In this review, we attempt to make a case for the establishment of a limited number of heavy ion cancer research and treatment facilities in the United States. Based on the basic physics and biology research, conducted largely in Japan and Germany, and early phase clinical trials involving a relatively small number of patients, we believe that heavy ions have a considerably greater potential to enhance the therapeutic ratio for many cancer types compared to conventional X-ray and proton radiotherapy. Moreover, with ongoing technological developments and with research in physical, biological, immunological, and clinical aspects, it is quite plausible that cost effectiveness of radiotherapy with heavier ions can be substantially improved. The purpose of this article is to heighten awareness within the oncology research and therapy community that major academic medical centers in the United States find the need to re-establish heavy ion cancer therapy in the United States. We want to emphasize that bringing heavy ion cancer therapy back to the United States is a national effort, and not just a wild idea of a few individuals. We provide this article to summarize the rationale to support the re-establishment effort and to publish our ideas and recommendations for how this should be accomplished.More than 60% of all cancer patients in the United States (U.S.) are treated with one or more courses of radiotherapy during the continuum of their cancer care –3. Despivia accelerated charged particles that are heavier than protons. First, a narrow beam of heavy ions is accelerated in a particle accelerator to give enough energy to the ions to penetrate to the depth of the cancer within the human body and kill cancer cells. In general, the speed of the ion correlates with the energy it carries. For example, a speed of approximately 2/3 to ¾ the speed of light is needed for the ions to achieve the energy needed to reach a deeply located tumor (30 cm) in a large patient. After the ions reach the desired speed and energy, they are extracted from the accelerator and are magnetically guided to patient treatment rooms. The ions leave the magnetic transport system and are focused on cancers. They enter through the patient’s skin and travel to the cancer to deposit the therapeutic dose of ionizing radiation. The narrow incident beam is magnetically scanned, and its energy changed to effectively form a broad beam to “paint” the entire volume of the tumor target with ionizing radiation. Typically, multiple such broad beams, incident from different directions, are used to lower the dose outside the tumor and to optimally spare the surrounding normal tissues.Heavy ion therapy is a unique form of radiotherapy for the treatment of cancer. It deposits ionizing radiation in cancer cells Like protons, heavy ions have a finite range in tissue. The speed of heavy ions is tuned in the accelerator in such a way that when they reach the cancer, they deposit most of their initial energy within the cancer, i.e., the ions abruptly stop within the cancer and only a minor, often clinically insignificant energy spills beyond the cancer target. The heavier the ion is, the more significant this spillage would be due to its fragmentation, thereby limiting therapeutic benefit to ions no heavier than oxygen. High energy X-rays, used conventionally to treat solid cancers, do not stop; they continue to travel and deposit energy to healthy tissue beyond the cancer until they exit the patient’s body. The maximum energy deposition for X-rays occurs when they enter the body upstream of the cancer in healthy tissues.Unlike X-rays or protons, heavy ions do not significantly scatter sideways in tissue, i.e., they have a sharper lateral penumbra, meaning the dose fall-off in the lateral direction perpendicular to the direction of the heavy ion beam outside the treatment volume is very rapid. This allows the therapeutic heavy ion beam to pass more safely closer to healthy organs on their way to cancers than protons or X-rays could. This property can be exploited in using heavy ions to treat cancers that are closer to organs at risk and would otherwise be too risky to treat with conventional X-ray or proton radiotherapy.Biologically, heavy ions cause a different type of damage to the cancer DNA and microenvironment than protons or X-rays. The reason for this is that they deposit a very large amount (~100 eV) of densely ionizing energy  on the DNA strand scale (nanometers) near the end of their range in tissue. Because of this, heavy ions cause primarily clusters of double-stranded DNA breaks which are more difficult for cancer cells to repair , 8 makinThe biological effectiveness of X-rays in the cancer is much lower than that of heavy ions and since the physical properties of X-rays do not allow for sparing of normal tissues as mentioned above, the therapeutic benefit is much lower than heavy ions. For protons, their biological effectiveness in the tumor is like that of X-rays, except for a small region near the end of their range where their RBE also increases due to an increased LET , 17. If To achieve the same cancer cell kill, one needs to deposit less energy with heavy ions than with protons or X-rays, leading to significant sparing of healthy tissues, especially distal and lateral to the tumor. The exact amount of increased cancer cell kill , 18–21 aHeavy ions seem to present immunogenic effects such as an increased production of tumor associated antigens and antitumor effects, which may result in reduced ability to metastasize or recur –36. The The effectiveness of immunotherapy depends on the health of the immune system. It is well known that conventional radiotherapy with photons can severely damage the immune system, which can lead to adverse clinical outcomes. Recent findings indicate that proton therapy, due to the compact nature of its dose distribution patterns, can significantly spare the immune system, and improve survival –46. RadiAt this nuclear physics research facility, the Bevalac accelerator was used in 1973 to treat the first patient with neon nuclei and in 1977 with carbon ions , 48. BetIn the early 1990’s, this primarily nuclear physics research accelerator was decommissioned making it the last time the U.S. had a therapeutic heavy ion beam for humans. While the U.S. has several high energy accelerator labs, it is challenging to operate a clinical environment in a research laboratory where all the necessary basic clinical infrastructure is missing. Also, therapeutic beam quality and beam reliability are difficult to achieve in non-clinically oriented physics research labs causing therapy interruptions. On days when access to the ion accelerator prevented treatment due to downtime, treatment with low LET radiotherapy, such as X-rays, is often not at or near the same facility. Moreover, in physics research labs the therapeutic program is highly dependent on the research direction of the lab and on the available beam time as these beams are also used for other research projects.After the closing of the world’s first heavy ion therapy center, three nuclear research facilities around the world adopted heavy ion therapy. In 1994 Japan opened its first carbon ion radiotherapy (CIRT) center, HIMAC, at the National Institute of Radiological Sciences (NIRS) in Chiba, Japan . They currently have an active program and have treated the largest number of patients in the world with carbon ions. The German nuclear research center, GSI Helmholtz Centre for Heavy Ion Research (GSI), commissioned a CIRT treatment room in 1997 and China commissioned a CIRT beam line at the Heavy Ion Research Facility in Lanzhou as part of the Institute of Modern Physics of the Chinese Academy of Science. Six more Japanese, three Chinese, one Italian, one Austrian, and two German sites have been built, all as clinical facilities dedicated for patient treatment. Each has a dedicated heavy ion therapy accelerator and multiple patient treatment rooms served by the same accelerator.The benefit of using heavy ions for cancer treatment was recognized by the government in these countries leading to insurance coverage for the cost of treatment for several cancer types –51. TypiTechnological development of heavy ion systems continued outside of the U.S. with implementation of significant improvements to the first system. For example, a novel beam delivery method for protons called raster scanning, which uses strong magnets to scan a narrow ion beam across the cancer for dose delivery while modulating the beam energy, was developed in Japan in 1984 . GSI devBoth NIRS and GSI have generated their own models to calculate the biological effective dose for carbon ion beams and they have implemented these models in their treatment planning systems –59. A GeDespite widespread proliferation of proton centers worldwide, only a small number of randomized clinical trials comparing proton radiotherapy to conventional X-ray radiotherapy have been completed to define the benefits from the improved proton physical dose distribution –65. A seAt the 14 clinical heavy ion facilities currently in operation worldwide, more than 37,000 patients have been treated with heavy ions; most of these patients received CIRT. The clinical indications are radiation resistant malignancies, such as adenoid cystic carcinoma, mucosal melanoma, non-small cell lung cancer, liver cancer, bone and soft tissue sarcoma; recurrent previously irradiated cancers , advanced gynecological malignancies, esophageal cancer, and pancreatic cancer and hypoxic malignancies. For these, conventional X-ray and proton radiotherapy typically cannot deliver enough therapeutic dose to be effective due to the high risk of severe toxicities of adjacent organs at risk.Locally advanced unresectable pancreatic cancer is a typical example where CIRT has shown benefit over conventional radiotherapy. The physical and biological characteristics of carbon ions allows for the delivery of larger and more effective doses than X-rays or protons. The Japanese centers conducted a phase II single arm clinical trial in patients with unresectable locally advanced pancreatic cancer where the 2-year overall survival in patients receiving CIRT reached a remarkable rate of 42 percent in comparison to the 12 to 30 percent achievable with conventional radiotherapy , 67. AddWith the ongoing construction and commissioning of the present heavy ion clinical centers, technology innovation continues. The systems that are under construction continue to benefit from the latest technological