Avian influenza A viruses (AIVs), as a zoonotic agent, dramatically impacts public health and the poultry industry. Although low pathogenic avian influenza virus (LPAIV) incidence and mortality are relatively low, the infected hosts can act as a virus carrier and provide a resource pool for reassortant influenza viruses. At present, vaccination is the most effective way to eradicate AIVs from commercial poultry. The inactivated vaccines can only stimulate humoral immunity, rather than cellular and mucosal immune responses, while failing to effectively inhibit the replication and spread of AIVs in the flock. In recent years, significant progresses have been made in the understanding of the mechanisms underlying the vaccine antigen activities at the mucosal surfaces and the development of safe and efficacious mucosal vaccines that mimic the natural infection route and cut off the AIVs infection route. Here, we discussed the current status and advancement on mucosal immunity, the means of establishing mucosal immunity, and finally a perspective for design of AIVs mucosal vaccines. Hopefully, this review will help to not only understand and predict AIVs infection characteristics in birds but also extrapolate them for distinction or applicability in mammals, including humans. Avian influenza A viruses (AIVs) remain one of the important viral pathogens that cause respiratory tract infections in various animal species, such as poultry and humans, and aquatic birds are considered the primordial source of AIVs infecting other animal species . InfluenInfluenza viruses undergo antigen mutations through antigen drift and shift. Circulating AIVs evolve constantly, resulting in the occurrence of new strains with variable antigenicity. Particularly, mutations occurring in the HA or NA usually cause antigenic drift, subsequently leading to an escape from earlier immune responses. Besides, an antigenic shift can take place in AIVs. In this case, co-infection of a host cell with AIVs strains of different origins can lead to the generation of novel virus subtypes via induced genetic reassortment; a newly formed HA subtype of AIVs can transmit easily in immunologically naïve individuals . To dateVaccination remains one of the most effective ways to control and prevent AIVs transmission in poultry. Current influenza vaccines are generally effective against antigenically matched strains. It has been demonstrated that the antigenic mismatch between the vaccine and circulating strains or inadequate vaccine protocols can cause an antigenic drift and failed vaccination ,14. AlthThe innate immune response constitutes the first line of protection from invading pathogens. AIV infection results in a recognition of viral conserved components called pathogen associated molecular patterns (PAMPs) by host pathogen recognition receptors (PRRs), including Toll-like receptors (TLRs), retinoic acid inducible gene-I (RIG-I) receptors (RLRs), and NOD-like receptors (NLRs); the above recognition subsequently activates innate immune signaling and induces various proinflammatory cytokines as well as antiviral molecules ,19. ThenTLRs were identified as the first PRRs family that are expressed on either the plasma membrane  or the surface of endosomes and lysosomes  . To dateThe RLRs—RIG-I and melanoma differentiation-associated protein 5 (MDA5)—recognize the cytoplasmic viral non-self RNA and transcripts. RIG-I preferentially binds cytoplasmic single-strand 5′-triphosphate RNA, while MDA5 is activated by long dsRNA species . Upon inThe roles of NLR signaling in bacterial infection have been broadly investigated . IAV infThe adaptive immune response comprising humoral and cellular responses at both systemic and mucosal levels constitutes the second line of defense against influenza viruses; this multifaceted immune response is complex  36]. In. In36]. Infection with influenza viruses initiates virus-specific cellular immune response involving CD4+ T and CD8+ T cells . Upon inDuring IAV infection, CD8+ T cells, a vital subset of immune cells, are activated after recognition of viral epitopes on DCs that migrate from the lung tissue to T-cell areas in the draining lymph nodes, resulting in their proliferation and differentiation into CTLs . CD8+ T The mucosal immune system plays a crucial role in controlling infection with influenza viruses in the URT . The URTAbs, particularly IgG and IgA, are the major immune components acting in the protective response to IAVs . IgG is In response to antigen stimulation, IgA class switching and IgA secretion occur in B cells stimulated by specific signals such as co-stimulatory molecules and cytokines and in Th cells via T-cell-dependent and T-cell-independent pathways . The aboAt present, the commercial vaccines against influenza available on the market mainly comprise inactivated influenza A virus (IIV) vaccine and recombinant influenza A virus (RIV) vaccine. Strains used in commercial influenza vaccines are selected based on the compositions of viruses from the surveillance, laboratory, and clinical observations . These vThe respiratory mucosa is the first target of influenza virus, constituting the first line of defense against the infection, which can effectively prevent the virus from entering . MucosalMoreover, it has been shown that mucosal vaccines induce cross-reacting Ab in the respiratory tract, providing cross-protection against heterologous virus infection. Inoculating the influenza HA vaccine together with cholera toxin B subunit (CTB) or B subunit of heat-labile enterotoxin (LTB) supplemented with cholera toxin (CT) intranasally enhanced anti-HA lgA and IgG Ab responses in nasal wash or serum, which protect mice against variant virus infection . OkamotoResearchers have been attempting to create universal influenza vaccines for providing broad and sustainable protection against diverse influenza viruses. In recent years, research on the prevention of influenza infection by nasal immunity has gained more and more attention. To effectively work in mucosal immunization, mucosal vaccines must be designed to possess the characteristics of mucosa and promote the specific immune responses to vaccine antigens in the mucosa. Currently, generating effective mucosal vaccines mainly involves the identification of efficient means for antigen delivery to the mucosal immune system and the development of safe and effective mucosal adjuvants or immunoregulatory agents.A growing number of pre-clinical studies and clinical trials have advanced our understanding of how live attenuated influenza vaccines (LAIVs) elicit mucosal antibodies via intranasal administration. Contrary to the wild-type forms, attenuated viruses have the capacity to replicate well at temperatures around 25 °C rather than at 37 °C, deterring their replication in the lower airway, including lung tissue, and the subsequent occurrence of influenza-like disease . The mosAmong developing live attenuated mucosal vaccines, the major class of vaccines, oral vaccines, are currently being assessed in clinical studies. Oral vaccines are classified into intranasal and sublingual vaccines that are developed for the control of influenza, rotavirus, norovirus and measles viruses . ExperimSuccessful development of LAIVs largely rests on the proper balance between attenuation and immunogenicity. It has been reported that serial virus passage in the host cells during vaccine development causes a decrease in the virulence of effective live attenuated vaccines for rotavirus . As a reAdjuvants can potentially increase the immunogenicity of mucosal influenza vaccines, while enhancing the efficacy of vaccines through modulating the quantity and quality of host immune responses. Commonly used adjuvants include a wide range of compounds . The comAdjuvants act via the following mechanisms: (1) a depot formation at the site of injection, which enables the vaccine agents to be slowly released and the host immunity to be constantly stimulated; (2) enhancement of the agent uptake via APCs and APC activation and maturation; (3) immune cell recruitment; and (4) innate immune receptor activation. Moreover, adjuvants can shape subsequent adaptive immunity for producing the most effective and protective responses to a given pathogen through targeting the subsets of innate immune cells and forming a unique cytokine milieu associated with Th1, Th2, and/or Th17.A number of adjuvants for inactivated influenza vaccines including TLR agonists are widely used to enhance the vaccine immunogenicity . StudiesDNA vaccines are capable of expressing immunogenic antigens in vivo, thereby inducing cellular and humoral immunities without causing host exposure to live viruses . ExtraceIt has been shown that intranasal administration of DNAs in mice leads to a fast and relatively even distribution of plasmid DNAs all over the body . DNA vacParticulate vaccines are capable of forming a close contact with the epithelial cells in the mucosa via included anchoring devices with adhesive properties  or included immunomodulating factors  ,121. TheRecombinant technology has been employed to engineer live vector vaccines to express target antigens. The vectors usually have minimal replicative ability to allow immune stimulation without causing infection. Delivery of vector vaccines via the mucosal routes mimics the natural infection, inducing strong mucosal, systemic, and cellular immunities against micro-organisms. Many candidate vectors. e.g., bacillus subtilis , FowlpoxAdministration of mucosal vaccines via the oral route is strongly recommended because it avoids an injection, is safe and painless, and does not require professionals for delivery. However, the efficacy of oral vaccination has proven less satisfactory due to the fact that vaccine degradation occurs in the harsh environment of the gastrointestinal tract, and mucosal tolerance suppresses immune responses to a foreign antigen. Thus, oral vaccination may require highly sophisticated formulations involving approaches for cell-specific targeting and immunomodulation. In the mucosal tissues, epithelial cells are coated by a viscous fluid called mucus containing a layer of glycoproteins (mucins). The layer of mucus serves as a physical barrier between the epithelium and invaded pathogens while harboring competitive binding sites for entrapping microbes and S-IgA Abs for binding to and neutralizing pathogens. Structurally, the intestinal epithelium formed by a single-cell layer constitutes the largest and most important barrier to the entry of foreign substances and functions as a selective barrier that only allows for nutrients and electrolytes to be absorbed while preventing the entry of intra-luminal antigens, toxins, and microorganisms ,134. TheThere exist continued efforts in developing oral live attenuated vaccines. However, compared with live-attenuated pathogen based vaccines with limitations in safety, recombinant subunit vaccines or non-living or non-infectious vector vaccines could be more attractive, albeit more difficult to deliver ,135. HenAs a major entering portal for pathogens, the nasal route becomes a promising option for mucosal vaccination due to its unique physiological and immunological characteristics. Intranasal vaccination is capable of stimulating immune responses in the nasopharynx-associated lymphoid tissue, eliciting systemic and mucosal immunities in the gastric mucosa and the respiratory and/or genital tract . Most soVaccination via the nasal cavity is the earliest mean of mucosal delivery, and nasal immunity can effectively prevent respiratory diseases. At present, mucosal immunity has made great contributions to human medicine from theory to practice, and various influenza vaccines such as LAIVs and cold-adapted influenza attenuated vaccines have been developed ,140. TheAvian influenza is a serious respiratory disease. Although currently used inactivated vaccines are effective, circulation of antigenically different strains could reduce the efficacy of vaccines due to the fact that almost all vaccines are administered via the i.m. route. The rate of antigenic variation of AIVs is accelerating, thereby increasing the risk of human infection and harm to the economy and society. Therefore, speeding up the research on AIVs vaccines and improving vaccine safety and reliability will have huge economic and social benefits. Mucosal immunity constitutes the first line of defense against AIVs; the mucosal delivery route elicits mucosal and systemic immunities simultaneously. Compared to inactivated vaccines, mucosal vaccines stimulate both cellular and humoral immunities and can be more effective in protecting against influenza variant strains, hence producing more cross-reactive and longer-lasting comprehensive immune responses. Overall, mucosal vaccines and delivery routes should play an irreplaceable role in remarkably reducing AIVs-caused burden.


