Individuals with rare diseases (RD) have been historically understudied. Previous publications reported that existing primary health care (PHC) workforces and associated infrastructure had been shown to improve their access and health-related outcomes in low- and middle-income countries (LMICs). As current evidence about the impact of PHC on patients diagnosed with RD is yet highly dispersed, this scoping review aimed to collate available evidence of the impact of PHC on patients with RD and summarize published information from multiple stakeholders about the perceived usefulness and barriers to effective use of the PHC system.We searched Embase, Health System Evidence, PubMed, LILACS / BVS, and The Cochrane Library, from inception to September 1, 2022, for publications providing clear expert- or experience-based insights or data from patients living with RD at the PHC level of care. We included publications highlighting barriers to integrated care of patients with RD, reported by multiple social actors involved in caring for patients with RD. Two investigators screened publications, extracted data, and clustered information among records deemed eligible for inclusion. Data synthesis was performed using narrative and thematic-based analysis. Major findings identified and coded through a semantic-driven analysis were processed in vosViewer software and reported using descriptive statistics.Eighty publications were included in this review. Quali-quantitative analyses evidenced that the PHC level is essential for approaching patients with RD, mainly due to its longitudinal, multidisciplinary, and coordinated care delivery. In addition, several publications highlighted that the medical curriculum is inappropriate for preparing health care providers to deal with patients presenting unusual signs and symptoms and being diagnosed with RD. PHC teams are essential in orienting patients and families on emergency events. Technology-related concepts were reported in 19 publications, emphasizing their effectiveness on early diagnosis, optimal treatment definition, improvement of quality of life, and long-lasting follow-up.We provided valuable information on the effectiveness of the PHC in fostering a creative, integrative, and supportive environment for patients living with RD. Our results can be helpful to several stakeholders in deciding what actions are still pending to achieve a solid and positive experience for patients with RD in the PHC.PROSPERO (CRD42022332347) According to the World Health Organization (WHO), rare diseases are pathologies or medical conditions affecting no more than 1.3 in 2000 individuals . This inAlong with several available pharmacological and non-pharmacological interventions to treat and long-term manage rare diseases, the primary health care systems and its professionals also stand as a fundamental level of care due to three core elements  . In counCurrently, hundreds of publications evaluating multiple features of rare diseases have been registered, suggesting the need for structured and integrated multidisciplinary care and the evolvement of frequently observed health care systems worldwide. Even though these publications reveal crucial elements regarding the diagnosis, treatment, and follow-up of patients presenting rare diseases, no summarization of these components have been published and analysed. Therefore, this systematic review aimed to answer the following guiding questions: “1. What is the state-of-the-art related to the role of the primary healthcare system in the care of individuals affected by rare diseases?”; “2. What is the current evidence suggesting the effectiveness of primary healthcare system approach on managing patients with rare diseases?”; and “3. What are the practice and structural gaps in the care network that hinders the integrality of care to patients with rare diseases?”.To map relevant publications in rare diseases, this study followed the published methodological framework for conducting a scoping review developed by Arksey and O'Malley . Our staRegardless of study design and publication type, relevant records were obtained from five databases . The searches were performed on September 1, 2022; therefore, we included records from inception until the before-mentioned date. Publications were included if they: 1. directly reported and evaluated the role and effect of primary health care-derived interventions to the genetic- or clinical-based diagnosis, treatment, management, and prevention of late diagnosis of rare diseases; 2. provided legal or institutional information regarding rare diseases patient's rights; 3. compared the impact of primary health care-related activities to secondary or tertiary level of care; and 4. reported barriers, facilitators, and opportunities to implement long-lasting direct health care programs successfully. It is worthwhile mentioning that the acronym PICO  was used in this review to guide the entire review process. As far as “population” is concerned, patients diagnosed with rare diseases, as internationally defined in the literature, were considered eligible for inclusion. Furthermore, the primary health care system (defined within each included study) was regarded as the direct “intervention” evaluated throughout retrieved studies. We did not exclude studies based on the existence or absence of a comparator or a particular discussed outcome to increase the potential number of records deemed to be included.We did not impose restrictions on published language and conference proceedings were considered eligible for inclusion. However, records were excluded if they did not assess the impact of primary health care on rare diseases. We used the Orphanet database for rare diseases and orphan drugs, created by the French National Institute for Health and Medical Records . FollowiAn information specialist and medical experts in rare diseases and public health care collaborated to define each database's most sensitive search strategy. Search string levels associated with primary health care included “Primary Health Care”, “Physicians, Primary Care”, and “Primary Care Nursing” and their synonymous. Additionally, rare disease elements were mostly represented by key terms such as “Rare Diseases” and “Orphan Diseases”. A complete description of keywords and identifiers used in each database is displayed in Section 1 in the Data extraction of studies deemed eligible was also performed independently by two research authors and the following variables were extracted: 1. study identification; 2. publication year; 3. journal name; 4. SCImago Journal Rank (SJR) indicator for each journal; 5. study design; 6. publication type; 7. study objective; 8. number of patients or individuals considered in the publication; 9. targeted health care professionals; 10. rare disease evaluated; 11. orphanet code; 12. country; 13. summary of findings or discussed topic; 14. any information platform provided throughout the record; 15. barriers to case management; 16. facilitators for case management; and 17. any future opportunities raised by original authors. If any data extraction conflict occurred, a discussion between the two conflicting authors was carried out to understand which elements should be finally displayed in the final materials.As we retrieved and selected qualitative and quantitative findings, we created a thematic synthesis of the results. The initial main findings of included studies were coded and thematically collated using NVivo software. Statistics data from quantitative studies were shown through text or table-based methods, while qualitative data were clustered by similarity and subsequently graphically presented using the vosViewer software. Moreover, a general summary of findings was created to systematically abstract the review's findings.We primarily planned to analyse the risk of bias assessment for those included records in which the evaluation was technically feasible and indicated. However, as our study focused on exploring the status quo of the available evidence regarding the delivery of care for rare diseases at the primary level of care, we decided not to evaluate it. Moreover, the quality of the evidence was not appraised because of the methodological and technical singularities of scoping reviews.Our search strategy retrieved 1351 records (as 1341 single studies), of which 145 were duplicates. The remaining 1206 records were screened, and 1078 studies were judged irrelevant. From the 128 shortlisted records, 90 were deemed eligible for inclusion. However, as some included records were literal translations of each other, we ended up with 80 unique publications in the qualitative summarization ,91-98. GThe main characteristics of the included citations are summarized in Our thematic-based analysis yielded 41 principal codes and scope-related findings, as shown in The development and incorporation of digital health technologies  were endorsed and suggested in several publications ,80,81,90Government agencies have also suggested the creation of tools and regulations and the use of digital health technologies for addressing cases of rare diseases assisted in the primary health care sector ,65,68,72This qualitative synopsis and thematic-based assessment highlighted several connected components between primary care and rare diseases. Eighty publications were published within the past 18 years, indicating an increasing interest of researchers and other stakeholders  in understanding the importance of primary care as a system that delivers holistic, coordinated, and long-lasting care. However, a focused and in-depth evaluation of a determined disease could not be carried out as most publications regarded “rare diseases in general” or several other targeted diseases. Eighteen publications suggested the importance of digital health technologies in diagnosing rare diseases promptly to enhance patients' and caregivers' experiences throughout the natural course of the disease. Most importantly, health care professionals stressed the insufficient knowledge of managing patients with rare diseases (stating that the topic was rarely approached in universities). Nevertheless, despite limited training and knowledge regarding these patients' diagnosis, management, and long-term follow-up, these professionals ensured the power and high effectiveness attributed to the primary health care system to guarantee the delivery of essential health elements for individuals living with rare diseases. Furthermore, the primary health care sector's ability and responsibility to identify signs and symptoms presented in daily medical consultations were notably observed among included publications. The least frequently generated codes related to the existence and effectiveness of non-pharmacological interventions  in treating patients with rare diseases, the importance of strengthening the primary health care system, and the potential advantages social health care workers have over other professionals in dealing with individuals living with rare diseases.As suggested in our findings, empowering the primary health care system positively affects patients with rare diseases. However, it might also improve the application intelligibility of this system in more complex medical conditions and emergencies, such as pandemics, health emergencies, and natural catastrophes ,36. The The singularities of each health care system  and the particularities of different diseases directly affect rare disease management and how patients experience care delivery within the health care system. Although health care systems in several places have increased their focus on a better understanding of the processes in that patients with rare diseases are involved, some features and concepts are still misunderstood, outdated, or disregarded by health providers and local administrative agencies, resulting in totally different perception of an identical condition ,55,60. NFrom a theoretical perspective, the achievement of the United Nations’ Sustainable Development Goals (SDGs) is directly affected by countries’ health care systems and institutionalized strategies for delivering care. Although a remarkable global improvement in population health outcomes has been observed over the last decades, the divisive private-based health care system will continue to set millions of people apart from a less unequal and unhealthy life. To note, it is inevitable not to assimilate the primary health care approach and public health care-based systems, as both processes are rooted in the capacity to respond equitably, inclusively, and cost-effectively to the health need of citizens. As our findings show, the primary health care approach of care positively affects health outcomes for the rarest diseases, from diagnosis to palliative care, making the creation of initiatives against the public health care system dismantling rhetoric critical. As advocated by the American Academy of Family Physicians and National Health