Infants master temporal patterns of their native language at a developmental trajectory from slow to fast: Shortly after birth, they recognize the slow acoustic modulations specific to their native language before tuning into faster language-specific patterns between 6 and 12 months of age. We propose here that this trajectory is constrained by neuronal maturation—in particular, the gradual emergence of high-frequency neural oscillations in the infant electroencephalogram. Infants’ initial focus on slow prosodic modulations is consistent with the prenatal availability of slow electrophysiological activity . Our proposal is consistent with the temporal patterns of infant-directed speech, which initially amplifies slow modulations, approaching the faster modulation range of adult-directed speech only as infants’ language has advanced sufficiently. Moreover, our proposal agrees with evidence from premature infants showing maturational age is a stronger predictor of language development than ex utero exposure to speech, indicating that premature infants cannot exploit their earlier availability of speech because of electrophysiological constraints. In sum, we provide a new perspective on language acquisition emphasizing neuronal development as a critical driving force of infants’ language development. Before birth and in the first months afterward, the electrophysiological spectrum of the brain is dominated by slow activity . Delta-bIn contrast, adult speech processing is thought to use a more extended range of exogenous oscillatory activity. Exogenous oscillations in the delta and theta bands, but also faster oscillations in the gamma band (> 20 Hz), are thought to serve the temporal segmentation of speech. This may be achieved via phase alignment of the gamma, theta, and delta bands to acoustic modulations in speech . The freNewborns display selective acquaintance with slow temporal patterns characteristic of the speech prosody of their native language . But thiInfant-directed speech (IDS) is marked by a slow articulation rate and lengthened, hyperarticulated vowels . MoreoveSlowness also aids language development —presumabIt is traditionally thought that fetuses cannot acquire temporal patterns faster than prosodic modulations mainly because the former cannot be heard in the womb , which covers frequencies that can phase-lock to phoneme-rate amplitude modulations in speech . In contIn adults, activity in the higher gamma band  is sensitive to phonological features . FeatureThe different proposed functional roles of the lower and higher gamma bands would entail that infants first learn to segment phonemes (= lower gamma) and afterward acquire their categorical properties . There is indirect evidence for this idea: First, the developmental shift from slow to fast electrophysiological activity does not stop at the lower gamma band but continues until the higher gamma band . Second,Although IDS is initially slow, caregivers accelerate their speech patterns across development; speech rate becomes comparable to adult-directed speech at around 2 years of infant age . In addiWe presented a new perspective on the relationship between electrophysiological maturation and language acquisition. Specifically, the prenatal prevalence of slow electrophysiological activity allows for the early development of native-specific speech processing of prosodic information, which is available to the fetus in utero. Faster electrophysiological activity in the gamma range, which is required for the segmentation and representation of native phonological information, emerges only postnatally and continues to develop across the first year after birth, therefore constraining the onset of the acquisition of acoustic-phonological knowledge to the second half of the infants’ first year. Parental speech adaptations fit the temporal granularity of infants’ electrophysiological tool kit. This provides a novel perspective for the neuroscientific investigation of language acquisition. Researchers should consider infants’ learning in relationship to their electrophysiological processing abilities as well as the speech they receive from their caregivers. Novel studies on infant’s electrophysiological speech processing should specifically focus on electrophysiological processing of frequency modulations, which are highly relevant for language development, as well as more directly on the role of gamma activity for infants’ early phonological acquisition.


The COVID-19 pandemic and resultant restrictions on social gatherings significantly impacted many peoples’ sense of social connectedness, defined as an individual’s subjective sense of having close relationships with others. Older adults living in long-term care homes (LTCHs) experienced extreme restrictions on social gatherings, which negatively impacted their physical and mental health as well as the health and well-being of their family caregivers. Their experiences highlighted the need to reconceptualize social connectedness. In particular, the pandemic highlighted the need to explore novel ways to attain fulfilling relationships with others in the absence of physical gatherings such as through the use of a hybridized system of web-based and in-person presence.Given the potential benefits and challenges of web-based presence technology within LTCHs, the proposed research objectives are to (1) explore experiences regarding the use of web-based presence technology (WPT) in support of social connectedness between older adults in LTCHs and their family members, and (2) identify the contextual factors that must be addressed for successful WPT implementation within LTCHs.This study will take place in south western Ontario, Canada, and be guided by a qualitative multimethod research design conducted in three stages: (1) qualitive description with in-depth qualitative interviews guided by the Technology Acceptance Model (TAM) and analyzed using content analysis; (2) qualitative description and document analysis methodologies, informed by content and thematic analysis methods; and (3) explicit between-methods triangulation of study findings from stages 1 and 2, interpretation of findings and development of a guiding framework for technology implementation within LTCHs. Using a purposeful, maximum variation sampling approach, stage 1 will involve recruiting approximately 45 participants comprising a range of older adults, family members (30 participants) and staff (15 participants) within several LTCH settings. In stage 2, theoretical sampling will be used to recruit key LTCH stakeholders . In stage 3, the findings from stages 1 and 2 will be triangulated and interpreted to develop a working framework for WPT usage within LTCHs.Data collection will begin in fall 2023. The findings emerging from this study will provide insights and understanding about how the factors, barriers, and facilitators to embedding and spreading WPT in LTCHs may benefit or negatively impact older adults in LTCHs, family caregivers, and staff and administrators of LTCHs.The results of this research study will provide a greater understanding of potential approaches that could be used to successfully integrate WPTs in LTCHs. Additionally, benefits as well as challenges for older adults in LTCHs, family caregivers, and staff and administrators of LTCHs will be identified. These findings will help increase knowledge and understanding of how WPT may be used to support social connectedness between older adults in LTCHs and their family members.PRR1-10.2196/50137 Social connectedness, defined as an individual’s subjective sense of having close relationships with others [The COVID-19 pandemic and resultant restrictions placed upon Canadians and residents of many other countries  significantly impacted elements of many people’s social connections over the last 2 years [h others ,4 is nech others . During h others . In Canah others . Older ah others ,9. Alongh others , almost h others . These dh others ,12,13.Before the COVID-19 pandemic, older adults in LTCHs were at risk of experiencing social isolation due to a variety of factors such as challenges with building new relationships, decreased autonomy, and geographical constraints on maintaining face-to-face or in-person connections with friends and family . In oldeWith the start of the pandemic, social connectedness among older adults within LTCHs was severely compromised both directly and indirectly by restrictions placed upon visitors and other infection control measures . This phIn the initial stages of the COVID-19 pandemic, research findings suggested that older adults may be less vulnerable to detrimental mental health effects of the disease and associated health measures, than their younger peers ,31. HoweAs COVID-19 led to widespread limitations on in-person gatherings and for a time halted in-person visits to LTCHs, attention turned to technology as a means to communicate and facilitate social connectivity between family members and older adults . As we mWeb-based presence is the use of networked digital telecommunications technology to create the impression that a user is present in another environment . DigitalEarly efforts to explore the application of technology within LTCH settings focused on aspects such as resident safety. However more recently, the role of technology to support social connectedness is also being investigated . Emerginhybridized web-based and in-person approaches for social connectedness in the context of distancing measures or other constraints on in-person engagement.WPT can provide family members of older adults in LTCHs with the opportunity to visually observe the well-being of the older adult in real time. Visual confirmation of these older adults’ well-being can contribute to family members’ trust and confidence in the care being provided by LTCH staff . Admitte.Given the potential benefits of WPT within LTCHs and the need to understand associated shortcomings, the proposed research goal is to explore experiences regarding the use of WPT in support of social connectedness between older adults in LTCHs and their family members, and to identify the contextual factors that must be addressed for successful WPT implementation in LTCHs. This study has 3 aims. First, to explore how older adults in LTCHs, their family members, and LTCH staff members experience, benefit from, and envision the role of WPT to support social connectedness in LTCHs. Second, to interview key stakeholders such as managers and directors of LTCHs, and to examine LTCH policy, funding, management, and operations in order to identify institutional challenges and facilitators impacting the uptake and spread of WPT within LTCHs. Third, to triangulate the findings from stages 1 and 2 to develop a framework that can inform the formal implementation of WPT in support of social connectedness within LTCHThe faculty team recognizes that there is an implicit bias against some groups’ progression to academia’s higher ranks. Our faculty team is deeply committed to equity and diversity in recruiting, hiring, and training students. This research team will comprise emergent and seasoned scholars and researchers and a research assistant who is a graduate student at the university where the principal investigator is employed.This study will use a qualitative multimethod research design conducted in 3 stages. The multimethod design will be informed by the Technology Acceptance Model (TAM) and entail the use of qualitative description using content analysis (stage 1) and thematic and document analysis methodologies (stage 2). The overarching objective will be to