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Climate change has rapidly altered marine ecosystems and is expected to continue to push systems and species beyond historical baselines into novel conditions. Projecting responses of organisms and populations to these novel environmental conditions often requires extrapolations beyond observed conditions, challenging the predictive limits of statistical modeling capabilities. Bioenergetics modeling provides the mechanistic basis for projecting climate change effects on marine living resources in novel conditions, has a long history of development, and has been applied widely to fish and other taxa. We provide our perspective on 4 opportunities that will advance the ability of bioenergetics-based models to depict changes in the productivity and distribution of fishes and other marine organisms, leading to more robust projections of climate impacts. These are (1) improved depiction of bioenergetics processes to derive realistic individual-level response(s) to complex changes in environmental conditions, (2) innovations in scaling individual-level bioenergetics to project responses at the population and food web levels, (3) more realistic coupling between spatial dynamics and bioenergetics to better represent the local- to regional-scale differences in the effects of climate change on the spatial distributions of organisms, and (4) innovations in model validation to ensure that the next generation of bioenergetics-based models can be used with known and sufficient confidence. Our focus on specific opportunities will enable critical advancements in bioenergetics modeling and position the modeling community to make more accurate and robust projections of the effects of climate change on individuals, populations, food webs, and ecosystems.

Results from a fully coupled end-to-end ecosystem model for the California Current Large Marine Ecosystem are used to describe the impact of environmental variability and prey availability on the foraging ecology of its most abundant apex predator, the California sea lion Zalophus californianus. The ecosystem model consists of a biogeochemical submodel embedded in a regional ocean circulation submodel, both coupled with a multi-species individual-based submodel for forage fish (sardine and anchovy) and California sea lions. Sardine and anchovy are explicitly represented in the model as they are commonly found in the diet of sea lions and exhibit significant interannual and decadal variability in population abundances that reflect variations in their environment and lower trophic level prey. Output from a 20 yr run (1989-2008) of the model demonstrates how different physical and biological processes control habitat utilization and foraging success of California sea lions on interannual time scales, with the dominant modes of variability linked to sardine abundance and coastal upwelling intensity. The results also illustrate how variability in environmental conditions, forage fish distribution, and prey assemblage affect sea lion feeding success. While specifically focusing on the foraging ecology of sea lions, the modeling framework has the ability to provide a more complete understanding of the physical and biological mechanisms impacting trophic interactions in the California Current, or other regions where similar fully coupled ecosystem models may be implemented.

Advances in computing technology, new and ongoing restoration initiatives, concerns about climate change's effects, and the increasing interdisciplinarity of research have encouraged the development of landscape-scale mechanistic models of coupled ecological-geophysical systems. However, communication barriers and uneven infiltration of new strategies for data-driven induction persist in the context of simulation model development across disciplines. One challenge is that ecology and the geosciences have embraced different modeling epistemologies, with ecologists historically favoring inductive inference from generalized, phenomenological models and geoscientists favoring deductive inference from detailed first-principles models. Today, many models used for environmental management, particularly for aquatic ecosystems, tend to be highly detailed, with ecological and geophysical components represented in different modules that are linked but often not closely integrated. These observations highlight a need for cross-disciplinary dialogue about landscape-scale modeling objectives and approaches. The philosophies of pattern-oriented modeling in ecology and exploratory modeling in geophysics have yielded advances in theoretical and applied knowledge in both of those disciplines, but they are not comprehensive across all aspects of landscape-scale modeling. Here we define and synthesize the “Appropriate-Complexity Method” (ACME), which builds upon these two philosophies to guide the development of process-oriented models across a spectrum of scientific and management objectives. ACME helps modelers efficiently converge upon an optimal modeling structure through: i) systematic evaluation of the attributes that comprise computational and representational detail, for which we have developed an operational decision tree; ii) iterative adjustment of models based on pattern-oriented model evaluation strategies; and iii) the use of appropriate datasets (where applicable) to build conceptual models and formulate predictions. Decisions about aspects of computational and representational detail are based on the landscape's emergent properties. They are also based on a hierarchy of classes of questions governing model objectives that represent a multi-attribute tradeoff among validation potential, interpretability, tractability, and generality as functions of computational and representational detail. Tradeoff curves, together with model objectives, provide further guidance for determining the “appropriate” level of complexity for representation of processes in models. Once deemed adequate for addressing the original research question of interest, models may be used for projection and scenario testing. They may next undergo expansion that moves them down the hierarchy, where they can then be used to address research questions of higher specificity, detail, and validation potential, though at a cost of lower tractability and interpretability on the tradeoff curves. This practical, systematic procedure provides clear guidance for the design and improvement of landscape models that may be used to address a wide variety of questions relevant to restoration, over a spectrum of scales.

