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An mHealth application framework to achieve personalized health integrating n-of-1 clinical trial with digital twins
No full textThe past few decades have marked a technological upheaval of the entire healthcare industry. The mandate to transition from paper-based medical records to electronic-based records has digitized patients’ entire medical histories, acting as a pivotal catalyst for ushering healthcare into the digital era. The explosive growth in digital health continues to be fueled by technology-driven solutions including mHealth, telemedicine, electronic health records (EHRs), AI-powered diagnostics, and health data analytics. Digital health includes any digital tool or platform used to enhance healthcare delivery and management. Armed with an arsenal of copious data, the transition from population-based health practices to personalized health is starting to take hold. Traditional evidence-based medicine and its key concepts of randomization and generalizability are the backbone of advancing medical treatments. However, the very pillars of randomized clinical trials that support population health contradict the aim of personalized medicine. Traditional randomized clinical trials are not viable approaches for personalized medicine, especially given that clinical trials often fail to meet enrollment criteria and face a dearth of participant diversity. Recent emerging trends and technologies have evolved to support and allow a more personalized approach to medicine. Patients with chronic conditions may benefit the most from or experience an improvement in the understanding of their condition by participating in a different type of evidenced-based practice - specialized n-of-1 clinical trials.
This paper aims to examine digital health trends that have shaped the landscape to view n-of-1 clinical trials as an attractive alternative. The rise in the use of artificial intelligence, machine learning, and digital twins has allowed for a more granular look at an individual patient. This paper explores and provides a comprehensive framework for building a digital health application designed to support n-of-1 clinical trials integrated with digital twins technology and incorporating AI/ML components as a mechanism to achieve personalized medicine
Effect of calcium supplementation in pregnancy on maternal anaemia and iron status: Findings from two randomized trials in India and Tanzania
No full textIntroduction: Iron-folic acid (IFA) and calcium supplementation are recommended during pregnancy; however, calcium may inhibit iron absorption. While recent trials have shown daily low-dose 500 mg calcium supplementation to be noninferior to the recommended high-dose 1500 mg regimen for prevention of preeclampsia, its effects on maternal anaemia and iron status remain unclear.
Methods: We conducted two individually randomized, non-inferiority trials in India and Tanzania (N=11,000 each) comparing daily 500 mg to 1500 mg calcium supplementation during pregnancy. All participants received standard IFA (60 mg iron) and were counselled to take calcium supplements several hours apart from the IFA. All participants had haemoglobin measured at baseline and at 32 weeks of gestation, while a random subset of participants had ferritin quantified at the same time points. Using an intention-to-treat approach, we assessed effects of 500 mg compared to 1500 mg calcium supplementation on mean haemoglobin and inflammation-adjusted serum ferritin concentrations using generalised linear models, and on anaemia, and iron deficiency anaemia using log-binomial models.
Results: Third-trimester haemoglobin and serum ferritin were measured in 8,953 and 1,336 participants in India, respectively. In Tanzania, 8,496 participants had haemoglobin and 882 had ferritin assessed. In both trials, there was no difference between 500 and 1500 mg calcium supplementation on third-trimester haemoglobin [India: mean difference (MD) 0.01 (95% confidence intervals (CIs): -0.03, 0.04); Tanzania: MD -0.02 (95% CIs: -0.07, 0.03)], anaemia [India: relative risk (RR) 1.01 (95% CIs: 0.95, 1.07); Tanzania: RR 1.00 (95% CIs: 0.96, 1.05)], or iron deficiency anaemia [India: RR 1.20 (95% CIs: 0.93, 1.57); Tanzania: RR 0.94 (95% CIs: 0.77, 1.15)].
Conclusion: Low and high-dose calcium supplementation showed no differences in third-trimester hematologic outcomes. Future studies should assess co-administering or combining calcium and IFA into a single tablet on adherence and maternal iron status.Author's Origina
Acceptability of routine high-dose calcium supplementation during pregnancy in South India
No full textObjective: Hypertensive disorders of pregnancy (HDP) cause 10-15% of maternal deaths globally. Calcium-supplementation can prevent preeclampsia in low- and middle-income countries (LMICs) with low dietary calcium intake, but data on acceptability and adherence to high-dose supplementation (≥1000 mg/d) in public health programs is limited.
Setting: We evaluated the acceptability and adherence to routine antenatal calcium-supplementation among pregnant women and healthcare providers in urban Bangalore.
