Altered functional connectivity density and couplings in postpartum depression with and without anxiety

Postpartum depression (PPD) is the most common psychological health issue among women, which often comorbids with anxiety (PPD-A). PPD and PPD-A showed highly overlapping clinical symptoms. Identifying disorder-specific neurophysiological markers of PDD and PPD-A is important for better clinical diagnosis and treatments. Here, we performed functional connectivity density (FCD) and resting-state functional connectivity (rsFC) analyses in 138 participants (45 unmedicated patients with first-episode PPD, 31 PDD-A patients and 62 healthy postnatal women, respectively). FCD mapping revealed specifically weaker long-range FCD in right lingual gyrus (LG.R) for PPD patients and significantly stronger long-range FCD in left ventral striatum (VS.L) for PPD-A patients. The follow-up rsFC analyses further revealed reduced functional connectivity between dorsomedial prefrontal cortex (dmPFC) and VS.L in both PPD and PPD-A. PPD showed specific changes of rsFC between LG.R and dmPFC, right angular gyrus and left precentral gyrus, while PPD-A represented specifically abnormal rsFC between VS.L and left ventrolateral prefrontal cortex. Moreover, the altered FCD and rsFC were closely associated with depression and anxiety symptoms load. Taken together, our study is the first to identify common and disorder-specific neural circuit disruptions in PPD and PPD-A, which may facilitate more effective diagnosis and treatments.     

Mucosal and systemic neutralizing antibodies to norovirus induced in infant mice orally inoculated with recombinant rotaviruses

Rotaviruses (RVs) preferentially replicate in the small intestine and frequently cause severe diarrheal disease, and the following enteric infection generally induces variable levels of protective systemic and mucosal immune responses in humans and other animals. Rhesus rotavirus (RRV) is a simian RV that was previously used as a human RV vaccine and has been extensively studied in mice. Although RRV replicates poorly in the suckling mouse intestine, infection induces a robust and protective antibody response. The recent availability of plasmid only-based RV reverse genetics systems has enabled the generation of recombinant RVs expressing foreign proteins. However, recombinant RVs have not yet been experimentally tested as potential vaccine vectors to immunize against other gastrointestinal pathogens in vivo. This is a newly available opportunity because several live-attenuated RV vaccines are already widely administered to infants and young children worldwide. To explore the feasibility of using RV as a dual vaccine vector, we rescued replication-competent recombinant RRVs harboring bicistronic gene segment 7 that encodes the native RV nonstructural protein 3 (NSP3) protein and a human norovirus (HuNoV) VP1 protein or P domain from the predominant genotype GII.4. The rescued viruses expressed HuNoV VP1 or P protein in infected cells in vitro and elicited systemic and local antibody responses to HuNoV and RRV following oral infection of suckling mice. Serum IgG and fecal IgA from infected suckling mice bound to and neutralized both RRV and HuNoV. These findings have encouraging practical implications for the design of RV-based next-generation multivalent enteric vaccines to target HuNoV and other human enteric pathogens.

Mucosal immunity plays a critical role in protecting against many pathogens in the respiratory and intestinal tracts. Live virus infections generally trigger more robust and effective mucosal immune response than oral administration of inactivated viruses or target protein antigens because they are self-amplifying and can more effectively elicit cellular as well as humoral immunity (1–4). Several studies have attempted to utilize recombinant viruses as vaccine vectors to induce an immune response against enteric pathogens (5–8); however, the most advanced of such enteric vaccine vectors are still in early stages of clinical development.Rotaviruses (RVs), the leading cause of acute gastroenteritis in infants, are a promising candidate for enteric vaccine vectors for several reasons. A) RV preferentially replicates in the small intestine, distinguishing it from several other enteric viruses that can also infect systemically or the colon. B) RV infection is acute, and the virus does not integrate into the host genome. C) RV is highly immunogenic and induces both systemic and mucosal immune responses in infected animals and humans (9, 10). D) Several live-attenuated human RV vaccines have been shown to be both safe and effective to use in very young children [e.g., RotaTeq (Merck) and Rotarix (GlaxoSmithKline)]. Other effective live-attenuated RV vaccines [Rotasiil, Rotavac, Lanzhou lamb rotavirus vaccine (LLR), and Rotavin-M1] are also licensed for use globally or primarily in their country of origin (11). E) Following substantial public health efforts, RV vaccines are now widely available in many low- and middle-income countries, as well as the more developed countries, and hence the administration of RV-based vaccines that included other heterologous antigens could potentially be piggybacked onto current RV immunization programs used globally. F) The RV double-stranded RNA (dsRNA) genome is segmented in nature, permitting easy genetic manipulation. G) With the insertion of heterologous antigens, RV replication can become attenuated in vitro (12, 13).Since a plasmid-based reverse genetics system was established in 2017, several studies have reported the generation of recombinant RVs that express fluorescent and bioluminescent reporter proteins (GFP, RFP, luciferase, etc.) and exogenous nucleotide sequences [e.g., endoribonuclease Csy4 target sequence and sequences encoding the receptor binding domain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein] in vitro (12–22). To facilitate the assessment and development of RVs as potential enteric vaccine vectors, the capacity of recombinant RVs to induce an enteric immune response against other gastrointestinal (GI) pathogens needs to be evaluated in well-characterized preclinical small animal models. Rhesus rotavirus (RRV) is a prototype laboratory strain of simian RV that efficiently replicates in vitro (23, 24). Although RRV does not replicate well in a murine model (25–27), it does induce both systemic and mucosal immune responses in infected mice (28). In addition, RRV itself and RRV-based RV vaccine candidates have previously been shown to be a highly immunogenic and protective in several human vaccine trials and were, for a time, licensed for use in children in the United States (29, 30).Human norovirus (HuNoV) is a major cause of acute gastroenteritis in both young children and adults. Although B cells and human intestinal organoids support HuNoV replication (31, 32), there is not yet a widely available robust cell culture system for efficient HuNoV cultivation, which has impeded both the assessment of HuNoV immunity and vaccine development. The HuNoV virion consists of major capsid protein VP1 and minor capsid protein VP2 surrounding a positive-sense RNA genome (33–35). Exogenously expressed VP1 can form virus-like particles (VLPs) that are structurally and antigenically similar to HuNoV virions (36–38), and the parenteral administration of such VLPs provides some level of protective immunity to HuNoV in adults (39–41). Moreover, expression of the protruding or P domain of VP1 that bears the major antigenic sites of HuNoV can yield subunit “P particles” that can also induce immune responses (42, 43). Here, we demonstrate the induction of both systemic and mucosal antibody responses against HuNoV in suckling mice using recombinant RRVs expressing HuNoV VP1 or P domain. Our data suggest that recombinant RVs represent a potentially effective small-intestine–targeted vaccination platform to express exogenous genes in the human intestine and to protect people from other enteric pathogens such as HuNoV as well as RV.     