Examining the neural correlates underlying racial differences in cognitive functioning is necessary to help clarify mechanisms and to improve the generalizability of findings related to brain-behavior relationships. This systematic review aimed to determine whether there are racial differences in structural markers of brain aging among community-dwelling, neurologically healthy adults aged 18 and older. We identified studies  from searches in Ovid Medline, Ovid PsychINFO, and Elsevier EMBASE published until February 13, 2020. We included original articles that examined structural markers of brain aging and neuropathology across individuals from more than one race or ethnicity. These measures included magnetic resonance imaging, positron emission tomography amyloid and tau, cerebrospinal fluid amyloid, tau, and neurofilament light chain and computed tomography. Two reviewers independently screened full-text articles. We will present ongoing results and discuss the current state of knowledge, quality of existing studies, and gaps in the literature and highlight potentially key next steps.


Stem cells have improved the treatment of several diseases. Their efficacy has been widely debated over the last few decades, but their contribution to medical research has constantly increased .Recently, a pivotal study supported by the National Institute of Dental and Craniofacial Research (NIDCR), leaded by Prof. Yang Chai, investigated stem cell-based therapies for children with craniosynostosis. Authors demonstrated that Mesenchymal Stem Cells (MSCs) combined with hydrogel were able to regenerate functional cranial sutures previously undergone craniosynostosis, restoring not only skull anatomy but also neurocognitive functions in an animal model . This stSeveral research groups have worked on the role of genetic and epigenetic factors on craniosynostosis development, confirming a pivotal role of TWIST-1 gene mutations in Saethre–Chotzen syndrome (SCS). The discovery of genetic and molecular pathways has increased attention on alternative treatments to surgery: the group of Prof. Stan Gronthos demonstrated that pharmacological targeting of Kdm6a/b genes activity may regulate aberrant osteogenesis by TWIST-1 mutant cranial suture mesenchymal progenitor cells via deregulation of epigenetic modifiers, thus preventing cranial prefusion and the related functional impairment . On the The use of stem cell therapy to reactivate functional sutures is a clinical breakthrough also in the light of the high incidence of resynostosis after complex cranial vault reconstruction. Nevertheless, an early combined surgical and regenerative approach to craniosynostosis, may reduce or definitely prevent several related dental and maxillofacial implications , in addiThe crosstalk among stem cell therapy and clinical outcomes has been investigated also in studies on muscular , neural Therefore, the results reached by Prof. Yang Chai and his group are a milestone that will promote novel less-invasive, stem cell-based therapeutic approaches that will benefit patients affected by craniofacial developmental disorder involving related brain and organs alterations. Overall, stem cell research has obtained an important achievement towards its future clinical application in minimally invasive therapeutic procedures.


Emergency providers should recognize that pneumothorax is a rare but serious complication of shoulder arthroscopy that may require a unique approach to decompression.We present a case of a 60-year-old female who presented to the emergency department with right-sided facial swelling, voice change, and shortness of breath three hours after an elective arthroscopic right rotator-cuff repair and was noted to have a right-sided pneumothorax. We also describe a potential novel approach to chest tube decompression that maintains shoulder adduction in patients with recently repaired rotator cuffs.Although most cases of post-arthroscopy pneumothoraces are reported in patients who received regional anesthesia or have underlying lung pathology, it can occur in lower-risk patients as was demonstrated in our case. We also suggest considering an alternative anterior approach between the midclavicular and anterior axillary lines for chest decompression in select patients when a traditional approach is less ideal due to the need to maintain shoulder immobilization postoperatively. Over the past few decades shoulder arthroscopy has become an increasingly common technique to treat shoulder pathology. Proponents cite a decreased complication rate when compared to open procedures.A 60-year-old female presented to the ED with right-sided facial swelling, voice change, and shortness of breath three hours after an elective, arthroscopic, right rotator cuff repair. The outpatient surgery comprised a subacromial decompression, major glenohumeral joint debridement, and rotator cuff repair for right shoulder chronic impingement syndrome, intra-articular biceps tear, and full thickness rotator cuff tear. The surgery was performed in the lateral decubitus position under general anesthesia and without regional nerve block. The anesthesia report was reviewed and showed no major complications or episodes of hypotension or desaturation. The patient reported feeling well postoperatively; however, three hours later she developed right-sided face and neck swelling , voice cThe patient denied significant past medical history including any history of smoking or underlying lung or connective tissue disease. On arrival, her vitals were heart rate 92 beats per minute, blood pressure 135/80 millimeters mercury, respiratory rate 18 breaths per minute, and pulse oximetry was 96% on room air. Her physical exam was notable for predominately right-sided facial swelling, diminished right-sided lung sounds, and crepitus of the right neck, face, and chest. A chest radiograph showed a right-sided pneumothorax of approximately 70% with mediastinal shift and extensive subcutaneous emphysema .A pigtail catheter-type chest drain was placed in the fifth intercoastal space between the right midclavicular and anterior axillary line so as to not abduct or displace the patient’s shoulder given her recent rotator cuff repair. Successful expansion of the lung was noted .On the third day of admission, the chest tube was removed and the patient was discharged home without further complications. At her two-week follow-up, her shoulder was healing well and she had no significant sequelae from her pneumothorax.Only a handful of case reports and case series describe an association between arthroscopic shoulder surgery and postoperative pneumothorax3CPC-EM CapsuleWhat do we already know about this clinical entity?Pneumothoraces have been reported as a possible complication of shoulder arthroscopy.What makes this presentation of disease reportable?We present a case of a rare complication of a common procedure and suggest a less common procedural approach to treating pneumothorax.What is the major learning point?Pneumothorax is a rare but serious complication of shoulder arthroscopy that may require a unique approach to decompression.How might this improve emergency medicine practice?This variation to traditional pneumothorax decompression technique could help avoid re-injury of the rotator-cuff repair site.Emergency providers have traditionally placed tube thoracostomy drains at the fourth or fifth intercostal space at the midaxillary or anterior axillary line11Limitations to this new approach include left-sided pneumothorax , obese patients, large area of breast tissue, or use of larger caliber chest tubes. Placing the pigtail catheter at the second intercostal space midclavicular line is a viable alternative in these casesEmergency providers should recognize pneumothorax as a rare but serious complication of shoulder arthroscopy. Although most cases reported are in patients who received regional anesthesia or have underlying lung pathology, it can occur in lower-risk patients as was demonstrated in our case. Patients may present with classical findings of pneumothorax including dyspnea, decreased breath sounds, and signs of tension including mediastinal shift. Postarthroscopy pneumothoraces nearly always present with crepitus on exam or subcutaneous air on imaging. The majority of these cases tolerate decompression without issues and patients are discharged within several days without complications. Providers may consider follow-up computed tomography imaging in patients without prior lung disease to assess for underlying lung disease or structural pathology including blebs. We also suggest considering an alternative anterior approach between the midclavicular and anterior axillary lines for chest decompression in select patients when a traditional approach is less ideal due to the need to maintain shoulder immobilization postoperatively; however, more research is needed to confirm safety and efficacy.


Previous research has identified cancer and cancer-treatment related effects on survivors’ mental impairment including memory and concentration. However, research has not systematically examined the relative impact of cancer in the context of age and other age-related health challenges common in later life. This paper compares the effects of cancer-related factors with other health challenges faced by 471 older adult long-term survivors from an NCI-funded study of a randomly selected tumor registry sample from a major comprehensive cancer center. Having had chemotherapy is associated with several cognitive outcomes including memory and concentration. Survivors who reported more cancer-related symptoms during treatment reported a greater number of cognitive symptoms even decades after treatment. Importantly, other comorbid health problems as well as social factors were found to be important in explaining symptoms of cognitive impairment in this older adult sample. These findings suggest that health care and mental health providers consider the range of health challenges, including those related to cancer and its treatment, as they provide patient centered care.


This special issue includes seven articles. We have a brief review of mental health issues among Asian and Pacific Island (API) communities. Two papers examine non-biological factors that may be associated with mood disorders, using a nationally representative sample of Asian Americans (AA). These papers are particularly informative because they report disaggregated results across four AA subgroups. Another two articles examine different interventions and their efficacy to improve mood and quality of life among APIs. Finally, the case of a clinical encounter during COVID-19 was examined through the lens of Asian critical theory. Although these papers differ in their focuses and methodologies, collectively, they provide valuable information about mental health issues among the API community.


