A literature review supports integrating vaccine-preventable diseases (VPDs) into broader communicable disease surveillance systems in Western Pacific Region countries while ensuring that the minimal World Health Organization–recommended standards for VPD surveillance are met. We document factors that influenced integrating surveillance functions for vaccine-preventable diseases (VPDs) and other communicable diseases in the Western Pacific Region (WPR).Barriers included insufficient coordination within the public and private sectors, inadequate engagement of national Expanded Program on Immunization programs, lack of surveillance and laboratory capacity, inability to link epidemiologic and laboratory data, and suboptimal scope and design of surveillance systems for achieving control and elimination goals.Best practices and innovations included developing guidelines for integrated VPD surveillance, standardizing processes for laboratory surveillance and testing of multiple VPDs, using multiplex testing for multiple diseases, and conducting joint epidemiology and laboratory surveillance data review meetings.National WPR stakeholders should consider (1) using the outcomes of this review to inform country implementation plans and (2) developing legal frameworks, guidance documents, and coordination mechanisms for reporting and investigation of cases and clusters of VPDs and other non-VPDs of public health importance.Public health program managers should consider opportunities for surveillance integration, such as in workforce and laboratory capacity, and information systems and data management. A strategic framework for 2021–2030 developed by the World Health Organization (WHO) Regional Office for the Western Pacific emphasizes the need for high-quality and integrated vaccine-preventable disease (VPD) surveillance. We conducted a literature review to document the barriers, enabling factors, and innovations for integrating surveillance functions for VPDs and other communicable diseases in Western Pacific Region (WPR) countries.We searched published and gray literature on integrated VPD surveillance from 2000 to 2021. Articles in English, Spanish, or French were screened to identify those relating to VPD surveillance in a WPR country and not meeting defined exclusion criteria. We categorized articles using the 8 WHO surveillance support functions and abstracted data on the country; type of surveillance; and reported barriers, enabling factors, and best practices for integration.Of the 3,137 references screened, 87 met the eligibility criteria. Of the 8 surveillance support functions, the proportion of references that reported integration related to the laboratory was 56%, followed by workforce capacity (54%), governance (51%), data management and use (47%), field logistics and communication (47%), coordination (15%), program management (13%), and supervision (9%). Several references noted fragmented systems and a lack of coordination between units as barriers to integration, highlighting the importance of engagement across public health units and between the public and private sectors. The literature also indicated a need for interoperable information systems and revealed the use of promising new technologies for data reporting and laboratory testing. In some WPR countries, workforce capacity was strengthened at all administrative levels by the implementation of integrated trainings on data monitoring and use and on laboratory techniques applicable to multiple VPDs.This literature review supports integrating VPDs into broader communicable disease surveillance systems in WPR countries while ensuring that the minimal WHO-recommended standards for VPD surveillance are met. Globally, most countries have national case-based surveillance for polio, measles, and neonatal tetanus. Some countries may also have sentinel site case-based surveillance for 1 or more of these diseases. For both types of disease-specific, case-based surveillance systems, standard components of surveillance include detection, notification, investigation, and laboratory confirmation of suspected cases, within a defined surveillance area. In parallel, countries may also have aggregate weekly reporting of nationally notifiable diseases, and in some cases, event-based surveillance to capture reports from the community and media.Recently, national governments adopted the World Health Organization (WHO) Immunization Agenda 2021–2030, which includes as a core principle using reliable and timely data to track progress, drive improvements in performance, and underpin decision making at all levels of the program.Many countries in the Western Pacific Region (WPR) conduct VPD surveillance using both disease-specific and integrated systems. A prominent example of the latter are the early warning and response systems originally designed for outbreak detection in emergency settings,Many WPR countries conduct VPD surveillance using both disease-specific and integrated systems.To support the implementation of the regional strategic framework, we conducted a literature review to document the barriers, enabling factors, and best practices including innovations for integrating surveillance functions for different VPDs and other communicable diseases in WPR countries.Supplement Table S1). The first search included terms combined with Boolean operators AND and OR relating to “vaccine preventable disease” or “vaccine preventable infection” or “vaccine preventable illness” and “surveillance” and “integrate” or “expand” or “comprehensive” or “link.” The second search included search terms relating to “syndromic surveillance” or “disease surveillance” or “outbreak surveillance.” Both searches were limited to the years 2000–2021 and conducted only in English. Additionally, key VPD surveillance staff from the WPRO, the WHO Headquarters, and the U.S. Centers for Disease Control and Prevention were consulted to provide any references relevant to this topic. Gray literature was included in the review using the definition by the Cochrane Handbook for Systematic Reviews of Interven-tions.Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines,Haemophilus influenzae type b, hepatitis A, hepatitis B, human papillomavirus, influenza, Japanese encephalitis, measles, meningococcus, mumps, tetanus, pertussis, pneumococcus, polio, rotavirus, rubella, typhoid, varicella, and yellow fever; (4) consisted only of an analytical study , not describing the surveillance system; (5) focused only on surveillance of adverse events following immunization; (6) language of the article other than English, Spanish, or French. We used the definition of integration provided by the Global Strategy on Comprehensive Vaccine-Preventable Disease Surveillance to determine the eligibility of references.Two reviewers independently screened titles and abstracts from the references, assessed the abstracts and the full-text articles for eligibility, and abstracted articles of the first literature search from 2000 to 2019; 1 reviewer screened and abstracted the first literature search references from 2019 to 2021 and the whole of the second literature search. The following exclusion criteria were used: (1) did not include individual or multicountry experience from any country of the WPR; (2) did not focus on human disease ; (3) did not include VPD surveillance, where VPDs are defined as cholera, congenital rubella syndrome, diphtheria, We categorized the areas of reported integration using the WHO-defined VPD surveillance support functions .2 For exWe categorized the areas of reported integration using the WHO-defined VPD surveillance support functions.,–Supplement Table S2). In terms of the type of surveillance described, 66 (76%) of the 87 references reported on integrated systems that included case-based surveillance while the rest included aggregate or event-based surveillance. Supplement Table S3 summarizes the 87 included references.The searches identified a total of 4,471 references from the first search and 680 references from the second search . After rOf the 8 surveillance support functions, the areas of reported integration related to laboratory (56%), followed by workforce capacity (54%), governance (51%), data management and use (47%), field logistics and communication (47%), coordination (15%), program management (13%), and supervision (9%) . We reviLaboratory confirmation is an important complement to epidemiological surveillance, especially in elimination settings, where confirmation of suspected syndromic cases is needed, as well as molecular typing of VPDs in every suspected case.Issues with domestic public health laboratory capacity were reported in several countries, inhibiting timely outbreak detection.,Due to demand, over the last decade, the laboratory networks in the region, the WPRO, and other partners, such as Japan International Cooperation Agency, have implemented integrated trainings on laboratory techniques  applicable to multiple VPDs, while strengthening quality assurance of laboratories.,,,,The use of multiplex tests on the same sample makes widespread laboratory confirmation of VPDs a more attainable goal while facilitating integration of syndromic surveillance.A pilot study of measles rapid diagnostic test use as part of the Malaysia surveillance program showed promising results for timely public health response while enabling virologic surveillance.Public health surveillance can be a challenge in underresourced and understaffed settings. The high turnover of surveillance staff was reported as a major issue in operationalizing integrated surveillance that includes VPDs in Cambodia,Preservice and on-the-job trainings of the surveillance workforce are key to ensuring guidelines are adequately implemented.,,,,,,,Inadequate knowledge among personnel in the Philippines, Vietnam, Malaysia, and China complicated reporting mechanisms, contributing to the underreporting of cases.Implemented in Lao PDR, the global data analysis and use training program called Stop Transmission of Polio Immunization and Surveillance Data Specialists, enabled building capacity on the management, analysis, and use of immunization and VPD surveillance data among the workforce at the subnational levels.,,,,,Different models of organizing and managing VPD surveillance impact its functionality . In case,,A challenge in multiple countries of the region is the insufficient role of the private sector in disease surveillance. The role of private practitioners in routine disease surveillance was found to be low in the Philippines, Vietnam, Malaysia, China, and Mongolia.,,Barriers to integration include parallel guidelines or a lack of guidance for surveillance and outbreak response. Reviews of VPD surveillance systems in Cambodia, Lao PDR, and Vietnam highlighted the need to develop VPD-specific guidelines to improve the quality of VPD case-based surveillance.,,Engagement with key political partners is needed to ensure that any new surveillance systems do not conflict with existing priorities and that the systems are country-owned.,Integrated information systems including different VPDs should be designed based on EPI user requirements and local context . The useExamples of surveillance data use for program decision making include the Solomon Islands’ target response to the 2016 dengue outbreak.,,–Logistical barriers to surveillance implementation were reported as inhibiting factors to timely outbreak detection in several countries/areas, including the Pacific islands.A new syndromic surveillance system should be integrated into existing reporting pathways and build on existing infrastructure.Promoting timely data analysis and sharing of information through bulletins or reports targeting different audiences can