A systematic review of economic evaluations of pharmacological treatments for active tuberculosis.

Objectives: The continuing spread of tuberculosis (TB) worldwide, especially drug-resistant TB, poses a major challenge to healthcare systems globally. Addressing this requires appraising the cost effectiveness of existing pharmacological interventions against TB to identify key drivers of cost effectiveness and value and guide pharmaceutical innovation and novel drug regimen development. Methods: Studies were identified from a search of six database: MEDLINE MEDLINE-In Process, MEDLINE Epub Ahead of Print, EMBASE, Cochrane Database of Systematic Reviews, and Econlit in July 2022. Two reviewers independently assessed all identified studies and reports using pre-defined inclusion/exclusion criteria. Study methodological quality was assessed, data were extracted in standard tables, and results were narratively synthesized. Results: Overall, 991 studies and 53 HTA reports were identified with 20 studies and 3 HTA reports meeting the inclusion criteria. Quality assessment of the 20 studies identified 4 with minor limitations, while the remainder were assessed as having potentially or very serious limitations. Sixteen studies conducted cost-utility analyses, 6 conducted cost-effectiveness analyses, and 2 conducted cost-comparison analyses with some studies performing multiple analyses. The majority (n = 16) were model-based. Eleven studies analyzed the cost-effectiveness of bedaquiline, 6 compared shorter to longer/standard duration regimens, 2 assessed ethambutol, and 1 assessed delamanid. Key drivers of cost effectiveness were drug costs, the number of TB cases, the portion of cases with sputum culture conversion, treatment delivery costs, and treatment efficacy. Common value elements considered included adverse events, drug resistance, and improving treatment adherence. Conclusion: Our results suggest that out of the pharmacological treatments assessed, bedaquiline is likely a cost-effective addition to existing treatment regimens/background treatment regimens, while ethambutol is not likely to be. Newer shorter regimens, even if more costly, seem to be more cost-effective compared to longer regimens. These results illustrate the limited number of novel cost-effective pharmacological interventions and highlight a need to develop new drugs/regimens against TB to overcome resistance, taking into account the key drivers of cost effectiveness and other value attributes identified from this review.

Optimising patient outcomes: temporal trends in remission rates of rheumatoid arthritis patients in the Australian OPAL dataset between 2009 and 2022.

OBJECTIVE: To describe the trends in remission rates among RA patients in the OPAL dataset, spanning from 2009 to 2022, and provide insights into the effectiveness of evolving RA management approaches in real-world clinical settings. METHODS: Patients with a physician diagnosis of RA and at least 3 visits between 1 January 2009 and December 2022 were identified in the OPAL dataset, an aggregated collection of data extracted from the electronic medical records of patients managed by 117 Australian rheumatologists. Demographics, disease history, prescribed medications and proportions of patients in Disease Activity Score 28-joint count C-reactive protein (DAS28CRP)) categories (remission, low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA)) were described. RESULTS: A large population (n = 48,388) of eligible patients with RA were identified in the OPAL dataset. A consistent and substantial improvement in DAS28CRP remission rates were found in (i) all patients, (ii) patients managed on conventional synthetic disease-modifying antirheumatic drugs (csDMARD) and (iii) patients treated with biological or targeted synthetic (b/ts)DMARD therapy, increasing from approximately 50% in 2009 to over 70% by 2022. The increase in DAS28CRP remission was accompanied by reduced proportions of patients in MDA and HDA states. CONCLUSION: This study highlights a consistent improvement in disease activity and rising remission rates among Australian RA patients within the OPAL dataset, offering the potential for enhanced patient outcomes and reduced disease burden.

Diagnostics and treatments of COVID-19: two-year update to a living systematic review of economic evaluations.

