Intercellular communication is a normal feature of most physiological interactions between cells in healthy organisms. While cells communicate directly through intimate physiology contact, other mechanisms of communication exist, such as through the influence of soluble mediators such as growth factors, cytokines and chemokines. There is, however, yet another mechanism of intercellular communication that permits the exchange of information between cells through extracellular vesicles (EVs). EVs are microscopic (50 nm−10 μM) phospholipid bilayer enclosed entities produced by virtually all eukaryotic cells. EVs are abundant in the intracellular space and are present at a cells' normal microenvironment. Irrespective of the EV “donor” cell type, or the mechanism of EV biogenesis and production, or the size and EV composition, cancer cells have the potential to utilize EVs in a manner that enhances their survival. For example, cancer cell EV overproduction confers benefits to tumor growth, and tumor metastasis, compared with neighboring healthy cells. Herein, we summarize the current status of knowledge on different populations of EVs. We review the situations that regulate EV release, and the factors that instruct differential packaging or sorting of EV content. We then highlight the functions of cancer-cell derived EVs as they impact on cancer outcomes, promoting tumor progression, metastases, and the mechanisms by which they facilitate the creation of a pre-metastatic niche. The review finishes by focusing on the beneficial  features of tumor-derived EVs that can be adapted and utilized for cancer treatments, including those already being investigated in human clinical trials. Several mechanisms of cell-to-cell and cell-to-microenvironment communication are used to maintain physiological processes in healthy organisms. These processes are numerous and often involve the production of soluble molecules such as cytokines and growth factors , 2. Therin vitro) or present within tissue extracellular space (in vivo) between cells  receptor SNAP, and tethering factors, are indicated in stimulating EV biogenesis and release  result e stress  and tumoe stress . Also, eotential . Furtherotential . In otheotential  or HRAS otential  modulateotential , and ERBotential . Of noteEVs have the capacity to interact with a wide variety of recipient cells i.e., any cell that engages with EVs, be it within tissue extracellular space, during or after blood or lymphatic distribution. This means that either the original EV donor tissue cells, or blood or lymphatic endothelium, or a distant tissue cell can be influenced by EVs. EVs therefore serve as an important vector of intercellular molecular exchange in diverse but both physiologically linked and unrelated tissues.It has long been known that EVs are carriers of genetic and proteomic information. It has not, however, always been appreciated that EV trafficked molecules can be present in a relatively concentrated form. In this regard EVs are frequently said to be “rich” in expression of certain molecules, for example, we and others have shown, EVs can contain high concentrations of certain molecules, such as p-glycoprotein - relative to the EV donor cells  Examplesin vivo (in mice) by facilitating the formation of endothelial capillaries  of EVs depends on their ability to interact with a recipient cell in a manner that inherently involves direct contact of membranes. When encountering a recipient cell, EVs may simply adhere and stably associate with the recipient cell membrane surface, then either dissociate, or become incorporated within the recipient cell membrane . Recipieper se.It is unclear whether EV internalization is selective or a completely random process. Current evidence suggests a degree of cellular control of EV internalization, dependent on factors such as the target cell type, the location, or physiological and environmental conditions, or even dependent even on the molecule being received/internalized e.g., nucleic acid, protein, carbohydrate, lipid. In most cases, however, the recipient cell specific interactions with EVs are regulated by adhesion molecules . For exaTumorigenesis was historically attributed to genetic and epigenetic alterations in the genome of an organism but there is compelling evidence that EVs are integral to cancer cell communication and cancer progression. This is essentially due to EV contents because when produced from tumor cells EVs are a reservoir of cancer-associated molecules. Not only can EVs aide tumor cell survival , 176 butV12 and c-myc oncogene transfected cells conferred tumorigenicity in vivo (in mice) via a mechanism involving oncogene transfer into recipient cells (cis), but nevertheless transferred DNA can have oncogenic potential via DNA-encoding oncogenes or the oncoproteins themselves, in some respects resembling certain instances of non-integrating viral transformation  and Akt pathways promoting anchorage independent growth and survival . When cont cells . The EV-ormation .Other pro-tumor EV effects include the role of the pro-coagulant transmembrane tissue factor molecule that modulates angiogenesis as well as metastasis in cancer [reviewed in ] and tisAs alluded to above, tumor-derived EVs can cause the activation of specific pathways that support tumor growth and survival. Tumor proliferation can be promoted by gastric cancer-derived exosomes through the activation of the phosphoinositide 3-kinase (PI3K), Akt, and mitogen-activated protein kinase/extracellular-regulated protein kinase (MAPK/ERK) pathways . Cancer Malignant cells modulate the tumor microenvironment via both their pro- or anti-inflammatory effects. The immunomodulatory effects of EVs are particularly well studied in macrophages due to their high propensity for endocytosis and the abundance and accessibility of their precursors - blood monocytes. Melanoma-derived exosomes have been shown to be capable of inducing a pro-inflammatory recipient cell effect by altering the cytokine and chemokine profiles of the target macrophage cells . Similarhow to specifically inhibit only EV:TGFβ-producing tolerogenic T cells and not tumor-specific cytotoxic T lymphocytes, and or anti-tumor Natural Killer (NK) cells. Such interventions would need to be cytokine-specific. Other anti-inflammatory mechanisms of EVs includes gastric carcinoma cell-derived MPs interacting with monocytes resulting the production of the immunosuppressive cytokine IL-10. This is directly immune suppressive and additionally acts indirectly to decrease pro-inflammatory cytokines GM-CSF and TNF (via feed-back loops). Hence, EVs skew the tumor cytokine milieu to either an anti- or pro-inflammatory signature  from tolerogenic T-cells that promotes the generation of myeloid-derived suppressor cells . This suignature . Interesignature ; curcumiignature . In factignature , 196. Ofignature .2+-permeable channel transient receptor potential channel-5 (TrpC5) (in vitro activation of Her2 (by heterodimerisation with EGFR or Her3) with ligands epidermal growth factor (EGF) and heregulin results in the increased production of exosomes  transporter p-glycoprotein (MDR1/ABCB1) , 151, mu (TrpC5) , and the (TrpC5) . The sig (TrpC5) , 151. Mo (TrpC5) , 203. EV (TrpC5) . Others  (TrpC5) . It is t (TrpC5) . In the  (TrpC5) . Indeed,exosomes . This suexosomes . Similarexosomes .in vivo (in mice) using a model tumor antigen of ovalbumin (OVA)-in melanoma cell derived exosomes  cell proliferation or enhancing their suppressive capacities -2, MMP-9, and MT1-MMP , their zll lines . Moreovell lines , and it in vitro , 244. Inin vitro , 246 thain vivo models of cancer. Pancreatic carcinoma cell derived exosomes carrying CD44v6 promote tumor growth and metastasis in lymph nodes and lungs of rats . It is capable of removing soluble factors and exosomes from the peripheral blood circulation  of a tumor. The EVs themselves, or the EV cargo molecules, can be used to track cancer risk, cancer presence, and as marker of treatment outcomes—cancer cure or relapse. In certain circumstances it would be highly beneficial to selectively diminish or deplete tumor-specific EVs in circulation, without affecting non-tumor EVs that have other physiologically important functions. A technology currently in development is capable of removing soluble factors and exosomes from the peripheral blood circulation  and is mculation . For exaOn the other hand, the production and presence of tumor-derived EVs can have undesirable effects for the host organism, although, the deleterious effects can also be modulated for better treatment outcomes for cancer patients. Thus, there can be benefits to developing and using compounds that inhibit or interfere with tumor cell EV biogenesis, release and recipient cell uptake. These include reagents that block phosphatidyl serine, surface heparan sulfate, proteoglycans, ICAM1 interactions with their receptors i.e., molecules that are critical for EV engulfment . For exain vitro storage conditions including several freeze-thaw cycles, making them excellent biomarkers of disease (per se does not necessarily equate to a need for treatment (as in prostate cancer), markers of cancer metastasis are particularly valuable to cancer clinicians. Periostin, is an example of an EV metastatic cancer bio-marker. Periostin is concentrated at high levels in EVs derived from metastatic cells in vitro and abundantly present in plasma exosomes in breast cancer patients with lymph node metastasis , with efficacy documented in animal models of disease. For example,  in mice , 291. Ot in mice , or exos in mice . In thes in mice . siRNAs  in mice , c-Myc  EVs themselves. If the therapy EVs were autologous (and patient specific) this would help address the potential for immunogenicity. Interestingly, the present thinking appears not to consider EV HLA-expression as being a significant factor, but we have evidence of some degree of immune cell activation by non-HLA-matched EVs . A deeper understanding of the benefits and/or limitations of EV immunogenicity may prove to be beneficial to the success of therapy EVs, and it may prove to be beneficial to examine this more deeply in current cancer clinical trials and more human data is desperately needed.The issue of immunogenicity is a double-edged sword. The potential for therapy EVs to enhance immunogenicity is particularly useful given that EVs are well known to carry tumor-associated antigens (TAAs). Therapy EVs have a documented capacity to elicit TAA-specific anti-tumor immune responses, which improves cancer survival in primary and metastatic mouse tumor models . FurtherAs with any new or emerging biotechnology there are technical issues surrounding its use in the clinic. For EVs these include difficulties in standardization of EV isolation techniques and EV detection methodologies, as well as issues related to the GMP production of therapy EVs.The potential uses of EVs as biomarkers is exciting but caution is needed as there are many different methods of isolating, detecting and using EVs in cancer detection and treatment , 308. ThAdditional innovative methods of EV detection and characterization include various microfluidic  approaches that allow for efficient molecular capture and quantification from relatively small volumes of circulating exosomes . Indeed,a priori the existence of true immunogenic “cancer antigens” but these are usually not well defined, if defined at all. The “antigen” might constitute a re-activated endogenous retroviral antigen or cancer-specific neo-antigen. Whether cancer-EVs are pan-specific  or whether they must be individually identified and isolated and used autologously, i.e., each individual patient, currently remains unclear. Furthermore, the optimal mode of EV delivery is also unclear in terms of achieving optimal clinical outcomes; delivery might be via i.v. infusion (single or repeated dose), or via an implanted medical device—for sustained release. Indeed, optimal delivery will possibly depend on the setting in which the EV vaccine is to be applied—an infectious disease, a certain cancer type, a primary cancer diagnosis or a cancer re-occurrence. On the other hand, the potential clinical use of tumor EVs carries with it potential dangers because of certain cargoes. For example, cancer cell derived EV can contain p-glycoprotein that confers resistance to chemotherapy drugs  agents. With the value of more precise analysis technologies, our understanding of the biological interactions of EVs for intercellular communication is rapidly expanding. This new knowledge has high relevance and high value for the use of EVs in cancer, including for innovative, even patient-specific “designer” cancer treatments. These developments offer the promise of more specific, less toxic, high-efficacy cancer treatments, especially in this era of personalized medicine.RJ wrote the first draft of the manuscript. RJ and LS both contributed to manuscript revisions, read and approved the final 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.