Influenza viruses rapidly diversify within individual human infections. Several recent studies have deep-sequenced clinical influenza infections to identify viral variation within hosts, but it remains unclear how within-host mutations fare at the between-host scale. Here, we compare the genetic variation of H3N2 influenza within and between hosts to link viral evolutionary dynamics across scales. Synonymous sites evolve at similar rates at both scales, indicating that global evolution at these putatively neutral sites results from the accumulation of within-host variation. However, nonsynonymous mutations are depleted between hosts compared to within hosts, suggesting that selection purges many of the protein-altering changes that arise within hosts. The exception is at antigenic sites, where selection detectably favors nonsynonymous mutations at the global scale, but not within hosts. These results suggest that selection against deleterious mutations and selection for antigenic change are the main forces that act on within-host variants of influenza virus as they transmit and circulate between hosts. As influenza viruses replicate within infected hosts, they quickly mutate into genetically diverse populations. A small proportion of within-host variants transmit between individuals , and somSeveral recent studies have used deep sequencing to identify within-host mutations in hundreds of clinical influenza infections . HoweverHere, we compare the genetic variation of H3N2 influenza virus within and between human hosts to infer the fates of within-host mutations in the global viral population. Individual within-host mutations are challenging to track on a global scale, but by comparing large numbers of genetic variants identified within and between hosts, we can infer the evolutionary forces that act on different classes of mutations. We analyze within-host viral variation in 308 acute influenza infections from three deep-sequencing datasets , and we Evolutionary rates provide a simple, quantitative framework for comparing viral variation across scales. Under neutral evolution, we expect within-host and global evolutionary rates to be identical, and deviations from these neutral expectations shed light on how selection acts across evolutionary scales. For instance, HIV and hepatitis C virus both evolve more rapidly within than between hosts, probably because viruses acquire adaptations to specific hosts that often revert after transmission .We sought to calculate the within-host and global evolutionary rates of influenza virus. Influenza’s global evolutionary rate is easily estimated from phylogenies of patient consensus sequences, which represent transmitted strains , but evoTo overcome these challenges, we developed a method to estimate rates of within-host evolution from deep sequencing of acute viral infections. In brief, we identified within-host mutations that were present in at least 0.5 per cent of sequencing reads  to estimWe tested the sensitivity of this method to common technical considerations. Estimates of evolutionary rates can be influenced by the frequency threshold used to identify within-host variation . We focuIn calculating within-host evolutionary rates, we sought to limit the influence of outlier samples with unusually high within-host variation . This hiWe calculated rates of within-host influenza evolution from deep-sequencing data in three published studies that together represented 308 acute H3N2 influenza infections  Dinis e. We estiTo assess sources of variation in our estimates, we calculated evolutionary rates separately for each deep-sequencing dataset . We alsoTo compare rates of evolution in acute and chronic influenza infections, we also calculated rates of influenza evolution in four chronic H3N2 infections that lasted multiple months  Supplem. We findWhat kinds of mutations reach detectable frequencies within hosts? We compared how quickly synonymous, nonsynonymous, and stop-codon (nonsense) mutations accumulate within hosts. Differences in how quickly these three classes of mutations accumulate can reveal how selection acts within hosts. Most synonymous mutations are nearly neutral; many nonsynonymous mutations are deleterious; and premature stop codons are lethal. In the absence of selection, all three types of mutations accumulate at the same rate. However, purifying selection purges deleterious mutations, and positive selection increases the frequency of any beneficial mutations.We find that deleterious mutations are purged detectably but incompletely within infected individuals. Synonymous mutations accumulate about twice as quickly as nonsynonymous mutations within hosts, with some variation across genes . Stop-coHow do mutations that arise within hosts fare as they circulate between hosts? We compared rates of evolution within hosts and globally to determine how selection acts across different scales of viral evolution. Neutral mutations should have similar rates of evolution within and between hosts. Purifying selection that acts between hosts to eliminate deleterious mutations will decrease global evolutionary rates compared to rates within hosts. Conversely, positive selection that acts on a global scale will increase rates of evolution between hosts relative to their within-host expectations for beneficial classes of mutations.To calculate the global evolutionary rates of influenza virus, we analyzed H3N2 influenza sequences in the Global Initiative on Sharing All Influenza Data (GISAID) EpiFlu database, where each sequence represents the consensus sequence of one patient infection . We usedSynonymous mutations accumulate at similar rates within hosts and globally . This coIn contrast, nonsynonymous mutations accumulate more slowly globally than within hosts in all six viral genes analyzed. In addition, while stop-codon mutations accumulate at appreciable rates within hosts, they never fix during global evolution. These discrepancies in evolutionary rates within and between hosts suggest that many nonsynonymous mutations that reach detectable frequencies within hosts are later purged by purifying selection as viruses transmit and circulate between hosts.An important exception to this trend occurs in the antigenic regions of the HA gene, which evolve more rapidly on a global scale than non-antigenic regions of HA  Caton e. Within The previous section shows that nonsynonymous mutations are less common among mutations that fix globally than they are within hosts. This result suggests that purifying selection eliminates many nonsynonymous within-host variants before they fix in the global population of influenza viruses. However, it remains unclear from this analysis how quickly deleterious, nonsynonymous mutations that are generated within hosts are eliminated as viruses transmit and circulate between hosts.de novo mutations are expected to be nonsynonymous. However, purifying selection reduces the fraction of nonsynonymous mutations by removing deleterious mutations after they arise and before they fix. By examining when nonsynonymous mutations are depleted from circulating viral strains, we can identify where in the evolutionary process most purifying selection takes place . The fraction of nonsynonymous mutations is even lower among between-host mutations that reach higher frequencies, and eventually, fewer than 20 per cent of the mutations that fix in these genes are nonsynonymous. Previous work has shown that rare variants in global viral populations are dominated by transient deleterious mutations , so thisMore nonsynonymous mutations are present between hosts in the viral surface proteins HA and NA. Nonsynonymous mutations are especially enriched between hosts in antigenic sites of HA, which experience strong positive selection on the global scale  Murphy,. In antiOur analyses show that transient deleterious mutations make up a large proportion of influenza’s genetic variation within hosts. Deleterious variation is common at the between-host scale as well  and can In this study, we quantitatively compared influenza virus’s genetic diversity within and between human hosts. Our results show that although viral diversity may seem low within acute human influenza infections, it is sufficient to explain the virus’s rapid global evolution. Synonymous mutations accumulate at similar rates within and between hosts, as expected for neutral genetic changes. Most nonsynonymous mutations that reach detectable frequencies within hosts are eventually purged between hosts, suggesting that within-host influenza diversity consists mostly of transient, deleterious mutations that are eliminated at transmission and global evolution. Antigenic sites of HA are the only region of the influenza genome where mutations are consistently favored between hosts beyond their frequencies within hosts.Our findings show how purifying and positive selection act on viral populations at different evolutionary scales. Influenza populations within hosts accumulate genetic variation as they expand during the first few days of an infection. However, most of this variation, which is deleterious, is purged as viruses circulate between hosts. One recent study estimates that influenza’s transmission bottleneck consists of one to two viral genomes , and furin vitro  mutations within hosts in each influenza gene . Random To calculate rates of viral divergence per day, we normalized per-site viral divergence by the timing of sample collection. Of the 308 H3N2 samples that we analyzed, 251 had metadata describing the number of days post-symptom-onset after which the sample was collected. For the remaining samples sequenced by For comparison, we calculated rates of evolution in acute patient infections through both the ‘point’ method described above, which averages rates of evolution calculated from each patient infection, as well as through linear regression . We perfTo calculate within-host rates of evolution in antigenic sites of HA, we used the antigenic sites defined by We downloaded all full-length H3N2 influenza coding sequences in the GISAID EpiFlu database collected from 1 January 1999 to 31 December 2017 . We randWe used a molecular-clock approach to calculate global evolutionary rates. We performed linear regression of the distances from a reference sequence by the timing of sample collection to estimate the rate of between-host evolution . MoleculWe previously deep-sequenced longitudinal samples of influenza from four chronic H3N2 influenza infections . We downTo calculate the fraction of mutations that are nonsynonymous within hosts, we tallied the total number of synonymous and nonsynonymous mutations in each frequency bin for each sample. Stop-codon mutations were counted as nonsynonymous mutations in this analysis. We then summed the variants in each frequency bin across samples. We calculated confidence intervals by performing 100 bootstrap resamplings of the viral samples and plotted the 95 per cent confidence interval from these bootstrap replicates .To calculate the fraction of mutations that are nonsynonymous between hosts, we must be able to determine when the same mutation has arisen multiple times in the global influenza population. We downloaded all full-length H3N2 influenza coding sequences in the GISAID EpiFlu database collected from 1 July 2015 to 30 June 2018, together representing the 2015–6, 2016–7, and 2017–8 Northern Hemisphere flu seasons . We grouhttps://github.com/ksxue/within-vs-between-hosts-influenza. Sequences downloaded from the GISAID Epiflu database are not available due to data-sharing restrictions, but acknowledgement tables for the sequences we analyzed are available at https://github.com/ksxue/within-vs-between-hosts-influenza/tree/master/data/GISAID/acknowledgements/H3N2.Raw sequencing data are publicly available from the NCBI SRA database for Bioprojects PRNJA577940 , PRJNA34Virus Evolution online.veaa010_Supplementary_DataClick here for additional data file.