advancements. For example, a CIRT facility in Yamagata prefecture in Japan and one under construction at Yonsei University in Seoul have the latest superconducting rotating gantry that is 2/3 the size of the gantry in QST Hospital, Japan. This is due to a more compact novel design of scanning magnets that are 1/3 smaller than the existing ones at QST Hospital and an increase of the magnetic field strength in the superconducting magnets .The next generation of heavy ion systems will feature even more utilization of superconductivity to further reduce system size which should translate into cost reduction. Operational cost will decrease with further automation of the accelerator control system. It will utilize high power ion sources that can provide an order of magnitude higher dose rate, which is crucial for large dose hypofractionated treatments. Fast magnetic field changing transport magnets should be installed in the entire heavy ion accelerator and beam transport system. Together with appropriate accelerator control system software modifications, such changes will enable ultrafast (on the order of 1 minute) switching times between various ion types which is crucial for personalized optimization of treatment plans based on biological effect capabilities . Novel, For CIRT, two biological effect models have been used, the Japanese microdosimetric kinetic model (MKM) and the German local effect model (LEM) –59. A coWhile it is true that a future system bearing these novel features at low cost is an attractive idea worth research and development, we first need to establish the clinical role and efficacy of heavy ions in patients. Therefore, we argue that current commercially available heavy ion solutions are adequate for today’s needs and if the first U.S. heavy ion centers are constructed now, novel clinical trials can immediately begin investigating the role of heavy ions in U.S. cancer care. Such a center could be operated more cost effectively if most of the treatments are hypofractionated.Heavy ion therapy has not been re-established in the U.S. due to the capital cost of equipment, operational costs, lack of FDA cleared equipment and lack of CPT billing codes and a reimbursement model. Despite its lack of a therapeutic heavy ion center, the U.S. has significantly contributed towards improving understanding of the biological effects of heavy ions and the heavy ion technology for medical use. In 2013, the Department of Energy (DOE), along with the National Cancer Institute (NCI) hosted a Community Input Workshop on Ion Beam Therapy . The worIn 2015 the DOE launched the Accelerator Stewardship program to make particle accelerator technology widely available to science and industry by supporting use-inspired basic research in accelerator science and technology, including medical applications for advanced cancer therapies . From 20The NCI also awarded several research grants aimed at high LET and heavy ion technology development. These included a grant investigating On-line PET Based Intra-Beam Range Verification and Delivery Optimization for Improved Particle Radiation Therapy and investigating Large-Area Plasma Panel Detectors for Particle Beam Radiation Therapy. In early 2020, the NCI announced a request for applications to investigate “Radiobiology of High Linear Energy Transfer (High LET) Exposure in Cancer Treatment” and awarded three to five grants. The private industry sector has also invested in developing an advanced cancer therapy accelerator .In April 2016, the NCI hosted a multidisciplinary workshop on the biology of charged particle therapy where internationally recognized experts gathered to discuss the current knowledge of particle therapy in cancer acknowledging the limitations of the research data generated so far to show biological benefits of heavy ions and identifying knowledge gaps that need to be filled with ongoing or future research . TherefoHowever, we would like to stress that the need for continuing basic science research should not be the primary reason for establishing heavy ion centers in the U.S. Presently, options, though limited, do exist to secure heavy ion beam time to perform scientific experiments either in the U.S –125 or iAlthough clinical data has been collected on more than 37,000 patients worldwide suggesting potential clinical benefit for heavy ion therapy over standard X-ray radiotherapy for selected cancers , 27, 132The NCI has mobilized the international community and funded a dose escalation phase I trial “A Prospective Phase I Clinical Trial of Carbon Ion Radiation Therapy for Locally Advanced, Unresectable Pancreatic Cancer” which irradiates Chinese patients at the Chinese Proton and Heavy ion center in Shanghai . To dateDespite the clear need to construct heavy ion clinical treatment centers in the U.S., there are fundamental practical challenges to overcome in the process. These include the lack of FDA clearance and the lack of a heavy ion therapy reimbursement model in the U.S. The lack of FDA clearance and a reimbursement model will make it impossible to recover the facility initial capital investment and ongoing operating costs. Without a realistic reimbursement model, health care organizations will not be able to create a viable business plan without substantial governmental or philanthropic support. The price of the heavy ion equipment at the first U.S. facility is at the mercy of international vendors and is strongly influenced by the global political and economic climate. The U.S. has no commercial vendor to offer a solution.In 2015, the NCI awarded two exploratory planning grants entitled “Planning for a National Center for Particle Beam Radiation Therapy Research” , 135. ThEvery third year, the Particle Therapy Cooperative Oncology Group (PTCOG) holds its annual meeting in the U.S. The education section provides a valuable opportunity for U.S. institutions to learn about heavy ion therapy benefits and the details of system design and setup while the scientific section is dedicated to presenting the latest basic science and clinical research results from the world experts on particle therapy and to stimulate research interest in the U.S . In addiMayo Clinic in Jacksonville, Florida has announced plans to build the first clinical/medical grade heavy ion therapy facility in the U.S./Americas. This facility will include a hybrid carbon ion and proton particle accelerator (synchrotron) which will be fully capable of accelerating other ions (such as helium). There will be two proton treatment rooms with gantries and one carbon ion room with a single fixed horizontal port. Groundbreaking is anticipated in the spring of 2022 with protons available for commissioning in late 2025 and carbon ions available for commissioning in 2026.The following recommendations are based on the reports of workshops and discussions at conferences on heavy ion cancer therapy including some organized by the authors (AP and HC) and planning efforts supported by the Department of Health and Human Services to plan for heavy ion cancer therapy research , 136.We note that there are ample clinical and scientific data confirming that heavy ion treatments are safe, effective, and can be beneficial in several cancer types.Therefore, we propose the following:1) The establishment of the first heavy ion therapy facilities in the U.S. should follow a dramatically different path from that of proton radiotherapy.a. We propose to build a limited number (2–3) of modest sized (1 or 2 treatment rooms capable of treating 300 to 600 patients per year) heavy ion centers, with capacity to accept the appropriate number of patients needed for rapid accrual into clinical trials but small enough to minimize the cost of construction, equipment, and operation. Using the SEER database cancer statistics and indications for heavy ion therapy used in Japan and Germany, the Mayo Clinic in Rochester, MN has estimated that there are approximately 44,340 patients diagnosed with cancers with indications for heavy ion therapy each year in the U.S. The Mayo Clinic in Rochester, MN treats approximately 1200 patients each year with proton therapy. In reviewing these patients, it is estimated that 12-13% would be eligible for heavy ion therapy. Therefore, a limited number of heavy ion therapy facilities in the U.S. would have negligible impact on the existing and planned proton facilities. A review of the Mayo Clinic Rochester Cancer Registry revealed that over 780 patients are evaluated each year who have indications for heavy ion therapy. Practically, the first heavy ion facilities will be developed sequentially rather than simultaneously. To accelerate the completion of phase III clinical trials for each indication for heavy ion therapy, near simultaneous development would be ideal to accrue patients to clinical trials expeditiously. Depending on the funding available, some of the centers may be gantry-less configurations with horizontal beams with upright (standing or sitting) patient positioning for basic research as well as clinical trials for an appropriate subset of disease sites.b. We hypothesize that the differential RBE and immunomodulatory effects of heavy ions in the cancer and healthy tissue sets heavy ions apart from proton radiotherapy. Hypofractionation should be the approach to test and implement heavy ion treatment clinically. If hypofractionation proves to be the most efficacious approach to deliver heavy ions, as appears to be the case based on past and ongoing trials in Japan and Europe, new reimbursement models that consider the entire course of treatment rather than per fraction reimbursement can be developed. This will help to keep the cost of a course of CIRT in line with a conventionally fractioned course of intensity modulated radiotherapy or proton radiotherapy. It will also allow for higher patient throughput. More importantly, the patients will complete their radiation treatment faster, return to work sooner, and require less support from their family, friends, and employers. Less acute toxicity also means requiring less costly supportive care and an increased ability to receive more systemic therapy if needed for the cancer treatment. Less acute and late toxicity also translates into better function and improved quality of life with lower costs associated with treating adverse events. Improved cancer control will also translate into fewer costs associated with treating recurrent cancer. The cost savings will be quantified in prospective clinical trials.c. We propose that the first U.S. heavy