Infusion reactions (IRs) are common immune-mediated side effects in patients treated with a variety of drug products, including, but not limited to, nanotechnology formulations. The mechanism of IRs is not fully understood. One of the best studied mechanisms of IRs to nanomedicines is the complement activation. However, it is largely unknown why some patients develop reactions to nanomedicines while others do not, and why some nanoparticles are more reactogenic than others. One of the theories is that the pre-existing anti-polyethylene glycol (PEG) antibodies initiate the complement activation and IRs in patients. In this study, we investigated this hypothesis in the case of PEGylated liposomal doxorubicin (Doxil), which, when used in a clinical setting, is known to induce IRs; referred to as complement activation-related pseudoallergy (CARPA) in sensitive individuals. We conducted the study in vitro using plasma derived from C57BL/6 mice and twenty human donor volunteers. We used mouse plasma to test a library of well-characterized mouse monoclonal antibodies with different specificity and affinity to PEG as it relates to the complement activation by Doxil. We determined the levels of pre-existing polyclonal antibodies that bind to PEG, methoxy-PEG, and PEGylated liposomes in human plasma, and we also assessed complement activation by Doxil and concentrations of complement inhibitory factors H and I in these human plasma specimens. The affinity, specificity, and other characteristics of the human polyclonal antibodies are not known at this time. Our data demonstrate that under in vitro conditions, some anti-PEG antibodies contribute to the complement activation by Doxil. Such contribution, however, needs to be considered in the context of other factors, including, but not limited to, antibody class, type, clonality, epitope specificity, affinity, and titer. In addition, our data contribute to the knowledge base used to understand and improve nanomedicine safety. Infusion reactions (IRs) are immune-mediated toxicities that occur within the first minutes to hours of the systemic administration of various drug products used at their relevant therapeutic doses to treat or diagnose a disease ,9,10,11.Among the mechanisms underlying infusion reactions to nanomedicines is complement activation-related pseudoallergy (CARPA) syndrome ,19,20,21In this study, we used PEGylated liposomal doxorubicin formulation (Doxil) to investigate the influence of anti-PEG antibodies on the complement activation. Doxil is a nanodrug approved by the U.S. Food and Drug Administration (FDA) in 1995 and used for the treatment of over 600,000 cancer patients worldwide. Current clinical experience with this drug demonstrates that Doxil causes CARPA in sensitive patients ,18,19,20To explore the role of PEG-reactive antibodies in the complement activation by Doxil, we used a library of well-characterized antibodies with known class, specificity, and affinity .If the binding of antibodies to the PEG component of Doxil contributed to the complement activation by this nanodrug, we expected to see higher levels of the complement split products in plasma incubated with the Doxil–PEG antibody combination than in plasma treated with Doxil alone. Phosphate-buffered saline (PBS) and cobra venom factor (CVF) were used as negative and positive controls, respectively. Potent induction of the complement system was observed with CVF , NC. VarWe observed a more than two-fold increase in the C3a levels in plasma treated by a combination of Doxil and one out of three tested anti-PEG IgG clones (All three tested clones of anti-PEG IgM resulted in a more than three-fold increase in the complement activation by Doxil A.p < 0.05) than those in the presence of anti-PEG IgG (+AB4)  were also stronger (G (+AB4) A. These Two murine antibodies in our library belonged to the same class (IgG) and differed in specificity to the various portions of the PEG polymer. The AB4 antibody was specific to the PEG backbone, while the AB6 antibody was specific to the terminal methoxy group. AB6 resulted in stronger induction of the complement activation by Doxil than AB4 B. One reCollectively, our data suggest that some anti-PEG antibodies can contribute to the complement activation by PEGylated liposomes. Such contribution depends on many factors, including, but not limited to, the antibody class (IgG vs. IgM), epitope specificity , and affinity. It appears that IgMs have a greater propensity to contribute to the complement activation. The anti-PEG IgG presence in plasma is insufficient to warrant complement activation by Doxil even though the antigenicity  is confirmed.Not all patients undergoing therapy with PEGylated liposomal doxorubicin develop CARPA ,41. HoweNext, we calculated SI to the positive control (CVF) and performed regression analysis to compare it with the SI of Doxil in the same donor specimens. The strong response to CVF coincided with the strong response to Doxil in only one donor (D0639). Likewise, a weak response to both Doxil and CVF was seen in one other donor (D0984) C. ExceptTo investigate if the donor plasmas used in our study contain antibodies reactive with PEG, we screened all plasma specimens using in-house ELISA. The protocol for this assay has been published earlier . In thisIn the first analysis, plasma from more than 50% of donors contained PEG, mPEG, and Doxebo-reactive IgM B. In theThe gender-dependent prevalence of PEG-reactive antibodies observed in our study is in agreement with the earlier report . The difTo understand the functional significance of the pre-existing antibodies reactive to PEG, mPEG, and PEGylated liposomes, we compared antibody titers with the stimulation index determined in our complement activation study with Doxil. This comparison revealed one donor (D1152) who demonstrated the highest level of the complement activation by Doxil and who contained the highest titer of the Doxebo-reactive antibody A, D1152.p < 0.05) only between CFI concentrations and the magnitude of the complement activation by CVF  perform the function of the negative regulation of the complement system ,46,47. Tn by CVF E. The CFn by CVF F. These Hirudin blood collection tubes were purchased from Roche SSC Budapest . PEG2000 and mPEG2000 were from Sigma  and Laysanbio , respectively. Donkey anti-human IgG-HRP, rabbit anti-human IgM-HRP, goat anti-rat IgM-HRP, and donkey anti-rabbit IgG-HRP were from Jackson ImmunoResearch Labs . Carnation nonfat dry milk was from Nestlé . BupH tris-buffered saline and carbonate-bicarbonate buffer packs were from Pierce . Anti-PEG antibodies  were purchased from Academia Sinica . Anti-PEG antibodies PEG-B-47 and ANPEG-1 were purchased from Epitomics/Abcam  and ANP Tech , respectively. Doxil and Doxebo were purchased from Avanti Polar Lipids . According to the material certificate of analysis, the concentration of the anticancer drug doxorubicin was 2 mg/mL in the Doxil formulation. Both Doxil and Doxebo had comparable total lipid concentrations. Physicochemical characterization of these particles included hydrodynamic size by dynamic light scattering, zeta potential, and endotoxin contamination by Limulus Amoebocyte Lysate assay. We previously published the results of this characterization . The matg for 10 min, after which they were aliquoted and stored at a nominal temperature of −20 °C before use. Human plasma from individual donors was used. Mouse plasma from individual animals was pooled before use. An analysis of all experimental endpoints  was performed on the specimens from the same batch .Human blood specimens were collected from twenty healthy donor volunteers under NCI at Frederick Protocol OH99-C-N046. Mouse blood was collected from C57BL/6 Charles River Laboratories (CRL) mice. Both human and murine blood was collected in tubes containing hirudin as an anticoagulant. Plasma specimens were prepared by blood centrifugation at 2500× The procedure described earlier ,27 was fThe procedure described earlier  was usedAnalyses were performed using commercial kits and according to the manufacturer’s instructions.Analyses were performed using GraphPad Prism 7 software .Our study demonstrated that some but not all purified, high-titer monoclonal anti-PEG antibodies contribute to the complement activation by Doxil in vitro in mouse plasma. Mouse monoclonal PEG-reactive IgM appeared as the most potent contributors. We also detected various levels of pre-existing antibodies in plasma from human donors. In our study, we used the assay that was reported previously . We furt


Flaviviridae family. TBEV is transmitted to humans primarily from infected ticks. The virus causes tick-borne encephalitis (TBE), an acute viral disease that affects the central nervous system (CNS). Infection can lead to acute neurological symptoms of significant severity due to meningitis or meningo(myelo)encephalitis. TBE can cause long-term suffering and has been recognized as an increasing public health problem. TBEV-affected areas currently include large parts of central and northern Europe as well as northern Asia. Infection with TBEV triggers a humoral as well as a cell-mediated immune response. In contrast to the well-characterized humoral antibody-mediated response, the cell-mediated immune responses elicited to natural TBEV-infection have been poorly characterized until recently. Here, we review recent progress in our understanding of the cell-mediated immune response to human TBEV-infection. A particular emphasis is devoted to studies of the response mediated by natural killer (NK) cells and CD8 T cells. The studies described include results revealing the temporal dynamics of the T cell- as well as NK cell-responses in relation to disease state and functional characterization of these cells. Additionally, we discuss specific immunopathological aspects of TBEV-infection in the CNS.Tick-borne encephalitis virus (TBEV) is a flavivirus that belongs to the  Flaviviridae family. Flaviviruses comprise many human pathogens including the commonly known Dengue virus (DENV), Japanese encephalitis virus (JEV), West Nile virus (WNV), Yellow fever virus (YFV), and Zika virus (ZIKV)  is a flavivirus that belongs to the s (ZIKV) . With res (ZIKV) .Ixodes family. The virus can also be transmitted from unpasteurized dairy products from infected livestock  cell- and T cell-mediated responses. Responses to TBEV are discussed in context of cell-mediated immune responses toward other flavivirus infections. We also discuss some immunopathological aspects of TBE with a particular emphasis on cell-mediated immune reactions in the CNS. Cell-mediated immune reactions in the CNS may contribute to neural damage with severe consequences of brain function, and could in the worst cases lead to fatal outcome. First, however, some