Objectives: As the initial crisis of the COVID-19 pandemic recedes, healthcare decision makers are likely to want to make rational evidence-guided choices between the many interventions now available. We sought to update a systematic review to provide an up-to-date summary of the cost-effectiveness evidence regarding tests for SARS-CoV-2 and treatments for COVID-19. Methods: Key databases, including MEDLINE, EconLit and Embase, were searched on 3 July 2023, 2 years on from the first iteration of this review in July 2021. We also examined health technology assessment (HTA) reports and the citations of included studies and reviews. Peer-reviewed studies reporting full health economic evaluations of tests or treatments in English were included. Studies were quality assessed using an established checklist, and those with very serious limitations were excluded. Data from included studies were extracted into predefined tables. Results: The database search identified 8,287 unique records, of which 54 full texts were reviewed, 28 proceeded for quality assessment, and 15 were included. Three further studies were included through HTA sources and citation checking. Of the 18 studies ultimately included, 17 evaluated treatments including corticosteroids, antivirals and immunotherapies. In most studies, the comparator was standard care. Two studies in lower-income settings evaluated the cost effectiveness of rapid antigen tests and critical care provision. There were 17 modelling analyses and 1 trial-based evaluation. Conclusion: A large number of economic evaluations of interventions for COVID-19 have been published since July 2021. Their findings can help decision makers to prioritise between competing interventions, such as the repurposed antivirals and immunotherapies now available to treat COVID-19. However, some evidence gaps remain present, including head-to-head analyses, disease-specific utility values, and consideration of different disease variants. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021272219], identifier [PROSPERO 2021 CRD42021272219].

Critical physiotherapy: a ten-year retrospective.

Critical physiotherapy has been a rapidly expanding field over the last decade and could now justifiably be called a professional sub-discipline. In this paper we define three different but somewhat interconnected critical positions that have emerged over the last decade that share a critique of physiotherapy's historical approach to health and illness, while also diverging in the possibilities for new forms of practice and thinking. These three positions broadly align with three distinctive philosophies: approaches that emphasize lived experience, social theory, and a range of philosophies increasingly referred to as the "posts". In this paper we discuss the origins of these approaches, exploring the ways they critique contemporary physiotherapy thinking and practice. We offer an overview of the key principles of each approach and, for each in turn, suggest readings from key authors. We conclude each section by discussing the limits of these various approaches, but also indicate ways in which they might inform future thinking and practice. We end the paper by arguing that the various approaches that now fall under the rubric of critical physiotherapy represent some of the most exciting and opportune ways we might (re)think the future for the physiotherapy profession and the physical therapies more generally.

Is physiotherapy a luxury? What can the perplexing absence of the physical therapies tell us about the profession's future?

Physiotherapists interested in the profession's future have turned in recent years to historical evidence to understand how the physical therapies were practiced before the advent of modern healthcare. However, studies to date suggest that their practice was largely confined to social elites, and those from working-class or poor populations rarely, if ever, experienced them. To test this theory further, this study focuses on British sailors during the Napoleonic wars (1803-1815). Utilizing historical and semi-fictional accounts, this study shows that healthcare on board naval fighting ships concentrated almost entirely on the prevention of disease, and the medical and surgical management of acute trauma. Even though sailors experienced shocking levels of traumatic injury, none appear to have experienced any form of physical therapy. This study supports the argument that prior to the 20th century, the physical therapies were luxuries available primarily to those with surplus time and money, and that widespread access to physiotherapy has relied on state-sponsored universal health coverage. It follows, then, that the decline of universalized healthcare may have profound implications for many marginal groups in society, as well as the physiotherapy profession itself.

California's harvested wood products: A time-dependent assessment of life cycle greenhouse gas emissions.

Following life-cycle assessment (LCA) methodology, this study presents a state-level estimation of embodied carbon of wood products harvested in 2019 from California and subsequently processed, manufactured, transported, used, and disposed at the end-of-life (EoL). In a conventional static approach to LCA, all GHG emissions were aggregated and considered to occur at year 0 of the given time horizon (500 years in this study) and used a static characterization factor (CF). In dynamic LCA, GHG emissions occurring in different years were considered, and their global warming impact (GWI) was determined using a time-dependent CF over the selected time horizon of 500 years. Four scenarios were developed to examine the impact of EoL choices on GWI. It was found that dynamic GWI for all scenarios ranged from 0.27 to 0.93 million tonne CO2e, which were 45-73 % lower than those estimated with static LCA approach, indicating that the static LCA approach could lead to an underestimation of the benefits of substituting wood for non-wood products, compared to those based on dynamic LCA approach. This analysis also demonstrated that the choice of EoL treatment option is a key factor affecting the estimated GWI as it directly determines the annual emission of GHGs released into atmosphere and subsequently their warming effect depending on the time harvested wood products (HWPs) spend in the horizon of assessment. Overall, the dynamic LCA performed in this study enabled more robust interpretations of embodied carbon by including temporal boundaries associated with the HWPs life cycle.