triangulate the findings from stages 1 and 2 to create a working framework to inform the implementation of WPT in LTCHs. Stage 1 is focused on data collection through in-depth interviews with stakeholders  to inform an initial understanding of the perceived usefulness, ease of use, challenges, attitude toward, and human resource availability to support social connectedness using WPT. Stage 2 will involve the examination of relevant documents  and in-depth interviews with key LTCH administrators such as directors and managers as well as salient staff  that will describe the LTCH environment, its functioning, and regulations to develop an understanding of the institutional factors that have a bearing on potential web-based presence implementation. In stage 3, the data from stages 1 and 2 will be used to triangulate the findings and interpret them to develop a working framework for WPT implementation within LTCHs.The first stage of this study will use qualitative description to explore how older adults in LTCHs, their family members, and LTCH staff experience and understand the use of WPT in support of the social connectedness of older adults in LTCHs . The outAs the initial step of stage 1, ethics approval for the proposed study will be sought from the applicable research ethics boards . Once ethics approval has been obtained, data collection will be initiated. The research team anticipates beginning the participant recruitment phase in late autumn 2023.The principal investigator will manage all data generated with this research to ensure effective data use and security. Standardized data file naming, storage (including metadata) and backup procedures will support data sharing and protect the data against catastrophic loss. Data will be stored on a password-protected university server to protect against unauthorized access, in keeping with research ethics board requirements (ID#2023-121993-78969).To conduct the interviews in stage 1, we will use purposeful and maximum variation sampling to recruit a range of older adults, family members (30 participants) and staff (15 participants) within several LTCH settings with a total recruitment goal of approximately 45 participants . A revieInclusion criteria for this stage will be English speaking and the ability to participate in a one-on-one interview using Zoom technology. Potential older adult participants with mild cognitive decline living in LTCHs or receiving outpatient care will be assessed for suitability to participate in this study by LTCH staff first before any study information will be shared with them. Exclusion criteria applied will be the inability to converse in English and advanced cognitive decline.The screening process will be conducted by partnering organizational staff. As part of LTCH guidelines a regular Montreal Cognitive Assessment screening  is used Individual in-depth interviews with older adults, their family members, and LTCH staff will take place in-person, via phone, or Zoom call depending on participant preferences and applicable COVID-19 restrictions at an agreed-upon date and time.After the screening and deeming an older adult eligible to participate in this study, a research assistant will connect with a recreational therapy department staff or a caregiver in order to assist older adult participants with setting a study interview appointment, securing a quiet room, accessing an electronic device at their LTCHs, and helping them join a Zoom meeting to participate in an interview at an agreed upon date and time.We will conduct semistructured in-depth interviews with a range of older adults, family members, and staff in several LTCHs. The purpose of conducting these interviews will be to explore participants’ perceptions of how WPT has been used and can be used, and to identify potential barriers to supporting social connectedness between older adults and family members within LTCH settings using WPT. Interview questions will be informed by extended the TAMs as widely applied to questions of health technology implementation -51. The Data will be analyzed using directed content analysis, a qualitative analytic technique characterized by a structured stepwise process of coding the data and organizing it into categories or themes . The goaTo further develop insights related to the challenges and facilitators impacting the spread of WPT within LTCHs, stage 2 will consist of 2 elements: interviews with stakeholders using a qualitative descriptive approach, and document analysis. The in-depth interviews will be analyzed using conventional content analysis, an analytic technique that will facilitate increased understanding in the absence of guiding theory . DocumenApproximately 10-15 stakeholder participants will be recruited using convenience sampling. Given the focused nature of the interviews in stage 2, it is expected that fewer participants will be required to reach data saturation (approximately 5 to 8 per participating LTCHs). Participants will be invited to participate through targeted outreach via the (anonymous) Long-term Care Associations and through current relationships with LTCHs and professional nursing organizations. Key stakeholders will involve a range of functions or positions including directors of care, chief executive officers, director of community connections, and director of information technology innovation. Interviews with key stakeholders will take place in person, via phone or Zoom call depending on participant preferences and applicable COVID-19 restrictions at an agreed-upon date and time.A qualitative description will be the methodological approach used to conduct in-depth interviews with key stakeholders  ,53. PurpContributing documents to the document analysis component of this stage of this study will include annual LTCH budget reports, annual reports, strategic plans, LTCH funding policy documents, and regulatory documents as well as relevant communication documents (anonymous). These documents can potentially add information that can inform understanding of WPT use in LTCHs such as resource and budgetary allocation for technology and support personnel.conventional content analysis. This will be an iterative process of reading the interviews, identifying initial coding categories based on the results from the interviews with key stakeholders and then organizing the codes into categories [In-depth interviews with participants will be audio recorded, transcribed verbatim, and analyzed using conventional qualitative content analysis with codes emerging through an iterative process of data collection and analysis . Identiftegories .Analysis of documents will entail an iterative process which includes scanning documents, preliminary reading in detail, and finally organizing the data using strategies such as coding and categorizing the data. Concomitant to the analysis will be ensuring that the documents are credible, accurate, and able to inform the research questions .explicit between-methods triangulation of the findings of the respective methodological approaches  used in stages 1 and 2 to develop a final conceptual framework [In the concluding stage, there will be ramework ,59. Findramework .The result of this iterative analytic process will inform theoretical understanding of how older adults in LTCHs, their family members and staff experience and envision the application of WPT to support social connectedness. After stage 1, a total of 45 participants will have completed in-depth interviews and their data will have been used to generate theory related to how WPT can be used within LTCHs to support social connectivity. The findings emerging from stage 1 will be used to directly inform stage 2’s data collection as well as the overall development of a conceptual framework (stage 3).explicit between-methods triangulation in stage 3 by expanding on findings through the inclusion of data obtained through other methods [Findings emerging from key stakeholders' interviews as well as document analysis will be used to inform  methods . ExpecteThe findings emerging from this study will provide deeper insights and understanding about the factors, barriers, and facilitators to embedding and spreading WPT in LTCHs and benefit older adults in LTCHs, family caregivers, and staff and administrators of LTCHs. Going forward, the conceptual framework will have utility to inform approaches to embedding web-based presence as a mainstreamed communication tool to support social connectedness among older adults in LTCHs and their family members.A growing body of literature demonstrates the benefits of various communications technologies such as social networking apps on older adults’ well-being, independence, and sense of connectedness with friends and family . KnowingAs society continues to experience evolving disruptions to the ability to engage with one another, there is a need to reconceptualize social connectedness and to identify novel ways to attain fulfilling relationships with others particularly in the context of LTCHs. In the context of LTCHs, this could be represented by a hybridized system of web-based and in-person presence. However, more evidence is required to determine whether older adults in LTCHs and their family members benefit from WPT  as an approach to support their social connectedness. Further, there is a need to better understand how WPT can be implemented in LTCHs.While WPT may have the potential to support meaningful social connectedness among many older adults in LTCHs and their family members, to date numerous uncertainties remain regarding leveraging WPT for social connectedness. These uncertainties include (1) the effectiveness of using WPT for social connectedness by older adults with cognitive impairments, (2) best practices related to the use of WPT by older adults with cognitive impairment, and (3) the role of extra supports for older adults with cognitive impairment when using WPT . AdditioThe proposed multistage approach and methodological triangulation will require the engagement of multiple stakeholders. Potential limitations may include challenges associated with conducting interviews with older adults living in LTCHs who may have cognitive or physical conditions that could limit their participation in in-depth interviews. Additional support from family members, LTCH staff or researcher staff may be required to facilitate interviews with older adults. Researchers will use flexible approaches to interviewing including in-person and zoom interviews, accommodating interview times and an honorarium to recognize their time and contribution. Researchers will also use strategies that can support older adults’ participation such as providing documentation in larger font size and providing a list of questions ahead of time.The data obtained through qualitative description will consist of subjective perceptions and recollections of using technology for social connectedness and therefore may be biased toward a particular type of experience. Direct user observations, attained using an ethnographic approach, might be able to produce data that have a lower likelihood of being biased toward memorable experiences. However, actualizing this approach within LTCHs would be very challenging to practically implement.The conceptual framework arising from this research on the role of WPT to support social connectedness between older adults in LTCHs and their family members will have a key role in informing LTCHs how to embed web-based presence as a mainstream communication tool to redefine and support social connectedness among older adults in LTCHs and their family members.


