Efficacy of Digital and Non-Digital Compensatory Strategies in Supporting Prospective Memory Task Completion among Community-Dwelling Mid-Life and Older Adults.

OBJECTIVE: Compensatory strategies can be used to help mid-life and older adults successfully manage instrumental activities of daily living that rely upon prospective memory. This study compared the quality of digital and non-digital compensatory strategies in supporting accurate completion of naturalistic, real-world prospective memory tasks. METHOD: Participants included 70 community-dwelling mid-life and older adults. In this cross-sectional study, participants were tested remotely via Zoom in their homes. They were tasked with completing four real-world prospective memory tasks and encouraged to use their typical compensatory strategies. Utilized strategies were categorized, counted, and assigned quality scores (rating of thoroughness and utility), and prospective memory performance was coded. RESULTS: Participants who used any digital strategies utilized significantly more (ηp2 = .17) and better quality (ηp2 = .12) strategies than participants who did not use any digital strategies. However, the groups demonstrated equivalent prospective memory performance (ηp2 = .006). Within the digital group, participants' digital and non-digital strategies were of similar quality (d = .14) and resulted in similar prospective memory task accuracy (d = .01). CONCLUSIONS: Digital and non-digital strategies led to similar performance on naturalistic prospective memory tasks. Findings suggest that many different types of strategies can provide adequate prospective memory support to healthy mid-life and older adults. To inform development of compensatory strategy interventions, future studies should explore other factors that lead to successful prospective memory, such as the specific strategy type and task type match, across the continuum of cognitive impairment.

Real-world compensatory strategy use in community-dwelling mid-life and older adults: An evaluation of quality.

Objective: Older adults often spontaneously engage in compensatory strategies (CS) to support everyday task completion, but factors that influence success of chosen CS remain unclear. This study examines whether real-world prospective memory (PM) task completion is better predicted by CS count or a CS quality rating. Method: Seventy mid-life and older adult participants were presented four novel, real-world PM tasks via remote assessment and encouraged to use their typical CS. The examiner captured detailed information about planned CS at task presentation (T1) and utilized CS at follow-up testing (T2). From this information, count (CS Count; quantity of CS) and quality (CS Quality; rating of CS thoroughness and utility) scores were coded separately for the planned and utilized CS. PM task performance accuracy was also coded (PM Accuracy). Results: Hierarchical regressions revealed planned CS Count and Quality did not predict PM Accuracy. In contrast, the utilized CS Quality predicted a significant amount of PM Accuracy variance over and above CS Count, global cognition, and age (R2 = .47, ΔR2 = .24, ΔF = 29.36, p < .001, f2 = .45). Furthermore, utilized CS Quality accounted for a similar amount of variance in PM Accuracy when utilized CS Count was removed from the model. Conclusions: This study's CS coding system can capture and quantify the quality of strategies, which uniquely predicts real-world PM performance. This coding system may provide researchers with a nuanced CS measure and lead to improved CS interventions designed to support everyday PM performance, such as targeted CS trainings.

Assessing Knowledge, Usage, and Perceptions of the Frazier Free Water Protocol: A Pilot Study.

INTRODUCTION: Dysphagia is very common among hospitalized patients and is associated with increased length of hospital stay, morbidity, and mortality. Diet restrictions for dysphagia cause dehydration and discontent. The Frazier Free Water Protocol (FFWP) was developed to improve hydration and quality of life in dysphagia patients by establishing the safety of allowing sips of water between meals. Despite these potential benefits, we hypothesized that the FFWP is not widely utilized. We sought to determine barriers to utilization by assessing the familiarity, usage, and perceptions of the FFWP among health-care providers at our institution. METHODS: We distributed an anonymous questionnaire to a convenience sample of nurses in the hospital during daily huddles. The questionnaire was adapted from a validated framework to assess provider acceptability of health-care interventions. RESULTS: Of the 66 surveys distributed, we had 58 completed (88%). Only 10 nurses (17%) had heard of the "FFWP" by name. For those that were familiar with the indications, benefits, and risks of giving free water to patients with dysphagia (n = 18), less than half (39%) reported doing so. No nurses that had less than 10 y of patient care experience gave water to dysphagia patients, even if they knew the indications, benefits, and risks. Similarly, less than a fifth (19%) of all nurses surveyed were comfortable giving water to dysphagia patients, but comfort increased for some if the protocol was recommended by a speech-language pathologist (33%) or physician (13%). Nursing experience of >10 y or in intensive care settings did not yield significant differences in knowledge, usage, or comfort level than those with less years or nonintensive care experience, respectively. CONCLUSIONS: Nurses are essential to the implementation of the FFWP, yet many are unfamiliar and uncomfortable with utilizing it. Education about the protocol is necessary to improve patient outcomes and quality of life. We plan to provide targeted education about the FFWP as well as assess other members of the health-care team, in an attempt to increase utilization of the protocol and improve dysphagia management.

