To reduce deaths, morbidity, and social problems from alcohol in Canada, a multi-dimensional robust response is needed, including a comprehensive alcohol control strategy at the provincial, territorial, and federal levels. Alcohol container labels with health and standard drink information are an essential component of this strategy. This commentary provides a rationale for the mandatory labelling of all alcohol products, summarizes Canadian initiatives to date to legislate alcohol container warning labels, and addresses myths and misconceptions about labels. Canadians deserve direct, accessible information about (1) the inherent health risks associated with alcohol consumption, (2) the number of standard drinks per container and volume of a standard drink, and (3) guidance for preventing or reducing consumption-related health risks. Enhanced health labels on alcohol containers are long overdue. Alcohol is a dangerous drug. Roughly 17,000 Canadians die annually from alcohol-attributable causes, with many more involved in alcohol-attributable hospital stays or emergency room visits  the health and safety risks associated with alcohol consumption, (2) the number of Canadian standard drinks in the container and the volume of a standard drink, and (3) alcohol and health guidance for preventing or reducing consumption-related risks.In this commentary, we provide a rationale for enhanced labels on alcohol containers. Also, we offer insights and evidence on why alcohol warning labels are not currently mandated on all alcohol beverages in Canada, and we refer to international experiences on this topic. We outline the components of proposed enhanced warning labels Table  and provFirst, alcohol is deserving of specific attention because of its widespread use and status as Canada’s most popular legal drug. Second, alcohol is associated with a number of social, chronic, and acute health risks and potential harms, many of which are not well known or are poorly understood by the general public. Consumers have a right to know about hazards of the products they are using, regardless of labels’ direct impacts on consumption  prevention groups, Mothers Against Drunk Driving (Canada), and other organizations, these legislative initiatives did not succeed. The alcohol industry lobbied MPs, claiming labels were ineffective, based on a selective assessment of the United States label’s experience. The industry also claimed high cost and threatened to withdraw funding for other educational programs if labels were introduced  and a pregnancy, impaired driving, and general health warning (Northwest Territories).In 2017, Erin Hobin and Tim Stockwell (two authors of this commentary) initiated a real-world study in Yukon and Northwest Territories using a quasi-experimental design to assess whether and how enhanced warning labels impact consumer perceptions, intentions, and behaviour. In the experimental site in Whitehorse, one of three new warning labels referred to alcohol as a carcinogen, namely: “Chief Medical Officer of Health advises Alcohol can cause cancer Including breast and colon cancers”. The alcohol industry threatened the Yukon Government with legal action and the labels referring to cancer were removed from rotation one month into the study. Legal scholars found that the industry objections were without merit  and a motion (M-61) put forward in the House of Commons speak to renewed public interest in this issue, yet the potential for industry resistance and interference remains, including via promotion of myths and misconceptions about alcohol labels Table .Achieving mandated enhanced labels on alcohol products in Canada will require strong advocacy and public support. In order to counter common myths and misconceptions about warning labels Table  and otheThe Federal Government of Canada is already in a position to use its existing authority under the Food and Drugs Act (FDA) to mandate alcohol labels with health warnings, national drinking guidance, and standard drink information to raise awareness among alcohol consumers, potential consumers, and the broader public about the risks associated with alcohol use. Taking such action would be in keeping with the recent call for labels that formed part of the new Canadian Guidance on Alcohol and Health (Paradis et al.,


The continuous use of antibiotics is associated with the spread of antimicrobial resistances and the not yet clear link to cancer development. Many conventional antibiotics have already shown different effects on a variety of cancer types raising questions for their rational use in cancer. However, discrepancy in the observed trend for some antibiotics reducing cancer development and being associated with higher risk of cancer underscores the lack of understanding the complex link between antibiotics and cancer. Here, we briefly summarize the possible antibiotic-mediated effects on cancer and conclude that those effects can be direct via i) specific targeting of tumor/cancer, ii) antimicrobial activity and iii) immunomodulatory activity whereby iv) indirectly caused effects primarily affect immune equilibrium between bacteria, cancer and immune cells. Furthermore, we also conclude that there is a great need for bulk profiling, comprehensive screening programs in all countries and in-depth studies to understand the risks and benefits of antibiotic use. These include the spread of antimicrobial resistances [Fleming's discovery of the first natural antibiotic Penicillin in the late 1920's [istances  and the istances , 5. Globistances .Fusobacterium, cancer cell proliferation, and overall tumor growth [Recent articles report a strong association of malignant tumors with fungi and bacteria, which exhibit high immuno-suppressive properties and strongly promote cancer progression –9. Varior growth  questionin vitro and in mouse models in vivo, whereby macrolides block autophagic flux by inhibiting lysosomal acidification, inducing accumulation of radioactive species (ROS) and integrated stress response promoting tumor proliferation [On the other hand, discrepancy in the observed trend for tetracyclines and macrolides reducing cancer development , 17 and feration . In patiferation , 13, 20.Apparently, there is no consensus, which antibiotic classes seem to be more associated with cancer prevalence. A summary by Gao and colleagues, discusses this double-edge sword of antibiotics used for cancer treatment and provides a rational basis for discussion of antibiotic use based on their modes of action . AntibioFigure 1) on a variety of cancer types raising questions for their rational use in cancer [Many conventional antibiotics have already shown different effects (n cancer , 27, 28.n cancer .Although the link between antibiotics and cancer is growing, in discussion with renowned scientists, there is clear evidence that there is a great need for bulk profiling, comprehensive screening programs in all countries and in-depth studies to understand the risks and benefits of antibiotic use .


Our understanding of the pathophysiology of the nervous system has advanced significantly in the last few years, but there are still many unanswered questions. The impact of acute and chronic inflammation on neurodegenerative mechanisms is particularly challenging as this response begins as a protective mechanism. Still, it often ends up exacerbating the progression of neurological diseases. Therefore, comprehending the pathways triggered in the inflammatory response and their temporal orchestration could be instrumental in identifying mechanisms and time windows to intervene appropriately to limit and redirect this process into an advantageous event. Inflammation occurs by recruiting different players in the central nervous system (CNS) and peripheral nervous system (PNS) and encompassing distinct cellular and molecular mechanisms. For example, blood cell infiltration and blood–brain barrier (BBB) disruption often characterize peripheral inflammation, while the central involvement of resident immune cells as microglia is a distinct tract of CNS-related responses . MoreoveIn this Special Issue entitled “Inflammation in the CNS and PNS: From Molecular Basis to Therapy”, two original and five review articles were published, aimed to define the role of inflammation in human diseases affecting the central and peripheral nervous system, including Friedreich’s, Huntington’s disease, multiple sclerosis, and peripheral neuropathies.The article by Pyka-Fościak and colleagues  sheds liTo trace common determinants in the pathophysiology of the nervous system, Tan and colleagues discuss the role of type I Interferons (IFNs) in different neurological contexts. They evidence that type I IFNs play an active function in regulating cognition, aging, depression, neurodegenerative diseases and pain through the modulation of the cross-talk between neurons and glia. The authors also discuss the role of type I IFNs in long-haul COVID-associated neurological disorders .Lastly, the issue regarding neuroinflammation in Huntington’s disease (HD) and Friedreich’s ataxia (FRDA) is tackled, respectively, by Paldino and Fusco  and ApolIn conclusion, while significant advances have been made in our understanding of the pathophysiology of the nervous system, many questions remain unanswered, particularly regarding the effects of inflammation. Neuroinflammation can have both harmful and beneficial effects on the nervous system, making it a challenging area of study.


