High demands create pressure on acute care services, such as emergency medical services (EMS), emergency departments (ED) and out-of-hours primary care (OOH-PC) services. A variety of patient- and organisational factors have been discussed as reasons why especially non-western migrants more frequently contact an ED or OOH-PC service than native born. We aim to investigate whether persons with a non-western and western migrant background more often contact an acute care service than native born and how this relates to the number of contacts with their general practitioners (GPs). In addition, we aim to explore how possible differences in acute care use by migrants can be explained.We performed secondary analysis of data collected for the EurOOHnet survey on OOH help-seeking behaviour in Denmark, the Netherlands and Switzerland. Differences in self-reported acute care use  between non-western and western migrants and native born were tested with a quasi Poisson regression analysis. Mediation analyses were performed to examine the impact of factors related to help-seeking on the relation between self-reported acute care use and migrant background.Non-western migrants had more acute care contacts than native born , whereas no differences were found between western migrants and native born. Migrants who regularly contacted OOH-PC or the ED also regularly contacted their GP. Mediation analyses showed that the factors employment, anxiety, attitude towards use of OOH-PC and problems in accessing the own GP could partly explain the higher acute care use of non-western migrants.The higher use of acute care services by non-western migrants compared with native born could partly be explained by feeling fewer barriers to contact these services, feeling more anxiety, more unemployment and problems making an appointment with the GP. Increasing awareness and improving GP access could help migrants in navigating the healthcare system. High demands create pressure on acute care services, such as emergency medical services (EMS), emergency departments (EDs) and out-of-hours primary care (OOH-PC) services . MigrantPrevious studies have suggested a range of explanations for the higher use of acute care services by migrants, some related to barriers in the healthcare system. Migrants perceive more problems with accessibility to primary healthcare services, mostly with their own general practitioner (GP) . In geneDo migrants more often contact an acute care service than native borns?How does this relate to the number of contacts with their GP?How can possible differences in acute care use by migrants be explained?Healthcare systems aim to provide equitable and patient-centred care for all citizens, making it important to support and improve care for migrants. To increase the equity of care, all citizens need to know how to navigate the healthcare system and to choose the most suitable healthcare provider. Instead of visiting the ED or OOH-PC services, contacting a GP during regular office hours can be a more suitable choice, at least from a medical and cost perspective. A greater understanding of the use of different healthcare services by various patients groups may help to find adequate strategies for interventions. In our study, we aim to answer the following questions:We performed secondary analysis of data collected for the European Research Network for Out-of-Hours Primary Healthcare (EurOOHnet) survey on OOH help-seeking behaviour in Denmark, the Netherlands and Switzerland , 24–26. In line with the overall aim of the primary study, individuals of three age groups were invited to participate in the survey . For this present study, we included the two adult age groups. Based on the power calculation for the primary study to detect differences between countries, we aimed to include 600 respondents per country . In DenmIn Denmark and the Netherlands, each patient has to be registered at a general practice of his own choice, with GPs acting as gatekeepers for secondary care. Outside office hours, patients can contact a GP cooperative by phone. A visit to the ED is possible, but it is highly recommended to first contact a GP. An ED visit is free of charge in Denmark, whereas Dutch residents must pay an annual tax-deductible fee of at least EUR 375 (2015 figures). Danish and Dutch residents can call 1–1-2 for an ambulance.In Switzerland, patients can visit all kind of services without referral. However, in return for lower premium costs, they can choose an alternative healthcare plan, which obligates patients to first contact a gatekeeper (i.e. GP or telephone hotline) . The orgA questionnaire was developed consisting of questions on citizen background characteristics, help-seeking  and factors related to help-seeking. The development of the questionnaire is described in detail elsewhere , 24. TheThe main outcome measure was the self-reported acute care use in the last year, defined as the sum of the number of contacts with OOH-PC, ED and 1–1-2/1–4-4. Furthermore, we measured the self-reported number of contacts with the own GP in the past year.The exposure was migrant background, for which we used the definition of Statistics Netherlands: a person of whom at least one of the parents was born abroad . The resWe included the following factors related to help-seeking: age, sex, education level, medical education, work status, living status, social support, health literacy , self-efficacy, anxiety, attitude towards the use of OOH-PC, degree of severity before contacting an OOH-PC service, travel time to closest OOH-PC service, problems with organising a consultation during the day , and self-assessed health. A detailed operationalisation of these factors is described elsewhere .Descriptive statistics were used to describe the characteristics of the population as well as self-reported acute care use  stratified by migration background.Differences in self-reported acute care use between migrants and native born were tested with a quasi Poisson regression analysis (model A). In a second model, we corrected for age, sex and education level, because we saw some (unexpected) differences between the migrant groups for these variables, which may influence the association between migrant background and self-reported acute care use (model B). The relation between use of the own GP and use of acute care was also tested with quasi Poisson regression analyse (model C). To test for differences in this possible relationship between the migrant groups, we tested the interaction effect of migrant background and contacts with the GP (model D).To examine whether factors related to help-seeking could explain the possible relation between self-reported acute care use and migrant background, we performed mediation analyses. To conduct mediation analyses, two assumptions have to be met: 1) there is a relation between exposure (migrant background) and outcome (acute care use), 2) there is a relation between exposure (migrant background) and the potential mediator . Therefon = 1,081), 64.5% in the Netherlands  and 19.4% in Switzerland . In the Netherlands and Switzerland, the data collection ended after reaching the required number of respondents. Of all respondents, 79.1%  was native born, 15.8% (n = 547) was western migrant and 5.1% (n = 175) non-western migrant. From 35 respondents we could not determine the migrant background. Table In total, 3,490 persons filled in the questionnaire. Due to the different recruitment methods in the three countries, we could only calculate national response rates: 44.2% in Denmark n = ,081, 64.Figure We tested the differences in self-reported acute care use between the groups of different migrant background Table . Non-wesIn Fig. Table First, we tested whether migrant background was associated with the factors related to help-seeking . The following factors were associated: employment, social support, health literacy: sufficient information, anxiety, attitude towards use of OOH-PC, degree of severity for contacting OOH-PC, travel time and problems in organising a consultation during the day because of own appointments and the accessibility of the own GP Table . Next, wAttitude toward use of OOH-PC explained 13.4% of the difference in acute care use between non-western migrants and native born . Furthermore, other factors explained a part of the differences in acute care use between non-western migrants and native born: level of anxiety 8.5% , employment 6.9% , problems in organising GP appointments due to own work or private appointments 5.8%  and problems in accessibility of the GP 4.2% . The other factors could not explain part of the difference in acute care use between non-western migrants and native born.Our data shows that persons with a non-western migrant background reported to use more acute care services than native born. We found no difference in self-reported acute care use between persons with a western migrant background and native born. The migrants in our sample who regularly contacted OOH-PC or the ED, also regularly contacted their own GP. Our sample had few migrants who had no contact with their own GP during the past year. Mediation analyses showed that the factors attitude towards use of OOH-PC, anxiety, employment, and problems with organising a GP appointment (due to own work or private appointments and accessibility of the GP) could partly explain the higher acute care use of non-western migrants. Thus, for example, feeling less barriers in contacting OOH-PC care among non-western migrants partly contributes to the higher acute care use by non-western migrants.Non-western migrants’ higher use of acute care services is also reported in other studies, as is the higher number of contacts for non-urgent problems that could also have been handled by the GP during office hours , 34–36. The effect of attitude toward use of healthcare service is hardly investigated. Our mediation analysis showed that non-western migrants felt less barriers in contacting OOH care, which partly explained the higher acute care use. Another study on non-urgent OOH primary contacts found that patients with medically unnecessary problems who contacted an OOH-PC service more often believed that this service is intended for all help requests and not just for urgent requests . The facAs far as we know, our study is the first one to examine why persons with a non-western migrant background use more acute care through mediation analyses and the relation with the use of GP care. Therefore, we used a comprehensive overview of relevant factors based on Andersen’s acknowledged behavioural model.Our study also had some limitations, in particular concerning our sample. Although the proportion of migrants seemed reasonable  , even asA qualitative study would be recommended as a supplement to this study. For example, interviews could be conducted to get insight into the considerations during the decision making process and final choice of a particular acute care service. Using interviewers who speak the language of the migrants could also reach the less well-integrated migrants.Non-western migrants make more use of acute care services than native born, while western migrants make as much use as native born. Non-western migrants seem to be able to find their way to their own GP, but may be more likely to go to OOH care services or the ED for the same medical problem than native born. This could partly be explained by feeling fewer barriers to contact these services, feeling more anxiety, more unemployment and problems making an appointment with the GP. Increasing awareness and improving GP access could help non-western migrants in navigating the healthcare system.