help strengthen surveillance systems, data collection, and analysis.The lack of coordination between the surveillance units that include VPDs can create redundancy and overlap.In many WPR countries, surveillance, outbreak investigation, and response are coordinated through an emergency operations center. Comprising senior-level MOH staff, provincial health authorities, local nongovernmental organizations, and development partners, the emergency operations center is instrumental to the country’s capacity to manage outbreaks.,,A reported barrier to integration is the lack of adequate domestic funding to sustain high-quality surveillance systems.To continue efforts toward strengthening VPD surveillance systems, governments of Lao PDR, the Philippines, Vietnam, Mongolia, Cambodia, Malaysia, Fiji, and PNG have requested external VPD surveillance assessments and reviews.,,Ongoing supervision was recommended to strengthen the surveillance workforce capacity in several countries including Lao PDR and Vietnam.Significant progress has been made toward the quality and sustainability of VPD surveillance systems in WPR countries, especially for diseases with eradication and elimination goals. Fifty percent of WPR countries have included all or some VPDs in an integrated surveillance system.Any approach to integrated VPD surveillance must be flexible and able to respond to local conditions.The literature review identified regional best practices, innovations, and pervasive challenges with laboratory, workforce capacity, governance, data management and use, and field logistics and communication. Issues related to coordination, program management, and supervision were reported to a lesser extent. Reported challenges in surveillance illustrate the need for improving efficiencies in resource utilization and strengthening integration of surveillance support functions at every level.Improving laboratory capacity through standardized test procedures, quality control, and integrated trainings is critical for successful implementation of an integrated system. The increasing availability of multiplex and rapid diagnostic testing kits offers the potential to address testing capacity constraints in limited-resource and remote settings.Reporting facilities and their staff are essential to any surveillance system. VPD surveillance workforce needs should be addressed at all administrative levels as part of national human resource planning. Implementing surveillance systems successfully requires a workforce adequately trained on case definition, detection, notification, and reporting. A systematic review by Rowe et al. highlighted that additional improvements in health care provider performance and the quality of health care in low- and middle-income countries occur when trainings are combined with other components, such as supervision, problem-solving, and mentoring programs instead of training alone.One critical requirement for a successful integrated VPD surveillance system is leadership convening stakeholders from different departments, including epidemiologists, microbiologists, and other key groups and sectors.The design of surveillance information systems should be aligned with the required elements for use by decision makers.The literature search retrieved more than 5,000 references following a search strategy that included terms related to “integration,” whereas more than 20,000 references were retrieved without specifying these terms. Our use of the former search strategy may have limited the retrieval of articles describing innovations and best practices for disease-specific surveillance systems that might be applied to comprehensive VPD surveillance. Differential yields between published and gray literature for information on some of the support functions, especially program management and supervision, were observed. Publication bias may also have affected the robustness of our findings. However, our findings were supplemented with published and gray literature from VPD surveillance experts at WHO WPRO, the WHO Headquarters, and the U.S. Centers for Disease Control and Prevention. Gray literature provided important perspectives that may not be captured in published sources alone; however, some did not describe the methods used, and by nature, they were not peer reviewed. The screening and the analysis of the references on syndromic surveillance were done by 1 reviewer. Although extra checks were performed to improve the analysis and all results were discussed by the research team, some bias may have resulted. Additionally, our review methods were limited to a desk review of published and gray literature from 2000 to 2021. It would benefit from a review focused on the most recent literature on coronavirus disease (COVID-19) integration into existing surveillance systems as well as an in-depth, field-based review of program operations at the national and subnational levels.VPD surveillance can be strengthened in the WPR and resources can be optimized by bolstering the support functions and further integration of VPDs and other diseases as part of a comprehensive health systems approach. Opportunities exist for integration, such as in the functions of surveillance workforce, laboratory capacity, and information systems and data management. The integration of VPDs into broader communicable disease surveillance systems is further encouraged while ensuring that the minimal WHO-recommended standards for VPD surveillance are met. The development of legal frameworks, guidance documents, and coordination mechanisms are critical to enable complete and timely reporting and investigation of VPD cases and clusters. The outcomes of this review could inform WPR country implementation plans, following the endorsement of the Regional Strategic Framework for Vaccine-Preventable Diseases and Immunization in the Western Pacific 2021–2030.


Introduction-With the high global prevalence of prostate cancer and associated mortalities, it is important to enhance current clinical practices for better prostate cancer outcomes. The current review is towards understanding the value of Zn towards this mission. Method-General information on Zn in biology and multiple aspects of Zn involvement in prostate health and disease were referred to in PubMed. Results-The most influential feature of Zn towards prostate health is its ability to retain sufficient citrate levels for a healthy prostate. Zn deficiencies were recorded in serum, hair, and prostate tissue of men with prostate cancer compared to non-cancer controls. Zn gut absorption, albumin binding, and storage compete with various factors. There are multiple associations of Zn cellular influx and efflux transporters, Zn finger proteins, matrix metalloproteinases, and Zn signaling with prostate cancer outcomes. Such Zn marker variations associated with prostate cancer recorded from biological matrices may improve algorithms for prostate cancer screening, prognosis, and management when coupled with standard clinical practices. Discussion-The influence of Zn in prostatic health and disease is multidimensional, therefore more personalized Zn requirements may be beneficial. Several opportunities exist to utilize and improve understanding of Zn associations with prostate health and disease. Global cancer statistics show that prostate cancer is the second most common cancer type and the fifth leading cause of cancer mortality in men . GreaterExcessive dietary intakes as in the Westernized diets however produce imbalanced levels of reactive oxygen species (ROS), reactive nitrogen species (RNS), and lipid oxidation (LOX) moieties causing damage to biomolecules, especially when insufficiently counteracted through the action of antioxidant systems . Alongsiaconitase (mACO2) and prostate; citrate and prostate; Zn absorption from gut and circulation in the blood and competition for albumin binding sites; Zn cellular and sub-cellular transporters, Zn influx transporters, and Zn efflux transporters; Zn storage in metallothionines and competition for binding sites; Zn regulation of matrix metalloproteinases and effects on prostate cancer; Zn finger proteins and effects on prostate; Zn signaling and prostate health; involvement of Zn in prostate associated proteins (prostate-specific antigen (PSA), prostate secretory protein of 94 amino acids (PSP94) also known as β-microseminoprotein, the unique human-specific transmembrane metalloprotease prostate-specific membrane antigen (PSMA) and prostatic acid phosphatase); single nucleotide polymorphisms (SNPs) of genes encoding Zn associated proteins or Zn interacting trace element associated proteins; Zn supplementation effects; interaction with other trace minerals, demographic, lifestyle and comorbidity effects; transgender women and prostate cancer; and Zn dependent technologies associated with prostate cancer.General information on Zn in biology and multiple aspects of prostate health and disease associations with Zn were referred to in PubMed articles and references therein. For some comparisons, the Zn association in breast cancer and work involving prostate cell lines and animal models were also reviewed. The selection of articles had no publication time limitation and therefore historical articles to the most recent up to November 2022 were reviewed. Search features included serum Zn levels and prostate cancer; tissue Zn levels, distribution, and prostate cancer; mitochondrial The human genome encodes over 2800–3000 Zn proteins, representing approximately 10% of the human proteome ,8. Zn is2+ ions and are capable of releasing them under oxidative stress conditions )Although this review cannot support a ‘one size fits all’ solution for optimal Zn intakes for prostate health, the evidence may be useful in multiple directions for prostate cancer prevention, diagnosis, prognoses, and treatment events alongside standard clinical practices. Level of serum Zn may be useful alongside other factors such as genetics, demographic and lifestyle, comorbidities, family history of cancer, previous biopsy details, and interacting trace element profiles for developing algorithms to improve the efficiency of current prostate cancer screening marker PSA or more effective methods such as PHI, and mpMRI PI-RADS score ,208,209.SLC30A8 gene encoding this protein [The Zn efflux transporter ZnT8 is known for the specific transport of Zn to insulin secretory granules of the pancreatic β cells for the required release of insulin . Galvez- protein . In a st protein . Therefo protein ,130.According to Costello and Franklin 2006, Zn content in a prostatic fluid is 8000–10,000 nmol/g . ProstatIt may be beneficial to understand the levels of elements in biological matrices that will interact with Zn and suppress the Zn supply needed for prostate health including Cd and those elements which are components of a battery of antioxidant enzymes  that have to act in harmony towards free radical removal ,181,182.Developing imaging methods may be the future non-invasive means of understanding Zn tissue distribution in the prostate ,189 thatSome aspects of Zn’s involvement in prostate health and disease are not yet known. For example, although IMA levels are implicated in many cancers including prostate cancer , the intThe influence of Zn on prostatic health is multidimensional. Due to various factors influencing Zn bioavailability and transport to the prostate, algorithms toward more personalized Zn requirements have not yet been achieved other than the Zn RDA. Optimizing the ingested Zn for prostate and general health can be achieved with lifestyle modifications and health. However, there are multiple opportunities to utilize and improve the understanding of Zn associations with prostate health and disease.