Long-Term Durability of Certolizumab Pegol in Patients with Rheumatoid Arthritis Over 5 Years: An Analysis of Pooled Clinical Trial Data.

INTRODUCTION: There is a paucity of data on how patient characteristics may affect the long-term durability of certolizumab pegol (CZP) in patients with rheumatoid arthritis (RA). This study therefore aimed to investigate CZP durability and reasons for discontinuation over 5 years between different subgroups of patients with RA. METHODS: Data were pooled from 27 clinical trials in RA patients. Durability was defined as the percentage of patients randomized to CZP at baseline who were still on CZP treatment at a given timepoint. Post hoc analyses of clinical trial data on CZP durability and reasons for discontinuation among different patient subgroups were conducted using Kaplan-Meier curves and Cox proportional hazards modeling. Patient subgroups included: age (18- < 45/45- < 65/ ≥ 65 years), gender (male/female), prior tumor necrosis factor inhibitor (TNFi) use (yes/no), and disease duration (< 1/1- < 5/5- < 10/ ≥ 10 years). RESULTS: Among 6927 patients, the durability of CZP was 39.7% at 5 years. Patients aged ≥ 65 years had a 33% greater risk of CZP discontinuation than patients 18- < 45 years (hazard ratio [95% confidence interval]: 1.33 [1.19-1.49]) and patients with prior TNFi use had a 24% greater risk of discontinuing CZP than patients without (1.24 [1.12-1.37]). Conversely, greater durability was observed among patients who had a baseline disease duration of ≥ 1 year. Durability did not differ in the gender subgroup. Of the 6927 patients, the most common reason for discontinuation was inadequate levels of efficacy (13.5%); followed by adverse events (11.9%); consent withdrawn (6.7%); lost to follow-up (1.8%); protocol violation (1.7%); other reasons (9.3%). CONCLUSIONS: CZP durability was comparable with durability data on other bDMARDs in RA patients. Patient characteristics that were associated with greater durability included younger age, TNFi-naïvety, and disease duration ≥ 1 year. Findings may be helpful in informing clinicians on a patient's likelihood of discontinuing CZP, based on their baseline characteristics.

A critical assessment of the role of creatine in brown adipose tissue thermogenesis.

Brown adipose tissue is specialized for non-shivering thermogenesis, combining lipolysis with an extremely active mitochondrial electron transport chain and a unique regulated uncoupling protein, UCP1, allowing unrestricted respiration. Current excitement focuses on the presence of brown adipose tissue in humans and the possibility that it may contribute to diet-induced thermogenesis, countering obesity and obesity-related disease as well as protecting cardio-metabolic health. In common with other tissues displaying a high, variable respiration, the tissue possesses a creatine pool and mitochondrial and cytosolic creatine kinase isoforms. Genetic and pharmacological manipulation of these components have pleiotropic effects that appear to influence diet- and cold-induced metabolism in vivo and modeled in vitro. These findings have been used to advance the concept of a UCP1-independent diet-induced thermogenic mechanism based on a dissipative hydrolysis of phosphocreatine in beige and brown adipose tissue. Here we review the in vivo and in vitro experimental basis for this hypothesis, and explore alternative explanations. We conclude that there is currently no convincing evidence for a significant futile creatine cycle in these tissues.

Fifty years on: How we uncovered the unique bioenergetics of brown adipose tissue.