The pandemic has reshaped the normality of life and affected mankind in the aspects of mental and physical health, financial, economy, growth, and development. The focus shift to COVID-19 has indirectly impacted an existing air-borne disease, Tuberculosis. In addition to the decrease in TB diagnosis, the emergence of the TB/COVID-19 syndemic and its serious implications , serve as primary reasons to equally prioritize TB. On a different note, the valuable lessons learnt for the COVID-19 pandemic provide useful knowledge for enhancing TB diagnostics and therapeutics. In this review, the crucial need to focus on TB amid the COVID-19 pandemic has been discussed. Besides, a general comparison between COVID-19 and TB in the aspects of pathogenesis, diagnostics, symptoms, and treatment options with importance given to antibody therapy were presented. Lastly, the lessons learnt from the COVID-19 pandemic and how it is applicable to enhance the antibody-based immunotherapy for TB have been presented. Initially reported at Wuhan City, China, in December 2019, the highly contagious airborne virus has spread all over the world, infecting approximately 199 million individuals with a staggering death toll of almost 4.3 million people worldwide (as of 59 pandemist 2021) . The prist 2021) , 8.Mtb after SARS-CoV-2 infection, COVID-TB co-infection which consequently may lead to the aggravation of an existing active TB condition or an existing Mtb infection may escalate the risk and severity of SARS-CoV-2 infection  but unfortunately found to be exhausted and reduced in COVID-19 patients   , malaria(RT-PCR) . Since t(RT-PCR) , Mexico (RT-PCR) , Saudi A(RT-PCR) , Italy, (RT-PCR) , with a (RT-PCR)  to poor (RT-PCR) .Overall, the evidence reported so far emphasizes the urgent need to focus on tuberculosis as much as COVID-19 from various perspectives to ensure efficient treatments are given and ultimately resolve the catastrophic effects of the COVID-19/TB syndemic. In this review, we have discussed the crucial need to focus on TB in the midst of COVID-19 pandemic. Besides, a general comparison between COVID-19 and TB in the aspects of pathogenesis, diagnostics, symptoms, and treatment options with importance given to antibody therapy were presented. Lastly, the lessons learnt from the COVID-19 pandemic and how it is applicable to enhance the antibody-based immunotherapy for TB has been presented.It is an undeniable fact that a parallel line can be observed between COVID-19 and TB although both diseases vary from each other.Mycobacterium tuberculosis complex (Mtb) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for TB . The Mtb bacilli engulfed by the alveolar macrophages, survive the defense mechanism and replicate in the macrophage leading up to its necrosis  and enzyme-linked immunosorbent assay (ELISA) and even rapid antigen testing using nasal samples or saliva (self-test) which has made COVID-19 testing easier to accommodate large routine testing in workplaces and standard testing prior to attending public events , imaging, and advanced molecular testing such as nucleic acid amplification testing (NAATs) , 48. Howc events .Mtb which ultimately reduced the efficacy of the anti-microbial drug. For instance, mutation of catalase-peroxidase KatG and promoter region inhA is associated the inefficiency of anti-TB drug, isoniazid , to be incorporated in COVID-19 therapeutics  and proper hydration , 64. Patin vitro , 67. In apeutics . Similarapeutics . The Omiapeutics . FurtherMycobacterium bovis was first introduced  vaccine which originated from attenuated troduced . Remainitroduced . Despitetroduced . Anothertroduced . Neverthtroduced . The ongtroduced , 76, 77]troduced . Moving troduced . LearninSince the COVID-19 pandemic was declared, researchers have worked tirelessly towards the development of COVID-19 vaccines in efforts to minimize the severity of the disease and hopefully to control disease progression. As mentioned above, the strong financial support from both private and public resources have made COVID-19 vaccine development rapid and very much possible in a short duration . In genein vivo  for several therapeutic monoclonal antibodies and anti-viral therapy in efforts to reduce the burden of the pandemic.th November 2020)  . Originaer 2020) . Bamlanier 2020) . Initialer 2020) . Similarer 2020) , 119. Sier 2020) , 121. Hoer 2020) . In specer 2020) . Unfortuer 2020) , 124. Oner 2020) . Based opatients .Joining the list of authorized monoclonal antibodies for COVID-19 therapeutics is a cocktail of non-competing antibodies (casirivimab and imdevimab) known as REGEN-COV . AdminisIn May 2021, the U.S.FDA granted EUA for another antibody with dual-functionality known as sotrovimab to treat mild to moderate COVID-19 and high-risk patients . SimilarAlthough viral neutralization by preventing the binding of the SARS-COV-2 spike protein RBD to the host ACE2 has been the fundamental approach for the development of most COVID-19 therapeutic antibodies, researchers are also looking into other strategies with targets such as cytokines , angiotensin II (Ang II), tumor necrosis factor (TNF), inhibitory immune checkpoints (PD-1), and complement components  . To dateDespite being in existence for a long time now, there are still no monoclonal antibodies approved for the therapeutics of TB to date. The endemic status of TB itself, whereby the disease is concentrated in several developing countries could be a possible reason for the delay in antibody development. This is a contrast to the drastic efforts taken for therapeutic antibody development and FDA approvals given to combat the COVID-19 pandemic. In terms of research developments, it comes as no surprise that researchers focus on developing a treatment for TB based on cell-mediated immunity (CMI) mainly due to the intracellular nature of the MTB pathogen. However, CMI cannot be solely reliable in treating TB, especially in immunosuppressive scenarios such as HIV and even COVID-19, whereby the dysfunctionality of T cells is observed. In addition, the inconsistency in the outcome of many studies on antibody-mediated immunity (serum therapy) could also be the reason for the shift of interest . Besidesin vitro and in vivo settings . In this approach, the serum that originated from various sources  were found to elicit favorable immune responses against MTB in both settings . Althougal model , human ilunteers , human slunteers  and evenlunteers  which alin vivo came along with the success in hybridoma and phage display technology. Several mAbs have been subjected for testing against different Mtb antigen targets as described in via Ig A  is first administered followed by passive transfer of the vaccinated mice serum to Mtb-induced mice , have taught us to crucially scout for alternative treatment approaches independent of T cell mechanisms. Therefore, it is about time for antibody-based TB therapeutic strategies to be given enough opportunity to move forward. Given the current emergency, there is very much a high possibility for these TB therapeutic antibodies to be authorized for further clinical evaluations and hopefully for use in treatments.Mtb infection may increase the susceptibility and severity of SARS-CoV-2 infection. There is substantial evidence to support these implications  resulting in a hyper inflammation state/syndrome (Mtb infection is linked to the elevated circulating myeloid-derived suppressor cells (MDSCs) during active Mtb infection . As such, this important factor should be considered in the development of therapeutic antibodies for TB.T cell receptor (TCR)-like/mimic antibody is a novel antibody class that has come to the limelight in recent years with the emergence of hybridoma and phage display technology. As the name suggests, the antibody mimics a T cell receptor’s role in identifying/detecting the antigenic peptide presented on the major histocompatibility complex (MHC) molecules class I and subsequently mediates a wide range of effector mechanisms . The antMtb survives and remains dormant within the alveolar macrophages   in humans). Sadly, MHC class I expressions are found to be downregulated by Mtb  and evenMtb . Howeverpression –190. Foro study) . Similarentation . Anotherentation . Previouentation , 181. Ovvia bacterial expression system  . This isn system  As such,The severity of COVID-19 has paused the entire world and reshaped the life of humankind on a grand scale. However, focusing solely on the pandemic has led to many negative implications. The TB/COVID-19 syndemic alone has significantly impacted the general public health, especially TB patients. Consequently, the aim to eradicate TB by 2030 is now further delayed due to the shift of focus to COVID-19. Moving forward, the valuable lessons learnt and experiences gained from the pandemic enable us to be prepared to handle any future syndemic/pandemic and pave new strategies/platforms to target TB. Notably, the dysfunctionality of T cells that has been associated with the implications of TB/COVID-19 syndemic serves as an ideal target for future research exploring other alternative therapeutic approaches, including therapeutic antibodies for TB. In addition, the advancement in technology, including phage display technology, enables the development of novel antibody classes such as T cell receptor (TCR)-like antibody that is primarily independent of T cell mechanisms with bright potentials to enhance the therapeutic efficacy of TB in both in an independent and syndemic scenario.Conceptualization, SD and GT. Writing—original draft preparation, SD. Writing—review and editing, SD, GT, VB, CL, NA, and FN. Supervision, GT and FN. Funding acquisition, GT and FN. All authors contributed to the article and approved the submitted version.Acknowledgement to “Ministry of Higher Education Malaysia for Fundamental Research Grant Scheme with Project Code: FRGS/1/2020/STG01/USM/02/12”, “Ministry of Higher Education Malaysia for Higher Institution Centre of Excellence (HICoE: 311/CIPPM/4401005)” and "Medical Faculty of Universiti Kebangsaan Malaysia research grants (FF-2020-327)".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.


