Editorial on the Research TopicImmune dysregulation in inborn errors of immunityThe number of inborn errors of immunity (IEI) is growing rapidly . They caGagne et al. provide a concise review of how Mendelian type I interferonopathies can masquerade as non-Mendelian autoimmune disorders like systemic lupus erythematosus (SLE) and dermatomyositis, which are also associated with increased type I interferon (IFN) expression. Similarly, Hetrick and Oliver described how autoinflammatory bone disorders characterized by sterile osteomyelitis can be seen with both monogenic forms including Majeed syndrome and deficiency of the interleukin-1 antagonist (DIRA) and the more common sporadic form chronic nonbacterial osteomyelitis (CNO) or chronic recurrent multifocal osteomyelitis (CRMO). Other autoimmune manifestations of IEIs include, but are not limited to, autoimmune cytopenia, endocrinopathies, inflammatory bowel disease, neutrophilic dermatoses, arthritis, and vasculitis as illustrated by the case of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) from Sood et al.This Research Topic “Immune Dysregulation in Inborn Errors of Immunity” highlights recent advances in the understanding of the prevalence, mechanisms, spectrum of manifestations, and management of immune dysregulation in IEIs. Sood et al.The highly variable clinical manifestations of IEIs can contribute to diagnostic delays, which in turn, can lead to poorer outcomes. Autoimmunity and autoinflammation can negatively impact morbidity and mortality and are an independent prognostic factor for death among individuals with IEIs . Immune Sood et al. Because type 1 IFN work through the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, Gagne et al. also consider the increasing use of JAK inhibition in autoinflammatory IFN-mediated monogenic diseases. The study by Berrueco et al. showed mycophenolate mofetil may be an effective and safe treatment for pediatric patients with autoimmune cytopenia and IEI, even cases of autoimmune cytopenia refractory to first-line therapies like corticosteroids and intravenous immunoglobulin (IVIG).Improving awareness and early recognition of IEIs is also critical because making a diagnosis can impact treatment and surveillance. There may be disease-specific treatments available like leniolisib, an oral selective PI3Kδ inhibitor, for APDS as discussed by These articles also nicely illustrate the need for a multidisciplinary approach to the immune dysregulatory manifestations in IEIs as there are contributions from Rheumatology (inteferonopathies and pediatric autoinflammatory bone disorders), Hematology (autoimmune cytopenias), and Allergy/Immunology (APDS). The conditions covered in this topic represent only a fraction of disordered immune conditions in IEIs and should be considered in more detail in the future.The recognition of immune dysregulation in IEIs continues to increase as the number of patients impacted expands. There is a clear need for ongoing investigation into the epidemiology and pathophysiology for clinical manifestations and the risk factors for developing immune dysregulation as well as a collaborative multidisciplinary approach to improve diagnosis and management of this population. Our hope is that this topic has piqued the interest of researchers and clinicians in this area to provide better understanding, care, and outcomes to these patients.Lastly, we would like to thank the reviewers for their time and valuable assessments. This important collection of articles would not be possible without their contributions.


Southeast Asia (SEA) has seen an increase in healthcare spending in recent decades,Strategic purchasing has been advocated as an important tool to effectively allocate health resources, free up fiscal space, and improve health outcomes.what goods and services to buy; selecting the providers from whom to buy; and deciding how to buy by setting contract terms, payment mechanisms, and provider incentives. Reforms to make healthcare purchasing more strategic (e.g. benefit specification and performance monitoring) have already contributed to improved care quality, access, and financial protection in Kenya“Strategic purchasing”—defined as the efficient allocation of funds for healthcare services and goods to achieve health system goals—is driven by information on a country's health needs, provider performance, and cost-effectiveness assessments among other data. Strategic purchasing involves deciding While several international consortia have focused on strategic purchasing—such as RESYST  and SPARC (Strategic Purchasing for Africa Resource Centre)—no Southeast Asia-focused strategic purchasing network currently exists. The region lacks cross-country learning opportunities and high-level assessments of its healthcare financing systems. The Southeast Asia Regional Collaborative for Health (SEARCH), housed at the Saw Swee Hock School of Public Health, National University of Singapore, initiated research in 2022 to review the health purchasing mechanisms of all ASEAN countries and provides national and regional-level policy recommendations, supported by six regional Country Convenors.Initial research shows three main themes. First, there is a high diversity of financing and purchasing mechanisms across Southeast Asia existing within equally diverse health systems and forms of government. Thailand, Vietnam, and Indonesia, among others, have a purchaser-provider split whereby the principal purchaser is separate from healthcare providers and has autonomy over fund distribution and contracting. Other countries, like Brunei and Malaysia, integrate the purchaser-provider function in their respective Ministries of Health.Jaminan Kesehatan Nasional national health insurance scheme in Indonesia and transforming provider payment mechanisms under PhilHealth, the national purchaser of health services in the Philippines. Lower-income countries like Lao PDR are also implementing health financing reforms which could lay a foundation for future strategic purchasing.Second, Southeast Asia's strategic purchasing capabilities are in the early stages. Innovators like Indonesia and the Philippines are testing new ways of purchasing—for example, scaling up the Third, Southeast Asia lacks the health and financing data necessary to enable strategic purchasing. Most SEA health systems are characterised by data fragmentation and non-interoperability.There are various challenges to a wide regional implementation of strategic purchasing. The lack of data and IT capabilities in Southeast Asia will hinder evidence-based purchasing decisions, and governments’ abilities evaluate the outcomes of such decisions on health systems once they are made. A majority of Southeast Asian countries also lack the human capacity to collect relevant data at health facilities due to technical barriers and skilled staff. Finally, regulatory capacity to govern health purchasing—for example, legislation defining clear mandates for purchasers—is also limited, as are continuous monitoring and enforcement capabilities.Our preliminary analysis shows three opportunities to improve strategic purchasing in Southeast Asia that SEARCH intends to pursue. First, collaborative learning networks can bring together policymakers, purchasers, and providers to identify best practices and common challenges. This could potentially mitigate the effects of having highly diverse health systems in the region. Second, the post-COVID emphasis on health systems resilience can spotlight strategic purchasing as an effective financing tool to SEA policymakers. Third, capacity-building efforts—including policy-relevant recommendations contextualised to individual health systems—can enhance governments’ preparedness for strategic purchasing.Leveraging these opportunities will help countries overcome their roadblocks to strategic purchasing by enhancing their data collection, IT systems, and human capacity. Our work will test the hypothesis that knowledge-sharing consortia can enhance strategic purchasing and that this, in turn, will be an effective tool to improve health outcomes and unlock UHC.Southeast Asia has demonstrated increasing commitment to UHC and health financing reform. Strategic purchasing should not be overlooked as an enabler of cost-efficient, equitable health systems. Regional collaboration for strategic purchasing is necessary for governments to manage a world of increasing inflation and rising healthcare costs.CB and SKK conceptualised and designed the draft. CB wrote the first draft. SKK and JL reviewed and edited the manuscript. All authors approved the manuscript for submission.Research for this project was granted approval from the National University of Singapore Institutional Review Board.No conflicts to declare.


Age specific considerations are integral part of quality care. Several burn units care for all age groups in a single unit, needing additional resources and infrastructure to provide quality care for extremes of age.An anonymous online survey was conducted among the multidisciplinary burn team members of a burn unit that cares for both pediatric and adults. Data for the last 4years found that 12-18% of all burn admissions were 2years or less, while 5-6% of burn admission were of over 75 years of age.45 members responded to the survey, including 56 % RNs and the remaining included therapists, pharmacist, psychologist, social worker, child life specialist, and case manager. The results showed that team members felt more comfortable caring for geriatric patients than pediatrics. Staff members reported higher importance for having intubated pediatric patient with leverage of 1:1RN assignment as well as daily rounding by pediatric intensivist and pediatric pharmacist. Majority (73%) of respondent s reported good or excellent in their assessment, skill, knowledge, and communication ability for caring pediatric patients aged and 2 and below. Elements that reported to be helpful for caring extremes of age in the order of its importance were weekly multidisciplinary rounds, burn debriefs of selected cases, monthly performance improvement meetings/ follow ups, weekly psycho social rounds and journal clubs. Low volume high acuity patient's care was kept up to date through various interventions which were prioritized by the respondents in the order of age specific continuing education classes, professional conferences, simulation/ skills day, and journal clubs.The current process shows satisfactory comfort level for most of the team members to care for all age groups. Availability of pediatric and geriatric specialty professionals along with sufficient supply of age specific equipment, and ample educational opportunities were noted by the respondents as the key to providing quality care for all age groups in a single setting.The current model may be continued with sustainment of different specialty services, educational resources, and age- specific supplies and equipment.


