Real-world outcomes for a digital prescription mobile application for adults with irritable bowel syndrome.

BACKGROUND: Mahana™ IBS is a Food and Drug Administration-cleared prescription mobile application designed to deliver 3 months of gut-directed cognitive behavioral therapy (CBT) to adults ≥22 years old with irritable bowel syndrome (IBS). We assessed whether gut-directed CBT delivered digitally improved outcomes in IBS management. METHODS: We studied users who had a dispensed physician prescription for Mahana™ IBS between August 2021 and August 2023. The primary outcome was change in IBS symptom severity (IBS-SSS) score. KEY RESULTS: For the 843 patients, 324 (38%) completed half of the program up to session 5, and 162 (19%) of participants completed the full program up to session 10. Median age was 41 years, median IBS-SSS was 270 (moderate severity), IBS-mixed subtype was most common (23%) followed by IBS-C (20%) and IBS-D (19%). The change in IBS-SSS was -81.0 (p = < 0.001) after session 5 and - 104.4 (p = < 0.001) after session 10. In multivariate analyses, a higher baseline IBS-SSS (OR 1.59; 95% CI 1.26-2.01) and high baseline Perceived Stress Scale (PSS) score predicted non-response (OR 0.95; 95% CI 0.91-0.98) while older age (OR 1.10 per decade; 95% CI 1.01-1.20), prescription source from a healthcare provider (as opposed to third party telehealth encounter, OR 1.48; 95% CI 1.07-2.05), and payment for the app (OR 1.93; 95% CI 1.41-2.63) predicted adherence. CONCLUSIONS & INFERENCES: Use of a digital mobile application for gut-directed CBT improved symptoms of IBS. Digital health applications have the potential to democratize CBT and allow integrated care to scale for patients with IBS.

Modelling six sustainable development transformations in Australia and their accelerators, impediments, enablers, and interlinkages.

There is an urgent need to accelerate progress on the Sustainable Development Goals (SDGs) and recent research has identified six critical transformations. It is important to demonstrate how these transformations could be practically accelerated in a national context and what their combined effects would be. Here we bridge national systems modelling with transformation storylines to provide an analysis of a Six Transformations Pathway for Australia. We explore important policies to accelerate progress, synergies and trade-offs, and conditions that determine policy success. We find that implementing policy packages to accelerate each transformation would boost performance on the SDGs by 2030 (+23% above the baseline). Policymakers can maximize transformation synergies through investments in energy decarbonization, resilience, social protection, and sustainable food systems, while managing trade-offs for income and employment. To overcome resistance to transformations, ambitious policy action will need to be underpinned by technological, social, and political enabling conditions.

SARS-CoV-2 infection of human lung epithelial cells induces TMPRSS-mediated acute fibrin deposition.

Severe COVID-associated lung injury is a major confounding factor of hospitalizations and death with no effective treatments. Here, we describe a non-classical fibrin clotting mechanism mediated by SARS-CoV-2 infected primary lung but not other susceptible epithelial cells. This infection-induced fibrin formation is observed in all variants of SARS-CoV-2 infections, and requires thrombin but is independent of tissue factor and other classical plasma coagulation factors. While prothrombin and fibrinogen levels are elevated in acute COVID BALF samples, fibrin clotting occurs only with the presence of viral infected but not uninfected lung epithelial cells. We suggest a viral-induced coagulation mechanism, in which prothrombin is activated by infection-induced transmembrane serine proteases, such as ST14 and TMPRSS11D, on NHBE cells. Our finding reveals the inefficiency of current plasma targeted anticoagulation therapy and suggests the need to develop a viral-induced ARDS animal model for treating respiratory airways with thrombin inhibitors.

Unlocking and accelerating transformations to the SDGs: a review of existing knowledge.