This study presents a novel hybrid optimization approach for intelligent manufacturing in plastic injection molding (PIM). It focuses on globally optimizing process parameters to ensure high-quality products while reducing cycle time, material waste, and energy consumption. The method combines a backpropagation neural network (BPNN) with a genetic algorithm (GA) and employs a multi-objective optimization model based on design of experiments (DoE). A BP artificial neural network captures the relationship between optimization goals and process parameters. Leveraging the genetic algorithm, it effectively optimizes process parameters for achieving global optimization goals. The case study involves a polypropylene product, considering dimensional deviation, weight, cycle time, and energy consumption during the PIM cycle. Design variables include melt temperature, injection velocity, injection pressure, commutation position, holding pressure, holding time, and cooling time. The results demonstrate that this approach efficiently adjusts process parameters to meet quality standards, significantly reducing raw material consumption (2%), cycle time (12%), and energy consumption (16%). This offers substantial benefits for companies in highly competitive markets demanding swift adoption of smart production methods. As this age-old method perseveres in the modern industrial landscape, the quest for superior quality, efficiency, and sustainability has become paramount.Plastic injection molding stands as a ubiquitous and indispensable technique in the production of plastic parts, wielding its influence across an array of industries such as automotive, electronics, medical, sports and recreation, construction, and consumer goods. The Handbook of Plastic Materials by Charles A. HarperProduct weight consistency: it necessitates adherence to stringent tolerance limits for maintaining product integrity and performance. Deviations beyond acceptable boundaries can potentially result in performance issues or assembly complications.Product size and dimension precision: accuracy, stability, deviation, and tolerance collectively contribute to achieving the desired dimensions for molded parts. Strict conformity to specifications ensures seamless integration within the intended applicationDefect minimization: an array of defects, from warping and flash to sink marks and air traps, poses a threat to both aesthetics and functionality. Addressing these issues is crucial for upholding customer expectations and product performance.The main principle of injection molding Fig.  revolvesCustomer satisfaction hinges on the fulfillment of these quality requirements. However, in the face of intensified competition, escalating raw material costs, and rising energy expenditures, manufacturers are under increasing pressure to optimize their production processes. This optimization must navigate a delicate balance between sustaining quality while concurrently reducing production time, conserving raw materials, and optimizing energy consumption. Striking this equilibrium holds the key to bolstering competitiveness, enhancing profitability, and delivering cost-effective products to the market.It is important to acknowledge that plastic injection molding is energy-intensive, primarily due to the high-pressure prerequisites during the injection and holding phases. These phases demand substantial mold clamping force, and the plasticization phase necessitates significant heating power to effectively melt the plastic material, culminating in substantial energy consumption. Moreover, the complexity of the injection molding process is further compounded by the multitude of machine setting parameters that must be configured precisely. Achieving optimal adjustments is an intricate endeavor, especially when dependent on traditional trial-and-error methods. This approach often results in significant time, raw material, and energy wastage during the process setup and implementation.To address these challenges, it is imperative to explore novel techniques that promise holistic optimization for both customer satisfaction and producer profitability. The goal is to infuse intelligence, sustainability, and profitability into the manufacturing process. By incorporating advanced optimization algorithms and smart process control systems, the injection molding process can be streamlined, eliminating inefficiencies, reducing energy consumption, and optimizing raw material usage. This approach ensures the fulfillment of customer quality requirements while concurrently augmenting the overall sustainability and profitability of the production process to ensure companies perinity in a competitive and unstable market.2. To achieve this goal, different approaches and methods have been used by researchers through traditional tools3 and advanced methods using artificial intelligence.Research work in the field of plastic injection molding has continued to appear in order to solve the problems linked to this process, which is considered to be very important and complicated due to its variety in terms of the product shapes and sizes obtained, the materials used, the requirements requested, the industrial sector of applications served. The effective optimization of the injection molding process has been and still remains the most sought after objective and the major concern of researchers and industrialists in new context of industry 4.010, Non-dominated Sorting Genetic Algorithm II (NSGA-II)11, Particle Swarm Optimization (PSO)12, Simulated Annealing Algorithm (SAA)13, and Self-Organizing Maps (SOM)14.However, A large number of research studies have sought to optimize the injection molding process by employing hybrid solutions, which combine Artificial Neural Networks (ANN) with various optimization algorithms such as Genetic Algorithms (GA)15 conducted a study to identify the most influential parameters among filling time, cooling time, pressure-holding time, and melt temperature in addressing three common defects in injection molding: short shot, shrinkage, and warpage. They employed the Taguchi method and combined it with an ANN and optimization algorithms. Results emphasized that filling time and pressure-holding time were the most crucial parameters affecting end-product quality. Guo et al.16 harnessed training data from finite element (FE) simulations to construct prediction models for warpage of microcellular foaming material. Their study compared three methods: BP neural network, GABP neural network, and PSOBP neural network. PSOBP was found to be the most precise prediction model for warpage. Optimization through genetic algorithms led to a significant reduction in warpage. Bensignth et al.12 investigated the injection molding of a bi-aspheric lens using PMMA material, aiming to minimize volumetric shrinkage for optical quality. They employed a hybrid ANN-PSO technique to predict optimal process parameters and achieved an optical power of 27.73 Diopter, significantly reducing spherical aberrations. Tsai and Luo5 integrated ANN and GA to create a reverse injection molding model for optical lens shape accuracy. Significant factors affecting the desired accuracy were determined, leading to a successful combination of ANN and GA that improved lens shape accuracy. Chen et al.6 introduced an optimization system combining the Taguchi method, analysis of variance, signal-to-noise ratio, BPNN, and genetic algorithms to enhance plastic injection molding (PIM). The system not only met quality specifications but also improved the stability of the PIM process.Moayyedian et al.17 followed the specific energy consumption profile of six hydraulic injection molding machines to assess the effect of different machine and process parameters and to find energy saving opportunities. Their results showed that throughput and total cycle time have the greatest impact on the specific energy consumption of the process. This effect becomes more significant as the peak power of the machine is greater.For work devoted to the study and optimization of energy consumption in the injection molding process, Mianehrow et Abbasian18 proposed a sustainable injection molding based on good choice of material and gate location to reduce warpage and injection pressure. The proposed method studied firstly the impact of four gate locations and four different materials on desired targets by using simulation software. Secondly the results obtained have been experimentally tested in part produced in the fiber-filled PP with a gate location judiciously chosen giving a successful reduction of warpage and injection pressure and then allow to reduce the production waste and energy consumption for defect-free sustainable manufacturing.Huszar et al.7 took into consideration in their optimization study the minimization of energy consumption by reducing the parameters that consume more energy by integrating it into the optimization constraints of the algorithm used. The main remark is that this energy optimization is not quantifiable to judge its importance.Yin et al.The literature review reveals that most optimization studies in injection molding focus on exploring the influence of process parameters on part quality. Researchers have obtained satisfactory results by employing hybrid techniques to optimize both single and multiple objectives of the desired product quality to satisfy customer requirements. However, there is a lack of attention given to the implications on production cost, including production time, energy consumption, and raw material usage. Considering the intense competition between companies and the rising costs of raw materials and energy, it becomes imperative to address these aspects.Intelligent manufacturing emerges as the key solution to tackle this challenge by providing optimal process parameter values for global optimization and sustainable production. By integrating design of experiments and a smart hybrid technique combining artificial neural networks (ANN) and genetic algorithms (GA), this paper aims to achieve multi-objectives modeling for global optimization to satisfy both customers and producers. Although this technique has been previously explored by researchers for the optimization of the injection molding process, its use has been restricted to compliance with the quality requirements requested by customers without worrying about the impacts on production. The major contribution of this work consists of demonstrating the effectiveness of the use of this hybrid method in a context of global multi-objective optimization combining quality and production requirements that are often contradictory and then requires the search for optimal solutions. ensuring a reasonable compromise. A case study was retained as technical support to apply the method and verify its effectiveness for an overall optimization of four objectives illustrating both quality and production requirements. A design of experiments was executed based on seven most important adjustment parameters according to experts in the field and previous work. The results obtained will be tabulated to build a training dataset for the artificial neural network to develop the most representative model of the case study. This model will be combined after validation with a genetic algorithm to find an optimal solution of the adjustment parameters for global optimization of all the objectives retained.The injected part used as a support for