Death rates from primary liver cancer (hepatocellular carcinoma [HCC]) have continued to rise in the United States over the recent decades despite the availability of an increasing range of treatment modalities, including new systemic therapies. Prognosis is strongly associated with tumor stage at diagnosis; however, most cases of HCC are diagnosed beyond an early stage. This lack of early detection has contributed to low survival rates. Professional society guidelines recommend semiannual ultrasound-based HCC screening for at-risk populations, yet HCC surveillance continues to be underused in clinical practice. On April 28, 2022, the Hepatitis B Foundation convened a workshop to discuss the most pressing challenges and barriers to early HCC detection and the need to better leverage existing and emerging tools and technologies that could improve HCC screening and early detection. In this commentary, we summarize technical, patient-level, provider-level, and system-level challenges and opportunities to improve processes and outcomes across the HCC screening continuum. We highlight promising approaches to HCC risk stratification and screening, including new biomarkers, advanced imaging incorporating artificial intelligence, and algorithms for risk stratification. Workshop participants emphasized that action to improve early detection and reduce HCC mortality is urgently needed, noting concern that many of the challenges we face today are the same or similar to those faced a decade ago and that HCC mortality rates have not meaningfully improved. Increasing the uptake of HCC screening was identified as a short-term priority while developing and validating better screening tests and risk-appropriate surveillance strategies. HCC is the third-leading cause of cancer death worldwide, resulting in an estimated 800 000 deaths annually . In the Increased HCC surveillance use and improved effectiveness of screening tests for early HCC detection are essential; early detection is critical because prognosis is strongly associated with tumor stage at diagnosis. However, most HCC tumors continue to be diagnosed beyond an early stage when cure would be possible . In 2015Most HCC occurs in individuals with cirrhosis from underlying chronic liver disease, such as viral hepatitis (HBV or hepatitis C virus [HCV]), alcohol-associated liver disease, or nonalcoholic fatty liver disease (NAFLD). In patients with HBV or NAFLD, studies suggest that one-quarter to one-third of HCC can occur in the absence of cirrhosis . AlthougCurrent guidance from the American Association for the Study of Liver Diseases recommends surveillance for HCC in patients with Child-Pugh A or B cirrhosis and patients with Child C cirrhosis who are on a liver transplant waiting list. The recommended surveillance approach is semiannual ultrasound with serum alpha-fetoprotein (AFP) level . SimilarThe best data for HCC surveillance comes from a large randomized controlled trial from China among HBV-positive individuals demonstrating reduced HCC-related mortality . AlthougMultiple factors affect the effectiveness of HCC screening and surveillance . The firOne of the most common barriers to implementing HCC surveillance is that screening for viral hepatitis and chronic liver disease is underperformed . It is eRisk-based surveillance (or “precision screening”), whereby an individual patient’s HCC risk is estimated and different screening strategies are recommended according to the level of risk, has been proposed to better target surveillance programs. Multiple HCC risk estimation models have been developed specifically for patients with HBV, such as PAGE-B , mPAGE-B , REACH-B (risk estimate for hepatocellular carcinoma in chronic hepatitis B), CU-HCC (Chinese University-HCC), and recently a machine learning model  . Risk esRisk stratification works best in those at risk of HCC and has a low positive predictive value when applied to the general population or other low-risk populations. Risk stratification also identifies people who may not benefit from surveillance because of having a very low risk of HCC. In the absence of risk-based surveillance strategies, providers often refer low-risk patients for screening for fear of missing the early stages of cancer .There is an extensive list of risk factors for HCC that could be considered for use in risk calculators . Not allImproved HCC risk calculators and algorithms are needed for integration into clinical care to aid providers in determining a patient’s level of risk for HCC and recommending risk-appropriate screening. In addition, the development of risk calculators that could be made available to patients should be investigated as an approach to raise awareness, motivate patients to seek care, and help them better understand their own risk for developing HCC.The effectiveness of HCC surveillance depends on whether the screening tests used can detect HCC at an early, treatable stage. The recommended screening tests (ultrasound and AFP) are widely available and low cost, but the sensitivity and specificity of these tests are suboptimal. In a noncirrhotic liver, the sensitivity of ultrasound for detecting small HCC lesions is estimated to be only 60% . In patiAlthough serum AFP level is commonly used for surveillance in those at risk, it has lower sensitivity for early detection of HCC and is more commonly elevated in advanced disease. Further, false positives occur (in association with liver inflammation and liver regeneration). Finally, some tumors do not produce AFP . AlthougAs efforts are being made to increase the use and uptake of current screening tools, there is a need for simultaneous development of better screening tests. Next-generation HCC screening will likely include improved biomarkers and/or advanced imaging techniques, such as abbreviated MRI (Magnetic Resonance Imaging) (aMRI) or radiomics.In addition to AFP, a range of other protein-based serum biomarkers for HCC are currently in clinical use or under investigation; however, sensitivity is suboptimal, and no single biomarker is sufficient for early detection. Serum biomarkers are being tested in panels in combination with diagnostic algorithms to enhance detection of HCC. One example of a statistical model for HCC risk assessment in patients with chronic liver disease is GALAD, a serum biomarker-based model that incorporates sex, age, AFP, lectin-bound AFP (AFP-L3), and DCP ,53. A reOther potential HCC biomarkers currently being studied are circulating RNA, including long noncoding RNA and micro RNAs, circulating tumor cells; cell-free DNA (cfDNA), and extracellular vesicle-based biomarkers. One can, for example, quantify total circulating cfDNA, assess fragmentation, look for somatic mutations in circulating cfDNA that are specific to HCC, or analyze the methylation of the circulating tumor DNA (ctDNA) fraction of cfDNA ,63. ctDNMulti-cancer early detection (MCED) tests that leverage cfDNA mutation-based and ctDNA methylation-based biomarkers have also shown high sensitivity for HCC in studies, both alone  and in cThe technology for developing optimized, robust HCC biomarker panels exists, and prospective studies are now needed to demonstrate reproducibility in a screening population compared with standard of care. Development and maintenance of longitudinal, high-quality, well-pedigreed biorepositories of HCC samples is also needed to facilitate clinical validation of new HCC biomarkers as they are identified  .MRI is statistically significantly more sensitive than ultrasound in detecting HCC lesions between 1 and 3 cm . HoweverAnother emerging technology with the potential to increase early detection of HCC is radiomics. Although radiologists review many images per patient, only a small fraction of the imaging features are used, and visual interpretation is subject to radiologists’ experience. Radiomics leverages mathematical models and artificial intelligence to extract a large number of imaging features. These imaging data are then synthesized with clinical data to aid clinicians in HCC diagnosis and prognosis .Deep learning tools, such as neural networks, are also being studied for a potential role in detecting HCC in clinical images. Neural networks use algorithms to help computers make decisions, learning through execution. In early studies, neural networks demonstrated high levels of sensitivity and specificity in classifying liver tumors (comparable with radiologists) requiring only milliseconds per lesion .Radiomics and neural networks would likely be used to assist radiologists by highlighting concerning images for a more careful review and are not meant to replace radiologists. Radiomics has been criticized as a “black box” method, and external validation can be difficult . Global Despite the demonstrated benefit of HCC surveillance, use is low ,89. A reAt the provider level, key barriers to effective HCC surveillance include providers not diagnosing HBV infection or other underlying chronic liver disease before the presentation of complications , not being aware of the benefits of surveillance, not understanding which patients need it, and not ordering screening tests for those with known cirrhosis ,102. ThePrimary care providers should play a role in conducting HCC surveillance because there are not enough specialists to take on this task and only a small proportion of patients with cirrhosis are under the care of a hepatologist. However, primary care providers report low awareness of surveillance guidelines and experience logistical barriers such as competing clinical concerns . In receMany people in the United States remain uninsured or underinsured, which affects their access to routine care (where underlying liver disease could be diagnosed) and their uptake of HCC screening. For individuals with health insurance, twice-yearly ultrasound screening for HCC is not specifically recommended by the USPSTF, which affects the extent of coverage by insurers. The lack of integrated electronic health record (EHR) systems can hamper the ability of providers to obtain reports of patients’ ultrasound exams and other testing if they are conducted at facilities outside the provider’s health system. System-wide stress on the health-care infrastructure can also result in overall reduced rates of screening for diseases, as was observed during the height of the COVID-19 pandemic .The need to increase the use and uptake of HCC screening was identified as a priority by workshop participants. There was much discussion of the need to raise awareness of patients, providers, and the public about liver cancer in general, who is at risk for HCC, and the critical importance of HCC surveillance for those at increased risk. Messaging needs to convey that there is hope because many people still think liver cancer is always fatal and do not know that HCC can often be prevented or that curative treatments for HCC are readily available when diagnosed early. Because HCC is asymptomatic when tumors are small, patients and providers need to understand that early diagnosis of HCC increases curative treatment options and overall survival.Patient-directed education should discuss the need to be aware of HCC risk as well as the importance of scheduling and completing testing and attending follow-up appointments. The importance of discussing screening results with their provider and that repeating testing at regular intervals (6 months) is crucial in addition to undergoing further assessment if an abnormality is found should be emphasized to patients. Provider-directed education should address identification of patients with potential of underlying liver disease  and among those with underlying liver disease who have early cirrhosis and are at risk for HCC. Once a provider has diagnosed cirrhosis, they need to be informed on applying risk stratification strategies for those who need to be screened for HCC, which HCC screening tests to order, and the importance of repeating the screening cycle at recommended intervals. Increased awareness is also needed regarding updates to the CDC recommendations for HBV and HCV screening, respectively .From a systems perspective, strategies discussed for improving uptake of HCC screening included EHR-embedded clinical decision support tools to identify at-risk patients and provide order sets for HCC screening  as well Princeton Workshop