aspects of the TBEV itself are covered.per se acts as messenger RNA upon entrance in the host cell. The RNA encodes for a polyprotein, which is co- and post-translationally cleaved by viral and cellular proteases into three structural proteins; capsid (C), precursor membrane (prM) and envelope glycoproteins (E), and seven non-structural proteins including NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 , CD56+ cells and represent about 15% of peripheral blood lymphocytes. These cells have for long been divided into two main subsets; CD56bright and CD56dim cells , KIRs, and CD57, which regulate their function and define distinct stages of NK cell maturation . Noteworthy in the context of acute TBEV infection, activation of NK cells may also occur very early, even before the onset of symptoms. This possibility is supported by the observation that the highest levels of NK cell activation in most TBEV infected patients were observed already at the time of hospitalization  . Reducedlization . This nolization . Accumullization –73; howenfection . It can,in vivo in different flavivirus infections, a protective role of NK cells is also supported by in vitro data. For example, primary activated human NK cells have been shown to inhibit WNV-infection of Vero cells , CD45RA−CCR7+ as central memory (TCM), CD45RA−CCR7− as effector memory (TEM), and CD45RA+CCR7− as effector memory RA (TEMRA) CD8 T cells  precedes that of CD8 T cells, and this may be of importance to elicit strong immunological memory . Furtherin vitro in cell culture-based models  in brain parenchyma , albeit in low numbers, in patients with severe TBE meningitis or encephalitis . ActivatKnowledge and experience gained in the field of the immunopathogenesis of other diseases affecting the CNS and its immunological compartments could be helpful in understanding TBE-specific diseases patterns. For example, in multiple sclerosis (MS), an inflammatory disease with pathology affecting the CNS , the conIn the present review, we have focused our attention to recent insights into the cell-mediated immune response to human TBEV infection, with an emphasis on studies of NK cell and CD8 T cell mediated responses. Until recently, the latter have been poorly studied. As yet, however, much more needs to be learnt with respect to these responses and research in this area should be encouraged. We have also addressed some aspects of TBEV CNS pathogenesis, a process still far from understood in detail. Clearly, however, cell-mediated immune responses likely play an important role in this process. As TBE continues to be an increasing global health problem and challenge, much more research is needed into this emerging disease. Several areas of research of the TBEV itself, and the clinical disease TBE merit further studies. Not the least, the specific organ pathogenesis caused by TBEV and the immune response, including infiltrating immune cells, needs more investigation. Furthermore, the possibility of antiviral treatment and other possible treatment modalities needs much more thorough investigation to prevent disease development and the often severe sequeale following infection of humans with TBEV.KB, AC, and H-GL wrote the manuscript. All other authors provided valuable contributions and insights into the manuscript.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.


Child stunting is a major public health problem, afflicting 155 million people worldwide. Lack of animal-source protein has been identified as a risk, but effects of animal protein supplementation are not well established.The aim of this study was to investigate effects of animal protein supplementation in mothers, preterm infants, and term infants/children on birth and growth outcomes.I2, stratified analysis, and meta-regression, and publication bias by funnel plots, Egger's test, and fill/trim methods.PubMed, EMBASE, Cochrane library, Web of Science, Cumulative Index of Nursing and Allied Health Literature, and Latin American and Caribbean Health Sciences Literature were searched for randomized controlled trials of animal protein supplementation in mothers or infants and children (≤age 5 y), evaluating measures of anthropometry (≤age 18 y). Main outcomes included birth weight, low birth weight, small for gestational age at birth; height, height-for-age, weight, weight-for-age, weight-for-length, stunting, and wasting ≤18 y of age. Data were extracted independently in duplicate, and findings pooled using inverse variance meta-analysis. Heterogeneity was explored using z-score was increased in the food-based (+0.06 z-score) but not formula-based (−0.11 z-score) trials reporting this outcome. In term infants, the weight-for-length z-score was increased in trials of formula (+0.24 z-score) and food supplementation (+0.06 z-score), whereas food supplementation was also associated with reduced odds of stunting (−13%).Of 6808 unique abstracts and 357 full-text articles, 62 trials were included. The 62 trials comprised over 30,000 participants across 5 continents, including formula-based supplementation in infants and food-based supplementation in pregnancy and childhood. Maternal supplementation increased birth weight by 0.06 kg, and both formula and food-based supplementation in term infants/young children increased weight by ≤0.14 kg. Neither formula nor food-based supplementation for term infants/young children increased height, whereas the height-for-age Supplementation of protein from animal-source foods generally increased weight and weight-for-length in children, but with more limited effects on other growth outcomes such as attained height. With se12 . Extreme12  and in s12 . HoweverIn animal models, linear growth is sensitive to total dietary protein, for instance acting through stimulation of insulin-like growth factor-1 and its binding proteins . In humaTo address these important gaps in knowledge, we performed a systematic review and meta-analysis of randomized controlled trials to determine the effects of maternal, preterm infant, and term infant/child supplementation of animal protein on child birth and growth outcomes. Elucidating these relations, as well as the remaining evidence gaps, is essential to inform strategies and policymaking to reduce undernutrition globally.We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines during all stages of implementation, analysis, and reporting of this meta-analysis.z-score (HAZ), weight, weight-for-age z-score (WAZ), weight-for-length z-score (WFL), and risk of stunting, assessed ≤18 y of age.The primary exposure of interest was the consumption of protein from animal sources, including meat, seafood (including fish), dairy products (including milk), and eggs, as well as animal milk-based infant formulas, by children aged 5 y or younger and pregnant women or postpartum lactating women. The primary outcomes included birth weight and risk of LBW (<2500 g), intrauterine growth retardation, or premature birth ; and height, height-for-age http://www.isrctn.com/); and contacts with experts. Searches were performed without restrictions on years or language through 25 February 2015 (and updated through to June 2018), with examples of search terms including: (dietary protein OR meat OR dietary supplements OR fortified food OR protein supplement) AND (body height OR growth child development OR pregnancy outcome OR birth weight OR stunting OR height) AND (child OR infant OR pregnant women) AND . Complete search strategies for each database are presented in the supplementary materials. Title and abstracts of all identified references were screened by 1 investigator (LP). For any potentially relevant article, the full text was retrieved and independently assessed in duplicate by 4 investigators  to determine eligibility, with discrepancies resolved by consensus.Multiple electronic databases were searched for relevant articles including PubMed, EMBASE, The Cochrane Library Web of Science, Cumulative Index of Nursing and Allied Health Literature, and Latin American and Caribbean Health Sciences Literature (LILACS). This was supplemented with hand searching of citation lists and electronic searching of the first 20 “related articles” on PubMed for all included full-text publications; searches of the international standard randomized control trial number register . When duplicate publications from the same study were identified, we included the publication reporting the largest number of participants for each outcome of interest.Data from included studies were independently extracted by 4 investigators in duplicate  using a standardized electronic form, with any differences resolved by consensus. Information was extracted on the study , participants , intervention , outcome types, follow-up , and growth outcomes . The dose of each intervention was standardized to grams of animal protein per 1000 kcal regular diet. If the precise protein content of the supplement was not reported, it was estimated using the American Diabetes Association and Academy for Nutrition and Dietetics Diabetic Exchange Lists  . When voStudy quality was assessed using the Cochrane Collaborations risk-of-bias tool, evaluating potential for selection bias, performance bias, detection bias, attrition bias, and reporting bias through a 6-question quality control checklist . Each quP value). We utilized the values from intent-to-treat analysis as the default. For trials reporting effects by stratum , we calculated the study-specific effect of animal protein by inverse-weighted meta-analysis across subgroups within that trial. Findings across trials were pooled using inverse variance-weighted meta-analyses , the primary effect measure was the mean difference in changes from baseline to follow-up in the intervention compared with the control group. If mean changes from baseline were not reported, the difference in follow-up measures between treatment groups was used. For binary outcomes , we extracted the reported OR across treatment groups. The SE for each effect measure was extracted or directly calculated from other reported uncertainty measures , baseline nutritional status , dose of protein supplementation (> or <median), energy supplementation , intervention duration (> or <median), and study quality score , using stratified analyses and meta-regression to test statistical significance of potential differences. We hypothesized that benefits of supplementation would be greater in low-/middle-income countries than in high-income countries, in malnourished than in average/unspecified nutritional status, in higher than in lower dose of protein, in energy-protein supplementation than in isocaloric-protein supplementation, and in studies with longer intervention duration, and higher study quality score. In post hoc exploratory analyses, we also