The American Association of Pharmaceutical Scientists (AAPS) Chemistry, Manufacturing, and Controls (CMC) Community hosted two virtual panel discussions focusing on several novel regulatory review pathways for innovative oncology products: Real-Time Oncology Review (RTOR), Project Orbis, and the Product Quality Assessment Aid (PQAAid). The panel sessions were held on August 27, 2021, for the discussion of RTOR, and January 21, 2022, for the discussion of Project Orbis and the PQAAid. Both panel sessions included representatives from the US Food and Drug Administration (FDA) and subject matter experts from the pharmaceutical and biotechnology industries, with the aim of facilitating knowledge sharing on CMC-specific advantages, challenges, eligibility criteria for participation, and operational modifications instituted through the utilization of these acceleration initiatives. Key topics included managing cross-regional regulatory CMC requirements, adapting to expedited development timelines, coordinating interactions between health authorities and industry, and potential opportunities for future improvement and expansion of these programs. As RTOR, Project Orbis, and PQAAid are relatively new initiatives, the experiences shared by the panel experts are valuable for providing deeper insight into these new regulatory pathways and processes. Patients with critical illnesses around the world rely on timely access to safe and effective therapeutics. For many complex and serious disease states, patients are adversely impacted by long development timelines that impede the availability of new drugs. Within the past decade, clinical development processes for innovator products have taken an average of 9.1 years to advance from initial clinical development to marketing approval in the USA  has leveraged the Oncology Center of Excellence (OCE) to establish new, unique regulatory acceleration and collaboration programs aimed at promoting regulatory efficiency  Community Virtual Panel Discussions focusing on RTOR and Project Orbis, held on August 27, 2021, and January 21, 2022, respectively. Both sessions featured speaker panels comprised of industry and FDA expert speakers who provided insights into their perspectives on the benefits and challenges of these new regulatory initiatives.Expert panelists, Xiao Hong Chen (US FDA) and Yiwei Li (US FDA), provided an overview of the RTOR program, its applicability to CMC data, and the involvement of the Product Quality Review Team. RTOR began as a pilot program in 2018, with the aim of facilitating early submission of key safety and efficacy data for oncology programs to allow regulators to initiate the review sooner than typically possible, particularly for cancer therapeutics of clinical significance that represent an improvement to the standard of care.Under the current regulatory submission and review paradigm, sponsors submit a complete regulatory dossier containing all required modules and data once all materials are available. However, assembling a major regulatory filing often requires several months for sponsors to collate and finalize all components due to the extensive quantity of data and information required. The investigational drugs under the current “Fast Track” program are allowed to be submitted containing individual modules in a rolling submission. However, each submitted module should contain all required information. Using RTOR, regulatory documents can be submitted asynchronously in waves, as they are finalized, in “split” or partial modules. This change in submission cadence enables FDA reviewers to initiate the review process at an earlier timepoint and to distribute the workload more efficiently over time.While the RTOR pilot was originally positioned to include only clinical data to support efficacy supplements, the program later expanded to support applications for new molecular entities, including CMC data. As of July 2021, there were 29 supplements and 10 new molecular entity (NME) applications approved using RTOR. Participation in RTOR is conducted on a voluntary basis and can be initiated by either sponsor or FDA request. Eligibility and acceptance are based on clinical considerations and discussion between the sponsor and Agency. Inclusion in the RTOR program does not influence or guarantee approval or impact upon federally endorsed review timelines as described in the most current version of the Prescription Drug User Fee Act (PDUFA).Wave 1 (CMC): Manufacturing process information; drug substance, drug product, and critical intermediate manufacturing and testing facilities with identification details  number) and responsibilities. Facility information should be prioritized because facility assessments are complex and require significant planning and coordination.Wave 2 (CMC): Stability data, which relies on real-time results and hence is often on the critical path, can be submitted in wave 2. This wave should include any other outstanding information needed to complete the application.Prior to submission, sponsors must meet with the Agency, including the Office of Pharmaceutical Quality (OPQ), to discuss and agree on the submission plan to ensure a logical and efficient submission and review schedule. For example, Module 3 sections that should be reviewed together are scheduled accordingly for simultaneous submission. While companies have used variable approaches due to product, modality, and situational differences that impact the submission strategy, general recommendations from FDA suggest that clinical data should be submitted 7–10 weeks early, with CMC information to follow at a later time. However, proactive discussion with the Agency on the submission schedule is vital, as companies have been able to leverage different approaches for submitting CMC data on a rolling basis. CMC data can be submitted in “waves”:Expert industry panelist Carol Krantz (Seagen) shared published data from February 2018 through April 2020 demonstrating the ability of RTOR to substantially reduce review and approval timelines. In comparison to Priority Review, another accelerated review mechanism used by FDA in which the review timeline is shortened to facilitate an action date within 6 months, RTOR enabled shorter median approval times for new molecular entities (2.2-month reduction) and supplements (2.7-month reduction), wherein 90% of applications using RTOR were actioned prior to the PDUFA date , Yiwei Li (US FDA), Carol Krantz (Seagen), and Timothy Watson (Pfizer). Nina Cauchon and James Bernstein moderated the panel discussion. Kim Huynh-Ba and Helen Strickland captured meeting minutes. Kin Tang was the AAPS lead organizer of the event and Scott Roberts provided meeting support. The key topic areas for the panel session included:Please share your experiences with RTOR or other relevant applications from the perspective of CMCCarol Krantz shared her experiences with Seagen’s product, TUKYSA® (tucatinib). While Seagen was not originally intending to pursue accelerated review for this product, upon receipt of the unblinded clinical study data, FDA invited their participation in RTOR and Project Orbis pilot programs and to use the AAid and Product Quality Assessment Aid (PQAAid) templates for clinical/nonclinical and CMC information, respectively. Upon Seagen’s acceptance, FDA and Seagen developed the overall submission strategy collaboratively.Throughout the submission and review process, communication between the sponsor and FDA is pivotal. During the review, Seagen worked closely with the FDA Quality Review team to discuss modifications in the submission plan as well as potential roadblocks. On the Agency’s side, FDA emphasized the importance of early interaction between cross-functional review team members, which enables critical issues to be identified and addressed more readily. Under RTOR, the Clinical Reviewer and the Quality Reviewer initiate their collaboration early in the review process, which is not typical for standard reviewing procedures as typically the Quality Reviewer joins the review team at a later stage.For the TUKYSA® New Drug Application (NDA), the first wave of submission activities occurred in November 2019, with the remaining sections submitted in December 2019. For RTOR filings, wave 1 includes the majority of the clinical data; however, the full CMC data package may not be available at this time. Components such as executed batch records, including complete translations from foreign manufacturing facilities, may not be available until a later time. The CMC development strategy should work in unison with the clinical development plan to ensure optimal efficiency when pursuing accelerated submission pathways.Seagen experienced difficulties adjusting to the dramatic acceleration in timelines, which were further complicated by technical challenges late in the product’s development. Despite these complexities, through efficient teamwork and open communication between Seagen and FDA, TUKYSA® gained approval within 120 days of full NDA submission.What are the learnings from other expedited programs that can be applied to RTOR?Several accelerated review programs predate the advent of RTOR, which has enabled sponsor companies and the FDA to advance their tools and strategies for navigating a dynamic submission and review paradigm. Quality by design (QbD), as outlined in ICH Q8, is a core concept in pharmaceutical development which emphasizes the establishment of pre-defined objectives that promote process and product control and understanding , there are many junctures at which acceleration can be further enhanced. For example, an EUA and an Investigational New Drug Application (IND) can be active at the same time, wherein the EUA builds upon the information provided in the IND. A similar concept could theoretically be adapted for RTOR, wherein an NDA/Biologics License Application (BLA) uses the IND as a foundation, which can be updated as development progresses.Similarly, the early development and engagement model utilized for RTOR could be considered for non-RTOR filings for incorporation into the overall CMC development strategy to support early action and timely development even outside of the context of oncology products. For example, for advice on the acceptability of a given test method, such as the dissolution assay, sponsors may submit supporting information directly to the IND, in advance of the NDA filing, to request a review on the suitability of the test method for commercial use.What workflow opportunities for enhancing the effectiveness of delivery and review of CMC information have been identified based on RTOR?While each company may have different internal processes or approaches for CMC development and submission assembly, the RTOR submission strategy should be based on the feasibility and timing of content delivery. Early and focused communication between FDA and sponsors remains significant throughout the submission and review process. When utilizing innovative approaches, the industry should be open to engaging in scientific dialogue with the Agency in collaborative problem solving.In regard to specific submission components, stability, facilities information, and validation data are often lagging behind other datasets due to logistical aspects and extended data collection timelines. For example, ICH guidance requires 12 months of stability data to be provided at the time of NDA/BLA filing, but for accelerated filings, this information may not be available at the time of initial submission due to compressed development timelines. In this scenario, the sponsor may be able to discuss with FDA the possibility of submitting partial stability information and providing an updated data package during the review. In some circumstances, it may be possible, pending Agency agreement, to provide supporting stability data if batches are considered to be representative.Validation data, like stability data, also presents challenges for accelerated programs, as process validation typically occurs at a late stage of CMC development and may not be complete at the time of filing. To solve for timeline constraints, potential strategies include performing certain confirmatory studies post-approval, concurrent release of batches to allow for quick distribution following approval, and use of prior knowledge obtained during clinical and registrational batch processing. As previously indicated, nontraditional strategies should be discussed and agreed upon with FDA. The FDA Process Validation: General Principles and Practices guidance document provides insight on the contexts and circumstances in which concurrent release may be appropriate  and Rakhi Shah (US FDA), provided an overview of the Project Orbis program, including eligibility