This article highlights three key projects on which economists at the UK's Competition and Markets Authority (CMA) have worked over the past year. First, we examine the Vodafone/Three merger in the telecoms sector: We focus on the role of econometric analysis in understanding consumer preferences and assessing the likely effect of the merger in the retail mobile market. We also explain how we assessed the anticipated efficiencies and the role of remedies in securing those efficiencies, which ultimately led to the merger's approval. Second, we discuss our infant formula (baby milk) market study, where we found that regulation and consumer behaviour contributed to weak price competition in this market. Third, we present empirical research that was undertaken by the CMA Microeconomics Unit to inform the UK Government's new industrial strategy. We look at the effect of past industrial policies and analyse the sectors that have been identified by the government to be 'growth-driving'.

AbstractINTRODUCTIONAddressing practical challenges in clinical practice after the recent approvals of amyloid antibodies in Alzheimer's disease (AD) will benefit more patients. However, generating these answers using clinical trials or real‐world evidence is not practical, nor feasible.METHODSHere we use a Quantitative Systems Pharmacology (QSP) computational model of amyloid aggregation dynamics, well validated with clinical data on biomarkers and amyloid‐related imaging abnormality–edema (ARIA‐E) liability of six amyloid antibodies in clinical trials to explore various clinical practice challenges.RESULTSTreatment duration to reach amyloid negativity ranges from 12 to 44, 16 to 40, and 6 to 20 months for lecanemab, aducanumab, and donanemab, respectively, for baseline central amyloid values between 50 and 200 Centiloids (CL). Changes in plasma cerebrospinal fluid Aβ42 and the plasma Aβ42/ Aβ40 ratio—fluid biomarkers to detect central amyloid negativity—is greater for lecanemab than for aducanumab and donanemab, indicating that these fluid amyloid biomarkers are only suitable for lecanemab. After reaching amyloid negativity an optimal maintenance schedule consists of a 24‐month, 48‐month and 64‐month interval for 10 mg/kg (mpk) lecanemab, 10 mpk aducanumab, and 20 mpk donanemab, respectively, to keep central amyloid negative for 10 years. Cumulative ARIA‐E liability could be reduced to almost half by introducing a drug holiday in the first months. For patients experiencing ARIA‐E, restarting treatment with a conservative titration strategy resulted in an additional delay ranging between 3 and 4 months (donanemab), 5 months (lecanemab), and up to 7 months (aducanumab) for reaching amyloid negativity, depending upon the timing of the incident. Clinical trial designs for Down syndrome patients suggested the same rank order for central amyloid reduction, but higher ARIA‐E liability especially for donanemab, which can be significantly mitigated by adopting a longer titration period.DISCUSSIONThis QSP platform could support clinical practice challenges to optimize real‐world treatment paradigms for new and existing amyloid drugs.

This article discusses three projects of economic significance that the Competition and Markets Authority (CMA) completed in the last year: First, we discuss the dynamic competition concerns that were at the heart of the CMA’s analysis of the Meta/GIPHY merger; this was the first case of a competition authority’s blocking an acquisition by one of the ‘Big Tech’ firms. Second, our work on the road fuels market study examined pricing behaviour in an important consumer-facing market and found that competition had weakened because historic price leaders have been taking a less aggressive approach to pricing, Third, we established a new research centre—the Microeconomics Unit—to bring economic expertise on competition, innovation, and productivity closer to regulatory and policy decisions.

This article discusses three important pieces of work that the Competition and Markets Authority (CMA) completed in the last year. First, we discuss the Microsoft / Activision Blizzard merger inquiry. We focus on the theory of harm that led to the CMA’s original prohibition decision: the input foreclosure of rival downstream cloud gaming platforms. We consider some of the challenges that were posed by assessing competition in a nascent market. Second, we summarise some of the findings from the CMA’s initial review into AI Foundation Models (FM). We detail the FM value chain, the economic characteristics of FMs, and the role of vertical integration and strategic partnerships in the FM ecosystem. Third, we describe the CMA’s econometric analysis to estimate diversion ratios between different brands of dishwashers as part of the Arçelik/Whirlpool EMEA merger inquiry. This is an interesting example of an econometric analysis in a competition case because it was the first time in several years that the CMA used a consumer demand model; and the application of the model was novel because it relied on primary data that are collected directly from retailers.