Older age has often, but not always, been associated with greater risk aversion. Some have suggested that age differences in risk may reflect age-related declines in cognitive abilities. This study investigated the robustness of age differences in risk aversion across three different risk-taking measures, after controlling for cognitive abilities. Community-dwelling younger  and older  adults completed self-report and behavioral measures of risk aversion and several measures of cognitive abilities. Results showed that older adults reported significantly greater risk aversion than young adults on the behavioral measure of risk , but not on the self-report measures (Framing Task and Choice Dilemmas Questionnaire). Greater risk aversion on BART was significantly associated with lower analytic thinking, slower processing speed, and worse shifting of attention. Therefore, we tested the relation between age and risk aversion on the BART while controlling for these three cognitive abilities. Age differences in risk aversion remained significant even after accounting for cognitive abilities. Our results suggest that the lack of consistent age differences in risk aversion in the literature may at least partly be due to measurement differences, which raises concerns about the construct validity of these measures of risk aversion. Moreover, cognitive decline may not explain age differences in risk. Further research is needed to understand factors that dampen and heighten risk aversion in people of diverse ages.


The Latinx population is disproportionately affected by HIV-infection and older Latinx persons living with HIV (PLWH) are at greater risk for neurocognitive impairment (NCI). However, no studies have examined whether intersectionality  increases NCI risk. This study investigated whether LGBT status increases NCI risk in 126 PLWH  who completed a comprehensive NC battery. Domain average T-scores were based on demographically-corrected norms. Multiple regressions revealed that after accounting for covariates  and other dimensions of intersectionality , LGBT status significantly contributed to NCI risk in attention/working memory  and executive functioning . LGBT status, a key dimension of intersectionality, should be considered in NC assessment of PLWH. Future research is needed to identify factors  that may confer increased NCI risk in this population.


The vagus nerve-based inflammatory reflex regulates inflammation and cytokine release. Recent successful clinical trials using implantable bioelectronic devices to modulate the inflammatory reflex in patients with rheumatoid arthritis and inflammatory bowel disease have demonstrated the efficacy of targeting neural circuits as an efficient alternative to drug treatments. However, the optimal vagus nerve stimulation parameters to achieve efficacious symptomatic relief for inflammation are still unknown. In this issue of Bioelectronic Medicine, Tsaava et al. tested whether altering these electrical stimulation parameters would change circulating cytokine levels in healthy mice. They found that specific combinations of parameters produced significant increases in serum TNF while other parameters selectively lowered serum TNF levels, as compared to sham stimulated mice. These results have considerable implications for determining the optimal stimulation parameters to better treat common conditions and diseases that involve immune regulation. Recent successful clinical trials using implantable bioelectronic devices that modulate the inflammatory reflex have reported efficacy of vagus nerve stimulation in the treatment of inflammatory diseases. However, the optimal neurostimulation parameters to achieve significant cytokine changes are still unknown.In healthy mice without inflammation, specific combinations of pulse width, pulse amplitude, and frequency produce significant increases of the pro-inflammatory cytokine TNF but other parameters selectively lower serum TNF levels. Serum levels of the anti-inflammatory cytokine IL-10 were also significantly increased by selective parameters but remained unchanged with others.These findings provide guidance for design of future studies on the neural regulation of inflammation based on the selection of optimal parameters to relieve conditions and improve organ function.Bioelectronic medicine is based on neuromodulation of the nervous system restoring organ functions and health with less adverse effects than drugs, thus minimizing adherence issues (Olofsson and Tracey i) invasive with surgical implantation of an electrode around the left VN linked to a neurostimulator positioned under the collarbone or ii) non-invasive through transcutaneous cervical (on the path of the VN) or auricular stimulation, based on the innervation of the cymba conchae by the auricular branch of the VN (Peuker and Filler VN stimulation (VNS) is approved for the treatment of drug-resistant epilepsy and well tolerated   vagal A-fibers are the largest and myelinated fibers and carry afferent visceral information and motor input, ii) vagal B-fibers are small and myelinated fibers carrying parasympathetic input, and iii) vagal C-fibers are small and unmyelinated and carry afferent visceral information. Antiepileptic property of VNS was supposed to be related to vagal C-fibers, but their destruction did not alter VNS-induced seizure suppression in rats (Krahl et al. Importantly, these results argue that serum cytokines may be controlled by specific fiber sets and firing patterns. The specific VN fibers mediating the inflammatory reflex are not known. The VN contains A-, B-, and C-fibers, defined in accordance to their conduction velocity, which, in myelinated fibers, is proportional to their size (Erlanger and Gasser Patients under VNS for epilepsy may experience improved seizure reduction by increasing the frequency and/or duty cycle of stimulation while VNS for heart failure is limited by the inability to activate the nerve fibers mediating therapeutic benefit without co-activation of side effect-inducing fibers (Musselman et al. The results of Tsaava et al.  indicate


As the US population continues to age, it is important to gain a better understanding of factors that differ between independently living older adults and those that require assisted living. Accidental falls contribute to decreased quality of life for many older adults, and considerable research has been conducted examining measures of fall-risk and potential interventions. In this pilot study, we investigated fall-risk via assessment of spatio-temporal variables associated with gait in independent and assisted-living older adults aged 65+. Two gender-matched groups of participants were tested on seven gait variables  utilizing Opto-Gait technology. Each group included sixteen participants. Independent living participants were recruited through word of mouth and flyers at local senior centers. Assisted living participants all resided in one local health care facility and were recruited via word of mouth and flyers posted in the facility. A one way ANOVA with an alpha level of .05 revealed significant differences between groups in contact time, foot flat, propulsive phase, and average speed. The independent living group performed better on each variable. These findings indicate that older adults living in assisted living facilities may be at much greater risk of accidental fall than their independent living counterparts. While this study identified several key factors related to instability among old adults, additional investigation is warranted to further examine the relationships among gait, fall-risk, and differentiators between independently living and assisted living older adults in these variables.


This systematic review examines current randomized clinical trials of therapeutic agents to treat coronavirus disease 2019 (COVID-19). In this systematic review, we characterize the landscape of current COVID-19 trials to better quantify these potential issues.High-quality evidence generated by appropriately powered and controlled trials is needed to advance care for patients with coronavirus disease 2019 (COVID-19) and those who are susceptible to it.PRISMA) reporting guideline.3Institutional review board approval of this study was waived because it exclusively used publicly available data without any protected health information. Screening and trial selection adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses . Data analysis was performed in June 2020.We performed a data query of the ClinicalTrials.gov registry for interventional trials in any clinical phase regarding COVID-19 on June 8, 2020. Advanced search parameters included Our search yielded 674 trials after removing suspended and halted trials . Most we4We found a high rate of trial multiplicity, particularly with chloroquines, which are being tested in 143 studies. Although these overlapping trials may afford opportunities for replication and validation, the high degree of multiplicity also enhances the likelihood of finding a positive result through chance alone, potentially resulting in widespread use of an ineffective and possibly hazardous intervention.5 Because the projected participant accrual for US-only COVID-19 treatment trials is approximately 45 942 participants , it seems unlikely that this target will be achieved given the intrinsic challenges of participant accrual during an active pandemic.The fragmentation of efforts could also lead to unnecessary competition for participants, which potentially compromises trial accrual and statistical power for all trials. This worrisome scenario has already occurred in China.Notably, our study is limited through the use of a single US-based clinical trials registry, potentially representing only a fraction of the worldwide COVID-19–related trials portfolio. Furthermore, the ever-changing landscape of COVID-19 clinical research amid this pandemic may complicate future interpretation of this report.6 Together, these factors endanger the capacity to rapidly produce meaningful evidence that is vital during this critical time. Avoiding these pitfalls requires coordination of efforts. This could be achieved, in part, through makeshift cooperative groups to improve participant accrual and decrease duplicative efforts. Institutional review boards and regulators (including the US Food and Drug Administration) must also work together to responsibly ease roadblocks to coordinate pooled analyses across trials. These efforts should include synchronization and standardization of end points, focusing on the most meaningful and objective outcomes . It is hoped that these measures will expedite generation of high-quality prospective data to guide effective treatments while maximizing resource allocation.Although current trials have been initiated with the best intentions, the medical community must be mindful of the potential issues of incomplete participant accrual and publication bias that are introduced by enabling dozens of similar trials simultaneously.