Design: An open-label study of 1000mg/d calcium-supplementation was conducted among 275 pregnant women, enrolled ≤20 weeks of gestation attending routine-antenatal-care (ANC), and followed-up until delivery. A mixed-methods approach was used to assess perception, acceptability, and factors influencing calcium-supplementation. Focus group discussions (FGDs) were conducted with pregnant women and healthcare workers.
Result: After the first-month of taking calcium, post recruitment, 13.4% reported to have disliked the calcium supplement and this decreased to 7.9% in third trimester. Overall, 157 (57.3%) had ≥75% adherence to the calcium-supplementation regimen. Disliking calcium pills at first ANC follow-up (OR:3.5, 95%; CI:1.58–7.57) or the third trimester visit (OR:7.5, 95%; CI:2.38–23.40) was significantly associated with <75% adherence to calcium-supplementation. FGDs in third trimester identified enablers such as self-perceived benefits, family, and healthcare worker support, while barriers included preference for private clinics (which did not provide free-calcium-supplements), the size and number of calcium tablets/day.
Conclusion: Achieving high adherence to calcium-supplementation was challenging during pregnancy. Interventions and strategies supporting pregnant women, while considering the roles of families and healthcare systems, should be assessed to enhance the effective implementation of calcium-supplementation during pregnancy.Author's Origina
Associations Between Socioeconomic Status Indicators, Baseline Activity and Continued Elevated Physical Activity following a 1-Week Step Challenge
No full textPhysical activity is an important dynamic of well-being. However, in 2020, the Center for Disease Control determined that only about 46.9% of adults met the recommended standards for leisure-time physical activity and nearly half as many for those below the federal poverty line. The current study investigated how socioeconomic status may be related to engagement in a short-term walking challenge and improved physical activity following the intervention. The study aimed to understand correlations between socioeconomic status and baseline step volume(Aim 1), achievement of the intervention goal of 15% increase in step volume (Aim 2). The investigation also considered who improves in terms of step volume during the intervention period/Week 2 whether or not the met their target step goal (Aim 3), and who improves in terms of step volume during the follow-up period/Week 3 above their baseline, whether or not the met their target step goal (Aim 4), and any other possible relationship between baseline steps, goal achievement and overall improvement in physical activity (Aim 5). The sample included 17 participants, recruited broadly throughout eastern Massachusetts with local recruitment through the East Bridgewater YMCA, Center for Wellness and Health Promotion at Harvard University. Results showed minimal significant relationships between any of the socioeconomic variables and intervention variables. Occupation, when coded for active vs sedentary showed a moderate correlation to intervention achievement. Additionally, the study findings confirm prior research suggesting that
those already primed for physical activity are those who are most likely to engage and benefit from physical activity and wellness interventions, with results showing a correlation between those with higher baseline step counts more likely to have higher step counts in the follow-up week and those who achieved their target goal being most likely to have higher step counts in the follow-up week. The study failed to confirm the presumed relationship between these variables and socioeconomic status. This however may be associated to the small sample size as well as possible human error in the self- report step count measures
Leveraging Border Carbon Adjustments for Climate Finance: Matching Carbon Tax Assets with Carbon Tax Liabilities
No full textThis white paper offers a policy proposal for how border carbon adjustments can increase global climate finance, with a focus on the EU Carbon Border Adjustment Mechanism (CBAM). This proposal is designed to offer a “carrot” to developing countries in the form of new funding for decarbonization, to complement the “stick” of carbon pricing introduced by CBAM. By offering a practical way forward for the CBAM to increase finance for clean energy and other carbon mitigation projects in developing countries, we hope to catalyze large volumes of new investment in the Global South, and also to re-energize support for the CBAM as a vital measure in the energy transition.
At its core, CBAM is designed to preserve the level playing field of European firms subject to the EU ETS by imposing an equivalent carbon price on foreign imports. At the same time, CBAM also has core environmental goals, aiming to encourage more countries around the world to adopt carbon pricing measures, and therefore to incentivize decarbonization.
While the positive impacts of CBAM have already begun, with several countries announcing domestic carbon pricing schemes in response to the policy, the EU has also faced significant backlash from its trading partners. Specifically, CBAM has been criticized for disproportionately affecting low- and middle-income countries, which often depend on carbon-intensive exports and may lack the financial resources to decarbonize in response to CBAM. In addition, the lack of domestic carbon pricing systems in most developing nations has left them unable to safeguard CBAM revenues through their own effective carbon price (ECPs), which firms can deduct from their CBAM dues. Critics therefore argue that CBAM risks exacerbating global inequalities, conflicting with principles such as Common but Differentiated Responsibilities.