Resolving these challenges requires multisector infrastructure, collaboration, and innovation to evaluate and eliminate rural–urban disparities. In this Editorial, we share lessons from the National Rural Health Association’s Rural Health Equity Conference and 46th Annual Rural Health Conference in San Diego, California, on 15–19 May 20233. As rural areas emerge from the devastating COVID-19 pandemic, the conference offered critical reminders of the unfinished business and shared responsibility in elevating US rural health and realizing the objectives of US Healthy People 20304.In the US, approximately 15–20% of the population live in rural areas and face a disproportionate burden of health disparities compared with urban counterpartshttps://www.ruralhealthinfo.org/toolkits/health-equity [https://www.ruralhealthinfo.org/toolkits/health-equity])5. The toolkit includes modules to frame the problem, implement and evaluate programs, and build capacity for sustainability through an equity lens. The toolkit and associated resources on general community health strategies are available for use by researchers and policymakers. Improving rural health at the individual, community and healthcare system levels will require multisector collaboration, as highlighted in presentations from the US Department of Agriculture’s Office of Rural Development, US Centers for Disease Control and Prevention, and Centers for Medicare & Medicaid Services Office of Minority Health (CMS OMH).Equity was a major theme of the conference. The opening sessions’ speakers set the stage for problems, solutions and toolkits to address rural health inequities. In his remarks, Dr Eduardo Sanchez, Chief Medical Officer for Prevention, American Heart Association, identified several factors contributing to lagging rural health: individual health factors in rural compared to urban areas , social determinants of health  and healthcare system factors . In their session, Luciana Rocha and Dr Alana Knudson from the University of Chicago Walsh Center for Rural Health Analysis discussed the Rural Health Equity Toolkit from the Rural Health Information Hub 8. The availability of regularly updated data will also inform progress toward the US Healthy People 2030 objectives. Availability of local data may also help with building and strengthening rural resilience, as discussed by Dr Alana Knudson, Kristine Sande and Dr Diane Hall in their session ‘Emergency preparedness and response tools’. The Rural Health Mapping Tool includes information for rural healthcare providers and policymakers to prepare for emergencies, build capacity, and promote resilience in communities and health systems. The Rural Health Mapping Tool and Rural Health Information Hub provide data on county deficits and assets , which can provide a comprehensive rural landscape while designing and implementing strategies.Several federal organizations explicitly acknowledged the need for rural-specific strategies and innovation. The Federal 2023 Omnibus Appropriations Bill included US$5 million (~A$7.5 million) to establish an Office of Rural Health at the US Centers for Disease Control and Prevention (CDC)10. The sessions underscored the heterogeneity of rurality and the subpopulations making up a diverse rural America. Of note were various sessions highlighting intersectionality – the idea that, to understand inequities, categories like gender, race, where one lives  and socioeconomic status are best understood as overlapping and additive rather than isolated and/or distinct. Such approaches have been advocated for within the extant literature to understand inequities in rural men’s health11, healthy aging12 and in the development of a sense of community to buffer social marginalization14. Other presentations extended these discussions. For example, Dr Carrie Henning-Smith and colleagues from the University of Minnesota Rural Health Research Center discussed rural–urban differences in health for lesbian, gay, bisexual and transgender (LGBT) adults, as well as identifying challenges and best practices for supporting rural LGBT individuals. Similarly, Danielle Lucero and Dr Xavier Morales from the Praxis Project shared their experiences building a community of practice for rural community organizers among Black, Indigenous and People of Color populations.Within the past decade, the COVID-19, opioid and HIV epidemics have demonstrated that socioeconomic factors, geography, cultural context and other syndemic conditions are driving epidemics, predominantly impacting urban spaces, into rural locations where public health and healthcare resources are limited. Most national efforts to address health inequities within rural communities have taken a one-size-fits-all approach that views rural communities as homogenous entities when – in reality – rural communities are more often heterogeneousAchieving rural health equity will require multisector collaboration to advance policy that addresses key rural health issues such as the current public health, mental health and medical workforce shortages. In the US in 2022, the Biden administration committed US$226.5 million in American Rescue Plan funding to enhance training programs for community health workers (CHWs) across the US. This cadre of health professionals, particularly in rural areas, play a critical role in connecting people to care, including COVID-19 care; mental health and substance use disorder prevention, treatment and recovery services; chronic disease care; and other important health services. The Community Health Worker Training Program is one example of bringing governmental agencies, academic institutions, community-based organizations and other stakeholders together to building a robust public health workforce. Beth Bowling and Michaela Amburgey from the University of Kentucky Center for Excellence in Rural Health provided examples of health career pipeline programs in Kentucky, including the implementation of apprenticeships for CHWs. Similarly, Floribella Redondo-Martinez and Susan Kunz from the Rural Arizona CHW Workforce Development Network described processes to building capacity of CHWs within rural organizations, while Michal Searls and colleagues from Ohio University discussed how CHWs in rural Appalachian Ohio have been leveraged to increase health literacy among community members.15 and workforce shortage16, and require targeted strategies for recovery, sustenance and resilience. The conference reinforced that action to improve rural health will require multisector collaboration from philanthropy, non-governmental organizations, governmental organizations, researchers, community organizations and others to ensure that people’s basic needs are met , while also preparing neighborhoods  and health systems (eg staffing) to transform rural health. In order to do this, we will require better, local data to evaluate and monitor progress toward local, regional, and federal health targets. While focusing on basic infrastructure, processes and systems that support overall health and care, it will be imperative to also focus on specific health conditions , which have been particularly devastating for rural communities.The conference was attended by more than 1000 rural health leaders with expertise in healthcare delivery, research and policy, with a clear focus on equity, collaboration and innovation. As acknowledged by several speakers, problems and interventions may be addressed locally, but solutions may be affected by regional and federal policies. In this context, multisector collaboration and advocacy become critical parts of any rural health strategy. The responsibility to advocate rests with individuals, communities and systems at all levels to highlight challenges and, importantly, to identify opportunities and build partnerships to resolve them. As outlined by John Gale and Eric Shell in their presentations on the Future of Rural Health and The Future of Rural Healthcare, rural health faces several challenges including resetting its capabilities and infrastructure after decimation by the COVID-19 pandemic. Many rural communities are threatened by rural hospital closure19. In 2021, a consortium of six organizations developed a global manual to define cities, towns and rural areas for international comparison20. This will facilitate international studies, permit comparison and allow for the identification of common themes affecting rural health. Notwithstanding the challenges for international studies, strategies to address workforce shortage, as well as inadequate funding, multisector collaboration in the US may be adapted to other countries. In turn, lessons from other countries will shape strategies and tactics in the US. This will allow for a dynamic exchange of information, knowledge and experience, which will elevate rural health globally.Lessons from these conferences are pertinent to rural populations beyond the US. An estimated 50% of the world’s population live in rural communities and, similarly to the US, experience various health disparitiesRural health and care are at an inflection point. Concerted multisector collaboration can direct attention toward problems and transformative solutions to advance health for people in rural areas. Rural health is public health, and the time to act is now. We cannot achieve health equity without advancing rural health.


