This review is a condensed summary of representative articles addressing the sex/gender bias in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). The strong effects of sex on the incidence and possibly also the activity and progression of these disorders should be implemented in the evaluation of any phase of clinical research and also in treatment choice consideration in clinical practice and evaluation of MRI parameters. Some relationships between clinical variables and gender still remain elusive but with further understanding of sex/gender-related differences, we should be able to provide appropriate patient-centered care and research. The predominance of females among patients with autoimmune central nervous system disorders such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) is well recognized. Several sex-specific factors, including sex hormones themselves and genetics - the presence of two X chromosomes versus one X and one Y chromosome, and environmental and societal factors including dietetic habits might play an important role in susceptibility and manifestation of autoimmune disorders –3. FurthPrevious research naturally focused on the influence of sex hormones, but it seems that hormonal variances between sexes explain clinical differences only to some extent as female sex bias is frequently observed even in autoimmune diseases with onset in childhood when estrogen levels do not differ between sexes, or in postmenopausal women . A possiMS is an acquired inflammatory demyelinating disorder predominantly affecting young females in 2-3:1 female to male (F:M) ratio for relapsing MS in developed countries –19. Furtvia binding to the steroid receptors and have various effects on cells of both the adaptive and innate immune systems  issues in patients with multiple sclerosis, who face substantial challenges stemming from chronic illness in combination with psychosocial and other health factors related to transgender issues . Gender-The female predominance in NMOSD occurring in children and adolescents is seen at the ratio of 1.5:1 and 3.25:1 respectively . The othBrain atrophy, including grey matter and white matter atrophy measurement, is recently becoming a routine marker to monitor the disease in clinical studies and clinical practice. Over the last 20 years, different studies reported significant differences between sexes in variable measures. Generally, it seems that males are showing more, traditionally associated with degenerative processes, grey matter pathology, and atrophy . It seemLesions, predominantly present in white matter, would have an impact on white matter (WM) volume too. This obvious relationship between white matter lesions and white matter volume would explain why studies looking at white matter atrophy are showing more contradictory findings. In some studies, it seems that males show more prominent white matter changes associated with axonal loss than females . In otheUnfortunately, no representative studies are focusing on MRI differences between sexes in NMOSD nor the impact of pregnancy on MRI parameters. In recent decades research paid attention to the role of iron and its metabolism in MS and NMOSD. Brain iron homeostasis is known to be disturbed in multiple sclerosis –81. The in vitro fertilisation) and MRI visible inflammatory activity in MS , therefore expected benefits from this treatment do not outweigh drug-associated risks, and its use in pregnant women is contraindicated . There wAs seen above, sex bias is an extremely important factor (summarized in PN has been involved in source collection and wrote the clinical and immunology section of the article. OD was involved in source collection and wrote the radiology section. Both authors participated equally in the graphic and clinical sections. All authors read and approved the final manuscript.The work was supported by the Czech Ministry of Education – project Cooperatio LF1, research area Neuroscience, by Czech Ministry of Health – project NU22-04-00193, and the project of National Institute for Neurological Research (Programme EXCELES, ID project No LX22NPO5107- funded by the European Union-Next Generation EU.PN has received speaker honoraria and consultant fees from Biogen, Novartis, Merck, Roche, and financial support for research activities from Roche and Merck. OD has received in the past funding for research, speaking honoraria, advisory boards, travel or educational support from Bristol-Myers Squibb, Sanofi Genzyme, Novartis, Biogen and Merck Serono pharmaceuticals.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Drugs administered to children in the United States fall into two broad categories: (1) those that have followed the US Food and Drug Administration (US-FDA) pediatric drug approval process and are marketed as finished dosage forms with pediatric labeling; and (2) all others, many of which are used “off-label”. The use of most drug products in pediatrics is still off label, often requiring special preparation, packaging, and, in some cases, compounding into preparations. The latter category includes compounded preparations that incorporate either a US-FDA approved finished dosage form , or rely on bulk active pharmaceutical ingredients (APIs). Compounded preparations are prepared for individual patients in 503A pharmacies, or on a larger scale and not just for specific patients, in licensed 503B establishments. Critical gaps in the current drug approval process for finished dosage forms have created a proverbial “Gordian knot” that needs to be untangled thoughtfully to facilitate increased production and approval of vitally needed medications for pediatric patients. This opinion will describe current regulatory processes pertaining to pediatrics-only drug approval in the United States. Additionally, discussed are steps required for a product to acquire pediatric labeling. Gaps in regulatory approval pathways for both manufactured and compounded pediatric drugs will be identified, especially those that complicate and slow development and availability to patients. Finally, suggestions for regulatory modifications that may enhance pediatric product development strategies for both manufacturers and compounders are suggested. Great progress has been made in the past 25 years to increase the number of US Food and Drug Administration (US-FDA) approved drugs developed specifically for children. Much of this is attributable to regulatory mandates and incentives enacted via the Pediatric Rule in 1994, the Food and Drug Administration Modernization Act (FDAMA) of 1997, the Best Pharmaceuticals for Children Act of 2002 (BPCA), the Pediatric Research Equity Act of 2003 (PREA) [Pediatric compounding performed in these establishments maintains a critical role in filling these gaps. These pharmacies and outsourcing facilities tailor medicine that can be administered to a child , and thereby foster improved patient compliance and safe use ,6,7,8.The main objective of this paper is to compare these two pathways to identify regulatory ambiguities and challenges, and to propose regulatory improvements to facilitate further development of manufactured products and compounded preparations designed for children.This section describes the US-FDA drug approval process in general terms. More detailed reviews of the overall drug approval process for New Drug Applications (NDA), Biologics License Applications (BLAs), Abbreviated New Drug Applications (ANDAs), and 505(b)(2) applications are available from other sources ,9,10,11.US-FDA approves a new drug and its labeling for public use only after careful review of data from preclinical studies in animals and human clinical trials which permit an assessment of the risks and benefits of the drug product . US-FDA’With an active IND in place, drugs then undergo a multistage process of human clinical testing. The first clinical trials, Phase 1 trials, are designed to assess drug safety, drug absorption, distribution, metabolism, and excretion (ADME), and evaluate different dosing levels. Typically, these studies are performed in a small number of healthy adult volunteers, although under specialized circumstances pediatric patient populations may be enrolled . Phase 2Phase 3 trials are typically randomized controlled trials that compare the safety and efficacy of the drug with a placebo or another drug product approved for the proposed indication. These trials may also study different populations and different dosages of the drug; in some cases, the drug may be studied in combination with other approved drugs to see if the combination improves outcomes. Phase 3 studies vary in size, depending on the number of patient available for study, and the magnitude of the effect of interest; some phase 3 studies are small, while others recruit thousands of research participants. Phase 3 trials are intended to provide the primary clinical evidence of the safety and effectiveness of the drug .If clinical trial results are positive and the drug demonstrates suitable safety and efficacy, the sponsor may file a new drug application (NDA) proposing that US-FDA approve a new drug product for marketing in the United States. The NDA is much more extensive than the IND, and it includes the results of all toxicology and clinical studies. Additionally, in the NDA Chemistry, Manufacturing, and Controls section , updated information is included about the active ingredient and drug product  physiochemical properties, which are now much better understood than at the time of IND filing, with detailed descriptions of drug product manufacturing, processing, and packaging. In addition, since many investigational study protocols require some type of compounding for oral or sterile drug delivery, storage and applicable compounding instructions are included. Other NDA sections include identification of the investigators conducting the research and proposed labeling.https://www.fda.gov/science-research/science-and-research-special-topics/pediatrics. Accessed on 29 November 2022).If US-FDA approves the drug product, further safety monitoring (phase 4 of the process) continues as sponsors are required to submit regular safety updates to US-FDA, summarizing the adverse event reports and complaints received. Additionally, if US-FDA requires additional post-marketing studies as a condition of approval, sponsors must oversee that work to completion, according to the timeline provided by US-FDA. On average, for innovative drug products, the time from IND filing to drug approval, is 9.1 years (range 5 to 20 years) with an average cost of USD $1.3 billion ,16. For The lack of pediatric drug development efforts by the pharmaceutical industry was recognized by legislators and regulators going back to at least the 1970s . Over thCollectively, these programs have been quite successful by many measures. For example, the additional six months of marketing exclusivity granted under BPCA has been applied to 280 US-FDA approved drugs. Under the PRV, drugs for rare pediatric diseases move more quickly through all phases of clinical testing and are more likely to be first-in-class, when compared against drugs for adult rare diseases ,19. NotaBPCA provides funding to National Institute for Child Health and Human Development (NICHD) to fund clinical trials that investigate off-patent approved drugs for pediatric use, with an objective to update product labeling with pediatric-specific safety and sometimes efficacy information .In pediatrics, large clinical trials studying new chemical entities (NCEs) under an initial IND for a pediatric indication are uncommon. Pediatric labeling is more commonly acquired via the supplementary NDA (sNDA) application process for products that are already US-FDA approved. In this case, rather than large clinical trials, studies required by an sNDA may be limited to single-dose PK bridging (adult to pediatric), and collection of safety data in pediatric populations. Use of bridging studies is limited to circumstances where the pharmacology in adults and children is known and expected to be similar.An Agency response to an sNDA can include, in some cases, a Complete Response Letter (CRL). As an example of a CRL, in the case of the drug palonosetron, the FDA issued a CRL to the sponsor’s Pediatric Study Plan (PSP) requesting that compounding instructions be added to product labeling (NDA 021372 and NDA 022233), which illustrates how specific the formulation issues can be incorporated in product labeling [“… a pharmacy compounded palonosetron extemporaneous liquid preparation for oral administration must be developed for chemotherapy -induced nausea and vomiting (CINV-MEC) prevention therapy in pediatric patients. The compounded palonosetron formulation must utilize appropriate oral ingredients . You must also provide the following information for the compounded formulation: active ingredients, diluents, and suspending and sweetening agents; detailed step-by-step compounding instructions; packaging and storage requirements; and formulation stability information. You must provide instructions to pharmacists and health care providers for accurately measuring the volume of IV solution or oral formulation for compounding. Compounding must be performed at 3 or more pharmacies to demonstrate adequacy of the compounding method. Analytical data and statistical results on the compounding method must be provided to the Agency for review .”