participants were disappointed in the lack of progress made since the 2015 meeting and the overall lack of urgency dedicated to addressing the continued increase in incidence and poor survival of HCC. Effective HCC surveillance is essential for saving lives, but screening to identify persons at risk for HCC and enrollment of these persons in a systematic program of ongoing surveillance for early detection of HCC continues to be underused. This is due to a range of challenges and barriers, which have been discussed for decades. Participants agreed that understanding HCC risk and risk assessment has matured and that HCC surveillance is now at an inflection point. New technologies are being studied that could transform early detection, diagnosis, and prognosis. This is an age of opportunity to improve detection and outcomes for patients with HCC, and there is much to do. Participants call for increased investment in early detection and surveillance research while implementing policies and practices that can help improve early detection of HCC using the tools we have now. We must act swiftly to prioritize early detection of HCC to save lives.Box 1.aWorkshop highlightsKey takeawaysLittle progress has been made in the past 7 years toward improving surveillance and early detection of HCC in the United States. Neither HCC surveillance nor mortality rates have meaningfully improved, and it is critical that we act swiftly to prioritize early detection of HCC to save lives.While there is a need for future research, the emphasis must be put on implementing the data and screening tools available now. We cannot wait for randomized controlled trials comparing different screening strategies, which take years, and randomly assigning at-risk persons to surveillance vs nonsurveillance is unethical.Systematic reviews have shown that surveillance for HCC is associated with improved detection of early-stage tumors, receipt of curative therapy, and overall survival. There is an urgent need to identify those at risk for HCC, improve and systematize HCC surveillance, and implement effective treatment for those detected with early-stage HCC.Abbreviated MRI has appeal as a novel screening strategy for HCC but needs to be investigated in randomized trials compared with liver ultrasound. New noninvasive biomarkers geared toward early detection of HCC and risk stratification are needed and important.Key challenges for HCC screening and surveillanceMany patients diagnosed with underlying liver disease are not in regular, longitudinal care and are therefore not being screened for HCC.Rates of HCC screening remain low, even among those identified as at risk.Sensitivity and specificity of the recommended screening tests (ultrasound with or without AFP) are suboptimal.Improving HCC surveillancePatients with liver disease should seek regular monitoring, understand their risk of HCC, discuss surveillance with their provider, and adhere to surveillance appointments as recommended.Providers should identify patients at risk for HCC, recommend surveillance as appropriate, review results, and follow up abnormal results as needed.Health systems should implement risk assessment algorithms to identify patients at risk for HCC , send automated screening reminders to patients and providers, provide care navigation, and implement a quality metric for HCC screening.Researchers, clinicians, patients, and advocates need to work together to generate a national sense of urgency that will lead to change in policy and practice to improve HCC surveillance.Areas for further study and actionConduct more studies to compare different screening modalities, including new biomarkers, MRI, and aMRI. Standardizing terminology and criteria will be a necessary step.Develop more data to support a USPSTF recommendation for HCC surveillance.Bring primary care providers to the table as allies in HCC screening.Develop an HCC risk calculator for use by and available to patients.Investigate approaches that address patient and provider challenges to improve implementation and uptake of HCC surveillance.Leverage knowledge from other cancers about effective screening tools and risk stratification.Develop and maintain longitudinal, high-quality, well-phenotyped biorepositories of HCC samples and prospectively collected sera and cells from patients at risk for HCC to:Facilitate clinical validation of potential new HCC biomarkers as they are identifiedEvaluate new markers retrospectively using established biobanks to ascertain when they first appear, before HCC diagnosis to evaluate their usefulness as a tool for early detectionTest new markers prospectively in at-risk persons to evaluate their effectiveness to detect HCC early at potentially curable stageaAFP = alpha-fetoprotein; EHR = electronic health record; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; NAFLD = nonalcoholic fatty liver disease; USPSTF = US Preventative Services Task Force.


A hospital-onset bacteremia and fungemia (HOB) metric will expand hospital surveillance of bloodstream infections beyond current state and provide an opportunity to re-evaluate infection prevention strategies. Here we consider the added value and potential pitfalls of HOB surveillance and present a framework for the standardized assessment of HOB events. In the enduring effort to reduce patient harm due to healthcare-associated infections (HAI), bloodstream infections (BSI) still loom large. However, after decades of intense scrutiny of – and success in preventing – central line-associated bloodstream infections (CLABSI), the time has come to broaden our perspective on preventable harm due to healthcare-associated BSI. In this commentary, we describe why stakeholders in quality and infection prevention should value a broader bacteremia event outcome, enumerate the advantages and potential pitfalls of a hospital-onset bacteremia/fungemia (HOB) measure, and share practical guidance on implementing quality improvement related to HOB events. While much of this success is due to true reduction in adverse patient events, the impelling agents of financial penalties and publicly reported quality measures also nudge organizations toward reducing reported CLABSI without real harm reduction through source misattribution, intentional manipulation of reported HAI rates, and shifting BSI risk from central venous catheters to other forms of intravenous access.With evidence-based toolkits and guidelines, acute care facilities achieved steady reductions in CLABSI rates prior to the COVID-19 pandemic.The transition from a focus on a parochial quality measure and “on paper” improvement with CLABSI to true and broader-scale harm reduction with HOB has precedent in the transition from ventilator-associated pneumonia to ventilator-associated events: a simpler and more objective definition, a broadening of the scope of harm, and new science demonstrating the preventability of these adverse events. A significant proportion of HOB events are attributable to a source that is not likely to be captured by traditional HAI surveillance and thus may not be included in current infection prevention toolkits. Early studies are establishing the preventability of this expansive proposed quality measure.The HOB definition is simple and objective: A bacterial or fungal pathogen from a blood culture specimen collected on the 4th calendar day of admission or later (where the date of admission to an inpatient location is day 1).Hospital-onset bacteremia/fungemia provides an opportunity to re-evaluate current HAI prevention strategies given the scope and complexity of underlying etiologies and root causes. Quality teams will need to innovate and expand notions of “preventable” infections Table .However, as with any other measure, there can be negative consequences and the potential to “game” the system, particularly if the measure is not supported by practice guidance and an implementation toolkit. Diagnostic stewardship will be necessary to prevent clinically unnecessary “surveillance” blood cultures on admission (to classify positive blood cultures as infections “present on admission”), and intentionally reduce blood culturing during hospital stay when clinically indicated .The HOB metric may work counter to antimicrobial stewardship by incentivizing clinically non-indicated antibiotic prophylaxis. This compunction may reflect an effort to reduce HOB events that do not appear preventable by current standards. To minimize this risk, HOB measurement and reporting should allow identification of potentially nonpreventable events, particularly HOB resulting from mucosal barrier injury or gastrointestinal translocation. This will include HOB events with sources of infection less familiar to Infection Prevention or Quality Improvement/Patient Safety teams. For the existing cadre of reported HAI metrics, there is robust, evidence-based guidance to prevent these infections. Thus, a practical approach to assessing HOB prevention that improves patient safety is needed to avoid the fate of previously failed healthcare quality measures, which led to unintentional and at times detrimental results.With the introduction of HOB as a novel quality metric, acute care hospitals across the country will find themselves collecting and reporting data on a larger number and a greater breadth of BSIs.One common method of evaluating the care delivery processes associated with HAIs is the root cause analysis (RCA). Considering the potential scope of HOB scenarios, variability in the structure and completeness of RCAs would hinder the ability of front-line care teams to utilize the new HOB metric to its fullest extent in identifying gaps in patient care. Therefore, as part of a study supported by the Centers for Disease Control and Prevention Prevention Epicenters Program, we developed a framework to help hospitals evaluate HOB events and identify root causes for quality improvement. We then filtered the JCAHO taxonomy through the lens of infection prevention for HOB event evaluations and expanded the framework to meet the current challenges and priorities of healthcare delivery.Anticipating that evaluation of HOB events would widen the lens of preventability, we sought to develop a comprehensive, yet adaptable framework that could be employed for routine use in RCAs. We performed a literature review of existing frameworks for the evaluation and categorization of patient safety events and selected the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) Patient Safety Event Taxonomy as the foundation for our framework. The HOB event is established as a problem statement, to which the moderator asks “Why did this occur?,” and repeatedly does so as the layers beneath the HOB event are revealed. In this process, there is opportunity for participants to explore contributing factors and generate robust discussion even before the more directed portion of the framework begins.The result of our work is a question-based, case review framework intended for multi-disciplinary engagement that greatly expands upon the current areas of focus for currently reportable HAIs Figure . The priIn an ongoing multi-center study of the usability of HOB as a quality improvement metric, we are using this framework to discuss real-world HOB events with stakeholders. More expansive and exploratory, yet standardized, approaches such as this will be required to assess HOB preventability beyond what traditional device and procedure-related infection prevention toolkits offer.Hospital-onset bacteremia and fungemia is a simplified BSI measure that pushes the boundaries of preventability, and as hospitals find themselves confronting unfamiliar root causes, new opportunities for harm prevention will be uncovered. The greatest benefit of an ambitious effort to reduce HOB rates may be its connectedness to other aspects of patient care, driving patient-centered quality improvement beyond the current scope of nosocomial infection prevention. It is critical, however, that infection prevention teams, hospital leaders, and public health agencies are prepared for this paradigm shift in HAI reporting to manifest the intended benefit and avoid gamesmanship. Development of standardized frameworks for HOB evaluation while in parallel identifying and investigating new strategies for prevention will be critical to a successful drive toward higher quality care.