This is commonly accomplished by the timed addition of soluble signaling factors, in conjunction with cell-handling steps such as the formation of 3D cell aggregates. Interestingly, when stem cells at the pancreatic progenitor stage are transplanted, they form functional insulin-producing cells, suggesting that in vivo microenvironmental cues promote beta cell specification. Among these cues, biophysical stimuli have only recently emerged in the context of optimizing pancreatic differentiation protocols. This review focuses on studies of cell–microenvironment interactions and their impact on differentiating pancreatic cells when considering cell signaling, cell–cell and cell–ECM interactions. We highlight the development of in vitro cell culture models that allow systematic studies of pancreatic cell mechanobiology in response to extracellular matrix proteins, biomechanical effects, soluble factor modulation of biomechanics, substrate stiffness, fluid flow and topography. Finally, we explore how these new mechanical insights could lead to novel pancreatic differentiation protocols that improve efficiency, maturity, and throughput.Insulin-producing beta cells sourced from pluripotent stem cells hold great potential as a virtually unlimited cell source to treat diabetes. Directed pancreatic differentiation protocols aim to mimic various stimuli present during embryonic development through sequential changes of  Cell therapies involve the transplantation of human tissues or cells to treat illnesses that progressively damage or degrade functional tissues. These treatments are typically limited by access to a reliable and cost-effective cell source. For a successful transplant, allogeneic matching requires identification, procurement and transport of donor material; and variations in quality of the donated tissue may affect therapeutic potential. Therefore, the large-scale production of biological material for cell therapies is a rapidly growing area of interest. The primary goal of such research is to produce adequate quantities of functional therapeutic cells in a cost-effective manner.Treatment of type 1 diabetes by islet transplantation is one example of a currently approved cell therapy. Here, donor islets are used to replace the insulin-secreting functionality lost from the autoimmune destruction of pancreatic beta cells. The Clinical Islet Transplantation Consortium trial (CIT-07) reported that 87.5% of patients were free from severe hypoglycemic events and achieved normal or near normal glycemic control at the 1 year end point . As with+ cells  (in vivo (in vitro (The production of insulin-secreting beta-like cells from pluripotent stem cells (PSCs) is a potential solution to the donor supply issues of islet transplantation. The first report of stem-cell derived insulin-producing cells via spontaneous differentiation was almost two decades ago and reported only 1–2% insulin+ cells . However+ cells . Therefo+ cells . More re 20 days . One of  20 days  and subs 20 days . Since teptide+) . Howevereptide+) . Maturat interactions , which cin vivo. Studies of developmental mechanobiology are challenging, and these parameters are often not considered as it is unclear what mechanics are present during human embryogenesis. Furthermore, the complexity of the in vivo microenvironment makes it difficult to control these biomechanical signals and to delineate their effects on differentiation from other correlated stimuli. Therefore, the field relies mainly on studies of biochemical pathways with in vivo mouse models or in vitro human models for information.Embryonic development is guided via highly dynamic signals from the surrounding cell microenvironment with remarkable precision and robustness. As cells differentiate, they relay different signals to neighboring cells by secreting soluble factors and matrix proteins. The soluble signaling cues associated with pancreatic differentiation have been well-studied using animal models and include the Wnt, Activin/Nodal, fibroblast growth factor (FGF), bone morphogenetic protein (BMP), retinoic acid, and sonic hedgehog (Shh), and Notch signaling pathways . HoweverCells respond to mechanical stimuli through mechanotransduction mechanisms, in which biomechanical stimuli are converted into biochemical signals . ReciproResident cells communicate with their neighbors during development by secreting soluble signaling molecules which can bias differentiation . The devin vivo cellular microenvironment is much more intricate than can be modeled by current in vitro systems. Although directed differentiation protocols that focus solely on the timed addition of soluble signaling factors can generate insulin-producing cells  perhaps due to improved paracrine signaling and cell–cell contacts . Paracricultures . In theiskeleton .In vitro, larger non-vascularized islets may develop central necrosis due to high metabolic demand and low oxygenation , thus retaining ECM proteins composition. Utilizing decellularized pancreas matrix scaffolds in bioartificial pancreas designs could also be a fruitful strategy to improve islet functionality by retaining pancreas stiffness and matrix architecture . HydrogeIn addition to the combinatorial effects of individual ECM components, the composition of the ECM is dynamically changing during development. While one composition may promote early pancreatic differentiation, the same composition may hinder downstream differentiation stages. During hESC differentiation, ECM and MMPs are secreted which remodels the exogenous ECM on the culture substrate . PSCs cuin vivo, a recent successful strategy has been to target specific mechanotransduction-associated pathways during directed differentiation to promote pancreatic differentiation and thus improve the capacity to produce insulin-secreting cells. Such factors include H1152 (a ROCK II inhibitor)  , vertepohibitor) , and lathibitor) . Nuclearhibitor) . Timed ihibitor) . Depolymhibitor) . AltogetCells interact with ECM proteins by binding with integrin receptors spanning across the cell membrane. These receptors can then activate downstream integrin-related signaling pathways that alter cell function and bias cell specification. In pancreas development, integrin-ECM signaling regulates collective cell migration and function . When plThe surrounding ECM matrix also propagates stress  which al+ endocrine progenitors, fibronectin promotes high cell spread area while laminin-coated surfaces were associated with lower spreading  or stiffness (MMP-mediated degradation or UV-based) could better accommodate the constantly changing requirements for beta cell differentiation. Finally, as our knowledge progresses, increasingly complex co-culture systems involving defined compositions of PSC-derived endothelial, islet endocrine cells, and other cells present during development, may be the route to a functional cell source for islet transplantation.To address these questions, some technologies that could be used to specifically identify the effect of these factors are highlighted in Overall, better understanding the mechanobiology of pancreas development could lead to new strategies to more efficiently produce functional glucose-responsive, insulin-secreting cells for cell therapies. Interdisciplinary approaches combining advances in materials science and developmental biology could accelerate the development and scale up of culture systems tailored for diabetes cell therapy.RT conducted the literature search and drafted the manuscript in consultation with CM and CH. All authors contributed to writing 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.


Most studies of middle-aged adults find blacks have higher levels of psychological distress compared to whites but have lower risk of common psychiatric disorders. For instance, there is evidence of lower rates of depressive and anxiety disorders among blacks relative to whites despite large disparities in stress, discrimination and physical health in midlife—commonly referred to as the black-white mental health paradox. We examine evidence of the black-white paradox in anxiety and depressive symptoms among older adults. Data come from 6,019 adults ages 52+ from the 2006 Health and Retirement Study. Unadjusted models show older blacks report more anxiety and depressive symptoms than whites. After adjusting for socioeconomic factors, everyday discrimination, chronic conditions, and chronic stress, there are no black-white differences in anxiety and depressive symptoms. Findings suggest the black-white mental health paradox only extends into older adulthood for blacks living under similar stress and health landscapes as whites.


Initially described as pneumonia of unknown aetiology in December 2019 in populations of Wuhan (China), the coronavirus disease (Covid-19) rapidly disseminated around the world . They alActually, nearly three billions people are confined at homes or in quarantine around the world. Brooks et al. in a recently published review including studies comparing psychological outcomes between people quarantined and not quarantined, found that quarantine had negative psychological effects such as post-traumatic stress symptoms, confusion and anger . All theShanghai government organized psychological care in four levels. At the first level, an onsite psychological support is provide to patients with severe symptoms of novel coronavirus pneumonia (NCP) by front-line medical staff, Centre for Disease Control researchers or administrative staff . The secThe current Covid-19 pandemic has tremendous consequences on population health around the world, with various degrees of mental health repercussions. Actual strategies are mainly targeting Covid-19 patients and healthy general populations, and are chiefly based on clear and secured communication as well as continuous onsite and online psychological support by appropriates professionals. However, these strategies should be disseminated to all countries, especially sub-Saharan African ones, and approved by concerned governments. Also, adequate psychological care policies have to be developed for health care workers fighting against this pandemic. All these measures would help to maintain optimal care of Covid-19 patients and prevent deleterious mental health outcomes including suicides.All authors declare no competing interests.


Dear Editor, Recently, Wu and colleagues published a study about hepatobiliary organoids generated from human induced pluripotent stem cells . For thSeveral studies have used human stem cells including hiPSC and reported that differentiation via definitive endoderm resulted in hepatocyte-like features  associated genes, potentially limiting hepatocyte maturation, which could be investigated by monitoring TWIST and SNAIL transcription factor activity. It should be considered that hepatocytes in vivo are arranged in sheets along sinusoids  is that19 is thaal., 2019). The usal., 2014; Hoehme al., 2014; Reif etin vitro systems for toxicity tests . Also, al., 2018), althouThe author declares no conflict of interest.


Creutzfeldt-Jakob disease (CJD) is a rare prion disease characterized by rapidly progressive dementia.A 76-year-old woman exhibited pronounced signs and symptoms of dressing apraxia for about seven weeks before the disease progressed and probable CJD was diagnosed supported by imaging and CSF findings.Dressing apraxia as the initial manifestation of CJD has been sparsely reported. This remarkably focal syndrome should be considered with view on movement and neuropsychological disorders in early CJD. Creutzfeldt-Jakob disease (CJD) is a rare prion disease mainly characterized by rapidly progressive dementia. Neuropsychological disorders however frequently occur in the initial phase of the disease with amnesia, impaired attention and frontal lobe syndrome as the most frequent . RecentlA 76-year-old woman developed difficulties in dressing. She had progressive problems dressing herself. In particular, she had difficulty handling buttons and arranging her clothing articles on her body. Dressing became more and more prolonged, and she began to manipulate her clothes incoherently until finally needing support from her husband. Her medical history included stable plasmocytoma, atrial fibrillation and residual effects from a minor stroke, and she was orally anticoagulated with phenprocoumon. Her neurological examination on admission revealed a slight right-sided motor impairment with finger tapping and slight dysarthria, which resulted from the previous minor stroke. Neuropsychologically pronounced signs and symptoms of dressing apraxia were found whereby performing simple gestures and pantomiming object use were preserved. Otherwise, there were no signs of constructional and limb ataxia, optic ataxia and visual disturbances. The MoCA test showed 28 of 30 points with slight impairment in the visuospatial items. Her family history was unremarkable. She had not had any previous neurosurgical procedures or corneal transplants [Her first cranial magnetic resonance images (MRI) showed marked cortical restriction of diffusion bilaterally (positive “ribbon sign”), most prominent in the parietal regions Figure . A cerebWith this case report, we wish to complement the observations on neuropsychological disorders in CJD for three reasons. First, dressing apraxia as an initial and for a certain time exclusive symptom of CJD has sparsely been reported . Most re465810