assessed heterogeneity by child age at baseline and at follow-up. Potential for small-study effects was evaluated by visual inspection of funnel plots and Egger's and Begg's tests (α = 0.05).Heterogeneity was assessed using the 's tests . For botOf 6808 articles, 62 randomized controlled trials met eligibility criteria   or small for gestational age (SGA)  , or increase height  or weight  during later childhood  and weight   and their children after birth, all with combined energy–animal protein supplementation: increases were seen in both child height  and reduced HAZ   , and 1 trial provided 2 estimates for weight for length, which also decreased   did not significantly affect child height   , but HAZ  was reduced   among term infants/children, supplementation significantly increased weight     and an increase in weight for length  , but no reduced risk of wasting  .Using stratified analyses and meta-regression, we evaluated prespecified potential sources of heterogeneity (N = 6) showed larger increases in both weight (P heterogeneity = 0.001) and height (P heterogeneity = 0.02) than studies from high-income countries (N = 18); similar stratification was identified by baseline nutritional status and intervention duration. Doses of animal protein supplementation below median showed larger effects. No significant heterogeneity was identified by study quality score or in multivariate meta-regression.For trials of formula-based supplementation in term children, univariate meta-regression suggested that studies from low- and middle-income countries (P heterogeneity < 0.001), whereas effects on WAZ and WFL were greater in studies of average/unspecified nutritional status (P heterogeneity < 0.026 for both). In univariate meta-regression, potential heterogeneity was also identified by dose of protein supplementation, presence of energy supplementation, intervention duration, and study quality score for studies of the effect of height. Heterogeneity was identified by dose and study quality score in studies of HAZ meta-regression, and for baseline nutritional status, intervention duration and study quality, for studies of the effect on WAZ. Only baseline nutritional status and animal protein supplementation dose shower heterogeneity effects in studies of WFL. None of these interactions remained significant in multivariate meta-regression. No variables were found to drive heterogeneity in studies of the effect on weight.Among trials of food-based supplementation in term children, effects on height were smaller, in studies of malnourished compared with average/unspecified nutritional status  but not formula-based trials (−0.11 z-score) reporting this outcome. Whether this latter difference is due to chance or benefits of nonprotein components of animal-source foods remains unclear, and the limited number of studies reporting on HAZ outcomes after term formula supplementation (N = 7) adds uncertainty about this finding. We conducted a post hoc meta-analysis of height and weight in studies of food-based supplementation in term children in the subgroup of studies that reported HAZ and WAZ, respectively, as an outcome. However, we still did not find a positive effect of food-based supplementation on height, and the significant effect on weight was maintained in this subgroup of studies. Supplementation in preterm infants did not significantly improve growth outcomes; in contrast, lower height for age, weight for age, and weight for length  were shown. In sum, these findings do not provide strong evidence for the benefits of animal-protein supplementation in mothers and preterm infants, and during infancy/early childhood on growth outcomes other than weight and WFL, and stunting for food supplementation in term children; the potential effects of food-based supplementation on HAZ require further study.This systematic review and meta-analysis of 62 controlled trials comprising over 30,000 participants across 5 continents found that supplementation of protein from animal-source foods generally increased weight in children; yet, it had limited effects on other outcomes such as attained height or stunting. For instance, maternal supplementation increased birth weight by 0.06 kg (with no significant effect on LBW or SGA), and both formula and food-based supplementation in term infants/young children increased weight by 0.14 and 0.09 kg, respectively. The strongest effects were seen in trials where both mothers and children were supplemented, with 100-g increases in weight and a mean 0.1-cm increase in height. However, neither formula nor food-based supplementation for term infants/young children increased height, whereas HAZ was increased in food-based . Increases in birth weight with the latter approach in pregnant mothers support recommendations from a 2013 narrative review , althougDuring exclusive breastfeeding, protein accounts for ∼5% of energy intake, which generally increases to ∼15% energy when complementary foods are introduced . In geneYet, it remains unclear whether the amino acid requirements for body maintenance are the same as those for new tissue deposition (recovery from undernutrition) , and theOur systematic review also highlights the variation in the populations studied, and the nature and doses of supplementation strategies. Continuing knowledge gaps are identified because trials have used varying kinds of foods, types and levels of protein, and forms of intervention, all of which continue to make a clear articulation of the role of animal-source proteins on nutrition outcomes challenging. The differences between food-based and formula-based interventions that we identified could indicate an effect of the overall food, although chance or other design and population difference could also explain these findings. Our results highlight the need for further studies of this question, including trials concurrently testing isocaloric animal protein, animal protein including its calories, and animal foods. The heterogeneity identified in our meta-analysis as well as prior reviews indicates a need for more standardized approaches to evaluate specific forms and doses of animal protein, repeated episodes of growth failure (wasting as well as linear growth retardation), and, of course, the role of aggravating factors beyond diet. Several recently completed or ongoing trials are testing various forms and levels of animal-source foods in products specifically designed to treat acute or severe wasting in children in low-income countries. As demonstrated by our current investigation, there can be wide variability in prevalence of wasting or stunting among such populations at baseline. Among term children, we found that formula-based supplementation had larger effects on weight and height in populations with lower baseline nutritional status, the at-risk group that would drive such interventions. These same groups consistently experience greater benefits on growth in studies of pregnant women or food-based supplementation in children. These interactions by baseline nutritional status are biologically plausible and policy-relevant. Of note, however, is that few studies document the background quantity or quality (completeness) of usual total protein intake at baseline. Relatively modest differences in baseline characteristics of undernutrition, background diets, and corresponding doses and durations of supplementation could have meaningful impacts on effectiveness.Our investigation has several strengths. Extensive searches of multiple databases, hand searching of citations, and searches of electronically linked studies reduce the likelihood that major studies corresponding to our inclusion criteria were missed. Strict inclusion criteria and duplicate data extraction reduced the possibilities of error and bias. Plausible sources of heterogeneity and the potential for small-study effects were quantitatively evaluated. Studies were identified across a range of countries, increasing generalizability. We evaluated supplementation in mothers, preterm infants, and term infants/young children, providing a more complete picture of effects across the early life course. We focused on randomized controlled trials, increasing inference for a cause-and-effect relation. Strengths of our investigation include the evaluation of different related outcomes , allowing assessment for concordance of findings and elucidating robustness of the results, as well as evaluation of prespecified sources of heterogeneity to identify potential reasons for differences across studies. The observed unexplained discrepancies  suggest that further research is needed to confirm the effects of animal protein and animal-source foods on these outcomes.Potential limitations should be considered. As with any meta-analysis, results are limited by the availability of studies focusing on specific outcomes of interest; for instance, relatively few studies evaluated age-specific growth outcomes, wasting, or stunting assessed using different metrics. Although we evaluated several potential sources of heterogeneity, other unknown sources, including the possibility of chance, remained. In terms of quality, many published papers evaluated using Cochrane criteria for risks of bias demonstrated elements that were either “unclear” or of relatively low rigor. This argues for much more attention to study quality going forward. For some outcomes, the small numbers and sizes of identified trials limited statistical power. On the other hand, this is the largest meta-analysis on this topic to date, serving to highlight the specific gaps in information for certain outcomes of concern.In summary, this meta-analysis summarizes available evidence for the role of animal protein supplementation on birth, weight, and linear growth outcomes early in life. Supplementation during pregnancy and infancy/childhood increased child weight and food-based supplementation in childhood increased WAZ and reduced the risk of stunting. Only supplementation of animal-source foods (but not formula) during infancy/childhood increased height for age. Benefits on growth outcomes in preterm infants were not identified. Overall, too few high-quality studies were identified to allow for definitive conclusions on linear growth. This does not negate the benefits of balanced (protein plus energy) supplementation for recovery from wasting in children of undernourished mothers or the consideration of other potential benefits, such as on cognitive outcomes, which require separate assessment. WHO continues to support its 2012 call for use of animal-source protein in food supplements intended to manage existing malnutrition. As such, many argue that protein quality  “is important to child health and not a fallacy” . We findnqy348_Supplemental_FileClick here for additional data file.