System England, the call for action poses a significant starting point to counteract the long-dated initiatives to set primary and public care apart ,100. HowEnhancing the number of high-quality genetics, experimental, and clinical research devoted to rare diseases, or improving the knowledge of the impact of primary care services for rare diseases are cornerstones of scientific improvement toward achieving Universal Health Coverage (UHC). Our data clearly suggested that several publications evidenced the minimum interest of pharmaceutical industries to identify and formulate new pharmacological therapies because of the low profitability and limited growth capacity attributed to rare diseases. Ultimately, the little research and production of new drugs directly hinder the achievement of SDG Goal 3 as highly advanced technologies and qualified professionals are not involved in improving health quality. Indeed, no substantial evidence has shown that pharmaceutical companies have been actively developing new drugs in a broad and non-selective way. For instance, although Pzifer has taken measures to create pharmacological alternatives for various diseases, 104 discovery projects have been reported as of July 28, 2022 . Of thosReducing social and economic disparities  among patients (and their families) diagnosed with rare diseases also has particular importance in the 2030 Agenda for Sustainable Development. Rare disease patients regularly face a shortage of health resources, precarious education, and a structured family core, which combined marginalize these patients over the years. Our data showed that the financial impact of rare diseases on the family budget is significant, driven mainly by expensive medications, especially biologics. Based on data reported by Gimenez-Lozano et al., approximately 58% of families with a rare disease-confirmed case reported not being able to afford adjuvant therapies . MoreoveVarious modalities of digital health solutions were reported in included studies. Despite these interventions' high efficiency, accuracy, scalability, and safety, several components should be considered before creating and implementing these systems. First, the design of digital health technologies should identify end-users' needs, perceived utility, and ability to use such technologies, particularly for physicians who frequently do not have any prior preparation for utilizing health technologies in most medical universities. Additionally, understanding barriers to the success of the intervention must analyse inherent infrastructure and technical difficulties experienced by users, health care providers' personal and psychological issues, legal and ethical variables, and cultural, social, and geopolitical factors. Therefore, the involvement of providers and other social actors in creating and employing digital health technologies, the evaluation of providers' willingness to use the technologies, and the existence of institutional and governmental incentives are of utmost importance.Pseudomonas aeruginosa or Staphylococcus aureus). We strongly recommend preparing such medical instruments early in disease recognition as information obtention in emergency conditions is usually chaotic and challenging. Therefore, there is no better and more controlled place than the primary health care offices to leverage guidelines about rare disease complications and unexpected clinical presentations. To the best of our knowledge, no previous template of an “Emergency Protocol for Patients Living with Rare Diseases” has been published elsewhere. However, we endorse that basic information containing the patient’s medical history and background, diagnosis, medications on use, allergies, and description of the acute complication must be written in these protocols. Moreover, intervention contra-indication and dangerous drug-to-drug interactions should also be inserted in these instructive and informative materials. In Section 3 in the The creation of standardized and instructive emergency protocols in the event of sudden decompensation or complication was interestingly ranked as the fourth most frequent concept among included publications. Due to inherent features of the primary care consultation approach , preparing these simple materials at the primary care level is timely and efficient. Not only does preparing these materials seem critical, but regular health assessments and preventive clinical actions are fundamental. For instance, based on regular lower respiratory tract cultures check-ups performed at the primary care level, previously generated data can guide physicians in managing acute pulmonary exacerbations in patients with cystic fibrosis, essentially due to chronic colonization of some bacteria (eg, Relying on information about the diagnosis, management, and treatment in general websites and by peer-to-peer consultation was frequently identified as the leading knowledge resource by health care professionals. Nevertheless, particular attention should be given to rare disease-related information resources as multiple platforms are not official, based on high-quality evidence, and are subjective to clinicians’ opinions and expertise. Recently, evidence-based reports have suggested the high prevalence of misinformation and disinformation on online pages with health content and digital devices, which significantly reduces the trustworthiness of unofficial health resources . As emphOur study has several strengths. First, we strictly followed international and standard methodological recommendations for evidence-based studies. Additionally, we included a relevant number of patients and health care professionals from the primary health care sector, which allows us to upgrade the general certainty of the evidence herein provided. To note, although the creation of a meta-analytic assessment was not feasible, we created a thematic analysis based on the occurrence of similar semantic terms or sentences verified among included publications. This evaluation process is highly subjective and the displayed mathematical results of the weight of occurrences might be affected by this subjectivity. However, we strictly attained critical methodological concepts, including criteria of credibility, transferability, dependability, and confirmability throughout the project execution. Significant limitations might be associated with patients' and health care professionals' selection bias in included studies, the lack of comprehensive description of demographic and epidemiological data from individuals being addressed among included studies, and the limited number of studies outside the Americas and European Regions. This could directly hinder the generalizability of our findings to other scenarios.Our study highlights the commonly reported concepts when merging “primary healthcare” and “rare diseases”. We observed relevant evidence suggesting the importance of primary health care level of care in managing and supporting individuals living with rare diseases. Our study suggests the strengths and weaknesses within this relationship and shows future perspectives which decision-makers, technology developers, and health care providers must follow to improve the quality of care delivered to patients with rare diseases.


Significant costs and utilisation of healthcare resources are associated with hospitalisations for non-specific low back pain despite clinical guidelines recommending community-based care. The aim of this systematic review was to investigate the predictors of hospitalisation for low back pain. A protocol was registered with PROSPERO international prospective register of systematic reviews (#CRD42021281827) and conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. Database search of Ovid Medline, Emcare, Embase, PsycINFO, Cochrane Library, PEDro and OTSeeker was conducted. Studies were included if they examined a predictor of hospitalisation for non-specific low back pain with or without referred leg pain. Data was extracted and descriptively synthesised. Risk of bias of included studies was assessed using the Critical Appraisal Skills Programme Checklists. There were 23 studies published over 29 articles which identified 52 predictor variables of hospitalisation for low back pain. The risk of hospitalisation was grouped into themes: personal, health and lifestyle, psychology, socioeconomic, occupational, clinical, and health systems and processes. There was moderate level evidence that arrival to an emergency department via ambulance with low back pain, and older age increase the risk of hospitalisations for low back pain. There was low level evidence that high pain intensity, past history of low back pain, opioid use, and occupation type increase the risk of hospitalisation for low back pain. Further research into psychological and social factors is warranted given the paucity of available studies. Hospital avoidance strategies, improved patient screening and resource utilisation in emergency departments are considerations for practice. It rpractice  and 4.4%practice  with clipractice , 7.There are challenges with implementation of evidence-based practice for LBP relating to both clinician and patient factors , 9. ManaThe burden and costs of LBP are substantial when seeking hospital-based care. A large multicentre observational study calculated a mean cost of AUD$13,137 per hospitalisation for LBP with an average length of stay of nine nights . The reaA protocol was registered with PROSPERO international prospective register of systematic reviews #CRD42021281827). This review was conducted and reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [281827. Tst November 2022. Grey literature searching was undertaken using a commonly available internet search engine (Google Scholar) and searching of reference lists of included studies was performed to identify additional records.Seven electronic databases were searched, including: Ovid Medline, Emcare, Embase, PsycINFO, Cochrane Library, PEDro and OTSeeker. The following search terms were used with MESH headings: exp back pain, exp low back pain, exp backache, exp sciatica and exp hospitalisation. The search was limited to humans, English language and published from inception to 1All search results were pooled and duplicates removed. Titles and abstracts were screened before analysing the full texts to determine their eligibility. The screening process was undertaken by two independent reviewers . Any disagreements were resolved and discussed with a third reviewer (MG), where required.All forms of primary research were considered, including prospective or retrospective cohort studies. Secondary research, such as literature reviews were excluded but their reference lists were searched to identify additional records. Studies were included if they examined a predictor of hospitalisation for non-specific LBP with or without referred leg pain. Hospitalisation was defined as a minimum overnight stay as a hospital inpatient. Predictors of hospitalisation expressed as risk ratio, odds ratio or equivalent were included in the review. There was no exclusion on the time at which data was captured, either before, during or following the LBP episode. All clinical contexts were considered, including emergency departments, inpatients, outpatients and community health clinics. Participants had to be adults 18 years of age or older at the time of hospitalisation for non-specific LBP including sprains and strains of the lumbar spine  or sciatica/ radicular leg pain. Studies that included participants with specific spinal disorders  were included provided that data for non-specific LBP was presented separately from specific spinal disorders and that the latter represented less than 5% of participants in studies set in primary care , as is rThe Critical Appraisal Skills Programme (CASP) was used to assess the risk of bias of included articles based on the study design: CASP Cohort Study Checklist  or CASP The data were extracted and collated into bespoke Microsoft Excel® spreadsheets by one reviewer (JO) and a sample cross-checked by a second reviewer (SK). The following domains were used to collate data: study design, level of evidence, setting, sample size, participant details , data sources, data capture period and follow-up, diagnostic criteria, hospitalisation details , predictor variables and findings. The predictor variables from each article were expressed as its odd ratio (OR), risk ratio (RR), hazard ratio (HR), prevalence ratio (PR), or equivalent and tabulated for analysis. Meta-analysis was initially considered, but preliminary review of included studies found large heterogeneity of participants, diverse settings, and different methods of measuring variables. A descriptive synthesis was deemed more appropriate and undertaken using the FORM framework to grade the strength of recommendations based on evidence base, consistency, clinical impact and generalisability . StudiesThe initial