® . The initial US-FDA approval in 2014 included no pediatric dosing or liquid formulation and package instructions still do not contain compounding information. Based upon the list of capsule ingredients, it could be a real challenge to compound a stable oral liquid [While there is a pediatric indication for palonosetron, it appears the sponsor did not include any extemporaneous preparation instructions in the approved labeling for either the IV or capsule dose forms . In addil liquid  for pedil liquid . CombineThroughout its history, compounding has been considered a critical part of the practice of pharmacy. This section focuses on current regulations and practice as shaped by the Drug Quality and Security Act (DQSA). More detailed historical and legal reviews are available elsewhere ,26,27,28Title I of the Drug Quality and Security Act (DQSA), called the Compounding Quality Act (CQA), organized state and federal oversight of compounding pharmacies into two categories, as 503A pharmacies and 503B outsourcing facilities. 503A pharmacies are more traditional pharmacies that compound preparations in response to an individual prescription and are state licensed. By compounding in an individualized per-patient manner, limiting the amount of compounding performed in advance of prescription receipt, and limiting the volume of prescriptions dispensed across state lines, these pharmacies are exempt from certain provisions of the Food, Drug, and Cosmetic Act. Those provisions include exemptions from the new drug approval requirement (as described above), labeling with adequate directions for use, and current good manufacturing practice (CGMP) requirements. Note the latter two provisions are also part of the new drug approval process. Oversight of 503A pharmacies rests primarily with the state government(s) that have licensed the pharmacy, although US-FDA has issued a guidance that addresses US-FDA inspections of 503A pharmacies .503B outsourcing facilities were created by the CQA and are permitted to compound preparations in bulk without the requirement of the receipt of an individual prescription. They may compound sterile and nonsterile individual prescriptions from bulk substances and also, unlike 503A pharmacies, may distribute compounded drugs to healthcare facilities and practitioners without first receiving a patient-specific prescription . Per theIt is important to note the definition of compounding here to fully understand how the process can benefit individual patient populations, including children. The definition of compounding according to the United States Pharmacopeia (USP) is the preparation, mixing, assembling, altering, packaging, and labeling of a drug, drug-delivery device, or device in accordance with a licensed practitioner’s prescription, medication order, or initiative based on the practitioner/patient/pharmacist/compounder relationship in the course of professional practice (USP <795>) .Preparation of drug dosage forms for both human and animal patients;Preparation of drugs or devices in anticipation of prescription drug orders based on routine, regularly observed prescribing patterns;Reconstitution or manipulation of commercial products that may require the addition of one or more ingredients that is not in the package instructions. [US-FDA does not consider reconstitution or manipulation according to the package instructions compounding; andPreparing a medication in accordance with the package insert instructions is compounding under the USP definition, while it is not under US-FDA’s definition .Drug compounding includes the following:Despite good progress made in getting new pediatric products approved by US-FDA, 503A pharmacies and 503B outsourcing facilities still must compound on a large scale to fill the unmet medical needs of children. While the magnitude of compounding for children is unknown, at least 6 billion prescriptions were dispensed in the United States in 2021, and roughly one-quarter were for oral dosage forms. Of these, anywhere from 1–3% of these prescriptions were for compounded sterile and nonsterile preparations. Approximately one-quarter of compounded prescriptions were dispensed to patients aged 0–19 years . TherefoMost of the newly US-FDA approved pediatric dosage forms are not suitable for the very young (including neonates) and most are not labeled for use in children < 6 years of age, an indicator of a shortcoming of current regulations. On the other hand, compounded dosage forms have been shown to enhance patient compliance to medication regimens and are widely and safely used now . Many ofDespite successes, there are recognized gaps in the US-FDA pediatric drug development initiatives. Regarding Priority Voucher Review programs (PRV), the Government Accounting Office found few studies that examined the PRV programs, and those that did found the programs had little or no effect on drug development overall ,35,36. PConcerns have been raised that delays and a high level of noncompliance with US-FDA post marketing study requests . It woulThe cost of drug development ranges from USD $92 million to $1.3 billion . FurtherOther more effective finished dosage forms that have been developed specifically for children and other special patient groups  can be prepared at 503B outsourcing facilities or 503A pharmacies with proper equipment and methods in place. More effective in this case means dose delivery by mouth is more reliable and caregiver administration is easier. Compounded pediatric preparation formulations can be developed at 503As and Bs that can meet high quality production standards in accordance with USP chapters <795> and <797>. 503A pharmacies are able to compound preparations of complex solutions and suspensions (sterile and non-sterile), lollipops, troches, and buccal preparations. Compounded dosage forms have also been shown to enhance patient compliance or adherence to medication regimens .Regarding post-marketing study requirements often put into place by US-FDA to prompt pharma companies to eventually complete pediatric research commitments, justifiable concerns have been raised about delays and noncompliance with these study requests. For example, overall, 64 percent of new drug and biologic indications deemed relevant to pediatric patients lacked pediatric prescribing information at five years after US-FDA approval .The costs to consumers for the BPCA, PREA, and PRV have been exceptionally high, in the 100′s of millions of dollars per approved drug product. Similarly, the standard level of patent protection (note many 505b2 products have patent protections as well as 505b2 exclusivity) commonly in place for 505b2 approvals  adds another time and cost barrier to development. When the target pediatric population is smaller, it is more difficult to justify the cost of patent and product development. One suggested alternative is that policymakers should consider direct funding of such studies rather than shifting much higher product costs to pediatric patients . Some in®) capsules, rifampin (Rifadin®) capsules, secubitril and valsartan (Entresto®) tablets, valacyclovir  tablets, and valsartan (Diovan®) tablets. US-FDA could encourage other sponsors to include these instructions in the package insert to facilitate proper preparation of alternate oral dosage forms for children and adults that cannot swallow solid oral doses.There are at least six drug oral products known to the authors with formulation and compounding information contained in the package insert, including oseltamivir  and breadth (number of different dosage forms dispensed) of compounded preparations to better understand the extent to which pediatric patients rely on them. This surveillance system will generate data that can be used to better understand the compounding industry and guide responsive policy. US-FDA’s Compounding Incidents Program that reviews MedWatch adverse event entries for compounded drugs is a first step towards better compounding surveillance in general .US-FDA could consider either (a) the creation of a pharmacy compounding grant program for 503A pharmacies and 503B outsourcing facilities in addition to the current grants directed to academic institutions that are involved in compounding practice or (b) foster partnerships between pediatric academic medical centers and registered 503A pharmacies and 503B outsourcing facilities to test and validate evidence-based formulations designed specifically for children.A simplified, safe, and reliable pathway for the authorization of compounded preparations for children, and other special populations, could be developed in conjunction with USP. This can include well defined active ingredient (API) and excipient specifications, along with methods of preparation and finished dosage form tests. Additionally, this pathway can include PK studies  to bridge pediatric findings to adult populations, as is currently allowed for many sNDAs.US-FDA could consider facilitating compounded pediatric preparations by not including frequently compounded APIs on the Bulk Substances Used in Compounding list . The BulUS-FDA could encourage the inclusion of alternate dosage form compounding instructions into the labeling of products that are commonly used in pediatrics. The palonosetron CRL, provided previously, is an example. This is especially important when an approved dosage form cannot be used in children, yet the active ingredient is commonly used in pediatrics, and the stability of compounded preparations limited.ANDA filers  could be permitted to augment labeling with compounding instructions. This would simply require additional in vitro stability studies of compounded formulations, for example a crushed tablet in a well characterized pharmaceutical vehicle. These studies are relatively simple for the generic manufacturers to perform and could add additional value and labeled uses for their specific product. US-FDA could facilitate dissemination of alternate dosage form stability into the product’s labeling when it becomes known, especially when a product is unstable in aqueous or non-aqueous vehicles.Numerous examples exist which illustrate the progress made in pediatric dosage form development. Despite this progress, regulatory challenges continue to stifle development of both US-FDA-approved products and scientifically derived compounded preparations. Notably, the majority of approved products used in pediatrics are used off-label and, in many cases, require compounding prior to dispensing. Specific examples include neuropsychiatric drugs, where development of new molecular entities (NME) for pediatric indications is often an afterthought to the pharmaceutical industry . As anotIn the absence of state regulations or professional or USP educational processes, US-FDA should expand existing surveillance systems to better understand pediatric compounded preparation needs and use. Further, the agency should resource and incentivize registered compounding pharmacies and outsourcing facilities to develop stable, reproducible, and validated preparations, perhaps in partnership with pediatric academic research centers. Finally, a pathway to authorize compounded preparations should be designed, with incentives for 503A, 503B and ANDA filers, that would foster the use of bulk substances as well as permit labeling changes to promote safe compounding practices for pediatric dosage forms.