ion facilities be supported for an initial period by Federal and State agencies, possibly in partnership with commercial vendors and institutions to conduct clinical trials to define the comparative effectiveness and cost effectiveness of heavy ions until the relevant regulatory approval and health care service reimbursement models are established and implemented to help sustain the operation of the centers.via responsive, respected radiation oncologists with particle therapy and subspecialty expertise who will communicate openly and in a timely manner with referring physicians, patients and their families; access to photon and proton therapy on site to ease randomization, radiation therapists, certified medical dosimetrists and medical physicists with particle therapy expertise; educational infrastructure to train the next generation of heavy ion therapy providers, research infrastructure to conduct basic science and clinical research with an established track record of clinical trial expertise, and an NCI-designated comprehensive cancer and comprehensive academic medical center to provide surgery, medical therapy, rehabilitative services, social services, psychologic support, chaplain services for spiritual support, and concierge services to help patients and family members with referrals, the intake process, transportation, food, housing, entertainment, and insurance coverage.2) The ideal heavy ion treatment facility would have existing patient volumes to match the capacity of the facility, allow easy, rapid and efficient access 3) To continue supporting research and development that will lead to more compact, efficient, and less expensive heavy ion technologies. These will help to make heavy ion treatment accessible to more patients once its benefit is defined by the clinical trials conducted in the initial U.S. centers. However, the initial centers will need to be established with the current state of the art technology to conduct the trials as soon as possible.a. We expect that the initial U.S. heavy ion therapy systems, as any other new technology in its infancy, need to be safe, effective, and function reliably. Their primary function would be to deliver clinical beam to conduct clinical trials with basic and translational research components.b. We theorize that if clinical trials prove the benefit of heavy ion therapy in selected patients, these results, combined with cost-effective treatment strategies and technology advancements, will lead to appropriate proliferation of heavy ion centers driven by reduced cost, increased health care demands, and other market forces. But first, the U.S. needs the establishment of a limited number of supported heavy ion therapy centers now.4) Private, federal, state, and philanthropic funding support are essential to establish, construct, and equip a limited number of heavy ion centers in the U.S. that utilize currently existing technologies in the market.There is strong basic physics, biology, immunomodulatory and clinical evidence to document the safety, efficacy, and potential benefits of heavy ion radiotherapy to the extent that it must be clinically tested and implemented in the U.S. A limited number of centers in the U.S. should be established and supported now to conduct clinical trials in conjunction with basic and translational research to ascertain the appropriate indications for heavy ion radiotherapy. In the meantime, technological development should continue to develop more compact, efficient, and less expensive sources of therapeutic energy heavy ion beams, ion delivery systems, and dose verification processes. New reimbursement approaches should consider the course of treatment based on the hypofractionation benefit of heavy ions, leading to improved oncologic, quality of life and functional outcomes, and reduced health care costs in the long term. We assert that, even with higher initial investments, the overall value may be equivalent and possibly better than protons and other conventional radiotherapy modalities.All authors  have made substantial contributions to conception and design , acquisition of data , analysis and interpretation of data ; and have been involved in drafting the manuscript or revising it critically for important intellectual content ; and given final approval of the version to be published . Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content ; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved .Author RF was employed by Mayo Clinic.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Unwanted remains, discarded residues, and byproduct materials that are not required by the initial user are known as wastes. In Ethiopia, improper solid waste management becomes endemic and it affects the health conditions, comforts, and freedom of town communities. Improper solid waste management can also adversely affect infrastructure damages, socioeconomic conditions, and environmental and health problems. So, awareness creation among the communities is necessary. The main objective of the study was to assess the management of existing solid waste activities and reverse logistic systems in Tepi town. The impacts of improper solid waste management were reduced through waste accumulation, transportation, recycling, and waste removal. Available pieces of information for the study were gathered from 450 near house places and 549 survivals. The collected data were analyzed by using Vensim system dynamics software, and the obtained results were modeled by a system dynamic cause and effect relationship diagram. Finally, the appropriate recommendations for communities, municipals, and institutions were provided. Unwanted remains, discarded residues, and by-products of materials that are not required by the initial users are called wastes . GovernmIn cities and towns of developing countries, solid waste management deficiencies were visible in many areas with little or no attention in those urban centers at all . 30–50% Solid wastes that are carelessly disposed of and end up everywhere can poison and contaminate the world . So, theThe outcomes of the study help in developing solid waste management problem-solving policies for the local policymakers. It is also used for conducting a similar study at a regional level. Solid waste management improves the development and progress of any country . HoweverThe objective of the study is to search the solid waste management practices of Tepi town in three kebeles, reverse logistics of wastes, and waste disposals to reduce improper management of solid wastes and their impacts on health and the environment.To assess the existing practices of the solid waste managementTo identify influencing factors for the improper management of the solid wastesTo investigate an improper solid waste management impactTo be aware of the role of logistics in the management activities of the solid wastesThe specific objectives are as follows:Tepi is among the Ethiopian towns found in the southwest of Ethiopia at 621 km south of Addis Ababa on a latitude of 7°12′N, a longitude of 35°27, and an elevation of 1097 meters above mean sea level . The towDue to the nature of the study, mixed type of research was employed.Primary data: from direct observation, existing dried and semiliquid dirt will be captured through the camera. An in-depth interview and the designed questionnaire were distributed to key informant respondents. The secondary data sources were referred to and collected from books, journals, and other unpublished research studies.The sample size determination formula is taken from the Cochran formula .N = (Z2(pq))/e2, where N is the total number of directly effaceable population size, the margin error (e) is 0.03, the confidence level (Z) is 99%, and the target design will satisfy 85%. Stratified sampling targets will implement according to key informant groups.System dynamics, Excel, and Microsoft word were used. Tables, graphs, and logical arguments by narration were utilized. From captured data in the community, the researcher recorded directly in Tepi town all kebeles as a sample. It is shown in p value < 0.05. A 92% response rate was achieved; 366 out of the 549 questionnaires sent out were returned. Descriptive statistics were used for reporting the analyzed results.The survey study design was conducted in the near house places of Tepi town. The required data were collected from 450 near house places and 549 respondent individuals of the three kebeles through a multistage sampling technique. Then, the collected data were analyzed by SPSS statistical analysis software. Bivariate and multivariate analyses were done to identification of the good practices of solid waste management predictors. The level of significance between determinant factors was assessed by using the odds ratio with a 90% confidence interval and The outcomes of the study show that the management practices of solid waste in the majority of the households were poor. The age of the respondents was significantly correlated with the management practices of the household solid wastes in the study area. A second analysis was done by Vensim (system dynamics software), and the factors considered are community attitude, municipal commitment, intellectual contribution, phenomena, and lack of infrastructure in the town. The basic cause-effect relationship analysis was done using the following five factors. Those are solid waste quantity in Tepi town, dirt accumulation, dirt removal, waste management practices, reverse logistic system, kinds of businesses, and then finally wastage rate.From In this study, the data were gathered from only one town (Tepi), the respondent responses may be biased, and the attitudes of the respondents may also be misinterpreted. So, those were the limitations of the study, and it is better to collect the data from different cities. In addition to this, the number of participants and the sample size were also not sufficient enough. In the future, it is better to call all stakeholders and shareholders to participate in both genders in an equal ratio better to take. In this research, no governmental support or environmental specialist was included. Since the current study was conducted during the recession-era, the results found on the suffering period may be different.Last, it is better to use more variables than the variables that were included in this study to obtain a better result. So, it is recommended to conduct other vast and frequent longitudinal research and managerial support to Tepi town at the zonal level and woreda level.


