The rapid advancement of telehealth technologies has the potential to revolutionize healthcare delivery, especially in developing countries and resource-limited settings. Telehealth played a vital role during the COVID-19 pandemic, supporting numerous healthcare services. We conducted a systematic review to gain insights into the characteristics, barriers, and successful experiences in implementing telehealth during the COVID-19 pandemic in China, a representative of the developing countries. We also provide insights for other developing countries that face similar challenges to developing and using telehealth during or after the pandemic. This systematic review was conducted through searching five prominent databases including PubMed/MEDLINE, Embase, Scopus, Cochrane Library, and Web of Science. We included studies clearly defining any use of telehealth services in all aspects of health care during the COVID-19 pandemic in China. We mapped the barriers, successful experiences, and recommendations based on the Consolidated Framework for Implementation Research (CFIR). A total of 32 studies met the inclusion criteria. Successfully implementing and adopting telehealth in China during the pandemic necessitates strategic planning across aspects at society level (increasing public awareness and devising appropriate insurance policies), organizational level , and technological level . WeChat, a widely used social networking platform, was the most common platform used for telehealth services. China’s practices in addressing the barriers may provide implications and evidence for other developing countries or low-and middle- income countries (LMICs) to implement and adopt telehealth systems. Telehealth2, which employs telecommunications and virtual technologies to deliver care outside of traditional clinical settings, has been proven to be effective in improving healthcare delivery, including patients triage3, consultation4, treatment5, clinical care6, and education of healthcare workers and patients7.The COVID-19 pandemic introduced extreme burden to health systems globally9. According to the World Bank, LMICs are defined as economies with a gross national income (GNI) per capita less than $12,535 in 202010. China, the largest developing country, has made significant strides in integrating rural and urban areas, agriculture, and industry into cohesive networks of capital, labor, and commodities in the past decades10. Despite these efforts, spatial separation, economic disparities, and differences in social service provision have contributed to persistent rural-urban inequalities11. In 2020, the rural population in China was reported to be 38.57% of the total population12. Despite the increased investment in healthcare and several major healthcare reforms in China, the rural-urban divide in healthcare resource distribution and health outcomes continues to widen15. This disparity poses an even larger threat during the COVID-19 pandemic, as timely and high-quality healthcare service is crucial for vulnerable populations in rural areas16.The pandemic has even more severe impacts on developing countries or low- and middle-income countries (LMICs) due to the limited medical resources and constrained economic situations18. These lessons and implications may not be applicable to developing countries or LMICs, where infrastructure is less established, and resources  are limited and unevenly distributed. Therefore, it becomes imperative to understand and share sustainable and scalable strategies for implementing and adopting telehealth systems in developing countries or LMICs. This systematic review aims to comprehensively summarize the characteristics, barriers, and successful experiences in implementing telehealth services in China during the COVID-19 pandemic. This systematic review has three contributions: (1) It offers an in-depth exploration of a specific country, providing detailed insights into the characteristics of telehealth implementation within that particular context; (2) by applying the lens of implementation science, the review synthesizes the findings and offers practical strategies that can be adapted to developing countries or LMICs with varying levels of economic development; (3) providing specific recommendations for building telehealth systems, including guidance on infrastructure and mechanisms, which may be useful to other developing countries or LMICs looking to develop their own telehealth capabilities.Although previous studies of telehealth implementation in developed countries or high-income countries provide some useful implications, the telehealth systems were often built upon established technological infrastructure with sufficient economic support, well-trained workforces, and target user populations with higher digital literacy19. The protocol for this systematic review was available at PROSPERO (CRD42023402844)20.This systematic review follows the latest version of the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guideline for identifying potentially related articlesA comprehensive search was conducted across five databases: PubMed/MEDLINE, Embase, Scopus, Cochrane Library, and Web of Science, for articles published until the end of June 2022. The search terms were prepared using the PICOS approach, which stands for patients, problem or population (P), issue of interest or intervention (I), comparison, control or comparator (C), outcome (O), and study type (S). To ensure the search’s comprehensiveness and relevance to the research questions, three domains were used to construct the search strategy: COVID-19, telehealth, and China. Studies that were conducted in Hong Kong and Macau were not included because they were developed economies. A combination of keywords and controlled vocabulary terms related to the target concepts was utilized. The search strategy was designed and developed by two authors (JY and LH) independently. To validate the search strategies, an experienced librarian (MB) reviewed and confirmed them. The search strategies for each of the databases were demonstrated in Supplemental Table PICOTS  elements to build eligibility criteria for the included studies:We used the following Health Systems: health insurance policy; strengthening infrastructure, health system financing, and other incentives ; regulation and governance; and other management techniques.Clinicians: education; group problem solving; health care provider-directed financial incentives; supervision; high-intensity or low-intensity training; information and communication technology for health care providers.Patients: patient education; insurance and employment improvement; and promotion of self-management .Studies that evaluated the effect of any intervention, including system- and provider-level implementation strategies as well as patient behaviors, aimed at adopting telehealth services. We included trials that tested interventions targeting:We considered any standard or usual care as the control group.Effectiveness between telehealth and control groups.The primary effectiveness outcome was:Cost of intervention.Cost-effectiveness.Secondary effectiveness outcomes were:We included experimental  and quasi-experimental  trials and studies using other experimental designs . Exclusion criteria based on study design were observational studies ; cross-sectional and case–control studies; and opinion-driven reports .The inclusion criteria for this systematic review included (1) studies that utilized telehealth or telemedicine platforms for activities such as screening, triage, prevention, diagnosis, treatment, or follow-up of patients, irrespective of their health conditions, during the COVID-19 pandemic; (2) the review encompassed a broad range of sources, including journals, conferences, scientific guidelines, and case reports, focusing on studies involving human participants with access to the full text (without requiring free article access); (3) studies conducted in either English or Chinese language.The exclusion criteria for this systematic review included (1) studies that lacked full-text availability; (2) studies that solely assessed participants’ attitudes toward telehealth services without presenting any tangible evidence or results related to the deployment of telehealth platforms or services; (3) studies that used telehealth tools to collect data for testing research hypotheses with no immediate and direct benefits for patients or health care providers; (4) studies that failed to describe any specific telehealth or telemedicine platform, service, or tools used in their research.First, duplicate articles were eliminated from the retrieved articles. Then, JY and LH independently screened articles based on titles and abstracts to identify the studies that potentially could fit into the research question and met the eligibility criteria. An article would be excluded if it was marked irrelevant by two of the reviewers. In cases where the decision couldn’t be made based on the title or abstract alone, the full text was thoroughly examined. In instances of disagreement, the authors held multiple meetings to resolve any discrepancies and achieve a consensus.A comprehensive data extraction form was developed to gather general and technical information from the included studies. For each included study, the first author’s name, publication year, research location (city/region), health care system/hospitals, diseases, platforms, outcomes, services, telehealth infrastructure, barriers/challenges, successful experiences, and recommendations were extracted.Regarding the service type, we considered ten categories, as shown in Table The data analysis commenced with an overview of the study and a comprehensive examination of the telehealth system properties, with the extracted data presented in a tabulated format. For articles published in Chinese, the two authors (JY and LH) translated the data into English and engaged in detailed discussions about the information. Simultaneously, the data were systematically categorized to encompass a wide range of values for each variable. We then refined the categories by introducing new ones and consolidating or omitting older versions, persisting until no further new categories emerged, ensuring a robust classification system.21.A narrative synthesis was employed to articulate the reported results of the studies. The data obtained were qualitatively elaborated and thoughtfully presented. During the qualitative synthesis, the two reviewers (JY and LH) collaborated closely to identify preliminary themes. Themes that lacked sufficient representation in the data were removed, and similar themes were combined to enhance clarity and cohesiveness22. In our study, we employed CFIR as both a theoretical and practical guide to systematically examine various aspects related to the implementation and adoption of telehealth in China. CFIR encompasses five essential domains, namely Outer Setting, Inner Setting, Intervention Characteristics, Characteristics of Individuals, and Process. By leveraging this framework, we meticulously analyzed potential barriers, successful experiences, and recommendations associated with the implementation and adoption of telehealth in China. This approach allowed us to gain valuable insights into the complexities of implementing telehealth services and to develop a robust understanding of the factors influencing its success in the region.The Consolidated Framework for Implementation Research (CFIR) is a well-established conceptual framework designed to facilitate a comprehensive assessment of multilevel implementation contexts, aiming to identify critical factors that could impact intervention implementation and overall effectivenessThe screening process is depicted in the PRISMA diagram in Fig. n = 28) were published and reported on telehealth services during the early stage of the pandemic (January 2020 to April 2020). The most common service supported by telehealth systems was remote consultation (n = 14). Table n = 21) did not assess or report any clinical outcomes following the implementation of telehealth systems. The most frequently reported outcomes were utilization (n = 27), satisfaction (n = 11), and effectiveness (n = 8) of the telehealth system after implementation. Figure n = 11) and COVID-19 (n = 7). Internet and smartphones were identified as the most necessary infrastructure for supporting telehealth services (n = 24), with WeChat being the most commonly reported technology in the selected papers (n = 18).Of the 32 papers included, most studies  developed a system enabling less experienced bedside physicians to communicate with a multidisciplinary team of senior and experienced physicians through videoconferencing before the COVID-19 pandemic35.To ensure the success of telehealth initiatives, we recommend conducting both short-term and long-term evaluations of the implemented systems. These evaluations can help increase buy-in and support from key stakeholders within the organizations. Additionally, gathering feedback and perceptions from relevant stakeholders can further enhance the effectiveness of telehealth systems. Some hospitals have reported positive outcomes with the introduction of telehealth, such as reducing the use of medical supplies and human resources. For instance, Zhang et al. found that implementing a vital sign telemetry system eliminated the need for nurses to check individual patients’ vital signs in-person, leading to a significant reduction in the consumption of personal protective equipment36. In order to accommodate and expand the coverage of telehealth systems, alternatives such as Short Message Services (SMS) could be utilized, which were easy to use, and affordable among populations with lower economic status, and could be applicable to a broader user group30.The technical features of the telehealth systems themselves may also hinder successful implementation and adoption. One concern is the stability and quality of telehealth services, especially synchronous patient-provider videoconferencing, where disruptions can occur, affecting remote consultations37. When telehealth encounters fail to provide adequate information, patients may receive inaccurate diagnoses due to insufficient data available to the providers for clinical decision-making38.Certain medical specialties, such as dermatology, heavily rely on images or video-based telehealth systems to ensure accurate diagnoses. However, the effectiveness of such systems depends on patients having access to devices with high-resolution cameras and a stable internet connection39. To safeguard patient information, it is imperative to have a dedicated Information Technology (IT) team that assesses the security features of the telehealth system, implements end-to-end encryption, and mandates the use of passwords and meeting locks for enhanced protection39.Privacy and security concerns also come into play during telehealth sessions, with instances of “Zoombombing” being a notable example. Such incidents can expose sensitive protected health information (PHIs) to unauthorized and malicious parties when commercial third-party software is used for telehealth services40. These platforms have the capacity to collect and analyze patient data on a large scale, offering valuable insights for population health management41. Additionally, hospitals can identify trends, risk factors, and best practices to optimize clinical decision-making42. A versatile telehealth system is capable of supporting multiple functions43, 44 and various modalities , thereby providing comparable services to in-person visits47.On the positive side, telehealth systems supporting advanced services, like real-time clinical treatments, have been associated with minimal or no adverse events48. The process of training and educating patients to use these systems can place a burden on the telehealth IT team37. In such cases, family caregivers have emerged as crucial stakeholders, providing essential support to patients facing technology-related challenges. For instance, for older adults using a home quarantine monitoring system that requires a stable internet connection and wearable device configurations, family caregivers who are more tech-savvy can play a vital role in assisting them50. Certain patient groups have expressed a preference for face-to-face interactions as it allows them to better communicate their health concerns48. To address this, some hospitals have adopted a hybrid approach, combining remote telehealth care with in-person visits, aiming to accommodate patients’ individual needs based on their health concerns and reasons for seeking medical attention19.Besides technical challenges, human factors are also known to pose significant barriers to the widespread adoption of telehealth systems. Patients, particularly those with lower digital literacy or limited access to technologies, may exhibit lower acceptance of telehealth systems51. To promote the acceptance of telehealth among such users, hospitals may opt to adopt widely used technologies or platforms like WeChat, rather than developing new and complex technologies37. This approach could potentially bridge the digital literacy gap and encourage more users to embrace telehealth services.Moreover, users with lower digital literacy may exhibit reduced motivation to utilize telehealth systems. A prime example is older adults, who have been reported as the smallest user group consulting dermatologists through mobile applications for remote diagnosis53. To address the issue, mental health hotline centers have effectively encouraged current users to share their positive experiences with telehealth systems on social media platforms54.Macro-level factors in society may impact the successful implementation of telehealth systems, necessitating an appropriate dissemination approach to streamline the process. For instance, a lack of awareness among the public about available telehealth services, such as mental health hotlines, may result in underutilization37. Ku et al. found that therapists expressed lower satisfaction rates with a rehabilitation app because they had to invest considerable time in assisting patients with app installation37. Furthermore, clinicians may lack adequate training in using telehealth systems. To resolve this, some hospitals have adopted the “train the trainer” model, where trained staff pass on their knowledge of telehealth to new users37. This strategy effectively reduced the cost of training clinicians and facilitated their onboarding experiences with telehealth.The adoption of telehealth systems requires comprehensive training for healthcare professionals, which can increase their workload, particularly during a pandemic55. Tailoring the telehealth systems based on the available technology infrastructure and the needs of the targeted patient populations is crucial, rather than implementing all components, some of which might not be affordable or accessible29.The development of telehealth systems during a pandemic may be impeded by a lack of technical and human resources within hospitals to build large-scale, robust systems. To overcome this challenge, partnering with third-party technology companies has been found to greatly accelerate the process and provide more scalable solutions beyond what hospitals could achieve independently56 In late 2019, an important milestone was achieved when online healthcare services were integrated into the national health insurance reimbursement system, a significant step towards digitizing the entire patient journey57. Furthermore, China made considerable progress in 2019 by launching one of the world’s largest fifth-generation (5 G) networks, significantly enhancing real-time coordination and capabilities in digital and telehealth services58. 5 G in health was critical for the “remote consultation platform” of Fangcang shelter hospital, for example, which connected its physicians with senior experts far away in Beijing in real-time43.China has provided valuable insights into promoting and supporting the development of telehealth systems. Since 2018, the Chinese government has implemented policies to encourage the growth of “Internet + health” initiatives, which involved establishing a “national telehealth network”59. However, many LMICs encountered challenges in integrating telehealth systems into their existing healthcare infrastructure. One of the main concerns in LMICs might be the high initial costs associated with technology, as well as the need for reliable internet connectivity and coordination between various sectors and stakeholders, such as health ministries, science and technology ministries, local governments, and different-level hospitals60. In LMICs, government approval is typically required for launching telehealth programs, necessitating clear regulations, legislation, and funding to facilitate system development and implementation, which could lead to delays in adopting telehealth, especially during the crisis like the COVID-19 pandemic61.For other developing countries to effectively implement and adopt telehealth systems, they should consider creating an enabling environment based on their unique characteristics, paving the way toward a national healthcare ecosystem. While the long-term goal for developing countries may be to build a comprehensive telehealth ecosystem, their immediate priorities for implementation can differ based on their current state. Countries like China, India, Brazil, and Lebanon have already successfully implemented telehealth systems that proved to be extensively useful during the COVID-19 pandemicWe summarized the various infrastructures and telehealth system in Table Moving beyond the basic level, the availability of internet connection, computers, and smartphones enables telehealth services like text-based remote consultations, through which patients can send symptoms and questions to providers and receive treatment recommendations.Building upon this foundation, a more advanced infrastructure involves the integration of audios, cameras, and a stable internet connection. These technologies facilitate more versatile telehealth services with flexible modalities. For instance, specialties such as dermatology often necessitate photos and videos from patients to make accurate diagnoses, and text-based communication alone may not be sufficient. The inclusion of stable internet connections and video capabilities allows for remote, synchronous video conferencing, enabling interactive patient-provider communication and allowing clinicians to gather more comprehensive information.62. Furthermore, healthcare providers can also perform real-time remote treatments, such as surgeries and deep brain stimulation, through remote control40.The highest level of infrastructure encompasses wearables and cloud-based data storage, along with health information exchange capabilities. These components enable telehealth services that go beyond remote consultations. For instance, patients can use wearables to continuously collect health data such as vital signs. The patient-generated health data (PGHD) can be synchronized in real-time with providers, supporting clinical decision-making processes64. To address this gap, our review, guided by the CFIR, identified barriers, successful experiences, and recommended practices related to the implementation and adoption of telehealth from multiple perspectives. These perspectives encompassed macro-level practices, such as leveraging social media to raise awareness about telehealth services at the societal level. We also examined technological features that supported flexible modalities of telehealth services. Additionally, we explored processes that facilitated individual uptake of telehealth, such as involving family caregivers to assist children’s or older adults’ use of telehealth services65. Further, we proposed a framework comprising layers of infrastructures to support various levels of telehealth services. This framework may serve as a useful tool for developing countries or LMICs with different infrastructural readiness to plan their telehealth implementation strategies.Telehealth played a vital role in supporting the continuity of care during the COVID-19 pandemic. It was especially crucial for developing countries or LIMICs where healthcare resources were limited and unequally distributed. While previous reports on experiences to implement and