This study enhances the existing literature on the role of trust and online perceived risk in shaping consumer purchase decision-making in social commerce. The aim of this article is to investigate consumers’ purchase decision-making process, the determinant components of social commerce purchase intentions and attitudes, the effect of perceived risk on intention to go shopping in online settings, and consumer trust and buying behavior on online retailing platforms. The insights obtained from our research extend current knowledge as regards determinants of consumer attitudes and intentions toward online purchases, consumers’ perceived shopping risk and repurchase behavior when buying products online, and perceived consumer online trust and purchase decisions. Limited research has considered consumers’ decision-making processes on social commerce platforms by investigating how their perceptual attitudes, behavioral intentions, and immediate gratifications affect the purchase of products and services online. Our study addresses this gap and extends prior research by focusing on the relationship between online consumer purchase intention, social commerce adoption behavior, and consumers’ trust together with risk factors affecting online buying decisions, in light of the characteristics of source credibility. Our findings point toward important avenues of research on psychological determinants of consumer engagement in social media, decision mechanisms lying behind evaluation of prices, the types of perceived risk incurred, and online repurchasing behavior and intention on social commerce platforms. Subsequent directions should clarify whether adoption of mobile payment services may shape online consumers’ impulsive buying behavior and decision-making, especially under the influence of online product reviews. Our study cumulates evidence that consumers’ decision-making process is a dynamic performance , but thaUsing exclusively empirical sources published recently (2017–2019) in Web of Science- and Scopus-indexed journals, our paper fills the gap in the literature by elucidating consumers’ evaluation, commitment, and choice throughout online decision-making, insisting on their cognitive processing behaviors and on how expectations shape their pre-purchase and post-purchase satisfaction.On Wu J. et al. (2017)’s reading, trust is the essential component of consumer purchase intention when buying things on peer-to-peer temporary rental platforms where both hosts and renters do not know each other. The empirical evidence we reviewed supports the belief that social platform users’ purchase intentions can be constituted taking into account the relationship between online trust and perceived risk. Limited research has considered consumers’ decision-making processes on social commerce platforms by investigating how their perceptual attitudes, behavioral intentions, and immediate gratifications affect the purchase of products and services online.Our study addresses this gap and extends prior research by focusing on the relationship between online consumer purchase intention, social commerce adoption behavior, and consumers’ trust together with risk factors affecting online buying decisions, in light of the characteristics of source credibility. As limitations in the present article, our findings point toward important avenues of research on psychological determinants of consumer engagement in social media, decision mechanisms lying behind evaluation of prices, the types of perceived risk incurred, and online repurchasing behavior and intention on social commerce platforms. Subsequent directions should clarify whether adoption of mobile payment services may shape online consumers’ impulsive buying behavior and decision-making, especially under the influence of online product reviews.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Medicare is the primary insurance provider for approximately 51 million older adults, including those who seek mental health care. Medicare provider eligibility was last updated in 1989, and approximately one-third of the graduate-level mental health workforce  is excluded from Medicare, despite these professionals participating in Medicaid, TRICARE, the Veterans Administration, and private insurance plans. This Medicare mental health coverage gap (MMHCG) raises concerns about older adults’ access to mental health care, resulting in a policy misalignment between Medicare’s provider regulations and a growing number of older adults seeking mental health care. However, little is known about the precise impact of the MMHCG. To better understand how the MMHCG impacts older adults, we interviewed 17 Medicare-insured individuals about their experiences accessing mental health services. Using a phenomenological framework to analyze our data, we found that Medicare recipients described several consequences, such as: 1) a detrimental impact on their mental health and well-being; 2) concerns about having to start over with new providers due to commencing mental health treatment only to have services interrupted once the provider is no longer Medicare-reimbursable; and 3) relying on pro bono services from Medicare-excluded providers with uncertainty about the long-term sustainability of these arrangements. The presenters will describe how these findings fit within the current Medicare mental health service context, including the direct impact on older adults’ mental health. Discussion will also focus on policy implications of the findings and possible solutions for addressing the MMHCG.