search identified 3784 records. After pooling searches and removing duplicates, titles and abstracts were screened leaving 37 potential articles. Grey literature search and searching through reference lists included five additional articles. The full texts were retrieved and assessed for eligibility and 23 studies published over 29 articles were identified as being eligible for review. The literature selection process is outlined in The majority of studies were conducted in Finland (n = 8), followed by Australia (n = 6), the United States of America (n = 4), Canada (n = 1), Chile (n = 1), Denmark (n = 1), Ethiopia (n = 1) and Sweden (n = 1). Studies were set across a range of settings including emergency departments (n = 8), community and outpatient clinics (n = 5), hospital inpatients (n = 2), hospital inpatients and outpatients (n = 1), workplaces (n = 3) and the remainder were population-based studies (n = 4). The total number of participants across studies included 2,026,834 with LBP and 435,663 without LBP pain at baseline. Most studies excluded or unequally represented women, especially in studies set in workplaces where the majority of the workforce comprised men. Two studies included adolescents at baseline but the hospitalisations occurred almost exclusively in adulthood , 48.All studies undertook audits of hospital records and databases except the cross-sectional study that used interviews and self-reported outcomes . The IntThere were 52 predictor variables investigated across all studies. They have been categorised into personal factors, health and lifestyle factors, psychological factors, socioeconomic factors, occupational factors, clinical assessment findings, and health systems and processes. These categories have been based on previous reviews supporting a biopsychosocial framework for LBP –58. Fig The results of the risk of bias assessment are outlined in Tables Gender as a predictor for hospitalisation due to LBP revealed inconsistent findings. Three studies found females were more likely to be hospitalised compared to males, including: a cross-sectional study of moderate risk of bias  , a cohorOlder age was a predictor of hospitalisation for LBP in people accessing a health service in five studies , 34, 47.Height, weight and body mass index were not predictors of hospitalisation due to LBP. One cohort study of moderate risk of bias conducted on a construction site found that men had greater risk of hospitalisation for LBP when body height was greater than 190 centimetres  and body weight greater than 100 kilograms  , but theOnly one study examined ethnicity as a predictor of hospitalisation in LBP. The cohort study with low risk of bias set across North Carolina state health services found hospitalisations for LBP were decreased in non-white populations . Whilst General health status self-rated as poor increased the risk of hospitalisation due to sciatica in women  and men  in a large cohort study with moderate risk of bias set in a community clinic . A furthComorbidities as predictors of hospitalisation for LBP were examined in a large cohort study set across inpatient and outpatient settings . ComorbiSleep disturbance as self-reported by participants in a cohort set in a workplace found increased risk of hospitalisation for LBP  . This fiSmoking as a predictor of hospitalisation due to LBP revealed inconsistent findings. Three cohort studies with moderate risk of bias found current smokers were more likely to be hospitalised compared to non-smokers , 41, 53.Alcohol consumption as a predictor of hospitalisation for LBP also revealed inconsistent findings. Two cohort studies with moderate to high risk of bias found no association of consuming three to five drinks per day with risk of hospitalisation for LBP , 52; whi2 max) in workers in a prospective cohort study with moderate risk of bias was not associated with risk of hospitalisation for LBP  [Physical fitness and activity during leisure time were examined by eight studies , 50, 52.51–1.50) . One stu51–1.50) . MeasureGeneral stress and depressive symptoms were not associated with increased risk of hospitalisation for LBP , 42, 50.Beliefs about LBP were examined by two studies of moderate risk of bias. In a cross-sectional study of people with LBP in rural Ethiopia, hospitalisation for LBP was not linked to negative pain beliefs, such as perceived pain prognosis and life impact due to pain . Odds ofLiving at home alone was associated with increased prevalence of hospitalisation for LBP  in a cross-sectional study conducted in rural Ethiopia . This stCompensable status of patients attending an emergency department with LBP may influence the risk of hospitalisation as per a retrospective cohort study with low risk of bias . PatientThere were inconsistent findings in other socioeconomic factors. Identifying with middle social class in Finland increased the risk of hospitalisation for LBP compared to upper class  in a cohort study set in community clinics , howeverOccupation type as a risk of hospitalisation for LBP was examined by six studies , 45, 53.Physical demands of work were examined by five cohort studies with moderate to high risk of bias , 52, 54.Work-absenteeism due to LBP was associated with increased risk of hospitalisation for LBP   as was lPain intensity was associated with increased hospitalisation for LBP when presenting to an emergency department with the odds increasing for each additional point on a 11 point numerical rating scale  in a cohort study with moderate risk of bias . HospitaThere were inconsistent findings amongst studies on the predictive value for hospitalisations for LBP when the symptoms included leg pain , 39, phyWhen attending an emergency department with LBP, the risk of hospitalisation is increased when a person arrives via an ambulance compared to self-presentation. The odds were lower in a private hospital  where patients’ average age was older and hospitalisation rates significantly higher compared to other studies , while tHealthcare access and resource utilisation in emergency departments also predict hospitalisations for LBP. In a private emergency department set in a high socioeconomic area, the odds of hospitalisation for LBP increased when ordering pathology tests , ordering computed tomography images of the lumbar spine  and with longer treatment times in emergency departments  . In a coHospital contextual factors also accounted for hospitalisations for LBP. A retrospective study of moderate risk of bias audited 37 emergency departments in New South Wales and found that hospitalisation rates for LBP were greater amongst centres with higher specialty classifications (levels 1–3) compared to lower speciality classifications (levels 4–6)  .There was no association between hospitalisation for LBP and access to primary care physicians, spinal surgeons or chiropractors (p>0.05) . On the There is moderate level evidence that arrival to an emergency department via ambulance with LBP, and older age increase the risk of hospitalisations for LBP. There is low level evidence that high pain intensity, past history of LBP, opioid use, and occupation type predict hospitalisation for LBP. There is emerging evidence from single study findings of increased risk of hospitalisation for LBP associated with pain distress, residing alone, ethnicity, compensable status, younger workers, residential and hospital contextual factors, emergency department triage category, hospital specialty classification, and utilisation of emergency department investigational resources. There was no evidence for gender, height and weight, self-rated health status, comorbidities, stress and depression symptoms, smoking, alcohol consumption, socioeconomic status, education level, employment status, duration of pain, leg pain, clinical examination findings, or primary care access on the risk of hospitalisation for LBP.The FORM framework  was usedWhile hospital-based care is sought for management by many people experiencing LBP, to date there has been limited quality research evidence to determine the predictors of hospitalisation for LBP. This systematic review aimed to address this knowledge gap and identified a body of evidence consisting of 23 studies published over 29 articles and examining 52 predictor variables. The summarised findings indicate that there is moderate level evidence that arrival to emergency departments with LBP via ambulance and older age; and low level evidence that high pain intensity, past history of LBP, opioid use, and occupation type increase the risk of hospitalisation for LBP.Closely related to age are other variables such as functional capacity, fitness and sedentary lifestyle , 60. InaThere remains a large knowledge gap for predictors of hospitalisation for LBP. There were no identified studies examining functional impairment and very few examining psychological factors. This review found some pain behaviours to be factors in hospitalisations for LBP, such as prior analgesic use, pain distress, and attending an emergency department for LBP via an ambulance. Low pain self-efficacy may be a characteristic of people hospitalised with LBP, but this has not been investigated. Negative beliefs about pain were associated with hospitalisations within the context of emergency departments , particuSocial and environmental contributors to hospitalisation for LBP are also suspected from this review such as geographical location, but specific causations are unknown. Residing in regional or metropolitan areas was not a consistent theme of hospitalisations for LBP in this review; rather, social and cultural influences of a local community and health system accounted for some of the geographical variations in hospitalisation for LBP. Clinician biases , 37, patUnderstanding the social and contextual factors of LBP is highlighted by this review to better recognise risk factors for poor prognosis and avoid escalating medical care such as hospitalisation in people with LBP. Clinical practice in hospitals and emergency departments has a primary focus on biomedical factors given the priorities in managing serious pathology and acute and urgent care . OperatiThe quality and access to community-based care are important in improving outcomes of people with LBP , 76. PooAs with any research, there are limitations to this systematic review. While the systematic searching of the literature identified a large body of evidence to inform the review topic, there were concerns regarding the methodological quality of the included studies. An area of concern is the subjective and psychometrically untested measurements of predictor variables, such as occupation type, physical activity levels, stress levels and socioeconomic status, rendering the measures as imprecise and requiring caution with interpretation of the results. The long follow-up periods weakened the associations of certain baseline predictor variables with hospitalisation outcome at baseline, especially for variables whose conditions are not fixed and can change over time, such as smoking status or body weight. While this systematic review process was underpinned by best practice in the conduct of systematic reviews (PRISMA), likely publication and language bias should be acknowledged. While strategies were implemented to avoid publication bias, such as grey literature and secondary searching, due to the complexity and imprecise nature of searching, some publications may have been missed.With the emerging evidence of various predictors of hospitalisation for LBP, there are implications for clinical practice in different settings. After exclusion of red flags and serious pathology, clinicians in emergency departments should screen patients’ risk of hospitalisation for LBP, such as age, pain intensity, distress and mode of arrival. Artificial intelligence may have a role in predictive modelling, patient monitoring and hospital operations and there has been evidence of its use in emergency departments for a variety of health conditions . ResourcWhilst this review found evidence of some predictors for hospitalisation for LBP, methodological concerns of the current evidence may guide the direction of future research. Future research should focus on psychological and social factors that may predict hospitalisation for LBP. Such factors are poorly documented in hospital medical records  and therThis systematic review, first of its kind, demonstrates the complex and multifactorial contributors to hospitalisation for people with LBP with or without leg pain. Specifically, arrival at an emergency department via an ambulance and older age appear to increase the risk of hospitalisation within this cohort. These findings could inform healthcare stakeholders’ decision-making in implementing evidence-informed strategies to better manage the condition and more efficient resource allocation.S1 Checklist(DOCX)Click here for additional data file.S1 Appendix(DOCX)Click here for additional data file.