To address these criticisms, this paper proposes expanding CBAM’s definition of an effective carbon price to account for investment in decarbonization. We suggest this could be enacted by recognizing the retirement of certified “carbon tax assets” representing emissions reductions from carbon mitigation projects such as clean energy. These “carbon tax assets” could be used by firms to match “carbon tax liabilities” arising from CBAM. Exporters to the EU could therefore reduce their CBAM bills by purchasing carbon tax assets, generating investment for decarbonization projects in the Global South.
It is crucial to note that our proposal preserves CBAM’s core objective of maintaining a competitive level playing field by denominating carbon asset deductions in monetary terms, rather than directly offsetting tons of carbon emissions. By linking CBAM deductions to the price paid for carbon assets, exporters face equivalent economic pressures to reduce emissions, avoiding risks of carbon leakage and perverse incentives towards low-quality assets. In other words, unlike previous links between carbon assets and carbon tax liabilities, for example the use of Clean Development Mechanism (CDM) credits in the EU ETS, our proposal does not simply allow a ton to offset a ton, but rather recognizes that the price paid for an offset can be considered a tax, and thus deducted as an ECP.
Mechanically, our proposal operates through two channels to support developing countries burdened by CBAM. First, the “external channel”, where exporters in developed nations purchase carbon assets from developing countries to pay their CBAM liabilities. This might be, for instance, a Japanese steel company exporting to the EU investing in a clean energy project in Mozambique. In this way, the external channel creates a new flow of external carbon finance from Global North to Global South by generating demand for carbon assets.
Second, we propose an “internal channel,” where developing nations can use our flexible definition of an ECP to retain carbon revenues and encourage green investment at home. This would allow domestic firms to offset CBAM obligations through investments in local decarbonization initiatives, for example a steel producer in Azerbaijan funding clean manufacturing and deducting its investment from its CBAM dues.
This proposal comes at a critical time both for border carbon adjustments and for climate finance. At the international level, the recent agreement on Article 6.4 methodologies at COP29 could provide a starting point to define robust eligibility standards for carbon assets. At the same time, the inclusion of border carbon adjustments as part of the COP29 agenda for the first time, within a Presidency’s Consultation to report by COP30, offers a multilateral forum to discuss how this proposal might be enacted.
For the EU, while the Article 6 methodologies establish a foundational framework for international carbon markets, there is the opportunity to “gold-plate” international standards with additional criteria on which carbon assets would count as an ECP. This gold-plating could include metrics such as additionality, permanence, transparency, social impact, and governance. This could enhance carbon market integrity and reinforce the EU’s leadership in global climate governance.
To operationalize our proposal, this white paper contains an appraisal of the next steps that will be necessary from both the EU and its trading partners. For the EU, these include issuing delegated or implementing acts under the CBAM regulation to explicitly recognize carbon mitigation assets as ECPs. As we discuss, it is also possible to directly amend the CBAM regulation via changes to Articles 2 and 9. Simultaneously, EU trading partners will need to enact national legislation governing the use of carbon assets, ensuring alignment with EU criteria. This could involve establishing registries for carbon asset certification and leveraging international standards like those defined at COP29.