this study and represented in Fig. Polypropylene copolymer of grade 49MK45 procured from SABIC has been used for this study. The properties of the material are given in Table The input variables in this study are chosen based on literature of previous studies, feedback and experimental knowledge from experts and engineers. The input process parameters of injection molding are found to be melt temperature, injection velocity, injection pressure, cooling time, holding time, position of commutation and holding pressure. The range of each process input variable in addition to the levels used in this study are given in Table The output parameters of injection molding are dimensional deviation, weight, production cycle time and energy consumed. The required output parameters of the injection molding of the plastic part used in this study are given in Table 3. The input variables can be introduced and adjusted within the range as given in Table These input–output parameters are used for modeling the part injection molding process by using Artificial Neural Network. The training data of the network are obtained by running an experimental design based on an orthogonal table (L27)The results of input–output of the part molded in the injection molding experiment are given in Table Response table for S/N ratio is used in Minitab software to give the rank for each factor based on the Delta value which is the difference between the highest and lowest average response values. The results in Table The main effects plots (S/N ratio) are used to show how each factor affects the responses characteristics as we ca see in Fig. In this section the signal-to-noise ratio (S/N ratio) is used to identify the levels of control factor settings that minimize the main quality index required by costumer which is the dimensional deviation. The optimal parameters configuration giving in Table 19, the architecture of ANN to use has been simplified to one hidden layer in the goal to increase its ability for generalization20 mainly because of the use of limited amount of data. The choice of the number of neurons in this layer is based on a practice rule that consists to retain a value less than twice the number of input variables12. The optimal value is obtained after tuning hyper-parameters step and it is finally set to 13. The activation function of hidden layer neurons was tan-sigmoidal and for output layer is a pure line functions. Three learning algorithms have been used which are Levenberg–Marquardt (LM), Bayesian regularization (BR) and scaled conjugate gradient (SCG). LM was especially developed for faster convergence in backpropagation algorithms. Essentially, BR, that naturally incorporates regularization, has an objective function that includes a residual sum of squares and the sum of squared weights to minimize estimation errors and to achieve a good generalized model21. SCG is an efficient optimization algorithm primarily applied in training neural networks. Therefore, the developed multilayer Neural Network is (7-13-4) as shown in Fig. Matlab 2022a software and Neural Network toolbox were used to develop the desired model of the part injection molding process. The number of input layer neurons is seven, the number of neurons in the output layer is four corresponding to targets followed. To avoid overfitting issue2), mean squared error (MSE), root mean squared error (RMSE) and relative percent deviation (RPD) as given below.The developed ANN was trained with all experimental data consisting 27 sets,  to keep the orthogonality characteristic of table used to ensure the good accuracy of the model. Additional experiments data consisting of 5 sets were used for model testing. The performance of the developed ANN was evaluated through coefficient of determination  is transformed to Matlab function and introduced as a fitness function with number of variables and bounds as shown in Fig. Population size of 200,Mutation probability is 0.35,Crossover probability is 0.8Maximum generation number of 100.The main set parameters of multi-objective genetic algorithm used are:The optimal configuration of process parameters and their corresponding predicted outputs parameters given by genetic algorithm are tabulated in Table To evaluate the precision of the developed model and verify the effectiveness of the global optimization approach, the optimal configuration obtained from the genetic algorithm was implemented in an experimental evaluation using an injection machine. The first objective, assessing the accuracy of the model, involved comparing the output parameter values proposed by the genetic algorithm with the results obtained through experimentation. Table To demonstrate the economic efficiency of the proposed technique combining ANN-GA, the production time, consumption of raw material, and energy for an order of 100,000 products  are presented in Table This study proposes an efficient global optimization approach for process parameters in injection molding using design of experiments (DoE), artificial neural networks (ANN), and genetic algorithms (GA). The aim is to produce a polypropylene plastic part in the industrial sector within the framework of intelligent manufacturing required by Industry 4.0. The design parameters selected are melt temperature, injection velocity, injection pressure, holding time, holding pressure, commutation position, and cooling time. The desired objectives include product weight, production cycle time, dimensional deviation, and energy consumption. The research begins by designing and conducting experiments to gather data for training and testing an artificial neural network model. This model serves as a multi-objective predictive tool for product quality and production parameters. Subsequently, a genetic algorithm (GA) is employed to determine the optimal configuration of the output parameters that satisfy the desired responses. The obtained results are then experimentally validated to assess the accuracy of the developed model, with a margin of error less than 2.5%. Furthermore, a comparison is made between the results of the experimental plan and those achieved through the proposed method. This comparison demonstrates the effectiveness of the approach, with notable gains observed in production time (12% reduction), raw material usage (2% reduction), and energy consumption (16% reduction). Additionally, the study suggests that the optimization method utilized can have a positive impact on other quality aspects of the injection molding process. Furthermore, it highlights the potential applicability of this approach in other industrial processes to address multi-objective problems and achieve smart, sustainable, and profitable production. In conclusion, this research contributes to the field of intelligent manufacturing by offering an efficient optimization method for injection molding processes. By combining DoE, ANN, and GA, it enables the attainment of optimal process parameters while considering multiple objectives and ensuring sustainable and profitable production. Finally, in future research studies, several improvements can be made to the proposed context of global optimization and notably its use on other parts and other plastic materials with more objectives and considering other parameters of the process. This will make it possible to detect the limits of the proposed method and thus to find solutions to overcome them or even to adopt other optimization techniques which will allow better generalization and thus effective control of the process and its use for parts intended for various industrial sectors.


The risk of sexual transmission of HIV from individuals with low-level HIV viraemia receiving antiretroviral therapy (ART) has important public health implications, especially in resource-limited settings that use alternatives to plasma-based viral load testing. This Article summarises the evidence related to sexual transmission of HIV at varying HIV viral load levels to inform messaging for people living with HIV, their partners, their health-care providers, and the wider public.We conducted a systematic review and searched PubMed, MEDLINE, Cochrane Central Register of Controlled Trials, Embase, Conference Proceedings Citation Index-Science, and WHO Global Index Medicus, for work published from Jan 1, 2010 to Nov 17, 2022. Studies were included if they pertained to sexual transmission between serodiscordant couples at various levels of viraemia, the science behind undetectable=untransmittable, or the public health impact of low-level viraemia. Studies were excluded if they did not specify viral load thresholds or a definition for low-level viraemia or did not provide quantitative viral load information for transmission outcomes. Reviews, non-research letters, commentaries, and editorials were excluded. Risk of bias was evaluated using the ROBINS-I framework. Data were extracted and summarised with a focus on HIV sexual transmission at varying HIV viral loads.244 studies were identified and eight were included in the analysis, comprising 7762 serodiscordant couples across 25 countries. The certainty of evidence was moderate; the risk of bias was low. Three studies showed no HIV transmission when the partner living with HIV had a viral load less than 200 copies per mL. Across the remaining four prospective studies, there were 323 transmission events; none were in patients considered stably suppressed on ART. Among all studies there were two cases of transmission when the index patient's  most recent viral load was less than 1000 copies per mL. However, interpretation of both cases was complicated by long intervals  between the transmission date and the most recent index viral load result.There is almost zero risk of sexual transmission of HIV with viral loads of less than 1000 copies per mL. These data provide a powerful opportunity to destigmatise HIV and promote adherence to ART through dissemination of this positive public health message. These findings can also promote access to viral load testing in resource-limited settings for all people living with HIV by facilitating uptake of alternative sample types and technologies.Bill & Melinda Gates Foundation. Viral load testing is the gold standard for monitoring the response to HIV antiretroviral therapy (ART) with the goal of durable suppression of viraemia to both promote health and longevity and decrease the risk of transmission. As access to ART and viral load monitoring has increased, data from various settings show that a small minority of people living with HIV on ART have viral loads that are detectable but below the threshold for virological failure .5From a public health perspective, low-level viraemia can also have implications in disease transmission risks and thus affect messaging for people living with HIV, including undetectable=untransmittable (U=U) campaigns.Evidence before this studyLow-level viraemia in people living with HIV on antiretroviral therapy (ART) has implications for both individual health outcomes  and public health messaging around transmission risks. Prevention campaigns such as undetectable=untransmittable provide positive messages that promote treatment adherence and decrease HIV stigma. It has generally been widely accepted that viral loads less than 200 copies per mL have no risk of sexual HIV transmission; however, the risk of transmission at higher ranges of low-level viraemia  is more controversial. This