The impact of SARS-CoV-2 on the cystic fibrosis foundation therapeutics development network

The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) global pandemic significantly impacted CF clinical research within the Cystic Fibrosis Foundation Therapeutics Development Network (CFF TDN). A Research Electronic Data Capture (REDCap) survey was developed and sent to network sites to monitor and understand the impact on research teams, ongoing and anticipated clinical research, and specific clinical and research procedures. Key findings indicated an early impact on participant enrollment, research team stability, and procedures such as spirometry and sputum induction. These trends steadily improved over the months as research activities began to recover across the TDN. While SARS-CoV-2 created a significant challenge it also highlights new opportunities to expand CF research with greater focus on data collection outside of research centers and increased access for remote participation.     

Bone Tissue Composition in Postmenopausal Women Varies With Glycemic Control From Normal Glucose Tolerance to Type 2 Diabetes Mellitus

The risk of fragility fracture increases for people with type 2 diabetes mellitus (T2DM), even after controlling for bone mineral density, body mass index, visual impairment, and falls. We hypothesize that progressive glycemic derangement alters microscale bone tissue composition. We used Fourier-transform infrared (FTIR) imaging to analyze the composition of iliac crest biopsies from cohorts of postmenopausal women characterized by oral glucose tolerance testing: normal glucose tolerance (NGT; n = 35, age = 65 ± 7 years, HbA1c = 5.8 ± 0.3%), impaired glucose tolerance (IGT; n = 26, age = 64 ± 5 years, HbA1c = 6.0 ± 0.4%), and overt T2DM on insulin (n = 25, age = 64 ± 6 years, HbA1c = 9.13 ± 0.6). The distributions of cortical bone mineral content had greater mean values (+7%) and were narrower (−10%) in T2DM versus NGT groups (p < 0.05). The distributions of acid phosphate, an indicator of new mineral, were narrower in cortical T2DM versus NGT and IGT groups (−14% and −14%, respectively) and in trabecular NGT and IGT versus T2DM groups (−11% and −10%, respectively) (all p < 0.05). The distributions of crystallinity were wider in cortical NGT versus T2DM groups (+16%) and in trabecular NGT versus T2DM groups (+14%) (all p < 0.05). Additionally, bone turnover was lower in T2DM versus NGT groups (P1NP: −25%, CTx: −30%, ucOC: −24%). Serum pentosidine was similar across groups. The FTIR compositional and biochemical marker values of the IGT group typically fell between the NGT and T2DM group values, although the differences were not always statistically significant. In summary, worsening glycemic control was associated with greater mineral content and narrower distributions of acid phosphate, an indicator of new mineral, which together are consistent with observations of lower turnover; however, wider distributions of mineral crystallinity were also observed. A more mineralized, less heterogeneous tissue may affect tissue-level mechanical properties and in turn degrade macroscale skeletal integrity. In conclusion, these data are the first evidence of progressive alteration of bone tissue composition with worsening glycemic control in humans. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Evidence-Based Practice Implementation Within a Theory of Planned Behavior Framework

Although significant progress has been made in the identification of youth evidence-based practices, the adoption of these interventions into community-based mental health care remains limited. Dissemination and implementation (DI) research has the potential to bridge this science-practice gap in clinical psychology. The theory of planned behavior (TPB) offers a useful conceptualization of individual behavior change including behavioral intention as defined by attitudes, subjective norms, and perceived behavioral control. To facilitate application of this model to DI efforts, the current study explores perspectives about using evidence-based practice from stakeholders in the field of youth mental health (including clinical supervisors, case managers, administrators at the departments of health and education, and direct service providers in clinic-based, school-based, and intensive in-home settings) within the TPB framework. A set of instrument items was created from this rich qualitative data using a rigorous mixed-method content validation approach. Instrument items are provided for future use in DI research.     

Cannabis Use Disorder and Post-Deployment Suicide Attempts in Iraq/Afghanistan-Era Veterans

The objective of the present study was to use retrospective data to test the hypothesis that cannabis dependence would be associated with an increased rate of post-deployment suicide attempts. Participants included 319 veterans who had deployed to either Iraq or Afghanistan. Study procedures involved completion of a structured clinical interview and a battery of self-report questionnaires. As expected, lifetime cannabis dependence was significantly associated with post-deployment suicide attempts, AOR = 7.963, p = .014, even after controlling for the effects of pre-deployment suicide attempts, posttraumatic stress disorder, depression, pain, non-cannabis substance use disorder, and gender. Although preliminary, our findings provide the first evidence to date that heavy cannabis use may be a unique risk factor for post-deployment suicide attempts among veterans.     