adopt telehealth during the pandemic offered valuable insights, they mostly focused on describing the systems that were adopted in their specific contexts rather than a holistic review of the process of how they were implemented and adoptedThis systematic review reported the lessons and evidence of telehealth implementation and adoption in China during the pandemic from different aspects as guided by the CFIR framework. The findings from different aspects of telehealth implementation provide crucial implications at various levels.66.In China, telehealth systems have proven to be instrumental in enabling patients to consult specialists beyond their physical reach. By using these systems for screening and triaging patients, hospitals have successfully reduced in-person visits, curbed in-hospital infections, and eased the burden on healthcare workers—crucial achievements during the pandemic. Furthermore, China’s experiences highlight that telehealth systems can also contribute to equalizing medical resource distribution and preventing in-hospital infections66. While such infrastructure may have been easily accessible and well-established in developed countries, they were not yet pervasive and affordable in most LMICs or resource-limited settings. Developing and maintaining such infrastructures may also be time-consuming and costly for LMICs. Therefore, policymakers and practitioners should make use of existing infrastructures to support immediate telehealth services and start strategic plans for long-term infrastructure development. In addition, developing countries have heterogeneous infrastructure readiness and need tailored solutions to successfully implement telehealth. In China, commercial apps and software, such as WeChat, played a significant role as telehealth platforms. However, other LMICs might find apps like WhatsApp more suitable due to their popularity and familiarity67. These social networking platforms, including WeChat, Zoom, WhatsApp, Facebook, and FaceTime in LMICs provided a low-barrier communication tool already widely used in healthcare settings for video calls, phone calls, voice messages, and the sharing of images and videos. The infrastructure model we recommended , any security breach could pose harm to patients. While telehealth services were available in many areas of China, there was no stringent regulatory authority to monitor the quality of these services and maintain ethical standards. To fully harness the benefits of telehealth while mitigating negative consequences, it is essential for China and other developing countries to develop policies that ensure the safety of patients’ privacy, especially those with compromised digital literacy. Establishing robust regulatory frameworks and promoting data protection measures will be crucial steps toward the responsible and secure expansion of telehealth services in these regions.69. Healthcare systems should establish incentive mechanisms, such as performance appraisal, social prestige, and financial bonuses to facilitate the adoption of telehealth.Adopting telehealth into clinical practice in developing countries or LMICs may be a means to lower costs and conserve resources in the long run, thereby alleviating the burden of out-of-pocket spending and boosting the population’s access to affordable health care. Particularly given that out-of-pocket payments for health care services make for a considerable share of overall health spending in many LMICs that have no general health insurance available. Several studies conducted in LMICs have demonstrated the cost-saving potential of telehealth services, as healthcare providers can offer online consultations at a lower cost compared to face-to-face visits, while also reducing transportation expenses when health institutions are distant71. To address this issue, researchers have recommended leveraging off-the-shelf technologies that are already widely accepted by the public, such as WeChat72. Additionally, family caregivers play a crucial role in assisting patients facing technological challenges49. To reach a diverse and wide population to disseminate knowledge and health information, it is preferable to choose technologies that presume low barriers and high accessibility such as SMS or phone calls. It is important to increase the awareness of telehealth services among the public, especially marginalized populations who may benefit more from telehealth services but are not aware of them. This awareness-building effort is especially critical for LMICs, where rural populations might not have sufficient exposure to telehealth services.In many developing countries, the digital divide is a constant concern that impacts the effectiveness and coverage of telehealth. For example, older populations, especially those with low income, need the most medical resources but are the least likely to have access to internet-based social networking services. In addition, they may find it difficult to use complicated apps on mobile phones73. Decentralization has been promoted as a means for improving the responsiveness and effectiveness of health systems in LMICs75. Telehealth enables the expansion of care away from a centralized location to primary care, communities, and into the home, with primary care provider groups integrating virtual care directly into their practice76. Telehealth makes it feasible to distribute medical resources to remote and rural areas by decentralizing resources and services to primary care clinics77. In LMICs, developing infrastructures and policies may be time-consuming and may not yield immediate benefits, especially during the pandemic. China’s experiences suggested that governments could support core hospitals  in developing telehealth systems and providing services to lower-level hospitals . Patients in rural and remote areas with limited medical resources can consult medical experts from core hospitals through telehealth systems and receive high-quality care without traveling. In the future, China and other developing countries should further explore how to best allocate the limited healthcare resources through telehealth systems.To achieve more relevant and responsive healthcare services, it is essential to expand access to these services and implement organizational reforms to attain “close-to-client” approaches78, could prioritize strengthening the national telehealth strategy by prioritizing telehealth implementation at the national level. Building a national telehealth ecosystem requires multiple enablers, including the healthcare-governance model  and digital readiness as a key element in defining a country’s implementation pathway for telehealth. In the near term, governments can intervene directly by creating dedicated teams responsible and accountable for the efforts around telehealth implementation strategy. The long-term strategy for these countries is to develop mechanisms for sustainable financing of the telehealth system.A developing country or LMIC can make strategic choices to guide the implementation and adoption of telehealth systems. These strategies are directly linked to or limited by the country’s governance and technology readiness. Countries that have government-led healthcare systems and robust technological foundations, such as China and Rwanda79. In the long term, LMICs’ governments should work with solution providers to evaluate how to integrate with national or regional telehealth systems and may depend on strong, top-level government leaders to champion system change and drive user adoption. Partnering with established organizations, service providers, or government agencies is often vital to reaching scale.Developing countries or LMICs that were with a private sector-led health technology effort and strong digital foundations could prioritize telehealth implementation at a national level through strategic partnerships with the private sectors. To attract private-sector investment and ensure the viability of telehealth initiatives, these countries could also consider enacting telehealth legislation and policies. For instance, India benefits from a flourishing digital- healthcare private sector and strong country-level action to develop a national telehealth ecosystem80. In the short term, the solution providers and governments should build interlocking relationships when deploying telehealth platforms. With government incentives, solution providers may start developing critical use cases such as health care payments to bypass the challenging financing mechanisms and remote care, to prove the concept and lay the foundation for a telehealth platform. In the long term, these LIMCs can also build a forward-looking, national strategy that demonstrates the government’s commitment to promoting telehealth.Developing countries or LMICs with nascent technology readiness may need to prioritize the development and improvement of digital technology readiness by investing in infrastructure and capability building81. The present review did not aim to assess the effect of the reviewed systems or the quality of the target studies. We sought to identify the properties of telehealth systems and recognize the state of telehealth systems or services in China during the COVID-19 pandemic. Second, the majority of studies were conducted in urban areas and major modern cities in China, where the population has high digital literacy and overall economic development that may not be fully representative of the nation as well as developing countries. Although we included articles that were published in Chinese, we acknowledge that it can be challenging for projects in less-developed regions in China to publish research articles, which could explain why many study sites were from major modern cities. However, the resources and infrastructures from the selected studies varied and could offer insights into different resource-limited settings. Third, the included studies may not be fully representative since most of them reported on telehealth services in the early stages of the pandemic. This might be because China altered its prevention and control policy after April 2020, and quarantine restrictions were relaxed after the first wave. As a result, the momentum for building new telehealth systems might have gradually decreased thereafter. Nevertheless, we compared the results with other studies83 and found that our findings were consistent with those from other LMICs, indicating that our results were representative. Fourth, the implications from China may be applicable to countries that are similar to China in terms of their economies, rural-urban divisions, and healthcare systems. What worked effectively in China may not be directly applicable or feasible in other countries due to variations in resources, technology level, and healthcare delivery models. Socio-cultural factors also influence healthcare practices and patient behavior. Approaches that were successful in China might not align with the cultural norms, beliefs, and preferences in other countries. Adapting telehealth practices to account for these factors is crucial to ensure acceptance and uptake. Future work should explore telehealth service delivery in rural areas in developing countries or LMICs to find best practices and practical solutions.This systematic review has some limitations. First, because many studies were published during the pandemic, which aimed to rapidly share evidence and experiences, the quality of the publications was relatively low; the study design for these publications was primarily observational in nature with modest methodological rigor. Prior research has indicated that COVID-19 research ranked low in the hierarchy of scientific evidence, with numerous articles published in lower impact factor journals and within a shorter timeframeThrough a systematic review of telehealth systems used in China during the COVID-19 pandemic, we summarized the characteristics of the infrastructures and identified the barriers and successful experiences in implementing the systems. Successful implementation strategies of telehealth systems necessitate collaborative efforts from various stakeholders, strong governmental support, tailored designs for marginalized populations, and strategic technological infrastructure development. The experiences and practices observed in China hold valuable insights and can serve as robust evidence for broader scaling in other developing countries and resource-limited settings.Further information on research design is available in the Supplementary MaterialReporting Summary


