Hill Criteria Research Articles

How Follow-Up Period in Prospective Cohort Studies Affects Relationship Between Baseline Serum 25(OH)D Concentration and Risk of Stroke and Major Cardiovascular Events.

Background/Objectives: Prospective cohort studies are useful for studying how biomolecular status affects risk of adverse health outcomes. Less well known is that the longer the follow-up time, the lower the association (or "apparent effect") due to "regression dilution". Here, we evaluate how follow-up interval from baseline to "event" affects the relationship between baseline serum 25-hydroxyvitamin D [25(OH)D] concentration and the later incidence of stroke and major cardiovascular events (MACEs). Methods: Findings for the relative risk (RR) of stroke and MACEs with respect to serum 25(OH)D concentrations at baseline from prospective cohort studies were plotted against mean follow-up time. Fifteen studies from mainly European countries and the United States were used for stroke and nine studies for MACEs. Linear regression analyses were used to study data for follow-up periods of up to 10 years and for more than 10 years. Results: For stroke, the linear regression fit for 1-10 years is RR = 0.34 + (0.065 × follow-up [years]), r = 0.84, adjusted r2 = 0.67, p < 0.001. No significant variations in association were found for studies with follow-up periods of 10-20 years. For MACEs, the linear fit for 1-8.1 years is RR = 0.61 + (0.055 × follow-up [years]), r = 0.81, adjusted r2 = 0.59, p = 0.03. Discussion: The shorter the follow-up period, the greater the apparent effect of better vitamin D status in reducing risk of stroke and MACEs. In addition, the apparent effect of higher 25(OH)D concentration found for the shortest follow-up time is more than twice as great as the estimate based on average follow-up intervals for all studies. Mechanisms have been found to explain how higher serum 25(OH)D concentrations could reduce risk of stroke and MACEs. Randomized controlled trials have not shown that vitamin D supplementation significantly reduces risk of either stroke or MACEs, probably because risk of both outcomes increases rapidly below 15 ng/mL (38 nmol/L) and it is difficult in Western developed countries to enroll enough participants with concentrations that low. Nonetheless, vitamin D's role in reducing risk of stroke and MACEs could be considered causal on the basis of an evaluation of the evidence using Hill's criteria for causality in a biological system. Conclusions: Serum 25(OH)D concentrations above 20 ng/mL are associated with significantly reduced risk of stroke and MACEs prospectively and in an apparent causal manner. Raising serum 25(OH)D concentrations to >20 ng/mL should, therefore, be recommended for everyone likely to be at risk for stroke or MACEs and indeed in the general population.

AOP report: Development of an adverse outcome pathway for deposition of energy leading to abnormal vascular remodeling.

Cardiovascular diseases (CVDs) are complex, encompassing many types of heart pathophysiologies and associated etiologies. Radiotherapy studieshave shown that fractionated radiation exposure at high doses (3-17 Gy) to the heart increases the incidence of CVD. However, the effects of low doses of radiation on the cardiovascular system or the effects from space travel, where radiation and microgravity are important contributors to damage, are not clearly understood. Herein, the adverse outcome pathway (AOP) framework was applied to develop an AOP to abnormal vascular remodeling from the deposition of energy. Following the creation of a preliminary pathway with the guidance of field experts and authoritative reviews, a scoping review was conducted that informed final key event (KE) selection and evaluation of the Bradford Hill criteria for the KE relationships (KERs). The AOP begins with a molecular initiating event of deposition of energy; ionization events increase oxidative stress, which when persistent concurrently causes the release of pro-inflammatory mediators, suppresses anti-inflammatory mechanisms and alters stress response signaling pathways. These KEs alter nitric oxide levels leading to endothelial dysfunction, and subsequent abnormal vascular remodeling (the adverse outcome). The work identifies evidence needed to strengthen understanding of the causal associations for the KERs, emphasizing where there are knowledge gaps and uncertainties in both qualitative and quantitative understanding. The AOP is anticipated to direct future research to better understand the effects of space on the human body and potentially develop countermeasures to better protect future space travelers.