is of particular relevance in resource-limited settings that use alternative viral load technologies, such as dried blood spots, to expand access to testing. The limitations of non-plasma-based viral load testing technologies have raised questions about the risks of sexual HIV transmission with low-level viraemia and the implications for public health messaging.Added value of this studyWe searched PubMed, MEDLINE, Cochrane Central Register of Controlled Trials, Embase, Conference Proceedings Citation Index-Science, and WHO Global Index Medicus databases, as well as relevant conference proceedings, for work published from Jan 1, 2010 to Nov 17, 2022, using broad search terms . Input from content experts on additional relevant cases and studies was also solicited. Eight studies were identified related to sexual transmission of HIV at varying HIV viral loads. In more than 7700 serodiscordant couples, only two potential transmissions were found when the index partner's viral load was less than 1000 copies per mL. In both cases, viral load testing of the index partner was conducted at least 50 days from the transmission event, complicating interpretation. This study is the first to collate evidence on sexual transmission of HIV at low levels of viraemia and address the risks with viral loads of 200–1000 copies per mL.Implications of all the available evidenceThe findings of this systematic review are important for ensuring dissemination of clear, consistent, accurate, and positive messages about the almost zero risk of sexual transmission of HIV in individuals with low-level HIV viraemia. Although an undetectable viral load is the goal for all people living with HIV on ART, these data demonstrate that the risk of sexual transmission of HIV at low-level viraemia is almost zero. These results should enable development and widespread dissemination of impactful prevention campaigns for all settings, including those without consistent access to traditional plasma-based viral load testing. Instilling confidence in all viral load results, coupled with positive messaging, is essential to expand access to treatment monitoring, promote better quality of care for all people living with HIV on ART, and reduce stigma and discrimination.The public health community is actively seeking to address the transmission implications of low-level viraemia and ensure that the most accurate and ethical messaging is provided to people living with HIV, their sexual partners, their health-care providers, and the public. To help to clarify this crucial issue, this Article summarises the evidence related to sexual transmission of HIV at varying levels of HIV viral load with a focus on determining the risk of sexual transmission of HIV at viral loads less than 1000 copies per mL.The systematic review described in this Article was one component of a larger systematic review conducted on Sept 15, 2020, to determine whether the HIV treatment failure threshold should be reduced from 1000 copies per mL.The systematic review was conducted according to PRISMA,We also searched conference abstracts using the Conference on Retroviruses and Opportunistic Infections, International Conference on AIDS and Sexually Transmitted Infections in Africa, African Society for Laboratory Medicine, and International AIDS Society conference websites. Bibliographies of screened and selected studies, as well as review articles, were also reviewed. Content experts identified key studies from before Jan 1, 2010 for inclusion and provided further data when relevant.In searching each database and conference website, we used the terms “(HIV) AND  AND  AND (transmission or HIV infection)”.All relevant studies were independently reviewed in full by two authors (RL and DB). Studies for the HIV transmission outcome were included if they met the following criteria: pertained to sexual transmission between serodiscordant couples at various levels of viraemia, pertained to the science behind U=U, and evaluated the public health effect of low-level viraemia. Studies were excluded if they did not specify viral load thresholds or a definition for low-level viraemia or did not provide quantitative viral load information for relevant transmission outcomes. Reviews, non-research letters, commentaries, and editorials were also excluded.On Nov 17, 2022, an identical, updated search was repeated with a focus on outcomes related to sexual HIV transmission to include articles published between July 1, 2020 and Nov 17, 2022. Content experts were also contacted to identify other studies that might contain relevant information with no restrictions on publication date. A third reviewer (LV) was available in case of discrepancies or disagreements in study selection; however, none were encountered.Study certainty  was evaluated using a tool created based on Grading of Recommendations, Assessment, Development and Evaluation; Quality Assessment of Diagnostic Accuracy Studies 2; and Standards for Reporting of Diagnostic Accuracy Studies criteria.Data from each of the studies were extracted and summarised by two authors (LNB and RL) outlining their principal components, including sample size, study design, patient characteristics, thresholds examined, and relevant study outcomes. Data from all studies were summarised descriptively. When quantitative data were available and common across comparable studies, such as sample sizes and proportions, frequency statistics were used to describe the populations evaluated and their results.The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.The initial search for the comprehensive review identified 241 potential studies for evaluation, of which 31 were included in the original review. Of those, seven focused on HIV transmission;The updated and expanded search on Nov 17, 2022 found no studies published since the original search that included sexual transmission outcomes at varying HIV viral loads. Content experts and citation review identified three additional papers—two published before Jan 1, 2010, and one published in 2016—that provided information relevant to sexual transmission at low levels of viraemia. A total of eight papers focused on sexual transmission of HIV at low levels of viraemia were included in this systematic review .26, 27, 28Following the GRADE framework, certainty was assessed with regards to potential inconsistency, indirectness, and imprecision of results. There was determined to be no serious risk of inconsistency or imprecision since several large, well characterised randomised controlled trials and cohort studies were available for review. However, there was serious indirectness because suboptimal data were available to assess the viraemic episodes  associated with transmission. This indirectness created uncertainty about when the HIV transmission event occurred and the viral load level at the time of transmission. On the basis of these assessments, the overall certainty of the evidence was rated as moderate.The risk of bias findings for each study is outlined in Eight studies on sexual HIV transmission were included in the systematic review, consisting of four cohort studies, three randomised controlled trials, and one cross-sectional study across 25 different countries . The anaThree of the studies  Study was a randomised controlled trial of 4747 heterosexual serodiscordant couples in Kenya and Uganda conducted in 2008–12.In a cohort study conducted by Fideli and colleaguesFinally, in Thailand in 1992–98, Tovanabutra and colleaguesThis systematic review of sexual transmission of HIV in individuals with low-level HIV viraemia on ART comprised eight studies and more than 7700 serodiscordant couples. Among the documented transmission events, only two were potential transmissions when the index partner's viral load was less than 1000 copies per mL. However, in both cases the viral load test was done at least 50 days before the transmission occurrence. This fact, coupled with the inherent variability in molecular viral load results,It is also worth noting that in the studies that provided the full range of viral loads in the index partners, transmissions occurred at viral loads much higher than 1000 copies per mL. Index partners with viral loads greater than 10 000 copies per mL constituted 81% and 92% of transmissions in the Rakai and Zambia studies, respectively. Similarly, in the HPTN 052 transmission events in which the index partner was taking ART, the viral loads of the index partners ranged from 43 486 copies per mL to more than 750 000 copies per mL.By demonstrating that the risk of sexual transmission of HIV is almost zero when the index partner has a viral load less than 1000 copies per mL, our findings underscore the importance of prevention campaigns, while also suggesting that the U=U message applies to people living with HIV experiencing low-level viraemia. This message is crucial for low-income and middle-income countries where the disease and infrastructure burdens are high and national programmes are often reliant on alternative sample types and technologies to fully expand access of viral load testing to all people living with HIV. Further, it might encourage more positive and clear messaging on the role of ART in preventing transmission to sexual partners. It will be essential, however, to ensure that the potential individual health risks of low-level viraemia  are clearly communicated and that providers reinforce the goal of an undetectable viral load for optimal personal health outcomes.Although the data quality was moderate, limitations of this systematic review included the varied definitions for low-level viraemia used in the studies, along with differences in the timing and frequency of viral load testing and patient follow-up, causing imprecision within the data. Despite these drawbacks, the data summarised in this Article are crucial because the possibility of deriving more definitive evidence on the risk of sexual transmission at low-level viraemia is most likely not feasible given current HIV standards of care  and the requirement for a very large sample size given the very low number of likely transmission events. The need for frequent viral load testing to better determine viral load levels at time of transmission would also be logistically challenging and highly resource-intensive.It is important to emphasise that these messages and results do not apply to transmission from mother to child. Because vertical transmission can occur during pregnancy , during childbirth, or through breastfeeding, the duration and intensity of exposure to viraemia is considerably higher than that of sexual transmission. There are also differences in transmission dynamics  that are distinct from sexual transmission.Low-level viraemia could have important health implications for individual patients; however, these outcomes have not been thoroughly studied in the context of current, optimal integrase inhibitor-based antiretroviral therapy. An undetectable viral load should be the ultimate goal for clinical management of all people living with HIV on ART. However, the evidence showing almost zero risk of sexual transmission when HIV viral loads are less than 1000 copies per mL provides a powerful opportunity to destigmatise people who are living with HIV and promote adherence to ART through dissemination of this positive public health message.All data are available in the manuscript.We declare no competing interests.