The recent approvals of amyloid antibodies for treatment of Alzheimer’s disease have heralded a new era in the physician’s treatment toolbox and the availability of individualized treatment guidelines for patients will greatly benefit an ever greater patient population. However, generating these guidelines using clinical experiments is not feasible. We used a mechanism-based Quantitative Systems Pharmacology model, well validated with published natural history and group average clinical trial data of six amyloid antibodies and applied it to individual scenarios, including APOE genotype. For baseline SUVR between 70 and 180 centiloids, the time to reach amyloid negativity was predicted to range on average from 25 to 64 months for aducanumab, 18 to 47 months for lecanemab and 10 to 25 months for donanemab. Interestingly, we derived a relationship between the baseline SUVR load and the changes in plasma Ab42/Ab40 ratio or CSF Ab42 level associated with reaching amyloid negativity. This relationship is different for each antibody with lecanemab more sensitive than donanemab and aducanemab and provides an alternative to PET imaging to determine the time of reaching amyloid negativity. ARIA-E liability for an APOE4 carrier ranges between 20 and 31% for aducanumab, 10-18% for lecanamab and 17-27% for donanemab during the time to reach Abeta negativity. After reaching amyloid negativity, stabilization over 10 years follow-up can be achieved with a 32-fold reduction in exposure for all three antibodies, either with a lower dose, lower frequency or a combination of both. For patients with a three-month dose holiday after an ARIA-E incident, the delay in reaching amyloid negativity is predicted to range from 3 to 6 months for aducanumab, 2 to 4 months for lecanemab and 1.7 to 3 months for donanemab, depending on the titration schedule after reinstatement of the treatment. Finally, after implementation of the trisomy 21 effect, we explored optimal trial designs for autosomal dominant Down syndrome patients for each of the three antibodies. This simulation can be applied to any newly approved drug given the pharmacology (affinities against different Abeta peptides) and PK profile and many individual case scenarios.

The Standard Auxiliary Boundary Stratotype (SABS) has been approved by the International Commission on Stra-tigraphy (ICS) as a formal replacement for the Auxiliary Stratotype Point to support a Global boundary Stratotype Section and Point (GSSP). The SABS provides a detailed complementary expression of the boundary interval with-out designating a specific point. More than one SABS may support a single GSSP and each will be subordinate to the GSSP. SABSs extend the correlative potential of a GSSP between continents, biogeographic provinces, climatic zones, depositional facies and preservational states. Require-ments for SABSs broadly follow ICS guidelines for GSSPs, and will require approval by their respective ICS subcom-mission. Following such approval, each SABS will be listed on the ICS website as well as that of the respective sub-commission, and future SABSs will be accompanied by an announcement published in the International Union of Geological Sciences journal Episodes.

Misfolded proteins in Alzheimer's disease and Parkinson's disease follow a well-defined connectomics-based spatial progression. Several anti-tau and anti-alpha synuclein (aSyn) antibodies have failed to provide clinical benefit in clinical trials despite substantial target engagement in the experimentally accessible cerebrospinal fluid (CSF). The proposed mechanism of action is reducing neuronal uptake of oligomeric protein from the synaptic cleft. We built a quantitative systems pharmacology (QSP) model to quantitatively simulate intrasynaptic secretion, diffusion and antibody capture in the synaptic cleft, postsynaptic membrane binding and internalization of monomeric and oligomeric tau and aSyn proteins. Integration with a physiologically based pharmacokinetic (PBPK) model allowed us to simulate clinical trials of anti-tau antibodies gosuranemab, tilavonemab, semorinemab, and anti-aSyn antibodies cinpanemab and prasineuzumab. Maximal target engagement for monomeric tau was simulated as 45% (semorinemab) to 99% (gosuranemab) in CSF, 30% to 99% in ISF but only 1% to 3% in the synaptic cleft, leading to a reduction of less than 1% in uptake of oligomeric tau. Simulations for prasineuzumab and cinpanemab suggest target engagement of free monomeric aSyn of only 6-8% in CSF, 4-6% and 1-2% in the ISF and synaptic cleft, while maximal target engagement of aggregated aSyn was predicted to reach 99% and 80% in the synaptic cleft with similar effects on neuronal uptake. The study generates optimal values of selectivity, sensitivity and PK profiles for antibodies. The study identifies a gradient of decreasing target engagement from CSF to the synaptic cleft as a key driver of efficacy, quantitatively identifies various improvements for drug design and emphasizes the need for QSP modelling to support the development of tau and aSyn antibodies.

Statins are the most popular and effective lipid-lowering medications beneficial in hypercholesterolemias and prevention of cardiovascular diseases. Growing evidence supports theory that statins exhibit neuroprotective action in acute stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis or epilepsy. Hereby, we present available experimental data regarding action of this group of drugs on seizure activity and neuronal cell death. The most commonly examined statins, such as atorvastatin and simvastatin, display anticonvulsant action with only inconsiderable exceptions. However, the mechanism of this effect remains unexplained. Simvastatin, as a lipophilic statin, which can pass blood–brain barrier easily, was recommended as the best candidate for an anticonvulsant agent. Nevertheless, it is still indistinct, whether the protective activity of statins depends on cholesterol lowering properties or its pleiotropic characteristics. One of the most interesting of 3-hydroxy-3-methylglutaryl-coenzyme A inhibitor's actions involves influence on nitric oxide metabolism.