Developing a Virtual Equity Hub: Adapting the Tumor Board Model for Equity in Cancer Care

We define cancer equity as all people having as the same opportunity for cancer prevention, treatment, and survivorship care. However, marginalized populations continue to experience avoidable and unjust disparities in cancer care, access to clinical trials, and cancer survival. Racial and ethnic minorities, and individuals with low socioeconomic status, Medicaid insurance, limited health literacy, disabilities, and mental health disorders are more likely to experience delays to cancer diagnosis and less likely to receive guideline-concordant cancer care. These disparities are impacted by the social determinants of health including structural discrimination, racism, poverty, and inequities in access to healthcare and clinical trials. There is an urgent need to develop and adapt evidence-based interventions in collaboration with community partners that have potential to address the social determinants of health and build capacity for cancer care for underserved populations. We established the Virtual Equity Hub by developing a collaborative network connecting a comprehensive cancer center, academic safety net hospital, and community health centers and affiliates. The Virtual Equity Hub utilizes a virtual tumor board, an evidence-based approach that increases access to multi-specialty cancer care and oncology subspecialty expertise. We adapted the tumor board model by engaging person-centered teams of multi-disciplinary specialists across health systems, addressing the social determinants of health, and applying community-based research principles with a focus on populations with poor cancer survival. The virtual tumor board included monthly videoconferences, case discussion, sharing of expertise, and a focus on addressing barriers to care and trial participation. Specifically, we piloted virtual tumor boards for breast oncology, neuro-oncology, and individuals with cancer and serious mental illness. The Virtual Equity Hub demonstrated promise at building capacity for clinicians to care for patients with complex needs and addressing barriers to care. Research is needed to measure the impact, reach, and sustainability of virtual equity models for patients with cancer.

Despite rapid advances in cancer treatment, disparities in cancer care persist. This article describes a virtual tumor board developed to provide a collaborative network of multi-disciplinary specialists, which showed promise at building capacity for clinicians to care for patients with complex needs and addressing barriers to care.     

Gut Microbiota Markers and Dietary Habits Associated with Extreme Longevity in Healthy Sardinian Centenarians

This study was aimed at characterizing the gut microbiota (GM) and its functional profile in two groups of Sardinian subjects with a long healthy life expectancy, overall named Long-Lived Subjects (LLS) [17 centenarians (CENT) and 29 nonagenarians (NON)] by comparing them to 46 healthy younger controls (CTLs). In addition, the contribution of genetics and environmental factors to the GM phenotype was assessed by comparing a subgroup of seven centenarian parents (CPAR) with a paired cohort of centenarians’ offspring (COFF). The analysis was performed through Next Generation Sequencing (NGS) of the V3 and V4 hypervariable region of the 16S rRNA gene on the MiSeq Illumina platform. The Verrucomicrobia phylum was identified as the main biomarker in CENT, together with its members Verrucomicrobiaceae, Akkermansia and Akkermansia muciniphila. In NON, the strongest associations concern Actinobacteria phylum, Bifidobacteriaceae and Bifidobacterium, while in CTLs were related to the Bacteroidetes phylum, Bacteroidaceae, Bacteroides and Bacteroides spp. Intestinal microbiota of CPAR and COFF did not differ significantly from each other. Significant correlations between bacterial taxa and clinical and lifestyle data, especially with Mediterranean diet adherence, were observed. We observed a harmonically balanced intestinal community structure in which the increase in taxa associated with intestinal health would limit and counteract the action of potentially pathogenic bacterial species in centenarians. The GM of long-lived individuals showed an intrinsic ability to adapt to changing environmental conditions, as confirmed by functional analysis. The GM analysis of centenarians’ offspring suggest that genetics and environmental factors act synergistically as a multifactorial cause in the modulation of GM towards a phenotype similar to that of centenarians, although these findings need to be confirmed by larger study cohorts and by prospective studies.