There is a global interest in institutionalizing health technology assessment (HTA) as an approach for explicit healthcare priority-setting. Institutionalization of HTA refers to the process of conducting and utilizing HTA as a normative practice for guiding resource allocation decisions within the health system. In this study, we aimed to examine the factors that were influencing institutionalization of HTA in Kenya.We conducted a qualitative case study using document reviews and in-depth interviews with 30 participants involved in the HTA institutionalization process in Kenya. We used a thematic approach to analyze the data.We found that institutionalization of HTA in Kenya was being supported by factors such as establishment of organizational structures for HTA; availability of legal frameworks and policies on HTA; increasing availability of awareness creation and capacity-building initiatives for HTA; policymakers’ interests in universal health coverage and optimal allocation of resources; technocrats’ interests in evidence-based processes; presence of international collaboration for HTA; and lastly, involvement of bilateral agencies. On the other hand, institutionalization of HTA was being undermined by limited availability of skilled human resources, financial resources, and information resources for HTA; lack of HTA guidelines and decision-making frameworks; limited HTA awareness among subnational stakeholders; and industries’ interests in safeguarding their revenue.Kenya’s Ministry of Health can facilitate institutionalization of HTA by adopting a systemic approach that involves: - (a) introducing long-term capacity-building initiatives to strengthen human and technical capacity for HTA; (b) earmarking national health budgets to ensure adequate financial resources for HTA; (c) introducing a cost database and promoting timely data collection to ensure availability of data for HTA; (d) developing context specific HTA guidelines and decision-making frameworks to facilitate HTA processes; (e) conducting deeper advocacy to strengthen HTA awareness among subnational stakeholders; and (f) managing stakeholders’ interests to minimize opposition to institutionalization of HTA.The online version contains supplementary material available at 10.1186/s12913-023-09673-4. HBPAP u‘We applaud the ministry for creating a HTA office. This office has been responsible for helping stakeholders walk the journey towards implementing HTA’ Participant 8, Semi-autonomous government agencyA focal point or office for HTA was created within the MOH in 2020. It was tasked with overseeing and coordinating HTA institutionalization activities within the country. According to participants, since its establishment, the HTA focal point has overseen several HTA capacity-building and advocacy creation activities.‘MAPAC was inaugurated to develop strategic interventions to bring down healthcare costs. One of the strategic interventions the group has identified is HTA which can promote price transparency and visibility to everybody’ Participant 1, Semi-autonomous government agencyMAPAC was established in 2021 to promote access, availability, and affordability of pharmaceutical products. To this end, MAPAC aims to use HTA to promote transparency of the healthcare priority-setting processes for medicines. MAPAC also aims to use HTA to regulate and negotiate pricing of medical products towards making them affordable .‘MAPAC wLastly, a HTA technical working group was established in 2021 to develop a HTA strategy for Kenya. This technical working group is an 18-member team comprising of technocrats from:- (a) the MOH such as the Department of Health Policy, Research and Development, Department of Health Products and Technology, Department of Health Financing, and UHC secretariat; (b) Semi-autonomous government agencies such as Pharmacy and Poisons Board and Kenya Medical Supplies Agency; and (c) local research organizations such as KEMRI-Wellcome Trust .‘We have institutions in strategic positions that deal with regulation, procurement and purchasing. Their presence provides a very good opportunity for introducing HTA as a priority-setting mechanism for their functions’ Participant 4, Semi-autonomous government agencyIn addition to the creation of new organizational structures for HTA, participants reported that the existence of multiple organizations involved in the regulation, procurement and purchasing of health technologies offered an opportunity to institutionalize HTA to inform these functions. Examples of these organizations included: - (a) the Pharmacy and Poisons Board which would use HTA outputs/ recommendations to inform entry and distribution of health technologies by ensuring they are of good quality to be efficacious and safe; (b) the Kenya Medical Supplies Agency which would use HTA outputs to inform procurement of health technologies for government-owned healthcare facilities; and (c) purchasers such as the national government, the county government, and the National Health Insurance Fund which would use HTA outputs to inform purchase of health technologies for government-owned healthcare facilities.‘We do not have many people with the technical skills required to conduct HTA. The country is still in its infancy stages with regards to skills in evidence synthesis and economic evaluation. This inadequate local capacity is a barrier towards HTA’ Participant 9, Semi-autonomous government agencyIn Kenya, the number of human resources with the technical skills to conduct HTA remain limited. A landscape analysis conducted in 2019 on HTA capacity in Kenya showed that more than 65% of health sector organizations had less than 5 individuals with formal training in HTA-related subjects such as health economics, mathematical modelling, statistics, evidence synthesis and epidemiology . In addi‘The lack of financial resources is a big stumbling block for institutionalization of HTA. At the moment, a lot of research activities are donor funded’ Participant 2, local research organizationThe Government of Kenya has historically underfunded research. For example, approximately 3.5% of the government’s health budget is allocated to research which accounts for less than 30% of the resources required . As a re‘HTA processes are data hungry. For example, we need a database of costs to conduct economic evaluation and budget impact analysis. However, we do not have such a database’ Participant 10, Semi-autonomous government agencyLimited availability of information resources for HTA was reported as another factor limiting institutionalization of HTA in Kenya. Participants reported that despite improvements in Kenya’s health management information system, completeness, and timeliness of data reporting at the facility, county, and national levels were still limited. They also reported that data on costs were not routinely reported, and databases across purchasers were poorly linked. All these factors undermined the availability and quality of data which limited the capacity to conduct HTA.Several legislation and policies on HTA exist in Kenya. These documents recognize various organizational and institutional aspects of institutionalization of HTA as shown in Table ‘We are already seeing HTA in action within the current life of the Kenya Health Policy with the establishment of the panel [HBPAP] and MAPAC’ Participant 1, Development Partner‘To institutionalize the proposed HTA process, it is proposed that a HTA policy be developed, and the requirement for HTA in benefit package decision-making be enshrined in the law. This could be in the form of an amendment to the Health Act’ Document excerpt [ excerpt While policies highlighting institutional and organizational arrangements for HTA exist in Kenya, they do not explicitly indicate sources and amounts of funding to be allocated for HTA-related activities. According to participants and document reviews, all organizational and institutional arrangements for HTA need to be explicitly defined and legislated to support institutionalization of HTA .‘To inst‘We do not have a cost-effectiveness threshold or a quality adjusted life year set for Kenya. We must develop these tools if we are to use HTA routinely for decision-making’ Participant 1, local research organizationKenya lacks standardized process and methods guidelines as well as decision-making frameworks for HTA. For example, there were no process guidelines that would inform which rules and procedures would guide the different stages  of the HTA process. There were also no methods guidelines or tools to inform choice of costing perspective and discount rates, or to measure quality adjusted life years. Lastly, there were no decision-making frameworks such as cost-effectiveness threshold to inform decision-making. The lack of HTA guidelines and decision-making frameworks undermined the country’s capacity to conduct and utilize HTA.‘We have had several workshops which are good for building technical capacity. They also sensitize people to understand the value of HTA. In turn, these people are getting other key stakeholders within the organizations to appreciate what HTA is about.’ Participant 7, Semi-autonomous government agencySeveral short-term HTA training workshops and courses have been conducted in Kenya since 2018 , 36. The‘Every month, we send out a newsletter with interesting topics related to HTA such as economic evaluations, HTA-related conferences, or any forthcoming trainings. We do this to keep HTA relevant on people’s minds.’ Participant 3, local research organizationA local research organization has also created a mailing list for sending monthly HTA newsletters. These newsletters aim to promote continuous dissemination of HTA knowledge to HTA doers and users.We need more HTA courses in our universities. Their curriculum should be structured to ensure that aspects of health economics and research methodologies such as data analysis and evidence synthesis are captured’ Participant 5, local academic organization‘Despite the increasing availability of short-term capacity-building intiatives, long-term capacity-building initiatives such as undergraduate and postgraduate training in HTA remain limited. This undermined the availability of skilled human resource for HTA. Study participants therefore called for the introduction of HTA-related courses at undergraduate and postgraduate level in public and private universities to strengthen individual and organizational capacity for HTA.Since 2018, there have been several advocacy and awareness creation initiatives for HTA in Kenya such as study tours, advocacy meetings, and stakeholder engagement workshops. For example, Kenyan stakeholders namely the Parliamentary Health Committee, the Senate Health committee, the MOH, the County Governments, Academics, HBPAP, and the National Health Insurance Fund Health Financing Experts Panel have gone on study tours to Thailand to learn about UHC and the role of HTA in UHC- related decisions .High-level policy advocacy meetings for HTA have also been held in Kenya with participants including officials from the Kingdom of Thailand and Kenyan stakeholders from the Council of Governors, MOH, and National Treasury. There have also been stakeholder engagement workshops for HTA involving policymakers from the MOH and semi-autonomous government agencies. These advocacy meetings and stakeholder engagement workshops were aimed at raising awareness among key policy and decisionmakers on the definition of HTA, its role in healthcare priority-setting processes and policy decisions and, its value in generating budget savings through price negotiations –40.The study tours, high-level policy meetings, and workshops have increased HTA awareness among key policy and decision-makers in government and semi-autonomous government agencies. A landscape assessment of HTA awareness among major health sector agencies at the national level in Kenya conducted in 2020 showed that over 60% of the respondents indicated that the leadership of these agencies were now aware of HTA and were willing to support development of HTA within their organizations by allocating resources .