Neurodegenerative diseases are characterized by the progressive degeneration of the neuronal cells and their networks, hampering the function of the central or peripheral nervous system. Neurodegenerative diseases are a heterogeneous group of disorders that might affect different tissues, such as the brain, retina or spinal cord. This group can include diseases such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s disease (PD), spinal muscular atrophy, spinocerebellar ataxias, age-related macular degeneration (AMD), glaucoma, retinitis pigmentosa (RP) or diabetic retinopathy (DR) . Five ofNeurodegeneration in these diseases seems to be tightly linked to increased oxidative stress and neuroinflammation . HoweverThus, understanding the link between oxidative stress, neuroinflammation and neurodegeneration processes is crucial to defining preventive and interventive measures and developing new therapies for these devastating diseases. This “Oxidative stress in Neurodegeneration and Neuroinflammation” Special Issue aimed to contribute toward clarifying these questions and gather the most recent findings on the role of oxidative stress and its relationship with neuroinflammation and neurodegeneration.The “Oxidative stress in Neurodegeneration and Neuroinflammation” Special Issue comprises seven review articles and six original research articles. Among the review articles, three of them focused on the involvement of oxidative stress in eye disorders, such as vitreoretinal diseases , disease12 analog) to prevent cytoplasmic aggregation of TDP-43 observed in many neurodegenerative diseases [Novel pathogenic mechanisms and therapeutic approaches for eye disorders were described here, holding hope for the development of new treatments for optic neuropathies, based on intravitreal injections of pegylated granulocyte colony-stimulating factor (G-CSF) , and fordiseases , of a nediseases , and on diseases , in the diseases .The works gathered in this Special Issue will certainly help clarify the role of oxidative stress in neuroinflammatory and neurodegenerative processes. This valuable new knowledge will contribute to unravelling new disease pathways, new diagnostic tools and new therapies for such devastating disorders.


Skin is a complex ecosystem colonized by millions of microorganisms, including bacteria, fungi, and viruses. Skin microbiota is believed to exert critical functions in maintaining host skin health. Profiling the structure of skin microbial community is the first step to overview the ecosystem. However, the community composition is highly individualized and extremely complex. To explore the fundamental factors driving the complexity of the ecosystem, namely the selection pressures, we review the present studies on skin microbiome from the perspectives of ecology. This review summarizes the following: (1) the composition of substances/nutrients in the cutaneous ecological environment that are derived from the host and the environment, highlighting their proposed function on skin microbiota; (2) the features of dominant skin commensals to occupy ecological niches, through self-adaptation and microbe–microbe interactions; (3) how skin microbes, by their structures or bioactive molecules, reshape host skin phenotypes, including skin immunity, maintenance of skin physiology such as pH and hydration, ultraviolet (UV) protection, odor production, and wound healing. This review aims to re-examine the host–microbe interactions from the ecological perspectives and hopefully to give new inspiration to this field. The skin is considered a barrier organ against the entry of foreign physical, chemical, and biological insults, thereby maintaining the internal homeostasis of the human body. In the past decades, Human Microbiome Project (HMP) has expanded our perception of the skin as not only a piece of placid “soil” but a vast “ecosystem” that harbors a myriad of microbial inhabitants  and environment   according to the physical properties of anatomical locations  groups are often found in the distal infundibulum, usually with their dorsal body oriented against the hair shaft  pathogen colonization resistance by ecological niche blocking for the invasion of opportunistic or pathogenic microbiota, (2) immune education during early phases, and (3) regulation of immunity and inflammation. Given many comprehensive reviews already on these functions, we will take a particular focus on other functions that were usually missed, including the maintenance of skin physiology, such as pH and SC hydration, UV protection, odor production, and wound healing, which were also important functions in skin homeostasis.C. acnes fermented carbohydrates into propionic acid  activity in skin keratinocytes (KCs) and stimulate inflammation through Toll-like receptor (TLR) signaling   can be metabolized by human skin microbiota into 5-hydroxytryptophan (5-HTP), indole-3-aldehyde (IAId) and other metabolites  -dependent mechanism to prevent excessive damage  and phosphatidylserine (PS), which then act as irritants, causing flaking and irritation under dandruff, a frequent scalp issue and seborrheic dermatitis conditions  that are largely undifferentiated and express abnormally low amounts of stem cell factor (SCF). Commensal bacteria induce KC-produced SCF, promote skin MCs mature. The migration of MCs in the skin is fully dependent on high levels of SCF, as produced by KCs , and enzymes, including superoxide dismutases (SOD), which counteract oxidative stress  is well known to inhibit the cellular growth of The metabolic activities of some skin microbes produce special odors. For example, human body odor is believed to result from bacterial growth and decomposition of secretions from specialized glands in the axillary region  and chemical (carbon sources and metabolites) conditions drive the microbiome composition. In turn, these microbes may reshape this environment via microbe–microbe or microbe–host interactions. Skin surface metabolome may be a critical approach to address causative correlations between the skin microbiome and skin phenome; therefore, future skin microbiome research should leverage those multi-omics to reveal these strong correlations and then validate them with the principle of Koch’s postulates. Furthermore, considering the higher complexity of the system due to the host genome and exposome, the longitudinal time-series study should be taken more into consideration for the control of these variables and for addressing the direction of those networks. Based on solid causative correlations, we can develop accurate interventions targeting specific skin microbe(s) and eventually reshape the skin conditions.Of note, recent studies revealed that microbiota at strain level varies in the local microenvironment  and skin explants) that can reliably simulate the complexity of the host–microbe interactions  was gradually shifted to isolation/culturomics and function validation (mechanisms). However, some significant issues still exist, such as the lack of ideal


Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects the joints. Microbial infection is considered a crucial inducer of RA. Alterations in the composition of intestinal bacteria in individuals with preclinical and established RA suggest a vital role of the gut microbiota in immune dysfunction characteristic of RA. However, the mechanisms by which gut dysbiosis contributes to RA are not fully understood. Furthermore, multiple therapies commonly used to treat RA may alter gut microbiota diversity, suggesting that modulating the gut microbiota may help prevent or treat RA. Hence, a better understanding of the changes in the gut microbiota that accompany RA should aid the development of novel therapeutic approaches. This mini-review discusses the impact of gut dysbiosis in the pathogenesis of RA, the selection of gut microbiota-related biomarkers for diagnosing RA, and provides examples of cross-modulation between the gut microbiota and some drugs commonly used to treat RA. Some suggestions and outlooks are also raised, which may help guide future research efforts. Rheumatoid arthritis (RA) is a chronic, immune-mediated disease in which multiple immune cell types and signaling networks misfunction to elicit a maladaptive tissue repair process; this leads to organ damage, predominantly in the vascular system, lungs, and joints . RA affeBacteroides fragilis is associated with enhanced activity of regulatory T cells (Tregs), which may alleviate autoimmune disease   . Tregs aesponses , 30. Stuesponses , 32. Micesponses . Therefoesponses   by disrupting the integrity of the intestinal mucosa  and leukotoxin A, which triggers in turn endogenous PAD activation in neutrophils  from patients with early RA into germ-free SKG mice can induce severe arthritis  mice, which develop spontaneous arthritis due to excessive IL-1 signaling, with indigenous Lactobacillus bifidus resulted in rapid onset of arthritis that reached incidence rate and severity scores comparable to those recorded in non–germ-free mice  reported that the abundance of microbes . Transplrthritis . In addiividuals . Studiesree mice . It was omyalgia .Haemophilus spp. in the patients’ gut, teeth, and saliva correlated negatively with RA severity and serum antibody levels. In contrast, Lactobacillus salivarius was present in increased amounts in cases of very active RA  refers to the introduction of gut microbiota obtained from the feces of a healthy donor into a patient’s gastrointestinal tract . NormaliDMARDs may indirectly affect and remodel the structure and function of gut microbiota to regulate systemic immunity. Studies have demonstrated that microbial differences in the gastrointestinal tract of RA patients may partially determine the bioavailability and subsequent clinical outcome of methotrexate , 64. In Clostridium perfringens and Escherichia coli , as well as with decreased abundance of Clostridiaceae and Deltaproteobacteria ; Construction Project of National TCM Clinical Research Base (2018 No. 131); Yunnan Provincial Fund for Medical Research Center: Clinical Evaluation and Basic Research on the Treatment of rheumatoid arthritis and gout by TCM (202102AA310006); Clinical Trial for the Treatment of Rheumatoid Arthritis with Warming yang and Smoothening Meridians ; Clinical Cooperative Project of Chinese and Western Medicine for Major and Knotty Diseases; Yunnan Provincial Key Laboratory Construction Project Funding; Yunnan Provincial Key Laboratory of Chinese Medicine Rheumatology and Immunology; Yunnan Provincial Ten Thousands Program Famous Doctor Special; Yunnan Province Qingguo Wang Expert Workstation Construction Project (202005AF150017); Yunnan Applied Basic Research Projects- Union Foundation [2019FF002(-031)]; Applied Basic Research Programs of Science and Technology Commission Foundation of Yunnan Province (2019FA007); Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Neuropsychiatric Diseases, Yunnan Provincial Department of Education; Scientific Research Projects for High-level Talents of Yunnan University of Chinese Medicine (2019YZG01); Young Top-Notch Talent in 10,000 Talent Program of Yunnan Province (YNWR-QNBJ-2019-235).