Non-communicable diseases (NCDs) have become the leading cause of deaths in China and many other countries worldwide. To call for actions in strengthening primary health care (PHC) and accelerate NCD prevention and control in the post-pandemic era in China, the 2023 Duke Kunshan Health Forum focused on innovative approaches and lessons learned during the pandemic that can be applied in addressing NCD challenges. In this article we summarize key points discussed by the participants in three areas: PHC as the foundation and ultimate solution for NCD prevention and control, post-pandemic opportunities to accelerate the NCD program with innovative approaches, and an action framework proposed by the Forum collaborators to address remaining challenges and achieve NCD control objectives in China. The core of the suggested action framework is to offer people-centered, lifetime, comprehensive, continued, and quality NCD prevention and control services, which rely on an integrated healthcare system connecting the primary, secondary, and tertiary levels of care. To achive this objective, six interconnected actions are recommended in the framework: prioritizing and integrating NCD in PHC and Universal Health Coverage (UHC) framework, engaging multiple stakeholders, directing resources to PHC for quality NCD services, leveraging advantages of new technology, encouraging the use of PHC and improving services, and strengthening best practice sharing. The COVID-19 outbreak further disrupted the services for NCD prevention and treatment among others, triggering a potential upsurge in the NCD disease burden in many countries . To addrNCDs are preventable and controllable. The PHC, known as the cornerstone of the health system, has been widely acknowledged as a key to NCD response. The strong political commitment and continuous efforts laid a solid foundation for tackling NCD at the PHC level in China. As part of the 2009 China health reform, the Basic Public Health Service (BPHS) program was launched for all Chinese citizens. Fully funded by the central and local governments, the service package had expanded from only 9 categories initially to 31 categories in 2022, adding more NCD-related services into its scope. Since 2009, the health financing reform also guaranteed health insurance coverage for over 95% of the Chinese population . For insMoreover, a series of key initiatives had been rolled out in recent years, including the National Demonstration Areas Program for Integrated NCDs Prevention and Control (NCDDA), China Healthy Lifestyle for All campaign, and the Whole-of-Care Intervention to the Prioritized NCD Population in Rural China. Many of these demonstration programs focus on the PHC capacity building and the PHC infrastructure improvement. Other ongoing health system restructuring, such as the Integrated County Healthcare Consortium, also witnessed positive results in the BPHS service provision .Building upon all these efforts, China has made impressive achievements regarding PHC strengthening and HUHC. The 2023 monitoring report issued by the World Health Organization and the World Bank showed that China has achieved the UHC service coverage index over 80 since 2019 as one of the Sustainable Development Goals . Future The COVID-19 pandemic heightened the understanding that the traditional boundaries separating communicable and non-communicable diseases were blurred. Individuals with pre-existing chronic health conditions were more vulnerable to experiencing severe illness and mortality if infected with the virus. Some successful experience of the pandemic control in China provided new insights and created an opportunity window for upgrading the NCD management, as described below.(1) The multi-sectoral coordination between health and non-health sectors and concerted actions within the health system among the three-level facilities (primary-secondarily-tertiary) during the pandemic could be valuable practices for future NCD prevention and control. (2) Innovative approaches developed by the public and private sectors to fight the pandemic are feasible for NCD prevention and control. Digital health interventions, such as medical consultation apps and Internet hospitals, integrated health services into one platform. NCD patients could seek consultation, obtain prescriptions, track medication delivery, and receive health education without commuting to health facilities. Studies found that digital health intervention generated consistently positive results in health service effectiveness in many low- and middle-income countries, as it improved service accessibility, upgraded user experience, and expanded healthcare providers’ capacity . HoweverAfter decades of efforts and resource inputs to accomplish the broad coverage of health services, the quality of care improvement at the PHC level remains essential to achieve NCD control objectives in the post-pandemic era. There are a few challenges that require attention from all relevant stakeholders.(1) Given the large size of the total population, the aging trend, and increased service demand from the patients’ side, the national BPHS program may face continuous financing pressure, especially in some less developed provinces . As the With the favored policy environment and the opportunities that emerged from the pandemic, an action framework was jointly proposed during the 2023 Duke Kunshan Health Forum Fig. , which aThe framework focuses on achieving a people-centered, lifetime, comprehensive, continued, and quality NCD prevention and control services. The service provision relies on a health care system that integrates the primary, secondary, and tertiary level care in a coordinative and synergetic manner. As addressed in previous sections, six interconnected actions can drive continuous improvement of the whole system Fig. . NCD serWith decades of efforts in forging UHC, China has laid a solid PHC foundation for NCD prevention and control. However, more robust actions are needed to bring NCD prevention and control to the next level through a people-centered and integrated PHC system. The pandemic posed the urgencies and the opportunities for future interventions, which require continuous political commitment and resource inputs. The action framework the Forum proposed also called for multiple stakeholders' engagement, leveraging the advantages of new technology, encouraging patients to use PHC and improving services, and sharing best practices. Lessons learned from the ongoing demonstration programs, especially the NCDDA mode, would enrich the framework and help build up future national and local implementation plans for extending the practice in all communities across China, paving the way toward fully achieving SDG targets and Healthy China 2030 goals.