Evidence confirmed that the demand for medical abortion (MA) increased significantly during the COVID-19 outbreak in many developing countries including Nigeria. In an abortion-restrictive setting like Nigeria, local pharmacies, and proprietary patent medicine vendors (PPMVs) continue to play a major role in the provision of MA including misoprostol. There is the need to understand these providers' knowledge about the use of misoprostol for abortion and the quality of information they provide to their clients. This analysis is focused on assessing the quality of care provided by both drug seller types, from drug sellers' and women's perspectives.This study utilized primary data collected from drug sellers (pharmacists and PPMVs) and women across 6 Local Government Areas in Lagos State, Nigeria. The core sample included 126 drug sellers who had sold abortion-inducing drugs and 386 women who procured abortion-inducing drugs from the drug sellers during the time of the study. We calculate quality-of-care indices for the care women received from drug sellers, drawing on WHO guidelines for medication abortion provision. The index based on information from the sellers had two domains—technical competency and information provided to clients, while the index from the women's perspectives includes an additional domain, client experience.n = 70), were pharmacists. However, far more than half of women 60% (n = 233) had visited PPMVs. Overall, the total quality score amongst all drug sellers  was higher than the total score calculated based on women's responses . Using our quality-of-care index, pharmacies and PPMVs seem to have similar technical competency , whilst PPMV's performed better on the information provided to client domain . Based on women's reports, PPMVs scored better on both quality of care domains  compared with pharmacies.Results show that the majority of drug sellers in the sample, 56% (In resource-constrained settings such as Nigeria, particularly in the context of health emergencies like COVID-19, there is the need to continue to strengthen and engage PPMVs' capacity and skills in dispensing and administration of MA drugs as a harm reduction strategy. Also, there is the need to target frontline providers in pharmacies for training and skill upscale in MA provision. Although there is limited documented evidence of its spread, the use of medical abortion (MA) to terminate pregnancies seems to be expanding in Sub-Saharan Africa (SSA) and drug vendors are expected to be important providers of these pills . BecauseGiven the role of local pharmacies and proprietary patent medicine vendors (PPMVs) as confidants and the immediate go-to sources of health care in Nigeria and other Sub-Saharan African countries, these drug sellers are likely to play a major role in the provision of misoprostol in the community. Because of their proximity, flexibility, as well as privacy, and less expensive services they offer relative to health facilities, drug sellers' services are mostly preferred, including visiting their outlets for the sale of misoprostol, a common MA drug , 7, 8.Medication abortion has been identified as partly responsible for the decline in severe abortion-related morbidity and mortality across the globe , 10. TheThe World Health Organization (WHO) has provided some clarity around safe abortion care and medication abortion provision guidelines. The updated guidelines for safe abortion, task sharing for abortion, and medication abortion recommend the task of conducting safe abortion and post-abortion care is within the purview of skilled healthcare professionals  . The guiThe focus of this analysis is therefore to assess the quality of care provided by both drug seller types, from drug sellers' and women's perspectives. The specific objectives are to (1) assess whether the quality of care differs by type of drug sellers (pharmacists vs PPMVs) and (2) to explore the consistency between the drug sellers' and women's reported quality of care by drug seller type.The National Health Research Ethics Committee in Nigeria and the Institutional Review Board of Guttmacher Institute, U.S.A. approved the study.This study is part of a larger prospective study that collected data from drug sellers and women aged 18 to 49 across 6 Local Government Areas in Lagos State, Nigeria . The samFor this analysis, we proposed quality of care (QoC) indicators within defined domains and computed indicator-specific QoC scores, an overall summary score for each domain, and a total QoC score drawing on the World Health Organization's guidelines for safe abortion, task sharing for abortion, and medication abortion guidelines , 21. We For some indicators (confirming completeness of termination and actions to address complications) there were no appropriate questions to evaluate quality available in the women's survey. Similarly, there was no question to evaluate the provision of pain relief in the drug sellers' survey. Each indicator within each domain was assigned a score of 1. If multiple questions were used to compute the score for an indicator, the score of 1 was split equally between the questions, and the relative contribution of the responses to the indicator score was measured. The scores for all questions associated with the indicator were then added up to derive the score for that indicator. For example, under the technical competence domain for drug sellers, the pregnancy confirmation indicator was defined using responses to two questions: whether they would ask the woman about their last menstrual period; whether they would ask if the women did a pregnancy test; and whether they know how to correctly calculate gestational age. For each drug seller, an affirmative to each of these three questions was assigned a score of 0.333 , and the scores were added up to derive a total score ranging from 0 to 1 with 1 representing the maximum pregnancy confirmation score see . The scoWe describe the socio-demographic characteristics of both categories of drug sellers and those of the women who obtained services from them. Thereafter we first compare the QoC reported by drug sellers and that reported by women, according to type of drug sellers. Then, we compare the QoC reported by women to those reported by the drug sellers who recruited them, by type of drug sellers. To ensure that these scores are comparable, we limit the indicators we use in both scales to those with questions available in both the women's and drug sellers' surveys. For this reason, we are unable to include the client experience domain in this comparison. Thereafter we performed a one-way analysis of variance (ANOVA) to assess whether the mean QoC score based on women's perspective varies by women's sociodemographic characteristics. We conducted this analysis for all drug sellers combined and separately by type. We used Stata version 16.0 for the statistical analysis.The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.n = 70) were pharmacists (n = 233) of women in our sample patronized PPMVs  and received more information than those who visited pharmacies . At the indicator level under technical competence, QoC from the women's perspectives was higher than from drug sellers' perspectives for pregnancy confirmation  and prescribed optimal dosage of misoprostol for first-trimester abortion . However, the score for the prescribed optimal route for misoprostol was lower according to women's perspectives . On the other hand, under the information domain, the quality of care for all three relevant indicators was higher based on drug sellers' responses compared to women's perspectives. For example, according to drug sellers, the results for information on the use of medication were higher for pharmacies  compared to PPMVs . Yet, according to the women, pharmacies were more likely to recommend pain relief to them than PPMVs .When we limit the computation of the QoC scores based on the drug sellers' perspectives to include only indicators with parallel questions available within the women's scale, there is no change from the pattern of results reported above. However, there was a reduction in technical competence scores and an increase in the information given to client scores for both categories of drug sellers . CompareF = 4.04, p = 0.003).Our findings show that women are more likely to obtain MA at PPMVs than at pharmacies. This is in line with existing evidence that shows that PPMVs act as the first point of care for health-seeking including for family planning and other reproductive health services among the majority of the Nigerian population, particularly in rural and lower-income communities , 22, 23.Comparing the QoC outcomes for PPMV and Pharmacies from both women's and drug sellers' perspectives yields interesting results. The similar levels of QoC  found among both groups of drug sellers further underscores the importance of the on-the-job training that the PPMVs received. The training reported appears to compensate for the lower level of education and formal health training reported by PPMVs which we initially hypothesized would result in poorer technical knowledge about MA and prescription skills. Several intervention studies across low- and middle-income countries, including Nigeria, point to the effectiveness of such on-the-job training concerning QoC , 28. WitThis is particularly critical as the role of drug sellers evolve and they are utilized more frequently for frontline SRH care , with thThe higher QoC score from the drug sellers' perspective compared with women in the information-provided domain, and the reversed case in the technical competence domain is noteworthy. The potential reason for these findings may not be unconnected with the experience and/or expectation of both groups on the subject. For instance, women with limited skills and knowledge about MA might be more likely to have overstated the technical competence of the drug sellers. On the other hand, the drug sellers, probably with the perception that self-medication is common in the society, may be more likely to have overstated the adequacy of the information they provided to the women. The implication of this kind of finding is the need for better education both at the provider and community levels, including education about ensuring that services are provided without an assumption about the state or level of knowledge of the client.Our study had several limitations. First, we selected LGAs purposively and our study is neither representative of Lagos State nor Nigeria. Our complete sample only included drug sellers who admitted selling misoprostol, participated in the KAP survey, agreed to recruit women, and successfully did so. Our sample of women was similarly limited. These drug sellers may thus differ in unmeasured ways