M&I/Partners

To evaluate the effect of erenumab treatment beyond monthly migraine days in patients with high-frequency episodic migraine who did not respond to at least one previous migraine preventive treatment. Reduction in monthly migraine days has been the efficacy standard for migraine preventive treatments; however, it does not fully capture the holistic benefit of the therapy. Erenumab, a monoclonal antibody targeting the calcitonin gene-related peptide pathway, has demonstrated reduction in monthly migraine days and improvement in function in patients with episodic and chronic migraine. In this phase 4, interventional, double-blind, randomized, placebo-controlled, multicenter, global study, treatment with erenumab was assessed over 4 months in adults with high-frequency episodic migraine. The study was conducted at 61 sites located across North America and Europe between September 2020 and October 2023. Patients with ≥1 qualifying oral triptan-treated migraine attack at baseline were randomized to receive erenumab 140 mg or placebo subcutaneously once monthly. The primary endpoint was change from baseline in mean monthly hours of at least moderate headache pain intensity over months 1, 2, and 3; secondary endpoints included change from baseline in mean monthly function, mean monthly duration of at least moderate pain intensity in migraine attacks, and mean monthly peak migraine pain intensity. Safety outcomes were also assessed. Of 512 randomized patients, 510 received erenumab 140 mg (n = 254) or placebo (n = 256) once monthly. Demographics and baseline characteristics were balanced between the two treatment arms. Erenumab 140 mg was superior to placebo in reducing duration of moderate or severe headache pain intensity over months 1, 2, and 3 (least squares mean [95% confidence interval {CI}] difference, -7.95 [-11.45, -4.46]; p < 0.001). Compared with placebo, erenumab significantly reduced migraine functional impact as assessed by the four domains of the Migraine Functional Impact Questionnaire, with a least squares mean (95% CI) difference of -7.36 (-10.80, -3.92) for physical functioning, -7.10 (-10.34, -3.87) for usual activities, -6.82 (-10.37, -3.27) for social functioning, and - 7.05 (-10.76, -3.34) for emotional functioning (p < 0.001 for all domains). Significant reductions with erenumab compared with placebo were also observed in duration of at least moderate pain intensity in residual or break-through migraine attacks (least squares mean [95% CI] difference, -1.07 [-1.92, -0.22]; p = 0.013) and peak migraine pain intensity (-0.48 [-0.85, -0.11]; p = 0.011). Incidence of grade 3 adverse events was 1.6% with erenumab and 1.2% with placebo; no grade 4 or fatal adverse events were reported in either treatment arm. Findings from the EMBRACE study demonstrated that treatment with erenumab in patients with high-frequency episodic migraine can provide positive therapeutic effects on ictal burden and pain, with residual migraine attacks tending to be shorter and less painful, with less overall impact.

The EU Deforestation Regulation (EUDR) requires all European Union–based companies to ensure that their imports and exports are free from deforestation and that human rights are upheld throughout their international supply chains, including with respect to palm oil commodities. The palm oil industry, which is closely associated with deforestation issues, is the most affected by the enactment of the EUDR. The issuance of the EUDR is therefore regarded as a form of non-tariff barrier imposed by the European Parliament to protect domestic products from competition with palm oil commodities. The EUDR may be considered as a form of green protectionism or a green barrier applied by the European Union under the pretext of environmental protection, specifically deforestation arising from oil palm plantation expansion in forest areas. Indonesia, as the world’s largest producer of palm oil, has undertaken various measures to address deforestation, including through regulatory frameworks such as the Indonesian Sustainable Palm Oil (ISPO) certification, the Roundtable on Sustainable Palm Oil (RSPO), and other national regulations. Numerous efforts have been advanced in response to the issuance of the EUDR, which is discriminatory in imposing unfair rules or requirements on products from certain countries. Diplomatic engagement with the European Union continues, in coordination with like-minded countries, with the objective of seeking solutions to the divergence of views arising from the implementation of the EUDR.