‘COVID not only highlighted but also amplified the gaps in our health system in terms of lack of finances, human resources, infrastructure and medicines. The ministry’s decisions on what to prioritize during the pandemic had to be made systematically using evidence and HTA provided that. It is one of the positive things that Covid did for us’ Participant 4, MOHParticipants reported that policymakers’ interest in achieiving UHC and the accompanying need to define a publicly funded health benefits package for the UHC programme drove their support for explicit and evidence-based approaches such as HTA. In addition, policymakers’ interests in allocating scarce health system resources optimally generated further interest in HTA as a tool for informing resource allocation decisions. This need intensified during the Covid-19 pandemic which exposed the inability of Kenya’s health system to meet increased healthcare needs. Consequently, MOH policymakers requested local research organizations to conduct HTA to inform government’s resource allocation decisions during the Covid-19 pandemic such as allocation of oxygen cylinders .‘COVID n‘Health economists and other specialists who sat in committees at the national level were instrumental in designing the content of those policies which catapulted the agenda for transforming the health system through evidence-based processes such as HTA’ Participant 7, MOHParticipants reported that technocrats supported institutionalization of HTA given their interests in evidence-based resource allocation processes. These technocrats included Kenyan health economists and health systems experts within the MOH, local academic and research organizations, and development partners. Technocrats supported HTA as they believed it would provide an evidence-based approach for improving affordability, sustainability, and equitable distribution of health benefits packages in Kenya. They were also responsible for recommending various institutional and organizational arrangements for HTA as presented in the health policies outlined in Table In Kenya, lack of price regulation of health technologies has resulted in importer mark-ups ranging between 54 and 256% and 133-748% for generic and originator products respectively . While t‘One barrier will be industries that have been benefitting from the lack of HTA. If we introduce HTA, then they are not going to benefit from the lack of transparency and they are likely to resist’ Participant 1, Semi-autonomous government agency.‘For institutionalization of HTA to take place, we need everyone to buy into HTA starting from the policymakers at the ministry to the frontline workers. For this to work countrywide, counties must be involved. There is need for further sensitization’ Participant 4, Semi-autonomous government agencyDespite growing awareness of HTA among policymakers at the national level, study participants reported that awareness of HTA and its value in policymaking was still low among policy and decision-makers at the county government and hospital levels. These stakeholders were important given Kenya’s devolved health system structure. Their limited awareness was therefore undermining institutionalization of HTA in Kenya. Participants called for greater inclusion of sub-national stakeholders in training and advocacy initiatives to support institutionalization of HTA through greater stakeholder awareness, acceptability, and ownership.‘The Kenyan government in partnership with the Kingdom of Thailand are working to do a technical transfer between the two countries showing goodwill bilaterally’ Participant 3, MOHInternational collaboration for HTA in Kenya occurred through a bilateral agreement between Kenya and Thailand. In February 2019, Kenya and Thailand’s ministries of health signed a bilateral memorandum of understanding on Health Collaboration to support institutionalization of HTA in Kenya . As part‘In terms of international efforts, the iDSI has been working with its local partner in Kenya to build capacity for HTA through workshops.’ Participant 6, local research organizationInternational collaboration for HTA in Kenya also occurred through global health networks such as the International Decision Support Initiative (iDSI). iDSI aims to support low and middle-income countries to reform their healthcare priority setting processes. Since 2019, the iDSI has financially supported several HTA workshops with the aim of building organizational capacity for HTA.‘JICA is financing HTA institutionalization efforts in Kenya’ Participant 4, Development partnerThe Japan International Cooperation Agency (JICA)- a bilateral agency- has offered Kenya a conditional grant to support institutionalization of HTA . The disIn 2018, Kenya introduced a reform on explicit healthcare priority-setting processes that aimed to institutionalize HTA to inform resource allocation decisions within the health sector. Given the limited availability of studies examining institutionalization of HTA in low and lower-middle income countries, we conducted this study to examine the factors that were influencing institutionalization of HTA in Kenya- a lower middle-income country. The key insights derived from this study include the following.Secondly, the availability of legislation and policies on HTA in Denmark [Thirdly, the availability of awareness creation activities increased the visibility of the value of HTA to health systems stakeholders in Spain [Fourthly, government’s interest in UHC and efficient allocation of resources promoted development of HTA in Netherlands [Fifthly, technocrats interests’ in the use of HTA to improve health system performance supported institutionalization of HTA in Mexico [Sixthly, international collaboration through iDSI contributed to increased HTA awareness creation and capacity-building initiatives in Indonesia [Lastly, involvement of bilateral agencies such as the World Health Organization and the World Bank supported funding of HTA projects and capacity-building initiatives in China [The first key insight was that Kenya’s journey towards institutionalizing HTA was being supported by the following factors: - (a) establishment of organizational structures to conduct, utilize, and/ or oversee HTA; (b) availability of legal frameworks and policies on HTA; (c) increasing availability of awareness creation and capacity-building initiatives for HTA; (d) policymakers’ interests in UHC and optimal allocation of resources; (e) technocrats’ interests in evidence-based processes such as HTA for informing resource allocation; (f) presence of international collaboration for HTA which supported HTA capacity-building and awareness creation activities; and (g) involvement of JICA- a bilateral agency- which supported capacity-building and development of a framework for institutionalization of HTA. The supportive influence of these factors on institutionalization of HTA has been reported in other settings. For example, the establishment of organizational structure(s) expanded the capacity of countries such as Canada  and the  Denmark , Germany Denmark  and Thai Denmark  supportein Spain  while thin Spain , 51. Fouherlands , 53. Fifn Mexico . Sixthlyndonesia , Ghana [ndonesia , and Soundonesia . Lastly,in China  and Indoin China .Secondly, limited availability of financial resources undermined institutionalization of HTA in Iran [Thirdly, limited availability and completeness of data for HTA undermined institutionalization of HTA in several high, middle and low-income countries globally [Fourthly, the lack or limited availability of contextually relevant process and methodological guidelines, and decision tools has undermined utilization of HTA in Sub Saharan countries [Fifthly, the limited awareness of HTA, its concepts and relevance among policy and decision-makers in Malaysia [Lastly, manufacturers’ interests in safeguarding pricing of their health technologies undermined institutionalization of HTA in the United States of America [The second key insight was that several factors were undermining Kenya’s journey towards institutionalizing HTA namely: - (a) limited availability of organizational resources such as skilled human resources, financial resources, and information resources for HTA; (b) lack of HTA guidelines and decision-making frameworks; (c) limited HTA awareness among policy and decision-makers at the subnational level- that is, county governments and health facilities; and (d) industries’ interests in safeguarding their revenue. The limiting influence of these factors on institutionalization of HTA has been reported in other settings. For example, limited availability of skilled human resource for HTA undermined capacity to conduct HTA in India , Iran 6, South A in Iran , South A in Iran  and Tanz in Iran . Thirdlyglobally , 17. Fouountries . FifthlyMalaysia  and SoutMalaysia  undermin America , 66.The third key insight was that some of the factors that were influencing institutionalization of HTA in Kenya were interlinked. These interlinkages have also been reported in other studies. For example, international collaboration for HTA increased the availability of HTA awareness creation and capacity-building activities in Kenya. Literature shows that countries involved in international collaborative networks across Europe and Asia reported similar findings , 68. SecThe study findings offer important policy implications on how the MOH can nurture and sustain the institutionalization process in Kenya. This can be achieved through a systemic approach that addresses the current limitations in Kenya’s capacity to conduct and utilize HTA. In this systemic approach, the MOH should earmark funds from the national health budget to ensure adequate availability of financial resources for HTA. The MOH should introduce a cost database and promote timely data collection through trainings and incentives to strengthen information resources for HTA. The MOH should collaborate with academic institutions offering health sector focused undergraduate and graduate training  to introduce and integrate HTA training in their undergraduate and postgraduate courses to ensure availability of skilled human resource for HTA. The MOH should develop contextually relevant process and methods guidelines and decision tools for HTA to facilitate how HTA processes are conducted and how HTA outputs are utilized in decision-making. The MOH should conduct wider advocacy to increase HTA awareness among national and sub-national stakeholders. The MOH should manage stakeholders’ interests through sensitization and persuasive framing of the value of institutionalizing HTA to minimize opposition. Lastly, the MOH should strengthen international collaborations through south-south collaborations to facilitate the institutionalization process.Lastly, by applying the conceptual framework outlined in this study Fig. , we demoA potential limitation of this