New Insights into Post-translational Modification of Proteins and Immune Regulation in Carcinogenesis, Heart Disease, Neurodegenerative Disorders, and Allergic Diseases. This Research Topic of articles aims to provide a comprehensive exploration of the latest advancements in understanding the role of PTMs and immune regulation in these diverse disease contexts.In recent years, there has been a growing recognition of the critical role played by post-translational modifications (PTMs) of proteins in various diseases, such as carcinogenesis, heart diseases, neurodegeneration, and allergic diseases. The intricate interplay between PTMs and immune regulation has emerged as a fascinating area of research, offering new insights into the pathogenesis and potential therapeutic targets for human diseases. In this context, we are delighted to present a Research Topic focused on Si et al. which provides valuable insights into the role of histone acetylation in ovarian cancer. The authors demonstrate that a novel pyridine derivative, compound H42 effectively inhibits the growth and proliferation of ovarian cancer cells both in vitro and in vivo, and exhibits inhibitory activity against ovarian cancer progression. Further mechanism study presented that this compound affected the expression of histone acetylase 6 (HDAC6) and the acetylation of α-tubulin and heat shock protein 90 (HSP90), and suggest that H42 functions through the regulation of HDAC6-mediated acetylation of HSP90 and α-tubulin, leading to downstream effects on cell cycle regulation and cancer cell proliferation. Ovarian cancer is a highly aggressive and difficult-to-treat cancer, and there is a great need for new therapeutic options. Their findings highlight the significance of histone acetylation and HDACs in ovarian cancer progression, and suggest that targeting HDACs with compounds could be a promising therapeutic strategy.Our Research Topic begins with an original research paper by Wang et al. utilizes global quantitative phosphoproteomic and proteomic analysis to investigate the molecular mechanism underlying post-infarction chronic heart failure. They identified differentially expressed phosphorylated proteins (DPPs) to elucidate the complex signaling pathways involved in this multifactorial systemic disease. Importantly, their findings highlight the enrichment of DPPs in nucleocytoplasmic transport and mRNA surveillance pathways, providing valuable insights into the dysregulation of these processes in chronic heart diseases. Furthermore, the identification of Bclaf1 Ser658 as a potential therapeutic target and the exploration of predicted upstream kinases offer promising avenues for the development of efficient treatments for post-infarction chronic heart diseases. These findings not only deepen our understanding of the molecular mechanisms underlying heart failure but also pave the way for the development of targeted therapies.Proteomics, as a robust scientific approach, provides unique insights into the complicated biological processes occurring at the protein level, and serves as an invaluable resource for understanding the complex interplay between proteins and disease, making it an indispensable tool in biomedicine research. Liu et al. explores the connection between oxytocin and its receptors (OT/OTR) signaling and bone metabolism. The authors provide a comprehensive review of recent studies that highlight the involvement of OT/OTR in regulating bone marrow mesenchymal stem cells, osteoblasts, osteocytes, chondrocytes, and adipocytes, and these cells are closely associated with post-transcriptional modifications, immunity, and inflammation in the process of bone metabolism. The authors elucidate the molecular mechanisms through which OT/OTR modulate bone formation, resorption, and microstructure, ultimately contributing to the understanding of their anti-osteoporosis effects. It highlights the multifaceted role of OT and OTR in bone metabolism and the potential implications for immune regulation and disease pathogenesis. This article serves as a valuable addition to our Research Topic on PTMs of proteins and immune regulation.In addition, the review by Yuan et al. reported their exploration on the neuroprotective properties of Liuwei Dihuang pill (LWD) in the APP/PS1 mouse model of AD. LWD is a traditional Chinese medicine formula, and has long been recognized for its therapeutic benefits in various diseases including neurodegenerative disorders. However, the active constituents and mechanisms of action of LWD have remained largely unexplored until the present. They explored a network pharmacological analysis to predict the potential targets and mechanisms of LWD in AD. And their results showed that LWD improved learning and memory abilities, reduced Aβ deposition, and attenuated neuroinflammation in the hippocampus of APP/PS1 mice. Furthermore, these effects were found to be associated with the autophagy activation pathway regulated by PI3K/Akt signaling pathway and the reduction of inflammation induced by the activation of glial cells. Their research offers new insights into the neuroprotective effects of LWD in AD, and present an additional opportunity of the development of novel clinical treatments. Further research is expected to explore the specific active compounds and their action mechanisms in LWD, which is believed to provide novel drug candidates for AD treatments.Alzheimer’s disease (AD) is a multifaceted neurodegenerative disorder characterized by cognitive impairment and memory loss. Despite extensive research, successful therapeutic interventions for AD continue to be elusive. In this special Research Topic, In summary, this Research Topic of research articles provides recent advances in protein post-translational modifications, immune regulation and inflammatory signaling implicated in various disease pathogenesis. And these researches hold significance in advancing our understanding of disease mechanisms and developing novel therapeutic approaches in various pathological conditions. We acknowledge the dedication and scientific rigor of all authors to enrich our understanding of the intricate relationship between PTMs, immune regulation, inflammation and disease pathogenesis.


Paneth cells (PCs) are intestinal epithelial cells (IECs) that contain eosinophilic granules, which are located in Lieberkühn crypts. An increasing number of animal and human experiments have indicated that PCs are involved in the progression of a variety of intestinal as well as systemic inflammatory responses including necrotizing enterocolitis (NEC). NEC is an enteric acquired disease with high mortality that usually occurs in premature infants and neonates, however the underlying mechanisms remain unclear. In this review, we summarize the features of PCs, including their immune function, association with gut microbiota and intestinal stem cells, and their mechanism of regulating IEC death to explore the possible mechanisms by which PCs affect NEC. Necrotizing enterocolitis (NEC) is one of the most common acute intestinal necrotizing diseases . In neonOne possible explanation may be suggested by Paneth cell (PC), a highly specific cell of the small intestinal, which have the function of coordinating the physiological environment of the small intestine. The history of this special type of intestinal columnar epithelial cell can be traced back to a century ago when it was first documented by Gustav Schwalbe and detailed in 1888 by Josef Paneth in Vienna . The ideIn this review, we explore the relationship between PCs and intestinal epithelial barrier, how PCs affect intestinal stem cell differentiation and gut microbiota ecological balance, and whether several modes of intestinal epithelial death contribute to NEC by affecting PCs function.PCs are highly specific cells of the small intestine, located within Lieberkühn crypts in a pyramidal shape . Under nMost of the functions of PCs are related to their secreted products. Specific antibacterial products, lysozyme, and a variety of antimicrobial peptides in PCs can form an immune barrier near the crypt epithelium to resist the invasion of pathogenic microorganisms . By secrThe intestinal barrier is an important defense against harmful substances and pathogenic microorganisms found in the external environment. It is composed of four parts: the biological barrier composed of intestinal flora, the chemical barrier composed of the mucus layer, the mechanical barrier composed of epithelial cells, and the immune barrier composed of immune cells and immune factors . IntestiPCs secrete antimicrobial peptides and proteins (AMPs), enzymes and growth factors, which form a biochemical barrier near the crypts, prevent bacterial invasion, and maintain stability of the intestinal environment . These dAMPs fall into two major classes in the human body: cathelicidins and defensins . During The main defensin secreted by PCs is α-defensin  . The humLysozyme is considered to be an indicator of PC localization . LysozymThe immunological changes of NEC include the deficiency of anti-inflammatory mediators and the increase of pro-inflammatory mediators, most of which are produced by PCs. Secretory immunoglobulin (Ig)A and M are produced at the apex of PCs. Secretory IgA is released through hydrolysis of the apical part of the PC membrane, which inhibits the adhesion and adsorption of pathogens (viruses and bacteria) in the intestinal mucosa that form the biofilm, thereby protecting the mucosal barrier . PCs arePCs also produce the pro-inflammatory tumor necrosis factor-α (TNF-α), which accumulates in secretory granules and enhances systemic inflammation . When PC+, encoded polypeptides, and butylactones, result in cell lysis and the release of immune-stimulating compounds, increasing the severity of NEC  basic regulator) in IECs leads to intraepithelial TNF-dependent apoptosis, followed by intestinal barrier rupture and bacterial translocation into the intestinal wall, triggering a cellular inflammatory response , which is a key component of the NOD1 and NOD2 complex, is a necessary ubiquitin ligase for NOD2 signaling . It is rNecroptosis is a special mode of death that exhibits similarities with both apoptosis and necrosis. The cytological morphology of necroptosis is similar to that of traditional necrosis, which is a highly inflammatory cell death. During necroptosis, RIPK1 recruits and activates RIPK3, which phosphorylates mixed-lineage kinase domine-like protein (MLKL), leading to MLKL oligomerization and transfer to the cell membrane; MLKL then depolarizes the cell membrane, leading to cell rupture . RIPK1 iNecroptosis may be an important form of NEC-related IEC death. The expression of RIPK1, RIPK3, and MLKL in the intestinal mucosa of children with NEC was significantly upregulated, and this upregulation correlated with the severity of NEC . IntestiPrevious studies have reported necroptosis of IECs in NEC mice and that inhibiting necroptosis of IECs could reduce inflammation in these mice. We further found necroptosis of PCs in the intestinal crypts in NEC mice . When PCAutophagy refers to the isolation of cytoplasmic substances into autophagosomes, which are then fused with lysozyme, resulting in content degradation that can help remove misfolded or aggregated proteins or resolve other intracellular damage . SimilarAtg16L1 is expressed in IECs  stress leads to phosphorylation of protein kinase RNA-like ER kinase (PERK) . p-PERK Atg16L1 and upstream autophagic Atg5 have a compensatory role in ER stress as they control the autophagy pathway and help to maintain IEC homeostasis. The disruption of mitochondrial homeostasis in PCs is caused by the synergism of Atg16L1 deletion and ER stress  or lipopolysaccharide stimulation, another inflammatory mode of cell death called pyroptosis can occur . Stress PCs are a type of IECs that play an important role in maintaining intestinal microbiota homeostasis, ISC growth, and IEC death. Various growth factors secreted by PCs are important for maintaining the intestinal barrier as a defense against pathogens. The loss of PCs causes loss of α-defensin, immunoglobulins, and other products, followed by disruption of the intestinal barrier, thereby leading to NEC. Disruptions of PCs can also reduce the production of lysozyme and other factors that maintain intestinal microbiota homeostasis, resulting in intestinal microbiota disorders and NEC. PCs secrete Wnt3, Notch, and other signaling factors to maintain the function of ISCs and prevent the occurrence of NEC. Autophagy, necroptosis, and apoptosis are also closely related to PCs. Reduced production of antimicrobial peptides by PCs makes the intestine hypersensitive and highly prone to NEC. The development of PCs, intestinal flora homeostasis, and pathogenesis of NEC are closely related; however, only few studies have investigated the possible mechanism of this relationship. Therefore, further exploration of the mechanism affecting the number and function of PCs is of great significance for the prevention, early diagnosis, and treatment of NEC.