Background: Biofield Therapies, with a historical lineage spanning millennia and continuing relevance in contemporary practices, have been used to address various health conditions and promote wellbeing. The scientific study and adoption of these therapies have been hindered by cultural challenges and institutional barriers. In addition, the current research landscape for Biofield Therapies is insufficiently documented. Objectives: This scoping review aims to comprehensively document the peer-reviewed research landscape of Biofield Therapies. Furthermore, an online searchable and dynamic Evidence Map was created to serve as a publicly accessible tool for querying the evidence base, pinpointing research gaps, and identifying areas requiring further exploration. Methods: A systematic search of PubMed, Embase, CINAHL, and PsycInfo databases was conducted from inception through January 2024. Peer-reviewed interventional studies in English involving human participants receiving Biofield Therapy were included. Data on study design, population, intervention, comparator, outcomes, citation details, and direction of results reported were extracted and synthesized into two summary tables and three data tables. Results: In total, 353 studies in 352 published reports were included: 255 randomized controlled trials, 36 controlled clinical trials, and 62 pre-post study designs. Named biofield interventions included Reiki (n = 88), Therapeutic Touch (n = 71), Healing Touch (n = 31), intercessory prayer (n = 21), External Qigong (n = 16), Spiritual Healing/Spiritual Passé/Laying-on-of-hands (n = 14), "distant or remote healing" (n = 10), and Gentle Human Touch/Yakson Therapeutic Touch (n = 9). Also included were 56 studies in 55 reports involving bespoke, unknown, or other interventions, 20 studies involving multimodal interventions, and 17 studies involving multiple biofield interventions. Studies encompassed a wide variety of populations, most commonly healthy volunteers (n = 67), pain (n = 55), and cancer (n = 46). As reported in the Abstracts, nearly half of the studies (n = 172) reported positive results in favor of the Biofield Therapy for all outcomes being investigated, 95 reported mixed results, 71 reported nonsignificant results, 3 reported negative results, and 12 studies did not report the direction of results. Conclusions: Despite rising interest in Biofield Therapies among researchers, practitioners, and patients, the integration of these interventions into allopathic medical systems is hindered by challenges in researching these therapies and inconsistent reporting. These issues contribute to inconclusive findings, which limit our understanding of the efficacy of Biofield Therapies for specific conditions. The resulting scoping review and interactive Evidence Map aim to empower stakeholders to overcome these obstacles, thereby strengthening the evidence for the potential adoption of Biofield Therapies as future integrative care options in allopathic medicine.

Abstract BackgroundDifferences in patient characteristics across geographical regions may result in heterogeneity in clinical trial populations. evoke (NCT04777396) and evoke+ (NCT04777409) are two phase 3, multinational, randomised trials investigating semaglutide versus placebo in individuals with mild cognitive impairment or mild dementia due to Alzheimer’s disease (AD) (early AD). We present baseline characteristics across the geographical regions in evoke/evoke+.MethodBaseline data were pooled into five regions (Asia, Europe, Latin America [LATAM], North America and Rest of World [RoW]). Demographic and clinical characteristics were calculated for individual trials (evoke; evoke+), along with pooled data (evoke/evoke+ combined) for each region. Inclusion criteria were the same for both trials; except that evoke+ allowed the inclusion of participants with significant small vessel pathology (&gt;1 lacunar infarct and/or &gt;2 age‐related white matter changes [white matter &gt;20 mm]).ResultOf the 3,806 individuals with early AD enrolled, there were 1,986, 707, 602, 303 and 208 in Europe, North America, Asia, LATAM and RoW, respectively. Screening failure rates were 54.6‐67.8% across regions and highest in North America. Mean age was 71.7‐73.3 years, and 46.3‐59.1% of participants were female (Table 1). Cognitive scores were similar across regions: mean (standard deviation) Mini‐Mental State Examination score was 23.6 (3.3) to 24.6 (2.9) and Clinical Dementia Rating‐Sum of Boxes score was 3.5 (1.6) to 4.2 (1.8) (Table 2). In evoke+, small vessel pathology was lowest in Europe (2.3%) and highest in Asia (3.8%). Apolipoprotein E4 carrier status was lowest in the LATAM region (51.4%) and highest in the RoW (70.5%), and the proportion of individuals with type 2 diabetes ranged from 11.3‐21.1%. Overall, 51.9‐64.3% of individuals received AD medication, with the highest and lowest use in Asia and North America, respectively.Conclusionevoke and evoke+ successfully recruited individuals with early AD from all over the world, ensuring that semaglutide will potentially benefit individuals of various races and ethnicities. Despite this diversity, cognitive scores were largely similar across all geographical regions. Understanding this baseline data will allow for generalisation of the evoke/evoke+ results to worldwide populations with early AD.

INTRODUCTIONCT1812 is in clinical development for the treatment of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) exploratory proteomics was employed to identify pharmacodynamic biomarkers of CT1812 in mild to moderate AD from two independent clinical trials.METHODSUnbiased analysis of tandem‐mass tag mass spectrometry (TMT‐MS) quantitative proteomics, pathway analysis and correlation analyses with volumetric magnetic resonance imaging (vMRI) were performed for the SPARCcohort (NCT03493282). Comparative analyses and a meta‐analysis with the interim SHINE cohort (NCT03507790; SHINE‐A) followed by network analysis (weighted gene co‐expression network analysis [WGCNA]) were used to understand the biological impact of CT1812.RESULTSCT1812 pharmacodynamic biomarkers and biological pathways were identified that replicate across two clinical cohorts. The meta‐analysis revealed novel candidate biomarkers linked to S2R biology and AD, and network analysis revealed treatment‐associated networks driven by S2R. DISCUSSIONEarly clinical validation of CT1812 candidate biomarkers replicating in independent cohorts strengthens the understanding of the biological impact of CT1812 in patients with AD, and supports CT1812's synaptoprotective mechanism of action and its continued clinical development.HighlightsThis exploratory proteomics study identified candidate biomarkers of CT1812 in SPARC (NCT03493282)Comparative analyses identified biomarkers replicating across trials/cohortsTwo independent Ph2 trial cohorts (SPARC and interim SHINE [NCT03507790; SHINE‐A]) were used in a meta‐analysisAmyloid beta (Aβ) & synaptic biology impacted by CT1812 and volumetric magnetic resonance imaging (vMRI) treatment‐related correlates emergeNetwork analyses revealed sigma‐2 receptor (S2R)‐interacting proteins that may be “drivers” of changes