AOP Report: Development of an adverse outcome pathway for deposition of energy leading to bone loss.

Bone loss, commonly seen in osteoporosis, is a condition that entails a progressive decline of bone mineral density and microarchitecture, often seen in post-menopausal women. Bone loss has also been widely reported in astronauts exposed to a plethora of stressors and in patients with osteoporosis following radiotherapy for cancer. Studies on mechanisms are well documented but the causal connectivity of events to bone loss development remains incompletely understood. Herein, the adverse outcome pathway (AOP) framework was used to organize data and develop a qualitative AOP beginning from deposition of energy (the molecular initiating event) to bone loss (the adverse outcome). This qualitative AOP was developed in collaboration with bone loss research experts to aggregate relevant findings, supporting ongoing efforts to understand and mitigate human system risks associated with radiation exposures. A literature review was conducted to compile and evaluate the state of knowledge based on the modified Bradford Hill criteria. Following review of 2029 studies, an empirically supported AOP was developed, showing the progression to bone loss through many factors affecting the activities of bone-forming osteoblasts and bone-resorbing osteoclasts. The structural, functional, and quantitative basis of each proposed relationship was defined, for inference of causal changes between key events. Current knowledge and its gaps relating to dose-, time- and incidence-concordance across the key events were identified, as well as modulating factors that influence linkages. The new priorities for research informed by the AOP highlight areas for improvement to enable development of a quantitative AOP used to support risk assessment strategies for space travel or cancer radiotherapy.

Anisotropic formability and deformation mechanism of near-α titanium alloy sheet under continuous nonlinear strain paths at high temperature

In the present study, the anisotropic formability and underlying deformation mechanism of near-α TA32 titanium alloy sheet under continuous nonlinear strain paths (CNSPs) at high temperature were investigated in depth. To achieve this goal, a new experimental method combining hot gas bulging with step-combined dies was proposed, and the hot CNSPs of metal sheets can be flexibly and conveniently realized by changing the number and shape of step-combined dies. Based on this method, the anisotropic deformation behavior and forming limits of TA32 sheet under fifteen CNSPs were tested at 800 ℃ with a strain rate of 0.001 s−1. Then, two advanced constitutive models with different scales were embedded into the classical Marciniak-Kuczyński (M-K) theory to predict the forming limits of TA32 sheet under different strain paths: the macro-scale viscoplastic model coupled with Hill48 yield criterion and non-associated flow rule (NAFR) as well as the meso-scale three-dimensional crystal plasticity finite element (CPFE) model coupled with cellular automata (CA). The results demonstrate that the CPFE-CA-MK coupled model exhibits higher accuracy in predicting the forming limits of TA32 sheet under linear and continuous nonlinear strain paths. Especially for the tension-tension strain paths, the CPFE-CA-MK coupled model improves accuracy by at least 3.1 % compared to macro-scale models. Due to the material anisotropy, the initial inclination angle of the groove in the CPFE-CA-MK model is closely related to the strain path and significantly affects the prediction accuracy. Based on the CPFE simulation, the effects of anisotropy and strain path change on the dislocation slip mode of different texture components was analyzed in depth, which provides a theoretical guidance for the optimization of hot forming process of TA32 titanium alloy complex components.