Cells compiles novel and exciting insights into the mechanisms of aging and senescence.Aging is the leading predictive factor of many chronic diseases that account for most of the morbidity and mortality worldwide, i.e., neurodegeneration, cardiovascular, pulmonary, renal, and bone diseases, as well as cancers. Oxidative stress and reactive oxygen species generation, over-production of inflammatory cytokines, the activation of oncogenes, DNA damage, telomere shortening, and the accumulation of senescent cells are all widely accepted mechanisms contributing to aging. Senescence is mainly thought to be provoked by negative cellular stress but might also be induced by physiological developmental stimuli. Senescence is characterized by irreversible cell cycle arrest independent of quiescence and terminal differentiation. However, more recent observations suggest that the status of developmental and cancer senescent cells might not be irreversible. Aside from cell cycle arrest, senescent cells are characterized by morphological changes and molecular damage, metabolic alterations, and a specific secretory phenotype (SASP). Senescent cells contribute to embryonic development and participate in tissue repair and tumor sup-pression, but they are also involved in detrimental tissue decline during aging. Thus, the application of senolytic or senostatic drugs to halt or reverse age-related pathologies could represent an interesting therapeutic option. This Special Issue of Carrillo-Salinas and colleagues describe the effects of short-chain fatty acids on the function of neutrophils in young and older women with relevance for HIV infection risk . HIV infCells the identification of dual oxidase (Duox) as a source for reactive oxygen species (ROS) in Drosophila melanogaster [2O2. Duox heterozygous male flies showed an expected reduced expression of Duox by 50%, as well as decreased ROS and H2O2 production. They survived longer under standard conditions as well when they were exposed to ROS-producing food. Whether neuroinflammation and senescence in this model are reduced remains to be determined. Nevertheless, the data nicely support the critical involvement of reactive oxygen species in lifespan determination in this model. Unfortunately, the relations between antioxidants, ROS production, and human health and longevity seem to be more complex [Oxidative stress is generally assumed to increase with aging and induce senescence which might have consequences for one’s lifespan. Reducing neuronal oxidative stress is known to extend the lifespan in Drosophila . Howevernogaster . Duox is complex ,5.Ke et al. determined ROS production in retinal pigment epithelial (RPE) cells . They coBesides the deleterious effects of ROS, telomere shortening is considered to be a hallmark of aging . ExercisUnfortunately, long telomeres and high telomerase activity might not only protect against aging but are also characteristic of cancer cells. Therefore, the inhibition of telomerase activity could represent an attractive therapeutic target for anti-tumor applications. Yan et al. screened a library of 800 natural compounds for potential inhibitors of telomerase activity . They idAnother important factor driving aging is cellular senescence. Senescence is characterized by the growth arrest of cells, which was first described in fibroblasts in long-term culture ,12 and tAlthough the authors describe p16INK4A as a marker for senescence and p16Ink4a-targeting models are frequently used to eliminate senescent cells (reviewed in ), we repCells [In addition, we reviewed the roles of p16INK4A, p14ARF/p19ARF, and p21 in organ development and homeostasis in this Special Issue of Cells .Chen and Skutella propose in their review partial senescent cell reprogramming as a strategy for anti-aging therapies . They suHong and colleagues focus in their review on the molecular mechanisms of alveolar epithelial stem cell senescence and the senescence-associated differentiation disorders in pulmonary fibrosis . The topCells by Aghali and colleagues [Cellular senescence in aging lungs and lung diseases is reviewed in this Special Issue of lleagues . They prCells entitled “Controversies and Recent Advances in Senescence and Aging”. The first article deals with the topic of senescence. The authors introduce the relation between cellular senescence and skin aging and analyze in great detail the major components of air pollution on lungs and mainly skin aging. Air pollution and the consequences for senescence and aging is a highly relevant topic for countries with increased industrialization and intensified transport. Fortunately, the authors also provide guidance for tackling the consequences of air pollution on the skin by reviewing the available information on therapeutics and cosmetics in this specific field [The group working with Maria Cavinato published two review articles in this Special Issue of ic field .In the second article, the group summarizes the current knowledge surrounding age-related lysosomal dysfunctions . DeregulJin and colleagues review the relation between pyroptosis, autophagy, and sarcopenia in aging . PyroptoBrauning et al. discuss natural killer cells’ phenotypes and functions in aging . The ageLast but not least, Cai and colleagues review mouse models of accelerated aging . Mice arTaken together, the Special Issue “Controversies and Recent Advances in Senescence and Aging” comprises an excellent collection of original articles and reviews highlighting different novel aspects in the fields of senescence and aging research. They will hopefully stimulate discussions and further research in these fields which are extremely important for a constantly aging human population.