Abstract Background Firearm purchasing records offer a potentially important administrative data source to identify individuals at elevated risk of perpetrating firearm violence. In this study, we describe individual, firearm, and transaction characteristics of purchasers in California who were arrested for a firearm-related violent crime (FRV) as compared to the general population of registered purchasers in the state. Methods Relying on a dataset of all individuals with transaction records in California (1996–2021), linked to criminal records (1980–2021), we enrolled a cohort of individuals for whom we could capture the legal firearm purchase history. We identified those arrested for FRV post purchase, and using incidence density sampling, gender-matched cases to ten purchasers (controls) who remained “at risk” at the time the case was arrested. We focused on the purchase closest in time prior to the arrest (“index” purchase). We implemented conditional logistic regression and included models with controls for individual- and community-level demographics, as well as interactions between firearm and purchasing characteristics and criminal history. Results The cohort included 1,212,144 individuals, of whom 6153 were arrested for FRV (0.5%). Cases were matched to 61,530 controls to form the study sample. The largest risk factor was a prior criminal history: purchasers had 5.84 times the risk of FRV if they had a prior arrest within three years of the index purchase (CI 5.44–6.27). Several transaction and firearm characteristics were also associated with FRV. For example, risk increased if the firearm was redeemed at a pawn shop (aIRR: 1.37, CI 1.05–1.77) and decreased if the transaction was a registered private party transfer (vs. retail purchase) (aIRR: 0.83, CI 0.76–0.90) or the firearm was a bolt action firearm (vs. semi-automatic) (aIRR: 0.64, CI 0.51–0.79). In the interaction models, most of the purchase and firearm features only remained significant among those with no criminal history. Conclusions Given limited data on firearm transactions, there has been little research on whether the type of firearm an individual purchases or the nature of the purchase might serve as indicators of risk for FRV. We found several transaction and firearm features were associated with risk of FRV. Notably, these features provided little evidence of additional risk for those with a prior criminal record.

Purpose: The purpose of this study was to develop a predictive model to evaluate pretreatment patient-specific quality assurance (QA) based on treatment planning parameters for stereotactic body radiation therapy (SBRT) for liver carcinoma. Materials and Methods: We retrospectively selected 180 cases of liver SBRT treated using the volumetric modulated arc therapy technique. Numerous parameters defining the plan complexity were calculated from the DICOM-RP (Radiotherapy Plan) file using an in-house program developed in MATLAB. Patient-specific QA was performed with global gamma evaluation criteria of 2%/2 mm and 3%/3 mm in a relative mode using the Octavius two-dimensional detector array. Various statistical tests and multivariate predictive models were evaluated. Results: The leaf speed (MILS) and planning target volume size showed the highest correlation with the gamma criteria of 2%/2 mm and 3%/3 mm (P < 0.05). Degree of modulation (DoM), MCSSPORT, leaf speed (MILS), and gantry speed (MIGS) were predictors of global gamma pass rate (GPR) for 2%/2 mm (G22), whereas DoM, MCSSPORT, leaf speed (MILS) and robust decision making were predictors of the global GPR criterion of 3%/3 mm (G33). The variance inflation factor values of all predictors were