A combined adjuvant approach primes robust germinal center responses and humoral immunity in non-human primates.

Adjuvants and antigen delivery kinetics can profoundly influence B cell responses and should be critically considered in rational vaccine design, particularly for difficult neutralizing antibody targets such as human immunodeficiency virus (HIV). Antigen kinetics can change depending on the delivery method. To promote extended immunogen bioavailability and to present antigen in a multivalent form, native-HIV Env trimers are modified with short phosphoserine peptide linkers that promote tight binding to aluminum hydroxide (pSer:alum). Here we explore the use of a combined adjuvant approach that incorporates pSer:alum-mediated antigen delivery with potent adjuvants (SMNP, 3M-052) in an extensive head-to-head comparison study with conventional alum to assess germinal center (GC) and humoral immune responses. Priming with pSer:alum plus SMNP induces additive effects that enhance the magnitude and persistence of GCs, which correlate with better GC-TFH cell help. Autologous HIV-neutralizing antibody titers are improved in SMNP-immunized animals after two immunizations. Over 9 months after priming immunization of pSer:alum with either SMNP or 3M-052, robust Env-specific bone marrow plasma cells (BM BPC) are observed. Furthermore, pSer-modification of Env trimer reduce targeting towards immunodominant non-neutralizing epitopes. The study shows that a combined adjuvant approach can augment humoral immunity by modulating immunodominance and shows promise for clinical translation.

Analysis of Obstetric Outcomes by Hospital Location, Volume, and Teaching Status Associated With Non-Medically Indicated Induction of Labor at 39 Weeks.

Importance: Non-medically indicated induction of labor has been demonstrated to potentially improve some obstetric outcomes, such as decreasing cesarean birth. It has been reported that rates of cesarean birth and other obstetric outcomes vary among hospitals with different characteristics. Objective: To assess whether obstetric outcomes differ between nulliparous individuals with low-risk pregnancies managed with non-medically indicated induction of labor compared with expectant management in different types of hospitals. Design, Setting, and Participants: This retrospective cohort study included non-medically indicated induction of labor at 39 weeks' gestation compared with expectant management of singleton, nonanomalous, births in nulliparous women with low-risk pregnancies in California between January 1, 2007, and December 31, 2011. The initial analysis of these data was performed in 2021. Outcomes were assessed by 3 hospital characteristics: location (urban vs rural), obstetric volume, and teaching (academic vs community) status. Volume was categorized based on the average number of births per year and grouped into low (<1200 births per year), medium (1200-2399 births per year), and high (≥2400 births per year). Births with previous or planned cesarean delivery were excluded, and non-medically indicated induction of labor was defined as induction of labor without a specific medical indication. Testing with χ2 and multivariable logistic regression analyses was used for statistical comparisons with a cutoff level of P = .01. Exposure: Non-medically indicated induction of labor at 39 weeks' gestation. Main Outcomes and Measures: The primary outcome was cesarean birth, and numerous secondary perinatal outcomes were also assessed. Results: There were 455 044 births included in this study. When stratified by hospital variables, a number of sociodemographic characteristics were significantly different, such as race and ethnicity, age, body mass index, and insurance type. The adjusted odds ratios (aORs) of cesarean birth were significantly lower in all settings with induction of labor except for low-volume hospitals, in which there was no significant difference (aOR, 0.95; 95% CI, 0.82-1.09). Chorioamnionitis and postpartum hemorrhage were lower with induction of labor among nearly every hospital when stratified by hospital characteristics. Neonatal outcomes were improved in all settings with induction of labor compared with expectant management. Conclusions and Relevance: These findings suggest that non-medically indicated induction of labor may be associated with a lower rate of cesarean births and some maternal and neonatal adverse outcomes in a range of hospital settings.