Border carbon adjustments, starting with the EU CBAM, represent a huge opportunity for the energy transition, creating incentives for decarbonization and revenue for governments. But for these policies to reach their potential, equity concerns amongst developing country exporters must be addressed. Our hope is to link two great challenges for the energy transition – the need for carbon pricing and the need for climate finance – letting one create a solution for the other. Allowing carbon assets to match carbon liabilities could turn CBAM into both a carrot and a stick. This aims to present a practical and just way forward.Version of Recor
Linking regulatory variants to target genes by integrating single-cell multiome methods and genomic distance
No full textMethods that analyze single-cell paired RNA-seq and ATAC-seq multiome data have shown great promise in linking regulatory elements to genes. However, existing methods differ in their modeling assumptions and approaches to account for biological and technical noise—leading to low concordance in their linking scores—and do not capture the effects of genomic distance. We propose pgBoost, an integrative modeling framework that trains a non-linear combination of existing linking strategies (including genomic distance) on fine-mapped eQTL data to assign a probabilistic score to each candidate SNP-gene link. We applied pgBoost to single-cell multiome data from 85k cells representing 6 major immune/blood cell types. pgBoost attained higher enrichment for fine-mapped eSNP-eGene pairs (e.g. 21x at distance >10kb) than existing methods (1.2-10x; p-value for difference = 5e-13 vs. distance-based method and < 4e-35 for each other method), with larger improvements at larger distances (e.g. 35x vs. 0.89-6.6x at distance >100kb; p-value for difference < 0.002 vs. each other method). pgBoost also outperformed existing methods in enrichment for CRISPR-validated links (e.g. 4.8x vs. 1.6-4.1x at distance >10kb; p-value for difference = 0.25 vs. distance-based method and < 2e-5 for each other method), with larger improvements at larger distances (e.g. 15x vs. 1.6-2.5x at distance >100kb; p-value for difference < 0.009 for each other method). Similar improvements in enrichment were observed for links derived from Activity-By-Contact (ABC) scores and GWAS data. We further determined that restricting pgBoost to features from a focal cell type improved the identification of SNP-gene links relevant to that cell type. We highlight several examples where pgBoost linked fine-mapped GWAS variants to experimentally validated or biologically plausible target genes that were not implicated by other methods. In conclusion, a non-linear combination of linking strategies, including genomic distance, improves power to identify target genes underlying GWAS associations.Accepted Manuscrip
Synaptic connectivity mapping among thousands of neurons via parallelized intracellular recording with a microhole electrode array
No full textMassive parallelization of neuronal intracellular recording, which can measure synaptic signals across a network and thus can enable the mapping and characterization of synaptic connections, is a challenge still open in neuroscience, with the state-of-the-art limited to a mapping of ~300 synaptic connections. Here, we report a 4,096 platinum/platinum-black microhole electrode array fabricated on a complementary metal-oxide semiconductor electronic chip that substantially advances parallel intracellular recording and synaptic connectivity mapping. The microhole-neuron interface, together with current-clamp electronics in the underlying semiconductor chip, allows 90% average intracellular coupling rate with rat neuronal cultures, generating network-wide intracellular recording data that abound with synaptic signals. From these data we extract 70,000+ plausible synaptic connections amongst 2,000+ neurons, and catalogue them into inhibitory, weak/uneventful excitatory, and strong/eventful excitatory chemical synaptic connections, and electrical synaptic connections, with an estimated overall error rate of around 5%. The reported scale of synaptic connection mapping, with the ability to characterize synaptic connections, provides a step toward functional connectivity mapping of a large-scale neuronal network.Chemistry and Chemical BiologyEngineering and Applied SciencesPhysicsAccepted Manuscrip
How the Evolution of American Society Has Made the American Populace Less Likely to Survive Should Nuclear War Occur
No full textThe “end” of the Cold War along with the technological and societal changes
which occurred thereafter within the United States, especially following the terrorist
attacks of September 11, 2001 have had an undeniable impact on the likelihood that
American citizens and American society as a whole could survive nuclear attacks on the
American homeland. While the Cold War required the American populace to face the
realities of the potential for nuclear war with the Soviet Union, and potentially the
People’s Republic of China, the post-September 11th era required Americans to shift their
focus to the realities of the potential for terrorist attacks on American soil. Although this
shift in priorities seemed justified following the terrorist attacks at the turn of the
millennium and has been further justified by subsequent attacks, both in the United States
and abroad, the threat posed by nuclear weapons has not dissipated nor disappeared. With
the Russian invasion of Ukraine and Vladimir Putin’s nuclear saber rattling directed
towards the West, and the United States in particular, paired with the tensions and
conflicts in the Middle East and the reality that Iran could obtain nuclear weapons in an
alarmingly short time span, it is clear that the importance and potential threat of nuclear
weapons was not relegated to the 20th century.
The shift from being concerned about nuclear weapons to being concerned about
terrorism was justified. However, in making this transition the American populace and
government have neglected to remember the important lessons of the Cold War and the
threat that nuclear weapons will pose, for as long as they exist. Thus, it is necessary to
better understand how American society has changed since the early days of the Cold
War so that it can be understood if America is prepared to survive a nuclear conflict
should it occur. The existence of nuclear weapons denotes the possibility of nuclear war
and this is an inescapable reality of the world we live in. The nuclear taboo is simply that,
a taboo, and there is nothing guaranteeing that nuclear weapons will not be used in any
war or conflict, either ongoing or upcoming, if the participants are nuclear powers. The
threat of nuclear war has not dissipated with time, yet our readiness for such a catastrophe has