Pelargonium quercifolium is an aromatic herb with a strong resinous scent. It is used traditionally to treat heart disease, hypertension, stress, rheumatism, combat hidden hunger, and inhibit HIV-1. The present study aimed to evaluate the toxicity, anti-HIV, antioxidant nutrients and anticancer potentials of the ethanol extract of P. quercifolium. In this study, high-resolution ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), high-performance liquid chromatography with diode-array detection (HPLC-D AD), xCELLigence real-time cell analyser single plate (RTCA-SP), MTT assays and luciferase-based assay were employed to elucidate the phytochemicals, cytotoxicity, anti-HIV, antioxidant nutrients and anticancer metabolites in P. quercifolium. Results show that the characterized metabolites in P. quercifolium most of which were flavonoids, phenolic derivatives, alkaloids and coumarins could arrest cancer cell proliferation and inhibit HIV infection given the high level of cytotoxicity of the tested plant extract. It was also observed and reported for the first time, the nutrient profile of P. quercifolium is higher than most vegetables consumed as a staple food. This study underpins the potential of using anticancer and antiviral metabolites from leaf extract of P. quercifolium as a pharmacological option.

Cow's milk allergy (CMA) is one of the most common presentations of food allergy in early childhood. Management of CMA involves individualized avoidance of cow's milk and other mammalian milk and foods containing these. Optimal elimination of cow's milk avoidance includes: label reading; information about safe and nutritious substitute foods; appropriate choice of infant formula or a plant-based food; establishing tolerance to baked milk and monitoring nutritional intake and growth. Substitute formulas are divided into soy formula (not hydrolyzed), milk-based extensively hydrolyzed formulas, rice based extensive, and partially hydrolyzed formulas and amino acid-based formulas. The use of other mammalian milks is not recommended for the management of cow's milk allergy due to a high level of cross-reactivity and nutritional concerns. For toddlers who are eating well, children, and adults, a suitable plant-based beverage may be a suitable alternative to a specialized formula, following careful nutritional considerations. Families need to be instructed on finding suitable nutritious foods and how to prepare suitable meals at home. Individuals with CMA also need to know how to identify and treat acute severe reactions.

The article looks at global, regional, national and local dimensions in a diverse setting of the interplay of governmental, university and civil society partners. Higher education (HE) is called to support the recent discussions on the importance of adult learning and education (ALE) within lifelong learning. Therefore, during the Adult Education Academy (AEA) on international and comparative studies which met in 2024 at University of Würzburg for the 11th year as a study opportunity for PhD and Master students as well as practitioners, the authors agreed to contribute this paper to examine thematic areas related to global policy recommendations that strengthen the relationship between HE and ALE in different forms. Findings should lead to a better understanding of ALE enabling the acquisition of skills for personal fulfilment and social enlightenment. Le istituzioni di Higher education promuovono l’apprendimento e l’educazione degli adulti: esempi, esperienze, aspettative. L’articolo esamina le dimensioni globale, regionale, nazionale e locale in un contesto diversificato di interazione tra partner governativi, universitari e della società civile. L’HE è chiamata a supportare il recente dibattito sull’importanza dell’apprendimento e dell’educazione degli adulti (EA). Pertanto, durante l’Adult Education Academy (AEA) sugli studi internazionali e comparativi, riunitasi nel 2024 all’Università di Wurzburg come opportunità di studio per dottorandi, studenti e professionisti, gli autori hanno concordato di contribuire alla stesura di questo articolo con la finalità di esaminare temi relativi alle raccomandazioni delle politiche globali che rafforzano il rapporto tra HE e AE. I risultati dovrebbero portare a un migliore riconoscimento dell’AE come mezzo per l’acquisizione di competenze utili alla realizzazione personale e alla crescita sociale.