Pathogens and pests are one of the major threats to agricultural productivity worldwide. For decades, targeted resistance breeding was used to create crop cultivars that resist pathogens and environmental stress while retaining yields. The often decade-long process of crossing, selection, and field trials to create a new cultivar is challenged by the rapid rise of pathogens overcoming resistance. Similarly, antimicrobial compounds can rapidly lose efficacy due to resistance evolution. Here, we review three major areas where computational, imaging and experimental approaches are revolutionizing the management of pathogen damage on crops. Recognizing and scoring plant diseases have dramatically improved through high-throughput imaging techniques applicable both under well-controlled greenhouse conditions and directly in the field. However, computer vision of complex disease phenotypes will require significant improvements. In parallel, experimental setups similar to high-throughput drug discovery screens make it possible to screen thousands of pathogen strains for variation in resistance and other relevant phenotypic traits. Confocal microscopy and fluorescence can capture rich phenotypic information across pathogen genotypes. Through genome-wide association mapping approaches, phenotypic data helps to unravel the genetic architecture of stress- and virulence-related traits accelerating resistance breeding. Finally, joint, large-scale screenings of trait variation in crops and pathogens can yield fundamental insights into how pathogens face trade-offs in the adaptation to resistant crop varieties. We discuss how future implementations of such innovative approaches in breeding and pathogen screening can lead to more durable disease control. R genes) e.g. fungicides, insecticides) Feeding the world population requires a stable production of safe food, which is threatened by factors such as climate change, land degradation and diseases. Pathogens and pests cause significant reductions in agricultural productivity worldwide, and control strategies remain ineffective for many pathogens Sustainable agricultural management practices critically rely on an understanding of the biology and evolutionary potential of the major crop pathogens. Emerging or re-emerging pathogens can only be contained by investigating their origins and migration routes, as well as their potential to counter-adapt to deployed control measures. Advancements in genomics, transcriptomics and proteomics have been instrumental to elucidate these questions and unravelled a broad range of molecular mechanisms governing host-pathogen interactions leading to more effective control strategies 1.1e.g. appressoria) i.e. temperature, pH, humidity) to thrive, changes in the environment can alter the pathogen's ability to cause damage 2 and ozone can affect plant disease severity e.g. wash-off of fungicides following strong rainfall). Hence, the challenge to contain pathogen damage in agriculture is to predict the emergence of virulent strains and the rise of fungicide resistance.Major crop diseases are caused by pathogens including fungi, bacteria and viruses . In addii.e. biotrophs) can feed on plant nutrients for a long period without causing apparent infection symptoms Given the possibly severe consequences, the early detection of resistance breakdowns in crops or loss of sensitivity to pesticides is critical. Detection early in the growing season and identifying previously uncharacterized pathogens remain major challenges. Classic plant disease diagnostics usually relies on visual symptom scoring by trained individuals categorizing disease severity on linear scales e.g. leaves, Disease symptoms may include any range of changes in the color, shape or functioning of the plant as it responds to a pathogen and can be visualized at specific wavelengths A. Depend1.2e.g. GF-1 from China or SPOT from Europe, can provide time-resolved phenotyping of individual fields at the meter scale Technologies suitable for screening plant diseases even in early infection stages have become widely deployed 1.3Proximal phenotyping is mostly deployed in greenhouse experiments or in well-controlled field experiments. Sensors covering a broad range of spectra can be mounted on stationary platforms or, for outdoor use, on suspension cables, robots and tractors i.e. qPCR) are often required to clearly establish what is likely to cause a disease. Interesting developments to overcome these limitations are e.g. the differential reflectance spectra (400–1050 nm) of sugar beet leaves, which helps distinguish three different fungal pathogens including Cercospora beticola, Erysiphe betae, and Uromyces betaeOidium neolycopersiciCorynespora cassicola and bacterial spot caused by Xanthomonas perforans on tomato in the asymptomatic phase. The multi-spectral imaging approach was successful both under laboratory and field conditions. Such robust phenotyping methods could make it possible to detect infection foci in the field. Emerging infections could then be isolated and treated individually by the deployment of specific fungicides.Current plant phenotyping technologies and image processing algorithms struggle to reliably differentiate disease symptoms originating from multiple or unknown pathogens Plant phenotyping technologies have generated data to populate public image databases  with a fluorescent readout sensitive to changes in gene expression or subcellular localization. The main goal of the technology is to accelerate drug discovery by screening large antimicrobial compound libraries at a rate of thousands of compounds per week. Efforts are as well made in the development of high-throughput approaches to generate mutated versions of drug targets in vitro screening of diverse pathogen population scans is very informative about possible standing resistance, which can prevent rapid efficacy failures under field conditions High-throughput phenotyping platforms for microbial organisms have dramatically advanced in automating cell culturing, liquid handling, spotting on culture medium as dense arrays and integration of fluorescence measurements and microscopy The wealth of information on phenotypic trait variation in pathogen species combined with low-cost sequencing can be exploited for GWAS 1.5etc.) influence the outcome of infections. The complexity arises in part from complex pathogen infection cycles starting from initial host contact to transmission to new hosts The application of imaging combined with computational techniques enabled enormous progress in breeding resistant crops and detecting the emergence of new pathogen threats. To reduce complexity, most studies until now focused either on variation on the plant or the pathogen side. However, the nature of host-pathogen interactions can vary across space and time omics datasets to build biological networks (e.g. gene co-expression or protein–protein interaction networks) has become a powerful approach to unravel genetic factors controlling biological interactions Arabidopsis thaliana - Xanthomonas arboricola interaction, Wang et al. Z. tritici, a large set of loci associated with pathogen virulence and reproduction on different hosts were identified Botrytis cinerea and 90 plant genotypes of eight species revealed a highly polygenic architecture of pathogen virulence and host specialization e.g. blackleg in canola) or at different growth stages. Bigger sample sizes in both host and pathogen will also improve heritability estimates (e.g. as shown in human studies Integration of different 1.6Plantago lanceolata-Podosphaera plantaginis interactions C. beticola have shown that resistant isolates have significantly lower virulence and spore production than sensitive isolates Ralstonia solanacearum mutants lacking the gene for synthesizing an exopolysaccharide virulence factor show increased growth rates compared to the wild-type strain Z. tritici. Performance of a global strain collection on twelve wheat varieties and in various abiotic conditions revealed a broad pleiotropic control of pathogen performance on and off the host How successful pathogens cope in diverse environments depends on life-history trade-offs, which arise from resource allocation dilemmas and antagonistic gene actions. A trade-off indicates that an increase in one trait is associated with a decrease in another trait. Such trade-offs are typically dependent on the host genetic background and abiotic conditions. Some pathogen strains have evolved specialization on certain hosts or climatic conditions to maximize their performance. Classic examples include the wild pathosystem of 2Technological progress in assessing susceptibility of large collections of crop plants to pathogen damage is crucial for modern resistance breeding efforts. A variety of image capture techniques allow to monitor plant damage at the cellular, leaf, whole plant or field level. Most applications focus on the visible spectrum but hyperspectral imaging platforms have recently gained the ability to detect pathogen infestation even before the appearance of symptoms. A major area of going research is to improve image analyses algorithms to detect and classify pathogen damage. Variation within individual pathogen species can be highly informative about the rise of new virulence or pesticide resistance. Robotics applied to automate the culturing of thousands of pathogen strains enables screening for metabolic variation, drug susceptibility and production of secondary metabolites improving our understanding how pathogens cope with the agricultural environment. Both high-throughput plant and pathogen phenotyping efforts can be combined with genome sequencing and GWAS applications. Unraveling the genetic basis of host resistance helps to speed up breeding efforts through marker-assisted selection. Analysis of pathogen populations can be informative about possible trade-offs in the emergence of virulence or pesticide resistance.Future directions of research should focus on a set of complementary research areas.- Create efficient pipelines merging imaging and molecular assays for pathogen detection. Such integrated systems could help farmers deploy appropriate counter-measures in the field prior to widespread damage and reduce overall pesticide application.- The susceptibility of crop cultivars to major pathogens should be re-assessed continuously to detect changes in the virulence profile of the prevalent pathogens. Rapid evolution in pathogens can lead to catastrophic resistance breakdowns and must be detected early enough. High-throughput imaging systems capturing disease symptoms should be combined with machine learning to effectively recognize changes in virulence profiles. The lack of curated and open access disease image databases is currently slowing progress.- Regional monitoring efforts of resistance breakdowns or the loss of pesticide efficacy can be achieved by high-throughput genomic screening of infected leaf material. Efficient genotyping assays focusing on major genes are likely to scale well to broad applications. Bioinformatic procedures for such genomic data analyses are largely in place. A successful implementation of such genomic monitoring will also help to detect the arrival of new pathogens early enough to deploy resistant cultivars or implement changes in pesticide application regimes.- The systematic identification of trade-offs faced by pathogens adapting to pesticides and resistant crop cultivars could lead to more durable control measures.Nikhil Kumar Singh: Conceptualization, Writing - original draft, Visualization. Anik Dutta: Writing - original draft, Visualization. Guido Puccetti: Writing - original draft, Visualization. Daniel Croll: Conceptualization, Writing - original draft, Supervision, Funding acquisition.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Intracortical bone pins are introduced as gold standard for analysing skeletal motion because of eliminating soft tissue artefact. However, excluding this methodological error might be in cost of intervening movement pattern by local anaesthesia and pain of external tool within body. The purpose of this study was to examine whether intracortical bone pins alter shoulder joint kinematics or coordination. Three subjects were analysed during arm elevation/depression in frontal and sagittal planes. Retroreflective skin markers captured the motion in two sessions, before and after inserting bone pins (SKIN and PIN sessions), respectively. Thoracohumeral and scapulothoracic kinematics and scapulohumeral rhythm (SHR) were compared between two sessions. Thoracohumeral exhibited lower elevation and internal rotation in PIN session especially close to maximum arm elevation. The highest differences were observed for scapulothoracic kinematics, with higher retraction during abduction as well as higher posterior tilt, lateral rotation and retraction during flexion in PIN session. In addition, no systematic changes in SHR between subjects was found. Statistically significant lower SHR in PIN session was observed over 87-100% of thoracohumeral elevation/depression cycle in frontal plane and over 25-61% in sagittal plane. Further studies should treat carefully toward the clinical validity of shoulder joint kinematics after inserting bone pins. Retroreflective markers mounted on either skin or intracortical bone pins are used to highly accurately capture shoulder motion and evaluate the shoulder dynamics  represents any changes in scapulothoracic/scapulohumeral movement and their coordination  at 300 Hz.Data collection was performed in two sessions in a single day, for each participant. For session 1 (SKIN), 22 skin markers were attached to the left clavicle (5), scapula (4), humerus (7) and thorax (6) based on the model introduced by Jackson et al. . Their lAnatomical and relaxed static positions were primarily recorded for each person per session. Thereafter, each participant was asked to perform movements in SKIN session and repeat these movements in PIN session. The movements included functional motion tasks and main tasks. Functional motion tasks were arm flexion, rotation, and circumduction performed in each session to find functional joint centres and axes. Main tasks involved 10 trials of arm elevation/depression in frontal plane (abduction/adduction) and sagittal plane (flexion/extension). In S4, the location of the scapula’s pin interfered with the skin markers which had to be repositioned more laterally. The post-surgery skin markers on the scapula were quasi-collinear. This resulted in the impossibility of accurate kinematics calculations. S4 data were removed.t-tests using statistical parametric mapping (SPM) were implemented, during elevation and depression separately, to determine whether any significant differences exist between SKIN and PIN sessions. The open-source SPM1d toolbox (http://www.spm1d.org) in MATLAB  was used for our SPM analysis.The systems of coordinates and sequences were defined based on International Society of Biomechanics (ISB) recommendations , while thoracohumeral kinematics just altered slightly. In fact, the subjects reduced their axial rotation and the plane of elevation after inserting pins. These alterations are consistent with findings of previous studies about shoulder abnormalities. Mell et al.  showed aThe changes in joint kinematics before and after pin insertion , Table 1n = 3) in our cross-comparison study, we compared the kinematics of each subject separately between SKIN and PIN sessions. In addition, the obvious differences in SHR between subjects might be due to individual movement strategies rather than different compensatory mechanisms. It is recommended that validation studies which mount both skin markers and bone-pin markers on the body estimate how they will interact with each other before data collection. Otherwise, repositioning skin markers because of interference with bone pins would deteriorate the kinematic results. In our study, one of our four available subjects was excluded due to this issue. A well-organized protocol especially for such invasive studies with small sample sizes will help in minimizing the between-subject differences derived from methodological errors. While only kinematics were assessed in the present study, electromyography and/or muscle force estimation may provide additional information about the effect of pin insertion on the upper-limb biomechanics. However, the estimation of muscle forces at the shoulder remains challenging due to co-contraction and the complex trajectories of (multi-articular) muscles (Behm et al. In addition to joint rotations, SHR was selected to look at the effect of inserting bone pins, since it can represent the movement quality index for shoulder complex for several reasons. The most important reason is that kinematic redundancy enables the central nervous system to generate a specific shoulder motion with different contribution of bony structures (Yang et al. Our results showed that inserting shoulder bone pins dominantly deteriorates the pattern and RoM of scapulothoracic joint rather than thoracohumeral joint. It was also observed that SHRmight be partially reproduced after pin insertion. Eliminating methodological errors from soft tissue artefacts using intracortical pins would not necessarily add more clinical value to the kinematic results, while the approach remains relevant to model/algorithm validation.


Public mental health response to coronavirus disease is essential. After reviewing systemic and local efforts in China, we found efficient coordination and human resources. We recommend better symptom assessment, monitoring of organizations, and basic needs protection. This recommendation can inform how other countries can overcome mental health challenges during this pandemic. The coronavirus disease (COVID-19) outbreak and quarantines have caused major distress in China   and psycCoordination and resource allocation were compiled from local efforts at the Wuhan epicenter . On JanuThe MoE and CPS recruited professionals and volunteers across China, which suggests adequate resource allocation (The Inter-Agency Standing Committee calls for assessment of mental well-being and program evaluation of psychsocial support effectiveness (CPS published a list of approved hotline organizations based on survey evaluation of organizations (Although COVID-19 does not cause intentional harm, there are human rights issues on access to basic needs (Our review suggests that China has overcome resource shortages with coordination and resource allocation in its mental health response. The government, universities, and academic societies provide coordination, and independent organizations provide local support. We recommend integration of assessment in direct support, monitoring of organizations, and advocating for affected persons. These recommendations can inform how other countries can overcome shortage of mental health resources when facing this pandemic.Additional information on review of mental health response to COVID-19, China.