The Cooperative Re-Engagement Controlled Trial (CoRECT) was a CDC-sponsored randomized controlled trial of a D2C model, which provided an opportunity to examine the process of implementing an intervention for people with HIV (PWH) who are out-of-care across three public health department jurisdictions. Using the EPIS  framework, we aimed to retrospectively describe the implementation process for each site to provide insights and guidance to inform future D2C activities implemented by public health agencies and their clinical and community partners.After completion of CoRECT, the three  trial sites reviewed study protocols and held iterative discussions to describe and compare their processes regarding case identification, interactions with partnering clinics and patients, and sustainability. The EPIS framework provided a structure for comparing key organizational and operational practices and was applied to the entire implementation process.The trial sites varied in their implementation processes and the specific elements of the intervention. Factors including prior D2C experience, data management and analytic infrastructure, staff capacity, and relationships with clinic partners informed intervention development and implementation. Additionally, this review identified key lessons learned including to: (1) explore new supplemental sources for public health surveillance data; (2) work with stakeholders representing core functions/components in the early stages of the intervention design process; (3) build flexibility into all components of the follow-up activities; and (4) integrate data sharing, project management, and follow-up activities within existing DPH organizational structure.The CoRECT study provides a general blueprint and lessons learned for implementing a D2C intervention for re-engagement in HIV care. Interventions should be tailored to local operational and structural factors, and responsive to evolving clinical and public health practices. The National HIV/AIDS Strategy, the United States plan for addressing and ending the HIV epidemic, prioritizes increasing rapid linkage to care and improving retention in care to achieve viral suppression , 2. The Various models of care have been developed to improve retention in care and viral suppression among people with HIV infection (PWH). An initial step in these care models is to define PWH who are out-of-care (OOC), which can vary . The CDCDifferent clinic-based and public health strategies have been used to improve retention in HIV care. “Data to Care” (D2C), is one strategy that uses a combination of public health surveillance and other, often clinical, data to increase the number of PWH receiving sustained HIV care and viral suppression , 10. TheThe Cooperative Re-Engagement Controlled Trial (CoRECT) was a CDC-sponsored randomized control trial (RCT) of a D2C model with a research goal to establish data-sharing partnerships between health departments and HIV care clinical providers designed to identify and re-engage PWH that are OOC. This goal was operationalized by: (1) identifying newly OOC PWH through a collaborative data-sharing approach using public health surveillance and clinical data; and (2) implementing a public health outreach intervention to improve HIV care re-engagement, retention in care, and viral suppression for OOC PWH. Each of these elements differed by site. All three sites in this trial , found that a collaborative D2C strategy was successful at re-engaging PWH into HIV care at 90 days compared to the standard of care . Only thCoRECT’s D2C approach varied among the three participating health department jurisdictions and therefore provides fertile ground for compiling experiences and insights across multiple contexts. The objective of this study was to use a standardized implementation framework, EPIS , to describe the implementation process for each of the three CoRECT sites as part of a retrospective assessment in order to better understand and appraise the components of the D2C intervention. Defining, clarifying, and analyzing D2C implementation within the EPIS framework enabled us to articulate lessons learned that can inform delivery, sustainability and replicability of future D2C activities.a priori definition for OOC included receiving HIV care at a participating clinic for at least 12 months and then subsequently neither a visit with a prescribing provider nor CD4 or viral load test result reported to health department surveillance for at least 6 months. Eligible OOC patients were randomized within each clinic to the clinic SOC for patient follow-up, or a D2C health department intervention in which patient follow-up was performed by public health field epidemiologists/Disease Intervention Specialists (DIS). There was a basic structure to the trial across all sites and participating clinics, but specific intervention characteristics varied across the three sites, with adjustments at each clinic consistent with variations in workflow, staffing, and capacity. Each site used a “case conferencing” methodology where health department staff interacted with clinic staff to reach consensus on persons who were OOC and eligible for randomization. After case randomization, public health field staff undertook patient outreach activities culminating in a warm handoff to clinic staff. The health department project management teams monitored surveillance data to determine re-engagement, viral suppression, and retention outcomes.CoRECT was a multisite, randomized controlled trial to implement and evaluate a public health intervention compared to clinic standard of care (SOC) for re-engaging OOC PWH, using D2C. Participants were recruited from 8/2016–7/2018. The The Connecticut Department of Public Health/Yale School of Medicine (CTDPH/YSM), the Massachusetts Department of Public Health (MDPH), and the Philadelphia Department of Public Health (PDPH) participated as the three CoRECT sites. In 2016, Connecticut, Massachusetts, and Philadelphia reported approximately 10,286 , 20,060 , and 19,113  PWH residing in their jurisdictions, respectively , 13. TheThe CoRECT intervention allowed for site-specific flexibility regarding the case identification process and the re-engagement follow-up activities. While the EPIS framework was originally developed to aid in the development, execution, and sustainment of research interventions in a prospective manner, we chose to use this framework retrospectively to review implementation outcomes, which has been done previously elsewhere. Our rational for including implementation outcomes is based on a systematic review that suggests that most RCTs fail to report implementation outcomes, including retrospectively , 15. TheTo understand the different outcomes at each site, the three jurisdictions decided to evaluate implementation and associated processes to inform continued and future interventions, and identify key lessons that could assist further implementation of D2C programs. The process consisted of reviewing study protocols and holding discussions among primary investigators and project team members from each site. Using the EPIS framework, sites described and documented their processes for case identification, collaboration, and communication with partnering clinics, and interactions with patients  and included community health centers, hospital-based, and other clinics funded by federal Ryan White HIV/AIDS Program. MDPH recruited nine clinics across four counties (out of 14 counties statewide) and included community health centers, a hospital-based practice, a public health hospital, and non-profit, academically affiliated teaching hospitals. Participating clinics represented a mix of funding sources (including Ryan White) and included facilities that received no dedicated HIV services funding. PDPH recruited eight clinical sites all within the City of Philadelphia. These participating clinics included Ryan White-funded community health centers and academic medical centers, as well as a Veterans Health Administration medical center and a private clinic .Strengthening collaboration between health departments and healthcare clinics was an explicit, secondary goal of CoRECT. Through strengthened collaboration, CoRECT provided sites with new tools to assist patients and healthcare providers with re-establishing engagement in HIV care .The leadership across the three participating DPHs prioritized applying data to public health action, developing/adopting methods for promoting and supporting quality improvement, promoting equity in access to healthcare, and achieving health outcomes. Additionally, primary consideration was given to addressing known gaps in HIV care including using novel D2C methods for improving care engagement.CTDPH, PDPH, and MDPH had varying levels of experience with D2C activities and participation in other HIV care research studies. Although CTDPH had no prior D2C experience, they relied on experienced HIV surveillance staff and prior experience working with Yale researchers on other related projects. PDPH staff had some prior D2C experience, in addition to the pilot, which preceded their CoRECT enrollment to test patient identification procedures. Prior to CoRECT, PDPH had received Gilead funding for START Care, which assessed data exchanges with providers to determine OOC patients. Unlike CoRECT, providers were responsible for directly administering the intervention. MDPH had prior D2C experience through SPECTRuM and Partnerships for Care .The three sites used their existing field investigation/patient follow-up activities as a base for implementing their public health field intervention. MDPH used existing field staff and integrated OOC engagement and navigation activities into existing functions associated with public health follow-up of syphilis and acute HIV, while PDPH and CTDPH/YSM hired designated CoRECT field staff focused primarily on re-engagement of OOC clients and assisted with other outreach activities as needed. The field staff (DIS) in Connecticut were hired and housed by local health departments . PDPH hired and managed designated CoRECT field staff through STD Control Program within the Division of Disease Control. CTDPH/YSM coordinated their CoRECT outreach activities based on a combination of local and state HD practices. All three sites provided training on study procedures to field staff; training of clinic staff regarding study goals and procedures varied at participating clinics.Data management staff varied among the sites. For MDPH, CoRECT data management activities were integrated with routine HIV/STD surveillance activities and coordinated by dedicated D2C staff. PDPH relied on a D2C data manager to work closely with a D2C project coordinator, both within the HIV Surveillance Unit, which would coordinate intervention follow-up activities with STD Control Program. Unlike the previous sites, CTDPH relied on their collaborators at YSM to perform data management including randomization and communication with local HDs.Sites had the flexibility to tailor both of the main study components . For example, sites used the initial general patient identification protocol  as a basFor follow-up of OOC patients by DIS, sites designed feasible public health outreach and patient navigation activities which encompassed short-term