from sellers operating within the study areas who do provide MA but did not disclose it to the study team. Second, we only interviewed one person behind the counter of the drug store and when comparing practice with the knowledge there is no guarantee that women received care from the same person we interviewed. Also, there is the possibility of clustering in the sample of women, given that some will have been served by the same pharmacy staff. That said, 61% of PPMV stores had only one staff member so for that subgroup, it is more likely the drug seller information is consistent. Third, we constructed a simple scale to assess the quality of care assigning equal weight to all the questions in each domain with no external validation of the scale or evidence of its impact on outcomes. However, there are currently no published validated scales to evaluate the quality of care for MA amongst drug stores, and the variables included were chosen based on the WHO guidelines for MA provision to reflect recommended practice during the study.Despite the relatively low quality of care scores and the knowledge-practice gap, our previous publication  shows thDrug sellers' knowledge about the correct usage of the medications and ability to convey key information to women seeking their services is crucial to ensuring women can safely and effectively self-manage their medication abortions. Therefore, on-the-job training for these kinds of frontline providers is an important harm-reduction mechanism to reduce the risk of morbidity and mortality due to unsafe abortions. It is also critical to facilitate independent access to clearly written information on what to expect when using MA, how to identify a complication and seek post-abortion care if necessary, and how to access post-abortion counseling in local languages to support women on this self-management pathway. However, studies have shown that such training for pharmacy and PPMV staff may not yield optimal results due to the high mobility and turnover of staff , 32. AlsThe COVID-19 experience and its effect on sexual and reproductive health behavior suggest the likelihood of increasing unwanted pregnancies and demand for MA in Nigeria. It is expected that drug sellers will continue to play significant roles in the provision of misoprostol for abortion, particularly during health emergencies. This highlights the need to promote their skills and experience with misoprostol service provision as a harm reduction strategy.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the National Health Research Ethics Committee in Nigeria and the Institutional Review Board of Guttmacher Institute, U.S.A. approved the study. The patients/participants provided their written informed consent to participate in this study.OO, AB, and AA conceptualized the research idea and developed the research plan. AA drafted the introduction and discussion. OO and TE drafted the methodology, conducted the data analysis, and wrote the results. All authors contributed to the article and approved the submitted version.This article was made possible by a grant from the Dutch Ministry of Foreign Affairs (#4000000282).Author OO was employed by Vital Strategies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.The views expressed are those of the authors and do not necessarily reflect the positions and policies of the donors.


Dietary intervention is generally accepted as the mainstay of treatment for patients with disorders of amino acid metabolism (AAMDs). However, dietary adherence to a low-protein diet is always reported as a common challenge among these patients. This study explored the perception of barriers and motivators to dietary adherence among caregivers of AAMD patients in Malaysia. Twenty caregivers of children with AAMDs receiving ongoing treatment at the genetic clinic participated in an online focus group discussion from November to December 2021. Findings showed a total of five interrelated main themes identified from focus group discussion (FGD) exploring parents’ experiences related to the management of their child’s daily diet. The barriers to dietary adherence were burden of dietary treatment, diet and dietary behavior, parenting challenges, limited knowledge related to dietary treatment, and challenges in healthcare system delivery. Key factors facilitating good dietary adherence include good knowledge of dietary treatment, parental coping strategies, social coping, and dietary behavior. In conclusion, despite the existence of several barriers to the implementation of dietary treatment, caregivers managed to use a wide range of coping strategies to overcome some, if not all, of the challenges. The important next step is to develop, in conjunction with multidisciplinary healthcare professionals, feasible implementation strategies that could address these barriers and at the same time improve the quality of life of caregivers. Disorders of amino acid metabolism (AAMDs) are among the groups of inherited metabolic disorders (IMDs) that lead to the accumulation of toxic substrates in the blood, urine, and body tissues, including the brain ,2. This It is now well established from a variety of studies that individualized dietary therapy plays an important role in the treatment of AAMD, as it is characterized by a disruption of the metabolism of amino acids, which are the main constituents of the daily diet ,7. The cDespite regular follow-up with multidisciplinary healthcare professionals, non-adherence to dietary treatment remains the main challenge in the management of patients with AAMDs ,15. FurtThe non-adherence to dietary therapy might be attributed to the extremely restrictive nature of the dietary treatment. Adherence to a rigorous dietary regime, such as a vegetarian-like diet, was found to be one of the biggest challenges for the patient and the entire family, particularly at the early stages of diagnosis . DifficuHowever, social support from friends and family, as well as healthcare providers, such as metabolic pediatricians and dieticians, was identified as a motivator for dietary adherence ,24. FurtOf late, researchers have increasingly utilized the focus group discussion (FGD) approach to elicit the perception of patients with regard to adherence to a dietary treatment . This meTo date, patient experiences regarding dietary management have been ascertained through the broader experiences regarding the management and treatment of disease, as well as its impact on child and family life, while neglecting the issue of dietary treatment, where diet was only a minor part of the study ,27. MorePhenomenology was used as a qualitative approach in this study. This approach was used to understand the context of the experience in managing daily diet, including the barriers and motivators among the caregivers. During the discussion, the caregivers expressed how they coped with the dietary restriction at home and within the social community including schooling and traveling into a phenomenon .The participants of this study included caregivers of patients diagnosed with AAMDs. In brief, the patients are receiving active treatment at the genetic clinic, Hospital Kuala Lumpur (HKL), which is the national referral center for IMD patients. Caregivers aged above 18-year-old with patients aged between 6 months - 18-year-old were included in this study. Patients who had not attended an appointment in the genetic clinic for the last 2 years since the date of data collection were excluded. Purposive sampling with the maximum variation strategy was used in this study to achieve a sample of caregivers of children of different races, age groups, clinical conditions, and types of AAMDs. Since metabolic disorders are a heterogeneous group of disorders, employing this strategy enabled the researcher to identify essential and variable barriers faced in dietary adherence experienced by caregivers within a varied context .According to Guetterman , a samplThis study was conducted by way of a virtual platform, with the use of 2 forms of video conferencing software: Google Meet and Zoom, from November to December, 2021, in view of the advent of the COVID-19 pandemic. The use of two different platforms served to accommodate participant preferences. The virtual focus group discussion (FGD) was conducted by 2 researchers: one to moderate the discussion, and the other to take down notes. The female moderator, the first author, is a postgraduate student researcher with a Bachelor’s degree in dietetics, trained in qualitative research. The link for participation in the meeting was provided to the caregivers one day prior to the FGD. The caregivers were reminded of the date and time of the discussion.The discussion guide was established to ensure consistency across the various focus groups. The questions covered a broad scope of literature related to AAMDs , which wThe Consolidated Criteria for Reporting Qualitative Research (COREQ) framework was used to guide the reporting of the findings . The ATLThe data collection and analysis were carried out concurrently so that new emerging themes could be queried or probed further in the subsequent FGD. A Microsoft Excel spreadsheet was used to generate a matrix; the data were ‘charted’ into the matrix, in which the codes were charted in columns, and the cases were charted in rows . SubsequMultiple approaches were used to enhance the rigor of data analysis. Firstly, member checking was carried out by sending back the transcripts, which were all verbatim, to the participants for checking. Next, triangulation was used by involving at least two related data sources, such as official records, observation, and field notes. The transcript was checked against the official records, such as the participants’ diet recall to determine whether any variation emerges from the two data sources. The ethical approval to obtain the official record was acquired from a previous retrospective cross-sectional study conducted to determine the nutritional status of the patients. Besides that, observation was used during the process of the participants’ recruitment throughout a previous cross-sectional study. The caregiver’s feeding practices and the children’s dietary behavior of the children were observed at the genetic clinic, Hospital Kuala Lumpur (HKL). Lastly, the transcript was checked against the field notes made by another research enumerator to ensure the validity of the data . BesidesA total of 20 caregivers from 18 families signed informed consent and took part in five virtual FGDs. Although there was refusal to participate in the study, data saturation was reached at the 5th focus group  and at tIn this study, five themes emerge as barriers to dietary adherence. Namely, these are the burden associated with dietary treatment, diet