The objective of this review is to provide an update on narrowband ultraviolet B (NB-UVB) as a treatment for various skin conditions. NB-UVB works by suppressing the cutaneous cell-mediated immune response and has been shown to be an efficacious and clinically tolerable treatment for a range of inflammatory dermatoses. A literature search was conducted by advanced searches of PubMed for NB-UVB treatment of dermatologic skin diseases with a focus on reports from 2010 to 2021, including both office-based and home-based phototherapy (HBPT). Data were prioritized based on studies with a high level of evidence using the Oxford Evidence-Based Medicine guidance.We found that NB-UVB continues to serve as an effective form of therapy for several cutaneous conditions, including vitiligo, psoriasis, atopic dermatitis, mycosis fungoides, and other inflammatory dermatoses. The recent introduction of Janus kinase inhibitors in combination with NB-UVB suggests future promise in the treatment of vitiligo. Despite its rise in popularity, a decline was seen in office-based NB-UVB treatment during the coronavirus disease 2019 pandemic. Options are available to deliver NB-UVB at home with comparable efficacy to office-based treatments. In conclusion, for a select group of patients and conditions, NB-UVB continues to serve as an effective treatment modality with minimal side effects, with HBPT serving as an option to improve patient compliance. The use of ultraviolet (UV) light as a treatment for skin disease was initially studied in 1903 by Dr. Niels Finsen, and later in 1925 by Goeckerman. UV phototherapy uses a selective range of UV light, which can be categorized into ultraviolet A (UVA), psoralen ultraviolet A (PUVA), and ultraviolet B (UVB) irradiation ranges. The UVB category of phototherapy includes broadband UVB (BB-UVB) at 280-320 nm and narrowband UVB (NB-UVB) at 311-313 nm. In comparison to previously mentioned UV phototherapy, NB-UVB has been shown to be more clinically tolerable with fewer side effects [Over the past several years, NB-UVB has proven to be an effective treatment option for conditions such as vitiligo, psoriasis, mycosis fungoides, atopic dermatitis, pruritus, photodermatoses, and other skin conditions. It can be used as monotherapy or in combination with topical or systemic agents. Despite its rise in popularity, in the era of the coronavirus disease 2019 pandemic, there was an initial decline in office-based NB-UVB treatments due to concerns of increased viral exposure . Recent Narrowband ultraviolet B monotherapy for vitiligoNB-UVB is considered a first-line treatment for patients with vitiligo. Areas affecting the face, neck, trunk, and proximal extremities are generally more responsive to NB-UVB compared to the distal extremities. Although the mechanism behind repigmentation with NB-UVB is not fully understood, it is believed to be caused by a decrease in inflammatory cytokines followed by a stimulation of melanocytes within the hair follicle . In the Narrowband ultraviolet B combination therapy for vitiligoA retrospective cohort of 109 patients compared twice-weekly NB-UVB therapy to a more intensified thrice-weekly treatment of NB-UVB therapy along with topical fluticasone propionate and/or tacrolimus . FurtherIn a recent study, treatment with Janus kinase (JAK) inhibitors in combination with NB-UVB for vitiligo showed promising results. A retrospective case series of 10 patients found that low-dose NB-UVB (office-based and HBPT) or sun exposure was required in conjunction with oral tofacitinib to achieve repigmentation. The five patients who achieved repigmentation with oral tofacitinib all had exposure to either low-dose NB-UVB or sunlight . AnotherHome-based phototherapy for vitiligoThe use of HBPT for vitiligo is considered experimental by most insurance companies, yet it has shown efficacy in several clinical trials. A pilot randomized controlled study of 100 patients found HBPT to be as effective as in-patient phototherapy . A signiNarrowband ultraviolet B therapy for psoriasisFor the treatment of psoriasis, NB-UV decreases the production of inflammatory cytokines and T-cells in the Th1 pathway and reduces keratinocyte proliferation . NB-UVB-Narrowband ultraviolet B therapy for mycosis fungoidesNB-UVB is considered first-line therapy for early-stage mycosis fungoides, with no significant difference compared to PUVA phototherapy in the treatment of early-stage disease -32. StudNarrowband ultraviolet B therapy for atopic dermatitisThe use of phototherapy in AD works by the suppression of Th2 immune response, improvement of the skin barrier, and decrease in skin infections . CurrentNarrowband ultraviolet B therapy for pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronicaNB-UVB is a treatment modality commonly used for pityriasis lichenoides et varioliformis acuta (PLEVA) , a relatNarrowband ultraviolet B therapy for granuloma annulareGeneralized granuloma annulare (GA) is more responsive to NB-UVB compared to other subtypes of GA. Furthermore, it is well tolerated in patients suffering from this condition. Two retrospective studies of patients with generalized GA showed at least 50% clinical improvement in more than half of the patients when treated with NB-UVB .Narrowband ultraviolet B therapy for pruritusThe cause of pruritus varies considerably. One way NB-UVB reduces the symptoms of pruritus is by decreasing the inflammatory cytokine, IL-31, involved in the itch pathway. Recent reviews support the use of NB-UVB in reducing pruritus for patients with uremic pruritus secondary to chronic kidney disease, cholestasis-induced pruritus, prurigo nodularis, HIV-induced pruritus, and other inflammatory dermatoses that cause chronic pruritus .Narrowband ultraviolet B therapy for photodermatosesPatients affected by photodermatoses such as solar urticaria and polymorphous light eruption (PMLE) can successfully respond to NB-UVB as a form of photoadaptation, demonstrating relapse in eruptive episodes. When treating these conditions, worsening of photodermatoses can occur which can be managed by topical corticosteroid and dose increment reduction . A recenNarrowband ultraviolet B therapy for lichen planusPhototherapy can be considered a treatment modality for patients with generalized lichen planus (LP). A randomized clinical trial of 46 patients comparing systemic corticosteroids to NB-UVB therapy found NB-UVB to be a significantly more effective treatment for generalized LP . AnotherNarrowband ultraviolet B therapy for pityriasis rubra pilarisFor NB-UVB treatment of recalcitrant pityriasis rubra pilaris (PRP), patients should undergo photoprovocation prior to therapy as there have been reports of photoaggravated PRP . Data arNarrowband ultraviolet B therapy for acneCutibacterium acnes and affects the products of inflammatory cytokines. A case report by Zeichner et al. showed improvement in inflammatory papules and pustules in a pregnant patient after two months of NB-UVB therapy [Very limited data exist for the treatment of NB-UVB therapy for acne. It has been suggested that UVB directly inhibits  therapy . A recen therapy .LimitationsLimitations of this review include the wide breadth of information covered; therefore, not all reviews which supported information included in this paper were analyzed in this study. In addition, the review was limited to articles written or translated to English. Variability in treatment outcomes with NB-UVB can result from variation in dose delivery, the number of treatments, and subjectivity in minimal erythema dose testing in correlation with appropriate Fitzpatrick skin types.This review serves as a reminder to clinicians that NB-UVB is generally well-tolerated with few side effects and remains an effective treatment for different skin conditions in pediatric, adult, pregnant, and geriatric patient populations. NB-UVB continues to be efficacious in treating patients with vitiligo, psoriasis, mycosis fungoides, AD, photodermatoses, pruritus, generalized LP, generalized GA, PLEVA, and PLC. Recent studies show future promise in combination NB-UVB with topical JAK inhibitors for patients with vitiligo. In comparison to PUVA, NB-UVB has not been shown to induce carcinogenesis.While office-based phototherapy serves as the main treatment for delivery of NB-UVB, home-based treatments can be considered as an efficacious option based on the evaluation of each patient’s unique situation. Numerous large studies have shown support for HBPT in the treatment of vitiligo. However, this option can be considered for all photoresponsive skin conditions. HBPT is not without its challenges which include patient training and education and insurance barriers. Additionally, future long-term studies in the form of large randomized controlled trials would solve any concerns about the safety of HBPT.


Background and Objective: Patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitizing epidermal growth factor receptor (EGFR) mutations show a good response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). The subsequent treatments influence the evaluability of the efficacy of front-line therapy on overall survival (OS). Consequently, we evaluated the associations of relapse-free survival (RFS) and post-progression survival (PPS) with OS in patients who exhibited postoperative relapse of EGFR-mutated NSCLC. Materials and Methods: We analyzed the data of 35 patients with EGFR-mutated NSCLC who underwent complete resection between January 2007 and June 2019. The correlations of RFS and PPS with OS were evaluated at the individual patient level. Results: Linear regression and Spearman’s rank correlation analyses demonstrated that the PPS highly correlated with OS , whereas the RFS weakly associated with OS . Age and performance status at relapse were significantly associated with PPS. Conclusion: Overall, PPS was more strongly and significantly associated with OS than RFS. These results suggest that the OS of our cohort may be affected by treatments, besides postoperative relapse. However, larger-scale prospective studies are needed to confirm these results. Lung cancer is a major reason for cancer-related mortality globally, and non-small-cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers . For earEGFR) mutations treated with first-line EGFR-TKIs. This means that treatment beyond disease progression after front-line treatment may have a significant influence on the OS of patients with NSCLC [With the increasing number of treatment options for NSCLC, the efficacy of front-line therapy on overall survival (OS) might be affected by subsequent treatments . A phaseth NSCLC .EGFR-mutated NSCLC versus those without EGFR mutations have been comprehensively investigated [EGFR mutations [EGFR [EGFR mutation status in surgically resected lung cancer remain controversial [The clinical characteristics and prognoses of patients with stigated ,12. Numeutations ,17,18,19ns [EGFR ,21,22,23ns [EGFR . Patientoversial ,26.EGFR-mutated NSCLC is currently unclear. Therefore, evaluating individual patient-level data to determine whether relapse-free survival (RFS) and PPS are considerably correlated with OS beyond postoperative relapse is of clinical relevance.It would be interesting to examine the contribution of postoperative relapse treatment to OS at the individual-level. An evaluation of individual patient-level data demonstrated that PPS, and not PFS, is strongly correlated with OS beyond front-line therapy in patients with metastatic NSCLC and small-cell lung cancer (SCLC) . ConsequEGFR mutations. In addition, we assessed the prognostic significance of a patient’s characteristics for PPS.In the current investigation, we evaluated the relationships of RFS and PPS with OS in postoperative relapse patients with NSCLC haboring sensitizing EGFR-mutated NSCLC who underwent a complete resection at Gunma Prefectural Cancer Center between January 2007 and June 2019. The histopathological diagnosis was determined according to the World Health Organization’s classification. The NSCLC stage was determined based on the American Joint Committee on Cancer’s tumor-node-metastasis (TNM) staging system [EGFR mutations . In addition, only lobectomies were included, not wedge resection or segmentectomy. Lymph node dissection was also included in this study. On the other hand, the exclusion criteria were