Physical inactivity is high within the Qatari population, particularly within females, and school-based environments, contributing to increased morbidity and mortality. School-based physical activity (PA) outcomes may be mediated by physical self-concept. Low physical self-concept may negatively impact PA engagement, compromising childhood and adolescent physical fitness, which may translate into adulthood. Normative physical fitness data for the Qatari population is unavailable. Stratifying normative physical fitness appears prudent, to not only allow comparisons to be made worldwide, but enable informed decisions for public health policy and future interventions in the Qatari population.To establish the physical fitness of young adults in Qatar, and examine differences between males and females for physical self-concept, and engagement in school-based and extra-curricular PA.186  healthy participants  completed the ALPHA-FIT test battery for adults , physical self-description questionnaire , and were asked to answer ‘yes’ or ‘no’ to whether they participated in school-based and extra-curricular PA.most likely performed better for dynamic sit-up , very likely better for the figure of eight run  and likely better for handgrip strength . Males likely had higher physical self-concept for coordination  and endurance  compared to females. There were no differences for school-based PA (p ≥ 0.78) or for extra-curricular PA for males (p ≥ 0.26) or females (p ≥ 0.21).Data is reported as effect size; ±90% confidence limit. Males compared to females The data suggests that the young Qatari adult population has variable, yet generally low, physical fitness traits compared to individuals worldwide, likely due to their low PA. The precise aetiology for this is not well documented, yet such data may be prudent to evidence-inform strategies to improve physical fitness through increased PA (synergistic relationship), given the strong association between physical activity/fitness and morbidity/mortality. This ge regions . Neverth regions –13, whic regions –17. Worl regions , 18–20,  regions , it is e regions , comprom regions .Physically active adults possess higher physical fitness , 10 and Therefore, the primary aim of this study was to characterize physical fitness and physical self-concept in young adults in Qatar. A secondary aim was to examine differences in physical fitness and physical self-concept for gender, and engagement in school-based or extra-curricular PA. It was hypothesised that (i) males would demonstrate superior physical fitness and physical self-concept compared to females, and (ii) that physical fitness would be higher in individuals that engaged in both school-based and extra-curricular PA.Ethical approval for this cross-sectional study was received from Qatar University Institutional Review Board (QU-IRB 428-E/15). Prior to any experimental procedure occurring, written informed consent was obtained in the spirit of the Declaration of Helsinki (1975). All testing was performed at Qatar University within the male and female indoor sports hall. Participants performed the tests individually, and all tests were performed on the same day. Testing occurred between October 2015 and February 2016. The physical activity and health questionnaire provided in the ALPHA-FIT manual for adults  was compA total of 186  healthy participants volunteered for this study. Participant characteristics are shown in All participants completed the short version of the physical self-description questionnaire (PSDQ-S), scored from 0 to 6 on a Likert scale. The PSDQ-S is comprised of nine specific self-concept scales , and two global scales , and has shown good validity across a heterogeneous sample, including Arab university students . Each PSAnthropometric measures were obtained using the KaWe wall mounted stadiometer , and OMRON  scales for body mass following the international society for the advancement of kinanthropometry standard procedures. Blood pressure was measured using a fully automated device , following standard procedures .The ALPHA-FIT test battery for adults aged 18–69 y was employed to measure seven field-based physical fitness components. As per the instruction manual , no warmStatistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 25  and magnitude-based inferences (MBIs) customizable spreadsheets, using the raw data . Prims8 BMI and engagement in school-based and/or extra-curricular PA are reported in Results from the LMM showed there were no differences for school-based PA (p ≥ 0.78) or for extra-curricular PA for males (p ≥ 0.26) or females (p ≥ 0.21) for the ALPHA-FIT test or physical self-concept. Therefore, in line with the principle of parsimony, only comparisons between males and females are reported below.Substantial differences in ALPHA-FIT test results between males and females were observed . IndividSubstantial differences in PSDQ-S results between males and females were observed . IndividThis is the first study within Qatar to obtain gender stratified objective measures of physical fitness. The main findings showed on average males were observed to have greater power, strength and speed compared to females . EnduranPhysical fitness results in the present study  are loweThe gender stratified physical fitness results  are simiEngagement in school-based PA was similar between males and females , howeverlikely had ‘moderately’ higher physical self-concept for coordination and endurance, , is a strength of this study as the measures are time-efficient, of low-cost, and can be easily administered with little equipment. However, there is currently no data examining the validity and reliability of the ALPHA-FIT test battery for adults, and therefore future research should either measure the test-retest reliability and/or use validated and reliable alternatives. It was clear from our results that the one leg stand (maximum 60 s), and dynamic sit-up test (maximum 15 reps), may not have been appropriate, given the majority of participants were able to reach the maximum performance for these tests . AlternaThis is the first study to obtain objective measures of physical fitness within Qatar. Overall, the results appear lower than worldwide stratified normative data, and in agreement with previous research showing higher physical fitness and physical self-concept in males compared to females. The reasons for higher physical inactivity, and lower physical self-concept and physical fitness in females in particular, is presently unclear. Future research should focus on elucidating the aetiology of this, in order to enhance PA engagement, subsequently improving physical fitness, and reducing morbidity and mortality.S1 Data(XLSX)Click here for additional data file.


As Veterans age, they may experience an emergence or exacerbation of stress symptomatology. Later-Adulthood Trauma Reengagement (LATR) is an intervention that provides psychoeducation on the LATR process, teaches mindfulness and coping, facilitates trauma re-integration, and fosters meaning-making in late life. This program evaluation project evaluated the LATR group offered in the Geriatric Mental Health Clinic at VA Boston. Twenty-one Vietnam Veterans with PTSD symptomatology were referred to the group between 2017-2018. Fifteen completed the 10-week group, and 12 completed pre- and post-intervention assessments and offered feedback. At the conclusion of the group, Veterans reported a decrease in depressive and PTSD symptoms. Of the 4 Veterans who endorsed suicidal ideation at the start of the group, 3 reported a decrease post-group. Veterans endorsed slightly more positive appraisals of their military service. Veterans reported that the group offered support, connection, and a sense of belonging with other Veterans, helped increase coping, and increased insight into thoughts, feelings, and behaviors. A suggested improvement to the group was to offer more sessions. Eleven Veterans sought continued mental health services following the group; three newly sought trauma-focused interventions. Four Veterans reported that their trauma-related symptoms were resolved and declined referral. Veterans found the LATR group helpful as evidenced by reduction in symptoms and responses to open-ended questions. A small number sought additional trauma-focused treatment; others reported that their symptoms were resolved and did not require additional treatment. Findings support the continued offering of the LATR group within this clinical setting.


The ability to rationally tune and add new end-groups in polymers can lead to transformative advances in emerging self-healing materials. Self-healing networks manipulated by supramolecular strategies such as hydrogen bonding and metal coordination have received significant attention in recent years because of their ability to extend materials lifetime, improve safety and ensure sustainability. This review describes the recent advancements in supramolecular polymers self-healing networks based on hydrogen bonding, metal-containing polymers and their nanocomposites. Collectively, the aim of this review is to provide a panoramic overview of the conceptual framework for the interesting nexus between hydrogen bonding and metal–ligand interactions for enabling supramolecular self-healing soft materials networks and nanocomposites. In addition, insights on the current challenges and future perspectives of this field to propel the development of self-healing materials will be provided. Self-healing in living organisms has played an essential role in sustaining and prolonging life. In contrast, synthetic materials are often susceptible to degradation, fracture or damage by external factors, leading to a limit to its lifetime –5. InspiSelf-healing polymers can be classified into two categories—intrinsic and extrinsic. Extrinsic self-healing relies on two components. First, micro-containers of healing agents that may be in the form of microcapsules , or hollIntrinsic self-healing relies on the presence of inherent dynamic bonds incorporated into the polymer, allowing it to sustain several healing cycles (break/reform) . The terH]-pyrimidinone (UPy) monomers for quadruple hydrogen bonding (H-bonding) noncovalent systems with a high degree of polymerization . Th. Th62]. and DMSO , which d2+ to obtain a multi-stimuli responsive self-healing metallosupramolecular nanocomposite. From this modification, the resulting metallosupramolecular CNT/PU nanocomposite displayed outstanding mechanical properties where the tensile strength, strain-at-break, and toughness of the metallosupramolecular polymer nanocomposite films increased from 14.2 MPa, 620%, and 51.4 MPa to 22.8 MPa, 1076%, and 141.2 MPa, respectively. In addition, multiple stimuli self-healing was obtained via remotely controlled near infrared (NIR) light, low temperatures or solvents with excellent healing efficiencies and short healing times. Therefore, by combining self-healing capabilities with superior mechanical properties, metallosupramolecular nanocomposite offers many promising applications including soft electronics, nano/microelectronic, sporting equipments, and structural components.Zheng et al.  developeIn a nutshell, we have highlighted the burgeoning trend of utilizing supramolecular association and re-association interactions for self-healing polymeric systems. From the examples discussed in this review, self-healing supramolecular polymers based on either H-bonding or coordinative bonds, have been demonstrated to be highly advantageous and versatile for next-generation self-healing materials capable of undergoing multiple healing cycles. The incorporation of supramolecular non-covalent crosslinks such as hydrogen bonding is the key component over the formation of associative groups and a wide range of responsive materials and dynamics. However, there remains to be a balance and trade-off between the network structures and bond dynamics properties. While a large number of self-healing concepts and approaches were introduced to describe the applications of these materials, there is still a need for a deeper understanding of the principles of self-healing and its basic mechanisms to address the many considerations in real-world applications.Adopting supramolecular polymers for self-healing applications remain highly challenging due to a multitude of factors. This includes the formation of crystallization aggregation, interfacial effects, clustering, and phase segregation. Nonetheless, it should be noted that the preparation of self-healing materials and composites for specific purposes are still in its nascent stage. Most of the reported self-healable materials require activation under different conditions . In addition, the well-known issue of hard supramolecular materials that arises from the incompatibility of dynamic supramolecular healing with low chain mobility to achieve high deformability remains to be a challenging task. Attaining effective healing over a short time span remains a critical need in the field of self-healing polymers.Several exciting breakthroughs have been made under the endeavors of intensive research. Major innovative approaches for new self-healing supramolecular soft materials are anticipated in the near future. Undoubtedly, the application of self-healing supramolecular soft materials is the impetus for the advance of this field. At this juncture, supramolecular polymers based on multiple hydrogen bonds and metal-coordination bond have had a strong impact on materials science. Developing self-healing and smart responsive materials remains to be a promising domain to extend and inject new vigor into this emerging research field of supramolecular soft materials.