study is social desirability bias whereby participants alter responses in the belief that this would make the responses more acceptable. However, by triangulating data sources and methods, we strengthened the trustworthiness of the findings. It is also possible that the previous involvement of 2 of the authors in HTA-related processes in Kenya may have biased the interviews and analysis. However, we mitigated against this bias by reviewing documents to corroborate the findings and by holding peer debriefing sessions as a study team to ensure that findings were based on collected data. Lastly, a potential limitation of this study is the absence of patient advocacy or patient representatives in the sample population. Future studies should consider incorporating the voice of this sampling population.Examining factors that influence institutionalization of HTA is substantially relevant in low and middle-income countries where institutionalization of HTA remains limited. In this study, we used a conceptual framework based on five sets of factors that were identified from a scoping review on factors influencing institutionalization of HTA across countries of different income levels. By applying this conceptual framework, we were able to identify factors that were supporting and limiting institutionalization of HTA in Kenya. These findings offer useful policy implications that policymakers within the MOH can implement to facilitate progress towards institutionalization of HTA in Kenya. Researchers and policymakers can use this study’s conceptual framework to examine factors influencing institutionalization of HTA or to develop a roadmap for institutionalizing HTA in contexts of interest respectively.Below is the link to the electronic supplementary material.Supplementary Material 1


This diagnostic study uses data for individuals who ever smoked to examine 2 approaches for incorporating race and ethnicity in a lung cancer prediction model and determine changes in screening eligibility. Using race and ethnicity in clinical prediction models can reduce or inadvertently increase racial and ethnic disparities in medical decisions.To compare eligibility for lung cancer screening in a contemporary representative US population by refitting the life-years gained from screening–computed tomography (LYFS-CT) model to exclude race and ethnicity vs a counterfactual eligibility approach that recalculates life expectancy for racial and ethnic minority individuals using the same covariates but substitutes White race and uses the higher predicted life expectancy, ensuring that historically underserved groups are not penalized.The 2 submodels composing LYFS-CT NoRace were refit and externally validated without race and ethnicity: the lung cancer death submodel in participants of a large clinical trial  who ever smoked (n = 39 180) and the all-cause mortality submodel in the National Health Interview Survey (NHIS) 1997-2001 participants aged 40 to 80 years who ever smoked . Screening eligibility was examined in NHIS 2015-2018 participants aged 50 to 80 years who ever smoked. Data were analyzed from June 2021 to September 2022.Including and removing race and ethnicity  in each LYFS-CT submodel.By race and ethnicity: calibration of the LYFS-CT NoRace model and the counterfactual approach (ratio of expected to observed [E/O] outcomes), US individuals eligible for screening, predicted days of life gained from screening by LYFS-CT.The NHIS 2015-2018 included 25 601 individuals aged 50 to 80 years who ever smoked . Removing race and ethnicity from the submodels underestimated lung cancer death risk  and all-cause mortality  in African American individuals. It also overestimated mortality in Hispanic American  and Asian American individuals . Consequently, the LYFS-CT NoRace model increased Hispanic American and Asian American eligibility by 108% and 73%, respectively, while reducing African American eligibility by 39%. Using LYFS-CT with the counterfactual all-cause mortality model better maintained calibration across groups and increased African American eligibility by 13% without reducing eligibility for Hispanic American and Asian American individuals.In this study, removing race and ethnicity miscalibrated LYFS-CT submodels and substantially reduced African American eligibility for lung cancer screening. Under counterfactual eligibility, no one became ineligible, and African American eligibility increased, demonstrating the potential for maintaining model accuracy while reducing disparities. What approaches to using race and ethnicity in the life-years gained from screening–computed tomography (LYFS-CT) prediction model, which is used to inform lung cancer screening eligibility, can best identify high-benefit individuals and minimize racial and ethnic disparities in screening eligibility?This diagnostic study found that removing race and ethnicity curtailed the ability of LYFS-CT to identify high-benefit racial and ethnic minority individuals and reduced screening eligibility for African American individuals while eligibility for other groups increased. The counterfactual eligibility model was found to increase eligibility, maintain predictive accuracy across all racial and ethnic groups, and avoid excluding individuals from screening based on racial and ethnic minority status.These findings suggest that thoughtful use of race and ethnicity data in prediction models may help reduce disparities. For screening, which involves asymptomatic individuals, the harms must not exceed the benefits. Individuals with little chance of benefiting nonetheless remain susceptible to the harms of screening.20 Thus, simply making more racial minority individuals eligible, for example, by lowering the eligibility risk- or benefit-threshold for individuals from certain races and ethnicities, could be a poor strategy for addressing disparities if individuals have low benefit. Furthermore, screening guidelines typically recommend 5 to 10 years’ minimum life expectancy22 to ensure that individuals are healthy enough for cancer treatments and are not likely to die soon from comorbid conditions. However, some groups may have lower life expectancy due to lack of access to care or historic discrimination, and it may be unfair to penalize individuals who are projected to have low life expectancy solely because of their self-reported race and ethnicity.Decisions based on clinical prediction models may reduce disparities when race and ethnicity are independent predictors of outcome risk, as for cardiovascular disease, lung cancer, and diabetes.23 individualizes lung cancer mortality risk and life expectancy and is recommended by the ACCP10 for supporting personalized shared decision-making for lung cancer screening. LYFS-CT is implemented in the Decision Precision+ clinical decision support tool for lung cancer screening.24 LYFS-CT is particularly interesting to examine from the perspective of fairness because, unlike risk models, it explicitly incorporates life expectancy. Here, we examined the effect of different approaches to incorporating race and ethnicity in the LYFS-CT model on screening eligibility for a contemporary representative US population.These considerations highlight the complexity of developing general strategies for using prediction models to improve the fairness of clinical rules. The life-years gained from screening–computed tomography (LYFS-CT) modelTRIPOD) reporting guideline. Data were analyzed from June 2021 to September 2022.The National Institutes of Health Office of Human Subjects Research deemed this study exempt from institutional review board approval. This report follows the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis . . The model includes self-reported smoking variables as well as demographic variables. This model was developed using data from 39 180 individuals aged 55 to 74 years in the control group of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO)27 who ever smoked, of whom 1092 died of lung cancer. Individuals were recruited into PLCO in the United States from 1993 to 2001, with follow-up data available until December 31, 2009. Individuals were censored at the earliest of death from lung cancer, death from other causes, or end of follow-up. Details on all the data sets used in this study are given in eTable 1 in We refit our 5-year LCDRAT modelWe validated the LCDRAT-NoRace model using National Health Interview Survey (NHIS) data from 1997 to 2001, linked to the National Death Index, providing cause-of-death data up to December 31, 2006. The NHIS is an annual cross-sectional, nationally representative survey of the noninstitutionalized US population. We included 28 232 individuals aged 50 to 80 years with known cause of death and without prior lung cancer who ever smoked (673 lung cancer deaths). Individuals were censored at the earliest of death from lung cancer, death from other causes, or end of follow-up. Multiple imputation was carried out to account for missing data  and validated  using data from NHIS 1997-2014 individuals aged 40 to 80 years who had ever smoked, linked to mortality data up to December 2015. Individuals were censored at the earliest of end of follow-up or death. Multiple imputation was carried out to account for missing data . The LYFS-CT CounterfactualACM model allows an ineligible person to become eligible if the only reason for ineligibility was low life expectancy due to their race or ethnicity. We additionally recalculated both lung cancer death risk and life expectancy in the absence of screening for White individuals with the same covariate values . Importantly, while removing race and ethnicity can change an individual’s eligibility status in either direction, applying counterfactual eligibility can only make ineligible individuals eligible.We compared the number eligible for screening from each race and ethnicity under the following models: (1) the standard LYFS-CT model, (2) removing race from only the ACM model component of LYFS-CT (LYFS-CT NoRaceACM), (3) removing race from both the lung cancer death risk (LCDRAT) component of LYFS-CT and the ACM model component of LYFS-CT (LYFS-CT NoRace), (4) taking the higher life-gained benefit from LYFS-CT NoRaceACM for racial and ethnic minority individuals using their own race and ethnicity or for a similar individual who is White , and (5) taking the higher life-gained benefit from LYFS-CT NoRace using their own race and ethnicity or for a similar White individual . When we refer to Asian American individuals, this group does not include American Indian, Alaska Native, Native Hawaiian, or Other Pacific Islander individuals.10 We applied these models to the NHIS 2015-2018 data and report the number eligible and the proportion of ever-smokers aged 50 to 80 years from that race and ethnicity who would be eligible. Race and ethnicity were self-reported; individuals were asked if they were of Hispanic ethnicity  and which race they were . We also calculated the number and proportion of preventable lung cancer deaths and gainable years of life, assuming the original LCDRAT and LYFS-CT models are correct for individuals of all races and ethnicities.We defined an individual as high benefit and therefore eligible for screening if they met the ACCP eligibility criteria of at least 16.2 days of life gained from attending screening.Analyses were carried out in R version 4.2 using the survey package to account for the NHIS sample design. Multiple imputation was carried out to account for missing data in NHIS 