re-engagement assistance  and longer-term case management . CTDPH/YSM  implemented short-term patient re-engagement assistance through the use of a modified Anti-Retroviral Treatment and Access to Services (ARTAS) , 22 inteCTDPH supplemented their in-house knowledge and skills by partnering with YSM, leveraging their history of collaborating on grant-funded projects. YSM provided CTDPH with additional capacity to manage and execute the CoRECT trial. MDPH and PDPH relied on and benefitted substantially from prior experience and partnership with the participating clinics to manage and execute the intervention. Many of their clinic partners had experience in participating in HIV-related research, both clinical and interventional. Additionally, PDPH partnered with the University of Pennsylvania CFAR to serve as the community advisory board for the CoRECT project.The trial sites collaborated closely with participating clinical partners to tailor the patient identification protocols  and provAll the trial sites highlighted the importance of establishing a strong buy-in internally among DPH staff and administration as well as the staff and administration of participating clinics with which the CoRECT teams would be working closely. Cultivating relationships with the clinics consisted of explaining the project’s importance, the benefits to patients and clinical practice, and clear expectations . Seeking buy-in of DPH staff differed based on their roles within the CoRECT team and other duties. Trial sites and their collaborating partners also established data sharing agreements.Both MDPH and PDPH relied on internal staff to coordinate project activities. This approach increased the sense of DPH “project ownership” which improved staff buy-in. For CTDPH/YSM, YSM staff served as project coordinator. Use of an external (third-party) coordinator in which clinic partners and CoRECT-specific DIS staff did not interact directly with CTDPH staff impacted staff “buy-in.” All three sites identified having a dedicated project contact within each collaborating clinic as critical for streamlining communication and improving implementation of patient follow-up activities.PDPH differed from the other sites in that they conducted a pilot study to assess procedures and collect feedback from clinic leadership and staff prior to the implementation of the full trial. Based on the findings from the pilot, PDPH CoRECT team modified the initial patient identification protocol to the one shown in The first stage of patient recruitment was case identification which had two components: data sharing/reconciliation and case conferences. Each trial site had a general protocol which could be adapted during the implementation phase. Through their pilot study, PDPH determined that it was most productive to have their clinic partners submit “in-care” or “all patients” lists and to have structured in-person case conferences led by the PDPH project coordinator.The trial sites used this phase to onboard and train staff. The ability of the CoRECT sites to adapt/modify general case identification protocols and patient follow-up activities were key innovative characteristics. DPH and YSM CoRECT teams worked closely with clinic partners to develop novel data sharing and case review protocols that were feasible for all parties and allowed for the timely identification of OOC cases.The implementation phase of active recruitment highlighted the need to address unforeseen challenges during the RCT or for later consideration in the sustainment phase .Throughout the RCT, CoRECT site teams continued to work closely with partnering clinics to maintain buy-in and address any challenges or concerns such as staffing changes within the clinic or CoRECT team.The sites and the participating clinics used case conferences to review and discuss the eligibility of each potential OOC case. These conferences generally entailed DPH CoRECT team members  meeting with individual clinic points of contact, typically case managers, to discuss every patient identified by the reconciliation process to be OOC with the goal of finalizing a list of eligible patients for randomization. Clinicians, social workers, and nursing staff were also invited to participate to provide additional case-specific information. CTDPH/YSM had multiple participating clinics which necessitated the adoption of quarterly case conferences. MDPH allowed clinics to submit either “all patients” or OOC lists via three methods based on their capacity and individual preference. PDPH continued with the procedures that they developed during their pilot study see .As for the case conferences, PDPH developed a structured procedure led by the D2C project coordinator, primarily in-person. However, when the list of cases to review were less than five, meetings could be held over the phone. MDPH developed a semi-structured procedure led by the MDPH D2C epidemiologist, while CTDPH/YSM took a more unstructured approach led by the YSM CoRECT data manager . All thrDuring the RCT, each site held monthly internal meetings and periodic project status meetings with clinical partners to provide support and discuss concerns and challenges. In retrospect, CTDPH/YSM did not hold regular monitoring meetings with local health departments that employed the DIS, which eventually posed a limitation. MDPH conducted routine reviews of field staff activities associated with HIV care re-engagement activities and held monthly meetings with field staff to discuss cases and new barriers/challenges.A common challenge faced was staff turnover throughout the course of the project among CoRECT teams, field staff, and partnering clinics which affected the productivity and efficiency of case conferences and patient follow-up. New team members or field staff required updated training to familiarize themselves with the project protocols and processes as well as to establish and build strong working relationships with the multiple different collaborators.CoRECT’s use of both surveillance and clinic data to identify truly OOC patients required ongoing flexibility to adjust procedures consistent with clinic capacity and operational features related to case identification and DIS field activities.Sites encountered challenges such as changes in leadership at health departments and participating clinics, health department reorganization, and funding after the trial ended, which impacted determining what components of the CoRECT study activities that could be sustained .While all sites endorsed general principles of D2C, namely, continuing to actively advocate for HIV re-engagement activities using combined public health and clinical data, leadership challenges were notable. CTDPH faced the dual challenges of external study leadership and organizational restructuring with the hiring of new leaders. PDPH expanded its leadership by transitioning their D2C project coordinator to the head of the HIV specific Field Services Program. In contrast, there were no major changes in MDPH’s leadership or structure.PDPH maintained similar case identification and patient follow-up activities and retained their dedicated field staff through the reallocation of resources and the development of the HIV-specific Field Services Program, which took the lead in managing the field staff responsible for OOC follow-up activities. Additionally, personnel responsible for data analysis and management were grouped together in the HIV Surveillance Unit. The creation of this program has allowed for the expansion of D2C activities based on CoRECT to all Ryan-White funded facilities. In MDPH, the integration of CoRECT activities into the routine workflow of HIV/STI field epidemiologists and surveillance epidemiologists allowed for the continuation of patient follow-up activities, although in a more limited capacity. In contrast, without YSM to provide project management support and resources to support dedicated field staff, CTDPH had to halt their CoRECT follow-up activities. CTDPH has since hired a D2C coordinator and continues to re-visit their approach.All three trial sites highlighted the need to include procedures to update OOC definitions based on application of evolving epidemiology and updated clinical guidelines and practices. Since CoRECT concluded, there were also the changes in health care delivery and access related to the COVID-19 pandemic that will certainly have impacts on how we ascertain whether someone is truly OOC and might need assistance.Staffing significantly impacts program sustainability, through turnover, maintenance of institutional knowledge and relationships, leadership, or existing organizational structure. PDPH and MDPH retained/sustained the field, surveillance, and D2C data management positions involved in CoRECT. Furthermore, PDPH was able to expand the number of dedicated D2C staff through the Field Services Program with new funding from the state of Pennsylvania. CTDPH were unable to retain their CoRECT-specific field staff and YSM project management staff; however, as part of an ongoing reorganization plan, they have included new internal positions such as a Data to Care Coordinator.Even with the expertise and other resources offered by an external academic partner for project management, such as with CTDPH, long-term sustainability due to sub-optimal infrastructure development is challenging. However, one advantage of having an academic partner is the ability to create post-hoc analyses and publish in peer-reviewed journals . OutsideTo our knowledge, CoRECT was the first prospective RCT to implement and assess the use of a D2C strategy accompanied by an intervention component for re-engaging newly OOC PWH , 11, 23.Utilization of the EPIS framework retrospectively was well-suited for this assessment given its emphasis on implementation, as well as initial planning and long-term sustainability. EPIS allowed us to explore pre-defined contextual factors across both jurisdiction and stage and enabled a more nuanced understanding of the complex interplay between the intervention, the stakeholders involved, and larger socio-ecological considerations. This provided valuable insights into challenges and facilitators as well as future D2C delivery and sustainability.Each trial site approached CoRECT grounded in their own context and informed by a multitude of factors including prior D2C experience, data management infrastructure, staffing capacity and roles relative to HIV patient recruitment navigation, and relationships with healthcare clinic partners. While CoRECT was a research study funded by the CDC, retrospective analysis using the EPIS framework, including the preparation and implementation components, highlighted the critical role of “ownership” of the D2C initiative by the health departments from the standpoint of leadership and organizational infrastructure. The approaches taken by PDPH and MDPH emphasized internal investment by using DPH HIV surveillance staff, building new processes to support OOC re-engagement, and incorporating OOC re-engagement activities of field staff into the existing health department organizational structure and processes. Although PDPH had prior D2C experience with a data exchange process, the pilot study proved to be extremely helpful in soliciting feedback from their CoRECT team and clinical