Supplementary Table from AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts

Recent clinical trials with amyloid antibodies have suggested a beneficial effect on cognitive scales after clearing most of the amyloid load. Interestingly, substantial reduction in plasma or CSF tau biomarkers were documented providing interesting insights into the amyloid-tau interactions in the human AD patient. We developed a Quantitative Systems Pharmacology (QSP) platform for late MCI-prodromal AD subjects that combined an earlier published Physiology-Based Pharmacokinetic (PBPK)- QSP model of amyloid aggregation with a novel QSP model describing the impact of amyloid monomers on glutamatergic and nicotinic neurotransmission and neuronal firing, the neuronal activity-dependent tau release, subsequent tau uptake in the afferent neuron and dynamics of tau biomarkers in CSF and plasma. The combined model quantitatively reproduced (1) the cortical hyperactivity and higher tau biomarker levels associated with increasing amyloid deposition in observational studies, (2) the differential decrease in CSF and plasma tau biomarkers in clinical trials with various amyloid antibodies. Dynamics of monomeric brain Ab40 and Ab42 and their effect on neuronal firing, rather than reduction in SUVR can better explain the clinically observed changes in CSF or plasma tau between aducanumab, lecanemab, donanemab and gantenerumab. The range of commonly used comedications and common dopaminergic and serotonergic genotype variants affecting neuronal activity can partially explain the variability of tau biomarkers response as downstream effects of amyloid removal. This study suggests a direct link between amyloid dynamics and plasma / CSF tau levels through modulation of neuronal activity. The calibrated QSP model sets the stage for modeling long-term effects of amyloid therapy on tau pathology progression and identification of optimal trial design for combination therapies.

We find that a reasonable reading of the available evidence indicates that there has been significant under-enforcement of merger control with respect to the digital platforms. We argue that this under-enforcement means that we should change the standard against which we assess whether such mergers are anti-competitive. We outline several possible ways in which the standard could be changed and highlight the importance of improving competition authorities' treatment of uncertainty. Finally, we discuss the type of analysis that competition authorities should carry out in order to give themselves the best chance of getting merger control decisions right in the digital arena. We highlight the importance of asking the right questions about dynamic competition, rather than focusing on traditional static competition approaches.

Auxiliary boundary stratotypes have unquestionable value in extending the knowledge of a Global boundary Stratotype Section and Point (GSSP) between continents, biogeographic provinces, climatic zones, depositional facies and preservational states.Two kinds of such stratotypes are in use, the Auxiliary Stratotype Point and the Auxiliary Stratotype Section, although only the Auxiliary Stratotype Point is recognised by the International Commission on Stratigraphy (ICS).The Standard Auxiliary Boundary Stratotype, which is based on the Auxiliary Stratotype Section, is proposed here as a formal replacement for the Auxiliary Stratotype Point.As such, it would provide a detailed complementary expression of the boundary interval without the designation of a specific point -no such points can replicate the precise level defined by a GSSP either conceptually or in practice.We recommend that requirements for future Standard Auxiliary Boundary Stratotypes broadly follow ICS guidelines for GSSPs but be applied with greater flexibility.Past practice reveals inconsistency in the protocols used for approving such auxiliary boundary stratotypes.We propose that in future they require approval by the respective ICS subcommission.More than one Standard Auxiliary Boundary Stratotype may support a single GSSP but restraint should be exercised in approving them, and each will always be subordinate to the GSSP itself.

Antibody-mediated removal of aggregated β-amyloid (Aβ) is the current, most clinically advanced potential disease-modifying treatment approach for Alzheimer's disease. We describe a quantitative systems pharmacology (QSP) approach of the dynamics of Aβ monomers, oligomers, protofibrils, and plaque using a detailed microscopic model of Aβ40 and Aβ42 aggregation and clearance of aggregated Aβ by activated microglia cells, which is enhanced by the interaction of antibody-bound Aβ. The model allows for the prediction of Aβ positron emission tomography (PET) imaging load as measured by a standardized uptake value ratio. A physiology-based pharmacokinetic model is seamlessly integrated to describe target exposure of monoclonal antibodies and simulate dynamics of cerebrospinal fluid (CSF) and plasma biomarkers, including CSF Aβ42 and plasma Aβ42 /Aβ40 ratio biomarkers. Apolipoprotein E genotype is implemented as a difference in microglia clearance. By incorporating antibody-bound, plaque-mediated macrophage activation in the perivascular compartment, the model also predicts the incidence of amyloid-related imaging abnormalities with edema (ARIA-E). The QSP platform is calibrated with pharmacological and clinical information on aducanumab, bapineuzumab, crenezumab, gantenerumab, lecanemab, and solanezumab, predicting adequately the change in PET imaging measured amyloid load and the changes in the plasma Aβ42 /Aβ40 ratio while slightly overestimating the change in CSF Aβ42 . ARIA-E is well predicted for all antibodies except bapineuzumab. This QSP model could support the clinical trial design of different amyloid-modulating interventions, define optimal titration and maintenance schedules, and provide a first step to understand the variability of biomarker response in clinical practice.