operations in other hospitals, incomplete resection, and incomplete data. At postoperative relapse, before treatment, each patient underwent a physical examination, a chest radiograph, a computed tomography of the chest and abdomen, a 18F-fluorodeoxyglucose positron emission tomography or bone scintigraphy, and a brain computed tomography or magnetic resonance imaging to determine the disease stage (TNM classification). The medical records of the identified patients were collected and checked. Furthermore, records on patient characteristics, chemotherapeutic regimens, radiotherapy, and subsequent-line treatments (if administered) were collected. First- and higher-line treatments were chosen by the principal medical oncologist and continued until disease progression, unacceptable toxicities, or treatment refusal. Beyond operative recurrence, the patients were permitted to choose any treatment modality following the first-line therapy.The current study involved patients with postoperative relapse of g system . The incEGFR mutations in exons 18–21 were evaluated, as previously demonstrated [EGFR mutations were identified, of which exon 19 deletion and exon 21 L858R were the major sensitizing mutations, whereas exon 18 G719X and exon 21 L861Q were the minor sensitizing mutations.Sensitizing nstrated ,30, by pThis study was approved by the ethics committee of Gunma Prefectural Cancer Center. Owing to the retrospective nature of the study, the requirement for informed consent was waived by the ethics committee. However, the opportunity to refuse participation through an opt-out method was guaranteed.Tumor response was evaluated as the best overall response. Radiological tumor responses were evaluated according to RECIST version 1.1 : disappep-value of ≤0.05. All analyses were conducted using JMP software for Windows, version 11.0 .We defined RFS as the time from operation to the first instance of relapse or death from any reason. Overall survival was defined as the time from operation until death or censoring at the last consultation. We defined PPS as the time from tumor relapse after operation until death or censoring at the last consultation. Survival curves were generated using the Kaplan–Meier method. Linear regression analyses and Spearman’s rank correlation coefficient were adopted to assess whether RFS and/or PPS were associated with OS. A Cox proportional hazards model with stepwise regression was adopted to identify factors that predicted PPS and to estimate hazard ratios and 95% confidence intervals. Some variables were converted to an appropriate scale unit because the hazard ratio was calculated based on a 1-unit difference. Differences were regarded as statistically significant at a two-tailed EGFR or unknown EGFR mutation status were excluded  months. The median patient age was 69 years . The baseline characteristics of the patients are listed in The median number of regimens after postoperative relapse for the 35 patients was 1 . The treatments administered following postoperative relapse are listed in r = 0.91, p < 0.0001, R2 = 0.85), whereas the RFS did not . The correlations of RFS and PPS with OS are demonstrated in p < 0.05)  at relapse, treatment with or without adjuvant chemotherapy, and presence of bone metastases at relapse were significantly associated with PPS ( < 0.05) . In addiEGFR mutations. The PPS was more significantly correlated with OS than RFS. Furthermore, age at relapse and PS at relapse were significantly associated with PPS. Most patients with postoperative relapse received regular follow-ups beyond surgical resection; therefore, the tumor burden might be lower than that in patients with metastatic NSCLC at initial diagnosis. These discrepancies in the burden and heterogeneity may favor PFS and OS in patients with postoperative relapse NSCLC [We evaluated the correlations of OS with RFS and PPS at the individual patient level in patients who exhibited postoperative relapse of NSCLC harboring sensitizing se NSCLC ,33,34.EGFR-mutated NSCLC. Our findings demonstrated that RFS did not consistently correlate with OS, suggesting it may not be a valuable marker for prolonged OS. In addition, RFS was considerably shorter than PPS in the current cohort. PPS was highly associated with OS, suggesting that future clinical studies should consider the factors that may influence PPS.Various trial endpoints have been examined in meta-analyses ,36, and EGFR mutations remains unclear. In the current study, the multivariate analysis revealed that the following two factors were closely correlated with PPS: age at relapse and PS at relapse. This observation indicates that age at relapse and PS at relapse in patients with postoperative relapse of EGFR-mutated NSCLC may be important for prolonging PPS. The high number of anticancer agents administered beyond postoperative relapse can be attributed to the wide availability of first- and subsequent-line treatment options for NSCLC, including EGFR-TKIs , platinum-based combination regimen, pemetrexed, docetaxel, S1, and immune checkpoint inhibitors (ICIs)  . Osimertutations . TherefoEGFR mutations were available at our institution. Moreover, we tried to assess patients with the same backgrounds. Although a relatively large number of these patients were treated at our institution, our clinical practices and strategies are largely uniform. Adjusting for various sources of bias in the current analysis ensured clinically relevant results. Future studies with a higher number of patients are needed. Second, the treatment methods after postoperative relapse were not uniform, varying from drug therapy to radiotherapy alone. Nevertheless, this study, which is based on the actual clinical course of treatment, is of clinical relevance. Third, the date of response was determined by different treating physicians, and this may have resulted in a variability in the RFS; however, this is a limitation inherent to retrospective analyses. Fourth, we also managed to obtain censored survival data, although this does not affect the conclusions. Even when patients did not reach the death event, the RFS did not change. Besides, PPS and OS were prolonged, and PPS was closely correlated with OS.The current analysis has some limitations. First, the cohort size was small. This limited our capacity to assess the relationships among PPS, the presence of T790M mutation, and the administration of osimertinib in first-line treatment and immune checkpoint inhibitors. Only a small number of postoperative relapse patients with EGFR-mutated NSCLC. Age at relapse and PS at relapse were also significantly associated with PPS. These outcomes imply that the course of treatment after postoperative relapse influences the OS of patients with EGFR-mutated NSCLC, though larger-scale prospective studies are needed to confirm these results in other clinical situations and patient cohorts.In conclusion, PPS is more highly associated with OS than RFS in patients with postoperative relapse of


Currently, research in nanoparticles as a drug delivery system has broadened to include their use as a delivery system for bioactive substances and a diagnostic or theranostic system. Nanogels, nanoparticles containing a high amount of water, have gained attention due to their advantages of colloidal stability, core-shell structure, and adjustable structural components. These advantages provide the potential to design and fabricate multifunctional nanosystems for various biomedical applications. Modified or functionalized polymers and some metals are components that markedly enhance the features of the nanogels, such as tunable amphiphilicity, biocompatibility, stimuli-responsiveness, or sensing moieties, leading to specificity, stability, and tracking abilities. Here, we review the diverse designs of core-shell structure nanogels along with studies on the fabrication and demonstration of the responsiveness of nanogels to different stimuli, temperature, pH, reductive environment, or radiation. Furthermore, additional biomedical applications are presented to illustrate the versatility of the nanogels. Drug delivery systems  and polyacrylic acid . This study demonstrated the successful fabrication of multifunctional materials using core-shell structure nanoparticles [In 2011, He F. et al.  developearticles . Gonzalearticles  introducarticles . The finThe homogeneity of the nanogel is critical for the stability of the system, and thus the nanogel macrostructure was frequently investigated using transmission electron microscope (TEM). A nanogel is a colloidal system consisting of a crosslinked, water-swellable, 3-dimensional polymeric network whose size can reach ~1000 nm in a fully-swelled state . The croThe presence of cationic moieties can destabilize the integrity of the cell membrane, which possesses a negative charge surface, leading to increased cell internalization. In addition, amphiphilic polymers were shown to be internalized by fungal cells in Horvat S. et al. . Thiol-fA polymeric nanogel was used as a DDS for gene delivery. Costa D. et al. used a conjugated polyamine  on an ethylene glycol diglycidyl ether (EGDE) backbone to encapsulate plasmid DNA. The polymeric nanogels facilitated the delivery of plasmid DNA and anti-cancer drugs, e.g., doxorubicin, epirubicin, and paclitaxel, by increasing the drug-loading capacity because the active substance chemically bonded with EGDE. Moreover, the EGDE crosslinking is broken by ultraviolet light, resulting in drug release .A hollow sphere, a unique structure that contains an empty space surrounded by a polymer has also been reported as a smart delivery system, because the core can facilitate drug encapsulation and controlled release . TogetheA combination of thermo-responsive polymers that were chosen to increase the advantages of the hollow sphere structure was described by Li G. et al. The thermo-sensitive polymeric hollow spheres were assembled using sodium alginate-graft-poly(N-isopropylacrylamide) (ALG-g-PNIPAM) and β-cyclodextrin (β-CD) for 5-fluorouracil (5-FU) controlled release. The nanoparticles in the nanorods and coils were prepared using β-CD/PNIPAM and sodium alginate, respectively. The fabricated hollow sphere nanoparticles were expected to increase 5-FU loading. At temperatures above the lower critical solution temperature (LCST) of PNIPAM or in an acidic environment, loaded 5-FU release was enhanced due to the morphological change of the nanoparticles . FurtherThe fabrication of a hollow shell-shell nanocontainer composed of thermo-responsive PNIPAM and poly(N-isopropylmethacrylamide) or PNIPMAM as an inner and outer shell was reported by Schmid AJ. et al. . An in sWang Z. et al. introduced gold hollow/nanoshells conjugated with small interference RNA (siRNA) designed to interfere with the expression of heat shock protein 70 (hsp70) that is produced during photothermal therapy (PTT) of a tumor and is associated with tumor resistance and tumor recurrence. In this study, siRNA was entrapped by the gold hollow/nanoshells that protected the siRNA from enzymatic degradation and effectively delivered it to the cell cytosol. Together with the light absorption and light-heat transformation potential of gold hollow/nanoshells, hsp70 was down-regulated, resulting in increased PTT efficacy . An inorFunctionalized polymers have also been fabricated using layer-by-layer techniques, the so-called nanofilms . In thesNumerous studies have demonstrated wide applications of metal-based nanomaterials, such as catalysts or nanoconductors. The distinct features of metal-based materials, quantum dots and metallic hybrid nanogels, have resulted in their use in biomedical fields . SeveralWu W. et al. developed silver (Ag)/gold (Au) dual-metal nanoparticles coated with a hydrophobic polystyrene (PS) layer as an inner core and shieled with PEG. These bimetallic nanoparticles emitted intense fluorescence, which could be used for cell imaging. Moreover, near-infrared (NIR) light can be absorbed by these nanogels, leading to photothermal conversion that can be beneficial for drug release . Au has Selenium (Se) was conjugated to sulfhydryl groups as Se-S to create reduction-responsive linkages. The linkages were designed to prepare a doxorubicin (DOX)-loaded superparamagnetic nanogel with reduction and pH-responsiveness for drug release. The release of DOX from the magnetic Se-S nanogels coated with alginate was enhanced in the high glutathione (GSH) tumor environment . 