targeting signals in a yet undefined manner. For the first time, we show that testicular as well as adrenal mitochondrial metabolic activity is dependent on more than one protein, where Tim50 and SCC are equally important, and depends on the specific unfolding conformation necessary for SCC. Following mitochondrial import of SCC, the N-terminus is first cleaved rapidly and then slowly cleaved a second time. The unfolded protein is transported to the IMS, where the C-terminus is inserted into the TIM23 complex, resulting in a significantly unfolded protein to interact and associate with Tim50 for metabolic activity. Therefore, Tim50 is possibly playing a role of a key factor for SCC metabolic activity in addition to the co-factors ferrodoxin and ferrodoxin reductase.

The formation of isonicotinyl-nicotinamide adenine dinucleotide (INH-NAD+) by the mycobacterial catalase-peroxidase enzyme, KatG, was known to be the major component of the mode of action of isoniazid (INH), an anti-tuberculosis drug. However, there are other enzymes that may catalyze this reaction. We have previously reported that neutrophil myeloperoxidase (MPO) is capable of metabolizing INH through the formation of INH-NAD+ adduct, which could be attributed to being a possible mode of action of INH. However, eosinophilic infiltration of the lungs is more pronounced and characteristic of granulomas in Mycobacterium tuberculosis-infected patients. Thus, the aim of the present study is to investigate the role of eosinophil peroxidase (EPO), a key eosinophil enzyme, during INH metabolism and the formation of its active metabolite, INH-NAD+ using purified EPO and eosinophils isolated from asthmatic donors. UV–Vis spectroscopy revealed INH oxidation by EPO led to a new product (λmax = 326 nm) in the presence of NAD+. This adduct was confirmed to be INH-NAD+ using LC-MS analysis where the intact adduct was detected (m/z = 769). Furthermore, EPO catalyzed the oxidation of INH and formed several free radical intermediates as assessed by electron paramagnetic resonance (EPR) spin-trapping; a carbon-centred radical, which is considered to be the reactive metabolite that binds with NAD+, was found when superoxide dismutase was included in the reaction. Our findings suggest that eosinophilic EPO may also play a role in the pharmacological activity of INH through the formation of INH-NAD+ adduct, and supports further evidence that human cells and enzymes are capable of producing the active metabolite involved in tuberculosis treatment.

Adrenal and gonadal mitochondrial metabolic activity requires electrons from cofactors, cholesterol, and a substrate for rapid steroid synthesis, an essential requirement for mammalian survival. Substrate activity depends on its environment, which is regulated by chaperones and mitochondrial translocases. Cytochrome P450 side-chain cleavage enzyme (SCC or CYP11A1) catalyzes cholesterol to pregnenolone conversion, although its mechanism of action is not well understood. We find that SCC is directly imported into the mitochondrial matrix, where its N-terminal sequence is cleaved sequentially, after which it becomes activated following the second cleavage, which is dependent on the folding of the protein. Following integration of the SCC C terminus into the TIM23 complex, amino acids 141 to 146 interact with the intermembrane-exposed Tim50 protein, forming a large complex. The absence of Tim50 or its mutation reduced enzymatic activity. For the first time, we report that a protein activated at the matrix remains mostly unfolded and is transported back to the IMS to integrate with the TIM23 translocase complex and align with the Tim50 protein. Amino acid changes that suppress the association of Tim50 with SCC ablate metabolic activity. Thus, the TIM23 complex is the central regulator of metabolism guided by Tim50.

As part of a programme examining the effectiveness of land tenure forms − tenure administration system combinations, the paper examines how and why beneficiaries use land registration in Project 2, a state subsidised housing project in Mbekweni, South Africa. The ownership − registration combination can have a number of negative consequences when policy makers focus on economics alone, rather than the complete set of factors that are critical for registered ownership to work in poor urban communities. South Africa’s state-subsidised housing programme has created up to 3.7 million housing opportunities. Off-register secondary transactions constitute a major problem when the properties registered in ownership. Building on a series of related case studies, an evaluative schema classifying an ownership − registration combination as strong, semi-strong, semi-weak or weak is presented, along with the main findings from three previously reported case studies where the combination was classified as semi-strong. The beneficiaries in Project 2 were predominantly in-migrants from a rural customary area, and based on earlier work and the literature, a weak or semi-weak classification was expected. However, the case was classified as semi-strong. Ongoing, visible administration is possibly a major factor underlying this classification.