First Failure Load of Rectangular Laminated and Sandwich Plates Using Isogeometric Analysis

This paper investigates the first failure load of simply supported and clamped laminate and sandwich plates loaded by a distributed normal traction on the top surface. A third-order shear and normal deformable plate theory, the isogeometric basis functions, and five failure criteria, namely, the maximum stress, the Tsai–Wu, the Tsai–Hill, the Hoffman, and the Hashin for laminated plates, and only the Tsai–Hill criterion for sandwich plates are used in this study. Of these, Hashin’s criteria distinguish between the fiber and the matrix failure. The in-plane stresses are found from the plate displacements and Hooke’s law, and the transverse stresses are recovered by integrating the equilibrium equations through the thickness. Effects of the plate aspect ratio, the fiber angle, the face sheet materials, and the core materials on the first failure load are identified. The computed results are found to agree well with those reported in the literature. Whereas the five failure criteria for laminated plates predict nearly the same value of the first failure load, they do not provide the same location of the failure initiation.

Towards improved description of plastic anisotropy in sheet metals under biaxial loading: A novel generalization of Hill48 yield criterion

Lightweight design and development of automobiles are strongly dependent on lightweight high-strength sheet metals. An accurate prediction of anisotropy and yield surface evolution of these materials under different sampling directions of biaxial tension (BT) is a necessary condition for the numerical analyses of stamping forming. In this work, the Hill48 model considering the principal stress direction is generalized to describe the anisotropic evolution and the yield loci on the normal and diagonal planes. The material parameters of the generalized M-Hill48 model (GM-Hill48) have analytical form and can be calibrated by the yield stresses and r-values expressed by the continuous equivalent plastic strain (EPS). A quadratic function interpolation method based on the near-plane strain (NPS) stress is established to control the yield locus under different plane stress states. In addition, a method for predicting the yield loci in arbitrary sampling directions under BT is proposed by tensor coordinate transformation. Different from the traditional model which can only determine material parameters by using equi-biaxial tension (EBT) or NPS stress along the rolling direction (RD) and transverse direction (TD), the yield stresses of BT in different sampling directions can be incorporated into the generalized model. The predictive capability of the GM-Hill48 model is verified by capturing the continuous evolution of yield stresses and strain for DP590 and AA6016-T4 materials. The convexity condition of the established modified model is given and discussed. Finally, the advantages of new model are further expounded in terms of the prediction accuracy and identified parameters compared with the advanced yield models.

Maternal modifiable factors and risk of congenital heart defects: systematic review and causality assessment

ObjectivePrimary prevention strategies are critical to reduce the global burden of congenital heart defects (CHDs); this requires robust knowledge of causal agents. We aimed to review associations between CHDs and...

New insights into the paradox between smoking and the risk of SARS-CoV-2 infection (COVID-19): Insufficient evidence for a causal association.

Previous studies have reported a 'smoker's paradox', where people who smoke appear to be protected against Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) infection (COVID-19). This conflicts with well-established evidence that people who smoke are generally more vulnerable to respiratory infections. In this study, we aimed to validate the association between smoking and SARS-CoV-2 infection in a general Dutch population, and to evaluate the evidence underlying the possible causal relationship between smoking and SARS-CoV-2 infection by applying a modern adaptation of the Bradford Hill criteria. In total, 57,833 participants from the Lifelines Cohort Study were included in the analysis. Smoking status, including never smoker, current smoker, and former smoker, was derived from the Lifelines general assessment between 2014 and 2017, while SARS-CoV-2 infection status was derived from an additional COVID-19 questionnaire from 2021 to 2022. Logistic regressions were used for the association between smoking status and infection status. The adapted Bradford Hill's criteria, including the strength of association (including an analysis of plausible confounding), plausibility, temporality and study design suitability, were applied to evaluate the existing literature. We found, compared with never smokers, an increased risk of SARS-CoV-2 infection for former smokers (odds ratio (OR)=1.07, 95% confidence interval (CI)=1.01-1.13), but a reduced risk for current smokers (OR=0.85, 95% CI=0.79-0.92), after adjusting for several relevant covariates. However, we discerned a possible explanation of the smoker's paradox since we observed that current smokers were more likely to be non-responders to the COVID-19 questions and, more importantly, these non-responders were more likely to have other established risk factors for SARS-CoV-2 infection. There is insufficient evidence to suggest that smoking protects against SARS-CoV-2 infection. According to the adapted Bradford Hill's criteria, we observed a high inconsistency between study results, a high possibility for residual confounding and no clear evidence for biological plausibility. Future studies should include linkage with the confirmed testing results from national healthcare registries to mitigate avoidable bias.