Experiences with voluntary buyouts of flood-prone properties provide lessons for managed retreat under climate change. Retreat from some areas will become unavoidable under intensifying climate change. Existing deployments of managed retreat are at small scale compared to potential future needs, leaving open questions about where, when, and how retreat under climate change will occur. Here, we analyze more than 40,000 voluntary buyouts of flood-prone properties in the United States, in which homeowners sell properties to the government and the land is restored to open space. In contrast to model-based evaluation of potential future retreat, local governments in counties with higher population and income are more likely to administer buyouts. The bought-out properties themselves, however, are concentrated in areas of greater social vulnerability within these counties, pointing to the importance of assessing the equity of buyout implementation and outcomes. These patterns demonstrate the challenges associated with locally driven implementation of managed retreat and the potential benefits of experimentation with different approaches to retreat. Development patterns and climate change are together increasing flood risk in many regions around the world  where voluntary buyouts of flood-prone properties take place, (ii) what flood-related hazards and damage occur in areas with and without buyouts, and (iii) what socioeconomic and demographic characteristics predict which jurisdictions implement buyouts and which neighborhoods are bought out.et al. : OpenFEMA datasets, the SHELDUS version 16.1 database of flood-related property damage, 100-year flood zones from the recently updated river and rainfall-driven flood hazard maps developed by Wing From 1989 to 2017, FEMA funded 43,633 voluntary buyouts of flood-prone properties for which data are publicly available  and 3. PThe locations of property buyouts broadly reflect locations with flood-related hazards, property damage, and disaster declarations , and most flood-related damage in the Midwest occurred during the same decades . By contThe number of properties purchased for buyouts has declined in each successive decade (The Hazard Mitigation Grant Program (HMGP) is the longest-running FEMA program providing grants for voluntary buyouts of flood-prone properties. Subgrantees administering buyout projects are eligible to receive HMGP funds only following a federal disaster declaration. Several types of disasters have historically established eligibility for HMGP funding for property buyouts , includiGiven FEMA’s eligibility requirements, we hypothesize that buyouts have occurred in areas with high levels of flood hazard or damage. This is supported. Counties in which buyouts have occurred have experienced more flood-related disaster declarations and property damage compared to counties in which buyouts have not occurred . These pThe types of properties acquired affect the nature of implementation and the risk reduction outcomes of a buyout program. Bought-out properties reflect a range of different structure and residency types , but mosOur analysis of which jurisdictions implement buyouts and, in turn, which neighborhoods are bought out considers three hypotheses emerging from existing literature. First, model-based evaluation of economically robust coastal adaptation predicts that retreat will occur in rural, low-income areas  were administered by a local government subgrantee: city or county government. In considering the capacity and willingness of the local government to apply for, receive, and administer federal funding, our analysis evaluates county-scale socioeconomic and demographic indicators, as these can be systematically compared across subgrantees. Then, within each county using buyouts, the same socioeconomic and demographic characteristics are evaluated at a finer scale to describe the neighborhoods where properties were acquired. We used ZIP Code Tabulation Area (ZCTA) as a proxy for neighborhood, because this was the smallest scale possible based on FEMA’s public reporting of buyout locations by ZIP code.Counties that have had locally administered buyout projects have higher income, education, population, and population density compared to counties without buyouts (Implementation of FEMA-funded buyout projects is slow (fig. S10), with implications for implementing jurisdictions and affected neighborhoods and residents. The average FEMA HMGP buyout project takes 5.7 years from the start of the associated disaster event to project closeout  (fig. S10). Projects that purchase only one property are slightly shorter: 5.1 years on average (fig. S10). By the time a project is closed, properties have been purchased, structure demolitions or relocations have occurred, and the land has started to be maintained as open space. As an important note, the duration from a disaster event to project closeout imperfectly proxies key time frames for subgrantees and property owners. For example, deed transfer could occur well before closeout for the associated FEMA grant.Integrating the above analyses, we use a random forest decision tree model to assess the comparative importance of different factors in distinguishing between counties in which buyouts have versus have not occurred . This anVoluntary property buyouts in the United States are among the longest-running programs of managed retreat globally, and they are the predominant means through which managed retreat has occurred in the United States to date . Our analyses at the ZIP code level are inexact, limited by the spatial detail in publicly available FEMA records. Nonetheless, this pattern of acquisition in poorer, less dense, more marginalized areas , which hPerhaps surprisingly, FEMA-funded projects supporting buyouts have frequently been small, only one to three bought-out properties each . But smaOur empirical analyses raise issues relevant to learning in the buyout policy process . The implications for participating communities, property owners, and residents merit further evaluation  where voluntary buyouts of flood-prone properties have taken place, (ii) what flood-related hazards and damage have occurred in areas with and without buyouts, and (iii) what socioeconomic and demographic characteristics predict which jurisdictions have implemented buyouts and which neighborhoods were bought out. For objective (i), our empirical treatment evaluated all buyouts for which information was publicly available. For objectives (ii) and (iii), we analyzed available indicators of exposure to flood-related hazards and of socioeconomics and demographics. We applied each indicator over the full geographic scope for which it was available, and in Results, we report on all analyses completed.In the United States, government acquisition of flood-prone properties has generally been funded by federal agencies and administered by state or local governments . The larhttps://www.fema.gov/openfema-dataset-hazard-mitigation-assistance-mitigated-properties-v1). On the basis of the “property action,” “title,” and “type” for each entry, the dataset was manually cleaned to identify 43,633 entries corresponding, with high likelihood, to voluntary property buyouts. In most cases, the entries were voluntary buyouts in which a property was acquired and then demolished, with the land subsequently maintained as open space. In a small number of cases (~1% of entries), the entries were voluntary buyouts in which a property was relocated rather than demolished, yet still with the land subsequently maintained as open space.Data on FEMA-funded voluntary buyouts of flood-prone properties, through all of these programs, were accessed in April 2018 from the OpenFEMA dataset of hazard mitigation assistance mitigated properties . For buyout projects, subgrantee information was accessed in May 2018 from the OpenFEMA dataset of hazard mitigation assistance projects (https://www.fema.gov/openfema-dataset-hazard-mitigation-assistance-projects-v1).A buyout project is defined in this study as a FEMA grant  that invhttps://www.fema.gov/openfema-dataset-disaster-declarations-summaries-v1). Flood-related major disaster declarations were defined as those containing “flood,” “hurricane,” “storm,” “coast,” or “tsunami” within the title or incident type of the disaster. Of 1462 major disaster declarations over 1989–2017, 1376 were designated as flood related on this basis. For the flood-related declarations of major disasters that involved individual assistance, the declarations have the following incident types: severe storm(s) (400 declarations), flood (134), hurricane (106), tornado (34), coastal storm (8), severe ice storm (7), fire (4), snow (1), and mud/landslide (1). Most counties across the United States experienced major disaster declarations over 1989–2017: Of 3220 counties and county-equivalent entities in U.S. states and Puerto Rico, only 73 had no major disaster declarations of any type, only 115 had no flood-related major disaster declarations, and only 254 had no flood-related major disaster declarations involving individual assistance.Major disasters declared were accessed in July 2018 from the OpenFEMA dataset of disaster declarations summaries . From the American Community Survey, 5-year estimates over 2012–2016 were used for the following variables: income, education, racial diversity, population, population density, and household English language proficiency  participating in FEMA-funded programs for voluntary buyouts of flood-prone properties. Socioeconomic and demographic data analyzed originate from the U.S. Census American Community Survey , county-scale socioeconomic and demographic indicators were used to evaluate the capacity of the local government to apply for, receive, and administer federal funding. County-scale data could be systematically analyzed for all local government subgrantees, which is why this scale of analysis was applied. County-scale socioeconomic and demographic indicators were evaluated in absolute terms and also in relative terms, comparing each county to its respective state.Within counties where local government has administered one or more buyout projects, the same socioeconomic and demographic characteristics were also evaluated at a finer ZCTA scale. This scale of analysis was applied to proxy the capacity and social vulnerability of neighborhoods and residents participating in buyout programs. ZCTA-scale indicators were similarly evaluated in absolute terms and also in relative terms, here comparing each ZCTA to the respective county.t test for differences in means, Kruskal-Wallis one-way analysis of variance, spatial statistics , and random forest classification analysis. All specified type I error rates in this article apply to only the particular test in question and not the series of tests.Data were analyzed in R 3.5.1 (RStudio 1.1.463), ArcGIS 10.5.1 ArcMap, and Microsoft Excel. Statistical analyses applied include Welch’s unequal variances The random forest analysis, which is a decision tree method, was performed with the randomForest package in R (