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Whether “population health” encompasses a concept of health or a field of study of health determinants is not yet defined, though the term is widely used in healthcare and research worldwide . CommonlBy focusing more on groups rather than on individual patients, population health is crucial for promoting improvements in the quality of health services through evidence-based decisions, the correction of social and economic determinants of health, and health expenditure revisions.International Journal of Environmental Research and Public Health offers insights into fundamental research on population health. A significant collection of contributions and studies is presented. Each of them adds interesting findings to meet the evolving challenges of population health, and suggests future directions for further research in the field. The collected articles cover, indeed, a wide range of thought-provoking topics , hepatitis C virus (HCV), and high-risk human papillomavirus (HPV) types—were found to be responsible for the vast majority of this burden. Since one-twelfth of cancer deaths were attributable to risk factors which are both preventable and treatable, this research provided data that may inform policies and promote targeted interventions to reduce the impact of infections on cancer mortality [The first Special Issue paper explored the burden of cancer mortality attributable to carcinogenic infections in Italy, which accounted for 8.3% of total cancer deaths. Four carcinogenic infectious agents—Hajek and König identified an unexplored association between post-materialism—the transformation of individual values that emphasize self-expression and quality of life over economic and physical security—and the frequency and reason for doctor visits. Compared with materialism, authors found a reduction in doctor visits associated with post-materialism, both in the total sample and women. Although the male subsample was rather small to reach firm conclusions, in post-materialistic women, visiting doctors was less likely for chronic illnesses and more likely for reasons of preventive medical check-up/vaccination. The study offers thought-provoking insights for further research to confirm results and understand underline mechanisms .In their research, Khodabandeh et al. developed a detailed mathematical model aimed at remodelling traditional home healthcare organization with the goal of minimizing total costs. By considering a travel balancing hypothesis, the authors proposed a straight-forward model that could be exploited to minimize the downgrading costs, which characterize the difference between the potential and actual skills of the nurses. The study also provides useful insights that are helpful to inform managerial decisions to better allocate available resources .Readmission after discharge from long-term home care leads to a relevant health burden and considerable costs. Su et al. suggested the application of the LACE index for readmission, a tool normally used to predict 30-day readmission or death in patients in hospital wards. Although accuracy issues need to be better addressed through further analysis, the strategy seems to halve readmission of long-term home care patients, with the highest effect for infection-related problems .Keeves et al. analysed allied health professionals’ (AHPs) awareness and perceptions towards factors impacting the access to healthcare for people following serious injury in Australia. Participants confirmed that barriers existed in both urban and regional areas, being particularly prevalent in the latter. Major barriers were related to the complexity of funding systems and health services. Authors suggested that more research should explore which improvements could ensure equitable access to healthcare, while also considering the heterogeneity of the trauma population .Kim et al. conducted a nested case–control study using Korean national health screening data to investigate the association between anaemia and an increased risk of osteoporosis, two globally widespread conditions in women ,9. The fIn an another study, the same authors also investigated the association between statin use and the occurrence of Meniere’s disease, considering previous evidence of statins having a protective effect against inner ear diseases. The findings did not support this relationship in the adult population, though a possible inverse association of previous lipophilic statin use with Meniere’s disease was suggested .Around 1.3 billion people use tobacco worldwide, and more than 7 million die prematurely every year due to smoking . DespiteTo learn how socio-environmental characteristics influence mental health outcomes differently among women and men , Gupta eLastly, Bae’s research aimed to identify factors that affect absenteeism and presenteeism in the Korean working population, suggesting that workers’ quality of life and productivity could be improved by focusing on factors including fatigue, high temperatures at the workplace, and lower back pain as predictors of presenteeism .Despite the variety and heterogeneity of the topics discussed in the presented articles, this Special Issue contributes both to advancing and stimulating the scientific debate about population health, and also enriches the current body of evidence, implications, and impacts. Taken together, all contributions emphasize that research needs to better integrate health outcomes’ distribution to inform health interventions and policies.


Digital health technologies applied by the pharmaceutical industry offer opportunities to improve access to care for patients with noncommunicable diseases in low- and middle-income countries. Pharmaceutical industry–led access programs have benefited from the application of digital health technologies (DHTs) to educate and empower patients with noncommunicable diseases (NCDs) to make better-informed decisions about their health and to enhance service delivery through telemedicine, telepathology, and capacity building of health care workers.DHTs applied by global pharmaceutical companies in their access programs that aim to improve NCD care in low- and middle-income countries are primarily implemented across sub-Saharan Africa and mostly directed toward health providers. Digital technologies targeting data services and patient populations were also commonly applied to respectively collect, manage, and use data, as well as to enhance patients’ disease management, awareness, and medication adherence.Evidence on pharmaceutical industry–led DHTs may enable national stakeholders to identify opportunities to promote access to NCD care in various health system contexts and prevent siloed work across sectors. Moreover, it may provide guidance and orientation to policy makers in identifying duplicative and redundant digital health efforts that may overburden local health systems. There is limited research on how digital health technologies (DHTs) are used to promote access to care for patients with noncommunicable diseases (NCDs), particularly in low- and middle-income countries (LMICs). We describe the use of DHTs in pharmaceutical industry–led access programs aimed at improving access to NCD care in LMICs.The Access Observatory is the largest publicly available repository containing detailed information about pharmaceutical industry—led access programs targeting NCDs. The repository includes 101 access program reports submitted by 19 pharmaceutical companies. From each report, we extracted data relating to geographic location, disease area, beneficiary population, use of DHTs, partnerships, strategies, and activities. Data were analyzed descriptively using SAS Statistical Software and categorized according to the World Health Organization Digital Health Classification Framework.A total of 43 access programs (42.6%) included DHTs. The majority of programs using DHTs were clustered across sub-Saharan Africa (72.1%) and targeted cancer (60.5%) followed by metabolic disorders (39.5%). The applied DHTs mostly related to program strategies on health service strengthening (74.4%) and community awareness (41.9%) and were largely directed toward health providers, followed by data services and clients. Only a few DHTs were used for health system management. To promote access, most DHTs focused on improving data collection, management, and use (51.1%); building health provider capacity through training (37.2%); and providing targeted patient information (34.8%).The range of DHTs applied by the pharmaceutical industry offers opportunities for more effective access to NCD care. Transparent reporting on DHT use and its contributions to access programs’ achievements may reduce duplicative and redundant efforts and provide learnings for private and public stakeholders that may contribute to greater access to NCD care in LMICs. However, few health systems in LMICs are organized to meet the needs of NCD care, which includes long-term and continuous care.,Reducing the burden of NCDs and achieving universal health coverage are among the United Nations’ 2030 Sustainable Development Goals, and the pharmaceutical industry plays an important role in achieving these goals. As a result of the global agenda combined with greater attention from investors, employees, and patients, the pharmaceutical industry has expanded its efforts to strengthen its environmental, social, and corporate governance initiatives.Several access initiatives focusing on NCDs in LMICs have been established by pharmaceutical companies in recent years.Pharmaceutical industry–led access programs have benefited from the application of DHTs to inform, educate, and empower patients to make better-informed decisions about their health.