criteria, participating countries, and review processes. Project Orbis is led by FDA, but enables participating regulatory authorities, known as Project Orbis Partners (POPs), to review sponsor application materials contemporaneously or in a staggered fashion. Currently, participating POPs include the Australian Therapeutics Goods Administration (TGA), Brazil’s National Health Surveillance Agency (ANVISA), Health Canada, Israel Ministry of Health Pharmaceutical Administration, Singapore Health Sciences Authority (HSA), Swissmedic (Switzerland), and United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA—Great Britain)  almost simultaneously, with all submissions occurring within a 30-day period. While some information requests were routed through FDA, others were received directly from other POPs. Overall, the collaborative approach enabled by Project Orbis facilitated harmonized yet independent review processes that yielded significant benefits, including reduction in overall review times as well as increasing Seagen’s efficiency for addressing regional differences across the participating POPs. The NDA approval was received in the US 4 months after the initial filing. Approvals were received in POP regions POPs within 4 months of the US approval, representing an average of 50.8% reduction in the review timeline across POP regions.Since its establishment in May 2019, Project Orbis has continued to evolve and adapt new ways of working. When Seagen’s NDA was under review, Project Orbis did not yet include different reviewing categories, such as type A, type B, and type C. To provide perspective on a more current version of the Project Orbis process, industry panelist Ajay Acharya presented his experiences with Merck’s product, WELIREG® (belzutifan). WELIREG® was the sixth NME to be approved under Project Orbis in August 2021. Reviewing POPs included FDA, TGA, Health Canada, and MHRA, whereas a different regulatory review pathway for orphan diseases was pursued in Brazil. Submissions were staggered throughout 5 months after the initial FDA filing, enabling the use of Project Orbis type A and type B processes. Information requests from POPs were not routed through FDA, but Merck noted that they did not receive duplicative or similar queries across POPs if a response had already been provided. In examining the feedback received, there was overall alignment across POPs, which suggests the effects of transparency and information sharing within Orbis. FDA approval was received in January 2022, 1 month ahead of the PDUFA date. At the time of the virtual panel discussion in January 2022, applications in other regions were still undergoing review.CMC-focused experiences participating in Project Orbis and PQAAidRole of the PQAAid in supporting Project OrbisScope of Project OrbisTimeline managementFuture opportunities for enhancing collaborationSimilar to the RTOR session, a question-and-answer session with the FDA and industry expert panelists was held following the introductory presentation. The expert panelists included Sherita McLamore (US Food and Drug Administration), Rakhi Shah (US Food and Drug Administration), Ajay Acharya (Merck) and Tao Li (Seagen). Nina Cauchon and Kin Tang moderated the panel discussion. Andrea Schirmer and Helen Strickland captured meeting minutes. Rita Algorri was the logistical coordinator of the event. Kim Huynh-Ba and David Schwinke provided organizational and logistical meeting support. The key topic areas for the panel session included:Please share your experiences, from the perspective of CMC, with using Project Orbis to collaborate and interact with other AgenciesFDA expert panelist Sherita McLamore shared that the Agency has had overall positive experiences using Project Orbis as a facilitatory mechanism for interacting with other Agencies, gaining further knowledge on regulatory processes used in other regions, and engaging diverse perspectives through scientific dialogue. While there are challenges, such as time zone-related complexities in conducting cross-regional POP meetings and logistical challenges when applications are not submitted concurrently, ultimately, the insights gained from collaborative meetings and information requests provided by other regulators are useful and support FDA’s review processes.From an industry perspective, Tao Li highlighted the time-saving benefits that Seagen attained as part of the concurrent submission, as all approvals from POPs were received in advance of standard timelines. In addition, there was also increased regulatory alignment across POPs, which reduced the burden of regional differences. As a specific example, most of the specification limits were aligned across POPs. Ajay Acharya noted the utility of regulator collaboration for managing staggered submissions, which helped to reduce the volume of follow-up questions and information requests from POPs. While using a simultaneous approach may have yielded a more consolidated set of questions, business needs and objectives vary, so the option to use different modes of collaborative review under Project Orbis can confer valuable flexibility. Sponsors must consider the different benefits and application-specific variables when selecting the regulatory submission strategy under Project Orbis.What is the Product Quality Assessment Aid, how is it used within Project Orbis, and what are the benefits and challenges associated with its use? Is it used for post-approval submissions?Rakhi Shah presented a blank PQAAid template and provided a brief overview of the document’s organization, which is subdivided into discrete sections to facilitate efficient review across disciplines within OPQ, including drug substance, drug product, manufacturing and facilities, and biopharmaceutics. The PQAAid was developed as part of the Project Orbis program and completion of the PQAAid within 30 days of the initial submission is a requirement for all original applications reviewed under Project Orbis. While no supplements reviewed through Project Orbis to date have contained CMC information, it can be envisioned that the PQAAid may also be useful for reviewing applicable supplements.Sponsors can utilize the PQAAid to concisely summarize the CMC data package, including their position on key CMC topics. This can aid in further streamlining CMC reviews by providing a centralized location for reviewers to access important information outside of Module 3. During the review process, FDA reviewers within the four aforementioned disciplines are expected to populate the PQAAid with their findings, including risk assessments and deficiencies. The PQAAid usually spans approximately 80 pages as a template, which typically expands to 150 pages once all reviews are complete.While the benefits of the PQAAid include streamlining communication across disciplines and POPs and providing a consolidated quality summary that all functions can view, challenges occur when FDA’s internal disciplines utilize division-specific or initiative-specific templates. Similarly, if POP reviews are occurring asynchronously, there is potentially less opportunity for collaboration using the PQAAid. Despite these potential challenges, both FDA and industry have found the PQAAid to be beneficial for enabling efficient review.Is the same CMC dossier submitted to all POPs? Were there variations in control strategies?There is no obligation to submit identical CMC dossiers to all participating POPs. The first section of the PQAAid addresses regional variations by requesting sponsors to identify and summarize key differences at a high level. Differences in packaging, specifications, and nomenclature are expected. While there is no formal requirement to submit similar data packages, it is beneficial for sponsors to limit differences across regional dossiers to avoid creating downstream complexities during submission management, collaborative review, and post-approval lifecycle management.Industry expert panelists Ajay Acharya and Tao Li noted that while there was some divergence in the control strategy across regions for their respective programs, collaboration and alignment between POPs generally supported a strong core dossier. Differing opinions were noted for particular circumstances, such as the use of near-infrared spectroscopy.How are manufacturing site inspections managed? Are results of pre-approval inspections shared or are the inspections coordinated?Inspections are managed independently, as some countries do not require pre-approval inspections. Additionally, review and inspection timelines may significantly differ across agencies, creating challenges for meaningful coordination. While the inspection reports are not shared amongst POPs, inspection outcomes are communicated. In the future, there could be opportunities for collaboration that leverage other harmonization programs that FDA participates in.What is the scope of Project Orbis? Does it apply to small and large molecules? Will other countries and/or therapeutic areas be added?Project Orbis can be used to review CMC information included in applications for both small and large molecules. As part of the program’s continued evolution, more complex applications are being considered, including diagnostic devices and advanced therapy products. When considering expansion to other regions, some limitations exist due to local regulatory processes. For example, the European Medicines Agency (EMA) stops the review clock when deficiencies are identified, but FDA does not. As Project Orbis is an initiative of OCE, other therapeutic areas have not been considered as these are out of scope and would need to be managed under their corresponding divisions.What were the challenges relating to internal or external timeline management? How were the complexities of cross-regional timelines addressed?Managing accelerated timelines is often difficult for both regulators and sponsors. From the Agency’s perspective, the Office of Pharmaceutical Manufacturing Assessment (OPMA) faces a particularly substantial burden due to challenges associated with scheduling and conducting inspections, which were further exacerbated during the COVID-19 pandemic as a result of international travel restrictions. Project Orbis is uniquely resource-intensive due to the need for additional meetings conducted with POPs, which span several time zones and require scheduling flexibility from participants. One of the first NDAs to be reviewed under Project Orbis required 21 meetings involving CMC. With experience and business process changes, efficiency has increased over time, requiring less meetings.Sponsors can utilize techniques such as staggering global submissions, or using other innovative review programs, such as RTOR, to help coordinate timelines. If global submissions are staggered, a core or baseline dossier can initially be developed and submitted for an initial region. The core dossier can then be modified based on region-specific requirements which may require additional time. If initiatives such as RTOR are used, facility information can be submitted in advance of the full dossier to facilitate early inspection.What opportunities do the Agency and industry see for further enhancing collaboration?Project Orbis has been greatly beneficial for patients by allowing products to reach multiple markets sooner. Type A and type B Project Orbis submissions that utilize a concurrent submission model have demonstrated the most success for reducing timelines. Opportunities that allow for increased alignment of the review process will further extend the benefits realized through Project Orbis.There is broad recognition across the pharmaceutical ecosystem that drug development and regulatory timelines must accelerate beyond their traditional pace to effectively address unmet medical needs in the context of serious and life-threatening illnesses. In the USA, 1 life-year is lost for every 2.2 min of delay in drug approval for oncology indications Helwick . RegulatThe diverse real-world experiences shared by the expert panelists during the AAPS panel discussions illustrated the many tangible benefits of OCE’s regulatory efficiency initiatives. Despite the challenges of navigating the uncertainties of participating in a new review paradigm and orchestrating abbreviated submission timelines, which can be particularly challenging for CMC applications which can have data requirements with extended timelines, sponsors and regulators emerged with overall positive perspectives and successes using RTOR, Project Orbis, and the PQAAid. Future opportunities that expand on these capabilities, their scope, and applicability across modalities and therapeutic areas will offer significant promise in transforming and reducing drug development timelines.