Exactly 50 years ago, I was a post-doc in the laboratory of Olov Lindberg in Stockholm measuring fatty acid oxidation by mitochondria isolated from thermogenic brown adipose tissue, when we noticed a curious nonlinearity in the respiration rate. This initiated a convoluted chain of experiments revealing that the mitochondria were textbook demonstrations of the then novel and highly controversial "chemiosmotic hypothesis" of Peter Mitchell and that thermogenesis was regulated by a proton short-circuit, mediated by a 32 kDa "uncoupling protein," UCP1, activated by fatty acid. This review is a personal account of the research into the bioenergetics of isolated brown adipocytes and isolated mitochondria, which led, after fifteen years of investigation, to what is still accepted as the "canonical" UCP1-mediated mechanism of nonshivering thermogenesis, uniting whole animal physiology with mitochondrial bioenergetics.

Physiotherapy, movement, and action.

Movement has always been central to physiotherapy practice and theory. But physiotherapists have largely focused on forms of human bodily movement governed by the neuro-mechanical body system in illness or injury. Many other forms of movement exist though, and we argue here that the exploration of these other movements might give physiotherapists new language, concepts, and tools, to guide its adaptation to forms of healthcare that are becoming increasingly complex, diverse, and inclusive. Drawing on Hannah Arendt's concept of vita activa (or "active life"), we examine how physiotherapists have traditionally captured and defined movement. Critiquing past practices for over-emphasizing what Arendt called labor, and work, we suggest that an approach governed by her concept of action, might offer physiotherapists a way to give movement greater significance. We explore what active life might mean for a revised approach to movement, and highlight examples of vita activa already emerging in physiotherapy. We close the paper by calling for a reevaluation of what movement means for the profession and its clients.

Data-driven design of thin-film optical systems using deep active learning.

A deep learning aided optimization algorithm for the design of flat thin-film multilayer optical systems is developed. The authors introduce a deep generative neural network, based on a variational autoencoder, to perform the optimization of photonic devices. This algorithm allows one to find a near-optimal solution to the inverse design problem of creating an anti-reflective grating, a fundamental problem in material science. As a proof of concept, the authors demonstrate the method's capabilities for designing an anti-reflective flat thin-film stack consisting of multiple material types. We designed and constructed a dielectric stack on silicon that exhibits an average reflection of 1.52 %, which is lower than other recently published experiments in the engineering and physics literature. In addition to its superior performance, the computational cost of our algorithm based on the deep generative model is much lower than traditional nonlinear optimization algorithms. These results demonstrate that advanced concepts in deep learning can drive the capabilities of inverse design algorithms for photonics. In addition, the authors develop an accurate regression model using deep active learning to predict the total reflectivity for a given optical system. The surrogate model of the governing partial differential equations can then be broadly used in the design of optical systems and to rapidly evaluate their behavior.

Monte Carlo-transformed field expansion method for simulating electromagnetic wave scattering by multilayered random media.

We present an efficient numerical method for simulating the scattering of electromagnetic fields by a multilayered medium with random interfaces. The elements of this algorithm, the Monte Carlo-transformed field expansion method, are (i) an interfacial problem formulation in terms of impedance-impedance operators, (ii) simulation by a high-order perturbation of surfaces approach (the transformed field expansions method), and (iii) efficient computation of the wave field for each random sample by forward and backward substitutions. Our perturbative formulation permits us to solve a sequence of linear problems featuring an operator that is deterministic, and its LU decomposition matrices can be reused, leading to significant savings in computational effort. With an extensive set of numerical examples, we demonstrate not only the robust and high-order accuracy of our scheme for small to moderate interface deformations, but also how Padé summation can be used to address large deviations.

How Do You Touch an Impossible Thing?

How, and how much, physiotherapists should touch in practice is once again being debated by the profession. COVID-19 and people's enforced social isolation, combined with the growth of virtual technologies, and the profession's own turn away from so-called "passive" therapies, has placed therapeutic touch once again in an uncertain position. The situation is more ambiguous and uncertain because, despite its historical importance to the profession, physiotherapists have never articulated a comprehensive philosophy of touch, taking-for-granted its seeming obviousness as either a bio-physical or inter-subjective phenomenon. But both of these approaches are limited, with one failing to account for the existential and socio-cultural significance of touch, and the other rejecting the reality of the physical body altogether. And both are narrowly humanistic. Since touch occurs between all entities throughout the cosmos, and human touch makes up only an infinitesimally small part of this, physiotherapy's approach to touch seems paradoxically to be at the same time both highly reductive and ontologically vague. Given physiotherapists' much vaunted claim to be experts in therapeutic touch, it would seem timely to theorize how touch operates and when touch becomes therapeutic. In this paper I draw on Gilles Deleuze's machine ontology as a new way to think about touch. Critiquing existing approaches, I argue that machine ontology provides a more robust and inclusive philosophy of touch, pointing to some radical new possibilities for the physical therapies.