Knee osteoarthritis (OA) is a prevalent degenerative disease affecting synovial joints, predominantly the knee, leading to various complications, including mental health conditions like depression and anxiety. This systematic review aimed to determine the prevalence of depression and anxiety in knee OA patients. A comprehensive literature search was conducted in various databases till September 15, 2023. Studies focusing on the prevalence of mental health issues in patients with knee OA were included, excluding narrative reviews, protocols, unpublished reports, editorials, case reports, abstracts, and commentaries. All statistical analyses were performed in R version 4.2.3. This review included a total of 14 studies involving middle-aged to elderly adult patients with knee OA, with ages ranging from 45 to 75 years. Among these, 13 studies involving 3390 adult patients with an average age of 59.75 years reported a pooled prevalence of depression of 30% (95% confidence interval: 18-43), demonstrating a substantial heterogeneity (I 2=98%). Additionally, anxiety was identified with a combined prevalence of 27% (95% confidence interval: 24-30) based on three studies that included 1407 older adult patients with an average age of 62.1 years. These studies displayed minimal heterogeneity (I 2=7%). The findings show a significant prevalence of depression among adult patients with knee OA and anxiety among older adults with knee OA, emphasizing the need for integrated healthcare approaches that address both orthopedic and mental health conditions. More comprehensive research is essential to deepen our understanding of the connection between mental illnesses and knee OA and to develop effective preventive and treatment strategies.

Child labor persists as a critical issue in Sierra Leone's diamond mining sector, where minors endure hazardous conditions contrary to international labor standards. This article delves into the complexities surrounding child labor in Sierra Leone's diamond mines, focusing on the discord between local legislation and international regulations aimed at safeguarding children's rights. Sierra Leone's rich diamond reserves attract significant investment, yet the industry is marred by the exploitation of vulnerable populations, particularly children. Despite domestic laws prohibiting child labor, enforcement remains weak, and regulatory frameworks often fall short of international standards. This disconnect exacerbates the plight of children engaged in hazardous mining activities, exposing them to physical dangers and health risks and denying them access to education and a dignified childhood. The juxtaposition of Sierra Leone's local laws with international conventions, such as the International Labour Organization's Convention on the Worst Forms of Child Labor (Convention No. 182) and the United Nations Convention on the Rights of the Child (CRC), highlights the urgent need for harmonization and effective enforcement mechanisms. While international treaties advocate for the elimination of child labor in all its forms, including mining, implementation at the national level needs to be more cohesive and adequate. Addressing the root causes of child labor in Sierra Leone's diamond mines necessitates a multifaceted approach. Strengthening legal frameworks, enhancing monitoring and enforcement mechanisms, and investing in education and alternative livelihoods are imperative steps towards eradicating this entrenched issue. Moreover, fostering collaboration between local authorities, industry stakeholders, and international organizations is indispensable for effecting sustainable change and protecting children's rights in Sierra Leone's diamond mining sector.

BackgroundMultimer detection system-oligomeric amyloid-β (MDS-OAβ) is a measure of plasma OAβ, which is associated with Alzheimer’s disease (AD) pathology. However, the relationship between MDS-OAβ and disease severity of AD is not clear. We aimed to investigate MDS-OAβ levels in different stages of AD and analyze the association between MDS-OAβ and cerebral Aβ deposition, cognitive function, and cortical thickness in subjects within the AD continuum.MethodsIn this cross-sectional study, we analyzed a total 126 participants who underwent plasma MDS-OAβ, structural magnetic resonance image of brain, and neurocognitive measures using Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease, and cerebral Aβ deposition or amyloid positron emission tomography (A-PET) assessed by [18F] flutemetamol PET. Subjects were divided into 4 groups: N = 39 for normal control (NC), N = 31 for A-PET-negative mild cognitive impairment (MCI) patients, N = 30 for A-PET-positive MCI patients, and N = 22 for AD dementia patients. The severity of cerebral Aβ deposition was expressed as standard uptake value ratio (SUVR).ResultsCompared to the NC (0.803 ± 0.27), MDS-OAβ level was higher in the A-PET-negative MCI group (0.946 ± 0.137) and highest in the A-PET-positive MCI group (1.07 ± 0.17). MDS-OAβ level in the AD dementia group was higher than in the NC, but it fell to that of the A-PET-negative MCI group level (0.958 ± 0.103). There were negative associations between MDS-OAβ and cognitive function and both global and regional cerebral Aβ deposition (SUVR). Cortical thickness of the left fusiform gyrus showed a negative association with MDS-OAβ when we excluded the AD dementia group.ConclusionsThese findings suggest that MDS-OAβ is not only associated with neurocognitive staging, but also with cerebral Aβ burden in patients along the AD continuum.