Numerical Analysis of Laminated Veneer Lumber Beams Strengthened with Various Carbon Composites.

Among the many benefits of implementing numerical analysis on real objects, economic and environmental considerations are likely the most important ones. Nonetheless, it is also crucial to constrain the duration and space necessary for conducting experimental investigations. Although these benefits are clear, the applicability of such models must be appropriately verified. This research subjected validation of numerical models depicting the behavior of unstrengthened and strengthened laminated veneer lumber (LVL) beams. As a reinforcement, a carbon fiber reinforced polymer (CFRP) sheet and laminates were used. Experiments were conducted on full-scale members within the framework of the so-called four-point bending testing method. Numerical simulations were performed using the Abaqus software. Two types of material models were examined for laminated veneer lumber: linearly elastic and linearly elastic-perfectly plastic with Hill's yield criterion. A distinction was made in the material properties of carbon composites based on their location on the height of the cross-section. The outlined numerical models accurately depict the behavior of real structural elements. The precision of predicting load-bearing capacity amounts to a few percent for strengthened beams and a maximum of eleven percent for unstrengthened beams. The relative deviation between numerical and experimental values of bending stiffness was at a maximum of seven percent. Applying the elastic-plastic model enables accurate representation of the load versus deflection relation and the distribution of stress and deformation of strengthened beams. Based on the findings, directives were provided for further optimization of the positioning of composite reinforcement along the span of the beam. Reinforcement design of existing laminated veneer lumber members can be made using presented methodology.

Design and validation of a new ring hoop plane strain test for characterizing the anisotropic plastic behavior of tubular materials

The accurate characterization of the plastic behavior of tubular materials is challenging due to the difficulties in acquiring proper specimens for mechanical testing. In this study, we propose a novel testing technique, namely the ring hoop plane strain Test (RHPST), as a supplementary test for characterizing materials experiencing distinct strain paths compared to standard uniaxial tensile tests. To design a suitable ring specimen’s geometry that satisfies the necessary plane strain conditions, we developed a meta-modelling approach merging response surface method (RSM) and the finite element method (FEM). Experimental tests are conducted on RHPST specimens, and 3D digital image correlation (DIC) technique is used to monitor the strain fields within the specimen's gauge section. However, observations indicate the presence of edge effects on the gauge specimen. These edge effects significantly influence and limit the homogeneity of the plane strain field. To tackle this limitation, a correction procedure is developed for separating the authentic plane strain area, constituting approximately 78% of the RHPST specimen's width. Furthermore, we successfully fabricated a novel grooved ring specimen (GRHPST), which exhibits a wider region of the plane strain state encompassing up to 90% of the gauge width, while minimizing the impact of edge effects. The true stress-true strain curve obtained from the GRHPST specimen exhibits exceptional agreement with the curve predicted using the Hill48 yield criterion. Notably, no additional corrections are required for the measured true stress-true strain curve, thereby affirming the efficacy of the GRHPST specimen as an adept test for characterizing the anisotropic plastic behavior of AA6063 tubes.