Congenital absence of the left pulmonary artery remains a rarely reported anomalous condition and is even less commonly seen in conjunction with a right-sided aortic arch. While most cases are identified during prenatal fetal ultrasonography and require early childhood intervention, some asymptomatic cases can go unrecognized until incidentally detected on chest imaging as an adult. This case details a 31-year-old male with a congenital absence of the left pulmonary artery and right-sided aortic arch with subsequent atretic and fibrotic lung, all found on imaging during admission for acute alcoholic hepatitis. The unilateral absence of pulmonary artery (UAPA) was first observed by Frantzel in 1868 . It has Isolated right-sided aortic arch incidence is estimated to be 165 in 1000 persons, with a significant association with DiGeorge syndrome [Although many cases of UAPA are asymptomatic, some present with vague constellations of pulmonary symptoms, including recurrent pulmonary infections, hemoptysis, dyspnea, reduced exercise tolerance, chest pain, pulmonary hypertension, and high-altitude pulmonary edema . It is hA 31-year-old male with a past medical history of alcoholic fatty liver disease and alcohol-induced cardiomyopathy presented to the Emergency Department with complaints of nausea, fatigue, sore throat, right lower quadrant abdominal pain, dark-colored stools, and yellowing of the skin and eyes. Otherwise, he had no known additional cardiac history, respiratory conditions, or prior surgeries. On examination, he had normal respiratory effort, diminished lung sounds on the left, and minimal left-sided tracheal deviation. A cardiovascular examination revealed a regular heart rhythm with no significant murmurs, rubs, or gallop. Distal radial and dorsalis pedis pulses were equal and 2+ bilaterally.Chest radiographs were obtained that showed left-sided volume loss with right-to-left tracheal deviation and a prominent cardiac silhouette overlying the left thorax Figure . RadioloThe patient was evaluated by hepatology and treated for acute alcoholic hepatitis with a four-week course of prednisolone 40 mg per day. Upon discharge, the patient was referred to outpatient hepatology for continued management of his liver condition. In addition, transthoracic echocardiography was ordered for the patient to complete in an outpatient setting and follow-up with outpatient cardiology.This case demonstrates the occurrence of a particularly rare cause of chronic volume loss and interstitial fibrotic change in an adult male without respiratory symptoms. CT of the thorax revealed the rare anatomical findings of UAPA with an associated right-sided aortic arch.The current gold standard of UAPA diagnosis is conventional computed tomography pulmonary angiography (CTA), as this has the advantage of highlighting spatial orientation and extent of peripheral blood vessels. UAPA is also sometimes referred to as unilateral interruption of the pulmonary artery since, classically, on CTA, it will show the beginning of the pulmonary artery branch with a blind end while the distal pulmonary arterial tree is maintained ,8. OtherAs it stands, there is currently no agreed-upon consensus for the treatment of UAPA. Management of UAPA revolves around treating any arising clinical symptoms and is dependent upon the potential congenital anomalies associated with it and the presence or absence of pulmonary hypertension. Early identification of UAPA in infancy with transthoracic color-doppler echocardiography and confirmatory chest MRI is crucial to establishing a correct diagnosis . The aduOne study by Tian and Zheng highlights the usefulness of echocardiography in the characterization of UAPA and monitoring of pulmonary hypertension, which was found to be a common complication in UAPA patients. In their study, the most common finding associated with a diagnosis of UAPA with pulmonary hypertension was growing collateral arterial supply, likely as compensation for hypoxemia. Over time, increased pulmonary artery pressures can lead to heart failure, which is why pulmonary hypertension leads to a worse prognosis in those with UAPA . The useCongenital unilateral absence of the pulmonary artery is a rare cardiovascular malformation that can present with associated cardiovascular anomalies. Isolated unilateral absence of a pulmonary artery can be asymptomatic; however, the congenital anomalies associated with it often require prompt childhood intervention. Early identification and appropriate diagnosis are critical components in the management and care of patients with this rare anomaly, especially those with complications such as pulmonary hypertension. Echocardiography in the characterization of UAPA with pulmonary hypertension appears to be a promising avenue for further study to ensure successful long-term patient outcomes.


Cardiovascular magnetic resonance (CMR) imaging offers a comprehensive, non-invasive, and radiation-free imaging modality, which provides a highly accurate and reproducible assessment of cardiac morphology and functions across a wide spectrum of cardiac conditions spanning from fetal to adult life. It minimises risks to the patient, particularly the risks associated with exposure to ionising radiation and the risk of complications from more invasive haemodynamic assessments. CMR utilises high spatial resolution and provides a detailed assessment of intracardiac and extracardiac anatomy, ventricular and valvular function, and flow haemodynamic and tissue characterisation, which aid in the diagnosis, and, hence, with the management of patients with cardiac disease. This article aims to discuss the role of CMR and the indications for its use throughout the different stages of life, from fetal to adult life. Cardiovascular magnetic resonance (CMR) imaging offers a non-invasive imaging approach which provides a highly accurate and reproducible assessment of cardiac morphology and function for use in the diagnosis and management across a wide spectrum of cardiac conditions spanning from fetal to adult life .CMR is a useful diagnostic tool in the antenatal diagnosis and assessment of cardiac conditions, demonstrating good correlation with post-natal neonatal findings and has an important role in assessing response to in utero cardiac surgery. In all types of congenital heart disease in children, and in acquired forms of cardiac disease in the paediatric population, CMR can provide a thorough and tailored anatomical and physiological assessment utilizing specific targeted sequences and scanning protocols. CMR assessment may include evaluation of cardiac and extra-cardiac anatomy, vascular and valvular flow haemodynamic, shunt quantification to guide therapeutic management, and assessment of myocardial function. Functional assessment can be measured accurately by CMR in childhood with high reproducibility and avoidance of ionising radiation, regardless of ventricular morphology ,3.CMR is not without its challenges. There are unique challenges in each of the populations discussed. Examinations may be time consuming and require management of arrhythmias and breathing, which can negatively impact the image quality . There aIn adults, serial CMR is preferred to serial CT in patients with congenital heart disease or aortopathies due to the absence of ionising radiation. The combined and accurate anatomical and haemodynamic assessment in adults with congenital heart disease has established CMR as a valuable tool in managing patients with adult congenital heart disease . CMR hasAdvances and technical improvements in CMR have facilitated the use of quantitative stress CMR for the evaluation of ischaemia and microvascular dysfunction as a non-invasive and comparatively accurate approach when compared with invasively derived parameters .Cardiac magnetic resonance imaging (MRI) has a high spatial resolution and offers tissue characterisation via a non-invasive approach. It has the benefit of high-resolution images without requiring ionising radiation and is not reliant on an optimal acoustic window for a high-quality image. Cardiac MRI is useful as a sole modality in the diagnosis of many cardiac conditions but offers an additive benefit in combination with other more frequently utilised and more easily accessible imaging modalities. This article aims to discuss the role of CMR and the indications for its use throughout the different stages of life .Congenital heart diseases (CHDs) are the most common lesions at birth affecting approximately eight in one thousand newborns . These dA fetal CMR study comprises different sequences that give information regarding anatomy, function, haemodynamics . BalanceIn both paediatric and adult CMRs, flow measurements are obtained through sequences named velocity-encoded cine phase-contrast (PC) that are ECG triggered as well. Consequently, flow quantification is triggered with other systems similar to the ones described above ,20,21.Finally, the magnetic resonance imaging (MRI) signal is sensitive to oxygen saturation and haemoglobin concentration changes. T1 and T2 mapping are sequences able to quantify the oxygen content of blood in fetal vessels providing an entirely novel approach to assessing fetal hemodynamics ,23.CMR sequences available for fetal studies allow the detection of cardiovascular anatomy, function, and hemodynamics data. Studies have indicated good agreement between fetal CMR and echocardiography information and between CMR and post-natal findings. In addition, other research has shown a good concordance between the echocardiographic and CMR measurements ,25,26. IIn the past 15 years, different technical strategies have been proposed to overcome the lack of conventional cardiac gating methods and to reduce heart motion artefacts improving image quality   and prodThe demonstration of reduced fetal oxygen delivery and cerebral hypoxemia in fetuses with CHDs has led to an interest in the use of maternal hyperoxygenation as a neuroprotective strategy . A pilotFetal CMR can aid decision making around fetal cardiac intervention and monitor the impact of an in utero procedure, such as for utero atrio-septostomy .Fetal CMR is an emerging technique that is improving the managing of CHDs in the pre-natal era. However, it has some limitations that require future studies and research. It is still limited to the third trimester, and despite the great postprocessing improvement, the moving artefacts sometimes remain challenging to overcome. The investigation and post-processing are still time-consuming and difficult to have. In addition, the method is expensive, and only specialised centres can assess it.Finally, intravenous gadolinium is teratogenic in animals at high and repeated doses because it crosses the placenta and is excreted by the fetal kidneys into the amniotic fluid. Thus far, no concerns have been reported in a human fetus. The current indication is to use gadolinium when the benefits outgrowth the potential risks, although most clinicians are inclined to avoid its administration .The survival of CHDs patients has also increased because of improvements in early diagnosis and treatment, which have led to more patients surviving into adulthood . HoweverImaging is fundamental to the diagnosis of CHDs and is required at all stages of patient care. As previously mentioned, from the fetal stage onwards, imaging outlines anatomy and physiology, helps to refine management, evaluates the consequences of interventions, and helps guide the prognosis. However, no single available imaging modality fulfils these roles for all patients and diseases. Specific challenges apply to imaging children and adolescents with a heart condition, and these include the even more pressing need to avoid ionising radiation, assessment of often complex anatomy that involves small structures, as well as imaging at a fast heart