Adipose Tissue Macrophages Function As Antigen-Presenting Cells and Regulate Adipose Tissue CD4+ T Cells in Mice

The proinflammatory activation of leukocytes in adipose tissue contributes to metabolic disease. How crosstalk between immune cells initiates and sustains adipose tissue inflammation remains an unresolved question. We have examined the hypothesis that adipose tissue macrophages (ATMs) interact with and regulate the function of T cells. Dietary obesity was shown to activate the proliferation of effector memory CD4⁺ T cells in adipose tissue. Our studies further demonstrate that ATMs are functional antigen-presenting cells that promote the proliferation of interferon-γ–producing CD4⁺ T cells in adipose tissue. ATMs from lean and obese visceral fat process and present major histocompatibility complex (MHC) class II–restricted antigens. ATMs were sufficient to promote proliferation and interferon-γ production from antigen-specific CD4⁺ T cells in vitro and in vivo. Diet-induced obesity increased the expression of MHC II and T-cell costimulatory molecules on ATMs in visceral fat, which correlated with an induction of T-cell proliferation in that depot. Collectively, these data indicate that ATMs provide a functional link between the innate and adaptive immune systems within visceral fat in mice.Obesity-induced inflammation contributes to the development of type 2 diabetes, metabolic syndrome, and cardiovascular disease (1–3). Accumulation of activated leukocytes in metabolic tissues is a driving force for obesity-associated metabolic inflammation (metainflammation) and insulin resistance (3,4). In adipose tissue, a vast array of leukocytes have been identified and reported to contribute to obesity-induced metainflammation. How adipose tissue leukocytes interact to shape the inflammatory environment within fat is an important unresolved gap in our current understanding of metabolic disease.In humans and rodent models, F4/80⁺ adipose tissue macrophages (ATMs) are the predominant leukocyte found in metabolically healthy and insulin-resistant fat (5). Resident (type 2) ATMs are distributed between adipocytes in healthy adipose tissue throughout development, express anti-inflammatory markers typical of “alternatively activated” or M2 polarized macrophages, and promote tissue homeostasis (6,7). Disruption of macrophage M2 polarization increases the susceptibility to insulin resistance induced by a high-fat diet (HFD) (8–10). Obesity triggers the accumulation of F4/80⁺ ATMs that coexpress the dendritic cell (DC) marker CD11c as well as genes typically expressed by “classically activated” or proinflammatory M1 polarized macrophages (11–13). M1 ATMs form multicellular lipid-laden clusters, known as crown-like structures (CLS), around dead adipocytes in obese fat (6,14,15) and produce inflammatory cytokines (e.g., interleukin [IL]-1β, IL-6, and tumor necrosis factor-α [TNF-α]) that can impair insulin action in adipocytes (16,17). Current models suggest that obesity promotes metainflammation in part by altering the balance between type 2 and type 1 ATMs in visceral fat (13,18).In addition to ATMs, adipose tissue contains lymphocytes (e.g., natural killer T cells [NKTs], conventional CD4⁺ T cells [Tconvs], regulatory CD4⁺ T cells [Tregs], cytotoxic CD8⁺ T cells, and B cells) that are also regulated by metabolic status (19–24). Treg content in visceral fat is inversely correlated with measures of insulin resistance and inflammation (19,25,26), suggesting that Tregs are anti-inflammatory. In contrast, T helper 1 (Th1) CD4⁺ T cells and CD8⁺ adipose tissue T cells (ATTs) accumulate in fat during obesity, promoting IFN-γ and TNF-α production and insulin resistance (20,21,27). Thus, analogous to ATMs, the imbalance between anti-inflammatory Tregs and proinflammatory CD4⁺/CD8⁺ ATTs contributes to metainflammation.The mechanisms that regulate ATTs in adipose tissue are largely unknown. Spectratyping experiments suggest that CD4⁺ ATTs (but not CD8⁺ ATTs) undergo monoclonal expansion within fat and have an effector-memory (CD44^High CD62L^Low) phenotype (19,21,28). This implies that ATT activation and expansion may be an adaptive immune response to an obesity-induced antigen. T-cell activation depends on an intricate relationship between T cells and antigen-presenting cells (APCs) (29). Classically, APCs (specifically, macrophages and DCs) shape CD4⁺ T-cell activation by three signals: 1) presentation of peptide antigens on major histocompatibility complex (MHC) class II (MHC II) molecules (signal 1), 2) expression of T-cell costimulatory molecules (e.g., CD40, CD80, and CD86) (signal 2), and 3) production of cytokines (e.g., transforming growth factor-β, IL-10, or IL-12) (signal 3). These three signals shape the differentiation of naïve CD4⁺ T cells into effector T-cell subsets (e.g., Th1, Th2, Th17, Treg).The APCs that interact with ATTs in fat have not been well characterized but could include ATMs, adipose tissue DCs, adipose tissue B cells, mast cells, and neutrophils (24,30–34). Quantitative changes in ATTs can precede the accumulation of type 1 CD11c⁺ ATMs in visceral fat in obese mice, suggesting that APCs present in lean and obese fat could trigger an adaptive immune response. Because ATMs are the predominant leukocyte population in lean and obese fat and ATMs from obese mice and humans express MHC II molecules (35–37), we tested the hypothesis that ATMs (CD11b⁺ F4/80⁺) are capable of functioning as APCs to regulate CD4⁺ ATT activation and proliferation. We report that ATMs within visceral fat from mice phagocytose and process antigens for presentation, express costimulatory molecules, and induce antigen-specific CD4⁺ T-cell proliferation in vitro and in situ. Furthermore, we found proliferating ATTs localized with ATMs in fat-associated lymphoid clusters (FALCs) where antigen-specific T-cell activation and proliferation may be initiated. Our data indicate that ATMs meet the functional definition of APCs and suggest that MHC II-restricted antigens presented by ATMs in visceral fat regulate Tregs and Tconvs CD4⁺ ATTs in mice.