2015-2018  would be eligible for screening . The proUnder the LYFS-CT NoRaceACM model, an additional 58 075 individuals would be eligible: 136 267 more African American individuals (12.9%) but fewer members of other races  . FurtherUnder counterfactual eligibility, by definition, eligibility for White individuals is unchanged and no one can change from being eligible to ineligible . For couUnder counterfactual eligibility for both lung cancer death and all-cause mortality , no additional African American individuals were chosen, because their predicted lung cancer death risk is underestimated when race and ethnicity are removed from the lung cancer death model. Instead, an additional 270 941 individuals would be eligible for screening, of whom 75% would be Hispanic American individuals (an increase of 94.0%), and the remaining 25% would be Asian American individuals (an increase of 71.6%). However, these newly eligible people may gain a mean of only 13.8 days (Hispanic American) and 13.9 days (Asian American) of life from attending screening (according to the standard LYFS-CT model), which is less than the 15.5 days of life gained among African American individuals chosen by the LYFS-CT CounterfactualACM model.This study found that removing race and ethnicity from the LYFS-CT submodels curtailed the ability to identify racial and ethnic differences in risk in favor of an average risk that more closely reflects the non-Hispanic White individuals who make up the majority of the cohorts in which these models were fitted. Excluding race and ethnicity from the lung cancer death risk model resulted in substantial underestimation of risk for African American individuals and may exclude many high-benefit African American individuals from screening.Removing race and ethnicity from the ACM model resulted in underestimation of life expectancy for Hispanic American individuals and Asian American individuals; hence, high-benefit Hispanic American individuals and Asian American individuals would become ineligible for screening. Removing race and ethnicity would substantially weaken the ability of LYFS-CT to identify high-benefit racial or ethnic minority individuals and would provide inaccurate risk and benefit estimates, which impairs shared decision-making.28 and also in a form that is integrated with electronic health records,24 now implements counterfactual eligibility .In contrast, counterfactual eligibility preserves model accuracy and ensures that every group can only gain in eligibility. Counterfactual eligibility for only ACM  increased eligibility for African American individuals who barely missed eligibility  due to lower life expectancy because they are African American. The latest version of LYFS-CT, accessible onlineNote that counterfactual eligibility for both lung cancer death and ACM together  was unable to identify any additional African American individuals for eligibility. This happened because substituting White race into the model reduced lung cancer death risk, and hence the benefit from screening for African American individuals, which in turn reduced the estimate of life-years gained. This highlights the importance of careful consideration of the quantity to consider as counterfactual.29 Additionally, comparative transcriptomic profiling has shown differences in non–small cell lung cancer tumor biology, indicating at least part of the difference may be biological.30Counterfactual eligibility, along with the LYFS-CT NoRaceACM model, attempts to account for race and ethnicity reflecting both biological and social constructs. Sometimes risk differs because of biological and genetic differences . African American individuals have an increased risk of lung cancer that is, in part, likely due to biological effects of smoking, and increased risk should lead to increased screening eligibility. Cotinine clearance has been shown to be slower in African American individuals compared with White individuals.32; leading them to inhale more nicotine per cigarette smoked (30% more in one study29), exposing them to more carcinogens despite smoking a lower number of cigarettes per day, with higher total nicotine equivalents in urine per cigarette compared with White individuals.33 Thus, race and ethnicity may often be a marker of risk rather than a true biological risk factor.34 Continuous efforts are required to incorporate social determinants of health into prediction models when such information can be more routinely collected in electronic health records.However, differences in risk can also reflect social differences between races and ethnicities and arise due to unmeasured social determinants of health, such as differences in environmental exposures, which it is currently not practical to include in prediction models. Additionally, mechanistic hypotheses include that African American individuals smoke more mentholated cigarettes, which can be inhaled deeper35 and both historical and ongoing social and economic marginalization.39Given this complexity, decision-makers should not only consider the importance of race and ethnicity for accurately measuring an individual’s risk but also consider how risk estimates will be used to inform decisions. It is especially important to avoid unintentionally perpetuating historical disparities. In the case of lung cancer screening, the lower life expectancy of African American individuals compared with White individuals partly results from lifelong reduced access to care, including a higher proportion being unable to see a doctor because of costWe note the importance of carefully considering the circumstances in which a counterfactual approach would be appropriate: when doing so can help reduce racial disparities while not depriving anyone  of their eligibility for services. We found that using the LYFS-CT CounterfactualACM model, where the predicted life expectancy of an individual with the same covariates but White race is also considered, (1) ensures model accuracy, (2) avoids making anyone ineligible because of the impact of their race and ethnicity on life expectancy, and (3) avoids making anyone eligible who has very low lung cancer death risk and therefore has low expected net benefit. Additionally, counterfactual approaches can immediately be applied to existing models, whereas developing new models excluding race and ethnicity would require revamping existing models. However, if using counterfactual eligibility, it is important to ensure that the life-years gained for individuals eligible only under the counterfactual scenario are not much below the accepted threshold because their actual benefit is lower than other eligible people (according to the LYFS-CT model). Alternative ways of incorporating race and ethnicity into estimates of outcome risk and ACM should be empirically examined as approaches to reducing disparities in eligibility.Because life expectancy is an important consideration for any preventive intervention, our findings on ACM could be relevant to other preventive services. As observed in this study, we expect eligibility for White individuals will be unaffected when removing race from predictions where the data are largely derived from White populations but will result in worse model calibration in racial minority individuals. Because African American individuals and Hispanic American individuals/Asian American individuals have HRs for ACM in opposite directions relative to White individuals, removing race and ethnicity from the ACM model will increase African American eligibility but decrease Hispanic American/Asian American eligibility. In situations where each racial and ethnic minority group has risk-increasing HRs for the outcome of interest, removing race and ethnicity would reduce eligibility for all racial and ethnic minority individuals.40 has produced a version excluding race41 for use outside the United States. Their conclusions were similar to ours: removing race and ethnicity reduced the proportion of African American individuals who developed lung cancer who would be eligible for screening and increased the proportion for Hispanic American individuals, with minimal impact overall or for White individuals.41A lung cancer incidence risk model, the PLCO-M2012,We used data that are representative of the contemporary US population to estimate the proportion of individuals who would be eligible for screening in each race and ethnicity. Similarly, we used population-representative data to develop and externally validate the life expectancy submodel.The main limitation of our study is that our model estimates of life-years gained assume the model containing race and ethnicity is accurate for all individuals. For White and African American individuals, model calibration is good for both the submodels, including across all risk quintiles for ACM; for Asian American and Hispanic American individuals, the confidence intervals around our calibration estimates are wide because of a lack of data, and ACM is underestimated among Hispanic American individuals in the lowest risk quintile.In this study, removing race and ethnicity miscalibrated LYFS-CT submodels and substantially reduced African American eligibility for lung cancer screening. Under counterfactual eligibility, no one became ineligible, and African American eligibility increased, demonstrating the potential for maintaining model accuracy while reducing disparities. These findings suggest that when race and ethnicity is truly an independent predictor of risk and its inclusion in prediction models increases predictive accuracy, excluding race and ethnicity can exacerbate racial and ethnic disparities. Race and ethnicity can represent risk pathways, such as environmental factors or other social determinants of health, that are difficult to ascertain in the clinic. Thoughtful use of race and ethnicity data may account for important historical factors that have led to disparities. Thus, appropriate use of prediction models that include race and ethnicity can provide a powerful tool for reducing disparities.


Empathy training directed at empathic abilities and/or aspects of providing care can be effective at increasing levels of this ability. Moreover, training in different care contexts can minimize the negative impacts of providing care.To identify empathy training models and the effects on psychological concerns in paid and unpaid caregivers of older people.“Empathy AND (Education OR Training OR Intervention) AND Caregiver”. No restrictions were imposed regarding language or year of publication.A systematic review was conducted. Searches for relevant articles were performed in the Embase, LILACS, PsycInfo, Pubmed, Scopus and Web of Science databases using the following search strategy: Empathy training for caregivers of older people were performed in six studies, three of which identified a significant increase in empathy levels and consequent reduction in psychological concerns. Empathy training focused on aspects of empathy and/or the caregiver had significant effects on the outcome variables. Moreover, training conducted online, by telephone and/or in person can generate satisfactory results. The other three studies that conducted training with a focus on aspects of dementia and/or old age did not present any effect on the outcome variables.Empathy training for caregivers of older people can increase levels of this ability, especially in the cognitive domain, as well as diminish psychological concerns caused by the negative impact of providing care.None Declared