rate. Therefore, assessment for CHDs must involve a variety of modalities that can be used in a complementary fashion, and that together are sensitive, accurate, reproducible, and cost effective .The imaging strategy for complex patients should be discussed in multidisciplinary meetings. The best risk-benefit imaging choice should consider age, clinical status, body size, radiation exposure and cardiac anatomy complexity.Echocardiography remains the first-line imaging investigation for paediatric patients, as it is portable, non-invasive, and provides immediate, high-resolution anatomical and physiological information . HoweverCardiac CT imaging is usually the best option in the context of poor acoustic windows when urgent imaging is needed, and prolonged general anaesthetic may carry a high risk.The potential vascular complications as pre-assessment of pressure and oxygen saturation  and the CMR provides a powerful tool, giving anatomical and physiological information that echocardiography and catheterization alone cannot provide . Extra-cFinally, CMR has proven to be better than both catheterization and echocardiography in providing high resolution imaging (without ionising radiation). In the paediatric population, CMR could be justified for any patient in whom clinical or echocardiographic data is insufficient for monitoring, decision making or surgical planning .The decision to perform a CMR depends on the information required, the clinical state of the patient, and anaesthetic risks when this is required. CMR in children and adolescents with CHDs has a safety profile that needs to be considered. Clinicians together with radiologists should take into consideration the need of sedation, general anaesthesia or gadolinium contrast in order to balance risk.An expert and trained anaesthetic team need to be involved with MRI safe equipment , and specific hemodynamic and imaging issues need to be discussed prior to each case. Prolonged and multiple breath-hold sequences are usually required and careful ventilation control is important to avoid hypoxia and hypercapnia . This prCMR requires significant expertise and training both in acquiring and interpreting the images. Patients’ body size, compliance, and rapid heart rate could represent technical and diagnostic challenges. CMR offers a comprehensive summary of the anatomical, post-surgical, and physiological status of the patient prior to being transferred to an adult service.a. Spin-echo or “black-blood” sequences (BB SE): blood appears dark whereas tissues are in shades of grey. These sequences are less susceptible to turbulent flow or metallic artefacts. Respiratory motion is controlled by breath-holding and multiple averages. Recommended for: anatomy definition, stents, complex CHDs [lex CHDs ,49.b. Steady-state free precession sequences (SSFP): blood appears bright. Two-dimensional (2D) SSFP is the most frequent sequence to assess anatomy, function, and valve motion in CHDs. SSFP cine slices stuck are usually used to assess ventricular volumes and ejection fraction. Cardiac motion controlled by retrospective ECG-gating. Recommended for: baseline heart assessment and CHDs including single ventricles [ntricles ; see Figc. Contrast-enhanced magnetic resonance angiography (CE-MRA): gadolinium-based contrast administration increases the contrast between blood pool and surrounding tissue. Breath-holding and high spatial resolution sequences. No ECG-trigger, images reconstruction on average cardiac cycle. Recommended for: vessel anatomy assessment  [vessels) .d. Three-dimensional (3D) SSFP sequences: both ECG and respiratory gating (through diaphragmatic navigator) compensates respiratory motion. Contrast medium can be administered. High resolution 3D dataset of whole heart and intrathoracic vasculature. Recommended for: complex CHDs, proximal coronaries anatomy, visualisation of vessels anatomy. Limitation in case of low-pressure flow and stent [nd stent ,52,53.e. Velocity-encoded phase-contrast (PC) cine sequences: blood flow measurement across a vessel. Blood flows comparison is also fundamental to assess complex CHDs physiopathology. Recommended for: shunt assessment, collaterals, assessment of regurgitation or stenosis.f. Late gadolinium enhancement (LGE) sequences: abnormal deposition of contrast agent within the myocardium late after contrast medium injection. To detect myocardial fibrosis/scar (bright) in the contest of healthy myocardium (dark). Recommended for: cardiomyopathies, ischemic heart disease, myocarditis, CHDs  [l scars) ,54,55.In contrast to scanning adults, the CMR in paediatric patients with CHD must be tailored and nearly all sequences need to be adapted to patient’s size, heart rate, and age and to respond specific clinical questions. Hence, the presence of both CMR and CHD experts is critical to optimize often long studies and to obtain high quality results ,47. MostIn our institution, the most common sequences performed during the MRI scan under general anaesthesia for patients with CHD are SSFP cines with mechanical breath-hold to assess anatomy, free breathing PC sequences for flow assessments, free breathing 3D SSFP  sequences with respiratory motion compensation by diaphragmatic navigator for high-resolution whole heart dataset and, if needed, free breathing LGE sequences to detect myocardial fibrosis.a. Aortic arch anomalies: anatomical assessment for vascular rings, interrupted aortic arch, truncus arteriosus, aortic coarctation, connective tissue disorders  [yndrome) . Three-dyndrome) . Blood fb. Pulmonary arteries: CMR can provide detailed visualisation of spatial alignment of pulmonary artery bifurcation and side branches, as well as anatomical combined with functional information of aorto-pulmonary collaterals. Through-plane flow measurements can quantify flow distribution in between the lungs [he lungs ;c. Pulmonary veins: CMR is a fundamental tool to assess anomalous connection and stenosis of pulmonary veins. It can combine luminal anatomy , accurate quantification of blood flow patterns (PC sequences) occurring in the presence of pulmonary venous obstruction and aorto-pulmonary collaterals [laterals ;d. Shunt lesions: CMR is considered the gold standard for flow assessment. CMR can provide non-invasive anatomical detection of intracardiac and extracardiac shunts, flow direction and shunt quantification. Velocity-encoded PC sequences can accurately calculate Qp/Qs [te Qp/Qs ;e. Tetralogy of fallot: CMR enables assessment of right ventricular outflow tract (RVOT) and pulmonary arteries, as well as quantification of right ventricle volume and function and pulmonary valve regurgitation. Assessment of pulmonary flow distribution. Scar quantification. Key-imaging for surgical and/or percutaneous treatment decision making and follow up [ollow up ;f. Complex CHDs: CMR provide complete anatomical and haemodynamic information about situs, segmental cardiac connections, ventricular looping anomalies, intracardiac and extracardiac malformations, as tracheo-bronchial or abdominal anomalies and relationship [tionship ,62; see g. Single ventricles: CMR provides detailed anatomical, functional and flow assessment throughout palliative stages in single ventricle setting as well as during follow up after completion of the Fontan circulation  [al flow) ; see Figh. Cardiac tumours: CMR represents a non-invasive instrument for tumour size and location, tissue characterisation, relationship and/or infiltration of surrounding structures, vascularisation and haemodynamic relevance [elevance ;i. Cardiomyopathies: CMR provides non-invasive myocardial tissue characterisation  as well as global and wall motion abnormalities in idiopathic cardiomyopathy or secondary to neuromuscular disorders. Gold standard for follow up to measure response to treatments as well as family screening [creening ;j. Myocarditis: in the acute phase of myocarditis, CMR study is used to assess global ventricular function and regional wall motion abnormalities, early myocardial inflammatory changes (T2-weighted sequences), as well as myocardial necrosis/fibrosis (LGE sequences). In chronic myocarditis, CMR can be used to monitor biventricular function and to demonstrate inflammatory and fibrosis evolution. The LGE sequences typically visualise a patchy with a subepicardial and mid-wall contrast distribution most commonly detected in the lateral and inferior walls of the left ventricle. The presence of pericardial effusion provides supportive evidence for myocarditis [carditis .Despite CMR being a widespread imaging approach in childhood, it still has some technical limitations.One of the challenges of CMR is that it is a long study, which can raise compliance problems for pediatric patients who may have difficulty remaining still for an extended period of time. However, the protocol can be tailored to include only the most essential images, reducing the length of the examination .Another challenge of CMR in pediatric patients is the need for general anesthesia or sedation. Apart from the risk of anesthesia per se, which requires adequately trained staff, it is important to consider that general anesthesia may alter the physiological status of the patient and it can make it more difficult to achieve a good level of stress during a perfusion study, potentially leading to false negatives .Device compatibility is another challenge of CMR. Some devices, such as pacemakers or implantable cardioverter-defibrillators (ICDs), are not MRI compatible. However, recent data in the adult population suggests that CMR may be safe for both MR conditional and non-conditional devices ,71,72,73The use of contrast agents in CMR is another potential limitation. Gadolinium-based contrast agents (GBCA) have been associated with allergic reactions in a very small percentage of patients, with the majority of reactions being mild. Moreover, the use of GBCA in patients with severe kidney dysfunction (eGFR < 30 mL/min/1.73 m) has been associated with nephrogenic systemic fibrosis (NSF). Finally, accumulation of gadolinium in the basal ganglia of the brain has been reported in patients undergoing multiple administrations of GBCA in short time frames .Inizio moduloFine moduloTechnological progress and the robust evidence published in the literature, along with the unique advantages of the modality have contributed to expand and establish the role of CMR in several clinical contexts in the adult population .In adults CMRs, the same type of sequences mentioned for the paediatric CMRs are used; in the following subparagraph, other specific sequences disease-based will be mentioned.As already described for the pediatric population, CMR is also key for the evaluation of adults with acquired cardiac diseases, cardiomyopathy, and repaired or unrepaired congenital heart disease, due to the unrestricted anatomical view provided and the possibility to accurately assessment volumes, flows, presence and extent of collaterals, thoracic and abdominal aorta. The absence of ionising radiation is an undoubtful advantage in these patients, often requiring serial assessment throughout their life. The accurate quantification of cardiac output and pulmonary to systemic flow (Qp:Qs) is often required to assess intracardiac shunts, guiding their therapeutical management .Four-dimensional flow CMR is a novel phase-contrast sequence allowing a more comprehensive assessment of the multidirectional blood flowing inside heart and great vessels . The fouCMR has a well-established role in both acute and chronic coronary syndromes, allowing not only the assessment of regional wall motion abnormalities and systolic function, but also the visualisation of acute myocardial injury and oedema ,78,79,80The pivotal role of CMR in patients with suspected or known ischemic heart disease is testified by current European and American guidelines. The 2019 European Society of Cardiology (ESC) guidelines recommend CMR in class I in patients with intermediate risk of CAD or as a non-invasive functional test if coronary computed tomography (CTCA) shows CAD of uncertain significance . In addiSeveral studies have been conducted to date to compare diagnostic accuracy among non-invasive imaging modalities, demonstrating