This review of monitoring and evaluation resources identified multiple performance indicators that can inform country-specific approaches to evaluating immunization systems. We reviewed monitoring and evaluation (M&E) resources to understand how national immunization system performance has been measured, identifying 631 distinct M&E indicators that reflect the increasing complexity of immunization programs and the changing policies, priorities, and reporting requirements of immunization actors at the global level.This study highlights the substantial workload associated with the large burden of data collection and routine reporting for immunization alone, especially in resource-constrained settings.Despite the large number of indicators identified, gaps remain in measuring key areas of immunization, such as adult immunization, data use in decision-making, and equity and diversity, where efforts are needed to develop and validate indicators.This review can inform country-specific approaches to measuring system performance moving forward, particularly as countries seek to strengthen immunization programs by leveraging investments made during the COVID-19 response.Public health practitioners can streamline how immunization is measured by selecting a core set of indicators that align with the priorities, values, and challenges within their specific setting. Vaccination coverage is widely used to assess immunization performance but, on its own, provides insufficient information to drive improvements. Assessing the performance of underlying components of immunization systems is less clear, with several monitoring and evaluation (M&E) resources available for use in different operational settings and for different purposes. We studied these resources to understand how immunization system performance is measured.We reviewed peer-reviewed and gray literature published since 2000 to identify M&E resources that include national-level indicators measuring the performance of immunization systems or their components . We summarize indicators by the system components or outcomes measured and describe findings narratively.We identified 20 resources to monitor immunization program objectives and guide national strategic decision-making, encompassing 631 distinct indicators. Indicators for immunization program outcomes comprised the majority (124/631 [19.7%]), largely vaccination coverage (110/124 [88.7%]). Almost all resources (19/20 [95%]) included indicators for vaccine logistics (83/631 [13.2%]), and those for regulation (19/631 [3.0%]) and demand generation (28/631 [4.4%]) were least common. There was heterogeneity in how information systems (92/563 [14.6%]) and workforce (47/631 [7.4%]) were assessed across resources. Indicators for vaccination coverage in adults, data use in decision-making, equity and diversity, effectiveness of safety surveillance, and availability of a public health workforce were notably lacking.Between the resources identified in this review, we identified considerable variability and gaps in indicators assessing the performance of some immunization system components. Given the multitude of indicators, policymakers may be better served by tailoring evaluation resources to their specific context to gain useful insight into health system performance and improve data use in decision-making for immunization programs. An immunization system contains health system components, including all the organizations, institutions, resources, processes, and activities involved in the delivery of vaccines.–Unlike immunization coverage, there is no clear consensus on how to measure the performance of immunization system components. Several monitoring and evaluation (M&E) resources exist to measure the performance of immunization systems or programs and are used for different purposes.Examining the current performance of immunization systems can help countries understand how to achieve integration and leverage COVID-19 response investments.We reviewed existing M&E resources used for immunization systems globally to understand how immunization system performance is measured. We were guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.,,We applied the World Health Organization’s (WHO) health system framework to categorize indicators by the components of immunization systems that they intend to measure. The framework describes health systems according to 6 building blocksSupplement 1).We defined the outcomes of immunization systems as the immediate and short-term effects achieved through the collective and synchronized functioning of immunization system components, namely, to vaccinate populations against a broad range of vaccine-preventable diseases. Impacts of immunization systems were defined as health effects and changes in disease burden associated with vaccine-preventable diseases and overall effects on the health of populations. This conceptualization was the basis for the immunization system framework developed as part of this study  and May (Google Scholar) 2022.We searched for M&E resources on immunization systems in the peer-reviewed (OVID MEDLINE) and gray literature (Google Scholar) using search terms related to immunization systems, evaluation, indicators, measurement, and surveillance. The detailed search strategy is available in We included contemporary M&E resources published in 2000 or later that examined system-wide immunization performance. Our selection process is illustrated in the BOXInclusion and Exclusion Criteria for Review of Monitoring and Evaluation Resources Measuring National Immunization System PerformanceInclusion criteriaExamines system-wide performance of immunization system or the system-wide impact of a disease-specific immunization program or initiativeIncludes performance indicators on overall system performance and at least 1 of the system components or examines the performance of multiple components of the systemIncorporates national-level indicatorsPublished in 2000 or laterExclusion criteriaIncluded only outcome  or impact-level indicators Did not include national-level indicators Focused on a single component of the immunization system without examining system-wide performanceEvaluated a disease-specific immunization program, intervention, or targeted initiative without examining its impact on system-wide performanceFollowing extraction of all indicators from the included M&E resources, we included all indicators where the value was numeric or categorical . We included indicators measuring performance at a global level that could be modified to the national level, as data for these indicators are typically collected nationally and then aggregated to obtain a global estimate . We excluded indicators that were not applicable at the national level related to goals requiring global effort and coordination, such as development of new vaccine platforms. In our examination of distinct indicators, we removed indicators that were duplicated across resources.,Supplement 1 for definitions). A formal quality assessment of resources and indicators was not done.We tabulated data on the M&E resources, including the tool’s author, year of publication, purpose, context or location where it was used, and the number of indicators in each tool. We used methods previously used to summarize and compare performance indicators, particularly those used to analyze indicators for health system performance.Data were extracted using Microsoft Excel and imported into NVivo 12 for coding. Two authors (CP and NR) independently coded the indicators. Discrepancies were resolved through discussion and consensus. We categorized each indicator into a single domain and measurement area. Where indicators could be categorized under 2 or more system domains, we used contextual information from the source document to understand which domain the indicator was intended to measure. For example, “the proportion of the immunization budget dedicated to advocacy activities” was categorized under demand generation rather than financing because it was used in the source document to measure commitment to engaging with communities to build demand for vaccines.We used summary statistics to calculate (1) the number of M&E resources, including indicators for each domain and measurement area, and (2) the number of indicators in each domain and measurement area. We summarize our findings narratively.,,,–,–,–,,,,,,After screening 3,707 titles in the peer-reviewed literature and 1,000 in the gray literature, we identified 20 M&E resources that met the inclusion criteria ; 13 from,,,,New Vaccine Post-Introduction Evaluation Tool) evaluated the introduction of new vaccines into national immunization programs.Supplement 3.The 20 included resources captured a total of 740 indicators, of which 631 distinct indicators (85%) were retained following exclusion of ineligible and duplicate indicators  and Box.The number of resources and indicators measuring the performance of immunization system components is summarized in Among indicators for vaccine logistics and supplies, almost half measured availability of supplies at point of service through frequency and duration of stockouts (40/83 [48.2%]). Indicators assessing the performance of cold chain and supply chain management and functionality were also common (37/77 [44.6%]). Among indicators for service provision, those examining the provision of services through the number of vaccination sessions held or the number of doses given were common across resources (39/63 [61.9%]). Nineteen indicators examined integration , with all but 1 of them from resources published in 2017 onwards. Nearly half of the 84 indicators for governance, planning, and program management (38/84 [45.2%]) assessed whether specific policies, protocols, or processes were in place. Twelve of 20 indicators assessing program management pertained to the existence or features of national immunization technical advisory groups.Indicators for information systems and workforce varied to a greater extent than the other domains. Under information systems, most indicators measured data quality (37/92 [40.2%]) and the existence of processes to collect immunization (26/92 [28.3%]) and disease surveillance data (24/92 [26.1%]). Although indicators examined whether specific processes, systems, or resources were available in the country, none examined their functionality, use, or acceptance by workers, and only 1 examined whether disease surveillance and immunization data systems were interoperable. Five indicators (5.4%) measured data use. Most indicators examining the performance of workforce pertained to the availability of health workers for immunization (20/47 [42.6%]) or the frequency and quality of supervision (15/47 [31.8%]). Those on health worker availability largely measured the density of the clinical workforce; 3 assessed the availability of workforce supporting nonclinical functions in the immunization system , but none assessed the size or capacity of the public health workforce.Indicators measuring the performance of regulation and pharmacovigilance and demand generation were the least frequent . Indicators for pharmacovigilance and regulation appeared in the fewest number of resources (8/20 [40.0%]). Indicators for safety surveillance largely included those for rates of adverse event reporting and whether a system for safety surveillance exists. Under demand generation, most indicators identified focused on the occurrence of community engagement sessions (16/28 [57.1%]). Indicators for assessing the level of demand for vaccines varied substantially but mostly examined if strategies were being implemented to improve communication and demand for vaccines and if systems were in place to measure vaccine confidence.,,,Our study found a multitude of indicators examining the performance of immunization systems and their underlying components, with 631 distinct indicators across 20 M&E resources. We identified variations in how domains were measured, including those where there was some consistency across resources, like those for coverage, service provision, and vaccine supplies and logistics. Although some differences may be due to the differing purposes of the resources or operational contexts in which they are used, the differences and multiplicity of resources reflect the increasing complexity of immunization programs and the changing policies, priorities, and reporting requirements of immunization actors at the global level. Recently, global focus has shifted from achieving high coverage of individual vaccines through disease-specific initiatives to achieving universal health coverage through system-wide strengthening approaches.The differences and multiplicity of identified resources reflect the increasing complexity of immunization programs