–,The World Health Organization (WHO) and others in the global health community have recognized DHTs as having a large potential to promote access to health care in LMICs.In this article, we aim to describe the use of DHTs in pharmaceutical industry–led access initiatives targeting NCDs in LMICs. The pharmaceutical industry plays an important role in digital health solutions targeted at NCDs with its plentiful resources and business agenda to enhance access in emerging markets. Our findings may shed light on potential pioneer technologies targeting NCDs that may be beneficial for national stakeholders in terms of strengthening health systems and reaching the health-related Sustainable Development Goals. Moreover, these findings may provide guidance and orientation to policy makers in terms of identifying duplicative and redundant digital health efforts that may overburden local health systems.There are many definitions of digital health. According to WHO, the term digital health is rooted in eHealth, which is defined as “the use of information and communication technology (ICT) to improve health.”Supplement 1). Clients are members of the public who are potential or current users of health services. Health care providers are members of the health workforce who deliver health services. Health system or resources management involves the administration and oversight of public health systems. Interventions target managerial functions related to supply chain management, health financing, and human resource management. Data services relate to data collection, management, use, and exchange. A DHT can be classified within multiple WHO categories.We use the WHO Digital Health Classification Framework to describe DHTs. The framework aims at providing a shared language to articulate functionalities of digital technologies for health. It includes 4 main categories of interventions for: (1) clients, (2) health care providers, (3) health system or resource managers, and (4) data services.In addition to using the WHO Framework to describe DHTs, we describe the functionality of the applied DHTs by using Rockers et al.’s taxonomy of program strategies, which includes 11 strategies that are organized into 4 broad categories .4 AccessBOXCommunity strategiesCommunity awareness and linkage to care: Programs providing communities and patients with health-related information on disease prevention and treatment or improve links between patients and the health care system.System strategiesHealth service strengthening: Programs designed to improve the availability, affordability, and quality of health services.Health service delivery: Programs designed to deliver health services, such as screening, diagnosis, and treatment, directly to the patient.Supply chain: Programs designed to improve medicine supply chains, to improve availability and lower costs.Financing: Programs designed to improve health financing systems and reduce catastrophic health expenditure.Regulation and legislation: Programs designed to improve government coverage and access to treatments and/or improve in-country regulatory processes through, for example, advocacy, training, and infrastructure.Production strategiesManufacturing: Programs designed to build capacity for medicine production.Product development and research: Programs designed to support product  development and research.Licensing agreements: Programs designed to facilitate the manufacture, importation, sale, or use of medicines through legally binding relationships, including voluntary licensing agreements and technology sharing.Price strategiesPrice scheme: Programs designed to increase the affordability of medicines for individuals and health care systems through a change in the price via subsidies or other means (excluding donations).Medicine donation: Programs designed to increase the availability and/or affordability of medicines through direct donation of medicines and other health care products to countries, health institutions, or nongovernmental organizations.Adapted from Rockers et al.The Access Accelerated is an initiative established by 23 biopharmaceutical companies, the World Bank, and the Union of International Cancer Control. Together, they are committed to expanding their efforts to improve access to NCD prevention, care, and treatment in LMICs.Supplement 1).Each program report registered within the repository was reviewed independently by the first (ACSH) and second author (CMC) of this publication. A spreadsheet was used to extract information systematically from the repository program reports on the following variables: whether the program applied DHTs to improve access to prevention, care, and treatment of NCDs; a description of the DHT, including countries of implementation and targeted disease area; stakeholders and partnerships involved in implementing the DHT; which program strategy the DHT related to according to Rockers et al.’s program strategy taxonomy 4; and clDiscrepancies in the 2 independently completed spreadsheets were discussed between the first and second author until agreement was reached. In cases of doubt, company and program websites were reviewed to learn more about the program and application of the specific DHT.The final spreadsheet with content agreed to by the first and second authors was imported into the statistical software SAS Studio 3.81. Subsequently, descriptive frequency analyses were performed to generate an overview of the range of technologies, their countries of implementation, targeted disease areas, applied strategy, and WHO classification. Bivariate analyses were performed to assess differences between access programs employing DHTs and programs where DHTs are not applied. Differences in proportions between groups by DHT use were tested with a Fisher’s exact test, which is recommended for small-sized samples.A total of 19 companies have registered their access programs in the repository. The majority of companies reported on multiple access programs resulting in 101 program reports for review. The registered programs were initiated between 2009 and 2020, and 61 remain active at current date.Supplement 2.Of the 101 programs, 43 programs (42.6%) from 12 companies (63%) included a DHT as part of their access program. An overview including descriptions of each of the DHTs, relevant strategies, and WHO classifications can be found in Supplement 2). Nine programs (20.1%) using DHTs were implemented across multiple regions, including 3 programs implemented in high-income countries. There were no statistically significant differences in countries of implementation between access programs employing DHTs versus programs without DHTs.The P=.03).The disease areas targeted by the DHTs were primarily cancer  or metabolic disorders , including type I and type II diabetes. Industry-led programs targeting metabolic disorders, particularly type 2 diabetes, were significantly more likely to apply DHTs than not (P=.03), health service delivery (P=.02), price scheme (P<.01), and medicine donation (P<.01).Of the 11 different program strategies listed in the Access Observatory taxonomy , 5 stratDigital health solutions applied in the programs mostly targeted health care providers , followed by data services , clients , and health system management .Programs aiming to enhance access to NCD care through health service strengthening, community awareness, and health service delivery mostly applied DHTs directed toward health care providers.Supplement 2). Other examples of digital training include virtual workshops to upskill primary health care providers on the topic of mental and neurological disorders  and eLearning platforms with online modules that health care providers can complete at their own pace with interactive webinars organized by local psychiatrists .In addition, client health records were the target of DHTs in multiple access programs (n=14) aiming at health service strengthening and health service delivery. These DHTs involve electronic patient medical record systems that securely document patient data that enable health providers to provide accurate referrals and follow-ups and to facilitate patient management and treatment, particularly in areas of oncology, diabetes, and cardiovascular diseases. As an example, 2 of these programs in Kenya used the Mobile Jamii Afya Link to enable community workers to accurately and efficiently collect and manage NCD patient data at the household, community, and medical facility levels. Electronic systems for health records were among other methods used to improve tracking of disease incidence and burden of disease cases at various hospitals, as well as to inform policy making.DHTs enabling health care provider decision support were also applied frequently (n=10). These include electronic risk factor screening tools for lung cancer and mental health; electronic medical records with decision-support functions that provide relevant prompts and alerts , and electronic classification tools that assess and alert health providers about patients’ risk of cancer treatment abandonment. Other decision support DHTs include digital protocols for treatments, patient information, and platforms to seek advice from specialists, such as psychiatrists and oncologists.DHTs enabling health care provider decision support were also applied frequently.Supplement 2) that enable diabetes and mental health–related consultations between remote health care providers and doctors during real-time visits with patients. DHTs, including text messages, phone calls, and mobile apps, were also used to monitor and inform patients about adherence to treatment and health management in relation to diabetes, cancer, and general NCDs.Telemedicine DHTs (n=10) include those that enable consultation for case management and knowledge exchange between health care providers or those, such as the Vula mobile app, (Supplement 2.Less frequent was the application of DHTs enabling laboratory and diagnostics imaging management (n=6). The ones included involved establishment and expansion of telepathology services that allow efficient and secure transmission of clinical pathology images between providers at a large hospital and between health centers participating in the respective access programs, targeting primary childhood and lung cancer, as well as cardiovascular disease and diabetes. Information about the additional DHTs that were applied less frequently  can be found in DHTs targeting data services mostly focused on enabling data collection, management, and use (n=22). The technologies include an online platform synthesizing data of all practicing and registered oncology professionals from East, Central, and Southern Africa . Moreover, digital data collection tools help securely register and track population and patient data. One mobile health care platform, M-TIBA, developed by PharmAccess Foundation, Safaricom, and CarePay and used by Ngao Ya Afya in Kenya, functions as a mobile health wallet that also generates data on costs and outcomes of care at an individual patient level. Another digital software used by the Save Her Ghana project collects data for inventory management.Six programs included DHTs that enable data exchange across systems that ensure secure communication and data governance, such as within hospital departments; between hospitals, collaborating partners, and lower-level centers; and between patients, providers, and payers. Digital software to upgrade and implement CanReg 5, a multiuser platform and open-source tool to input, store, check, and analyze cancer registry data, was also an integral part of the Secure the Future access program in Swaziland. Lastly, DHTs enabling location mapping were used by the Remember I Love You project for dementia patients in China and by AMPATH for oncologists in East, Central, and Southern Africa.Client-focused DHTs often entail targeted client communication (n=15). Technologies include digital patient education materials on disease and treatment, disease-specific websites and social media channels, disease awareness SMS campaigns, phone-based treatment reminders, disease management support and free-of-charge medicine arrangements, artificial intelligence–enabled chatbots for patients, and electronic toolkits in multiple languages and cultural adaptations developed for Android and iOS. The Mobile Healthcare Field Clinic Services included a DHT aimed at more untargeted client communication, namely general awareness campaigns on immunization and disease prevention in selected