As the largest organ of the human body the skin offers a protective role, providing a tough but pliable covering that provides the major barrier between the internal organs and the environment. It actively regulates water loss and is both oxygen and carbon dioxide permeable, and influences temperature regulation and immunological functions through its sensory properties. Both intrinsic and enhanced environmental factors contribute to the progressive deterioration of the skin with increasing age. Cutaneous problems are therefore an unavoidable and inevitable consequence of aging skin, which can prove to be both cosmetically unacceptable to those who succumb to these problems, as well as even life threatening if skin breakdown becomes chronic as is case with leg ulceration. This in turn has major implications for long-term impact on those looking after them (e.g., family, carers, etc.) and a huge burden on the health care system.

This article discusses three important pieces of work that the Competition and Markets Authority has completed over the last year. The first two are market studies: The Mobile Ecosystems Market Study was launched over concerns that Apple and Google have too much control over operating systems (iOS and Android), app stores (App Store and Play Store), and web browsers (Safari and Chrome) that together form their 'ecosystems', the Electric Vehicles Charging Market Study took actions and provided recommendations in a nascent but critically important market. The final piece of work is "State of Competition": a research project that assesses the evolution of competition in the UK over the past two decades.

Racial and ethnic minority groups are underrepresented in clinical research, and disparities in health outcomes between minority and non-minority groups are well documented. The FDA released guidance in 2022 to improve enrollment from underrepresented groups in clinical trials, and similar issues of representative inclusion exist in patient-centered research. The objective of this conceptual piece is to reflect on barriers and strategies for achieving a racially/ethnically representative sample in COA research as an aspect of clinical research.

Une entrevue avec Cristina Caffarra, Vice President, Head of European Competition Practice, Charles River Associates International, Londres. Avec la participation de Rupprecht Podszun,…

Barnicarndy 1 is a stratigraphic well drilled in the southern part of the Canning Basin’s Barnicarndy Graben under Geoscience Australia’s Exploring for the Future program in collaboration with the Geological Survey of Western Australia to provide stratigraphic data for this poorly understood tectonic component. The well intersects a thin Cenozoic section, Permian–Carboniferous fluvial clastics and glacial diamictites and a thick pre-Carboniferous succession (855–2585mRT) unconformably overlying Neoproterozoic metasedimentary rocks. Three informal siliciclastic intervals were defined based on core lithology, well logs, chemical and mineral compositions: the Upper Sandstone (855–1348.1mRT), Middle Interval (1348.1–2443.4mRT) and Lower Sandstone (2443.4–2585mRT). The Middle Interval was further divided into six internal zones. Both conventional methods and artificial neural network technology were applied to well logs to interpret petrophysical and elastic properties, total organic carbon (TOC) content, pyrolysis products from the cracking of organic matter (S2) and mineral compositions. Average sandstone porosity and reservoir permeability are 17.9% and 464.5mD in the Upper Sandstone and 6.75% and 10mD in the Lower Sandstone. The Middle Interval claystone has an average porosity and permeability of 4.17% and 0.006mD, and average TOC content and S2 value of 0.17wt% and 0.047mgHC/g rock, with maximum values of 0.66wt% and 0.46mgHC/g rock, respectively. Correlations of mineral compositions and petrophysical, geomechanical and organic geochemical properties of the Middle Interval have been conducted and demonstrate that these sediments are organically lean and lie within the oil and gas window.

BACKGROUND:All fibrous wound dressings are considered to have the same action and value to the support of wound healing. Although clear distinction has been accepted between cotton gauze and calcium alginates, there is still no formally recognised distinction between calcium alginates and the more rapidly gelling fibre dressings.METHOD:Scientific and clinical evaluations were used to differentiate two different fibrous wound care products. One is derived from polymer extraction of algae (alginate dressings); the other has been manufactured from a uniquely patented carboxymethylation process that produces 100% carboxymethyl cellulose (CMC)-based dressings. Structural differences between these dressings were evaluated with respect to three important areas of wound care management: optimal wound moisture control; the ability to reduce risk of complication by locking away harmful components (e.g. bacteria); and reducing the overall cost of wound care by promoting more efficient use of nursing time.RESULTS:Clear differentiation was illustrated through both scientific and clinical evaluations.CONCLUSION:This study supports the potential advantages of using a technically advanced fibrous wound dressing over the traditional fibrous alginate wound care product.