and global changes in policies, priorities, and reporting requirements.,Global attention is also increasing toward expanding immunization across the life span, but our review found that indicators measuring vaccination coverage in adolescence and adulthood are limited in number and scope. Fourteen of 17 indicators examining vaccination after early childhood were identified from the WHO-UNICEF Joint Reporting Form, and 11 of these pertained to influenza vaccine uptake in high-risk populations. COVID-19 vaccination is the first large-scale program targeting adults globally. Before this, 62% (120/194) of countries reported having at least 1 adult immunization program, but high- and upper-middle-income countries were almost 22 times more likely to have such a program compared with low- and lower-middle income countries.,,We found that the processes by which immunization data are collected, analyzed, reported, and accessed, and the systems used to do so, are not consistently measured across resources. Most indicators examined whether a system was in place but not its functionality, acceptability, or use. Experience with interpreting data collected and reported at a global level highlights the data quality issues that arise. For example, data on 14 of the 27 indicators proposed to measure progress against the goals of the Global Vaccine Action Plan (which preceded the IA2030 strategy) were difficult to interpret due to poor data quality and variability in reporting across countries.Although data on numerous indicators are often collected and reported by countries, we identified few indicators in the resources included in our review that measured data-driven decision-making and program planning at the national level. Availability of data does not necessarily translate into action; mechanisms and accountability frameworks to incorporate data into decision-making are needed. Interventions to improve data use can drive improvements in data quality and increase demand for better data.Although countries collect and report data on numerous indicators, we identified few indicators for data-driven decision-making and program planning at the national level.We identified few indicators measuring the performance of regulation and pharmacovigilance systems for vaccines, likely because efforts to implement and strengthen national safety surveillance for vaccines are relatively more recent compared to initiatives targeting other components of the immunization system. The impetus to introduce and enhance safety surveillance systems increased for COVID-19 vaccination.Our review found that few M&E resources measuring the performance of immunization systems include indicators that measure the confidence in vaccines or social and behavioral drivers of demand for immunization, despite growing concerns over vaccine hesitancy.,Indicators examining equitable coverage largely focused on disparities by geographical areas (such as districts), and 5 examined coverage by socioeconomic status. Our review identified some disease burden indicators disaggregated by sex but none for coverage or any that examined or collected data on the role of gender and diversity in making decisions about or implementing immunization programs. Despite known differences in immune responses to certain infections and adverse events following immunization, studies of vaccine effectiveness and safety often do not report results by gender.The absence of indicators in our study on disability, diversity, and inclusion was a gap that requires further work to address.Although 11 of the 17 indicators examining integration of immunization services related to co-delivery of immunization alongside other health services  or in nontraditional settings , it is unclear if this is the best way to measure integration of primary care services.The M&E resources in this review did not identify any indicators examining the capacity or competency of the public health workforce or the surge clinical capacity available to draw on in the event of a public health emergency. The need for defining, mapping, and measuring the workforce, including the public health workforce, is recommended in WHO’s Global Strategy on Human Resources for Health 2030.,Our study identified 47 distinct indicators across 9/20 (45.0%) M&E resources that measure the impact of immunization programs on disease burden and elimination targets. This small number is likely due to (1) our inclusion criteria and focus on metrics assessing immunization system performance and (2) exclusion of resources that did not measure the operational aspects of immunization systems. Although the indicators identified disease-specific and some summary metrics of disease burden and disease elimination and eradication targets, metrics evaluating wider economic and societal benefits, such as reductions in poverty, improvements in productivity, and financial returns on investment,To our knowledge, this is the first published review of indicators used to measure system-wide performance of national immunization systems that includes M&E resources published over 2 decades. This review intentionally focuses on M&E resources used globally. Previous global immunization strategies were viewed as top-down strategies, but there is growing recognition that country-specific goals and targets are needed.Our review provides a starting point for national governments and partner agencies to assess immunization system performance in their own contexts.,,Importantly, our study highlights the large burden of data collection and routine reporting for immunization alone, with 169 indicators identified in the 2019 WHO-UNICEF Joint Reporting Form and 112 indicators for national monitoring in the IA2030 M&E framework. We removed 93 duplicate indicators identified in our review but were still left with 631 indicators. Many indicators measured the same construct but in slightly different ways, which means that data collected with 1 resource may not be appropriate for use with another resource, resulting in duplication of efforts if reporting on those indicators is required by development or financial partners. The workload associated with collecting and reporting data using different M&E resources is significant, especially in resource-constrained settings, where dedicating resources to meet reporting requirements has opportunity costs.A Guide for Monitoring and Evaluating Child Health Programs,Although we systematically searched the literature, we identified only 6 peer-reviewed publications. This is unsurprising as the majority of widely used M&E resources are published in the gray literature by global partner agencies. The Medical Subject Headings used in the MEDLINE database for this topic area are not well-defined and provide a substantial volume of false results. A further limitation is that we only included resources that were publicly available, whereas many countries may report on performance directly to their funders. We ensured that our search strategy captured the Medical Subject Headings against which the identified articles were indexed, and 2 authors of this article are content area experts who checked that we included all major or influential M&E resources. We excluded some widely used and well-established resources, particularly those published by the WHO’s Immunization Analysis and Insights group, such as the Effective Vaccine Management assessment tool and vaccine-specific post-campaign assessment resources . Some of these were focused on a specific aspect of immunization systems rather than system-wide performance or had a disease-specific or context-specific focus. M&E resources on child health programs, such as MEASURE Evaluation’s We did not conduct a quality assessment of indicators using a standardized quality assessment framework. Not all of the indicators were clearly defined, and few were accompanied by a data dictionary clarifying how to calculate statistics and where to source data. It is possible that some indicators may be interpreted differently depending on the context. Although most resources were developed through iterative and consultative processes, it is unclear if indicators have been validated and are associated with improvements in performance. Thus, the existence of M&E resources and indicators does not necessarily mean they are used or provide insightful information. It is likely that countries are tailoring assessments to suit their contexts and measuring indicators that best match their goals and available resources. Furthermore, performance indicators often have limited use in understanding the drivers of performance. Several M&E resources provide guidance on using other data collection methods, such as interviews and focus groups, to generate information to supplement quantitative indicators that together can inform future actions. Further research is needed to better understand how these evaluation resources are used, whether they drive improvements in performance and the pathways for doing so, and which system-level indicators most closely correlate with improvements in vaccine coverage, equity, and reductions in disease. Measuring implementation strength ,Developers of M&E resources should assess the quality of indicators included to ensure they are measurable, easy to interpret, linked to performance improvements, and relevant to decision-making.,We elected to use the WHO health system framework as the basis for the components of immunization systems, which we used to categorize indicators. This framework has rightly been criticized for focusing on the infrastructural and resource-related components of health systems and insufficiently accounting for the interdependencies between components as well as intangible components such as trust and social value.Supplement 1.Finally, the inductive method we used to identify measurement areas based on the themes that emerged from our review introduced unavoidable risk of measurement and selection bias. As content area experts, we acknowledge that our prior experiences, assumptions, and beliefs have the potential to influence the research process. We have attempted to minimize this bias by having 2 authors independently code indicators and agree on the definitions set out in This review identified a multitude of indicators to measure immunization system performance. We identified heterogeneity in metrics assessing the performance of some immunization system components; further studies are needed to reach consensus on how to measure performance in these areas. This summary of indicators can inform country-specific approaches to measuring system performance moving forward, particularly as countries seek to evaluate the impact of the COVID-19 pandemic and leverage the investments made during the response. As countries look to identify focus areas for improvement, they can benefit from selecting indicators that are aligned with national goals, values, and priorities and establishing accountability frameworks to monitor performance and take action. Establishing a country-focused set of core indicators and improving the quality of data on these select metrics will position decision-makers to have better access to data that is useful in decision-making, enabling countries to achieve their immunization goals.