Improving the efficiency and effectiveness of an industrial SARS-CoV-2 diagnostic facility.

On 11th March 2020, the UK government announced plans for the scaling of COVID-19 testing, and on 27th March 2020 it was announced that a new alliance of private sector and academic collaborative laboratories were being created to generate the testing capacity required. The Cambridge COVID-19 Testing Centre (CCTC) was established during April 2020 through collaboration between AstraZeneca, GlaxoSmithKline, and the University of Cambridge, with Charles River Laboratories joining the collaboration at the end of July 2020. The CCTC lab operation focussed on the optimised use of automation, introduction of novel technologies and process modelling to enable a testing capacity of 22,000 tests per day. Here we describe the optimisation of the laboratory process through the continued exploitation of internal performance metrics, while introducing new technologies including the Heat Inactivation of clinical samples upon receipt into the laboratory and a Direct to PCR protocol that removed the requirement for the RNA extraction step. We anticipate that these methods will have value in driving continued efficiency and effectiveness within all large scale viral diagnostic testing laboratories.

Diagnostics and Treatments of COVID-19: A Living Systematic Review of Economic Evaluations.

OBJECTIVES: As healthcare systems continue to respond to the COVID-19 pandemic, cost-effectiveness evidence will be needed to identify which tests and treatments for COVID-19 offer value for money. We sought to review economic evaluations of diagnostic tests and treatments for COVID-19, critically appraising the methodological approaches used and reporting cost-effectiveness estimates, using a "living" systematic review approach. METHODS: Key databases (including MEDLINE, EconLit, Embase) were last searched on July 12, 2021. Gray literature and model repositories were also searched. Only full economic evaluations published in English were included. Studies were quality assessed and data were extracted into standard tables. Results were narratively summarized. The review was completed by 2 reviewers independently, with disagreements resolved through discussion with a senior reviewer. RESULTS: Overall, 3540 records were identified, with 13 meeting the inclusion criteria. After quality assessment, 6 were excluded because of very severe limitations. Of the 7 studies included, 5 were cost-utility analyses and 2 were cost-effectiveness analyses. All were model-based analyses. A total of 5 evaluated treatments (dexamethasone, remdesivir, hypothetical) and 2 evaluated hypothetical testing strategies. Cost-effectiveness estimates were sensitive to the treatment effect on survival and hospitalization, testing speed and accuracy, disease severity, and price. CONCLUSIONS: Presently, there are few economic evaluations for COVID-19 tests and treatments. They suggest treatments that confer a survival benefit and fast diagnostic tests may be cost effective. Nevertheless, studies are subject to major evidence gaps and take inconsistent analytical approaches. The evidence may improve for planned updates of this "living" review.

A systematic approach to understand hydrogeochemical dynamics in large river systems: Development and application to the River Ganges (Ganga) in India.