On June 14, 2021, an industrial manufacturing facility in Winnebago County, Illinois caught fire and released smoke, dust, and debris, requiring evacuation of the area in the vicinity of the facility for 4 days. Following the emergency response, the Illinois Department of Public Health (IDPH) and Winnebago County Health Department (WCHD) requested assistance from the Agency for Toxic Substances and Disease Registry (ATSDR) to conduct a community Assessment of Chemical Exposure (ACE). That assessment found that almost one half of respondents reported symptoms during the 2 weeks after the fire  completed the follow-up survey. In the follow-up survey, 39% (265) of respondents reported new or worsening mental health symptoms since the fire, among whom 98% were still experiencing these symptoms 1 year after the fire; 59% (400) reported new or worsening physical health symptoms, among whom 90% were still experiencing these symptoms 1 year after the fire.Semistructured interviews enriched the quantitative information from the electronic survey and revealed themes related to anxiety, disappointment in communication, and overall poor mental health. More formal qualitative analysis is underway; however, preliminary findings suggest that residents were unable to easily access information related to environmental exposures or fire-site cleanup efforts. In addition, when information was available, respondents found it to be overly technical and difficult to interpret.The semistructured interviews also provided an opportunity for residents to offer unprompted remarks. Residents reported avoidance of previous activities, such as gardening, because of concerns about fire-related contaminants. This information provides local authorities with specific actions such as targeted community environmental risk education.This follow-up ACE investigation provided informative and immediately actionable data. Communities that have experienced a similar type of fire or environmental disaster would benefit from a consolidated source of information, summarized in easily understandable, plain language. The CDC Clear Communication Index is a set of research-based criteria that can be used to craft messages in an effective, interpretable way, especially for complex scientific information related to toxic substances (Lessons learned from the follow-up survey are being applied to both the chemical fire and other environmental exposures such as per- and polyfluoroalkyl substances in water systems in Winnebago County. WCHD is working with IDPH and the Illinois Environmental Protection Agency on communications about chemical exposures that incorporate the concepts highlighted by this qualitative study including transparency about what is unknown and simple communications based on the CDC Clear Communication Index.This investigation documented persistent mental and physical health symptoms reported among residents 1 year after a chemical fire, highlighted the importance of clear and accessible public health communications (


The morbidity and mortality of coronary heart disease (CHD) has remained high, which greatly increases people’s economic burden. Several studies have showed that Tiaogan formula (TGF), as a kind of Chinese herbal medicine, was of benefit to relieving angina pectoris symptoms and improving the quality of life for CHD patients. However, the intensity of evidence has been poor, limiting the further clinical application of TGF to CHD. This systematic review and meta-analysis will assess the effectiveness and safety of studies of TGF in CHD patients.A systematic search for literature up to December 2022 will be conducted in following public electronic databases: PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journals Database Database, and Wanfang Database. Inclusion criteria are randomized controlled trials of Tiaogan formula in the treatment of coronary heart disease. The primary outcome measures will be mortality, acute cardiovascular events, total efficacy rate, and improvement of angina symptoms. The secondary outcome measures will be electrocardiogram, levels of blood lipid, and adverse events. RevMan 5.4 software Cochrane Collaboration  will be applied for data synthesis, sensitivity analysis, subgroup analysis, and risk of bias assessment. A funnel plot will be developed to evaluate reporting bias and Egger tests will be used to assess funnel plot symmetries. We will use the Grading of Recommendations Assessment, Development and Evaluation system to assess the quality of evidence.This study will provide a systematic review of Tiaogan formula in the treatment of CHD.This study will provide a high-quality synthesis of the effects and safety of Tiaogan formula in the treatment of CHD patients. The morbidity and mortality of CHD has remained high, which greatly increases people’s economic burden.,3 Several factors involving inflammatory response, abnormal lipid, amino acid, carbohydrate and bile metabolism can exacerbate the pathological development of CHD.–6 In the early stage of CHD, coronary atherosclerosis is the initial pathology which is characterized by lipid deposition and chronic inflammatory response. Not only can CHD increase mortality, but also severely influence patients’ daily activities and quality of life.,8 Current conventional therapies  have been utilized in the treatment on CHD, however, there have been plenty of CHD patients impotent to alleviate angina related symptoms totally and accompanied by adverse effects like dizziness and headache.–11 As far as the disadvantages of conventional therapies are concerned, Chinese herbal medicine, which has been applied for thousands of years, may provide a potential complementary treatment strategy for CHD.It has been estimated that cardiovascular diseases, principally coronary heart disease (CHD) and stroke, are the leading cause of global mortality and a major contributor to disability. The etiology and pathogenesis of CHD are related to blood stasis and qi stagnation, which blocks blood circulation of the body. The movement of blood and qi in the body is strongly associated with the function of “liver (gan)” based on the TCM theory.–16 Therefore, the TCM therapy principle of “Tiaogan (improving the liver function)” has been applied to regulating qi stagnation and activating blood circulation commonly.,16 Xuefu zhuyu decoction, one of the representatives of “Tiaogan” formulas, has been utilized to treat CHD and originated from “Yi Lin Gai Cuo” since Qing Dynasty.,18 Currently, more and more evidences prompt that Tiaogan formula (TGF) is of benefit to relieving angina pectoris symptoms and improving the quality of life for CHD patients.–23According to the basic theories of traditional Chinese medicine (TCM), CHD belongs to the category of “Xiong Bi (chest pain or heartache),” recorded in the TCM classic “Huang Di Nei Jing” since Western Han Dynasty.Although increased numbers of clinical studies and reviews about TGF applied on CHD patients, the intensity of evidence has not been strong enough and there has been lack of meta-analysis to assess the effectiveness and safety of TGF in the treatment of CHD systematically. In virtue of the lack of systematic review about this crucial issue, this meta-analysis will be designed to systematically evaluate the effectiveness and safety of TGF in the treatment of CHD patients.This protocol has been registered on international prospective register of systematic review. The trial registration number of prospective register of systematic review is CRD 42018094538. The procedure of this protocol will be conducted according to the Preferred Reporting Item for Systematic Review and Meta-analysis Protocols guidance.We will include all the randomized controlled trials that study the effectiveness and safety of TGF combined with conventional medication in the treatment of CHD.The study will include patients diagnosed as CHD regardless of their age, sex, ethnicity, education or economic status and whether or not they were outpatients or inpatients. The diagnostic criteria of stable angina pectoris are as follows. or “ACC/AHA 2002 guideline update for the management of patients with chronic stable angina task force on practice guidelines (committee to update the 1999 guidelines).”The diagnostic criteria of CHD should be confirmed according to one of the past or current definitions. The diagnostic criteria include “Nomenclature and criteria for diagnosis of ischemic heart disease”Interventions involving the combination of TGF with conventional medication are eligible in intervention group. The same conventional medication must be used in the control group.The primary outcome measures will include: mortality, acute cardiovascular events, total efficacy rate, improvement of angina symptoms, and adverse events. The secondary outcome measures will include: changes of electrocardiogram, levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels, and TCM syndrome score.The following electronic bibliographic databases will be retrieved from inception to December 2022: PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journals Database Database and Wanfang Database. There are no limits on the language of publication. Only clinical trials as a limitation will be included and searched. The following sources will also be searched to identify clinical trials which are in progress or completed: Clinical Trials.gov and World Health Organization clinical trials registry. The additional relevant studies will also be retrieved from the reference lists of systematic reviews and included studies. We will map search terms to controlled vocabulary if possible. In addition, the search strategy for selecting the fields of title, abstract or keyword will be different referring to the characteristics of databases. Search terms are grouped into 3 blocks . Two authors (CM and ZG) will screen the titles and abstracts of the all studies retrieved in above electronic databases independently to find potentially eligible studies. Articles which are duplicated or not accordant with eligibility criteria, intervention and outcome in this study will be excluded. After filtering the final eligible articles, the data from the included articles will be extracted independently from 2 authors (CM and ZG). Disagreements will be resolved by discussion or arbitrated by a third author if needed. The following data items will be extracted: first author, publication year, diagnosis information, age, sex, trial characteristics, interventions and controls, participants, study methodology, outcomes, adverse events and etc. see Fig. . The assessment details include: sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective reporting and other sources of bias. Each domain will be assessed as “low risk” or “high risk” or “unclear risk” according to the description details of eligible studies.The methodological quality of the eligible studies will be evaluated according to the Cochrane Collaboration’s tool is included in RevMan 5.4 software for assessing risk of bias.I2 test will be calculated to determine the amount of heterogeneity. The results of the studies could be used the fixed-effect model to combined unless I2 statistic is >50%, in which cases, the random-effects model will be used.Statistical analyses will be conducted with RevMan 5.4 software provided by Cochrane Collaboration. Data will be presented by risk ratio or odd ratio with its 95% confidence interval for dichotomous outcomes and standardized mean difference or weighted mean difference with its 95% confidence interval for continuous outcomes. The If the heterogeneity or inconsistency among the studies was detected, sensitivity analysis or subgroup analysis or meta-regression analysis will be performed. Subgroup analysis will be conducted to explore potential sources of heterogeneity according to the characteristics of studies, including sample size, severity of angina, dose of Chinese herbal medicine formulas, treatment duration and other relevant parameters. If data extraction is insufficient, we will create a qualitative synthesis.P < .1 as showing statistical significance.A funnel plot will be developed to evaluate reporting bias of the included studies. We will use Egger tests to assess funnel plot symmetry and will interpret values of We will also assess the quality of evidence for the main outcomes with the Grading of Recommendations Assessment, Development and Evaluation approach. The 5 items will be investigated, including limitations in study design, inconsistency, inaccuracies, indirectness and publication bias.Patients and/or public were not involved due to this study belonging to the secondary sources analysis.,17 Nowadays, TGF is commonly and widely applied as a complementary treatment strategy for CHD patients in China. Previous studies have indicated that TGF contributes to downregulating levels of blood lipid, relieving angina pectoris and improving the electrocardiogram for CHD patients.–23 Increased numbers of clinical studies prompted that TGF has been widely used and beneficial in improving clinical indicators for CHD patients, however, there has been no comprehensive assessment of the clinical evidence regarding TGF as intervention for CHD in evidence-based medicine.–23 Consequently, this meta-analysis intends to assess the effectiveness and safety of TGF for CHD patients. The results of this meta-analysis may provide more appropriate and objective clinical recommendation for clinician to apply TGF therapy to CHD patients.It has been known that TGF has been applied to treating CHD for a long time.Zhihao Luo and Mingtai Chen conceived the study and drafted the protocol. Jienan Luan and Guofu Zhong revised it. Mingtai Chen, Ling Men, Junteng Chen and Guofu Zhong developed the search strategies, will conduct data collection, and analyze the data independently.Conceptualization: Mingtai Chen, Zhihao Luo.Data curation: Guofu Zhong.Formal analysis: Guofu Zhong.Funding acquisition: Mingtai Chen, Jienan Luan.Investigation: Mingtai Chen.Methodology: Mingtai Chen.Project administration: Mingtai Chen, Jienan Luan.Resources: Ling Men, Jienan Luan.Software: Ling Men.Supervision: Jienan Luan.Validation: Junteng Chen.Visualization: Junteng Chen.Writing – review & editing: Zhihao Luo.