communities in Tanzania.Client-focused DHTs often entail targeted client communication that deliver patient education information, treatment reminders, and disease management support.Digital health technologies targeting clients also include the mobile app for personal health tracking (n=1) developed under the Sparta project that enables patients receiving therapies to track and self-monitor diet, weight, exercise, and test results. Novartis Access and Ngao Ya Afya included DHTs that enable clients to look up their own health information (n=2).Lastly, the mobile wallet M-TIBA facilitates financial transactions for clients related to health service delivery. The wallet allows people to save money and receive insurance or other entitlements ring-fenced for health care that can be spent in connected clinics. By using M-TIBA, the Ngao Ya Afya program gives patients access to discounted diabetes and hypertension consultations, medical tests, and discounted company medicines.Programs using health system management DHTs (n=9) were largely focused on strengthening supply chain management (n=3), which included technologies for management of oncology and general NCD medicine stock and support functions for demand planning and inventory management. The DHT used in Blueprint for Innovative Healthcare Access also enables rapid communication and solutions between the different hierarchical levels of the supply chain, such as collaboration between facilities.Other DHTs targeted human resource management (n=2). The Integrated Cancer Curriculum program in Kenya included a DHT aimed at training primary health care providers in cancer care management. Once trained, each health provider is certified and becomes a resource for the National Cancer Institute and Ministry of Health Kenya. The DHT then allows for identification of trained providers for cancer management training opportunities with other primary health care providers. The AMPATH program also used an online platform with an accessible database of all practicing and registered oncology professionals, including their qualifications and contact information, within East, Central, and Southern Africa.Two programs applied DHTs for health financing (n=2), including Rightmax software for management of funds used by the Secure the Future Uthukela lung cancer program in South Africa and the mobile wallet M-TIBA, used by Ngao Ya Afya to allow diabetes and hypertension patients to manage health budgets and expenditures.A single program applied a DHT that enables digital birth registration and strengthening of civil registration and vital statistics in Kenya. Another program, Instrumental Access, developed by the U.S.-based nonprofit organization Seeding Labs and implemented across LMICs in multiple regions, included an online portal for local universities to submit requests for equipment to support their local general NCD research programs.,–There is a need for more research and information on the use of DHTs within health systems, particularly in LMICs.Overall, the programs that applied DHTs were similar to programs that did not use DHTs in terms of country of implementation and targeted disease areas. However, industry-led access programs targeting type 2 diabetes in LMICs were significantly more likely to apply DHTs than not. This finding may be explained by the fact that DHTs to support people with type 2 diabetes have been growing rapidly and are among the most commonly available.In terms of access strategy, programs targeting health service delivery and community awareness were surprisingly less likely to apply DHTs. Digital technologies evidently exist to facilitate community awareness, such as providing communities and patients with health-related information on NCD prevention, as well as health service delivery, such as screening, diagnosis, and treatment. Our finding may reveal an opportunity for sharing best practices among stakeholders on how DHTs can be used effectively to facilitate community awareness or health service delivery. For example, only 2 companies used DHTs to provide screening for cancer and mental health disorders, respectively. For programs focusing on patient medicine donation and pricing schemes, DHTs may be less relevant.We used a combination of the Access Observatory Strategy Taxonomy and the WHO Digital Health Classification Taxonomy to present the employed DHTs by health system function  and target . Among the identified DHTs, most were applied in relation to health service strengthening followed by community awareness and health service delivery. The programs focused on health service strengthening, health service delivery, and community awareness mostly used DHTs to target health care providers. This finding aligns with existing literature that attests to the potential of DHTs to achieve health workforce improvements in LMICs.The reviewed DHTs reveal existing opportunities that can be scaled to upskill health providers, enabling them to facilitate patient management and treatment and to provide accurate referral and follow-up.Global Strategy on Digital Health, the WHO stresses the need for a strong legal and regulatory base to protect the integrity and availability of data.Data-focused DHTs were employed in more than half of the programs that used DHTs. These DHTs hold tremendous power to generate real-world data on the delivery of care, clinical outcomes, and epidemiology of NCDs, which can be harnessed to help address the disease burden of NCDs at global, national, regional, and local levels.For client-focused DHTs, we found that pharmaceutical companies largely focus on delivering disease-specific communication and general awareness to patient populations. This trend is likely connected to the rapid increase in mobile phones, smartphones, Internet, and social media across LMICs, which provides an opportunity to digitally educate patients suffering from NCDs in an effective, efficient, and cost-saving way. Digital medical reminders, prescription assistance, advice, and support to change lifestyle behaviors and manage disease and pharmaceuticals have proven to be effective in terms of improving NCD risk factors and health outcomes,,Lastly, only a few DHTs targeted health system management . Management of these aspects within health systems is critical, particularly in low-resource settings where efficient use of resources is necessary to achieve health-related goals. Strengthening core health system functions, such as management, are likely to be less of a priority for pharmaceutical companies compared with, for example, enhancing provider knowledge and patient awareness, as these may yield more rapid results in terms of market expansion. Nonetheless, most data-focused DHTs, particularly those involving data collection, use, and management, also facilitate health system management in LMICs. By introducing digital data collection tools, such as DHIS2,,,,,This article found that a plethora of technologies is being implemented within and across LMICs. The general descriptions of the DHTs in program reports made it difficult for the authors to assess whether similar technologies described in multiple program reports were identical. Specifically, many DHTs implemented by various companies used similar-sounding digital platforms for provider training, tools for collecting patient records, and data systems. Efforts have been made to strengthen the coordination of ICT investments made by international NGOs to reduce duplicative efforts,,Moreover, few program reports in the Access Observatory repository include data values demonstrating DHT implementation outcomes and impact in terms of improving NCD care. Most of the program reports in the Access Observatory provide data on output indicators . Meanwhile, there is limited data on outcomes and impact indicators .To facilitate improvements in digital health governance, policy makers and investors should make the case for robust measurement and transparent reporting on industry-led DHT implementations in LMICs.P<.05) could prove significant in a larger sample. Finally, the reporting of access programs to the Access Observatory is voluntary; as a result, the sample of access programs studied is not representative of all pharmaceutical industry–led access initiatives. However, the Access Observatory contains reports from 19 of the world’s leading pharmaceutical companies, differing in size, product portfolios, and geographical reach, and thus serves as the largest and most comprehensive repository of pharmaceutical industry–led access programs with data on DHT use. Currently, it is the best available data source to study these programs.The following limitations need to be taken into consideration. The focus on NCDs in the Access Observatory database may likely have caused companies to report solely on DHTs that target NCDs specifically. Other DHTs that may be in use by the industry to address broader health system challenges may thus not have been captured, despite these potentially having indirect yet significant effects on NCDs in LMICs. Moreover, shortcomings exist in company reporting on their access programs, including their descriptions of applied DHTs. Limited information is provided on functionalities of the DHT, potential barriers and facilitators of DHT implementation, developers, costs, fruitful partnership models, and level of integration in local health systems. The program reports were not intended to collect information on DHTs specifically; thus, more comprehensive insights into the mentioned aspects of DHTs use are encouraged in future research, ideally through in-depth case studies of pharmaceutical companies’ application of DHTs. The reports’ shortcomings may have affected the authors’ ability to correctly identify whether DHTs were applied in the access program. Through the systematic review of 101 access program reports, we found that less than half of the reviewed programs employed DHTs. Naturally, not all access programs are prone to apply DHTs. Secondly, the limited level of detail provided in the reports may have hindered the authors’ ability to classify the DHTs accurately in terms of the WHO Digital Health Classification Framework. Thirdly, the test of statistically significant differences between programs using DHTs versus those not using DHTs may have been influenced by the small sample; an effect that failed to be significant (The pharmaceutical industry plays a significant role in achieving the United Nations Sustainable Development Goals, including those related to NCDs, and thus, their efforts are important to explore. The DHTs implemented by pharmaceutical companies addressing access barriers should be recognized and so should their efforts in reporting on these and making the information publicly available in the Access Observatory. However, in the future, companies should aim and be held accountable to provide more robust measurement and reporting on their digital health implementation efforts. Transparency on the use and effect of DHTs can reduce the number of duplicative and redundant efforts and facilitate partnerships that can have greater impact on reducing NCDs in LMICs.