Large river systems, such as the River Ganges (Ganga), provide crucial water resources for the environment and society, yet often face significant challenges associated with cumulative impacts arising from upstream environmental and anthropogenic influences. Understanding the complex dynamics of such systems remains a major challenge, especially given accelerating environmental stressors including climate change and urbanization, and due to limitations in data and process understanding across scales. An integrated approach is required which robustly enables the hydrogeochemical dynamics and underpinning processes impacting water quality in large river systems to be explored. Here we develop a systematic approach for improving the understanding of hydrogeochemical dynamics and processes in large river systems, and apply this to a longitudinal survey (> 2500 km) of the River Ganges (Ganga) and key tributaries in the Indo-Gangetic basin. This framework enables us to succinctly interpret downstream water quality trends in response to the underpinning processes controlling major element hydrogeochemistry across the basin, based on conceptual water source signatures and dynamics. Informed by a 2019 post-monsoonal survey of 81 river bank-side sampling locations, the spatial distribution of a suite of selected physico-chemical and inorganic parameters, combined with segmented linear regression, reveals minor and major downstream hydrogeochemical transitions. We use this information to identify five major hydrogeochemical zones, characterized, in part, by the inputs of key tributaries, urban and agricultural areas, and estuarine inputs near the Bay of Bengal. Dominant trends are further explored by investigating geochemical relationships (e.g. Na:Cl, Ca:Na, Mg:Na, Sr:Ca and NO3:Cl), and how water source signatures and dynamics are modified by key processes, to assess the relative importance of controls such as dilution, evaporation, water-rock interactions (including carbonate and silicate weathering) and anthropogenic inputs. Mixing/dilution between sources and water-rock interactions explain most regional trends in major ion chemistry, although localized controls plausibly linked to anthropogenic activities are also evident in some locations. Temporal and spatial representativeness of river bank-side sampling are considered by supplementary sampling across the river at selected locations and via comparison to historical records. Limitations of such large-scale longitudinal sampling programs are discussed, as well as approaches to address some of these inherent challenges. This approach brings new, systematic insight into the basin-wide controls on the dominant geochemistry of the River Ganga, and provides a framework for characterising dominant hydrogeochemical zones, processes and controls, with utility to be transferable to other large river systems.

Løgstrup's thinking: a contribution to ethics in physiotherapy.

Ethics is ever-present in all aspects of human interaction and, in any physiotherapy situation there is an inherent claim to act and care for the patient in the best possible way. The physiotherapy profession is provided with rules, guidelines and codes to support and ensure ethical professional conduct. In recent decades however, physiotherapy literature has emphasized how ethical agency is immersed in clinical reasoning in each particular situation, in the doing of physiotherapy. The Danish philosopher and theologian Knud E. Løgstrup offers a bottom-up approach to ethics, which may augment the philosophical underpinning of this development in ethical thinking. Løgstrup departs from the given pre-conditions of life; a point of departure where the ethical claim emerges from sensation in the concrete situations. This paper introduces Løgstrup's situational ethics and its ontological framing, with four foci: how we can tune in to sensation and sense the ethical claim of the other; how human interdependence can be heard in what Løgstrup calls sovereign life utterances; relational responsibility and ethical norms; and the metaphorical importance of poetic understandings of the world. In four themes we reflect on how these ethical issues are at stake in physiotherapy practice with regards to: (1) uncertainty, tuned sensation and therapeutic attitude in physiotherapy; (2) sensuous, narrative and poetic meaning-making in physiotherapy; (3) physiotherapy and coming to oneself in new embodied experiences; and (4) ethical claims and codes of conduct in physiotherapy.

Environmental physiotherapy and the case for multispecies justice in planetary health.

BACKGROUND: Global environmental change is fundamentally altering the composition and functioning of our planetary ecosystem. Effectively presenting the largest threat to the health of present and future generations, these changes and their health impacts are forcing us to think and practice healthcare in much broader terms than ever before. OBJECTIVE: In this article, we provide an early outline for a radically otherwise, yet strangely familiar, environmental physiotherapy developed through a succession of carefully developed arguments. DISCUSSION: We show how an underpinning belief in human exceptionalism has engendered an exploitative relationship with our natural planetary environment that has both shaped Western science and healthcare and led to our current environmental health crisis. Building on the dependence of human health on our planetary ecosystem, approaches like planetary health hold great promise for a corresponding, paradigmatic turn in healthcare. They fall short of this however, where they perpetuate anthropocentric interests and interventionist practices that have underpinned healthcare to date. Drawing on ethical and post-human philosophies we argue against human exceptionalism and for a solidarity that includes other-than-humans as the primary characteristic of planetary existence. CONCLUSION: Building on this foundation, we provide an early outline for a radically otherwise, yet strangely familiar, environmental physiotherapy, grounded in ecological awareness, multispecies justice, and a range of consonant practices of passivity and accompaniment, conceived as an alternative to the commonplace interventionism of healthcare.