Implementation of antimicrobial stewardship programs (ASPs) in well-resourced countries has been associated with reductions in antibiotic-resistant infections and improved patient outcomes. Several guidance documents providing recommendations on how to structure antimicrobial stewardship activities at the national and hospital level in resource-limited settings have been published. However, few hospitals in Latin America report having a structure or resources needed for a successful ASP. Given the alarming increases in antimicrobial resistance in Latin America, better understanding of barriers to promote implementation of effective ASPs is urgently needed. We have summarized past and present antimicrobial stewardship activities in Latin American hospitals, and we describe key elements needed in future efforts to strengthen antimicrobial stewardship in the region. Several South American countries are reporting the emergence of new carbapenem-resistant Enterobacterales (CRE) that produce >1 carbapenemase. These trends highlight the urgent need to build and strengthen antimicrobial stewardship activities in the region. National plans including both antimicrobial stewardship and infection prevention and control (IPC) programs can result in significant reductions in the spread and incidence of multidrug-resistant (MDR) organisms, including CRE.Antimicrobial resistance (AMR) in Latin America has reached critical levels. Carbapenem nonsusceptibility among gram-negative organisms has increased drastically in the region from 0.3% in 2002 to 21% in 2016, with some countries reporting a prevalence of 20%–50% according to the Latin American Network for Antimicrobial Resistance Surveillance . We have summarized the history of hospital antimicrobial stewardship activities in Latin America. We have described current hospital antimicrobial stewardship activities, and we have highlighted unaddressed issues and gaps to effective implementation of ASPs in the region. We use the term Latin America to refer to countries south of the United States, not including the Caribbean.According to the Pan American Health Organization (PAHO), 30 of 33 countries in Latin America and the Caribbean are in the process of developing or have completed national action plans to combat AMR, and 19 of 33 countries report to the Latin American Network for Antimicrobial Resistance Surveillance. At the time, however, data were limited regarding both the effectiveness of these approaches and how to accomplish strategic goals. In 1994, Quiros et al showed a significant reduction in antimicrobial use  and in inappropriate prescribing  with implementation of hospital-specific treatment guidelines, preauthorization, autostop of antibiotics at 24 hours for surgical prophylaxis, and daily handshake stewardship at a tertiary-care center in Argentina. Similarly, in 1999, Bantar et al showed that implementation of an antimicrobial stewardship program (ASP) including implementation of a prescription form, education, and prescribing control at a 250-bed public tertiary-care center in Argentina resulted in a significant improvement in antibiotic use as well as methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant P. aeruginosa infections, crude mortality, and length of stay. The intervention was developed and implemented by a multidisciplinary team including an infectious disease (ID) physician, a clinical microbiologist, 2 pharmacists, and 1 data analyst. This team had the critical advantage of having resources to extract and analyze data, and they integrated key disciplines in the management of antibiotics such as microbiology, medicine, and pharmacology.In 1997, the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America published Guidelines for the Prevention of AMR that included both strategic goals  and general approaches to improve antibiotic use in hospitals . However, 63% lacked a pharmacist dedicated to antimicrobial stewardship activities, 33% did not have treatment guidelines , and only 48% performed prospective audit and feedback. Although most participants (78%) reported developing periodic antibiograms, only half of them shared the information with their prescribers. Although 48% reported access to information and technology support for antimicrobial stewardship activities, only 44% monitored antibiotic use. These data may be an overestimate of the current situation of ASPs in the Latin America region because hospitals with better established ASPs may have been more likely to participate in the study. Moreover, an earlier global survey on antimicrobial stewardship also showed low ASP implementation in Central and South America: only 46% of Central and South American hospitals had implemented an ASP.Despite these early successful demonstrations, many hospitals in Latin America have struggled to implement multidisciplinary teams to execute effective antimicrobial stewardship activities. A 2015 survey assessing the development of ASPs in 27 hospitals in 10 countries throughout Central and South America showed that 59% of hospitals had a written statement supporting antimicrobial stewardship activities. led a study evaluating implementation of ASPs in 111 hospitals in Argentina through a scored self-assessment based on Centers for Disease Control and Prevention (CDC) core elements . These investigators found that, on a scale from 0 to 100 (a higher score indicating a more advanced program), only 28 (25%) of 111 participating hospitals had an average score of 52, whereas 75% scored an average of 32. Most sites scored poorly in training and education, and having a full-time ID physician was associated with a higher score. More recently, the impact of ASPs in 77 intensive care units (ICUs) from 9 Latin American countries  was evaluated through a similar self-assessment and point-prevalence surveys. In this study, hospitals with a high global score on the self-assessment  had lower antibiotic consumption , lower rates of hospital-acquired infections due to MDR organisms, and were more likely to have more robust IPC programs than hospitals with a low score. Like the previous study, education, tracking antibiotic use, and assessment of antibiotic appropriateness scored lowest .In 2016, Quiros et al The previously mentioned study by Bantar et al showed that implementation of the ASP resulted in US$1,000,000 in cost savings. One study evaluating the cost-effectiveness of 2 antimicrobial stewardship strategies in a 550-bed university hospital in southern Brazil found that while more labor intensive, an intervention that included prospective audit and feedback through face-to-face interactions was more cost-effective than the intervention that included review of antimicrobials by the clinical pharmacist and discussion of recommendations with the ID physician only , underscoring the value of interacting with prescribers.Lastly, several studies have shown that ASPs are cost-effective in Latin America. Next, we summarize key elements to promote effective antimicrobial stewardship in Latin American hospitals.A recent scoping review evaluating the implementation of hospital ASPs in Latin America and the Caribbean showed that although there has been a steady increase in published studies on antimicrobial stewardship interventions in recent years, ∼60% of the reports come from only 3 countries , suggesting differences in antimicrobial stewardship stage development among countries in the region. that affect implementation of effective measures to counteract AMR. In many Latin American countries, limited national resources are dedicated to public health, including AMR; thus, infrastructure to allow for tracking AMR and antibiotic use rates at the national level are scarce. Furthermore, 30%–50% of the population of Latin American counties rely on public healthcare, but funding for these services, which is derived from federal taxation, is inadequate. As a result, most public hospitals operate with very limited budgets and lack resources to establish ASPs or other programs and tools needed for optimal ASPs, such as robust microbiology laboratory capacity and implementation of electronic health records, from which antibiotic use data can be obtained. Most countries in Latin America do not have federal legislation or regulations that compel hospitals to implement ASPs or prioritize efforts to combat AMR. The World Health Organization (WHO) through its regional office, the Pan American Health Organization (PAHO), has been working to address some of these gaps, including development of policy guidance to facilitate implementation of national antimicrobial stewardship activities. The guidance includes, among other activities, regulation of remuneration policies to promote responsible antimicrobial prescribing.Although Latin American countries share the origin of the languages spoken  they have very diverse sociopolitical environments, economies, and health systems Correlation between cultural determinants and both antimicrobial use and AMR have been described. At the country level, societal characteristics  are associated with an increased prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum β-lactamase–producing organisms, antibiotic use, and inferior IPC practices compared with societies in which these characteristics do not predominate. A study of cultural determinants in Guatemala reported that only 53% of prescribers were highly receptive to recommendations from the antimicrobial stewardship team, and almost 40% felt that it was wrong to make modifications to antibiotics prescribed by a colleague . These cultural determinants may represent critical barriers to integrating pharmacists, bedside nurses, and infection preventionists in antimicrobial stewardship and to empowering them to lead quality improvement interventions in Latin America.Social and cultural factors can impact the effectiveness of ASPs in Latin America. Clinicians and patients historically have been reassured by prescribing and taking antibiotics, respectively. Understanding what may help mitigate uncertainty avoidance is crucial to designing strategies to improve prescribing habits. For example, while ambulatory prescribers in the United States indicated that being concerned about adverse events may help reduce inappropriate antibiotics; this was not prioritized by ICU prescribers in England whose antibiotic