and dietary behavior, parenting challenges, limited knowledge regarding dietary management, and challenges associated with healthcare system delivery. Selected quotations that exemplify each theme and subtheme are provided as The dietary treatment for AAMD patients includes the restriction of natural protein in the daily diet to a limited amount. This poses a challenge for caregivers and children under their care in terms of food selection when eating out, making decisions on daily food choices and portions, and the preparation of daily meals. Moreover, a diet low in natural protein is viewed as contradictory to the ‘healthy eating’ concept. The dietary treatment during sick days, which includes omitting the consumption of natural protein and replacing it with the consumption of a medical formula, is also considered a challenge.One of the most frequently perceived burdens was the tedious and complex process associated with the preparation of a low-natural-protein diet. In order to deliver an accurate amount of natural protein in each meal, the caregivers were required to weigh and calculate every food item before serving, which is perceived as time-consuming and stressful. Furthermore, caregivers faced difficulties in calculating the accurate amount of protein, especially when it came to new food items. Some caregivers experienced problems during the preparation of unfamiliar low-protein food for their children.Caregivers also faced difficulties deciding on a suitable low-protein diet when eating out, as most of the foods on the menu in restaurants and school canteens are prohibited to the children under their care.Issues related to patient dissatisfaction regarding the limited food portion served were also raised during the discussion session. The food portion needed to be strictly controlled so as not to exceed the prescribed natural protein intake. It is notable that the majority of cereal-based food comes with a small amount of natural protein.A variety of perspectives were expressed in terms of food choices. Among the most daunting challenges was the need to completely exclude high-protein foods, such as meat, eggs, milk, and cheese, as well as their products, from the patient’s diet. This drastically reduced their food choices. However, a problem also arose when it came to snacks such as chocolate, ice cream, cookies, and cakes, which come with prohibited ingredients but are usually highly favored by children. Another issue was the limited variety of special low-protein food (zero protein) available in this country.Concerns were raised regarding the nutritional value of low-protein products, which are high in carbohydrates and sugar, as their consumption is in contradiction to the ‘healthy eating’ concept.The need to omit the consumption of intact protein  during sick days was one of the challenges mentioned by the caregivers, as the child under their care still craved prohibited natural protein food during this period.The diet and dietary behavior of AAMD children were also identified by the caregivers as major challenges. This broad category was further divided into two subthemes: food choice and eating behavior. The results from our investigation indicated that some children were exceedingly selective about certain food items (such as vegetables) and special low-protein food. Eating behavior refers to the actual act of consumption, including eating habits, portions, frequency, and disordered eating symptoms .Food preferences varied among AAMD children. While some are content with the same diet routine, and shy away from trying something new, others are not in favor of consuming low-protein products.Several issues related to the children’s eating behavior were reported. Among them were the issues of vomiting due to overeating, a prolonged mealtime duration due to poor self-feeding and sensory processing skills, and undesirable weight gain due to overeating.The imposition of strict restrictions poses many challenges for parents and children. These challenges included the stress encountered during meals with peers, a poor understanding of the conditions that need to be complied with, and personal factors, such as poor self-control with regard to food portions and poor self-care ability due to emotional problems.Some caregivers mentioned that their children experienced feelings of discomfort during certain social situations such as when eating with their peers or siblings. While their craving to try the food consumed by their peers or siblings increases as they grow older, their condition prohibits them from doing so.During this study, it was uncovered that the dearth of pre-school establishments willing to accommodate the dietary needs of children with AAMD was among the sources of stress for their parents. Furthermore, parental stress also occurred when there was a demand from the parents for their child to consume more food and metabolic formula, but the child was unable to take them and vomited them out. In addition to that, the awareness and understanding of the dietary requirement, clinical signs, and symptoms related to metabolic disorders seem to be poor and limited among the public, resulting in parental stress.Poor self-control often took over when children were left without parental supervision. In such a situation, children may consume more food than the recommended portion, as well as skip the consumption of their metabolic formula, in favor of consuming food prohibited to them.Poor self-care ability of children with AAMD can be attributed to the impact of their condition on their neuropsychological profile. Some caregivers reported that the children under their care were not up to the mark when it came to managing their own daily activities. This included the preparation of their metabolic formula, which often requires the assistance of a teacher.Limited knowledge was observed to be among the major barriers to good dietary management. This issue was mainly associated with uncertainty about the nutritional value of a certain food, poor food preparation skills, and limited knowledge about dietary management for sick days, as well as for a metabolic crisis.Several participants were generally uncertain about the accurate protein content in food. This led to less variation in the daily diet of the children, as the caregivers were reluctant to introduce food without verifying its protein content. Uncertainty in this area also led to underestimation of the daily natural protein intake.The limited knowledge and lack of creativity with regard to low-protein food preparation led to food boredom among children and consequently the consumption of less (inadequate) food.Several caregivers felt challenged when it came to dietary management in a sick-day situation. In our study context, the challenges include solutions to a metabolic crisis, as well as remedies to a lack of appetite and vomiting, which can lead to an inadequate intake of natural protein.A few participants expressed their concerns regarding the current healthcare system. To begin with, they were of the opinion that the hospital’s provision of low-protein food is exceedingly limited.Furthermore, the lack of communication between healthcare providers was looked upon as a hindrance to the delivery of good service and information.The key factors motivating good dietary adherence include good knowledge of dietary treatment, parental coping strategies, social coping skills, and good dietary behaviors. Selected quotations that exemplify each theme are provided in the Generally, the participants demonstrated good knowledge of the risk factors, complications, and dietary treatments related to metabolic disorders in terms of daily diet planning and protein calculation, as well as specific management abilities to cope with sick days.Most of the caregivers were able to identify natural food sources low in protein content and estimated the required food portion visually or with the use of household measurements. Their efficiency in this area improved with experience. Generally, the caregivers were aware of the children’s natural protein requirements and prepared their daily diet according to the directives from healthcare professionals. Several caregivers were also familiar with the sick-day regime and were able to execute remedial steps such as increasing the dosage of branched-chain amino acid (BCAA) supplementation and restricting the consumption of solid food.Some caregivers displayed creativity with regard to the preparation of the children’s daily diet. This included the use of a wide variety of low-protein ingredients, such as corn starch instead of normal flour, so that the children would not be bored by the same food every day.Most of the caregivers emphasized the importance of taking natural protein within the recommended intake to prevent complications such as hospitalization, neurological impairment, and disability. A few participants emphasized the importance of an accurate protein intake for the children to ensure their proper development. Aside from the focus on natural protein, the significance of consuming a prescribed metabolic formula to ensure the child’s adequate energy intake was also mentioned.Apparently, caregivers managed the complexity associated with restricted diets and treatment regimens through the employment of various coping strategies. These include flexibility and moderation with regard to the child’s diet, self-preparation of food when eating away from home, education on nutrition, and equipping the child with effective self-care attributes.Caregivers practiced moderation by reducing the normal portion of prohibited food to satisfy the child’s craving for such food. Caregivers also reduced the normal portion of certain food in situations where they were uncertain about its protein content level. As for flexibility, this comes into play with adjustments to the daily meal plan to counteract the effects of overconsumption or inadequate consumption of certain food.To cope with the challenge of providing the children with suitable food, when eating away from home, the majority of caregivers equipped themselves with a cooker and raw ingredients and self-prepared the meal for the children or prepared the children’s food and the metabolic formula at home for consumption during break time at school.Caregivers also provided education for their children on the complications associated with the consumption of ‘prohibited’ food and coached them on the proper selection of food when eating away from home.As children grow in maturity, they are expected to take on more responsibilities when it comes to their diet treatment. These responsibilities include the preparation of their metabolic formula and the selection of suitable food when eating out.In the context of this