2+, because the level of Zn2+ in the human body impacts several biological mechanisms, such as growth and neurotransmission. These nanogels can be localized due to their increased photoluminescence intensity from the transition between the dispersed and aggregated state of CuNCs@GC in the presence of Zn2+. This feature provides an interesting tool for live cell imaging.Nanoclusters embedded in nanogels were reported by Gao X. et al. . Copper,Quantum dots or QDs exhibit outstanding properties, such as photo-luminescence with less dye fading compared with traditional dyes. This property makes QDs efficient tools for in vitro and in vivo imaging. Adipic acid dihydrazide-modified QDs were conjugated to the carboxyl groups of hyaluronic acid as an initial nanogel polymer. The obtained nanogels demonstrated an intense fluorescence signal after cell uptake, which was related to the affinity of the modified hyaluronic acid-based nanogels to CD44 receptors on the cell surface . Colloid2+-doped CdS/ZnS, which was a glutathione sensitive QD core, attached to dopamine as an intracellular simulation moiety and model drug. The complex core was coated with chitosan functionalized folic acid as a targeted ligand for cancer cells and fluorescein isothiocyanate (FITC). The interaction between this QD nanogel and cells that expressed different levels of folic acid was demonstrated along with being nontoxic up to 100 mg/L. [In multiple QD studies, a QD-modified core–shell structure was designed to replace metals, which significantly reduced the cytotoxicity of the materials. QDs-chitosan core-shell nanogels as an “OFF”/“ON” biosensor were fabricated as a cancer cell targeted probe. This system was composed of Mn00 mg/L.  Cancer has become a worldwide health issue because it exhibits complicated pathologies  and can Tan L. et al. reported that ZnO nanoparticles decorated with 2,3-dimethylmaleic anhydride (DMMA) and loaded with DOX exhibited a synergistic cytotoxicity to cancer cells under acidic conditions. The ZnO QD system prolonged the retention time in the blood and an accumulated at the tumor that improved the efficacy of the loaded chemotherapeutics . NotablyQDs can also be modified by a stimuli-responsive polymer as described in Gui R. et al. In this study, nanospheres of QDs-embedded mesoporous silica nanoparticles (Q-MS) coated with chitosan-functionalized PNIPAM or PNIPAM-g-CS shell were fabricated. The results suggested the potential of nanospheres as a cell imaging agent in Hep2 cells along with the thermo-responsive behavior of PNIPAM, which can further facilitate the specificity to particular target sites .Over the past decade, various smart polymers have been introduced as drug carriers with increased effectiveness, specificity, and fewer side effects. Improving polymers by incorporating proteins or other polymers can enhance specific characteristics and overcome some limitations of the base polymers. Furthermore, polymer modification can increase site specificity or cell internalization that can result in increased therapeutic effects.Arteche Pujana M. et al. demonstrated a biodegradable crosslinker, genipin, grafted on chitosan to modify the water solubility of a chitosan derivative by minimizing its hydrogen bonding. Compared with the unconjugated chitosan, the modified structure exhibited improved water solubility and was pH-responsive that can be used for pH-triggered drug release . The eleStimuli-responsive behavior is an important feature for biomedical applications. As presented in Temperature is a stimulus that has been investigated in stimuli-responsive drug carriers because most therapeutic substances have been designed to be activated at physiological temperature. Moreover, some diseases, e.g., cancers, have specific temperatures that can be exploited for targeted therapies. Luckanagul J.A. et al.  reportedThe thermo-responsiveness of PNIPAM-modified nanogels is finely tunable using β-CD as reported by Yi P. et al. . The res2MA), a thermo-responsive monomer, was incorporated into silver nanoparticles (AgNPs) generating metal-based nanoparticles that were thermo-responsive. Soto-Quintero A. et al. [2MA-conjugated AgNPs and the interfacial energy reduction between MEO2MA monomer and the metal surface. The curcumin-incorporated AgNPs exhibited antioxidant and thermo-responsive activities. The metallic core enhanced the capacity to encapsulate the hydrophobic curcumin and provided luminescence that can be beneficial for diagnostic and therapeutic purposes. In addition to PNIPAM, 2-(2-methoxyethoxy)ethyl methacrylate  were initially reported by Kolouchova K. et al. . Two bloIn addition to drug delivery and diagnostic devices, thermo-responsive polymers can be employed as an initial material in the self-assembly of polymeric nanoparticles. Poly (ethylene glycol)-methacrylate-based maleimide-bearing copolymer was used as the initial nanoaggregate in the reaction of a Clickable-nanogel due to its stability in an aqueous solution. Cell imaging and internalization of the nanogel were evaluated in the study .rod@PNIPAM-PEGMA nanogels (PNIPAM-PEGMA = cross-linking of PNIPAM and poly-(ethylene glycol)-methacrylate (PEGMA)), which responds to NIR light stimulation. Nanoparticles containing the Au rod absorbed the NIR light and converted it to heat. The elevated temperature caused the thermo-sensitive PNIPAM-PEGMA nanogels to shrink and release the payload. Moreover, the molar ratio of PNIPAM to PEGMA was varied and these nanogels demonstrated increased LCST at a reduced molar ratio, revealing the fine tunability of thermo-responsive behavior of the polymer that is useful for its controlled release of a material [Thermal triggering can occur by other sources, such as NIR light, which generates heat from the excitation of specific molecules. Moreover, NIR light can penetrate to deep tissues with less damage compared with direct heat or UV light. Shang T. et al. used the core-shell structure of Aumaterial . NIR light-sensitive nanogels with photo-sensing properties were designed by Wang H. et al. as bifunctional nanoparticles composed of a fluorescent carbon dot core coated with PNIPAM-co-acrylamide-based hydrogels. The photo-sensitivity of the carbon dots was used for in vivo imaging of tumor tissue together with the NIR light-triggered temperature increase, resulting in the thermo-responsive behavior of the nanogel for specific drug release .Ma X. et al.  reportedpH is a physiological factor that affects the ionization state of drug molecules, and influences the behavior of pH-sensitive drug delivery systems. Typically, the pH value at the target sites in several diseases differs from the physiological pH. Thus, designing a drug carrier with a specific pH-responsiveness can enhance the therapeutic efficacy and reduce side effects to the surrounding organs or tissues. Due to the different charge characteristics of each polymer, chemical modification or polymer blending could convey advantages to the distinct functionalities among other nano-carriers. The morphology transition of anionic nanogels under different pH conditions was reported by Ashrafizadeh M. et al. . They uspH-responsive hyaluronic acid-based nanogels have been fabricated to deliver a terephthalaldehyde (TPA) protein drug, cytochrome C (CC) and enhance cell uptake in the tumor environment . HyaluroMetallic nanoparticles can be pH-responsive, as demonstrated by Wu W. et al. Ni-Ag nanoparticle core/PEG-co-methacrylic acid shell nanogels were used as a targeted drug carrier for cancer treatment using 5-FU as a model drug. In this study, the metallic core was photoluminescent and its intensity depended on the pH value being 5.0–7.4. The nanogels also exhibited the rapid release of 5-FU at the tumor site due to acidic pH-triggered release. In addition, the drug loading capacity of the hybrid nanogels was high due to the intermolecular complex between the polymeric shell, the ether oxygens of PEG, and carboxyl groups of the methacrylic acid moiety .Tumor cells typically exhibit a higher amount of reducing compounds compared with normal cells. This distinct environment has led to the development of targeted cancer chemotherapy using a drug delivery system that is affected by a reducing environment . GSH-resReduction-responsive nanogels have been extensively reported as intracellular targeting delivery systems, because the intracellular concentration of GSH ranges from 1–10 mM, which is relatively high compared with the extracellular space . This ceThis reduction-triggered release system was also used for siRNA delivery, due to the instability of siRNA in the circulatory system and the low transfection efficiency of bare nucleotides. The siRNA was conjugated with polyvinylpyrrolidone to form nanogels with reduction-sensitive bonding without losing the inherent silencing properties . FurtherThe use of metal-containing GSH-responsive nanogels, composed of poly [methacrylic acid-co-poly(ethylene glycol) methyl ether methacrylate, as a tumor-targeted drug carrier was reported . N,N-bisGlucose is also a stimulus that can be used when designing a responsive drug delivery system, especially for diabetes mellitus  or infecStaphylococcus aureus (MRSA).Infected cells exhibit a high level of mannose receptors on their surface, and thus mannosyl ligand-functionalized nanogels were fabricated target infected tissues. The nanogels were then ingested by macrophages at the infection site. Additionally, the bacteria at the infected site can secrete vesicles containing phosphatase and/or phospholipase, which disassociated the PEG grafted-polyphosphoester. Nanogels made of this material showed an accelerated release of loaded vancomycin and cytotoxicity to methicillin-resistance To provide additional functionality to nanogels, multi-responsive features, which are responsive to two or more stimuli, were introduced to deliver drugs with higher efficacy and safety. Temperature-, pH-, and NaCl-sensitive nanogels were demonstrated by Xu Y. et al. to be dual-function injectable nanocarriers that enhanced drug delivery and functioned as biological probes . This muCombined pH/temperature sensitive nanogels were designed to facilitate controlled release at a specific tumor site with an acidic pH and to improve the thermal stability and biocompatibility of the materials. Nita L.E. et al. fabricated this type of system using poly  undecane) copolymer crosslinked with 1,12-dodecandiol . ChanginLou S. et al. fabricated hepatocyte-specific multi-responsive nanogels consisting of poly  or P . β-D-galAn effective delivery system for cancer therapy was demonstrated using crosslinked hyaluronic acid (HA) and keratin to fabricate multi-responsive nanogels . KeratinGraphene oxide (GO), an inorganic compound, exhibits a distinct drug loading capacity. Due to its strong polarity, GO forms an electrostatic interaction with some cancer therapeutics, and it was combined with PNIPAM monomer to improve thermal responsiveness when exposed to NIR light, as well as enhancing its colloidal stability . The resMoreover, GO-DOX coated with crosslinked hyaluronic acid nanogels were used as a theranostic system . When inAs smart drug carriers, the modified polymeric nanogel systems are expected to enhance the efficiency of drug delivery, which can reduce side effects by enhancing the specificity to target sites and improve the drug’s pharmacokinetics that can prolong the circulation time, leading to a greater bioavailability and an elevated therapeutic efficacy. Moreover, with the stimuli-sensitiveness of polymers, polymeric nanogels can act as diagnostic tools for tracking specific organs or tissue with a higher precision. Furthermore, there are various modifications based on a combination of therapeutic and diagnosis, the so-called theranostic systems, which indicate the multiple functionalities of the modified nanogels.To enhance the therapeutic properties of the nanogels, nano-carriers were designed to release their payloads upon the application of a stimulus, known as stimuli-responsive nanogels. The nanogels formulated as a therapeutic eye drop were typically made of chitosan, which was known for its mucoadhesive properties . A chito2, or O2 without the loss of Hb’s inherent bioactivities. Higher oxygen affinity compared with free Hb and increased stability of the protein in physiological buffers were observed. The nanoparticles also showed an enhanced biocompatibility and hemo-compatibility features because there were no signs of significant cell death or hemorrhagic abnormalities in the tested conditions. The development of biopharmaceutical products containing macromolecules, i.e., proteins, has increased. The major limitation of protein delivery is maintaining its stability during storage or exposure to physiological enzymes, which affects its structure. Hemoglobin (Hb), a functional protein that transports oxygen, carbon dioxide, and other gases to support normal body functions in mammals, was used as a model protein in Wei X. et al.  