Experimental and numerical study on mechanical behavior of 3D printed adhesive joints with polycarbonate substrates

AbstractAdhesive joints play a crucial role in enhancing the structural integrity and performance of 3D printed parts. The purpose of this study is to investigate the failure load and behavior of polycarbonate (PC) single lap joints (SLJs) produced by fused deposition modeling (FDM) using experimental and finite element analysis (FEA) methods. The FEA of joints presents a new approach by integrating PC substrates with Hill yield criterion, transversely isotropic material and adhesive layer with cohesive zone modeling (CZM). The study focused on the effect of printing angles (0°, 45°, and 90°) and overlap lengths (12.5 and 25 mm) on the performance of SLJs. The influence of 3D printing parameters on the mechanical behavior of PC joints was investigated by tensile testing of SLJs. The experimental failure load was 1586 N for a 12.5 mm joint at 90° and 4115 N for a 25.4 mm joint at 0°. Comparison of the experimental and FEA failure loads of the joints showed maximum and minimum differences of 11.98% and 1.34%, respectively. This result showed that the proposed model is applicable for determining the joint strength as a function of the printing angle and monitoring the joint damage behavior.

AOP report: Development of an adverse outcome pathway for deposition of energy leading to cataracts.

Cataracts are one of the leading causes of blindness, with an estimated 95 million people affected worldwide. A hallmark of cataract development is lens opacification, typically associated not only with aging but also radiation exposure as encountered by interventional radiologists and astronauts during the long-term space mission. To better understand radiation-induced cataracts, the adverse outcome pathway (AOP) framework was used to structure and evaluate knowledge across biological levels of organization (e.g., macromolecular, cell, tissue, organ, organism and population). AOPs identify a sequence of key events (KEs) causally connected by key event relationships (KERs) beginning with a molecular initiating event to an adverse outcome (AO) of relevance to regulatory decision-making. To construct the cataract AO and retrieve evidence to support it, a scoping review methodology was used to filter, screen, and review studies based on the modified Bradford Hill criteria. Eight KEs were identified that were moderately supported by empirical evidence (e.g., dose-, time-, incidence-concordance) across the adjacent (directly linked) relationships using well-established endpoints. Over half of the evidence to justify the KER linkages was derived from the evidence stream of biological plausibility. Early KEs of oxidative stress and protein modifications had strong linkages to downstream KEs and could be the focus of countermeasure development. Several identified knowledge gaps and inconsistencies related to the quantitative understanding of KERs which could be the basis of future research, most notably directed to experiments in the range of low or moderate doses and dose-rates, relevant to radiation workers and other occupational exposures.

Experimental investigation and numerical modelling of the cyclic plasticity and fatigue behavior of additively manufactured 316 L stainless steel

This study addresses the critical need for a constitutive model to analyze the cyclic plasticity of additively manufactured 316L stainless steel. The anisotropic behavior at both room temperature and 300 °C is investigated experimentally based on cyclic hysteresis loops performed in different orientations with respect to the build direction. A comprehensive constitutive model is proposed, that integrates the Armstrong-Frederick nonlinear kinematic hardening, Voce nonlinear isotropic hardening and Hill's anisotropic yield criterion within a 3D return mapping algorithm. The model was calibrated to specimens in the 0° and 90° orientations and validated with specimens in the 45° orientation. A single set of hardening parameters successfully represented the elastoplastic response for all orientations at room temperature. The algorithm effectively captured the full cyclic hysteresis loops, including historical effects observed in experimental tests. A consistent trend of reduced hardening was observed at elevated temperature, while the 45° specimen orientation consistently exhibited the highest degree of strain hardening. The applicability of the model was demonstrated by computing energy dissipation for stabilized hysteresis loops, which was combined with fatigue tests to propose an energy-based fatigue life prediction model.

NUMERICAL SIMULATION OF BENDING STEELS USED IN AUTOMOTIVE INDUSTRY WITH EMPHASIS ON SPRINGBACK

In this work, the influence of material models used in the FE simulation on the springback prediction of various steels is investigated. The aim of this work is to extend the knowledge base regarding springback prediction of steels used in car production. The springback effect after V-bending operation was studied on TRIP, HSLA and EDDQ steels. The bending angle was set to 90°. In the numerical simulation, Hill48 and Barlat yield criteria were used in combination with Ludwik's and Swift's hardening models. Achieved data from the numerical simulations were compared and evaluated with experimental test results. The experimental results showed the relation between springback and mechanical properties, mainly the yield strength. Higher values of yield strength have negative impact on the final angle of the bent part, thus increasing springback of the part. The numerical results of the springback were not identical with the experimentally achieved springback values in most cases. Particularly, when Swift yield criterion was used in the simulation.