Our knowledge of the role of parental and child-care staff behavior in the development and prevention of obesity is rapidly increasing. Potential interaction between both settings in so-called meso-systems, as hypothesized by the ecological systems perspective, is however often ignored. Specifically, inconsistency between home and child-care is hypothesized to have negative effects on child outcomes.Participants were recruited through 23 child-care centers in the Netherlands. Data regarding 161 child-parent-child-care staff triads were available. Parenting and child care practices were assessed using validated questionnaires for parents  and child-care staff (Child-care Food and Activity Practices Questionnaire), using similar items in both settings. Absolute difference scores between parents and child-care staff were calculated for each triad as a measure of meso-system consistency. Child outcomes were physical activity (as assessed by accelerometry), dietary intake , and measured BMI z-scores. Paired t-tests were used to examine consistency between practices in both settings. Linear regression analyses were used to explore the association of parenting practices, child-care practices and difference scores on the one hand, and child outcomes on the other.Significant differences between settings were found for almost all practices, and in most cases child-care staff scores more favorable on the practices than parents. Inconsistencies were mostly associated with unhealthy dietary intake and lower physical activity levels, but not with BMI.The current study showed that inconsistencies in parenting and child-care practices exist, and that these inconsistencies seem to be associated with unhealthy behavior in children. The results underline the importance of studying meso-system influences on behavior in general, and children’s energy balance-related behavior specifically. Various studies seem to indicate an increased overweight risk in children attending child-care e.g. –4), alth, alth4])or home influences [While our knowledge of the role of parental and child-care staff behavior in the development and prevention of obesity is rapidly increasing, studies into determinants of children’s behavior and weight status have almost exclusively focused on examination of the influence of either child-care fluences . Howeverfluences , 16 argufluences , 18. Thefluences . Within fluences . Althougfluences , qualitafluences –23. Parefluences –27). Simfluences , 29, andfluences . In addifluences , 31, butfluences . Parentsfluences , 34. Parfluences . Inconsifluences . Also fofluences .The notion that inconsistency might result in negative effects on child outcomes is not new. Although quantitative studies examining home-child-care meso-system inconsistency are lacking , previouThe current study examines the role of inconsistency between parents’ and child-care workers’ practices, based on the ecological perspective. In line with the studies described above, we hypothesize that inconsistency is associated with undesirable child outcomes.Formal center-based child-care in the Netherlands is typically organized in centers that house one or more groups of around 15 children during the day. Opening hours vary around 10–12 hours, from 7-8am to 6-7pm. Depending on the age of the children, two to three staff members supervise a group. Parents can get funding for child-care from the Dutch government, depending on parents’ income and working hours.A total of 174 child-care centers in the southern provinces of the Netherlands (Noord-Brabant and Limburg) were approached to participate in the current study. Twenty-three child-care centers (13.2%) agreed to participate in the study. All parents of the children aged 1 to 4 years old from these child-care centers were invited to participate either by letter or email, as well as face-to-face on-site recruitment at drop-off and pick-up times. In total, parents of 218 children agreed to participate. All parents of participating children provided written informed consent. In addition, participating child-care staff also provided written informed consent. Eight children were excluded because of severe food intolerances or allergies, not being able to walk independently or being indicated as too young for the study by the parents, resulting in a sample of 210 children. The data collection period ranged from November 2014 to January 2016. The study was approved by the Maastricht University Medical Centre+ medical ethics committee.For each child-parent-child-care staff member triad, several measures were completed: Parents and child-care staff filled out a questionnaire, children were measured and weighed at the child-care center, and children wore accelerometers to assess physical activity. For 161 triads (76.7%) the parenting practices questionnaire and child-care staff practices questionnaire were available. These triads were included in the analyses. Reasons for missing data were for instance absence of the child due to illness on the measurement day. The measures are described in more detail below.Parents filled out a questionnaire regarding their parenting practices. Parenting practices were assessed using the validated Child Feeding Practices Questionnaire  for dieNine out of 49 items of the CFPQ  and 9 itTo ensure comparability between and scale reliability in both settings, the same scales had to be applied to both the child-care items and the parental items. The following procedure was used. Reliability for the child-care instrument was examined by calculating Cronbach’s alpha values, applying the CFPQ and PPAPP scales. Items were removed until all scales reached acceptable Cronbach’s alphas . These Home-child-care inconsistencies were operationalised by the absolute difference score between the parenting practice and child-care practice score on each scale and single item.Children’s physical activity level was objectively measured using an accelerometer , applying a validated wearing protocol . The epoOverall dietary intake (including both intake at home and elsewhere) was assessed using a food frequency questionnaire in the parental questionnaire. Parents were asked how often their child consumed biscuits and cake, sweets, savory snacks, water (including unsweetened tea) and sweet beverages . Answering options were ‘never or less than once a week’, ‘1–3 times a week’, ‘4–6 times a week’, ‘once a day’, ‘twice a day’, and ‘3 or more times a day’. Intake was recoded into weekly intake frequency using the midpoint value of each category comprising a range (e.g. 2 times a week for the category ‘1–3 times a week’).Children’s height and weight were measured at the child-care center by trained research assistants. Height and weight were used to calculate body mass index (BMI), which was converted to BMI z-scores, reflecting the number of standard deviations the child differed from the age- and gender-specific mean of the national reference population .2, calculated from reported weight and height) of both parents, child-care use of the child , and educational level of the parents). Child-care use was converted into whole days. Educational level was converted into low , medium  and high ; and then recoded into dummy variables for low and high compared to medium.In addition, several background characteristics were assessed through the parental questionnaire: which parent filled out the questionnaire , gender and age (in months) of the child, parental age (in years), country of birth (the Netherlands vs. other) and BMI  of the child-care staff were assessed through the questionnaire for child-care staff.Finally, gender, age (in years) and BMI .All analyses were conducted using SPSS 24.0. Multiple linear regression analyses were conducted to examine the associations between parenting practices on the one hand, and children’s overall dietary intake , total physical activity  and BMI z-score, adjusted for children’s background variables as described above . This procedure was then repeated for staff practices, creating a new set of regression analyses. In a final set of regression analyses, the absolute difference scores between each parenting and child-care practice were added to the model with both parenting and child-care staff practices, as well as children’s background characteristics. Considering the exploratory nature of the meso-system research question, the number of variables in the final models (including the difference scores) and the consequential risk of suppression, trends toward statistical significance (p <.10) were also assessed.Background characteristics of the children, parents and child-care staff are presented in Children were somewhat heavier than the reference population , with anParents having healthy foods available was significantly associated with children eating less biscuits and cake . Parental modeling of healthy food intake was associated with lower savory snack intake of the children , but with higher child BMI . Parental emotion regulation by giving a child food if the child was fussy  or bored  was associated with higher savory snack intake. Parental emotion regulation if a child was upset was associated with higher sweet drink intake . Parents who encouraged balance and variety had children who ate more savory snacks .As regards physical activity parenting practices, parents having outdoor toys available at home was associated with higher overall activity levels , more MVPA , and less sedentary time . Parents promoting inactivity was associated with more MVPA .With regard to child-care workers, encouraging children to eat healthy foods before unhealthy ones was associated with lower sweets intake . Staff modeling of healthy intake was associated with higher water intake . Use of food to calm a fussy child down was associated with higher sweet drink intake . Child-care workers teaching about nutrition was associated with higher biscuit and cake , sweets  and savory snack  intake. Child-care workers giving children much control over their intake was associated with lower child BMI .Child-care workers promoting inactivity was associated with lower overall activity level , and more sedentary time . Child-care staff limiting children’s activity out of fear of them getting dirty was associated with more MVPA .For the majority of the practices (16 out of 20), there was a significant difference (p <.05) between parents and child-care staff, with three out of the four remaining practices showing a marginal significant difference , as well as for a lower CPM . Inconsistencies in letting children not being active out of fear of them getting dirty, was marginally significantly associated with lower average activity levels .The current study explored the association between inconsistency of practices in the home and child-care setting on the one hand, and children’s diet, physical activity and BMI on the other. The research question is in line with the hypothesized existence of meso-systems (interactions between two or more micro-systems), as proposed by the ecological systems perspective . This stAs for the effect of inconsistency on the child, most associations pointed in the direction that inconsistencies were associated with unhealthy child outcomes. However, there were a few associations pointing in the opposite direction, and a large number of non-significant associations. Hence, cautious interpretation is needed, also in light of the limitations of the current study. Nonetheless, the findings mostly seem to confirm the hypothesis that meso-system inconsistencies have negative effects, in line with qualitative studies (see e.g. ). In facboth settings in the desired direction. Opposing these hypotheses, however, some authors propose that for children’s cognitive and socioemotional development, high child-care quality is particularly important for children from low-income families [Also general child development literature points in the direction that inconsistencies in parents’ and child-care staff’s general child-rearing practices affect children’s wellbeing negatively . This unfamilies , and thafamilies , 51. In families .between determinants are often ignored [A growing number of studies recognize the multivariate and multilevel structure of determinants of behavior , or as H ignored , disrega ignored , 63. We  ignored  showed t ignored .There is another important factor to consider when examining meso-systems influences. De Schipper and colleagues reported that especially for children with a more difficult temperament, several parallel care arrangements can interfere with the process of adapting to the child-care setting . This inThe current study has several strengths and limitations that need to be taken into account. A strength of the study is its design, which provided data regarding 161 child-parent-child-care staff triads. The same items for assessing diet- and activity-related practices were used in both settings, from questionnaires validated in both settings –41. In aIn conclusion, the current study showed that inconsistencies in parenting and child-care practices exist, and that these inconsistencies seem to be associated with lower diet quality and lower activity levels in children. While qualitative studies provide us with ample indications of meso-system interactions, quantitative research is still lacking. We call for increased recognition of between-settings interaction in future research.S1 File(DOC)Click here for additional data file.S2 File(SAV)Click here for additional data file.