PTJ’s readership the latest update of the 2020 Dutch recommendations published in PTJWith the surge of COVID-19 in China and seasonal fluctuations across the globe, it seems appropriate to share with Regarding the safety recommendations, we deem it no longer necessary to minimize contact with patients with COVID-19 because personal protective equipment (PPE) is sufficiently available in the Netherlands. If hospital-based physical therapists use the recommended PPE, as indicated by hospital policy, it is safe to work “hands on” with patients with COVID-19.We still recommend starting with inspiratory muscle training (IMT) in patients with evident clinical signs of inspiratory muscle weakness, perceived dyspnea, or both. Physical therapists should be aware that patients are suspected to be at risk for respiratory muscle weakness in the case of (prolonged) mechanical ventilation. This recommendation is supported by one study that evaluated the effects of IMT  after weaning from mechanical ventilation in patients who recovered from COVID-19.We recommend that physical therapists should monitor and support passive range of motion when patients are sedated in the intensive care unit (ICU). When patients are lying in prone position, plexopathy is a high-risk complication caused by tension and compression of the brachial plexus. Contralateral head rotation and shoulder abduction beyond 90 degrees should be prevented when patients are lying in a swimmer’s position.We recommend that physical therapists need to be alert for the development of heterogenic ossifications. During the first wave of the pandemic, it was noted that patients with prolonged ICU stay due to COVID-19 developed heterogenic ossifications in their elbows, shoulders, knees and hips.In the previous report of our recommendations, we were hesitant to recommend neuromuscular electrical stimulation (NMES) in sedated patients with COVID-19 in the ICU because of the lack of evidence of effectiveness, the hygienic challenges, the absence of the equipment in most Dutch hospitals, and our concerns about the feasibility during the hectic care of patients who are severely or critically ill. Recently, more scientific literature has become available supporting NMES as a potential treatment modality for patients with COVID-19 who are sedated and lying in a supine position.We recommend that physical therapists should have an active role in mobilizing and activating patients on both the hospital ward and in cooperative patients in the ICU. Physical therapists should be aware that patients with COVID-19 are at risk to develop ICU-acquired weakness, even when they have no prior physical comorbidities. Experts in the field reported that patients with COVID-19 had disproportional rises in heart rate and strong deoxygenation during low-intensity active mobilization sessions. Patients experienced this low-intensity physical activity as extremely exhausting. As a result, physical therapists need to be aware of an increased risk of overload and exhaustion in this population. We still recommend that physical therapists should strictly follow safety criteria during their treatment.In summary, our goal was to develop up-to-date recommendations based on new clinical insights, scientific literature, and best practices in the Netherlands that were feasible and acceptable in daily practice, facilitating their adoption and implementation. Although our recommendations overlap with other comprehensive, international acute care physical therapy guidelines for COVID-19,


The biochemical changes occurring are well-studied and involve macromolecular breakdown and remobilisation of nutrients to developing seeds or other young organs in the plant. However, the initiation and regulation of the process and inter-organ communication remain to be fully elucidated. Although ethylene emission, which becomes autocatalytic, is a key regulator in some species, in other species it appears not to be as important. Other plant growth regulators such as cytokinins, however, seem to be important in floral senescence across both ethylene sensitive and insensitive species. Other plant growth regulators are also likely involved. Omics approaches have provided a wealth of data especially in ornamental species where genome data is lacking. Two families of transcription factors: NAC and WRKY emerge as major regulators, and omics information has been critical in understanding their functions. Future progress would greatly benefit from a single model species for understanding floral senescence; however, this is challenging due to the diversity of regulatory mechanisms. Combining omics data sets can be powerful in understanding different layers of regulation, but  Flowers are complex structures typically composed of four separate organs: sepals, leaf-like organs that protect the developing bud, petals: that act as attractants for pollinators, stamens that produce pollen and pistils that enclose the ovary in which seeds will develop. Floral senescence is a key developmental stage that allows a plant to remobilise nutrients from flowers to other organs such as the developing seeds  once theArabidopsis thaliana and rice (Oryza sativa), have enabled an explosion of data, and new understanding of plant developmental processes and biochemistry over the last 25 years [Model organisms such as 25 years . However25 years   suppresses downstream ethylene signalling regulators, but FYF-like genes, have evolved to suppress or promote flower senescence and regulate abscission through the formation of heterotetrameric abscission complexes with other MADS box transcription factors [Arabidopsis belongs to the ethylene-regulated group whose petals abscise turgid  and has  factors . However factors .Ipomoea nil) and roses. The publication of genome sequences for these species relatively recently [Substantial progress has been made in the field of floral senescence through the study of a few important ornamental crops, most importantly carnations, petunias, Japanese morning glory (recently  will enhrecently . Moreoverecently  which farecently ). HoweveMajor advances in our understanding of ethylene-sensitive floral senescence from the study of petunias has been in the interactions between ethylene and cytokinin through the use of transgenics in which cytokinin production was switched on by a senescence-induced promoter. Elevated cytokinin reduced both ethylene sensitivity and the accumulation of abscisic acid (ABA), another phytohormone that accelerates floral senescence, by promoting the production of endogenous ethylene in the flowers . RevisitRhHB1 which regulate both ethylene and ABA-induced senescence [Rosa hybrida ‘Samantha’, petals change colour as they senescence and this was exploited by using petal discs floated on different hormone solutions, an approach which would not have been possible in Arabidopsis.In roses, recent advances in understanding phytohormone regulation and key transcription factors has rested on the identification of genes through homology to Arabidopsis, coupled with transgenics . Large dnescence . In addiDcWRKY75 and DcHB30 were recently identified in carnation, which together regulate ethylene-induced petal senescence [DcHB30 for further study.In addition to the transfer of understanding from models such as Arabidopsis, omics also enables the transfer of understanding between different ornamental species. For example, two transcription factors, nescence ,34. Bothnescence . Howevernescence ,36 and hA major strength of omics approaches is also their versatility and use in species for which there is much more limited knowledge of genetics. Lilies have some of the largest genomes of any organism , which Transcriptomics is also helping to understand senescence in complex floral architectures such as those of composite chrysanthemums and dahlias ,40. ThesWhereas many earlier studies on floral senescence were mainly based on transcriptomics, more recently combinations of omics are being applied revealing unexpected complexity . For exaEurya japonica which is a subdioecious species with individuals producing male, female or hermaphrodite flowers, the emission of VOCs decreases in male flowers after pollination as the flowers senescence but does not in female or hermaphrodite flowers. This is presumed to be to reduce the energetic costs in male plants [in vitro biochemical assays [Advances in the sensitivity volatile organic compound (VOC) detection have enabled a flourishing of floral volatilomics . Floral e plants . Combinee plants ,44. For l assays .Agave amica) multivariate analysis of transcriptomes, metabolomes and volatilomes showed a synchronisation between tABC transporter gene expression and emission of terpene VOCs [In tuberose  was up-regulated in the petals and style + stigma + stamen suggesting light/circadian clock regulation of senescence in this flower. Interestingly circadian control seems to also be important in longer-lived flowers such as rose [RhBBX28 that regulates floral senescence and night time mitochondrial ROS homeostasis. In turn, this gene is regulated by interaction with PHYTOCHROME-INTERACTING FACTOR8 (RhPIF8).For example, the NAC family transcription factor s stigma . Underst ovaries . For exa as rose . TranscrThe combination of omics approaches is extremely powerful in discovering new pathways that may be important in regulating complex processes such as floral senescence. One key to full understanding is in large datasets, for example with highly detailed time courses. These have been important in leaf senescence in revealing the exact sequences of pathways activated and thus understanding causal relationships . AnotherEPHEMERAL 1 in Japanese morning glory . Howeveing made .Another limitation in much of the omic work on flower senescence is the lack of data for individual cell types or even regions of individual floral organs. Even petals, which are relatively simple, develop differently in their edge and midrib and tip and base as well as showing differences between epidermal and inner structures. Laser microdissection and fluorescence-activated cell sorting (FACS) approaches, together with single-cell transcriptomics  will enaFinally, it is important in a field that focusses on ornamental flowers that the information gained can be applied to the commercial sector through breeding, treatments to improve longevity or gene editing. Interaction with the industry will ensure that the omics data gained is not only of fundamental interest but also of practical relevance.Flower senescence is of relevance to ornamental flower production, reproductive ecology but also to our understanding of a fundamental plant developmental process.Omics has opened the way to study floral senescence in a myriad of different ornamental species but without a common model progress is slow. The diversity in floral senescence hampers the identification of a suitable model system.Key steps are the integration of omics datasets within species and databases that can facilitate cross-species information. Another major step will be a spatial understanding of floral organ senescence across organs and within individual cells.