Next-generation plasmids for transgenesis in zebrafish and beyond.

Transgenesis is an essential technique for any genetic model. Tol2-based transgenesis paired with Gateway-compatible vector collections has transformed zebrafish transgenesis with an accessible modular system. Here, we establish several next-generation transgenesis tools for zebrafish and other species to expand and enhance transgenic applications. To facilitate gene regulatory element testing, we generated Gateway middle entry vectors harboring the small mouse beta-globin minimal promoter coupled to several fluorophores, CreERT2 and Gal4. To extend the color spectrum for transgenic applications, we established middle entry vectors encoding the bright, blue-fluorescent protein mCerulean and mApple as an alternative red fluorophore. We present a series of p2A peptide-based 3' vectors with different fluorophores and subcellular localizations to co-label cells expressing proteins of interest. Finally, we established Tol2 destination vectors carrying the zebrafish exorh promoter driving different fluorophores as a pineal gland-specific transgenesis marker that is active before hatching and through adulthood. exorh-based reporters and transgenesis markers also drive specific pineal gland expression in the eye-less cavefish (Astyanax). Together, our vectors provide versatile reagents for transgenesis applications in zebrafish, cavefish and other models.

Quantification of 3,4-Dimethyl-1H-Pyrazole Using Ion-Pair LC-MS/MS on a Reversed-Phase Column.

BACKGROUND: Few methods exist for the analysis of the soil nitrification inhibitor 3,4-dimethyl-1H-pyrazole (3,4-DMP), which is a pesticide with the ability to reduce the production of nitrogenous greenhouse gases in soils as a result of fertilizer application. Due to its small size and polar nature, 3,4-DMP can be difficult to retain on an LC column, which makes diversion of a co-extracted soil matrix away from the MS/MS impossible. OBJECTIVE: The current study aims to better control the retention time (RT) of 3,4-DMP. Additionally, 3,4-DMP-15N2 was synthesized and used as an internal standard for the soil extraction of 3,4-DMP. METHODS: Perfluoroalkanoic acids were used as ion-pair reagents and were compared for their abilities to improve peak shape and RT, to better separate 3,4-DMP from the soil matrix without the need for cleanup during soil extraction. RESULTS: RTs increased with both the carbon number and the concentration of the perfluoroalkanoic acid, and this improved peak shape and height. Perfluorooctanoic acid performed best, and improved peak height (PH) and shape were obtained by increasing the flow rate, resulting in a better S/N than from formic acid. The method provided a 10-fold improvement limit of quantitation on the most sensitive existing method and the use of 3,4-DMP-15N2 as an internal standard resulted in recoveries of 101-107%. CONCLUSION: Ion-pair reagents drastically increased the retention of 3,4-DMP and allowed the re-use of old LC columns that may otherwise be discarded. Improved separation of 3,4-DMP from the soil matrix allowed much of the matrix to be diverted from the MS/MS spray chamber. HIGHLIGHTS: Greater control of 3,4-DMP retention by the LC column resulting in the ability to separate 3,4-DMP from the soil matrix. The inclusion of ion-pair reagents only in the aqueous phase reduced ionization suppression of the analytes in the MS source.

Long-primed germinal centres with enduring affinity maturation and clonal migration.