higher sensitivity and diagnostic accuracy in CAD detection of CMR compared to single-photon emission computed tomography (SPECT) ,88.Approximately half of the patients presenting with anginal symptoms have no evidence of obstructive CAD at coronary angiography . QuantitThe presence and pattern of distribution of fibrosis detected by CMR is particularly helpful in the assessment of patients with known or suspected cardiomyopathy. Despite the fact that abnormalities in volumes and function can be easily picked up by echocardiography, an etiological diagnosis often requires further assessment with CMR and the identification of the distinctive pattern of fibrosis. The presence of mid-wall LGE characterizes approximately 1/4 of dilated cardiomyopathy (DCM) patients and is associated with an increased risk of death and arrhythmias . In patiCMR allows detailed description of the pericardium, its thickness , its relation with the surrounding structures and the presence of oedema and or fibrosis ,72. Fat A combination of cine images, T1- and T2-weighted, fat saturation, first pass, EGE and LGE sequences can be used to assess, localize and characterize cardiac masses . Fat, reDespite the fact that echocardiography remains the modality of choice for the evaluation of valvular heart lesions, CMR can be complementary, particularly in the case of poor acoustic windows. In addition, phase contrast images allow quantification of regurgitant volumes and transvalvular velocities without the geometrical limitation of Doppler assessment. Attention should be paid to adapt velocity encoding to the lowest value without aliasing and to use the lowest echo time (TE) when dealing with high flow jet velocities. Contrast-enhanced (CE) magnetic resonance angiography (MRA) is used to visualise lumen vessel with high spatial resolution, and can be used for a radiation-free assessment of the aorta or other vessels . A contrast-free lumen visualisation is also feasible through other MRA techniques  MRA) and may be particularly useful in young patients or patients undergoing multiple serial assessments . Next, 4There is often clinical concern when referring pregnant women to advanced imaging modalities. However, CMR is safe during pregnancy after the first trimester. Given the absence of radiation exposure, it is an attractive modality of choice to further assess pregnant patients with unconclusive echocardiographic examination, poor acoustic window ,112 or fCardiac MRI offers a comprehensive and accurate cardiac assessment which can be performed safely and is highly reproducible throughout the different stages of fetal to adult life. When undertaken, CMR provides a detailed anatomical and functional evaluation at the different stages of life in a patient with cardiac disease and combines the ability to evaluate complex intracardiac and extracardiac anatomy with an accurate assessment of function, flow haemodyanmics and tissue characterisation, as well as providing a thorough assessment of progress or the response to cardiac surgery or cardiac interventions.Additionally, three-dimensional (3D) reconstruction in CMR allows for a more comprehensive view of the heart’s structure and function, making it easier for clinicians to identify any abnormalities or changes that may be present. 3D reconstruction can provide better visualisation of complex structures, supporting clinicians to plan surgical or interventional procedures.CMR minimises risks to the patient, particularly the apparent risks associated with more invasive haemodynamic assessments or from imaging modalities requiring exposure to ionising radiation such as cardiac catheterisation and cardiac CT. CMR as a modality is well established as the gold standard in chamber quantification and ventricular function assessment, with an extensive evidence base for use in the diagnosis and evaluation of a variety of cardiac pathologies in adults. As CMR technologies continue to develop, the image quality and breadth of data provided from this comprehensive assessment tool, when utilised independently or in combination with other more affordable and easily accessible imaging modalities, will continue to improve the diagnostic and therapeutic management of patients with cardiac disease.


Recent data suggest that patients with advanced cancer who participate in biomarker/genomically informed early-stage clinical trials experience clinical benefit. While most early-stage clinical trials are conducted in major academic centers, the majority of cancer patients in the United States are treated in community practices. Here, we describe ongoing efforts at the City of Hope Cancer Center to integrate our network community oncology clinical practices into our academic, centralized biomarker/genomic-driven, early-stage clinical trial program to build an understanding of the approaches that provide the benefits of early-stage clinical trial participation to community patients. Our efforts include three key initiatives: the development of a virtual “Refractory Disease” phase 1 trial matching televideo clinic, the construction of infrastructure to support the expansion of phase 1 clinical trials to a distant regional clinical satellite hub, and the implementation of an enterprise-wide precision medicine, germline, and somatic testing program. Our work at City of Hope may serve as an example to facilitate similar efforts at other institutions. Clinical development of a new molecular or biological entity is a long and costly process ,2. AdvanThe complexity of performing early-stage trials and the burden posed to patients in terms of time, frequent travel, required procedures, and traditionally low response rates impacts referral patterns, and has historically limited the access of most patients to new anticancer agents until much later stages in the process of drug development ,9. MajorClinicians as well as non-clinicians may question whether it is worthwhile for patients treated in community practices to pursue clinical trials with drugs being tested in early clinical drug development. Previous work in the field arguing against or encouraging referrals and participation is limited. Decoster et al. conducted a review of the antitumor activity and toxic deaths reported in single-agent phase I clinical trials in cancer patients using cytotoxic compounds between 1972 and 1987 . A totalIn contrast, Chihara et al. reported on National Cancer Institute (NCI) sponsored phase 1 trials conducted between 2000 and 2019 . The oveAdditional studies evaluated the impact of biomarker treatment strategies compared to an “all comers” approach in clinical trials. These analyses are limited in the phase 1 setting. Schwaederle et al. conducted a meta-analysis comparing patient outcomes in phase 1 studies that used a biomarker selection strategy with those that did not . The anaVon Hoff et al. conducted a pilot study using molecular profiling (MP) of patients’ tumors to find potential targets and select treatment based on these findings . This grImportant caveats in analyses of the clinical benefit of phase 1 trials in cancer patients, molecularly driven or not, include the multiplicity of tumor histological types usually accrued and the required multiple-dose evaluation steps for safety evaluation and regulatory agency mandates. Thus, even when a target is identified and there is an agent reasonably expected to result in efficacy, the range of doses tested include some below target inhibition and some unnecessarily toxic, beyond the requirement for target inhibition. Importantly, in order for a biological target to be clinically relevant and a molecularly targeted approach beneficial, potent drugs should be available that can interact successfully with the target without significant off-target toxicity. Thus, overall, it is reasonable to conclude that it is worthwhile for an academic center to pursue systematic rational efforts to obtain promising targeted or immune-interacting agents, and to provide increased access to patients and care providers in community practices of these agents at the time when patients need them the most. That is, to provide these agents when their disease has become refractory to the available standard of care therapeutic approaches.Although the numbers of clinical trials with novel agents have increased, and expansion cohorts have become the routine, the number of clinical sites involved in a typical industry-sponsored clinical trial have exponentially increased, limiting the slots available to individual sites. This practice comports with corporate mandates to fill out available slots as quickly as possible in order to decrease the time to completion of the clinical trial. Safety issues arising from the coordination of multiple sites have been partially offset by the institution of frequent investigators’ calls and virtual meetings. However, these meetings often involve multiple time zones, substantial time demands and incomplete or stale data sets that may frustrate participants and result in attendee attrition. Unintentionally, these circumstances create competition among the sites for patients’ slots, resulting in insufficient slots for patients who have time-sensitive needs for these investigational therapeutics. From the participating sites’ perspective, challenges include insufficient staff recruitment and retention, low capacity of treating units and hospitals (such as during the SARS-CoV-2 pandemic) ,18, incrFrom the community oncology perspective, and impacting community sites integration into clinical trials, referring patients to be placed on phase 1 waiting lists is, at a minimum, inconvenient and impractical. Furthermore, the necessity for patients to travel long distances for very frequent clinic visits, the requirement in many cases for tumor sample prescreening with uncertain outcome, together with multiple patients’ procedures, and imaging while on trial, dampen the enthusiasm of previously motivated patients and families. An additional, sometimes insurmountable, challenge to community patients’ participation is the approval process and financial limits of health management organizations (HMOs) .The COH Clinical Practice Network serves populations located in four Southern California counties: Los Angeles, Orange, San Bernardino/Inland Empire, and Riverside, encompassing 33,109 square miles and approximately 18 million residents . These sThe COH clinical practice network provides access to a very large cancer patient population ; . The patients served are spread throughout a very large geographical territory and the network practices have different capabilities. Thus, concerted efforts are needed if we are to provide on-site access or directed channeling of patients to early-stage clinical investigations when appropriate. A number of initiatives have enhanced early-stage clinical investigation at COH. These include rapid clinical trial activation times (<90 days on average); uniform protocol templates; a single application form used by the protocol review committee, data safety monitoring board, and institutional review board; upstaffed regulatory start-up and contracting teams; specialized teams to build Epic Beacon and OnCore content; increased use of Master Clinical Trial Agreements with biotech and pharmaceutical companies that reduces the involvement of the general counsel; and participation as a leading academic organization in the NCI Early Therapeutics Clinical Trials Network. Through an institution-sponsored Precision Medicine program, tumor whole exome and transcriptome sequencing together with germline gene panel sequencing are performed for City of Hope patients and their families. A digital infrastructure and informatics platform provides logistical and analytic support. During this televideo-medicine-enabled clinic, interested patients referred by COH oncologists (community and academic) or regional HMO oncologists are evaluated. Referred patients have incurable tumors for which standard effective conventional therapies have been exhausted or are non-existent. A full-time dedicated coordinator oversees the preparation of the clinic ahead of the scheduled appointment. The coordinator contacts referring physicians and patients