Poor eating habits, such as the increasing consumption of highly processed products, have deleterious effects on health status and represent a serious challenge for public health systems. They are not “real food” but formulations of food substances often modified by chemical processes and then assembled into ready-to-consume hyper-palatable food (cosmetic food) . In thisIn a recent paper, Bleiweiss-Sande et al.  evaluateFrom a public health view, it is important to choose the best tool to measure consumption of ultra-processed food  in order to examine their influence on the onset of obesity and non-communicable diseases, such as cardiovascular diseases, diabetes, respiratory diseases, or cancer . Rauber following the Nova system) was associated with added sugar content in the diets or even influenced anthropometric and glucose profile [Recently, prospective studies conducted in children indicated that consumption of ultra-processed foods ( profile ,10. Nota profile . First,  profile  showed a profile  found th profile . IndividAlthough these results need to be validated in other populations and study designs, a number of public health authorities worldwide have advised limiting the consumption of ultra-processed foods . Current


Statistical significances in the post hoc analysis were corrected by a small volume correction with a cluster-level threshold of p < 0.05 . Correlations of clinical and neuropsychological assessments  with the regional ALFF were performed in the PD-MCI group. Compared with the HC, both PD groups exhibited reduced ALFF in the occipital area . Specially, the PD-MCI group additionally exhibited increased ALFF in the opercular part of right inferior frontal gyrus . Comparing with the PD-NC, the PD-MCI group exhibited significantly higher ALFF in the Frontal_Inf_Oper_R and left fusiform gyus (ps < 0.05). The correlation analysis revealed that the ALFF in the Frontal_Inf_Oper_R was positively correlated with the UPDRS total score (p < 0.05), but marginally negatively correlated with the MoCA score. For cognitive domains, the ALFF in the region also showed a significantly negative correlation with the score of SF test (p < 0.01) and a marginally negative correlation with the score of Symbol-Digit Modalities Test. Together, we concluded hyperactivity in the right inferior frontal gyrus in early PD with MCI, suggesting a compensatory recruitment in response to cognitive decline, which may shed light on thought of dementia progression and potentially comprehensive treatment in PD.Mild cognitive impairment (MCI) is a common symptom at the baseline of early Parkinson’s disease (PD) diagnosis, but the neural mechanism is unclear. To address the issue, the present study employed resting-state functional magnetic resonance imaging data of 19 drug-naïve PD patients with normal cognition (PD-NC), 10 PD patients with MCI (PD-MCI) and 13 age- and gender-matched healthy controls (HC) from the Parkinson’s progression markers initiative (PPMI) (http://www.ppmi-info.org/), and examined abnormal spontaneous brain activities in the PD-MCI. The pattern of spontaneous brain activity was measured by examining the amplitude of low-frequency fluctuations (ALFF) of blood oxygen level dependent signal. Voxel-wise one-way analysis of covariance and  Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized primarily by motor symptoms of bradykinesia, tremor, rigidity, and gait/postural disturbance. However, growing evidence suggests it may commonly lead to many non-motor psychiatric symptoms as well since at the early stage of this disease, such as cognitive impairment  and depression , and demOver the past decade, resting-state functional magnetic resonance imaging (R-fMRI) has been widely developed as a non-invasive and effective technology to examine spontaneous brain activity in both normal functions and neuropsychiatric disease pathophysiology . AmplituRecently, several studies have reported a range of abnormal brain areas that are associated with cognitive decline in PD. For example, R-fMRI functional connectivity analysis has suggested patients of PD with MCI could be characterized by dysfunction in the default mode network and dorsal attention network . A longi1 to detect the abnormalities of brain activity that is widely associated with cognitive decline in PD. To address this issue, we used early diagnosed PD patients who do not suffer from depression and are untreated. Then, we used R-fMRI and ALFF measurement to investigate regional differences in spontaneous brain activity in the patients of PD with MCI (PD-MCI), PD with normal cognition (PD-NC) and healthy controls (HC), and also examined correlations of the ALFF values with scores of clinical and neuropsychological assessments.In the present study, we employed MRI and clinical/neuropsychological data of baseline PD patients without drug-treatment from Parkinson’s progression markers initiative (PPMI)1, which is a first large-scale multicenter project of PD progression biomarkers . A 3D magnetization prepared rapid gradient echo (MPRAGE) sequence was used for imaging brain anatomy . A gradient-echo echo-planar imaging (GE-EPI) sequence was used for imaging brain functional activity over 210 volumes or time points during resting state .Table 1.For the clinical characteristics, the disease stage was scored using the H&Y stage score, and the disease severity was captured by the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). Global cognition was assessed with the MoCA, because it is sensitive to the detection of executive deficits in PD  and cons2 and Data Processing Assistant for R-fMRI (DPARSF)3 toolkit  toolkit . For MRI toolkit , then we toolkit , and fin toolkit . With th toolkit , global  toolkit .The ALFF calculation was performed using the DPARSF toolkit within a group GM mask that was generated by greater than 0.2 of the mean GM probability map of all 42 participants. As described in previous studies , the ALF4 to determine the significant voxels, and it provides an extensible framework for non-parametric permutation tests based on a GLM. The ANCOVA statistical significance level was not corrected by multiple comparisons but to just obtain a small volume mask using a threshold of p < 0.05 and cluster size >50 voxels, which could as much as possibly contain candidate voxels that may show truly significant differences between groups. The following subsequent post hoc analysis was performed within the mask, and the multiple comparisons were used with small volume correction based on non-parametric permutation tests, at a cluster-level threshold of p < 0.05  with a cluster-forming threshold at the voxel level p < 0.01.To examine between-group differences in ALFF, a one-way analysis of covariance (ANCOVA) was first performed in a voxel-wise manner (within the group GM mask) under non-parametric permutation tests in a general linear model (GLM) among the three groups, with age, gender and data center treated as additional covariant factors. Here, we used Statistical non-Parametric Mapping software (SnPM13)To investigate the relationship between regional ALFF values and clinical scores  as well as cognitive domains , we performed multiple linear regression analysis with age, gender and data center treated as additional covariates. First, we examined correlations of regional ALFF values within the regions that showed significant differences between the PD-MCI and HC with the UPDRS total score and the MoCA score in the PD-MCI group. Second, to examine possible contributions of cognitive domains in the relationships between the regional ALFF values and cognitive impairment, we examined correlations of regional ALFF values within the regions that showed significant differences between the PD-MCI and PD-NC with the test scores of cognitive domains  in the PD-MCI group.Table 1. There was no significant difference among the three groups in gender, age, DRH and IFR in HVLT-R (HVLT-R-DRH and HVLT-R-IFR) and SF scores. Moreover, no significant difference in disease duration, UPDRS total score and H&Y stage score was found between the PD-MCI and PD-NC subtypes. However, the PD-MCI patients had significantly lower MoCA, BJLO, and SDMT scores than the PD-NC and HC group, in consistent with clinical diagnosis of each subtype.Clinical and demographic profiles of the 42 participants are shown in p < 0.05, cluster size k > 50, uncorrected; see Figure 1). These areas mainly covered regions of inferior cerebellum, occipital, right fusiform and right inferior frontal lobes. This analysis aimed to result as a small volume mask for the following post hoc analysis, which could as much as possibly contain candidate voxels that may show truly significant differences between PD-MCI and NC, between PD-NC and HC, or between PD-MCI and PD-NC.ANCOVA analysis revealed a range of regions showing uncorrected significant differences in ALFF among the PD-MCI, PD-NC, and HC groups . Specially, the PD-MCI group additionally exhibited increased ALFF in the opercular part of right inferior frontal lobe  . Comparing the PD-NC, the PD-MCI group exhibited significantly higher ALFF in the Frontal_Inf_Oper_R and left fusiform gyrus .Compared with the HC, both PD groups exhibited ALFF decreases in the occipital areas , and the PD-NC group additionally showed ALFF decreased in the right fusiform area as well (p < 0.05), but marginally negatively correlated with the MoCA score . Second, we also examined correlations of regional  ALFF values with the test scores of cognitive domains. Interestingly, the neural activity in the Frontal_Inf_Oper_R showed a significantly negative correlation with the score of SF test (the executive function and working memory) (p < 0.01) and a marginally negative correlation with the score of SDMT (the processing speed-attention) .First, we examined correlations of regional  ALFF values with the UPDRS total score and the MoCA score in the PD-MCI group. We found that the neural activity in the Frontal_Inf_Oper_R area was positively correlated with the UPDRS total score . With regarding to cognitive domains, the present study showed a significantly negative correlation with the score of SF test (the executive function and working memory) and a marginally negative correlation with the score of SDMT (the processing speed-attention) . Thus, these findings may indicate that more cognitive deficit induced higher neural activity in the right inferior frontal lobe. In a cognitive task study (planning set-shift task), The cognitive profile in PD-MCI is heterogeneous, but differs from that of MCI due to AD by showing relatively more severe visuospatial and executive deficits and relatively less severe memory impairment . In the Moreover, the presence of MCI at early stages of PD could affect both cognitive and motor corticostriatal loops . The spoIn addition, we also found hyperactivity in the left fusiform in the PD-MCI. Similar findings have been found in AD or MCI patients during both cognitive task and resting state. For example, We acknowledge several limitations in our study. First, the sample size in the present study was relatively small. Because the PPMI project mainly focused on structural MRI and diffusion tensor imaging (DTI), very few R-fMRI scanning has been conducted. Second, other MRI modality and gene data were not investigated in this study. The underlying basis of structural  and functional connectivity or network and genetics of impaired brain activity in the occipital lobe and hyperactivity in the inferior frontal gyrus needs to be investigated in the future. Recently, several studies have found a range of abnormal functional network that is associated with cognitive decline in PD. For example, a white-matter (WM) study has revealed that PD-MCI patients showed a distributed pattern of WM abnormalities, including anterior and superior corona radiata, genu, and body of the corpus callosum, and anterior inferior fronto-occipital, uncinate, and superior longitudinal fasciculi . R-fMRI In summary, our study concluded hyperactivity  in the opercular part of right inferior frontal gyrus and hypoactivity in the occipital areas in early PD with MCI, which may be associated with cognitive decline and contribute to thought of PD dementia progression and further clinical treatment in PD. Further investigations of longitudinal changes and interaction in brain activity with the right inferior frontal gyrus as well as intervention are needed in future.ZW conceived and analyzed the study, and wrote the manuscript. XJ arranged the clinical data and participated in the manuscript revision. HC and TF were involved in the writing and discussion. HW contributed to clinical diagnosis and was involved in writing and discussion. All authors read and approved the final manuscript.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. The reviewer CL declared a shared affiliation, with no collaboration, with several of the authors, XJ, HC, and TF to thehandling Editor.