Hb was lDandan Li et al.  used redAnother intriguing example is multifunctional polymeric nanogels that were developed for improving the specificity of a rescue drug for stroke and decrease fatal side effects, including pulmonary edema and intracranial hemorrhage. PEG-conjugated glycol chitosan hollow nanogels were used to stimulate drug release after ultrasonic stimulation, which limited their specific target release and enhanced uPA thrombolysis activity and stability in circulatory system. The developed nanogels with ultrasonic stimulation showed a decreased risk of hemorrhage because the loaded uPA did not penetrate the blood-brain barrier ,96. In aThe tumor microenvironment displays distinctive conditions that allows for wide functional design of drug delivery systems. A co-release system of DOX and cisplatin made of a tri-coblock polymer, poly (acrylic acid-b-PNIPAM-b-acrylic acid), or PNA, was fabricated . DOX wasE. coli and S. aureus with prolonged inhibition for up to 10 days. Gel@CLN hydrogels treatment also accelerated wound healing due to its high water content, which enhanced its moisturizing effects and supported rapid wound closure [Topical nanogel formulations have also been widely investigated. Zhu J. et al., fabricated chlorhexidine diacetate-loaded nanogels enclosed in aminoethyl methacrylate hyaluronic acid and methacrylated methoxy polyethylene glycol crosslink system, referred to as Gel@CLN hydrogels as a wound dressing. The results demonstrated that Gel@CLN hydrogels reduced infection by  closure . Apart from using nanogels as drug delivery systems to improve their therapeutic effects, the nanogels also possess multi-functional features that can be used for diagnosis. QD-containing polymeric nanogels that emitted a specific light/fluorescent signal were used as biological dyes for live cells or in vivo imaging. Multi-responsive biosensing nanoparticles containing Cadmium-Selenium (CdSe) QDs shielded with chitosan-poly (methacrylic acid) were fabricated to combine the optical properties of QDs and the pH-responsiveness of the modified chitosan . Therefo2 ternary composite nanogels (ACM-TNGs) were fabricated as a radio-assisted cancer therapy [2 nanorods that absorbed low frequency radio waves. To minimize the toxicity from the metals, chitin nanogels were used as a biocompatible shell that wrapped the AuNPs and MnO2 nanorods. Various targeted diagnostic nanogel platforms have been evaluated for their potential biomedical application; however, for those containing metals, their toxicity is a concern. Hence, several core-shell structured nanogels were used to reduce the cytotoxicity by shielding the metals from being exposed to the cell surface. Gold nanoparticles (AuNPs)-based chitin-MnO therapy . This syA cytotoxicity study using L929 HDF, MG63, T47D, and A375 cell lines demonstrated the cytocompatibility of ACM-TNGs and that their cell internalization did not alter cell morphology. Moreover, this nano-system also killed breast cancer cells at a 100 watts/2 min radio frequency. The potential of the nanogel as a cell tracker was investigated using NIR light-triggered drug release . Kimura A. et al. used ultra-small Galodium-gelatin nanogels as an MRI contrast agent because the coated gelatin shell minimizes the risk of nanoparticles leaking through the blood-brain barrier and blood-cerebrospinal fluid barrier . The devTheranostic is a term used to describe tools, devices, or systems that have combined diagnostic and therapeutic features. For a drug delivery system, these platforms were designed to improve the therapeutic potential and decrease side effects, along with being able to diagnose or indicate the drug’s biodistribution after administration. Wu W. et al. used pH-responsive polymers, PNIPAM-co-acrylic acid with embedded Au nanoparticles, as an imaging probe . The nanA graphene-DOX-entrapped hyaluronic acid nanogel was evaluated as a theranostic system . The nanPeng N. et al. formulated novel hybrid nanogels composed of a disulfide-modified alginate shield covering superparamagnetic iron oxide nanoparticles . In addition, the adjustable design of polymers results in the stability of active compounds in the physiological environment and having feature-specific functions. Moreover, the stimuli-responsive behavior of nanogels allows them to be used as biocompatible diagnostic tools that provide precise results. The practical biomedical use of nanogels is being increasingly investigated to develop efficient and specific medical tools and advance the use of nanotechnology in drug delivery systems.


Here, we review the structural details of the PSI tetramer in cyanobacteria and the PSI-LHCI and PSI-LHCI-LHCII supercomplexes from different algae and plants, and then discuss the diversity of PSI-LHCI in oxygenic photosynthesis organisms.Photosystem I (PSI) is one of the most efficient photoelectric apparatus in nature, converting solar energy into condensed chemical energy with almost 100% quantum efficiency. The ability of PSI to attain such high conversion efficiency depends on the precise spatial arrangement of its protein subunits and binding cofactors. The PSI structures of oxygenic photosynthetic organisms, namely cyanobacteria, eukaryotic algae, and plants, have undergone great variation during their evolution, especially in eukaryotic algae and vascular plants for which light-harvesting complexes (LHCI) developed that surround the PSI core complex. A detailed understanding of the functional and structural properties of this PSI-LHCI is not only an important foundation for understanding the evolution of photosynthetic organisms but is also useful for designing future artificial photochemical devices. Recently, the structures of such PSI-LHCI supercomplexes from red alga, green alga, diatoms, and plants were determined by X-ray crystallography and single-particle cryo-electron microscopy (cryo-EM). These findings provide new insights into the various structural adjustments of PSI, especially with respect to the diversity of peripheral antenna systems arising  PSI is among the most efficient nano-photochemical machines in nature: it converts solar energy into condensed chemical energy at nearly 100% quantum efficiency  and photosystem II (PSII), which are embedded in thylakoid membranes and responsible for light-driven electron transport. Both PSI and PSII are multi-subunit pigment-protein supercomplexes consisting of the core complex and a light-harvesting complex  in eukaryotic algae and plants. PSII mediates the electrons’ transfer from water to the plastoquinone pool and produces electrons, protons, and molecular oxygen, whereas PSI mediates electron transfer from plastocyanin to ferredoxin and generates the power to reduce NADPficiency ; hence, olecules .via primary endosymbiosis, leading to the formation of chloroplasts. These photosynthetic eukaryotes later divided into three lineages according to their color: chlorophytes , rhodophytes , and glaucophytes. Red algae and those algae with secondary plastids of red algal origin are known as the “red lineage,” distinguishable from the “green lineage”   . Despitermed FCP . Both lirmed FCP . Collectrmed FCP .Recent advances in single-particle cryo-electron microscopy (cryo-EM), X-ray free electron laser (XFEL), X-ray diffraction (XRD), and other techniques have revealed unprecedented structural and catalytic details of how photosynthetic electron transfer occurs in cyanobacterial PSI and PSII cores , as wellin vivo. Almost 20 years ago, the structure of the prokaryotic PSI trimer from the cyanobacterium Thermosynechococcus elongatus was resolved at a high-resolution of 2.5 Å by X-ray crystallography  to which 127 cofactors are non-covalently bound. Normally, cyanobacteria’s PSI lacks the peripheral antenna system of eukaryotic algae, but in some cases the hydrophilic phycobilidomes can be used for additional light-trapping antennas . Interessed ring . The larsed ring .Pisum sativum (lhca1/lhca4 and lhca2/ lhca3) (Lhca genes (lhca1–6), both lhca5 and lhca6 are only expressed at sub-stoichiometric levels (Cyanidioschyzon merolae) and a green alga (Chlamydomonas reinhardtii) provided strong evidence that, indeed, algae do harbor more abundant forms of PSI-LHCI structures. In C. merolae, a typical thermophilic, acidophilic red alga, each PSI core binds 3 or 5 LHCRs  , which tc levels . Unlike c levels . Recentl 5 LHCRs , whereas10 LHCIs . These svia phagocytosis, and their PSI also evolved a peripheral antenna system with a stronger light-harvesting ability during the evolutionary process. In the red lineage, algae (Rhodophyta) have similar characteristics to cyanobacteria, namely an absence of flagella and the presence of phycobiliproteins in their plastids (chloroplasts)  ; thus, roplasts) , and loswith PSI , b. Compwith PSI , while t merolae . EvidentC. reinhardtii, Bryopsis corticulans, and Dunaliella salina), a moss (Physcomitrella patens) and two terrestrial plants (P. sativum and Zea mays)—has been determined, providing valuable insights into the evolution of PSI in this lineage  and four LHC proteins (Lhca1–4). Compared plants and green alga (C. reinhardtii and B. corticulans) binding with 14–16 subunits, D. salina forms the smallest known PSI-LHCI and may represent an acclimation response to hypersaline environments  diverged from the ancestor of seed plants and the structure and function of their PSI-LHCI represents PSI’s evolution from aquatic to terrestrial life . The PSIe latter . Yet the. patens . The PSI. patens . Hence, C. reinhardtii has been determined to a 3.42 and 2.84-Å resolution by cryo-EM  is smaller than that identified from C. reinhardtii and P. patens and it contains only one LHCI belt (Lhca1-Lhca4) and one LHCII trimer. The LHCII trimer in plants is located at a position similar to that in the PSI-LHCI-LHCII supercomplex of green alga and moss. However, the other LHCII trimer in CrPSI-LHCI-LHCII is specific to green alga and bridges the gap between the conserved LHCII trimer and Lhca2. In summary, compared with PSI of green algae and mosses, which has diverse structure of the peripheral light-harvesting complex, the plants’ PSI-LHCI and PSI-LHCI-LHCI evolved to become more stable, likely because vascular plants face stronger light exposure conditions after moving from an aqueous to terrestrial environment.Interestingly, in the green lineage, exists a short-term light-adaptation process to regulate the light-harvesting capacity of PSI and PSII, this termed “state transition”. During this process, a portion of LHCII is phosphorylated and dissociated from PSII and moved to PSI, forming a PSI-LHCI-LHCII supercomplex. To date, the molecular structure of PSI-LHCI-LHCII supercomplex has been reported for green algae, mosses, and land plants . The PSI cryo-EM . ExaminaI trimer . The PSIa/c-binding proteins) supercomplex from the diatom Chaetoceros gracilis was reported at a 2.38 and 2.40-Å resolution, respectively, by cryo-EM (a/c antenna proteins in diatoms can help to efficiently harvest blue-green light under water (400–550 nm), which is essential for their survival and fitness in aquatic environments , we still know little of dynamic interaction processes in the thylakoid membrane—such as cyclic electron flow and binding of photoprotective proteins to photosystems—involved in light-acclimation responses. In particular, the recent discovery of the PSI-LHCI homodimer from y of PSI . WhetherTB and LG wrote the manuscript with the help of MX. LT reviewed and revised the manuscript. All authors contributed to the article and approved the submitted version.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.