Anisotropic yielding model of lattice material and influencing factors

Experiments and numerical simulations were used to study and analyze the anisotropy of lattice materials, and the elastic-plastic properties of lattice materials were obtained. The equivalent continuum hypothesis was used to approximate the lattice material as a homogeneous continuous orthotropic material. The relevant equivalent yield parameters and plastic yield surfaces of the lattice materials were calculated using the Hill yield criterion. Comparisons of numerical simulations and experimental data show that they match very well. The effect of strut radius on anisotropic yield property and yield surface of lattice material was investigated.

Reporting of tumor lysis syndrome with targeted therapy for hepatic cancer in the FDA adverse events reporting system

ABSTRACT Background Hepatic cancer is a common cancer in clinical practice. Current drug therapies for this condition include targeted therapy, chemotherapy, and immunotherapy. Tumor lysis syndrome (TLS) is the most serious complication of oncology treatment. According to the literature, several cases reported TLS occurred with targeted therapies for hepatic cancer. Methods Reporting odds ratio and information component were used to measure the disproportionate signals for TLS associated with targeted therapies, using data from the FDA’s Adverse Event Reporting System (FAERS). A stepwise sensitivity analysis was conducted to test the robustness of signals. Time-to-onset analysis was used to describe the latency of TLS events associated with targeted therapies. The Bradford Hill criteria were used to perform a global assessment of the evidence. Results Sorafenib, lenvatinib, cabozantinib, and bevacizumab showed higher disproportionate signals for TLS than chemotherapy. The median number of days to TLS occurrence after drug therapy was 5.5, 6.5, and 6.5 days for sorafenib, lenvatinib, and bevacizumab, respectively. Conclusions There is a significant association between tumor lysis syndrome and targeted therapies for hepatic carcinoma, with particularly strong signals for sorafenib and lenvatinib. Clinicians should be aware of the potential for tumor lysis syndrome in targeted therapies for hepatic carcinoma.

Strength-based topology optimisation of anisotropic continua in a CAD-compatible framework

In this paper, a new method to address strength-based topology optimisation (TO) problems is proposed. Specifically, failure criteria for anisotropic materials are integrated into a TO algorithm making use of Non-Uniform Rational Basis Spline (NURBS) hyper-surfaces to represent the pseudo-density field describing the topology of the continuum, thus providing solutions that can be easily exported to any computer-aided design software. The notion of failure load factor is introduced to obtain optimised topologies that do not depend on the magnitude of the applied loads. A unified formulation of the main phenomenological criteria for anisotropic materials, i.e., Tsai–Wu, Hoffman and Tsai–Hill criteria, is used and typical issues related to stress-based TO problems, such as local behaviour and singularity of stresses, are handled thanks to: the properties of NURBS blending functions, a special adaptive χ-norm aggregation function that avoids overflow/underflow issues, and a modified pq relaxation approach. The effectiveness of the proposed approach is demonstrated on 2D and 3D problems. A sensitivity analysis of the optimised topologies to the integer parameters involved in the definition of the NURBS entity is performed. Moreover, the influence of the penalisation scheme used for the elasticity and the stress tensors, the failure criterion, and the orientation of the material on the optimal solution is also investigated.

Material Behavior of PIR Rigid Foam in Sandwich Panels: Studies beyond Construction Industry Standard.