perceptions were strongly influenced by beliefs that antibiotics would protect patients from deterioration and themselves from the ethical and legal consequences of undertreatment. These findings highlight the need to better understand prescribers’ perspectives on antibiotic management in different settings to develop effective approaches to improve antibiotic use in different patient populations. Recently, in the United States, Cosgrove et al led a national program to improve hospital antibiotic use built on patient safety. The program included training of frontline providers in technical  and adaptive factors . The authors found that hospitals more actively engaged in the program had greater reduction in antibiotic use than those with lower engagement, with −34.2 days of therapy versus −15.6 DOT, respectively, between the beginning and end of the program. A separate intervention that focused on education on patient safety, quality improvement, effective teamwork, and communication resulted in a 30% increase in compliance with infection prevention best practices and a significant reduction in central-line–associated bloodstream infections in ICUs from 5 countries in Latin America; however, this approach has not been utilized to improve antibiotic prescribing in the region, although it may be key to changing behavior regarding antibiotic use.Another important cultural determinant that can result in inappropriate antibiotic prescribing is uncertainty avoidance.Pseudomonas and Acinetobacter, which can persist in aqueous environments). Transmission of resistant organisms to patients must be addressed through robust infection prevention approaches, and hospitals must support and allocate resources for both antimicrobial stewardship and IPC activities in Latin America. This issue was nicely illustrated in the study by Lopardo et al, which showed an increase in use of colistin and carbapenems associated with an outbreak of Acinetobacter and Pseudomonas related to suboptimal IPC practices despite having an ASP in place with prospective review and feedback.Reduction in AMR depends on both decreasing the selective pressure exerted by antibiotics that can lead to emergence of resistance as well as strong IPC activities to prevent transmission of resistant organisms. MDR organisms are transmitted via hands of healthcare personnel, through contaminated medical equipment, or via an environmental reservoir  have already implemented standards or have passed laws regarding the role of clinical pharmacists in hospital ASPs; however, this remains largely unaddressed in most countries in the region. In addition to pharmacists, other healthcare professionals can contribute to antibiotic stewardship efforts. Recently, the role of bedside nurses in antimicrobial stewardship has been emphasized. Nurses can help optimize use of microbiologic tests, such as avoiding unnecessary urine or sputum cultures (which often result in unnecessary antibiotic treatment) or collecting specimens appropriately for accurate results, including aseptic techniques and specimen collection prior to antibiotic administration. Another area in which nurses can contribute to antimicrobial stewardship efforts is appropriate documentation of antibiotic allergies.Physicians and pharmacists have complementary skills and expertise in antimicrobial stewardship. An important barrier to ASP implementation in Latin America has been the lack of availability of physicians and clinical pharmacists. Figure  The minimum recommended full-time equivalent support (includes physician and pharmacist) for a successful ASP is 1 for a 100-bed hospital, 1.3 for a 101–300-bed hospital, 1.6 for a 301–500-bed hospital, 2.6 for a 501–1,000-bed hospital, and 4 for a >1,000-bed hospital.Infection preventionists are expected to work closely with antimicrobial stewardship colleagues, and in some countries, they have been tasked with implementing antimicrobial stewardship activities as well. In these situations, careful balance of activities and allocation of resources and support of individuals with drug expertise and knowledge on infectious diseases management must be considered to ensure appropriate dedication to both activities. Recommendations on the minimum requirement for successful antimicrobial stewardship and IPC programs have been published. This free platform allows for longitudinal storage of deidentified data such as antibiotic consumption, point-prevalence survey data, and ASP core elements data. Hospitals can track their own data over time and compare themselves against other hospitals in the same country (benchmarking). Studies to evaluate the impact of the platform are needed. The app contains treatment guidelines that hospitals can adapt based on their local epidemiology antimicrobial-specific information  and renal- and liver-function calculators.Improvement is needed in hospital access to technology both to track antibiotic use and AMR more efficiently and to help display these data in a meaningful way to the ASP for action, as well as improving clinicians’ access to evidence-based information  at the point of care, which can be challenging in Latin America where computer availability and access to scientific journals are limited. To address these needs, a free phone app and a free web platform have been developed and are available in all countries.Finally, increased microbiology capacity is needed for accurate detection of resistance and to improve access to results at the point of care for timely antimicrobial actions. This barrier is more challenging to overcome because digitalization of electronic medical records is costly both to implement and maintain. Free resources for antimicrobial stewardship implementation are summarized in the Supplementary Table. National action plans have slowly been developed and implemented, and hospitals antimicrobial stewardship activities have grown despite limited allocated resources. In addition to better resource allocation, there needs to be an evaluation of how current hospital reimbursement models affect implementation of effective ASPs.AMR remains a public health emergency in Latin America.Previous assessments of ASPs have focused on traditional evaluations of program structure, processes, and outcomes. Although these are fundamental aspects to evaluate, assessments should be complemented with evaluations that incorporate behavior and context determinants, which occur at the individual level as well as the wider organizational and social levels and can affect the implementation of antimicrobial stewardship activities. These frameworks are used to assess potential barriers and facilitators within local settings , mechanisms to provide timely results to prescribers, and prescribers perceptions and attitudes towards rapid diagnostics . A summary of domains and potential determinants to consider when evaluating antimicrobial stewardship interventions in Latin America is presented in Figure Several determinant frameworks include a wide range of factors (determinants) that may influence outcomes and program implementation and that should be considered to decrease the risk of implementation failures.; however, more training on strategic planning and systematic approaches to quality improvement , as well as other key factors, are needed for successful ASPs, such as guideline development, how to approach the C-suite, and how to adopt and promote teamwork and effective communication.As previously discussed, increased ID and antimicrobial stewardship expertise is needed among the healthcare work force, including the members of the antimicrobial stewardship team. Several regular training courses exist; although many are in English and could be quite expensive, which challenge wider use in Latin America. Recently, free training programs on antimicrobial stewardship implementation have become available online in SpanishAs previously mentioned, better promotion of safety culture and better training of healthcare workers are needed to empower pharmacists to take a more active role in antimicrobial stewardship and to help prescribers accept their recommendations. These include the most common infectious syndromes and prescribed antibiotics, and certain practices such as lack of microbiologic cultures prior to initiating antimicrobial treatment, and the high use of certain antibiotics despite high prevalence of organisms being resistant to these antibiotics.Another area for improvement in Latin America is quantifying and benchmarking antibiotic use. Point-prevalence surveys of hospital antibiotic use have provided useful data to define antimicrobial stewardship priorities. Point-prevalence surveys do not allow for evaluation of duration of therapy, and more research is needed to understand current antibiotic prescribing patterns with respect to duration because this has been a major driver of inappropriate antibiotic use in other countries such as the United States. As a start, assessing prescriber’s awareness on duration of therapy by evaluating documentation of duration in the chart during point-prevalence surveys could shed some light on this topic. Antibiotics are used among higher proportions of ICU patients relative ward patients in Latin America. Hence, given limited resources, most antimicrobial stewardship activities in Latin American hospitals have concentrated on the ICU. However, most hospitalized patients are outside the ICU, and better understanding of antibiotic use is needed to improve the reach of antimicrobial stewardship to non-ICU patients.The limitations of the point-prevalence survey methodology include misclassification of patients due to bed shortages, discordant data when mixed electronic and paper records exist, and lack of familiarity among data abstractors with electronic health records. These issues are exacerbated in hospitals in resource-limited settings.In summary, antimicrobial stewardship resources and antimicrobial stewardship activities differ significantly among Latin American countries. Progress has been made in antimicrobial stewardship across Latin America at the hospital level, but it has been slow. Better understanding of the major challenges is needed to promote effective antimicrobial stewardship in the region, including through evaluation of the culture of safety and human factors that influence antibiotic prescribing.