Objectives: To compare the aqueous concentrations of inflammatory and angiogenetic factors in vitrectomized vs. non-vitrectomized eyes with diabetic macular edema (DME).Methods: Aqueous samples were obtained from 107 eyes with DME before intravitreal injection of anti-VEGF, 36 eyes with previous pars plana vitrectomy (PPV) combined with pan-retinal endolaser photocoagulation (PRP), and 71 treatment-naïve. Interleukin (IL)-6, IL-8, interferon-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, and vascular endothelial growth factor (VEGF) were measured by cytometric bead array (CBA). Optical coherence tomography (OCT) was used for measuring central retinal thickness (CRT).Results: IL-6, IL-8, IP-10, and MCP-1 in aqueous humor of DME vitrectomized eyes were significantly higher than in non-vitrectomized DME eyes, while VEGF was lower than in non-vitrectomized DME eyes. VEGF in aqueous humor significantly correlated with CRT for DME in non-vitrectomized DME eyes. IL-6, IL-8, IP-10, and MCP-1 in aqueous humor were not significantly associated with VEGF for DME in vitrectomized eyes.Conclusions: Inflammation might play an important role in the pathogenesis of DME in vitrectomized eyes. Moreover, inflammation might play a central role in the development of DME via the VEGF-independent pathway. Thus, anti-inflammatory therapy might be a strategy for DME in vitrectomized eyes. Anti-VEGF intravitreous injection is emerging as first-line therapy for diabetic macular edema (DME) . Still, The study by Yanyali et al.  demonstrIn order to investigate and analyze the role of inflammatory factors in post-operative DME, we compared the levels of the inflammatory cytokines mentioned above and VEGF in the aqueous humor of vitrectomized vs. non-vitrectomized DME eyes. The purpose of this study was to determine the optimal treatment for post-operative DME patients. Steroids, including slow-release steroids, might be an option for DME in vitrectomized eyes if the inflammation factors are proven to be an important factor in DME after PPV.This study was approved by the Ethical Committee of The Second Xiangya Hospital (LYZ2020009), and all enrolled patients were treated in accordance with the Declaration of Helsinki. All patients provided informed consent before inclusion in the study. To reduce selection bias, all patients were recruited consecutively.We obtained undiluted aqueous humor samples from 109 DR patients (109 eyes) prior to receiving an anti-VEGF intravitreal injection, including 38 eyes that had previously undergone PPV combined with pan-retinal endolaser photocoagulation (PRP) due to vitreous hemorrhage (referred to as the vitrectomized group), and 71 treatment-naïve eyes (referred to as the non-vitrectomized group). The PPV-combined PRP in the vitrectomized group was performed at The Second Xiangya Hospital of Central South University  by the same surgeon.The inclusion criteria were:- patients aged 18–80 years with type 2 DM- diagnosed with PDR- best correct visual acuity <20/40- DME involving macular- vitrectomized group: PPV was performed at least 4 weeks before enrollment- non-vitrectomized group: all patients were treatment-naïveThe exclusion criteria were:- vitrectomized group: intravitreous injection after PPV- non-vitrectomized group: prior ocular surgery, including intravitreous injection- any history of ocular inflammation- an abnormal vitreoretinal interface- history of renal and hematologic diseases, uremia, prior chemotherapy, and chronic diseases other than diabetes .Aqueous humor samples (50–100 μl) from patients with DME were obtained by anterior chamber paracentesis at the beginning of the vitreous injection. The specimens were manually aspirated using a 30-gauge needle and then transferred immediately into sterile tubes. The scheduled vitreous injections were subsequently performed. All samples were stored at −80°C until assayed.Central retinal thickness (CRT) was measured using spectral-domain optical coherence tomography  in all included eyes before the collection of aqueous humor samples. A macular profile of the central 6-mm zone was obtained using the fast macular scan protocol. CRT was calculated by extrapolating radial measurements as an average value within a circle with a 500-μm radius centered on the fovea. In the presence of vitreoretinal traction or epiretinal membrane, an OCT signal strength <4, or the OCT featured retinal border detection algorithm artifacts, the OCT result was excluded from the analysis.The quantitative determination of IL-6, IL-8, IP-10, MCP-1, and VEGF levels in the aqueous humor samples was performed using the CBA Human Cytokine kit , according to the manufacturer's protocol. A sample volume of 10 μl (either the standards or the patient samples) was added to 50 μl of a cocktail consisting of capture beads and detector antibodies, and the mixture was incubated for 18 h at room temperature in the dark. Before data acquisition, the excess unbound detector antibody was washed off. For statistical analyses, a measured value below the threshold of detection was conservatively omitted from the analysis.U-test. Spearman's correlation analysis was used to examine the correlations between cytokine concentrations and CRT values. p-values < 0.01 were considered significant when comparing data between two groups, and Bonferroni-corrected alphas were used for the evaluation of the results. There were two groups, and five pairwise tests were performed. The resulting p-values were evaluated at an alpha = 0.01 and with a p-value < 0.01 which was judged significant. When doing correlation analysis, we will find a significant p-value after Ryan–Holm step-down Bonferroni correction.Statistical analysis was performed using SPSS 24.0 . The results are presented as the mean ± SD. The mean cytokine levels, as detected by CBA, were compared between groups using the Mann–Whitney The clinical characteristics of all patients are shown in p < 0.001). However, the levels of VEGF were significantly lower in the vitrectomized group than in the non-vitrectomized group .The mean interval between vitrectomy and the anti-VEGF intravitreal injection in the vitrectomized group was 17.8 weeks (range 4–78 weeks), and none of the inflammatory or VEGF levels were associated with the days after PPV  did not have a significant relationship with any of the cytokines measured in this study. Therefore, the interval after vitrectomy in this study did not influence the results.One limitation of our study is that we did not examine all cytokines, and the ultimate effects of these cytokines in vitrectomized DME eyes remain to be explored. Moreover, the number of samples in our study was limited.In conclusion, this study showed that the levels of inflammatory factors in the aqueous humor were higher, whereas the VEGF levels were lower in vitrectomized DME eyes than in non-vitrectomized DME eyes. In addition, inflammatory factor levels had no relationship with VEGF levels in vitrectomized DME eyes. These findings indicate that inflammation might play an important role in the pathogenesis of DME in vitrectomized eyes. Anti-inflammatory therapies might represent another strategy for the treatment of DME in vitrectomized eyes. Further studies are needed to investigate the mechanism and treatment strategy of DME in vitrectomized eyes.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Our study was approved by the Ethical Committee of The Second Xiangya Hospital (LYZ2020009), and all enrolled patients were treated in accordance with the Declaration of Helsinki. All patients provided informed consent before inclusion in the study. To reduce selection bias, all patients were recruited in a consecutive manner.YL was responsible for designing the study, conducting the search, screening potentially eligible studies, extracting and analyzing the data, interpreting the results, and writing the paper. BY was responsible for extracting data. ZM, MX, ZL, ZZ, YM, JM, and BM were responsible for extracting data. XY was responsible for the data collection and modifying the language. JL was responsible for designing the study. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China (81570847), Natural Science Foundation of Hunan Province (2020JJ4800).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.