and retrieves medical records which are made available to the phase 1 oncologist prior to the visit. The retrieval of all prior pathology data and reports and tumor genomic analyses is particularly challenging. In our experience, outside, often diverse, genomic analyses are frequently not incorporated into electronic medical records. If targetable alterations are identified during review, patients will be offered targeted treatment with therapies tailored to their tumor biology if not previously performed. In addition, in some cases, historical genomic analyses provide clues to potential targets amenable to not yet approved investigational agents when biological rationale exists supporting potential efficacy. If no such mutations are found (or while waiting for testing), available non-target specific phase 1 trials, such as those with novel mechanisms of action or immune-system-targeted therapies, are discussed. If the patient agrees to participate in a trial and they meet preliminary eligibility criteria during the virtual visit screening, the patients will visit the COH Duarte campus  to undergo examination and consent to the particular study; subsequently, they receive screening for trial initiation. However, if a tumor-specific later stage trial is available that better fits the patient, a recommendation and referral to the proper tumor-specific physician(s) is made, after obtaining approval from the referring physician. These clinics (once a week with rotating phase 1 oncologists) were initiated during 2022 with great acceptance from patients and medical providers alike. Feedback communication with referring physician within 48 h is routinely performed. Patients are also provided access to our centralized germline and somatic genomic testing, if not previously performed (see below). The large community oncology practice network at COH has increased our catchment area, enabled the enrollment of patients from diverse ethnicities and backgrounds as well as providing the patients the opportunity to seek specialized clinical care closer to home. However, early-phase trials can only be opened at sites that have the capabilities to conduct these trials. These requirements include the handling of research samples that may involve frequent and long hours of pharmacokinetic sampling and specialized on-site research pharmacy and radiology. Patients identified through the COH community network eligible for early-phase trials still must travel to the main campus in Duarte multiple times a month. One recent development in the COH enterprise has been the opening of the City of Hope Orange County Lennar Foundation Cancer Center in Irvine, Orange County, in August 2022.The Orange County Cancer Center offers all comprehensive cancer services with a dedicated clinical research unit and allows the conduct of on-site early-phase cancer trials. Within the County, this cancer center serves as a ‘hub’ offering a full array of clinical operations serving as the ‘spokes’ or regional community sites within Orange County. These ‘spoke’ sites typically provide only clinical services and late-phase trials. As the new cancer center is located within 25 miles from each of these regional sites , patientAdding early-phase trials to a second campus beyond the academic Duarte campus created a number of challenges: increased regulatory processing, the establishment of an efficient clinical workflow for each trial, and the coordination of Orange County laboratories with laboratories at the Duarte campus for sample processing and shipping. Dedicated efforts have succeeded in ensuring that most services required for conducting early-phase trials are now operational at the Orange County site, such as contracting, institutional board review, data safety monitoring, budget review, and an electronic health system as well as phase I disease team management.The efficient and successful conduct of early-stage drug trials depends critically upon the investigators’ ability to identify patients whose tumor mutational profiles match the molecular target of an investigational drug ,22,23,24Implementing Next-generation Sequencing for Precision Intervention and Risk Evaluation) study, a universal access investigation open to all patients at COH with a personal and/or family history of cancer. The advent of targeted cancer therapies ushered in the era of precision medicine in clinical oncology . City ofCOH-INSPIRE participants receive germline genetic assessment through testing with a custom 155 cancer gene panel . Tumors Genetic counselors and cancer genetics physicians conduct the Genetics Case Conference with the aim of resolving challenging problems related to germline findings and genetic risk. The INSPIRE study has observed that nearly 1 in 5  patients carry a germline pathogenic variant requiring clinical review and management; this significantly elevated pathogenicity rate ensures a full volume of complex case reviews but also, more clinically significant, validates a universal access model of precision medicine availability. The second weekly conference, the POTB, complements the Genetics Case Conference. The POTB provides interpretation, targeted therapeutic insights, and clinical trial eligibility information related to tumor whole exome and transcriptome sequencing results. The POTB enlists the expertise of a multidisciplinary team comprising, among others, medical and surgical oncologists, genomic scientists, genetic counselors, and computational biologists. To date, the POTB has completed over 150 deep-dive analyses to help the tangible delivery of precision medicine to COH patients, positively impacting their treatment, health, and well-being. Inaugural COH-CPM INSPIRE activities focused on optimizing precision medicine operations at the central, academic COH Duarte campus. Initial efforts sought to design, implement, and iteratively improve four core precision medicine operations: patient enrollment, specimen processing, germline and somatic tumor next-generation sequencing, and clinical management. Most patients enroll in the INSPIRE study through assigned study consenters stationed in the oncology subspecialty clinic where they receive treatment. Consenters may also enroll a patient remotely via a televideo protocol should in-person consenting prove infeasible. For germline DNA assessment, patients provide blood samples to a central specimen collection laboratory situated on campus. The COH Pathology department assumes responsibility for retrieving fresh-frozen, paraffin-embedded tumor blocks for somatic sequencing. Furthermore, the COH Pathology department oversees delivery of the germline and somatic tumor specimens to commercial NGS vendors who perform CLIA/CAP-grade germline panel and somatic whole exome and transcriptome sequencing. Vendors typically complete the sequencing of specimens within 10–14 days of specimen receipt and deliver test reports directly to the COH electronic medical record as primary BAM, FASTQ, and VCF sequencing files. A centralized electronic data warehouse, POSEIDON, receives copies of the primary BAM, FASTQ and VCF sequencing files . Data anIterative improvements in the INSPIRE protocol established an efficiently functioning, fully interoperable, and incrementally more agile precision medicine workflow. Since initial optimization, COH-CPM has continued expansion of INSPIRE with serial introduction of the study across COH community oncology practices. To achieve streamlined integration of INSPIRE across the community practice enterprise, COH-CPM adopted a “hub-and-spoke” mode of operational logistics. Administration and pathology processing operations remain anchored at the Duarte campus hub, while specimen collection and in situ INSPIRE consenting takes place nodally at the community oncology clinic spokes. As with INSPIRE cases originating at the Duarte campus, all community oncology INSPIRE cases qualify for review through the Genetics Case Conference and POTB. Precision Medicine teams organize and conduct reviews at the central Duarte campus with remote televideo participation of community practices.In 2021, COH-CPM successfully commenced network community INSPIRE participation. Among the first community oncology sites to participate, the COH Upland clinic, located in San Bernadino County, approximately 30 miles east of the central Duarte campus, serves a racially and ethnically diverse, historically underserved patient population. To date, over 1000 Upland community oncology patients have completed germline and somatic sequencing through the INSPIRE study. To expedite timely and convenient genetics care at the Upland clinic, a cancer genetics-trained surgical oncologist provides in-person services to INSPIRE patients requiring ancillary management. COH-CPM has recently expanded INSPIRE to 20 COH community oncology practices; ongoing expansion efforts continue towards achieving full participation of all COH community oncology practices. Full expansion of INSPIRE promises the diverse community oncology patient population not only facilitated access to precision medicine resources but also widened avenues for potentially clinically impactful early drug development participation. Over the past 2 decades, the number of clinical trials requiring genomically informed biomarker qualification has increased exponentially from 15% to greater than 50% ,38. OfteExpansion of INSPIRE across the COH community network affords the early drug development program four transformational opportunities to 1—increase early-stage clinical trial enrollment; 2—optimize investigational drug and clinical trial matching; 3—improve drug response rates; and 4—enhance healthcare equity for COH oncology community participants. The INSPIRE study promotes not only improved quantity of enrollment, but also higher quality. INSPIRE’s comprehensive assessment of germline, somatic whole exome and transcriptome alterations allows more specific drug matching and, consequently, more precise enrollment into early-stage drug development trials. More precise enrollment and optimized drug matching predicts improved drug response rates and, consequently, accelerated drug development ,41. ConvHistorically underserved populations frequently demonstrate compromised awareness of genetics and genomics and the impact that these areas of medicine may have on their health and oncology treatment options ,46. The Community participation in the INSPIRE study promotes patient health agency and autonomy. Knowledge of individual genetic alterations, both germline and somatic, empowers patients to make informed decisions regarding therapeutic options as well as clinical trial participation. Informed engagement with genetic specialists and early-stage drug development trialist moves the patient closer to the ideal of authentic shared decision-making in their cancer care ,49.Overcoming several significant practical challenges, our ongoing initiatives at COH have allowed our community clinical network to leverage the ever-transforming landscape of genetics, genomic, and novel therapies that is impacting cancer care. Our program has achieved excellent clinician and patient satisfaction. To date, the program has performed >12,000 germline and >6000 somatic tumor unique patient tests for a diverse patient population comprising 47% Hispanics/Latinx, 29% API, 12% African Americans, and 1% Native Americans. Precision medicine-based innovation and discovery provide new opportunities for the early-stage drug development bench to clinic translational programs. In turn, these programs offer the COH community oncology patient population access to promising treatments.We believe that the COH experience of developing and implementing a hub and spoke, early drug development program can serve as a model for other community oncology practices nationwide. Only with community integration can novel therapeutic discoveries reach their true clinical potential. However, such integration requires careful consideration and thoughtful deliberation regarding value versus cost, understanding not only therapeutic dividends but also the societal and ethical benefits of providing advanced genomic oncology care to underserved, disadvantaged populations.