The Penn Medicine COVID-19 Therapeutics Committee—an interspecialty, clinician-pharmacist, and specialist–front line primary care collaboration—has served as a forum for rapid evidence review and the production of dynamic practice recommendations during the 3-year coronavirus disease 2019 public health emergency. We describe the process by which the committee went about its work and how it navigated specific challenging scenarios. Our target audiences are clinicians, hospital leaders, public health officials, and researchers invested in preparedness for inevitable future threats. Our objectives are to discuss the logistics and challenges of forming an effective committee, undertaking a rapid evidence review process, aligning evidence-based guidelines with operational realities, and iteratively revising recommendations in response to changing pandemic data. We specifically discuss the arc of evidence for corticosteroids; the noble beginnings and dangerous misinformation end of hydroxychloroquine and ivermectin; monoclonal antibodies and emerging viral variants; and patient screening and safety processes for tocilizumab, baricitinib, and nirmatrelvir-ritonavir. The Penn Medicine COVID-19 Therapeutics Committee served as a forum for rapid evidence review and the production of dynamic practice recommendations during the pandemic. We describe how the committee went about its work and how it navigated specific challenging scenarios. As the United States anxiously awaited the arrival of the coronavirus disease 2019 (COVID-19) pandemic in early 2020, clinicians and researchers began a frantic search for guidance in how to manage patients with this novel disease—first by extrapolation from known potentially related respiratory viruses and the associated basic and clinical science literature , and theThese concerns, and our institution's mandate to provide optimal care for our patients and to serve as a leader and model for COVID-19 care, motivated the formation of the Penn Medicine COVID-19 Therapeutics Committee on 11 March 2020. Over the next 3 years and continuing to the present, this committee—an interspecialty, clinician-pharmacist, and specialist–front line primary care collaboration—has served as a forum for rapid evidence review and the production of dynamic practice recommendations during the COVID-19 public health emergency, with corresponding objective improvements in outcomes for this novel disease . The objOur target audiences for this article are clinicians, hospital leaders, public health officials, and researchers invested in the preparedness for inevitable future threats. Our learning objectives are to discuss the logistics and challenges of forming an effective committee, undertaking a rapid evidence review process, aligning evidence-based guidelines with operational realities, and iteratively revising our recommendations in response to changing pandemic data. We specifically discuss the arc of evidence for corticosteroids; the noble beginnings and dangerous misinformation end of hydroxychloroquine and ivermectin; monoclonal antibodies and emerging viral variants; and patient screening and safety processes for tocilizumab, baricitinib, and nirmatrelvir-ritonavir.Penn Medicine—the combination of the University of Pennsylvania Health System and the University of Pennsylvania Perelman School of Medicine—includes 6 acute care hospitals that span a quaternary academic referral center, an urban teaching hospital and trauma center, and urban, suburban, and rural community-focused hospitals. These hospitals together include 6 emergency departments, >20 intensive care units, and >2900 inpatient beds accommodating annually >337 000 emergency department visits and >129 000 inpatient hospital admissions. Penn Medicine ambulatory clinics see >5.6 million outpatient visits per year. The health system serves a broad surrounding community and large referral area across urban, suburban, and rural eastern Pennsylvania and southern and central New Jersey.The Penn Medicine COVID-19 Therapeutics Committee was formed with multidisciplinary physician and pharmacist representation from infectious diseases, pulmonary and critical care medicine, microbiology, and infection prevention and control. Committee membership included representation from all hospitals within the health system to allow for local expert input, which was helpful for aligning guidelines with operational realities and for uniform dissemination and implementation. As the pandemic progressed and therapeutics emerged from new drug classes, such as monoclonal antibodies and antivirals for early disease, the committee membership expanded to include outpatient primary care and infusion center clinicians to maintain necessary expert input across the full spectrum of COVID-19 care. The committee met weekly at the start of the pandemic, less frequently as time passed, and emergently ad hoc when immediate updates were needed, such as due to viral variant shifts and regulatory changes that added or removed agents from the US market.Potential therapeutic agents were identified on a rolling basis selected by local and global expert opinion, extrapolation from agents with efficacy for other pathogens or with plausible mechanisms, and from the rapidly emerging COVID-19 literature . To rapiHighlights from these monographs were curated into a master table that tracked notable updates. These master table updates, in turn, informed the discussion agenda for committee meetings at which reviewers gave evidence presentations on new therapeutic agents or existing agents with new data. Determination for guideline inclusion was by committee consensus, and specific therapeutic recommendations and revisions, including inclusion and exclusion criteria, dosing regimen, and safety monitoring, were drafted and circulated for iterative feedback. The committee was delegated authority by the standing health system Pharmacy and Therapeutics Committee to create, update, and approve health system guidelines based on these reviews. If guidelines required adding a new therapeutic agent to hospital formulary or the use of a medication with an US Food and Drug Administration (FDA) emergency use authorization (EUA), the recommendation to add that therapeutic agent was sent to the Pharmacy and Therapeutics Committee for additional approval.To focus efforts on the highest yield therapeutic agents, the committee also had a process of retiring agents from active review when data reached a certain threshold of inefficacy, definitive trials were published, or other therapeutics were clearly preferred. However, there was a less frequent periodic ongoing review of retired agents, and in some instances, agents were unretired. For example, tocilizumab initially had data that was unfavorable, but subsequent studies demonstrated more promising safety and efficacy , 17. In Outfacing deliverables from the committee included the web-based, publicly available “Penn Medicine COVID-19 Treatment Guidelines,”  a livingGuideline updates were always accompanied by communication to pertinent healthcare providers, which was facilitated by the diverse committee membership. Specifically, guideline updates and revisions were announced in daily health system–wide email communications with dynamic links and further transmitted directly to highly affected service lines  via committee communication with service line leaders for internal dissemination. Similarly, the committee had close relationships with health system information systems and operational leadership so that medication orders and clinical decision support could be integrated rapidly into the electronic health record and instructions on ordering and administration could accompany treatment guidelines. The committee went through a standard checklist of steps when implementing novel therapeutics .Serving a large health system with heterogeneous acute care hospitals and ambulatory practices and interacting frequently with city and state public health departments regarding the procurement of government-distributed therapeutics, the health system chief medical officer identified the benefit of establishing a single point of contact, which was done through the chief pharmacy officer, an infectious diseases–trained pharmacist and administrator. This single point of contact served as a longitudinal liaison between the committee, the Philadelphia Department of Public Health, the Pennsylvania Department of Health, and the Centers for Disease Control and Prevention (CDC). One critical decision made between the chief medical officer, the chief pharmacy officer, and the public health departments was the distribution of limited-supply therapeutics with FDA EUAs to a single health system hospital, which would in turn distribute internally among the other health system hospitals. This centralization allowed for internal titration of limited-supply therapeutics to meet the heterogeneous demands across our care sites. Of note, this internal sharing was possible among our Pennsylvania-based facilities but could not be extended to our New Jersey–based facilities, which were within a different state regulatory silo.Among the committee's earliest recommendations was one we would soon reverse: a recommendation against routine use of corticosteroids, unselective anti-inflammatory drugs, in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), based on extrapolated data from other respiratory viruses. Systematic reviews and meta-analyses of influenza studies had found that corticosteroid therapy was associated with increased mortality rate, longer intensive care unit stay, and increased odds of hospital-acquired infection , 22. StuDespite these concerns, there was continued interest in modulating the severe inflammation and cytokine-related lung injury that some patients with SARS-CoV-2 were developing. Many initial studies of corticosteroids in SARS-CoV-2 were small and suffered from confounding by indication, with more severely ill patients more likely to receive corticosteroids and more likely to have poorer outcomes. Our clinical practice changed dramatically in July 2020 with release of the first results from the Randomised Evaluation of COVID-19 Therapy (RECOVERY) platform trial demonstrating a significant mortality benefit of dexamethasone for patients hospitalized with SARS-CoV-2 and requiring supplemental oxygen, with the greatest benefit seen in patients requiring mechanical ventilation . With thAlthough there remain questions about optimal corticosteroid choice and dose, dexamethasone has become standard of care for hospitalized patients with severe or critical COVID-19 . The corAmong the earliest COVID-19 therapeutics candidates evaluated by the committee in March 2020 were hydroxychloroquine and chloroquine, immunomodulatory antiparasitic agents, based on a plausible mechanism of action and animal and in vitro data showing activity of these drugs against SARS-CoV-2 and other coronaviruses . We reviDuring March and April 2020, we continued to review the evidence as it evolved, including our own internal observations regarding cardiac arrhythmias , and by Ivermectin, another antiparasitic agent, was likewise identified as an early potential COVID-19 therapeutic candidate based on preclinical, in vitro data demonstrating reductions in SARS-CoV-2 viral RNA , 47, butAs the pandemic marched on, ivermectin, alongside antivaccination efforts, became a central tenet of COVID-19 misinformation spread and believed by a swath of politicians, physicians, and members of the public. Despite its absence from every major COVID-19 treatment guideline (and indeed many overtly cautioning against its use), the dearth of high-quality supporting data, and an overt statement of no efficacy by the US manufacturer , ivermecAnti–SARS-CoV-2 monoclonal antibodies, which aim to bind to and neutralize viral particles, became an important, and highly dynamic, tool for the treatment of high-risk outpatients with mild-to-moderate COVID-19 infection, but their use posed significant logistical challenges . EffectiAll monoclonal antibody referrals were screened by a centralized team to verify eligibility. When the number of referrals exceeded drug or infusion capacity, a weighted lottery was used. Created in collaboration with institutional bioethicists and following Commonwealth of Pennsylvania guidance, the lottery incorporated augmented weighting for eligible patients who were pregnant, met the Commonwealth definition of an essential worker, or resided in a location with a high area of deprivation index , 59; eliDedicated infusion locations with trained nursing staff were created for monoclonal antibody administration so that actively infected patients would not be colocated with uninfected immunocompromised patients. A physician was available on site in infusion locations to assess any clinical emergencies. While a modest number of monoclonal antibody infusions were provided in emergency departments, a more common practice in community hospitals nationally, for most of our hospitals sustained emergency department capacity strain precluded routinely referring patients to the emergency department solely for a monoclonal antibody infusion.Our monoclonal antibody infrastructure was modified for tixagevimab-cilgavimab , the duaUnfortunately, resistance to monoclonal antibodies swiftly developed with the emergence of new SARS-CoV-2 viral variants, limiting the use of specific monoclonal antibodies at sequential points during the pandemic . In respThere were several points at which cessation of use of a particular monoclonal antibody was considered by the committee before withdrawal of the FDA EUA. In each instance, we assessed multiple factors, including regional and local prevalence of resistant variants  including the pattern of Philadelphia often following trends seen in New York; risks of monoclonal antibody infusion; availability of alternative monoclonal antibodies and other outpatient therapeutics, including the efficacious antiviral nirmatrelvir-ritonavir; discussion with other local institutions and public health authorities; and for tixagevimab-cilgavimab preexposure prophylaxis specifically, the possibility of future susceptible viral variants.At the time of this writing, all once-used monoclonal antibodies for the treatment or