study, social support refers to the emotional or instrumental support extended to caregivers by the community, which includes family members, other caregivers, teachers in schools, and operators in the healthcare system.In the context of the dietary treatment process, the healthcare system represents the main support of caregivers. Most caregivers considered the printed nutritional booklet provided by the dietitian as their main source of information. Several participants stated that they would consult the dietitian and/or doctor when in doubt about issues relating to food or the metabolic formula. Meanwhile, several caregivers were in favor of dietetic counseling sessions as a means of improving their knowledge of nutrition-related issues.Caregivers seek the support of teachers when the children under their care begin schooling. By adhering to the instructions from parents, teachers ensure that the children afflicted with AAMD are provided with an appropriate diet while at school. Teachers also carry the responsibility of preparing the metabolic formula for children who are self-care impaired.The involvement of family members (such as the patient’s grandparents and siblings) with regard to the patient’s food consumption can go a long way towards ensuring that their diet complies with parental instructions.The information and experiences shared by peers can serve to enhance the quality of care delivered by a caregiver.Good dietary behaviors, such as non-picky food consumption, having a consistently good appetite, and adherence to a regular timing for meals, will serve to ensure the effectiveness of the dietary treatment.Caregivers of children who are not picky about the food they consume will face lesser challenges when it comes to the preparation of suitable food.Caregivers of children who maintained a good appetite, even throughout sick days, have less cause for worry about their nutritional status.A participant reported that the child under her care is very consistent when it comes to the timing for main meals, and no snacks or other food are taken in between. This facilitated adherence to the prescribed natural protein requirement.This study employed a qualitative approach of the FGD to investigate the barriers and motivators to dietary adherence among caregivers of AAMD patients undergoing medical and dietetic treatment in Malaysia. With this undertaking, we offer healthcare professionals innovative information on patient needs and strategies aimed at improving the patient’s self-management of their nutritional requirements.The burden of dietary treatment tops the list of barriers to dietary adherence. We discovered that the majority of caregivers consider the daily diet preparation process complex and arduous. They also perceived the need to comply with dietary restrictions in terms of natural food choices and portions, as well as the strict sick-day regime, as extremely challenging. Previous studies have demonstrated that the dietary treatment significantly affected the quality of life (QoL) of both the patients and their caregivers ,40,41. AAnother barrier identified through this study was the parenting challenges encountered during the care of children with AAMDs. According to the results attained, most caregivers of older children (>7 years old) faced greater challenges in their effort to maintain the natural protein intake within the amount prescribed by healthcare professionals. This finding is in close agreement with those from previous studies, which reported that the decline in dietary compliance and metabolic control accelerates in tandem with the increase in age ,49. ThisThe findings from this study also showed that certain dietary behaviors significantly hampered the caregiver’s effort to practice dietary adherence. In terms of food choice, the majority of caregivers stated that their children were choosy about food and reluctant to try new food. This behavior could be attributed to the limited exposure to varied foods in the weaning period . ConsequGenerally, this investigation revealed that the majority of caregivers were knowledgeable about the recommended daily natural protein intake requirement and the protein content in food products . FollowiMost of the caregivers rated the disease-specific care provided by the inherited metabolic disorder specialists and metabolic dieticians as excellent. Similarly, qualitative work involving caregivers of children with inherited metabolic disorders revealed that they are highly satisfied with the treatment their child received at the specialist metabolic clinic, and the metabolic health care providers were appreciated for their supportive attitude ,23. ThesTo the best of our knowledge, this is the first undertaking in Malaysia to explore the barriers and motivators to dietary adherence among the caregivers of AAMD patients. Some of the findings attained through this study are unique and can serve to improve the dietary adherence of AAMD patients in Malaysia. Our use of a virtual meeting platform to conduct the FGD ensured a low dropout rate and a demographically diverse group of participants with a wide variety of AAMDs. However, the use of an online platform is not without drawbacks. Some caregivers were unable to participate in the FGD due to their lack of expertise regarding the use of online platforms, their poor access to an internet connection, or their busy work schedule. Some caregivers were also forced to turn off their video due to poor connectivity to improve the quality and clarity of the audio input. Consequently, this hindered the ability of the moderator to discern the verbal expressions of the participants. Generally, however, although the verbal expressions were not clearly apparent, the virtual FGD facilitated the open sharing of information, opinions, and feedback among the participants regarding the subject matter.This study successfully identified several factors, which represented the barriers and motivators to dietary treatment adherence. These factors include knowledge of dietary treatment, eating behaviors, and parenting strategies. To mitigate parental stress due to poor self-control and social stressors, patients should be encouraged to be their own best advocates in the medical decision-making process. The patient with self-care ability should be educated on their condition is lifelong and requires lifelong dietary management. Tailored counseling for individuals, or psychoeducational group interventions, should be made available to patients equipped with the mental capacity to independently care for themselves. This will enable them to enhance the understanding of their medical condition and related treatment needs, as well as execute the required adjustments to their behavior ,60. Futu


Identifying the technologies that will drive technological changes over the coming years is important for the optimal allocation of firms’ R&D resources and the deployment of innovation strategies. The citation frequency of a patent is widely recognized as representative of the patent’s value. Thus, identifying potential highly cited patents is an important goal. A number of studies have attempted to distinguish highly cited patents from others based on statistical models, but a more effective and applicable method needs to be further developed.This paper treats the prediction of later patent citations as a classification problem and proposes a novel framework based on machine learning methods. First, a indices system to identify highly cited patents is constructed using multiple factors that are believed to influence citation frequency. Second, various machine learning models are utilized to identify highly cited patents. The optimized model with the best generalization capability is selected to predict the future impacts of newly applied patents, which may be representative of emerging significant technologies. Finally, we select the electric vehicle (EV) domain as a case study to empirically test the validity of this framework.The optimized support vector machine (SVM) model performs well in identifying highly cited EV patents. Technological frontiers in the EV domain are identified, which are related to the topics of information systems, batteries, stability control, wireless charging, and vehicle operation.The good performance in prediction accuracy and generalization capability of the method proposed in this paper verifies its effectiveness and feasibility. The anticipation and forecasting of technological changes are important because technological advances have become increasingly fast and complex. The core issue is the identification of current technologies that will drive technological changes over the coming years . While aCompared with citation prediction research on academic papers , 10, relThese studies have shed light on the impact factors that are correlated with citation frequency. However, most studies have not comprehensively considered multiple factors. For instance, even though many previous studies have demonstrated the close relationship between science and technology , 16, stuThis paper is organized as follows. First, we describe the source data used in the analyses and explicate the methodology, including the variables representing the quantitative characteristics of patents and the machine learning models. Second, we present the results of the analyses, in which the optimized model is selected and the contributions of the factors to citation frequency are calculated based on the model and are used to predict potential highly cited patents. We use the EV domain as a case to illustrate this method and verify its effectiveness. The last section concludes.The patent data were downloaded from the patent search tool PatSnap, and keywords related to the research domain were searched in US patents. The obtained data included the patent number, associated classifications, numbers of inventors, number of claims, and other useful information that may contribute to the citation frequency. The citation frequency within 3 years could also be obtained directly from PatSnap.Fcited), which is proven to be representative of the core technology [The response variable in this paper is the citation frequency within 3 years of the patent : the number of International Patent Classification (IPC) codes attributed to the patent, which can indicate the breadth of technological knowledge of the patent. It has been proven to be positively related to citation frequency [Number of associated classifications (requency . A previrequency . TherefoVCnew): the number of IPC codes that first appeared in the domain. Previous studies have shown a correlation between innovation and new technological knowledge [Number of new associated classifications : the number of new combinations