Zostera marina). Sampling seawater along transects extending alongshore outward from eelgrass beds, we demonstrate that eDNA provides meter-scale resolution of communities in the field. We evaluate eDNA abundance indices for 13 major phylogenetic groups of marine and estuarine taxa along these transects, finding highly local changes linked with proximity to Z. marina for a diverse group of dinoflagellates, and for no other group of taxa. Eelgrass habitat is consistently associated with dramatic reductions in dinoflagellate abundance both within the contiguous beds and for at least 15 m outside, relative to nearby sites without eelgrass. These results are consistent with the hypothesis that eelgrass-associated communities have allelopathic effects on dinoflagellates, and that these effects can extend in a halo beyond the bounds of the contiguous beds. Because many dinoflagellates are capable of forming harmful algal blooms (HABs) toxic to humans and other animal species, the apparent salutary effect of eelgrass habitat on neighboring waters has important implications for public health as well as shellfish aquaculture and harvesting.Seagrass beds provide a variety of ecosystem services, both within and outside the bounds of the habitat itself. Here we use environmental DNA (eDNA) amplicons to analyze a broad cross-section of taxa from ecological communities in and immediately surrounding eelgrass ( Seagrass species are ecosystem engineers throughout the world’s coastal zones , generatIn addition to these broad ecological and chemical functions, such habitats demonstrate important antimicrobial properties. Seagrass meadows have been shown to reduce exposure to bacterial pathogens affecting humans and marine life, relative to areas lacking such meadows . AdditioZostera marina) is the dominant seagrass along temperate coasts of the Northern Hemisphere  or ostrich (genus Struthio) tissue. We selected these organisms because they are absent from the sampling sites and common molecular biology reagents, but amplify well with the universal primer set used in this study. Additionally, they can be used to identify possible cross-contamination: reads from other taxa that appear in these positive control samples allow us to estimate and account for the proportion of sequences that are present in the incorrect PCR reaction (see “Bioinformatics” below). We also amplified negative controls (molecular grade water) in triplicate alongside environmental samples and positive controls, and verified by gel electrophoresis that these PCR reactions contained no appreciable amount of DNA.Finally, we generated amplicons with the same replication scheme for positive controls, comprised of extractions from either kangaroo . We then performed sequencing on an Illumina MiSeq  platform in four different sets of samples: two MiSeq V.2 runs and two MiSeq V.3 runs. We processed each batch separately through the initial bioinformatics analysis (see below). We employed hierarchical clustering on transects containing six PCR replicates sequenced across two different runs  and found that these samples were each other’s nearest neighbors ; thus seWe followed updated versions of previously published procedures for bioinformatics, quality control, and decontamination . This pr11), false-positive rate (P10) and commonness (psi) in a Bayesian binomial model. We then used these parameters to estimate the overall likelihood of occupancy (true presence) for each ASV; those with low likelihoods (<20%) were deemed unlikely to be truly present in the dataset, and therefore culled. 25 million reads from 3143 ASVs survived this step.To address possible cross-sample contamination , we subtLastly, we removed samples whose PCR replicates were highly dissimilar: we calculated the Bray–Curtis dissimilarity amongst PCR replicates from the same bottle of water and discarded those with distance to the sample centroid outside a 95% confidence interval. Of 84 bottles of water collected, 3 technical replicates survived QC in 72 cases (86%), two replicates in 9 cases (11%), one replicate in 2 cases (2%), and zero replicates in a single case (1%) . The finPRJNA606519).All bioinformatic and analytical code is included in GitHub repositories , and proe-values of 10−30 (culling limit = 5), and reconciling conflicts among matches using the last common ancestor approach implemented in MEGAN 6.4 .Our analysis revealed strong habitat associations for dinoflagellates and not for other taxa (see “Results”). To examine patterns specifically within the phylum Dinoflagellata, we further refined our annotations for these ASVs. Specifically, we considered the geographic range of taxa involved (restricting possible annotations to those taxa known from the North Pacific) and assigned taxonomy conservatively to the level of family  only in cases of >95% sequence identity between the subject and query sequence; ASVs we could not confidently assign to the level of family we excluded from further analyses. Multiple dinoflagellate sequences with identical amino-acid translations occurred within To confirm the spatial resolution of our eDNA communities, we used non-metric multidimensional scaling (nMDS) ordination of eDNA indices for all ASVs within each technical replicate . To deriTo examine the relative abundance of phyla in eelgrass habitat relative to bare substrate, we determined eDNA indices for the sum of sequences within each phylum at the two transect extremes (within-eelgrass versus bare), calculating a relative eDNA abundance measure by subtracting the mean eDNA abundance index over bare substrate for each site-month combination from the corresponding mean eDNA abundance index in the eelgrass habitat. Positive values of this measure thus denote higher abundance in eelgrass, while negative values of this index indicate higher abundance over bare substrate. To assess the statistical significance of these phylum-level differences between habitat types, we compared the distributions of mean eDNA abundance indices for individual phyla in samples taken from eelgrass relative to their counterparts taken over bare substrate, using a paired Wilcoxon signed-rank test with Bonferroni correction for multiple comparisons.k-means function of the R stats package . Next, to determine whether dinoflagellate abundance measures at intermediate alongshore transect samples  were more closely associated with eelgrass habitat or bare substrate, we additionally performed Gaussian mixture modeling with two groups . We thenWe assigned over 3,000 unique ASVs to 13 eukaryotic phyla comprising a diverse set of single- and multicellular taxa including Arthropoda (arthropods), Annelida (annelid worms), Bacillariophyta (diatoms), Chlorophyta , Chordata (chordates), Cnidaria (cnidarians), Dinoflagellata (dinoflagellates), Echinodermata (echinoderms), Heterokonta (stramenopiles), Mollusca (molluscs), Nemertea (ribbon worms), Ocrophyta  and Rhodophyta . This represents a broad—although by no means comprehensive—survey of eukaryotic communities in and around our sampled eelgrass beds.Ordination via nMDS revealed consistent differentiation between eDNA communities across transects within a sampling site and date; technical replicates consistently clustered together. An example plot of samples gathered along the transect from eelgrass to bare substrate at Willapa Bay in July  shows thR2 = 0.186, p = 0.001), month , and transect distance  each explain a significant portion of the variance in the dataset. Thus, despite strong effects of location and time, these results confirm that we can consistently distinguish nearshore eDNA communities (as sampled by our primers) at spatial scales of meters for each site and month of sampling. Moreover, we see a highly significant effect of proximity to eelgrass on the complement of organisms present.PERMANOVA apportioned the variance in Bray–Curtis distance among samples as follows: site . Other single-celled microalgae such as diatoms (Bacillariophyta) and green algae (Chlorophyta) have no significant relationship with eelgrass.To determine the habitat preference of major taxa in our dataset at a coarse spatial scale, we classified ASVs to the level of phylum and plotted an index of their relative sequence abundance in eelgrass versus bare positions . Positivk-means clustering) to define a set of high- and low-abundance transects for each dinoflagellate sequence across all sites and months .In this subset of high-abundance transects, the negative interaction of eelgrass and dinoflagellates is taxonomically universal. The taxa represented include two unique variants from the genus  species . All arep < 0.02; p > 0.85).After demonstrating a preference of all dinoflagellate taxa towards the bare substrate extreme (when highly-abundant), we then characterized their patterns as a function of distance from the edge of the contiguous eelgrass beds, using data from entire transects . ExaminiIn a broad-spectrum eDNA survey of the organisms living in and near to eelgrass, we track the relative abundance of a diverse group of taxa from thirteen phyla. We demonstrate the ability of eDNA to distinguish communities represented in samples taken only meters apart, and to reveal a significant axis of variance based on proximity to habitat type, despite strong influences of geography and time across sampling events. One major and significant pattern emerges in our analysis: dinoflagellate taxa are more common over bare substrate than within eelgrass beds when highly-abundant, and this effect extends at least 15 m beyond the edge of the contiguous beds themselves. Because ours was an observational field study, rather than an experiment, we cannot rigorously distinguish among plausible mechanisms for the observed dinoflagellate distributions. Instead, we use the patterns in our own data as well as the relevant scientific literature to evaluate a number of potential hypotheses.One plausible mechanism is that of an ecological edge effect acting in nearshore zones at the interface between eelgrass and non-eelgrass habitat. “Edge effects” are changes in the distribution or abundance of a species at a boundary between habitats , such tA third possibility is that predatory taxa exist in greater abundance within eelgrass beds and thereby consume dinoflagellates in larger quantities within this habitat , and is mediated locally by a variety of strains of eelgrass-associated algicidal and growth-inhibiting bacteria, particularly from Erythrobacter, Teredinibacter, Gaetbulibacter and Arthrobacter genera  causes paralytic shellfish poisoning via production of saxitoxin  produce yessotoxins (YTXs), whose effects on human consumers of contaminated shellfish are complex and unclear (reviewed in Alexandrium) are intensifying with recent ocean warming in the North Pacific  gigas, in particular, has recently been shown to lessen the effects of eelgrass wasting disease on Z. marina , transect direction , transect position , month, technical replicate, and sequencing run.Click here for additional data file.10.7717/peerj.8869/supp-2Supplemental Information 2Click here for additional data file.


Cross-sectional findings showed that education differences in memory performance were moderated by frequent cognitive activity . The present study examined whether frequent cognitive activity could compensate for lower education when focusing on change in cognitive performance across nine years. The study also explored whether cognitive activity can slow down declines in retired adults as previous research suggested that retiring is associated with an increased risk of cognitive decline . Longitudinal data from the MIDUS study included N = 3,325 middle-aged and older adults. Outcome variables were two factors of cognitive performance: Episodic Memory (EM) and Executive Functioning (EF). Independent variables were years of education, work status (working vs. retired), and frequency of cognitive activity. The results suggest that cognitive activity moderated the effect of educational attainment on change in EM. Individuals with both higher education and cognitive activity showed the smallest declines in EM. Individuals with lower educational attainment but high cognitive activity had less decline in EM compared to their low education counterparts. Those who increased their cognitive activity over time showed less decline in EF. In terms of work status, working adults had less decline in EM and EF compared to retired adults and retired adults who did not maintain their cognitive activity declined more in EF. The results emphasize the importance of frequent engagement in cognitive activity across the lifespan, which can attenuate cognitive declines especially among those who have lower education or have retired.