prevention of early COVID-19—bamlanivimab with or without etesevimab, casirivimab-imdevimab, sotrovimab, bebtelovimab, and tixagevimab-cilgavimab—had withdrawal of their FDA EUA approval and ceased to be used in the United States owing to emerged resistance patterns. As additional outpatient therapeutics became available , we created a recommended treatment pathway for outpatients, accounting for patient factors and availability of therapeutics, which was iteratively revised in parallel to the main treatment guidelines  67]..67].Tocilizumab, an interleukin 6 receptor antagonist, and baricitinib, a Janus kinase 1 and 2 inhibitor, have each become important adjunctive immunomodulatory agents for patients who progress to severe respiratory failure owing to SARS-CoV-2 infection. The committee outlined eligibility criteria and approaches to safety screening and monitoring informed by large clinical trials and prior literature and experience with these agents in other patient populations. The RECOVERY and COV-BARRIER trials supported the use of baricitinib, while RECOVERY and Randomized Embedded Multifactorial Adaptive Platform for Community-Acquired Pneumonia (REMAP-CAP), another large platform trial, supported the use of tocilizumab, both in combination with dexamethasone and in patients with <14 days of COVID-19 symptoms and early, rapidly progressive severe respiratory failure .Points of debate that evolved over the pandemic included how quickly therapy must be initiated after hospitalization and the development of severe disease and how exactly to define severe disease, including intensive care unit status  and degree of respiratory support . Exclusion criteria and/or dose adjustments existed for the presence and degree of renal failure, hepatic impairment, and cytopenias. The totality of evidence suggested a general preference for baricitinib, with tocilizumab available in situations where baricitinib was contraindicated or otherwise not available.Because both agents are immunomodulatory with an infection risk, a significant case-by-case patient evaluation focused on whether or not there was a concomitant uncontrolled non–SARS-CoV-2 secondary or coinfection, such as a bacterial pneumonia. Likewise, preexisting immunosuppression was considered to be a relative, but not absolute, contraindication for both agents since these patients were excluded from clinical trials and deemed to be higher risk with additional immunomodulation. All patients were assessed for tuberculosis risk factors and hepatitis B virus serologic status. Given the pharmacologic complexity, potential adverse effect profiles, and rapidly evolving evidence base, we opted to require approval by a specialized baricitinib/tocilizumab team or an infectious diseases consultation accompanied by documentation before administration was permitted.The ritonavir-boosted SARS-CoV-2 protease inhibitor nirmatrelvir, the first oral SARS-CoV-2 antiviral agent, was granted FDA EUA in late 2021 . DespiteEfforts shifted to combining information technology optimization with the use of a specialized pharmacy consultation . A cliniA significant challenge throughout the committee's efforts was aligning optimal guidelines most supported by available evidence and the operational realities of our health system at that time. At the same time that therapeutic agents for COVID-19 provided novel treatments for an evolving pandemic, many also necessitated new processes to deliver the treatments in healthcare facilities that were already stressed by staffing, infrastructure, and resource shortages. Navigating the exponentially growing data and emerging therapeutics was only one piece. National guidelines for treatments such as monoclonal antibodies, outpatient remdesivir, and oral antivirals were often broader than could typically be fully accommodated by local capacities and drug availability. Unlike many other infectious diseases treatment guidelines, local COVID-19 therapeutic guidelines had to be informed not only by the data but also by the practicality of implementing the treatments. Eligibility criteria often needed to be adjusted based on the operational realities, usually making them more targeted to highest-risk populations.Understanding the capacity and availability of specific therapeutic agents was essential to creating practical and sustainable treatment guidelines. This practical knowledge allowed the committee to embed eligibility criteria that prioritized patients who would benefit the most. Similarly, it facilitated setting up allocation frameworks that attempted to equitably distribute therapeutics to racially, ethnically, and socioeconomically diverse patients. In parallel, these guidelines needed to pivot rapidly as dictated by changes in data and operational realities, and these updates needed to be broadcasted to a large, complex health system, an onerous but essential process. If there was not a bidirectional flow of information between operational realities and guideline creation, guideline implementation would likely not have been as successful.This article represents one health system's experience and provides a selection of discussion points but is not a comprehensive accounting of the Penn Medicine COVID-19 Therapeutics Committee's work and all related issues. In particular, we did not discuss certain therapeutic agents in depth, including the antiviral remdesivir , COVID-19 convalescent plasma, anakinra, and molnupiravir, among others. We also did not discuss important related issues that were governed by other groups within our health system including COVID-19 clinical education, respiratory care and critical care guidelines , testingPenn Medicine would ultimately care for >20 000 patients hospitalized with COVID-19. The success of the Penn Medicine COVID-19 Therapeutics Committee in achieving a method for rapid evidence review and dynamic practice recommendations during a public health emergency was anchored in a diverse committee roster across disciplines, subspecialties and primary care, and hospitals; a commitment to, and standardized approach for, rigorous review of emerging evidence, including the explicit self-imposed mandate to revisit and revise prior recommendations based on new data; and clear attention to communication, standardization, dissemination, and version control across health system facilities. Future threats from inevitable yet-to-emerge novel pathogens may be countered with a similar or further adapted approach.


An updated Council of the EU recommendation on cancer screening was adopted in December 2022 during the Czech EU presidency. The recommendation included prostate cancer as a suitable target disease for organised screening, and invited countries to proceed with piloting and further research. To support further discussions and actions to promote early detection of prostate cancer, an international conference in November 2022 (Prostaforum 2022) resulted in a joint declaration. Here we describe the EU policy background, summarise the preparation of the declaration and the key underlying evidence and expert recommendations, and report the text of the declaration. The declaration summarises the striking inequalities in prostate cancer burden in Europe and calls on all stakeholders to consider and support concrete steps for advancement of organised early detection of prostate cancer. Our aim is to request endorsement of the text and potential initiation of practical actions by all stakeholders to support the aims of the declaration.Prostate cancer is among the most frequent cancers and is one of the most common causes of cancer death among men. The European Union has recommended new pilot programmes for prostate cancer screening. The Prostaforum 2022 declaration invites all stakeholders to support this new recommendation with specific steps. Cancer control was one of the key priorities of the recently concluded Czech presidency of the Council of the EU. In December 2022, the updated council recommendation on cancer screening was adopted In November 2022, the international Prostaforum conference Conference speakers presented underlying evidence and practical experience with organised testing; presentations are available at the conference website https://prostaforum.uzis.cz/en/prague-prostaforum-declaration/.To support further policy discussions and actions to promote early detection of prostate cancer across the EU, a declaration with a call for policy actions at the national and EU level was drafted and presented at the Prostaforum conference. The full text of the declaration, as well as a list of individuals and organisations endorsing the declaration and a form for its endorsement, is available at During a meeting in September 2022, the Ministers of Health of the European Union expressed their support for the Call to Action on Oncology, which was the main output from the Modern Cancer Control: Saving Lives Through Smart Solutions expert conference on oncology, which called on all stakeholders to consider support of EU-wide accessibility of quality cancer screening programmes Prostate cancer is the most frequently occurring male cancer in many European countries and one of the most common causes of cancer death among men. Estimated prostate cancer incidence rates varied twofold and mortality rates threefold in 2020 across the EU •Adopt and implement in a timely and ambitious manner the new council recommendation on cancer screening to promote EU-wide state-of-the-art provision of evidence-based cancer screening.•Make available in a timely manner new technologies for early detection of prostate cancer.•Investigate these new technologies in screening algorithms applied to population-based screening programmes.•The European Commission should promote the development and implementation of European guidelines and quality assurance schemes for prostate cancer screening through a European initiative on prostate cancer, so that countries can adhere to the best evidence-based recommendations, while at the same time recognising their local circumstances and resource constraints, among other factors.•The European Commission should consider the possibility of supporting collaborative efforts to implement actions to support early detection of prostate cancer at the national level, including health literacy and raising of awareness.•The European Commission, together with member states with reference to their national context, should make every effort to reduce the striking differences between EU countries in the burden of prostate cancer.•Structured sharing of good practices in prostate cancer screening and early detection among EU countries, including timely sharing of data on agreed quality assurance indicators and the results of implementation/pilot studies, should be further strengthened.•Support all stages of research  aimed at improving prostate cancer screening and early detection as measures to decrease the striking differences in prostate cancer mortality between EU member states.Taking the above-mentioned considerations into account, the Prostaforum declaration calls on all stakeholders to consider and support the following steps specifically for prostate cancer control through early detection:We hope that the preparation of the EU Council recommendation following the EAU recommendation and this declaration indicate a new phase of evidence-based EU policy for early detection of prostate cancer. We agree that vast differences in cancer mortality within the EU are partly a reflection of uneven implementation of effective medical practices, including recommended screening programmes Author contributions: Ondřej Májek had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Study concept and design: Májek, Babjuk, Roobol, Bratt, Van Poppel, Zachoval.Acquisition of data: Májek, Babjuk, Roobol, Bratt, Van Poppel, Zachoval.Analysis and interpretation of data: Májek, Roobol, Bratt, Van Poppel.Drafting of the manuscript: Májek, Roobol, Bratt, Van Poppel, Collen.Critical revision of the manuscript for important intellectual content: Májek, Babjuk, Roobol, Bratt, Van Poppel, Zachoval, Ferda, Koudelková, Ngo, Gregor, Collen, Hejduk, Dušek, Válek.Statistical analysis: None.Obtaining funding: Májek, Hejduk, Dušek.Administrative, technical, or material support: Koudelková, Ngo, Gregor.Supervision: Májek, Babjuk, Roobol, Bratt, Van Poppel, Zachoval, Dušek, Válek.Other: None.Financial disclosures: Ondřej Májek certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript , are the following: None.Funding/Support and role of the sponsor: This work was supported within the framework of the European Social Fund, Operation Programme Employment . The sponsor played no role in the design and conduct of the study, interpretation of the data, and preparation of the manuscript.