Leptospira spp. include culture, histopathology and immunostaining of tissues or clinical specimens, and nucleic acid amplification tests (NAATs). Indirect serologic methods to detect leptospiral antibodies include the microscopic agglutination test (MAT), the enzyme-linked immunosorbent assay (ELISA), and lateral flow methods. Rapid diagnostics that can be applied at the point-of-care; NAAT and lateral flow serologic tests are essential for management of acute infection and control of outbreaks. Culture is essential to an understanding of regional knowledge of circulating strains, and we discuss recent improvements in methods for cultivation, genomic sequencing, and serotyping. We review the limitations of NAATs, MAT, and other diagnostic approaches in the context of our expanding understanding of the diversity of pathogenic Leptospira spp. Novel approaches are needed, such as loop mediated isothermal amplification (LAMP) and clustered regularly interspaced short palindromic repeats (CRISPR)-based approaches to leptospiral nucleic acid detection.A One Health approach to the epidemiology, management, surveillance, and control of leptospirosis relies on accessible and accurate diagnostics that can be applied to humans and companion animals and livestock. Diagnosis should be multifaceted and take into account exposure risk, clinical presentation, and multiple direct and/or indirect diagnostic approaches. Methods of direct detection of  Leptospira. Recent advances in diagnostic approaches have led to a growing awareness of the broad distribution and diversity of leptospiral pathogens both in infection and in the environment. Human infection is a leading yet neglected source of morbidity and mortality, with more than 1 million cases and ~60,000 deaths per year type a) as ubiquitous and represented most horse and all canine isolates whereas type B2b (Bratislava subserovar 2 [geno]type b) was only isolated from pigs. Type M2a (Muenchen subserovar 2 [geno]type a) represented most pig isolates whereas type M2b (Muenchen subserovar 2 [geno]type b) were only isolated from wildlife [A positive FAT result confirms morphologic and antigenic detection of a pathogenic leptospire; but no serovar or species information is provided. A positive PCR result can be further analyzed to identify species, but not serovar. Livestock animals are susceptible to multiple species of pathogenic leptospires. In addition to wildlife .Leptospira spp. that have not yet been assigned to a designated serogroup. For example, L. tipperaryensis serovar Room22 was only ever cultured in Ireland and represents an entirely new serovar and serogroup, as no reference serogroup antisera react with serovar Room22. The USDA’s National Veterinary Services Laboratories (NVSL) recently started including serovar Room22 in their MAT surveillance panel and occasionally observe agglutination of this organism with serum samples from cattle in the U.S. and other international samples being screened for import . Although it is unknown whether there is an association between infection with serovar Room22 and disease in livestock, this serovar circulates outside Ireland and agricultural animals can be exposed to it. Equally important is the inclusion of representative serogroups/serovars from local geographic locations. When 855 sera from dogs in Greece were screened for seroreactivity by MAT, the highest seroprevalence was to the novel, local serovar Altodouro belonging to the Pomona serogroup [Given the global movement of agricultural animals across borders and their frequent interactions with wildlife and invasive feral animals, comprehensive MAT panels representing most serogroups are required to effectively determine serogroups that livestock are exposed to . MAT panerogroup . AlthougMycobacterium tuberculosis and Listeria monocytogenes [Novel diagnostic methods with lower barriers to implementation are urgently needed in regions with underdeveloped medical resources. Pathogen detection diagnostics with high sensitivity and specificity in early infection have the greatest potential for impacting care for patients with leptospirosis. Isothermal nucleic acid amplification systems including loop mediated isothermal amplification (LAMP) are an approach for the detection of leptospiral DNA near-to-care . Potentiytogenes ,171. Recytogenes . The adaThe conclusions, findings, and opinions expressed by authors do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors’ affiliated institutions. Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the U.S. Department of Agriculture, the Public Health Service or the U.S. Department of Health and Human Services.


As an innovative tactic, the core aspects of green products should be comprehensively demonstrated and firmly promoted to enhance their adoption. For doing so, continuous governmental support and interventions through distinct sets of networking and relationships could be crucial for synthesizing and diffusing the extent of green production demonstration households. Interestingly, the structural relationship between these two has not yet been evaluated comprehensively by the existing literature. Therefore, the study empirically analyzes the impact and mechanism of government relationships embedded in fostering green production demonstration households. The study compiles the empirical data from 963 farmers which were collected from the major tea-producing areas of Shaanxi, Sichuan, and Anhui provinces, China. In order to craft the findings, first we constructed the ordered Probit for benchmark regression analysis. Meanwhile, the Ordinary Standard Error Ordered Probit model, Ordered Logit model, and multivariate linear model were constructed for the robustness test. Third, the Extended Ordered Probit model and Bootstrap mediation effect model were used to test the path diagram. Finally, robustness testing and endogeneity processing test were used to explore the reliability of the findings. The results showed that: (i) Government relationship embedding has a positive effect on fostering green production demonstration households. In particular, factors such as relationships with general government staff, professional and technical personnel, and village cadre are most significant. (ii) Seemingly, the heterogeneity analysis shows that the farmers with large operating scales and low family economic status have a relatively stronger impact. (iii) Further mechanism research results show that government relations are embedded through government identification , improving farmers’ behavioral ability , and strengthening farmers’ perceived value of green production . Therefore, the government should strengthen the interactive mechanism embedded with farm households and extend support for green production demonstration zones. The farmers’ information-sharing facilities and platforms should be modernized and highlighted according to the local conditions and long-term targeted strategies. Since the reforming and opening up in 1978, the agriculture sector of China has witnessed an outstanding and quick transformation phase from traditional to relatively modern agriculture tactics through the greater interaction of technological and social transitions . MoreoveAs with most other agricultural products, tea production and distribution are also contributing to massive environmental issues from altering biodiversity, degrading soil, and water pollution to shrinking the forest area which results in a massive impact on climate change and possesses greater vulnerability to its impact as well . MoreoveHowever, tea is produced globally by following conventional methods and thus it is challenging to foster green production within this dynamic industry ,17. LikeTherefore, how to form green production demonstration households has become a key issue for the government in promoting a green production promotion system and enhancing the adoption level of green production applications. As dynamic and multidimensional aspects, the effective embedding of government relations in the cultivation of green production demonstration households has become a focal point for the government . MoreoveInterestingly, the existing literature has not paid much attention to critically exploring the interrelationships between the effects of government support and relationship embeddedness in formulating and popularizing green production demonstration households. Which eventually results in the frequent occurrence of “demonstration breaks” and the gradual loss of the diffusion effect of green production within the rural regions ,30. In rThe above-mentioned discussion has led us to the following research questions that need to be explored more critically and comprehensively: (i) what are the key channels by which government can foster relational embeddedness? (ii) What factors may impact the relationships most? (iii) Whether, and how do, the behavioral capabilities and socioeconomic factors and perceptions possess an impact on the relationship between government and the green production demonstration households? Therefore, to answer those research questions, the study constructs a theoretical framework for empirically exploring the interrelationship between the relational embeddedness of government and green production demonstration households. In the theoretical framework, we particularly integrated various core channels and major statutory and behavioral factors that may possess influence in rectifying governmental relational embeddedness based on an extensive literature review. The study uses the survey data of 963 farmers collected from the major tea-producing areas of Shaanxi, Sichuan, and Anhui provinces, China to craft its findings. The principal contribution of the study is to expand the “diffusion of innovation theory” proposed by Rogers . MoreoveThe prime objective of the study is to explore the connection between governmental relational embeddedness and green production demonstration households in an integrated manner. Governmental relational embeddedness is a form of social embeddedness, that is the connections between socioeconomic activities and interpersonal behavior and includes things such as social communication, having shared common attributes, and ecological protection . AccordiCurrently, the tea industries are facing several socioeconomic and environmental challenges, such as the widespread overuse of pesticides and fertilizers , the insGreen production demonstration households are embedded in the interaction network between farmers and the government ,45. ThisHypothesis 1 (H1).The embeddedness of government relations may influence the formulation of green production demonstration households.According to the core concept of different embedded subjects, government relationship embedding can be subdivided into three forms: relationship embedding with (i) the government’s general staff, (ii) professional and technical personnel, and (iii) village cadre relationship embedding (for more details see Wei and Li ). HoweveInterestingly, compared with general governmental bodies, professional and technical personnel enjoy higher acceptance among farmers because of their superior technical status and professional knowledge ,63. In mThe relationship between village cadres is built based on generational familiarity, close daily interactions, and a high attribute of trust ,72. WhenHypothesis 2 (H2).The relationship between general government staff, professional and technical personnel, and village cadres may impactfostering the embeddedness of green production demonstration households.The existing literature .The age of the household head and the knowledge regarding internet usage may impact the formulation of governmental relations embeddedness for fostering green production demonstration households.The scale of management and the degree of non-agricultural income are important indicators of the characteristics of family management. Compared with ordinary farmers, farmers with large operating scales are more capable of green production behaviors ,95, moreHypothesis 4 (H4).Households’ farming scale and income from the non-agricultural source may have an impact on green production demonstration households embedded in government relations.Familial technical status and knowledge, economic status, and political status are extremely important to farmers’ behavior ,104. In Hypothesis 5 (H5).The improvement of the technical, economic, and political status of farmer households may impact fostering green production demonstration households.The social environment can effectively activate the intrinsic traits of individuals and then affect their behaviors . As an iGovernment identification is the degree of farmers’ approval of the government itself, or government policies . The embHypothesis 6 (H6).Government identification  may have an impact on fostering green production demonstration households.Behavioral capability represents the possibility and confidence of farmers to achieve their goals, and government relationship embedding may play a fostering role in cultivating green production demonstration households by improving farmers’ behavioral capabilities, such as by improving their production knowledge reserves and self-efficacy . This isHypothesis 7 (H7).Farmer’s behavioral capabilities  may have impacts on formulating green production demonstration households through governmental relationship embeddedness.Perceived value is an individual’s overall evaluation of a certain behavior, which includes three dimensions: self-interested value perception, altruistic value perception, and social-interested value perception . The embHypothesis 8 (H8).Farmer’s perceived value  may have impacts on fostering green production demonstration households through governmental relationship embeddedness.The dependent variable of green production demonstration households changes from low to high, which is an ordered variable, so it is