collaborators to craft the full-scale field intervention and fine-tune their D2C process. This initial prioritization in the exploratory and preparation phases facilitated the development of a more sustainable intervention, which was further supported by the creation of an intraorganizational HIV-specific Field Services Program and leveraging other funding sources. MDPH incorporated lessons learned from prior D2C experience and through experience with routine HIV patient navigation to leverage existing infrastructure for data sharing and incorporated case assignments into existing field staff’s workflow. This sustainability focused approach allowed MDPH to continue some aspects of the CoRECT intervention after conclusion of the CoRECT study.In contrast, CTDPH lacked prior D2C experience but prior research efforts and a commitment to principles inherent in D2C led them to partner with an academic institution, YSM. Newly created processes and infrastructure including hiring of dedicated CoRECT field staff through local health departments aided in the successful implementation of CoRECT, however, they negatively impacted sustainability because the YSM and field staff were outside of the CTDPH structure. Fortunately, the CTDPH was able to identify ways to address future D2C activities including the use of pilot testing, centralizing DIS activities within the CTDPH, designating a D2C coordinator, and including field and healthcare clinic staff in discussion regarding long-term feasibility.A fundamental principle that emerged was adaptability, specifically the importance of being able to modify the procedures because there is no one-size-fits-all approach to designing/implementing a D2C project given the variability in target populations, health department characteristics/structure, and participating clinic characteristics. This was particularly critical given the changing clinical standards of care, evolving public health approaches such as integrated data systems, and updated goals of the National HIV/AIDS Strategy and Ending the HIV Epidemic initiatives . AdaptabChallenges identified during this assessment, including those related to leadership, staffing and turnover; evolving clinical practices regarding OOC definitions; sustainability of community and academic partnerships, fidelity monitoring and data management discrepancies, and inconsistent buy-in, underscore the importance of evaluation and integration steps throughout the process. While many of these challenges were addressed through prioritization of establishing standardized protocols, streamlined communication, consistent training practices, and clear expectations, flexible strategies that can accommodate changes within public health and clinical settings remain paramount for continued D2C evolution as it is refined in new contexts.This retrospective assessment not only provides an overview of each trial site’s approach to the CoRECT intervention and the implementation process, but also provides some key take-aways, which may prove useful for those interested in developing and implementing their own D2C activities. We would like to highlight the following key principles as a guidance for health departments considering implementing or enhancing similar activities.Tailor D2C structures and activities to the jurisdictional needs based on their unique characteristics in order to be effective across varying contexts.Develop appropriate and sufficient technical and staffing infrastructure to enable the use of multiple different sources of data to supplement surveillance data  even as integrated data platforms continue to be explored.Appoint a health department “champion” for D2C who will serve as the internal point person for health department staff and clinic personnel. Ideally, the “champion” will have extensive HIV experience and existing relationships with the clinics, including knowledge of their patient population and data.Create follow-up and outreach activities by health department personnel that are feasible and sustainable within the jurisdiction’s capacity, organization, and infrastructure.Include stakeholders representing core functions/components  in the early stages of the intervention design process. This could entail the implementation of a pilot study to allow for feedback to address challenges prior to initiating the full intervention.Create ongoing and regular opportunities, such as project status meetings, for health department and clinic staff to provide feedback regarding barriers/challenges that have been identified. These meetings can also serve to maintain good intra- and interorganizational communications and serve as learning collaboratives.Build flexibility into all components of the activities, including, but not limited to the case reconciliation process , OOC definitions, and have the flexibility to align/respond to organizational capacity, infrastructure, and operational efficiencies.Develop and incorporate the administration of D2C data sharing/management and follow-up activities within the existing health department organizational structure. This may include establishing and supporting cross department/division engagement .Use a structured format for case conferences to review cases with clinic staff in a timely and efficient manner.Develop and document written procedures and fidelity processes early in the implementation process to ensure consistent implementation and accommodate for changes in health department and clinic staff and organization. Apply standardized procedures that can be periodically revisited to ensure they remain maximally responsive to environmental and contextual factors, so interruption in activities can be kept to a minimum.Monitor changes in guideline implementation, clinical practices, and standards of care to make timely updates to D2C OOC case identification algorithms and follow-up activities as necessary.Organize regular training and educational opportunities to sustain the D2C activities for health department and clinic staff.A limitation of this evaluation was the inability to obtain comprehensive feedback on the implementation process from field and clinic staff due to staff turnover. Future evaluation projects could address this by collecting feedback prospectively during the four EPIS framework stages. There were several strengths including a comprehensive appraisal of comparing the implementation processes across three CoRECT sites in a structured format and generate lessons learned for future D2C activities. By combining all three sites into a single evaluation, lessons learned are more robust, nuanced, and useful for future implementation.In conclusion, we found that while the CoRECT study framework successfully provided a general blueprint for health departments to implement a D2C intervention for improving re-engagement in HIV care, it is important for jurisdictions to customize it based on their own needs and evolving practices. The lessons learned in the exploratory, preparation, implementation, and sustainment phases of implementation by CTDPH/YSM, PDPH, and MDPH provide initial starting points and critical aspects that are critical for leadership to consider when implementing D2C.The original contributions presented in the study are included in the article/HE led the review and the writing processes. SGL assisted with major draft revisions and provided site specific information. BJ, KR, BG, and MB provided site specific information and assisted in the editing process. MV, KAB, AD, and LR contributed to the concept, site specific information. FLA provided guidance in the use of implementation frameworks. All authors contributed to the article and approved the submitted version.


Approximately 25% of facility births take place in private health facilities. Recent national studies of maternal and newborn health (MNH) service availability and quality have focused solely on the status of public sector facilities, leaving a striking gap in information on the quality of maternal and newborn care services.A rapid cross-sectional assessment was conducted in November 2022 to assess the quality of MNH services at private hospitals in Iraq. Multi-stage sampling was used to select 15% of the country’s 164 private hospitals. Assessment tools included a facility assessment checklist, a structured health worker interview tool, and a structured client exit interview tool. Data collection was conducted using KoboToolbox software on Android tablets, and analysis conducted using SPSS v28.All hospitals visited provided MNH services and had skilled personnel present or on-call 24 h/day, 7 days/week. Most births (88%) documented between January and June 2022 were cesarean births. Findings indicate that nearly all hospitals have the human resources, equipment, medicines and supplies necessary for quality antenatal, intrapartum and early essential newborn care, and many are also equipped with special units and resources needed to care for small and sick babies. However, while resources are in place for basic and advanced care, there are gaps in knowledge and practice of high-impact interventions that require few or no resources to perform, including skin-to-skin thermal care and support for early initiation of breastfeeding. Person-centered maternity care scores suggest that private hospitals offer a positive experience of care for all clients, however there is room for improvement in provider–client communication.This assessment highlights the need for deeper dives into factors that underly decisions about how and where to give birth, and both understanding and practice of early essential newborn care and pre-discharge examinations and counseling at private healthcare facilities in Iraq. Engaging private health facility staff in efforts to monitor and improve the quality of maternal and newborn care, with a focus on early essential newborn care and provider–client communication for all clients, will ensure that women and newborns benefit from the best care possible with available resources. The Ministry of Health of Iraq recognizes that the health of women and children is key to progress on all development goals, and has committed to improving equity of access to quality maternal and newborn care services in an effort to reach global targets for maternal and neonatal mortality and stillbirth reduction by 2030 , 2. The Lancet Global Health Commission on High Quality Health Systems, which called for a better understanding of the dimension of quality for health systems in resource-limited settings, lays out compelling evidence that merely accessing or reaching the doorstep of a healthcare system does not equate to or ensure receipt of high-quality care [The ity care . Similarity care , 6. A reity care . Howeverity care , 9.Several countries, including Iraq (an upper-middle-income country in the Middle East), have seen a rapidly expanding private sector involved in the delivery and acceptance of basic health services over the past decade , 11. A sIn Iraq, there are 164 private hospitals distributed throughout the country; roughly two thirds (106) are located in the capital city of Baghdad and the Kurdistan Region of Iraq (KRI) and the remaining third across the other 15 governorates in the country . HoweverWhile the Ministry of Health’s private sector department must