To elucidate the role of neighborhood walkability and crime on weight loss, we examined data from older adults residing in Chicago who participated in a randomized controlled trial lifestyle intervention. Controlling for individual demographic characteristics and the intervention assignment, the neighborhood homicide rate was significantly associated with weight change. Participants who resided in neighborhoods above the 50th percentile of homicide rate actually gained weight between pre- and post-intervention. On the other hand, there was no significant relationship between the level of walkability and weight loss. Our findings suggest that the social environment related to neighborhood crime may play a more important role in weight loss than the built environment, such as walkability. Urban characteristics related to walkability, such as sidewalks, may increase physical activity, however, interventions aiming to increase physical activity to promote weight loss will benefit by addressing the neighborhood social environment that determines how people navigate space. The prevalence of adult obesity with Body Mass Index (BMI) greater than 30 is expected to reach nearly 50% of the United States (U.S.) population by 2030  lifestyle intervention. This original RCT included predominantly Black older adults who lived on the South Side of Chicago, which is highly racially segregated and affected by increased crime. We hypothesized that neighborhood walkability and homicide would have differential effects on participants’ weight loss and physical activity. Specifically, pre- and post-intervention weight loss would be greater for participants living in neighborhoods with high walkability and lower for participants living in neighborhoods with high homicide rates.Building Research in Diet and CoGnition (BRIDGE). Details on the trial have been published previously , MedDiet (MedDiet-A) without a weight loss intervention, and a Control group (TDC) with a typical diet without caloric restriction . Individual-level measures included age (ranging between 55 and 81 years), sex , race , income , and education . We also included the level of pre-intervention moderate to vigorous physical activity in minutes per day measured by the ActiGraph wGT3X triaxial accelerometer , proximity to transit stops (distance), and mix of employment and household types (diversity) (Ewing & Cervero, Neighborhood crime was measured using homicide incident cases from the Cook County Medical Examiner’s archive, which includes all homicide deaths along with the address of each incident (Cook County Medical Examiner’s Office, Table Table Our findings showed that neighborhood crime measured by the homicide rate was significantly associated with less weight loss, controlling for all other variables including the intervention assignment. Participants who resided in neighborhoods at or above the 50th percentile of homicide rate actually gained weight between pre-and post-intervention, regardless of randomization to one of the three intervention arms. On the other hand, the relationship between neighborhood walkability and weight loss was not statistically significant.Current literature suggests that individuals living in high walkability areas tend to be more physically active. High walkability seems to decrease the risk of excessive weight gain (Lovasi et al., Conversely, high-crime neighborhoods are associated with a variety of poor health outcomes Sampson, , and criAlthough much of the scientific literature finds that urban communities with high walkability may also have high levels of crime (Foster et al., Regular physical activity can positively influence weight management, but not all communities benefit equally from this component of the built environment because walkability is subject to the effects of the social environment, such as high crime. While the built environment represents the physical aspects of where one lives, the social environment creates space for residents to engage with their neighborhood. Interventions aiming to increase physical activity and promote healthy weight management will benefit by incorporating factors of the neighborhood social environment that determine how people navigate space. The social environment related to neighborhood crime may play a more important role in weight loss than aspects of the built environment such as walkability. The social environment and built environment may affect different aspects of urban neighborhood characteristics. Accordingly, urban policy and planning must take into account the interaction between the built and the social environments to facilitate residents’ health and well-being.


This short communication makes the case for targeted vaccine research when attempting to counter hesitancy, especially amongst vulnerable or rarefied patient groups. Far from disincentivizing vaccination, the freedom to research and publicize the limitations of these technologies for certain groups and personalizing dosing, pacing, adjuvants, and time-sensitive alternatives in response is essential for optimizing health outcomes while neutralizing the vaccine research landscape itself. Vaccine evangelism only arouses suspicion when it is not tempered by rigorous research into differential vaccine benefit-risk in this way. That said, the long-standing politicization of vaccination—a topic vulnerable to misinterpretation and media sensationalism—along with the commercial incentives associated with universal adoption makes more comparative and critical research difficult to fund and promote in practice. Likewise, a prescriptive approach to vaccination does little to address the issues of vaccine inequality that contribute to both hesitancy and conspiracy globally and will likely prove financially prohibitive in certain markets. These obstacles are not insurmountable, however, provided that comparative research is centrally subsidized, regulations ensure that vaccine development trials explore differentiated outcomes, especially amongst high-risk or rare groups, and findings are used to prioritize global vaccine allocation to those that stand to benefit most from them. Even prior to the emergence of SARS-Cov-2, vaccine hesitancy appeared in the World Health Organisation’s 10 leading threats to global health . VaccineHowever, it would be wrong to conceptualize such vaccine hesitancy as static or in any way singular with work by Kumar and colleagues  characteThese nuances within vaccine hesitancy are not reflected in the vaccine research landscape that aims to tackle it. There is therefore a real need to establish more specialized vaccine benefit-risk profiles than the mass market focus of the pharmaceutical complex currently allows for. For example, despite their well-documented vulnerability to vaccine-preventable illness , the immFurthermore, unlike any other product or procedure in medicine, we do not currently expect our doctors to know what brand, dose or schedule of vaccine would prove best for us despite having the both the data and maturity in clinical informatics to find out . LikewisEnsuring the decision to vaccinate feels as personable and personalized as possible for patients is a vital first step for improving uptake  while coPersonalizing vaccine benefit-risk profiling will also depend upon the active championing of scientific investigators and academic outlets. However, long-standing issues of interpretation bias and publication bias  will havFinally, it is important to note the apolitical forms of vaccine hesitancy and obstacles that exist to achieving precision vaccinology. With access still far from equal , vaccineThis short commentary has demonstrated the ways in which better targeting vaccine research and policies can counter the diverse underpinnings of hesitancy. The obstacles it has summarized can be addressed through a combination of subsidized research efforts—especially those that explore differentiated outcomes or ensure new products are tested to satisfaction within high-risk or rare patient groups—and the self-reflection of investigators and journals as to their own investigation and publication biases against moderating or dissenting views. Furthermore, although the COVID-19 pandemic has been seen to exacerbate ongoing issues of vaccine hesitancy, the global coordination of research efforts it engendered has proved the greatest asset for precision vaccinology . Researc


Despite rapidly growing academic and policy interest in health system resilience, the empirical literature on this topic remains small and focused on macrolevel effects arising from single shocks. To better understand health system responses to multiple shocks, we conducted an in-depth case study using qualitative system dynamics. We focused on routine childhood vaccination delivery in Lebanon in the context of at least three shocks overlapping to varying degrees in space and time: large-scale refugee arrivals from neighbouring Syria; COVID-19; and an economic crisis.Semistructured interviews were performed with 38 stakeholders working at different levels in the system. Interview transcripts were analysed using purposive text analysis to generate individual stakeholder causal loop diagrams (CLDs) mapping out relationships between system variables contributing to changes in coverage for routine antigens over time. These were then combined using a stepwise process to produce an aggregated CLD. The aggregated CLD was validated using a reserve set of interview transcripts.Various system responses to shocks were identified, including demand promotion measures such as scaling-up community engagement activities and policy changes to reduce the cost of vaccination to service users, and supply side responses including donor funding mobilisation, diversification of service delivery models and cold chain strengthening. Some systemic changes were introduced—particularly in response to refugee arrivals—including task-shifting to nurse-led vaccine administration. Potentially transformative change was seen in the integration of private sector clinics to support vaccination delivery and depended on both demand side and supply side changes. Some resilience-promoting measures introduced following earlier shocks paradoxically increased vulnerability to later ones.Flexibility in financing and human resource allocation appear key for system resilience regardless of the shock. System dynamics offers a promising method for ex ante modelling of ostensibly resilience-strengthening interventions under different shock scenarios, to identify—and safeguard against—unintended consequences. Research and policy interest in understanding dynamics influencing health system resilience is strong, but existing studies have focused primarily at macrolevel and on analyses of single shocks.This study presents the first analysis of vaccination delivery system responses to multiple, overlapping shocks in a humanitarian setting, using system dynamics.We show how shocks in Lebanon spurred potentially transformative change through task-shifting to support vaccination, but that early adaptive changes  may have undermined system resilience to later shocks.System dynamics offers a promising avenue for ex ante modelling of resilience-promoting measures, to identify potential unintended consequences.Rather than single interventions, meaningful promotion of long-term health system resilience likely requires packages of measures reflecting local contextual factors and varying in composition according to changing on-the-ground conditions.Academic and policy interest in health