Background: The rising incidence of cancer is a major concern globally being a leading cause of early mortality in most countries. This burden is projected to increase to 28.4 million cases worldwide by 2040 and yet, may be worsened by continuous exposure to risk factors due to a sheer shift from consumption of natural nutrients. To reverse this trend, it is imperative to source novel anticancer metabolites from plants that could minimize carcinogenic effects by suppressing the proliferation and survival of cancer cells. Purpose: This study aimed at characterizing and quantifying index anticancer and antioxidant metabolites, in the cultivars of T. portulacastrum. Methods: The Ultra-High Performance Liquid Chromatography Mass Spectroscopy (UHP-LCMS) was used to quantify and characterize index anticancer and antioxidant metabolites in shoot, root and whole plant extracts of Trianthema portulacastrum (T01,T02,T03,T04,T05,T06). The biological activity of the tested samples was monitored on the xCELLigence Real Time Cell Analyzer to determine the cytotoxicity of the extracts as a function of cell index at a specific time post dose using the concentration range of 0.16–2.5 %. Results: Based on the responses observed 48 h post exposure, all extracts showed high levels of cytotoxicity as determined by the xCELLigence apart from the root extracts. Rapid decreases in cell index (CI) values observed at higher extract percentages are highly indicative of cell death. These biological activities may be attributed to different anticancer metabolites such as epigallocatechin, glucaric acids, byakangelicin, xanthotoxin, apaensin, acetoxy-6-gingerol among other compounds of significant therapeutic benefits that were quantified with UHP-LCMS. Conclusion: These findings suggest that T. portulacastrum contains diverse anticancer metabolites which could be leveraged to develop plant-based anticancer drugs or novel chemicals with extended therapeutic utility.

Background: Cow's milk allergy (CMA) is the most common food allergy in infants. The replacement with specialized formulas is an established clinical approach to ensure adequate growth and minimize the risk of severe allergic reactions when breastfeeding is not possible. Still, given the availability of multiple options, such as extensively hydrolyzed cow's milk protein formula (eHF-CM), amino acid formula (AAF), hydrolyzed rice formula (HRF) and soy formulas (SF), there is some uncertainty as to the most suitable choice with respect to health outcomes. Furthermore, the addition of probiotics to a formula has been proposed as a potential approach to maximize benefit. Objective: These evidence-based guidelines from the World Allergy Organization (WAO) intend to support patients, clinicians, and others in decisions about the use of milk specialized formulas, with and without probiotics, for individuals with CMA. Methods: WAO formed a multidisciplinary guideline panel balanced to include the views of all stakeholders and to minimize potential biases from competing interests. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to review by stakeholders. Results: After reviewing the summarized evidence and thoroughly discussing the different management options, the WAO guideline panel suggests: a) using an extensively hydrolyzed (cow's milk) formula or a hydrolyzed rice formula as the first option for managing infants with immunoglobulin E (IgE) and non-IgE-mediated CMA who are not being breastfed. An amino-acid formula or a soy formula could be regarded as second and third options respectively; b) using either a formula without a probiotic or a casein-based extensively hydrolyzed formula containing Lacticaseibacillus rhamnosus GG (LGG) for infants with either IgE or non-IgE-mediated CMA.The issued recommendations are labeled as “conditional” following the GRADE approach due to the very low certainty about the health effects based on the available evidence. Conclusions: If breastfeeding is not available, clinicians, patients, and their family members might want to discuss all the potential desirable and undesirable consequences of each formula in infants with CMA, integrating them with the patients' and caregivers’ values and preferences, local availability, and cost, before deciding on a treatment option. We also suggest what research is needed to determine with greater certainty which formulas are likely to be the most beneficial, cost-effective, and equitable.