suitable for estimation by the Ordered Probit model, which has been widely used by the related literature  to complete the Ordered Probit model, robustness test, endogeneity processing, moderating effect model, and mediation effect model. Stata is an integrated multi-departmental statistical analysis software that is very popular as it has an easy-to-use interface, speedy and reliable output, a total customization option, and comprehensive technical support .To ensure the validity of the data, random interviews were used to determine the survey objects, and the survey objects were limited to farmers over the age of 18 who were familiar with the production and operation of their families, as suggested by Meyer-Aurich . The datThis study adopted the model’s variable according to the core concept of the theory of diffusion of innovations developed by Rogers et al.  and adjuThe green production demonstration households changed from low to high, which is an ordered variable, so the Ordered Probit model was used for estimation . First, In Equations (1) and (2), The government relationship embedding can act on the cultivation of green production demonstration households through intermediary variables such as farmers’ government identification, behavioral ability, and perceived value . TherefoIn Equations (6)–(8), https://www.stata.com (accessed on 27 June 2022)] regression and robust correction were used to rectify the benchmark of the estimated results. It can be seen from STATA15.0 [StataCorp, The results of Model 4 show that the relationship embedding of general government staff, professional and technical personnel, and village cadres has a positive impact on the green production demonstration households at the 1% significance level, and the coefficient value gradually increases. The outcome is consistent with the study of Bukchin and Kerret . CompareIn Model 3 and Model 4, the proportion of non-agricultural income, age, and internet familiarity of the head of the household has a significant positive impact on the green production demonstration households. It shows that an older household head possesses relatively greater agricultural production experience and deeper affection for the land. Moreover, the regression analysis shows that their willingness and ability to implement green production are also high which eventually led them to become a green production demonstration household. This is parallel with the research of Li et al. . SeemingThe status of household technology has a significant positive impact on the green production demonstration households. The farmers with a high level of tea planting technology are proficient in using green production literacy and skills, so they are more likely to become green production demonstration households. Interestingly, in their review study, Bukchin and Kerret  found siBased on the benchmark model, the robustness test is carried out in various ways. In p value of the correlation of the residuals between the equations is significant [The above models may suffer from endogeneity problems caused by simultaneous causal or omitted variables. This is because, first, there may be missing variables. Although the model controls variables such as household head characteristics, family characteristics, policy environment, and market environment, it may still miss some of the factors that are related to the embeddedness of government relations and affect green production demonstration households. Second, there may be a simultaneous bias problem. Government relationship embedding can cultivate farmers into green production model households through government identification, behavioral ability, and perceived value, and at the same time, the demonstration effect of green production model households can also counteract the government relationship embedding. The introduction of instrumental variables is an effective method to solve the problem of missing variables and simultaneous causality, as recommended by Mogstad and Wiswall . The artnificant .However, the government relationship embedding is indeed an endogenous variable. Therefore, such an endogeneity treatment method is reasonable. Interestingly, the village road condition  has a significant positive effect on the embeddedness of government relations and has good explanatory power, which also proves that it is not a weak instrumental variable . The resTo clarify the role of the mechanism of government relationship embedded in the cultivation of green production demonstration households, the 5000 sampling Bootstrap method is used to test the mediation effect, as recommended by Yang et al. . The spe(1) The coefficients of the two channel of government relationship embedded  are positive, and they pass the 1% significance level test without containing 0 value. Therefore, it can be assumed that the government relationship embedding can play an important role in cultivating green production model households through policy recognition and government trust. The embedding of government relations is conducive to assisting farmers to facilitate green production behavior, alleviating conflicts and contradictions in the implementation of new policies, establishing a positive and promising image of the government, improving farmers’ recognition, and eventually building the farmer’s trust in the government and directly encouraging them to foster GPDH;(2) The coefficients of the two paths  are positive, and they pass the 5% and 1% significance level tests, respectively. The value of 0 is not included, indicating that government relationship embedding can play a crucial role in cultivating green production demonstration households through self-efficacy and production knowledge reserves. Moreover, it also illustrates that the government relations embedding significantly enhances the communication between the government and farmers, and various policy measures such as persuasion, mobilization, education, and training can effectively enhance farmers’ production knowledge reserves and self-efficacy, and eventually encourage farmers to develop green production demonstration households;(3) The coefficients of the three paths  positively pass the 1% significance level test and the confidence interval not containing 0 value. It illustrates that the government relationship embedding influences the cultivation of green production demonstration households through the self-serving value perception, altruistic value perception, and social value perception. The diffusion and adoption of new and improved farming practices have provided a major area of research conducted by modern rural sociologists. Therefore, the notion of “innovation diffusion” becomes prominent within the agriculture sector. However, governmental interventions and support always account for a better transition of any innovation. The prime objective of the study is to test the influence and mechanism of government relationships embedded in fostering green production demonstration households by employing the expansion of the diffusion of innovation theory. Therefore, we constructed a theoretical framework that can firmly capture the direct and indirect influence of three forms of relational embeddedness, namely (i) Governmental organizations and bodies, (ii) Technical and professional support personnel, and (iii) Embeddedness of village cadres in fostering green production demonstration households. The empirical aspects of the article used the survey data of 963 farmers in key tea areas in Shaanxi, Sichuan, and Anhui for crafting the findings.The main conclusions are as follows: (i) The embeddedness of government relations has a positive function in formulating green production demonstration households. In terms of dimensions, the green production demonstration households are embedded in the relationships of general government staff, professional and technical personnel, and village cadres, who all have a significant and increasing role in cultivating green production demonstration households. Therefore, we accepted H1 and H2. (ii) Heterogeneity analysis shows that the development and incentive effect of green production demonstration households embedded in government relations gradually increases with the expansion of the farmer’s business scale, and gradually weakens with the improvement of the economic status of the farmer’s household. The household head’s age, internet familiarity, and the proportion of non-agricultural income, family technical status, and family political status cannot effectively adjust the government relationship embedding in fostering green production demonstration households. Therefore, H3 was rejected. (iii) As the heterogeneity tests show that farmers with large operating scales and low family economic status have a relatively stronger impact, therefore the study partially verified H4 and H5. (iv) Further mechanism analysis showed that government relationship embedding can strengthen government identification  and improve farmers’ behavioral ability . Moreover, formulating green production demonstration households can strengthen farmers’ perceived value . Therefore H6–H8 were accepted.Based on the above conclusions, the following specific policy recommendations can be drawn: (i) The government should strengthen the interactive mechanism embedded in the agricultural extension services. The embedding of government relations can help farmers correctly understand the government, policies, and green production itself, improve their abilities and qualities, and allow farmers to actively participate in green production practices and develop into green production demonstration households. Therefore, the government should strengthen relationship embedding by setting up new working methods such as “special work classes” and “assistance groups”, based on strengthening the interaction of village cadres, interactive and targeted rural policies, and consultation for opinions. The government should strengthen rural network facilities and build an interactive platform with the help of effective usage of information and communication technology to mitigate the limitations of time and space, and better play the embedded role of political and policy support, village cadres, and agricultural technicians;(ii) The government should formulate targeted strategies based on the differential effect of green production demonstration households embedded in government relations under the scale of operation and household economic status. Likewise, the notion of government relationship embedding has greater impacts for those cultivating farmers with large operating scales and low family economic status. Therefore, in practice, the government should take these two types as the key training objects, continue to strengthen the relationship embedding between these two, and at the same time cooperate with large-scale management. Relevant policies, such as subsidies and technical support for farmers, should be transmitted through green production demonstration households, which can foster relatively better transitional effects;(iii) Strengthen the mechanism of action embedded in government relations. In the relationship embedding, the government needs to grasp the two links of “knowledge” and “trust”. Information, such as policy and technical knowledge, needs to be effectively transmitted so that farmers can easily obtain the correct and legitimate information regarding governmental core objectives and policies. Therefore, they are more willing to actively implement green production and act as a new green production demonstration household. Government should organize purpose-based training through village cadres and extend support for on-the-spot training along with learning by watching and doing tactics. The effective circulation of bulletin boards, lectures, and demonstration videos should be extended to effectively help farmers in mastering scientific and technical skills. Seemingly, the targeted awareness-building campaigns, frequent arrangement of commendations, and mobilization meetings should be organized regularly to improve the farmer’s daily communication skills and enhance their self-efficacy as farmers and promote the development of the farmers’ knowledge about green production technology. The government should play the subjective role to promote the effect of green production through training, on-site demonstrations, and other means, so that farmers recognize the value of green products to allow the thriving of themselves, their communities, and society, and to encourage farmers to develop new green production demonstration households.The study has the following main deficiencies and areas which can be explored by the potential studies: (i) China has a vast land mass and abundant resources, and there are differences in management methods and technical choices among farmers who grow different crops. The data used in the study are based on the central tea farming areas in Shaanxi, Sichuan, and Anhui. Therefore, the scope of the research objects should be expanded in the future to include farmers who produce different agricultural products in different regions; (ii) Variables such as green production demonstration households and government relationship embeddedness were obtained by a questionnaire survey. In future research, the crossover and integration with other disciplines should be strengthened, and the farmer household questionnaire survey should be combined with methods such as experiments, observations, and behavior traces; (iii) As the study compiled the key factors affecting the formulation of the green production demonstration household, future research should explore those factors with more robust tactics, such as structural equation modeling (SEM) and interpretive structural equation modeling; (iv) The study proposes that future studies should also explore the ranking and indexing of these critical factors into specific criteria.