As we cross the 2030 deadline to achieve the Sustainable Development Goals (SDGs), there is a growing sense of urgency around the need to accelerate the necessary transformations. These encompass a broad range of systems and require fundamental changes in system goals and design. In this paper, we undertake a narrative review of the literature relating to the acceleration of transformations and offer a framework for unlocking and accelerating transformations to the SDGs. While there is no blueprint for acceleration, there is an expanding knowledge base on important dynamics, impediments and enabling conditions across diverse literatures which can help to inform strategic interventions by actors. The emerging literature on positive tipping points and deep leverage points identifies opportunities to rewire systems design so that important system feedbacks create the conditions for acceleration. Transformation takes time and actors will need to build momentum to reorient systems around new goals, informed by knowledge of common policy, technology and behavioural feedbacks that govern system dynamics. Where resistance is strong, actors can seek to augment system design in ways that weaken balancing feedbacks that stabilise existing system configurations and strengthen reinforcing feedbacks that promote emerging system configurations oriented towards the SDGs. Well-designed and sequenced interventions can promote innovation and behaviour change and build and maintain political support. This can build critical enabling conditions and push systems towards large-scale tipping points, paving the way for decisive policy action that is crucial for triggering acceleration. We conclude by highlighting gaps and priorities for further research.

City footprints and SDGs provide untapped potential for assessing city sustainability.

Cities are recognised as central to determining the sustainability of human development. However, assessment concepts that are able to ascertain whether or not a city is sustainable are only just emerging. Here we review literature since the Sustainable Development Goals (SDGs) were agreed in 2015 and identify three strands of scientific inquiry and practice in assessing city sustainability. We find that further integration is needed. SDG monitoring and assessment of cities should take advantage of both consumption-based (footprint) accounting and benchmarking against planetary boundaries and social thresholds in order to achieve greater relevance for designing sustainable cities and urban lifestyles.

Delivering an enabling environment and multiple benefits for land degradation neutrality: Stakeholder perceptions and progress.

Achieving land degradation neutrality (LDN) was adopted by countries in 2015 as one of the targets of the global Sustainable Development Goals (SDGs). As LDN is a relatively new concept there is an increasing need for evidence on the potential socio-economic and environmental benefits of LDN as well as how an enabling environment for implementing LDN measures can be developed. This paper summarises the results from a global survey of LDN stakeholders, and a review of national progress in target setting that was commissioned by the United Nations Convention to Combat Desertification (UNCCD) in 2018. The study presents the perceptions of relevant stakeholders on the key components of an enabling environment for achieving and maintaining LDN (institutional, financial, policy/regulatory, and science-policy) as well as expectations of multiple benefits from its implementation. We also highlight key challenges and gaps in progress to date that are emerging from ongoing national target setting programs to implement LDN. The study finds that progress in implementing LDN has been widespread across countries. However there remains a lack of awareness of LDN and its key concepts along with high-level political buy-in. This may be impeding the integration of LDN into national development planning and budgeting processes where progress was assessed as limited. National capacities for securing land tenure and governance arrangements and integrated land use planning were perceived as comparatively low, further hampering the implementation of LDN. Despite these gaps, most stakeholders (>90 %) who participated in the global survey expected LDN to deliver a broad range of multiple benefits for human wellbeing, livelihoods and the natural environment. We argue that greater efforts are needed to raise awareness of LDN, educate core stakeholders in its concepts, enablers and benefits, raise its political profile, and provide evidence on national measures that will support implementation of LDN.

Acute intravenous synaptamine complex variant KB220™ "normalizes" neurological dysregulation in patients during protracted abstinence from alcohol and opiates as observed using quantitative electroencephalographic and genetic analysis for reward polymorphisms: part 1, pilot study with 2 case reports.