The expected progress in SARS-CoV-2 vaccinations, as anticipated in 2020 and 2021, has fallen short, exacerbating global disparities due to a lack of universally recognized “safe and effective” vaccines. This study focuses on extracts of South African medicinal plants, Artemisia annua and Artemisia afra, to identify metabolomic bioactive compounds inhibiting the binding of the SARS-CoV-2 spike protein to ACE2 receptors. The extracts were monitored for cytotoxicity using a resazurin cell viability assay and xCELLigence real-time cell analyzer. Chemical profiling was performed using UPLC-MS/MS, orthogonal projection to latent structures (OPLS), and evaluated using principle component analysis (PCA) models. Identified bioactive compounds were subjected to in vitro SARS-CoV-2 enzyme inhibition assay using standard methods and docked into the spike (S) glycoprotein of SARS-CoV-2 using Schrodinger® suite followed by molecular dynamics simulation studies. Cell viability assays revealed non-toxic effects of extracts on HEK293T cells at lower concentrations. Chemical profiling identified 81 bioactive compounds, with compounds like 6″-O-acetylglycitin, 25-hydroxyvitamin D3-26,23-lactone, and sesaminol glucoside showing promising binding affinity. Molecular dynamics simulations suggested less stable binding, but in vitro studies demonstrated the ability of these compounds to interfere with SARS-CoV-2 spike protein’s binding to the human ACE2 receptor. Sesaminol glucoside emerged as the most effective inhibitor against this interaction. This study emphasizes the importance of multiplatform metabolite profiling and chemometrics to understand plant extract composition. This finding is of immense significance in terms of unravelling metabolomics bioactive compounds inhibiting the binding of the SARS-CoV-2 spike protein to ACE2 receptors and holds promise for phytotherapeutics against SARS-CoV-2.

AbstractThis formative study was undertaken between June 2020 and April 2021 to provide evidence to inform the design and delivery of comprehensive sexuality education (CSE) in Malawi for young people living with HIV (YPLHIV) and young people with disabilities (YPWD). The study included a desk review of the situation of these two groups and a mapping of CSE programmes and delivery approaches in Malawi. The study findings show that YPWD and YPLHIV in Malawi are marginalised groups, face stigma and discrimination, and are more vulnerable to abuse, warranting CSE that addresses their needs. Yet, they are often left out of sexuality education such as school-based programmes (due to early school drop-outs) and out-of-school programmes, as well as traditional modes. Furthermore, in instances where they have access to sexuality education, there is little evidence to suggest that the sexuality education that they receive is designed to address their needs, thus raising questions about its relevance. There is need for tailored CSE that addresses the needs of these groups and that is delivered using an approach that is easily accessible to them.

Abstract The acidification of water in mining areas is a global environmental issue primarily catalyzed by sulfur-oxidizing bacteria (SOB). Little is known about microbial sulfur cycling in circumneutral pH mine tailing impoundment waters. Here we investigate biological sulfur oxidation over four years in a mine tailings impoundment water cap, integrating aqueous sulfur geochemistry, genome-resolved metagenomics and metatranscriptomics. The microbial community is consistently dominated by neutrophilic, chemolithoautotrophic SOB (relative abundances of ~76% in 2015, ~55% in 2016/2017 and ~60% in 2018). Results reveal two SOB strategies alternately dominate across the four years, influencing acid generation and sulfur speciation. Under oxic conditions, novel Halothiobacillus drive lower pH conditions (as low as 4.3) and lower [S2O3 2−] via the complete Sox pathway coupled to O2. Under anoxic conditions, Thiobacillus spp. dominate in activity, via the incomplete Sox and rDSR pathways coupled to NO3 −, resulting in higher [S2O3 2−] and no net significant acidity generation. This study provides genomic evidence explaining acidity generation and thiosulfate accumulation patterns in a circumneutral mine tailing impoundment and has significant environmental applications in preventing the discharge of sulfur compounds that can impact downstream environments. These insights illuminate opportunities for in situ biotreatment of reduced sulfur compounds and prediction of acidification events using gene-based monitoring and in situ RNA detection.