of IPC codes (at the bottom level) in the patent. Based on technological convergence theory, the fusion of different technological categories can lead to disruptive technology [Number of new combinations of associated classifications : a commonly used index in the assessment of patent value. A previous study showed that patents representing large international patent families are particularly valuable [Number of patents in patent family , number of pages (PG) and number of claims (CL), which can represent quantities of descriptions or can be specific to patent applications, as the explanatory variables [In addition, referring to previous studies, this paper adopts the number of figures : previous studies have found that highly cited patents have more citations than others [Number of backward patent citations : this indicator reflects the diversity of technological knowledge sources. Many researchers have found that technological diversity is correlated with the novelty of patents, which is related to citation frequency. Examples include Rosenkopf and Nerkar [Number of associated classifications with backward patent citations (d Nerkar  and Yoshd Nerkar . Their sNTciting): A previous study showed that the novelty of backward citations is related to patent value [Novelty of backward patent citations , number of scientific citations (VSciting), number of categories associated with the scientific citations (SCciting), and novelty of scientific citations (NSciting) as the quantities specific to the scientific knowledge source. In this paper, the scientific citations are papers indexed by Web of Science, which are identified using the MATLAB tool. The classifications of journals by Journal Citation Report (JCR) are utilized in this paper to define the scientific categories.The relationship between scientific knowledge development and technological development is widely recognized as one of the most important and complex aspects of technological evolution. Gittelman and Kogut  establisIV): A previous study found that the number of inventors has a positive relation with citation frequency in most IPC sections [Number of inventors (sections . This inVPaverage) is utilized as the explanatory variable. Many studies have shown the important role of personal capabilities on patent value [VPfirst) are used to measure personal capability.In addition, the average number of patents of all inventors , random forest (RF), and extreme gradient lifting (XGBoost).SVM is a data classification technique developed by Cortes et al.  accordinRF was proved and completed by Breiman in 2001 , is a clXGBoost was proposed by Chen and Guestrin , is baseThe accuracy rate, precision rate, recall rate, and F1 score  are usedThis study takes the electric vehicle domain as an example to verify the validity of the identification model we proposed. We searched the patent data using the keywords “electric vehicle” and “electric car” by utilizing the patent search tool PatSnap, which searched 13732 US patents from 1976 to 2021 . Considering the balance and feasibility of the data requirements, the median of the cited frequency data in each class is used to decide the threshold values. The difference between the medians in C0 and C1, should be approximately equal to the difference between the medians in C1 and C2. VC and CCnew, FG and PG, VTciting and TCciting, VPaverage and VPfirst. Considering the multicollinearity between variables judged from the observed values of the correlation coefficients, we included only one variable in each pair of them in the following analyses. VC, PG, TCciting and VPaverage are selected because they show slightly stronger correlations with the response variable. Thus we obtained 13 explanatory variables.After classification, we discussed the relationships between explanatory variables and between each of these and the response variable based on Pearson correlation test. VC and FM have positive values of the Pearson correlation coefficients with Fcited. And compared with the other variables, PG and FG show relatively strong correlations with Fcited. These are followed by TCciting and CL. However, correlations between the explanatory variables and Fcited are generally weak. Most of the absolute values of the correlation coefficient with Fcited are less than 0.20. Fcited.In general, all explanatory variables except At last, we obtained the highly cited patent identification indicator system of the EV domain , which iBased on the SVM, RF, and XGBoost models, we randomly selected 80% of the data for training, and the other 20% of the data are utilized for performance testing. The parameters of each model are optimized based on their performance, and the accuracy, precision, recall, and F1 score are used to measure the performance of the models. To compare with the previous methods, this study also conducts the regression models, including the multiple linear regression and multiple logistic regression, which have been widely used in the previous studies , 12–14. This paper utilizes patents published in 2017 and 2018 to verify the generalization ability of the machine learning models. According to the methods utilized in Section 3.2, the index system for the 1840 patents is constructed and applied to the various machine learning models to predict their citation frequency after 3 years. Compared with the actual data, the accuracy of the three models of SVM, RF, and XGBoost is 0.998, 0.997, and 0.986, respectively, which further supports the feasibility of our method. The SVM model, with the best generalization ability, is used to construct the index system of highly cited patents  and predIt is also interesting to note that in contrast to the important effect of the reputation of the author on the citation frequency of a paper , the chaNPL) are only informative about the value of pharmaceutical and chemical patents but not other technical fields [Finally, the scientific source indices, which include the number of scientific citations and the number of scientific categories, show weak relationships with the citation frequency. This might be because patents rarely cite scientific papers. For example, in this study, only 392 patents cite 1732 scientific papers. In addition, a previous study showed that references to nonpatent literature (l fields .Cortext) based on the titles and abstracts of the patents. Jointly considering the coherence score [Based on the optimized SVM model, we predict the potential highly cited patents by applying a total of 4522 newly published patents in the years from 2019 to 2021. A total of 245 potential highly cited patents are identified, and the related topics are extracted using the LDA model and the extraction of terms  cloud system is regarded as a potentially synthetic solution for high-level automated driving to improve safety and optimize traffic flow in intelligent transportation . Among tStability control is related to insulated and fire-retardant, tire state detection, and braking technologies. The operation of an electric vehicle produces a significant amount of heat, which requires coolant to help control temperature and guarantee safe operation . In addiWireless charging is a challenging issue in the domain of EVs. It includes the magnetic coupling design, charge monitoring, and power transmission technologies. It has the advantages of convenience and high speed and is expected to have bright development prospects. Magnetic field coupling has high reliability, flexibility, and security and has been successfully used in wireless charging in several domains . HoweverVehicle operation topics include the technologies of power management, parking space detection, brake operation, and reaction operation. Due to the large current, the graphene cell can be charged quickly and has excellent future prospects . With thEarly identification of the technological frontier is important for the optimal allocation of enterprises’ R&D resources and the formulation of government innovation strategies. Many scholars have used bibliometric methods to identify the technological frontier, and the citation analysis method has been widely used. However, it takes a certain amount of time to accumulate citations of patents. The existing citation analysis method cannot incorporate newly published patents, which are potentially highly cited, into the data collection of the important patents used to identify the technological frontier. Therefore, this paper proposes a novel framework for identifying the technological frontier by utilizing classification algorithms based on machine learning models. The electric vehicle domain is used to verify the availability of our method.Compared with the multiple regression model used in previous studies, the classification algorithm based on machine learning models used in our study has many advantages. First, the citation frequency of patents often shows a long-tail effect, which is not suitable for a regression model. Second, coarse-grained models perform better in fitting accuracy and have better generalization abilities. In addition, this study considers a broader scope of factors that may affect citation frequency than previous studies, which could increase the accuracy of the results. Even though our new additional indices related to the characteristics of scientific citations show weak correlations with citation frequency, their positive correlations also support the relationship between science and technology.The frame we propose to study the technological frontier is open, and additional machine learning models could be used to analyze the highly cited patents in a domain and examine the relations between different variables and citation frequency. Thus, one can predict the citation frequency of new patents once published and identify the technological frontier based on potential highly cited patents. This study can help us further understand the relationships between influencing factors and the citation frequency in a domain and contributes to the intelligent identification of the technological frontier in a timely and accurate manner.There are also some limitations in this study. First, we suggested the indices using the literature reviews, in future studies, more factors that may affect the citation frequency of patents should be introduced. Second, more machine learning models could be utilized to analyze the technological frontier, and we could select the model with high classification accuracy. In addition, to clarify the different factors that affect the citation frequency of patents in different domains, we would like to conduct further analysis of various technological domains, especially the domains with significantly different technological knowledge.S1 File(XLSX)Click here for additional data file.