It is concluded that the prospects of MBRs for petroleum industry effluent treatment are more favorable than implementation of membrane filtration for offshore PW treatment.Low-pressure membrane technology (ultrafiltration and microfiltration) has been applied to two key effluents generated by the petroleum industry: produced water (PW) from oil exploration, a significant proportion being generated offshore, and onshore refinery/petrochemical effluent. PW is treated physicochemically to remove the oil prior to discharge, whereas the onshore effluents are often treated biologically to remove both the suspended and dissolved organic fractions. This review examines the efficacy and extent of implementation of membrane technology for these two distinct applications, focusing on data and information pertaining to the treatment of real effluents at large/full scale. Reported data trends from PW membrane filtration reveal that, notwithstanding extensive testing of ceramic membrane material for this duty, the mean fluxes sustained are highly variable and generally insufficiently high for offshore treatment on oil platforms where space is limited. This appears to be associated with the use of polymer for chemically-enhanced enhanced oil recovery, which causes significant membrane fouling impairing membrane permeability. Against this, the application of MBRs to onshore oil effluent treatment is well established, with a relatively narrow range of flux values reported (9–17 L·m Refining refers to the fractionation of crude oil primarily into transportation fuels, along with heating oils and other more minor oil elements. Petrochemicals are the intermediates used to produce industrial and consumer products .For such on-shore installations, where footprint is a less critical factor, relatively low-energy/high-footprint technologies can be applied. These are often based on biological treatment processes, frequently applied to industrial effluents including refinery and petrochemical effluents. For offshore applications, where space is limited ,3,4,5,6,Within the petroleum sector, low-pressure (or “porous”) membrane technologies have been extensively studied based on abiotic ,21,22,23the influent water quality,system hydraulics, and specifically sustainability of flux and permeability ,organic carbon removal, as represented by the oil and/or chemical oxygen demand (COD), andrequirement for supplementary system components, and specifically pretreatment and post-treatment.Given that both on-shore and off-shore installations are faced with similar challenges in terms of the nature of the effluent, ostensibly from the biorefractory organic matter and oil content, it is of interest to compare the overall performance of the abiotic and biological processes with reference to:The above facets are reviewed, based on all accessible information . The collated and synthesized data are subsequently used to inform an assessment of the current and future likely implementation of the two membrane technologies.Different treated water quality objectives apply to PW for sea discharge and land-based petroleum effluents. For the former, the discharged water quality is based on the oil concentration, and physicochemical removal of the suspended oil is normally sufficient to meet the requirement. The required water quality for effluents discharged inland, on the other hand, is normally based on the total organic concentration measured as the COD or BOD.The ranges of concentration of the key PW bulk water quality parameters  vary widThe organic fraction derives largely from the oil itself, which is partitioned between the dissolved/emulsified and suspended (or “free”) fractions. Free oil presents a greater challenge than dissolved or emulsified oil due to its high membrane fouling propensity. The organic chemicals making up the oil fraction are classified according to the general molecular chemistry , functional groups  or individual species. Of the latter, benzene, toluene, ethylbenzene and xylene are collectively expressed as BTEX, these chemicals being ubiquitous in PW. Polycyclic aromatic hydrocarbons (PAHs) are also expressed as a single group of compounds, their toxicity having been long recognized .Another key component of the organic fraction is the additives , synthettank bottom drawsdesalter effluentstripped sour water, andcooling tower blowdown.Refineries generate products from crude oil (or “crude”) by thermal fractionation: separation of the crude constituents takes place by virtue of their differing boiling points. Wastewater streams generated from the refining process include :tank botEntrained water in crude originates from the oil well extraction process and/or from ingress during transportation . It is uThe principal water stream in a refinery is the cooling water (CW), which makes up 50–55% of all the water in a refinery . At timeSince oil refining combines a number of different processes  that genNotwithstanding the temporal and site/installation-related fluctuations in refinery effluent quality, a review of the data sets given in bench-scale studies,crossflow operation of tubular or square-channel membrane elements to sustain high shears and thus suppress membrane surface fouling,analogue (or synthetic) effluent feeds,refinery wastewaters, andlimited duration (<6 h) trials conducted under constant transmembrane pressure (TMP) conditions.UF membranes have been used for treating small volumes of oil-laden industrial wastewaters since the mid 1970s , primariStudies have demonstrated the expected effective rejection of emulsified and suspended oil down to levels well below legislated discharge limits ,21,22,23The literature reveals an increased interest in ceramic membranes for this duty, with some commercial suppliers apparently collaborating in site-based demonstration trials ,15—thougOutputs of the various of studies  have beeA key reported observation regarding the application of low-pressure membrane technology to PW concerns the impact of polymers, employed in chemical enhanced oil recovery (CEOR) ,45. PolyCritically, the polymer has been demonstrated to cause rapid fouling of ceramic membranes . Given t3/d and was installed in 2005. The largest congregation of petrochemical industry MBR plants is in China: by the end of 2010 there were at least 12 MBRs treating petroleum effluents, each of more than 5000 m3/d individual capacity, providing a combined treatment capacity of more than 130,000 m3/d in mainland China [In contrast to the apparent absence of implemented UF/MF polishing of PW on offshore oil platforms, MBRs have been employed for treating refinery and petrochemical effluents for more than 15 years. An early example is the landmark Syndial plant at Porto Marghera in Italy, which treats an average daily flow of 38,400 mnd China ,47. Againd China .A crucial facet of the MBR technology, and biological processes generally, is that they provide removal of both dissolved and suspended organic material rather than just the suspended oil. A review of data reported for COD removal from refinery and petrochemical effluents based on both bench and pilot scale studies ,50,51,52Unlike the abiotic UF-MF application to PW treatment, where a very significant range of pseudo-steady state fluxes have been reported from bench and pilot scale studies , the ranIn the case of the sidestream configuration (sMBR), where the sludge from the bioreactor is pumped under pressure through an external multitube (MT) module c, the flAs with abiotic membrane filtration of PW, MBR treatment of RE is often immediately preceded by flotation to reduce the load of free oil onto the membrane separation process, though sedimentation pretreatment appears to be favored for petrochemical effluents in China . In the Moreover, MBRs are more tolerant of feedwater free oil than the abiotic process since the effluent flows initially into the biological process tank b,c. This2 membrane area, the membrane life is envisaged as being at least double that of the polymeric materials and the fluxes sustained significantly higher—partly because the mechanical strength and chemical resistance of the ceramic material permits more aggressive chemical cleaning [Whilst most MBR membrane products are polymeric, and more than half of these polyvinylidene difluoride (PVDF) , implemecleaning .PW UF/MF membrane filtration studies have been limited in scale and duration, and largely based on synthetic/analogue feedwaters, which are not necessarily representative of real effluents. A wide range of final fluxes (4–700 LMH) and permeabilities (5–1240 LMH/bar) have consequently been reported, which may not be representative of full-scale operation.The most economical method of enhanced oil recovery (EOR) is through dosing with polymer. Whilst this improves the yield of oil from reservoirs, it also causes significant membrane fouling ,45. ThisCeramic membranes have been successfully implemented for onshore applications, with examples from 1997 onwards of abiotic potable water installations in Japan,  and, froOnshore treatment of refinery and petrochemical effluents specifically using MBR technology, providing advanced biological treatment, has been established since the early noughties. Such treatment is appropriate since removal of both the suspended and dissolved organic matter (manifested as the COD) for this duty rather than just suspended oil removal as for PW treatment.The main contributors to MBR operational costs have been shown to be labor effort, sustainable flux, energy, and membrane replacement . The comSome key observations can be made regarding the relative extent of implementation of membrane technology for offshore PW treatment and onshore refinery/petrochemical effluent treatment:A simple SWOT analysis of the two technologies and applications  suggestsMBR technology has been applied to oil industry effluents for over 15 years. It is particularly favored if water reuse is a key objective, since the process provides robustness pretreatment upstream of reverse osmosis demineralization. It is nonetheless relatively high in energy consumption, and the membrane replacement  adds significantly to the operating costs. The drive towards low-energy treatment solutions could present a significant threat to MBR technology implementation in the future, though energy efficiencies and general robustness of the process continue to improve.It is concluded that the prospects of MBRs for onshore petroleum industry effluent treatment appear favorable. The implementation of abiotic UF/MF for offshore duties, on the other hand, appears to be hampered by the challenge imposed by membrane fouling and the associated impaired membrane permeability.


Preclinical indicators of disease such as inflammation, cortisol and glucose dysregulation, and multisystem dysregulation  are related to individual differences in the level of cognitive functioning across adulthood. This study examined whether individual biological systems and allostatic load are related to differential patterns of change in cognitive functioning over 9 years. Data are from the Midlife in the United States (MIDUS) study second (biomarker and cognitive) and third waves (cognitive). The sample includes 863 men and women who ranged in age from 35 to 85 when the data were first collected. MIDUS biomarkers include a comprehensive range of biological and anthropometric measurements reflecting cardiovascular functioning, glucose metabolism, lipid metabolism, inflammation, HPA axis function, as well as sympathetic and parasympathetic nervous system function. Summary indices of dysregulation in each of these major systems as well as an overall index of multi-system dysregulation, or allostatic load were examined in relation to 9-year changes in episodic memory and executive functioning from the Brief Test of Adult Cognition by Telephone. Regression analyses, controlling for preexisting diseases and medications, showed that higher allostatic load was associated with decreased executive functioning over time for those who started out with higher cognitive performance at baseline, after adjusting for age, gender, race, English language, education, neurological conditions, medication use and smoking. Identifying biomarkers as antecedents of cognitive changes in midlife and old age, can potentially aid in the early detection of cognitive impairments and increase the possibilities for preventive interventions.