authorize private hospitals before they may set up maternal and newborn health units and services, there is no routinized audit or oversight of the quality of care offered in private hospitals and no uniform criteria for monitoring this. Currently private hospitals are only required to report to the Ministry of Health on the number of births occurring on site each month, disaggregated by spontaneous vaginal births and cesarean births. In 2021, the Ministry of Health reported that cesareans account for 35% of births in public facilities and over 80% in private facilities . There aIn order to understand the contribution of the private sector to universal health coverage and progress towards targets for maternal and newborn mortality reduction in Iraq, a better understanding of the private sector’s involvement in delivering maternal and newborn health care is needed.Demographic and Health Surveys (DHS) Program Service Provision Assessment which was revised in 2022 to better capture structures and processes required for quality maternal and newborn health service provision (https://www.dhsprogram.com/Methodology/Survey-Types/SPA.cfm). Where content on priority topics in Iraq’s National Reproductive, Maternal, Neonatal, Child and Adolescent Health Strategy were lacking, namely management of select obstetric complications and small and sick newborn care, additional content was added from the Averting Maternal Death and Disability EmONC Assessment Toolkit (2015)  and NEST360/UNICEF Health Facility Assessment Toolkit (2021) (https://nest360.org/project/hfa/).A rapid cross-sectional assessment was conducted in November 2022 to assess the quality of maternal and newborn health services at private hospitals in Iraq. Assessment tools included a health facility inventory and document review checklist (Tool 1), a structured health worker interview tool (Tool 2), and a structured client exit interview tool (Tool 3). Tools were adapted from the n = 24) of the private hospitals in the country was determined to be sufficient to allow the assessment team to measure indicators of interest (such as the proportion of facilities with equipment and supplies necessary for routine intrapartum and newborn care) with ± 15% precision, 95% confidence and 80% power. A multi-stage sampling strategy was used to select hospitals for participation in this assessment. First, governorates in Iraq were stratified into three regions: north (KRI), central and south. Next, two to three governorates in each region were purposively selected in consultation with representatives of the Ministry of Health of Iraq and Ministry of Health in KRI. Selected governorates included Erbil and Sulaymaniyah (KRI), Baghdad, Karbala, and Salahaddin , and Thi-Qar and Basra (south). Finally, a sample proportional to the distribution of hospitals across these governorates was randomly selected using SPSS v28.Assuming a minimum of 85% of health facilities meet national maternal and newborn health quality standards, a sample of 15% , interview up to four health workers responsible for maternal and newborn care (Tool 2), and interview up to four women being discharged after childbirth. Teams were instructed that health worker interviews should include a mix of doctors, midwives and nurses (depending on staffing at the facility), and where possible postpartum exit interviews should include a mix of women with spontaneous vaginal delivery and cesarean birth.All data collection was conducted using KoboToolbox software on Android tablets. Interviews were primarily conducted in Arabic at facilities in central and southern Iraq, and in Kurdish in KRI. Following completion of all assessments, data were exported from KoboToolbox and analyzed using SPSS v28. Analysis included descriptive statistics, and calculation of person-centered maternity care score using a 13-item scale developed by Afulani et al. to measure experience of care .The assessment protocol was reviewed and endorsed by the Ministry of Health of Iraq and Ministry of Health in the Kurdistan Region of Iraq, and approved by the Kurdistan Higher Council of Medical Specialties Research Protocol Ethics Committee .All 24 selected private hospitals agreed to participate in the assessment, resulting in a total of 24 health facility inventory and record review checklists completed, 92 interviews with skilled health personnel responsible for intrapartum care, and 93 postpartum client exit interviews including 22 (24%) with spontaneous vaginal births and 71 (76%) with cesarean births.n = 13) allow birth companions to be present during labor and delivery for vaginal births. Of the 24 private hospitals visited, 96% (n = 23) perform both spontaneous vaginal births and elective cesarean births. Only one facility reported only performing elective cesareans. The vast majority (88%) of births documented between January and June 2022 were cesarean sections. During this period, these hospitals recorded an average of 23 spontaneous vaginal births per month (range 0–155) and 152 cesarean births (range 10–818) per month.All private hospitals visited provided maternal and newborn health services and had skilled health personnel present at the facility at all times or officially on call 24 h/day, 7 days/week in case of emergencies. Approximately half of the hospitals visited  reported keeping mothers and babies together (rooming-in) after birth, which is a WHO-recommended evidence-based practice for all mother/baby dyads without complications, including after cesarean births.On average, hospitals had two delivery rooms and six operating theaters. All supporting spontaneous vaginal births had a newborn corner in the delivery room, and all 24 hospitals had special units for care of small and sick newborns. Only 42% (n = 17) had a fetal stethoscope for monitoring of fetal well-being  facilities. However, only 71%  have a designated focal person for managing referral communications and only 67% (n = 16) have emergency transport available.Approximately two-thirds of hospitals visited report receiving patients referred in from other facilities, and also referring out patients with obstetric and/or newborn complications. Of the 24 facilities visited, only 38% (n = 19) indicated that they have standard operating procedures for reporting maternal deaths, and approximately two-thirds  indicated that they have procedures for reporting perinatal or newborn deaths. Although nearly all facilities  were able to produce data on the number of births in the first six months on 2022, fewer  stated that they regularly compile reports on maternal and newborn health services. Only 42% of facilities (n = 10) reported having a functional mechanism for recording and sharing outcomes of cases referred in and out. The number of facilities able to share data on other key maternal and newborn health indicators varied, as shown below  work in multiple facilities and approximately half  are dual practitioners working in both public and private sector facilities, it is fair to assume that investments in quality improvement are needed across the entire health system. As a rapid assessment conducted to provide the Ministry of Health with initial insights on quality of health services at private hospitals with limited government oversight, this study has a number of limitations. First, the sample size was limited to the most precise estimate feasible within practical resource and time constraints; a larger sample of health facilities would have allowed for more precise estimates of resource availability. Sample size and power calculations were used to ensure a representative sample of health facilities, not necessarily of health workers or clients giving birth at facilities. A more robust study powered to provide a statistically representative assessment of health worker knowledge and behaviors, as well as of client experiences of care, would provide greater certainty in identification of areas of concern. Additionally, Afulani et al.’s person-centered maternity scale incorporated in Demographic and Health Surveys (DHS) Program Service Provision Assessment was created and validated for interviews of women with vaginal births; it has not yet been validated for cesarean births where there may be additional factors to consider. Finally, there are also risks of response or courtesy bias that should be considered in interpretation of results. Data collectors were identified as being affiliated with the Ministry of Health, which may have biased participant responses. Client exit interviews were conducted on site around the time of discharge, which also may have biased responses if participants felt information provided could affect care for themselves or their families. These limitations notwithstanding, this study is an important first step in closing the gap in information on quality of maternal and newborn care in Iraq, particularly in the context of a continually expanding private healthcare sector and rising cesarean rates.This rapid assessment provides a snapshot of the quality of maternal and newborn care services at a representative sample of private hospitals in Iraq in late 2022. Overall, findings indicate that nearly all private hospitals have the human resources, equipment, medicines and supplies necessary for quality intrapartum care and early essential newborn care, and many are also equipped with special units and resources needed to care for small and sick babies. However, while resources are in place for basic and advanced care, there are apparent gaps in knowledge and practice of high-impact interventions that require little to no resources to perform, including skin-to-skin thermal care and support for early initiation of breastfeeding. Considering nearly all health workers interviewed (91%, Concerns about quality of care and maternal and newborn outcomes, including breastfeeding initiation and support, in settings with rising cesarean birth rates are not unique to Iraq , 21. CesIn this context, reducing the practice of non-medically indicated cesareans has proven challenging, but there is substantial evidence that introduction of action-oriented monitoring strategies and systems to evaluate trends in cesarean rates, care practices and outcomes have identified opportunities to improve quality of care for mothers and newborns , 26. OthAlthough research on drivers of cesarean rates and quality of care for mothers and newborns after cesarean births in Iraq is relatively scarce, concerns about the potential contribution of the expansion of the private healthcare sector to increasing cesarean rates and impacts on breastfeeding rates and health outcomes have been documented for over a decade , 30. ThiCooperation of national and subnational Ministry of Health authorities as well as all selected private hospitals in this assessment is a signal of both government and private sector interests in collaborating to ensure women and children receive quality care. Establishing a policy framework to promote public–private partnership and engaging private health facility staff in efforts to monitor and improve the quality of maternal and newborn care, with a focus on early essential newborn care and provider–client communication for all clients, will ensure that women and newborns benefit from the best care possible with available resources.