Vector-borne plant viruses are a diverse and dynamic threat to agriculture with hundreds of economically damaging viruses and insect vector species. Mathematical models have greatly increased our understanding of how alterations of vector life history and host–vector–pathogen interactions can affect virus transmission. However, insect vectors also interact with species such as predators and competitors in food webs, and these interactions affect vector population size and behaviors in ways that mediate virus transmission. Studies assessing how species’ interactions affect vector-borne pathogen transmission are limited in both number and scale, hampering the development of models that appropriately capture community-level effects on virus prevalence. Here, we review vector traits and community factors that affect virus transmission, explore the existing models of vector-borne virus transmission and areas where the principles of community ecology could improve the models and management, and finally evaluate virus transmission in agricultural systems. We conclude that models have expanded our understanding of disease dynamics through simulations of transmission but are limited in their ability to reflect the complexity of ecological interactions in real systems. We also document a need for experiments in agroecosystems, where the high availability of historical and remote-sensing data could serve to validate and improve vector-borne virus transmission models. Insect-borne plant viruses are a major threat to agricultural productivity and to the stability and function of natural ecosystems ,2. In reMathematical models are used to simulate biological and environmental processes that affect the transmission of vector-borne pathogens through plant communities with a goal of informing management decisions in a variety of agricultural ecosystems ,8. Most a priori [Although there are many models of insect-borne pathogens, few capture the breadth of the interactions that affect vectors and pathogens. For example, within food webs, vectors interact with individuals of other species, including predators, mutualists, and competitors, which can affect the vectors in a variety of ways that cascade to affect pathogen transmission. Interactions with other species, for example, can alter vector abundance through changes in reproduction and mortality and also alter vector behaviors, such as rates of movement and host preferences ,15,16. Fa priori ,21,22, an = 9). Studies were included if the models examined how variation in a vector trait  influenced virus prevalence. We describe how the models identify important mechanisms through which vectors affect transmission rates but are parameterized almost exclusively from laboratory or greenhouse studies that may poorly reflect natural ecosystems. To fill in these important gaps in knowledge, we document the need for certain community ecology experiments in agricultural systems that could be designed to better test the model predictions and improve the applicability of the models to management decision-making. Our overall goal is to promote more proactive management of vector-borne pathogen outbreaks through a combination of realistic models and field work that measure key vector traits.In this review, we discuss how the interactions between vectors, predators, mutualists, and competitors are likely to affect the rates of vector-borne virus transmission. We also review the studies published from 2016 to 2021 that modeled how insect vectors affected plant virus transmission  with vectors and indirectly by altering host traits. Herbivory by competing species, for example, can affect when, where, and how vectors feed on hosts through displacement or by affecting host quality . A studyculation . Furtherculation . While nAt their core, all models of vector-borne virus transmission incorporate vector–host contact rates and transmission efficiency to predict virus spread within the host and vector populations . The modBarley yellow dwarf virus (persistent) and Potato virus Y (non-persistent) transmission, Shaw et al. [By exploring the contributions of individual vector traits to the transmission of both non-persistent and persistent viruses (and both propagating and non-propagating viruses), the models of virus spread have identified key concepts for understanding disease dynamics. For example, in models of w et al.  found thw et al.  also shoPotato virus Y transmission with communities of colonizing Myzus persicae and 20 non-colonizing aphid species having varying transmission efficiencies [Potato virus Y transmission more than colonizing aphids, supporting the field results where Potato virus Y outbreaks have occurred in the absence of aphids [To build on the models that only include vectors and plant hosts, some models have begun exploring how multiple species could affect virus transmission. For example, Galimberti et al.  evaluateciencies . They fof aphids . Non-colf aphids . Crowderf aphids  similarlf aphids ). ThoughM. persicae transmission efficiency from Galimberti et al. [M. persicae were based solely on estimates for initial flight of winged aphids rather than long-term movement [However, empirical studies documenting virus–vector and virus–host interactions often occur in small laboratory or greenhouse settings, and few include species other than the vector, pathogen, and host of interest. The limited scope of such studies used to parameterize the models of vector-borne virus transmission can limit their applicability to field scenarios. Of the twenty-six studies used to parameterize vector traits in nine recently published models, only six (23.1%) were conducted outside of a greenhouse or laboratory . Given ti et al. , the movmovement . Winged movement  with a mmovement ,88. WhilThe frameworks for understanding vector-borne virus transmission that the models have generated suggest a need for further empirical testing. Through generalizations of vector traits and simulated disease dynamics, the models have identified scenarios where the interactions between vectors, hosts, pathogens, and other species could generate unpredictable outcomes for virus transmission. Importantly, the model analyses have unequivocally advocated for more field-based estimates of parameters and examinations of transmission to validate their predictions ,19. The Acyrthosiphon pisum and the herbivorous weevil Sitona lineata, and the aphid-transmitted Pea enation mosaic virus [A. pisum vectors are attacked by a diverse guild of arthropod predators [Hippodamia convergens is consistently numerically dominant in the Palouse region . The limited number of drivers of vector behavior in this system has enabled studies to evaluate virus transmission within realistic food webs [Agricultural fields have several characteristics that indicate their usefulness in supporting the models of vector-borne virus transmission. A massive amount of data is available that documents the traits and phenology of the prevalent pest and natural enemy communities through sampling and empirical studies , growth ic virus . While Aredators , the preood webs ,55. The ood webs ,55. The ood webs , allowinSome models of pathogen transmission can be used in agricultural decision-support tools, allowing growers to make more cost-efficient and effective management decisions. Examples of commonly used pathogen models are fire blight  and applIt is important to recognize that the efforts to examine virus transmission in agroecosystems have been understandingly limited given the difficulties in conducting field experiments using pathogens. Finding experimental sites where viruses can be introduced and isolated is difficult, and some vectors such as leafhoppers disperse across habitats too broad to be manipulated , which cAs previously described, the existing models of vector-borne virus transmission parameterized vector traits using life history data from lab or greenhouse studies almost exclusively . Vector The field experiments in such systems could be expanded upon to examine further levels of complexity. For example, the field mesocosms used to evaluate vector traits could include predator or competitor species to evaluate the short-term effects of species interactions on vector responses, as in Lee et al. . AlternaPredicting vector-borne virus transmission in natural and agricultural systems requires an abundance of data on vectors, viruses, hosts, and community interactions. Models have expanded our understanding of disease dynamics through simulations of transmission based on vector traits and their assumed relationships with other factors, but most models are limited in their ability to reflect the complexity of ecological interactions in real systems. Further experimentation using representative communities and environmental conditions are needed to examine how vectors respond to realistic scenarios and improve future models of transmission. We suggest that future studies in agricultural systems could provide the controlled conditions needed to parameterize models while providing opportunities for the emergent effects of species interactions to manifest.