High dimensional multi-omics data integration can enhance our understanding of the complex biological interactions in human diseases. However, most studies involving unsupervised integration of multi-omics data focus on linear integration methods. In this study, we propose a joint deep semi-non-negative matrix factorization (JDSNMF) model, which uses a hierarchical non-linear feature extraction approach that can capture shared latent features from the complex multi-omics data. The extracted latent features obtained from JDSNMF enabled a variety of downstream tasks, including prediction of disease and module analysis. The proposed model is applicable not only to sample-matched multiple data  but also to feature-matched multiple data , and therefore it can be flexibly applied to various cases. We demonstrate the capabilities of JDSNMF using sample-matched simulated data and feature-matched multi-omics data from Alzheimer’s disease cohorts, evaluating the feature extraction performance in the context of classification. In a test application, we identify AD- and age-related modules from the latent matrices using an explainable artificial intelligence and regression model. These results show that the JDSNMF model is effective in identifying latent features having a complex interplay of potential biological signatures. With the development of high-throughput technology, large amounts of omics data have been produced. These resources enable us to understand disease- and patient-specific variations. Each omics datapoint contains different forms of information and is complementary to other data. By integrating multi-omics data, we can capture more complex interactions of the biological system.Motivated by this, many studies using various machine learning methods have been performed to integrate multi-omics data, including MOFA  based onTo enhance the understanding of complex relationships from multi-omics data, we developed a novel method called the joint deep semi-NMF model (JDSNMF) A. This m1.It introduces a hierarchical non-linear unsupervised learning model for capturing complex information from multi-omics data.2.It introduces a flexible integration model for multiple data which does not require matching samples.3.We compared the feature extraction performance of JDSNMF using sample-matched simulated data and feature-matched AD data.4.We identified the interpretability of JDSNMF through module analysis using an explainable artificial intelligence (xAI) D and regIn summary, the main contributions of this work include:In this section, a brief review of the most relevant works, i.e., NMF, joint NMF, semi-NMF, and deep semi-NMF, is provided.NMF ,11 is a I matrices ith coefficient matrix, and the rank Z is a feature extracted matrix in which multiple data are integrated, and a coefficient matrix i dataset. It is useful for integrating heterogeneous data such as multi-omics data.jNMF is an advanced NMF model that decomposes multiple data into a common basis matrix and multiple coefficient matrices . Given nH matrix. Matrix X and matrix Z may have mixed signs. Semi-NMF decomposes with Z matrix as the cluster centroid, and the H matrix can be viewed as the cluster indicator.Semi-NMF  is a relX matrix into m layers as follows:Deep semi-NMF  is a mulImplicit representations of layers are suitable clusters according to the corresponding attributes. The multi-layer model helps learning multiple low-dimensional representations of the original matrix.I is the number of multiple datasets, C is the number of samples (or features), and M is the number of individual features (or samples). JDSNMF decomposes the given original matrices by minimizing the following objective function.g such as a sigmoid activation function and a ReLU activation function to make the decomposed H matrix non-negative with non-linearity.Our proposed model, JDSNMF, has advantages of non-linear dimensionality reduction and heterogeneous data integration. It adapts several advanced NMF approaches for feature extraction to learn complex non-linear manifolds from complex heterogeneous data. JDSNMF adapts joint NMF  to integThe feature latent matrix and the sample latent matrix of the first layer are used in module construction. In the application of NMF, researchers have used two different approaches to construct modules. One is to assign each feature (or sample) to a module with a maximum value ,14, and U is a feature latent matrix, and U, U are smaller than a negative threshold for each module. We assumed that genes with values larger than a positive threshold (positive genes) increase GE or DM values of corresponding samples in the original data matrix and that genes with values less than a negative threshold (negative genes) decrease GE or DM values of corresponding samples in the original data matrix. In the K3 module, AD samples from the GE data and NL samples from the DM data were selected by thresholds; Gene 1 and Gene 4 are positive and negative genes, respectively. This result indicates that Gene 1 is more likely to be overexpressed and hypermethylated, and Gene 6 to be underexpressed and hypomethylated, in some of the AD samples. We conducted four experiments to validate the effectiveness of the proposed JDSNMF. First, we evaluated the feature extraction performance in the context of classification on sample-matched simulated data. Second, we evaluated the feature extraction performance on feature-matched multi-omics data.The performance of JDSNMF using the GE data of the Addneuromed (ANM) and DM data of the MRC London Brainbank cohort as feature-matched data was compared with models using only GE data of the ANM cohort. We provide details of the comparison of the performances of AD/normal (NL) classification and mild cognitive impairment (MCI)/NL classification on the GE data of the ANM cohort. Third, we compared the performance of AD/NL classification according to the reduced dimension K on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Fourth, we highlight AD- and age-related modules and match the module to the known database, indicating that JDSNMF is effective in module analysis.n = 20,017). We normalized ANM Cohorts 1 and 2 to reduce the batch effect using the Combat method from the ‘SVA’ R package [We used a blood GE profile from the ANM consortium, a large cross-European AD biomarker study, and a follow-on Dementia Case Register (DCR) cohort in London. We downloaded the normalized RNA profile from the GEO: ANM Cohort 1 (GSE63060) and ANM Cohort 2 (GSE63061). The ANM Cohort 1 contains blood GE data of 145 patients with AD, 80 MCIs, and 104 NL, and the ANM Cohort 2 has those of 140 patients with AD, 109 MCIs, and 135 NLs after removing three borderline MCI samples and one other sample. We averaged the expression levels of probesets with the same RefSeq IDs, and then filtered out the uncommon RefSeq IDs between two cohorts . We filtered out the uncommon RefSeq IDs between the GE profiles and the DM profile. We also mapped RefSeq IDs to gene symbols and averaged the values of the same gene symbols in the GE and DM profiles .We used a peripheral whole blood DM profile from the MRC London Brainbank for Neurodegenerative Disease . We downhttp://adni.loni.usc.edu (accessed on 1 September 2019). Both GE and DM profiles were obtained from whole blood. Because the GE profile did not contain diagnostic information, we obtained diagnosis of GE samples using the subject ID and visit code of the diagnostic information file (DXSUM_PDXCONV_ADNIALL.csv). The GE profile from ADNI consisted of 362 participants . We averaged the expression values of the same gene symbols . Because ADNI has longitudinal data, there are samples with different diagnosis for each participant. Thus, we selected the DM samples examined on similar dates with GE samples for each participant. We obtained 294 participants , and we converted the IDAT file into a beta-value format using a “minifi” R package [n = 21,099). We filtered out the uncommon genes between the GE profiles and the DM profile .For the ADNI database, we downloaded robust multichip average normalized GE and raw DM profiles (IDAT format) from In this section, the hyperparameters and settings of JDSNMF, NMF, deep semi-NMF, and classification models are described.Our JDSNMF model has four key hyperparameters: the number of layers, the reduced dimensions of each layer, a layer to use for classification, and an L2 norm parameter. In the NMF method, the hyperparameters were the updated algorithm, the number of reduced dimensions, and the initialization method. The hyperparameters in the deep semi-NMF method were the same as those in the JDSNMF model.For JDSNMF and deep semi-NMF, the Adam Optimizer  and earlhttps://github.com/dmcb-gist/Joint-deep-semi-NMF, accessed on 30 January 2020. The scikit-learn python library [We used an NMF method in the scikit-learn library  and impl library  for the  library  was usedWe evaluate the robustness performance and feature extraction performance of our proposed JDSNMF model on sample-matched simulated datasets.sth sample and jth feature. The class label probability jth feature, and Three datasets with small sample sizes and high dimensionality are simulated, while most of the features are irrelevant to the objective. We generated the predictor matrix  follows :(7)ys=exWe evaluate the feature extraction performance with NMF, deep semi-NMF, and JDSNMF on simulated data . We measure the classification performance of the output from each feature extraction model using SVM. The optimal hyperparameters of each feature extraction model are searched by validation data. The hyperparameters of SVM were fixed. We repeated the analysis 20 times with different simulated datasets. To evaluate our model’s ability to identify latent information predictive of AD from feature-matched omics data, we compared it with a feature selection approach based on differentially expressed genes, NMF, and a deep semi-NMF. The GE data of the ANM cohort were used for all models. Additionally, the DM data of the MRC London Brainbank cohort were used for JDSNMF.p-value. For the baseline, we randomly selected the same number of genes selected in the feature selection model  was employed to evaluate performance. In AD/NL classification, we divided samples into training, validation, and test sets (3:1:1 ratio) in each fold. The optimal hyperparameters were searched by validation data. In MCI/NL classification, we used optimal hyperparameter sets that had the best performance in the AD/NL classifications . The classification performances of each of the three classifiers are shown in In this section, we attempt to interpret the clinical and biological meanings of the latent matrices from the GE data of the ANM cohort and the DM data of the MRC London Brainbank cohort. We identified AD- and age-related modules and matched the module to the known database. We used the GE sample latent matrix, DM sample latent matrix, and feature latent matrix from the JDSNMF model with the best performance in the “Feature-matched real dataset experiments” section . We constructed the 60 modules from the GE sample latent matrix, DM sample latent matrix, and feature latent matrix.We used a locally interpretable model-agnostic explanation (LIME)  as the xq-value < 0.0001) in module 7. Among them, the “Alzheimer disease” pathway was statistically significant  were positive genes and 12 were negative genes . We surveyed these genes from previous studies for relevance to AD. SNCA , NADH-ubiquinone oxidoreductase, and ubiquinol-cytochrome c oxidoreductase, which are components of the mitochondrial respiratory chain. Previous studies reported that mitochondrial dysfunction is related to AD [Module 7 had the highest sum of LIME values for the three classifiers . At the ed in AD . The samal cells . In a pral cells , althouged to AD . Reduceded to AD .Other pathways are known to be directly or indirectly related to AD. For example, differential expression of oxidative phosphorylation genes is observed in AD . In wildFor each module, we performed linear regression analysis and calculated the Pearson correlation coefficient between the LIME importance score in the AD classification and the number of genes overlapped with the AD pathway in KEGG pathway analysis. i in module j, i with coefficient i with coefficient i with coefficient k-th principal component of the sample latent matrix for the i-th sample with coefficient N is the number of PCs that are not related to age. p-value = 4.58 To study other modules further, we used age information and found age-related modules by applying the following linear regression model to the GE and DM sample latent matrix.d to age . We focuq-value < 0.05) in module 1 . We selected 750 ADNI2 samples with both data types. The numbers of NL, significant memory concern (SMC), early MCI (EMCI), late MCI (LMCI), and AD are 180, 102, 170, 156, and 142, respectively.As brain imaging data are also important for the diagnosis of AD, we evaluated the feature extraction performance of our proposed JDSNMF model on sample-matched bioimaging datasets. The experiments were performed on magnetic resonance imaging (MRI) regions of interest (ROIs) and AV-45 amyloid positron emission tomography (PET) ROI datasets from ADNI-TADPOLE ( K of each model was selected by a validation set from each fold. The AUC values for one-vs-rest were calculated for multiclass classification. We measured the classification performance of extracted features from each feature extraction model using SVM. The reduced dimension We introduced a novel JDSNMF model—a non-linear feature extraction model—that can capture shared latent representations from complex multi-omics data. The proposed model is applicable to the existing sample-matched multi-omics integration and the new feature-matched multi-omics integration. JDSNMF demonstrated significant improvements in multi-omics feature extraction tasks on sample-matched simulated data and feature-matched multi-omics data. In AD experiments, we identified AD-related and age-related modules through the recent xAI model and traditional regression approaches. We observed that many AD-related genes were included in modules important for AD prediction and that genes in the age-related modules were significantly enriched with known aging-related genes. These results suggest that it is applicable not only to analysis of large cohorts with multi-omics data but also to integration analysis between single omics cohorts. Furthermore, feature-matched integration analysis can be applied to cross-species comparison, cross-disease comparison, and cross-cohort comparison. We also confirmed that our model is applicable to bioimaging data by further experiments.However, this method has some limitations. Our model involves simple multi-task learning with uniform loss weights. This can lead to an optimization conflict while learning to reconstruct each omic datum. In the future, we will apply advanced multi-task learning methods  to the J