It is well established that in both food- and drug-addicted individuals, there is dopamine resistance due to an association with the DRD2 gene A1 allele. Evidence is emerging whereby the potential of utilizing a natural, nonaddicting, safe, putative D2 agonist may find its place in recovery from reward deficiency syndrome (RDS) in patients addicted to psychoactive chemicals. Utilizing quantitative electroencephalography (qEEG) as an imaging tool, we show the impact of Synaptamine Complex Variant KB220™ as a putative activator of the mesolimbic system. We demonstrate for the first time that its intravenous administration reduces or "normalizes" aberrant electrophysiological parameters of the reward circuitry site. For this pilot study, we report that the qEEGs of an alcoholic and a heroin abuser with existing abnormalities (ie, widespread theta and widespread alpha activity, respectively) during protracted abstinence are significantly normalized by the administration of 1 intravenous dose of Synaptamine Complex Variant KB220™. Both patients were genotyped for a number of neurotransmitter reward genes to determine to what extent they carry putative dopaminergic risk alleles that may predispose them for alcohol or heroin dependence, respectively. The genes tested included the dopamine transporter (DAT1, locus symbol SLC6A3), dopamine D4 receptor exon 3 VNTR (DRD4), DRD2 TaqIA (rs1800497), COMT val158 met SNP (rs4680), monoamine oxidase A upstream VNTR (MAOA-uVNTR), and serotonin transporter-linked polymorphic region (5HTTLPR, locus symbol SLC6A4). We emphasize that these are case studies, and it would be unlikely for all individuals to carry all putative risk alleles. Based on previous research and our qEEG studies (parts 1 and 2 of this study), we cautiously suggest that long-term activation of dopaminergic receptors (ie, DRD2 receptors) will result in their proliferation and lead to enhanced "dopamine sensitivity" and an increased sense of happiness, particularly in carriers of the DRD2 A1 allele. This is supported by a clinical trial on Synaptamine Complex Variant KB220™ using intravenous administration in > 600 alcoholic patients, resulting in significant reductions in RDS behaviors. It is also confirmed by the expanded oral study on Synaptose Complex KB220Z™, published as part 2 of this study. Future studies must await both functional magnetic resonance imaging and positron emission tomography scanning to determine the acute and chronic effects of oral KB220™ on numbers of D2 receptors and direct interaction at the nucleus accumbens. Confirmation of these results in large, population-based, case-controlled experiments is necessary. These studies would provide important information that could ultimately lead to significant improvement in recovery for those with RDS and dopamine deficiency as a result of a multiple neurotransmitter signal transduction breakdown in the brain reward cascade.

Overcoming qEEG abnormalities and reward gene deficits during protracted abstinence in male psychostimulant and polydrug abusers utilizing putative dopamine D2 agonist therapy: part 2.

BACKGROUND: It is well established that in both food- and drug-addicted individuals there is "dopamine resistance" associated with the DRD2 gene A1 allele. Based on earlier studies, evidence is emerging wherein the potential of utilizing a natural, nonaddicting, safe, putative D2 agonist may play a significant role in the recovery of individuals with reward deficiency syndrome, including those addicted to psychoactive chemicals. FINDINGS: Positive outcomes demonstrated by quantitative electroencephalographic (qEEG) imaging in a randomized, triple-blind, placebo-controlled, crossover study involving oral Synaptose Complex KB220Z™ showed an increase of alpha waves and low beta wave activity in the parietal brain region. Using t statistics, significant differences observed between placebo and Synaptose Complex KB220Z™ consistently occurred in the frontal regions after week 1 and then again after week 2 of analyses (P = 0.03). This is the first report to demonstrate involvement of the prefrontal cortex in the qEEG response to a natural putative D2 agonist (Synaptose Complex KB220Z™), especially evident in dopamine D2 A1 allele subjects. Independently, we have further supported this finding with an additional study of 3 serious polydrug abusers undergoing protracted abstinence who carried the DRD2 A1 allele. Significant qEEG differences were found between those who received 1 dose of placebo compared with those who were administered Synaptose Complex KB220Z™. Synaptose Complex KB220Z™ induced positive regulation of the dysregulated electrical activity of the brain in these addicts. The results are indicative of a phase change from low amplitude or low power in the brain to a more regulated state by increasing an average of 6.169 mV(2) across the prefrontal cortical region. In the first experiment we found that while 50% of the subjects carried the DRD2 A1 allele, 100% carried ≥ 1 risk allele. Specifically, based on the proposed addiction risk score for these 14 subjects, 72% had moderate-to-severe addiction risk. Similar findings were obtained by repeating the experiment in 3 additional currently abstinent polydrug abusers carrying the DRD2 A1 allele. CONCLUSION: This seminal work will provide important information that may ultimately lead to significant improvement in the recovery of individuals with psychostimulant and polydrug abuse problems, specifically those with genetically induced dopamine deficiency. Based on this small sample size, we are proposing that with necessary large populations supporting these initial results, and possibly even additional candidate genes and single nucleotide polymorphisms, we may eventually have the clinical ability to classify severity according to genotype and possession of risk alleles, along with offering a safe, nonaddicting, natural dopaminergic receptor agonist that potentially upregulates instead of downregulates dopaminergic receptors, preferably the D2 subtype.