system resilience has grown exponentially in recent years but the literature on this topic is emergent and empirical analyses of resilience are few.2–4Understanding of resilience is particularly limited in humanitarian settings, where challenges to health system functionality can be acute, and resources to support meaningful responses to shocks may be more limited, unpredictable and dispersed than elsewhere. Delivery of essential services such as vaccination is challenging and liable to disruption.In this study, we apply a resilience definition, distinguishing capacities to absorb, adapt or even transform in response to shocks, while maintaining system structures and continuing to deliver essential services.16 17Although each of these aspects of resilience describes a process of change, most work in health systems research has adopted a static view focused on discrete resilience capacities .22We used qualitative system dynamics to understand responses to shocks because this method focuses on aggregate-level, system behaviours contributing to outcome trends, and in particular, the role of feedbacks in explaining why systems behave as they do.Lebanon is a small Middle Eastern country with an estimated population of just over 6 million in 2021.We focused on vaccination delivery system responses to four shocks .Interviewees were sampled purposively from stakeholders working at national, regional and local level in Lebanon, including government (the MoPH), donors and agencies supporting the humanitarian response work in-country, implementing partners and service managers and practitioners involved in front-line primary care. Regional and facility-level data collection was designed to better understand dynamics affecting service delivery in two governorates in Lebanon, Beirut and Akkar, chosen to reflect the diversity of service delivery challenges in an urban (Beirut) and rural (Akkar) setting, respectively, and historical variations in health service access (much lower in Akkar than in Beirut). A substantial majority of participants (89%) were female. In total, 38 semistructured interviews were carried out in 2 waves (February–March 2020 and July 2021–January 2022). Of these, eight were in-person and the remainder were carried out remotely via Zoom due to COVID-19 restrictions. Interviews gathered information on participant roles, generic structures supporting vaccination delivery, and system behaviours and policy responses identified as linked to the various shocks. Interviews were recorded and transcribed into MS Word. Most were performed in English by the lead author (SI); the small number of interviews performed in Arabic  were jointly conducted by SI and AN, transcribed, translated into English and then analysed. Interviews were then separated into two sets: one (n=33) for analysis and a reserve set (n=5) for validation.The CLD was generated in three consecutive steps. In step 1, a CLD was developed for each individual interviewee to represent their mental model of shock effects on childhood vaccination delivery in Lebanon, and the range of system responses. Transcripts were coded using purposive text analysis to identify causal language.39In step 2, individual CLDs were combined using a stepwise process. First, diagrams were grouped according to the stakeholder set from which they originated  and then ordered in terms of their complexity.In step 3, the combined CLD was validated by comparing it to five individual CLDs generated from interview transcripts from the validation set, using RIQ analysis as above.Vaccination delivery system responses to shocks shown in the CLD were classified using the absorptive–adaptive–transformative approach outlined in the introduction. Categorisation was based on assessment of the extent to which new system structures were introduced (transformation), new resources mobilised or existing structures modified (adaptation) as responses to the vulnerabilities identified elsewhere, with reference to the CLD.In the sections that follow, we map some of the key pathways of system response to these shocks. A detailed list of system responses is given in Immediate responses included macrolevel, mesolevel and microlevel mobilisation to address what was perceived as a high risk of vaccine-preventable disease (VPD) outbreaks  in the context of population movement. At the macrolevel, adaptive measures included national vaccination campaigns, launched in 2013 and 2014 with donor funding support. An early policy change concerned the relaxation of rules around access to care for refugees, so that displaced Syrians could access vaccination through publicly supported facilities at nominal cost . The motivation for this change was to stimulate demand by addressing cost barriers. However, hidden fees  continued to create barriers to access for refugees and other vulnerable populations:The product is free, however, it is very important to know that a major challenge that is facing the accessibility of refugees and vulnerable populations to free vaccination is sometimes the hidden fees. Two additional policy changes were introduced to improve access to vaccination. First, vaccination points were established linked to border crossing sites and refugee registration centres to allow for administration of key vaccines  to displaced Syrians either as they arrived in Lebanon or as they registered for access to services through the United Nations High Commissioner for Refugees (UNHCR). Second, the MoPH-supported PHC network was progressively expanded. Facilities in the network received no direct funding from the MoPH, but in exchange for ministry accreditation received vaccine doses free of charge (procured via UNICEF) and capacity-building support. A principal condition of membership of the network was to administer vaccines according to the national schedule at the fee rates set out nationally (see above).Mesolevel changes—again predominantly adaptive—also occurred. A key initial response from implementing partners was intensified the use of mobile medical units (MMUs) . These hThe use of MMUs was progressively scaled back from 2017, however, as part of a strategy of encouraging refugees and host communities into fixed-site clinics instead (loop B2). Interviewees highlighted concerns regarding the effectiveness of the MMU model including perceived challenges regarding quality of care and a supposed dampening effect on motivation of service users to attend fixed sites:At the beginning of the Syrian influx, there was vaccination at the borders, and there were a lot of campaigns and having mobile units going to the places of…Syrian groups and providing them there with vaccines. So they thought…we can stay home and the medical teams will come to us and provide vaccines and we don’t need to go, so they were a little bit passive. [LFS12]Following a new measles outbreak in 2018–2019, doubts also emerged regarding the cost-effectiveness of this delivery approach (loop B3).Over time, community engagement activities were stepped up to strengthen demand by (1) reinforcing the importance of vaccination as a preventive measure, (2) offering opportunities to cross-check vaccination records to make sure children were up to date with the national vaccination schedule (3) and strengthening household-level knowledge in areas likely to promote a decision to vaccinate—including information on the national schedule, on the actual cost of vaccination to refugees through the PHC network, and the location of the nearest PHC(s). These activities depended on stepped up recruitment of community engagement workers and increases in implementing partner funding—both of which depended on donor funding that took time to mobilise.Microlevel (within facilities) changes revolved principally around changes to the role of nurses in vaccine administration, as set out in the next section. However, interviewees also highlighted the importance of progressive improvements in workforce skills at facility level as clinic staff became more accustomed to managing increased workload and to better attuned to needs among refugee populations.Task-shifting to nurse-led vaccine administration was a key response to refugee arrivals , combiniProgress in implementing task-shifting was, however, limited by the availability of financial material resources to support it initially. This ensured that previously dominant loops favouring physician-led administration (loops R1 and R2) continued to drive most vaccination delivery. Physician administration of vaccines was an important source of revenue for both clinicians, and for PHCs that hosted them. On one hand, a long-standing preference among host communities for private medical care (including for vaccination) ensured steady revenues for physicians from private vaccination delivery. On the other hand, PHC managers who referred children to physicians privately for vaccine administration could expect to receive a cut from the resulting consultation fees.The introduction of incentive payments to PHCs (via implementing partners) helped to ensure that task-shifting at facility level was finally implemented. It did so by (1) providing additional income to PHCs to offset losses as fewer children were referred to private physicians, (2) increasing PHC motivation to promote nurse-led administration to patients in the wider context of scepticism especially from host communities (loop R3), (3) freeing up physician time for more lucrative specialised activities (loop B4) and (4) indirectly supporting nurse pay and thereby improving their retention at facility level. Implementing partners tested various modes of incentivisation, including payments directly to nurses, but these were found to increase the risk of pressure on staff to subsidise other PHC activities (loop B5), so they were phased out in favour of payments to PHC managers to then distribute among nursing staff (loop R4).Interviewees described a range of responses to COVID-19, many of them operating at microlevel. In the near term, there were absorptive responses to the perceived risk of contracting infection in facilities, influenced by perceived inability to socially distance and by health worker concerns about the probability of exposure in a context of rising caseloads nationally. Ad hoc measures included local clinic cancellations and reductions in staffing levels to reduce the potential for health worker exposure. However, these reduced access opportunities for patients in the short-term, contributing to declines in vaccination uptake. At national level, interviewees highlighted the concentration of resources on COVID-19 surveillance at the expense of monitoring for other VPDs, increasing the risk of delayed outbreak detection.Responses elsewhere were adaptive and primarily focused on reinforcing supply and demand through improved risk management across the system, although lead times to implementation were longer. Stocks of personal protective equipment were mobilised and staff trained in infection prevention and control introduced to reduce health worker perceived risk of contracting infection in health facilities. On the demand side, community engagement activities continued but were shifted online or via tools such as WhatsApp, although quality of engagement with service users was perceived as poorer as a result of this. Messaging focused on reinforcing the importance of vaccination as a preventive service, and emphasising that clinics remained open despite COVID-19-related movement restrictions.Responses to the economic crisis were similar in nature but generally