A deep understanding of the material parameters and the behavior of sandwich panels, which are used in the construction industry as roof and façade cladding, is important for the design of these construction components. Due to the constant changes in the polyurethane (PU) foams used as a core material, the experimental database for the current foams is small. Nowadays, there is an increasing number of failures of façade and roof panels after installation. This article presents a variety of experimental investigations on sandwich panels from two manufacturers with a core of polyisocyanurate (PIR) rigid foam (density: 40 kg/m3). As part of this study, compression, tension, shear, and bending tests were performed in several spatial directions and over the range required by the standard. The results of the tests showed the orthotropy of the core material and the dependence of the material on the direction and type of load. The stress-strain curves showed linear and non-linear areas. Using the data from this experimental study, a numerical model was implemented which utilized the Hill yield criterion to represent the orthotropy of the core material. The present investigation suggests that the classical von Mises failure criterion, used in many studies, is not suitable for the foam system applied in these sandwich panels. Instead, the Tsai-Wu criterion is more appropriate for defining the failure stresses.

Autopsy findings in cases of fatal COVID-19 vaccine-induced myocarditis.

COVID-19 vaccines have been linked to myocarditis, which, in some circumstances, can be fatal. This systematic review aims to investigate potential causal links between COVID-19 vaccines and death from myocarditis using post-mortem analysis. We performed a systematic review of all published autopsy reports involving COVID-19 vaccination-induced myocarditis through 3 July 2023. All autopsy studies that include COVID-19 vaccine-induced myocarditis as a possible cause of death were included. Causality in each case was assessed by three independent physicians with cardiac pathology experience and expertise. We initially identified 1691 studies and, after screening for our inclusion criteria, included 14 papers that contained 28 autopsy cases. The cardiovascular system was the only organ system affected in 26 cases. In two cases, myocarditis was characterized as a consequence from multisystem inflammatory syndrome. The mean age of death was 44.4years old. The mean and median number of days from last COVID-19 vaccination until death were 6.2 and 3days, respectively. We established that all 28 deaths were most likely causally linked to COVID-19 vaccination by independent review of the clinical information presented in each paper. The temporal relationship, internal and external consistency seen among cases in this review with known COVID-19 vaccine-induced myocarditis, its pathobiological mechanisms, and related excess death, complemented with autopsy confirmation, independent adjudication, and application of the Bradford Hill criteria to the overall epidemiology of vaccine myocarditis, suggests that there is a high likelihood of a causal link between COVID-19 vaccines and death from myocarditis.

Impact of health system strengthening interventions on child survival in sub-Saharan Africa: a systematic review protocol

BackgroundStrengthening healthcare systems is a practical approach to enhance healthcare delivery and services. Although there has been a rise in the number of health systems strengthening (HSS) interventions in sub-Saharan Africa (SSA), there is limited evidence on the causal effect of these activities on child survival. Furthermore, the findings reported so far have been varied, and how they relate to each other remains unclear. This systematic review study aims to assess all available evidence to understand the impact of HSS activities on child survival in SSA.MethodsWe developed a search strategy to retrieve all relevant studies from electronic databases such as PubMed/MEDLINE, Web of Science, and African Journals Online. We will use a combination of search terms such as “under-five mortality,” “child mortality,” “infant mortality,” “neonatal mortality,” “child survival,” and “health systems strengthening.” The review will include studies that establish a causal relationship between HSS interventions and child survival. This will include studies with designs such as randomized controlled trials and quasi-experimental and methods like difference-in-difference. Two reviewers will independently screen all citations, abstracts, and full-text data and a third reviewer will act as a tiebreaker in case of disagreements. The primary outcome of interest is the impact of HSS activities on under-five survival. We will evaluate the quality of each study using the Bradford Hill criteria for causation.DiscussionOur systematic review will identify and evaluate all relevant evidence that establishes a causal relationship between HSS activities and the survival of children under five years in SSA. The review’s findings regarding the impact of HSS activities on child survival could be of significant interest to the donor community and policy actors in the region. We also anticipate that the review’s conclusions could serve as a valuable guide for the development of future health system interventions and strategies in SSA.Systematic review registrationPROSPERO CRD42022333913.