Cow's milk allergy is rare in exclusively breastfed infants. To support the continuation of breastfeeding an infant after diagnosis with a cow's milk allergy, it is critical to examine the evidence for and against any form of cow's milk elimination diet for lactating mothers. In this narrative review, we highlight the lack of high-quality evidence, hence subsequent controversy, regarding whether the minuscule quantities of cow's milk proteins detectable in human milk cause infant cow's milk allergy symptoms. Current clinical practice recommendations advise a 2–4 week trial of maternal cow's milk dietary elimination for: a) IgE-mediated cow's milk allergy only if the infant is symptomatic on breastfeeding alone; b) non-IgE-mediated associated symptoms only if the history and examination strongly suggest cow's milk allergy; and c) infants with moderate to severe eczema/atopic dermatitis, unresponsive to topical steroids and sensitized to cow's milk protein. There should be a clear plan for home reintroduction of cow's milk into the maternal diet for a period of 1 week to determine that the cow's milk elimination is responsible for resolution of symptoms, and then subsequent reoccurrence of infant symptoms upon maternal cow's milk reintroduction. The evidence base to support the use of maternal cow's milk avoidance for the treatment of a breastfed infant with cow's milk allergy is of limited strength due to a lack of high-quality, adequately powered, randomised controlled trials. It is important to consider the consequences of maternal cow's milk avoidance on reducing immune enhancing factors in breast milk, as well as the potential nutritional and quality of life impacts on the mother. Referral to a dietitian is advised for dietary education, along with calcium and vitamin D supplementation according to local recommendations, and a maternal substitute milk should be advised. However, for most breastfed infants with cow's milk allergy maternal cow's milk dietary elimination will not be required, and active support of the mother to continue breastfeeding is essential.

Easy-to-use libraries such as scikit-learn have accelerated the adoption and application of machine learning (ML) workflows and data-driven methods. While many of the algorithms implemented in these libraries originated in specific scientific fields, they have gained in popularity in part because of their generalisability across multiple domains. Over the past two decades, researchers in the chemical and materials science community have put forward general-purpose machine learning methods. The deployment of these methods into workflows of other domains, however, is often burdensome due to the entanglement with domain-specific functionalities. We present the python library scikit-matter that targets domain-agnostic implementations of methods developed in the computational chemical and materials science community, following the scikit-learn API and coding guidelines to promote usability and interoperability with existing workflows.

BackgroundUganda has a draft National Health Insurance Bill for the establishment of a National Health Insurance Scheme (NHIS). The proposed health insurance scheme is to pool resources, where the rich will subsidize the treatment of the poor, the healthy will subsidize the treatment of the sick, and the young will subsidize the treatment of the elderly. However, there is still a lack of evidence on how the existing community-based health insurance schemes (CBHIS) can fit within the proposed national scheme. Thus, this study aimed at determining the feasibility of integrating the existing community-based health financing schemes into the proposed National Health Insurance Scheme.MethodsIn this study, we utilized a multiple-case study design involving mixed methods. The cases (i.e., units of analysis) were defined as the operations, functionality, and sustainability of the three typologies of community-based insurance schemes: provider-managed, community-managed, and third party-managed. The study combined various data collection methods, including interviews, survey desk review of documents, observation, and archives.FindingsThe CBHIS in Uganda are fragmented with limited coverage. Only 28 schemes existed, which covered a total of 155,057 beneficiaries with an average of 5,538 per scheme. The CBHIS existed in 33 out of 146 districts in Uganda. The average contribution per capita was estimated at Uganda Shillings (UGX) 75,215 = equivalent to United States Dollar (USD) 20.3, accounting for 37% of the national total health expenditure per capita UGX 51.00 = at 2016 prices. Membership was open to everyone irrespective of socio-demographic status. The schemes had inadequate capacity for management, strategic planning, and finances and lacked reserves and reinsurance. The CBHIS structures included promoters, the scheme core, and the community grass-root structures.ConclusionThe results demonstrate the possibility and provide a pathway to integrating CBHIS into the proposed NHIS. We however recommend implementation in a phased manner including first providing technical assistance to the existing CBHIS at the district level to address the critical capacity gaps. This would be followed by integrating all three elements of CBHIS structures. The last phase would then involve establishing a single fund for both the formal and informal sectors managed at the national level.