targeted different pathways within the system . Adaptivhumanitarian one—contributed to strengthening resource mobilisation to PHCs nationwide via implementing partners. It also helped support vaccine procurement to maintain delivery through the PHC network, and—as the following section outlines—recruitment of private sector capacity to support childhood vaccination delivery. However, interviewees highlighted the length of time it took both for declines in vaccination uptake to be identified, and for the implications of the economic crisis for health needs to be recognised. This contributed to delays in funding mobilisation.Mobilisation of donor funding was a key adaptive response to the compound crisis. This was triggered by (1) changes in the COVID-19 caseload, (2) a collapse in demand for childhood vaccination observed especially during the first COVID-19 lockdown in Lebanon (loop B6), (3) an emergency appeal following the Beirut blast and (4) needs assessments identifying rapid growth in the proportion of households  identified as vulnerable , private clinics were required to drop the cost of vaccination to levels equivalent to those in PHCs and to report vaccination uptake data to the MoPH.Interviewees highlighted three areas in which responses to earlier shocks contributed to potentiating the impact of later ones. The first was cold chain integrity , where aChallenges were also noted for electronic record systems, originally introduced as a mechanism for improving service efficiency and record completeness following refugee arrivals from Syria. As electricity supplies became more unreliable, facilities sometimes had to revert to paper-and-pen methods for which later online reconciliation would be needed to ensure records were complete:Because now we are working on an electronic system…sometimes to search the name of the child or their parents and to check all the vaccines received by this child at the centre or elsewhere previously, it’s difficult due to the cut or interruption of internet. A third point of interaction concerned donor and agency policy regarding financial support for salaries. In 2016 and 2017, a decision was taken to provide direct salary support for posts in the MoPH to support the vaccination programme (among others), boosting central oversight and programme support capacity. However, this policy was later reversed contributing—alongside a general government hiring freeze—to severe staffing shortages:[Agency X] alone supported us with like 100 staff on [district] and central level for two years, 2016, 2017. And they stopped…so now we are in real, real shortage of staff at central and at peripheral level…because all the donors, they don’t want to pay for staffing, they only want to pay for activities, and we cannot do activities without staffing. On the other hand, workforce attrition among nursing staff was lower than for physicians as economic conditions worsened. In this sense, task-shifting in vaccination delivery was important in strengthening resilience to a series of shocks—refugee arrivals in the first instance, and then the economic crisis.To our knowledge, this is the first study to apply system dynamics to investigate shock responses to support vaccination delivery system resilience in a humanitarian setting, and the first to address multiple, overlapping shocks. Responses occurred at multiple system levels, and almost all were adaptive—via mobilisation of additional financial, human or other resources. We identified two potentially transformative changes, the first being a policy change to bring some private clinics under the MoPH’s fold for lower-cost access to vaccines. This policy was introduced in 2015 but did not result in significant behavioural change until demand collapsed in the private sector in 2021/2022, helping to push host communities towards PHCs for vaccination and other health services. The second was the implementation of task-shifting to nurse-led vaccine administration in PHCs. Although neither of these resulted in large-scale goal reorientation across the system, both introduced new mesolevel and microlevel system pathways promoting vaccination delivery that had not previously existed.System responses were sometimes maladaptive for vaccination uptake. Many early responses to COVID-19  helped preserve workforce well-being in the short-term and contributed to reducing transmission of infection, but also reduced service access opportunities for patients. The greater focus on absorptive responses to COVID-19 and particularly the economic crisis by comparison with earlier changes following refugee arrivals from Syria see  emphasisOur findings also show points of interaction between system responses, and ways in which changes implemented to address effects arising from earlier shocks influenced vulnerability to later ones over the long term. The introduction of imported solar fridges into the cold chain, for example, made an important contribution to strengthening cold storage capacity at facility-level following the refugee arrivals, but growing difficulties obtaining spare parts as import restrictions intensified in 2021/2022 increased cold chain vulnerability at a time when mains and generator electricity supplies were also less and less reliable. By contrast, the use of task-shifting reinforced long-term system resilience by expanding delivery capacity but also because nurses proved less likely than their physician colleagues to leave their posts or emigrate despite deteriorating economic conditions. These challenges may reflect the primarily technical, absorptive and adaptive emphasis of interventions introduced in response to earlier shocks in Lebanon, as opposed to transformative changes likely to reinforce system resilience to a range of shocks in the long term and especially ones of the scale and scope of the economic crisis. The need for attention to long-term time horizons in formulating appropriate approaches to supporting system resilience is well recognised in the system dynamics literature and should be a focus of response and recovery work in Lebanon and other humanitarian settings.41Findings also support those identified in other empirical analyses of health system resilience in humanitarian settings. Our work underscores the need for flexible approaches to human resource management,Findings also mirror those elsewhere regarding the importance of parallel service delivery pathwaysLimitations to this analysis include that a detailed evaluation of demand side responses, drawing in service user perspectives, was not attempted for reasons of practicality and representativeness across populations in Lebanon. Insights on community-based resilience strategies are therefore limited, although anecdotal evidence indicates these have been important during the economic crisis. Second, recall bias may have affected reporting of system responses to refugee arrivals, given the time that elapsed between peak cross-border movement (in 2014/2015) and this analysis. Measures taken to minimise this included recruiting participants with a spectrum of experience in the system  and inviting participants to focus only on areas where their recollections were strongest.We highlight a number of policy implications from this analysis. Evidence in this study emphasises the extent to which long-term system resilience depends on delivery using a variety of service delivery models and underscores the importance of continual demand reinforcement through community engagement (for which multiple strategies were used in Lebanon). It also underscores the need for measures to address multisystemic risk. Household income proved to be a key determinant of demand and changes contributed to fundamental shifts in patterns of demand in Lebanon in 2019–2022.On the supply side, our findings emphasise that reactive campaigns are likely to remain a mainstay of efforts to improve vaccination coverage in acute and protracted humanitarian settings, especially because population movement often does not immediately translate into increased demand for preventive services. Second, policy changes introduced at macrolevel need to be supported by appropriate, and suitably financed, cascaded actions to ensure on-the-ground implementation. This was evident in the initially slow progression of task-shifting to nurse administration, a policy that proved hard to implement in the face of powerful vested interests without direct incentivisation at mesolevels and microlevels. Finally, policies should be designed for the long term. Although the mutability of on-the-ground conditions in humanitarian settings makes this challenging, we identified examples where external actions amplified long term risks—for example, the decision to import solar fridges with difficult to access spare parts in an import-heavy economy, and a ‘boom-and-bust’ pattern of agency support for civil service salary financing.Flexibility in financing and human resource allocation was key in enabling the publicly supported childhood vaccination delivery system in Lebanon to continue functioning despite accumulating vulnerabilities in the face of overlapping shocks, as was structural transformation in discrete areas of the system. However, by early 2022, the wide-ranging effects of the economic crisis on both demand side and supply side dynamics appeared close to overwhelming the compensatory effects of response mechanisms and highlighted the growing dependence of the system on external support.


This approach significantly reduces patientmortality.We read the study titled “Early Mortality Predictors in Infective Endocarditis Patients:A Single-Center Surgical Experience” with interest. Infective endocarditis is a diseasefor which it is increasingly difficult to decide on diagnosis and treatment modalitiesbecause of its clinical course, causative microorganisms, and previous interventions. Althoughantibiotic therapy and surgical methods have evolved in recent years, there has been nodecrease in mortality. For this reason, it is recommended that infective endocarditis beevaluated by an - such as abscess, pseudoaneurysm, enlargement ofvegetations, and conduction disturbances like heart block -, the indication for surgerycan be readily given. The timing of surgical intervention for infective endocarditisdiagnosed after the occurrence of a neurologic event should be determined depending onthe patient. While the causativemicroorganism , the size of the vegetation (> 10mm), and the endocarditis ofthe prosthetic valve necessitate surgical intervention, it should not be overlooked thatthe initiation of antibiotic therapy reduces the possibility of embolism and surgeryshould not be rushed (waiting three weeks is recommended) in cases of bleeding-relatedneurologic events.When heart failure develops due to infective endocarditis or when findings indicate thatheart failure cannot be controlled despite antibiotic therapyAnother significant issue is the presence of splenic abscess in a patient with infectiveendocarditis. It is clear that an untreated abscess after surgery for infectiveendocarditis is a source of reinfection. Therefore, it is critical to perform asplenectomy first, if possible, to prevent recurrence of endocarditis.With the increase in TAVIs in recent years, infective endocarditis after TAVI has becomeone of the problems we have to deal with. The incidence of infective endocarditis afterTAVI is more frequent than after biological valve replacement. TAVI endocarditis is apathology with high mortality in patients who are considered high-risk for surgery.