Background: Development assistance for health (DAH) is an important mechanism for funding and technical support to low-income countries. Despite increased DAH spending, intractable health challenges remain. Recent decades have seen numerous efforts to reform DAH models, yet pernicious challenges persist amidst structural complexities and a growing number of actors. Systems-based approaches are promising for understanding these types of complex adaptive systems. This paper presents a systems-based understanding of DAH, including barriers to achieving sustainable and effective country-driven models for technical assistance and capacity strengthening to achieve better outcomes Methods: We applied an innovative systems-based approach to explore and map how donor structures, processes, and norms pose challenges to improving development assistance models. The system mapping was carried out through an iterative co-creation process including a series of discussions and workshops with diverse stakeholders across 13 countries. Results: Nine systemic challenges emerged: 1) reliance on external implementing partners undermines national capacity; 2) prioritizing global initiatives undercuts local programming; 3) inadequate contextualization hampers program sustainability; 4) decision-maker blind spots inhibit capacity to address inequities; 5) power asymmetries undermine local decision making; 6) donor funding structures pose limitations downstream; 7) program fragmentation impedes long-term country planning; 8) reliance on incomplete data perpetuates inequities; and 9) overemphasis on donor-prioritized data perpetuates fragmentation. Conclusions: These interconnected challenges illustrate interdependencies and feedback loops manifesting throughout the system. A particular driving force across these system barriers is the influence of power asymmetries between actors. The articulation of these challenges can help stakeholders overcome biases about the efficacy of the system and their role in perpetuating the issues. These findings indicate that change is needed not only in how we design and implement global health programs, but in how system actors interact. This requires co-creating solutions that shift the structures, norms, and mindsets governing DAH models.

Background: Allergy to cow's milk is the most common food allergy in infants and it is usually outgrown by 5 years of age. In some individuals it persists beyond early childhood. Oral immunotherapy (OIT, oral desensitization, specific oral tolerance induction) has been proposed as a promising therapeutic strategy for persistent IgE-mediated cow's milk allergy. We previously published the systematic review of OIT for cow's milk allergy (CMA) in 2010 as part of the World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines. Objective: To systematically synthesize the currently available evidence about OIT for IgE-mediated CMA and to inform the updated 2022 WAO guidelines. Methods: We searched the electronic databases including PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and the websites of selected allergy organizations. We included all studies irrespective of the language of the original publication. The last search was conducted in February 2021. We registered the protocol on Open Science Framework (10.17605/OSF.IO/AH2DT). Results: We identified 2147 unique records published between 2010 and 2021, including 13 randomized trials and 109 observational studies addressing cow's milk OIT. We found low-certainty evidence that OIT with unheated cow's milk, compared to elimination diet alone, increased the likelihood of being able to consume ≥150 ml of cow's milk in controlled settings (risk ratio (RR): 12.3, 95% CI: 5.9 to 26.0; risk difference (RD): 25 more per 100, 95% CI 11 to 56) as well as accidently ingest a small amount (≥5 ml) of cow's milk (RR: 8.7, 95% CI: 4.7 to 16.1; RD: 25 more per 100, 95% CI 12 to 50). However, 2–8 weeks after discontinuation of a successful OIT, tolerance of cow's milk persisted in only 36% (range: 20%–91%) of patients. OIT increased the frequency of anaphylaxis (rate ratio: 60.0, 95% CI 15 to 244; rate difference 5 more anaphylactic reactions per 1 person per year, 95% CI: 4 to 6; moderate evidence) and the frequency of epinephrine use (rate ratio: 35.2, 95% CI: 9 to 136.5; rate difference 268 more events per 100 person-years, 95% CI: 203 to 333; high certainty). OIT also increased the risk of gastrointestinal symptoms (RR 6.9, 95% CI 1.6–30.9; RD 28 more per 100, CI 3 to 100) and respiratory symptoms (RR 49.0, 95% CI 3.12–770.6; RD 77 more per 100, CI 62 to 92), compared with avoidance diet alone. Single-arm observational studies showed that on average 6.9% of OIT patients (95% CI: 3.8%–10%) developed eosinophilic esophagitis (very low certainty evidence). We found 1 trial and 2 small case series of OIT with baked milk. Conclusions: Moderate certainty evidence shows that OIT with unheated cow's milk in patients with IgE-mediated CMA is associated with an increased probability of being able to drink milk and, at the same time, an increased risk of serious adverse effects.