Germinal centres are the engines of antibody evolution. Here, using human immunodeficiency virus (HIV) Env protein immunogen priming in rhesus monkeys followed by a long period without further immunization, we demonstrate germinal centre B (BGC) cells that last for at least 6 months. A 186-fold increase in BGC cells was present by week 10 compared with conventional immunization. Single-cell transcriptional profiling showed that both light- and dark-zone germinal centre states were sustained. Antibody somatic hypermutation of BGC cells continued to accumulate throughout the 29-week priming period, with evidence of selective pressure. Env-binding BGC cells were still 49-fold above baseline at 29 weeks, which suggests that they could remain active for even longer periods of time. High titres of HIV-neutralizing antibodies were generated after a single booster immunization. Fully glycosylated HIV trimer protein is a complex antigen, posing considerable immunodominance challenges for B cells1,2. Memory B cells generated under these long priming conditions had higher levels of antibody somatic hypermutation, and both memory B cells and antibodies were more likely to recognize non-immunodominant epitopes. Numerous BGC cell lineage phylogenies spanning more than the 6-month germinal centre period were identified, demonstrating continuous germinal centre activity and selection for at least 191 days with no further antigen exposure. A long-prime, slow-delivery (12 days) immunization approach holds promise for difficult vaccine targets and suggests that patience can have great value for tuning of germinal centres to maximize antibody responses.

Maternal and infant hospitalization costs associated with hypertensive disorders of pregnancy in a California cohort.

BACKGROUND: The United States has higher health care costs than other developed nations. Hypertensive disorders of pregnancy are increasingly common, and longer hospital admissions and utilization of additional therapies are costly. OBJECTIVE: We sought to estimate maternal and neonatal hospital costs in a large cohort of pregnant women with and without hypertensive disorders of pregnancy. STUDY DESIGN: This was a retrospective cohort study of women in California with singleton, non-anomalous births with gestational ages between 23-42 weeks. Women were categorized into seven mutually exclusive groups: no hypertension, chronic hypertension (HTN), chronic HTN with superimposed preeclampsia, gestational HTN, mild preeclampsia, severe preeclampsia, and eclampsia. Hospitalization costs were estimated for women and neonates separately and included the cost for admission for delivery only. We used Chi squared and Kruskal-Wallis equality-of-populations rank tests for statistical analysis with a significance level of 0.05. RESULTS: In a California cohort of 1,918,482 women, 16,208 (0.8%) had chronic HTN, 5,912 (0.3%) had chronic HTN with superimposed preeclampsia, 39,558 (2.1%) had gestational HTN, 33,462 (1.7%) had mild preeclampsia, 17,184 (0.9%) had severe preeclampsia and 1252 (0.1%) had eclampsia. Median hospitalization costs and length-of-stays were statistically significantly different for women in each group (p<.001). Women with eclampsia had the highest median hospitalization costs ($25,437, IQR: $16,893-$37,261) and women without any hypertensive disorder of pregnancy had the lowest ($11,720, IQR: $8019-$17,530). Costs were significantly different between groups based on gestational age and mode of delivery, and with severe maternal morbidity and neonatal intensive care unit admission status (p<.001). CONCLUSIONS: We found that hospitalization costs of hypertensive disorders of pregnancy were significantly higher than women without hypertension in pregnancy. These results highlight the economic burden of hypertensive disorders of pregnancy.

Maternal and infant hospitalization costs associated with maternal pre-pregnancy body mass index in California, 2007-2011.

BACKGROUND: In the United States, the number of pregnant women who are overweight or obese is increasing. While such individuals are at increased risk of pregnancy complications, data regarding costs associated with pre-pregnancy body mass index (BMI) and maternal and infant outcomes are lacking. OBJECTIVE: To estimate maternal and infant costs associated with pre-pregnancy BMI in a large cohort of pregnant women. MATERIALS AND METHODS: We conducted a retrospective cohort study of women with singleton, non-anomalous births in California from 2007 to 2011. Women with preexisting diabetes mellitus and chronic hypertension were excluded. Hospitalization costs were estimated separately for women and infants using hospital charges adjusted using a cost-to-charge ratio. These costs included hospitalization costs for admission for delivery only. We estimated the differences in median costs between seven categories of pre-pregnancy BMIs, including underweight (BMI <18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9), class I obesity (BMI 30.0-34.9), class II obesity (BMI 35.0-39.9), class III obesity (BMI 40.0-49.9) and obesity with BMI ≥50.0. We also performed stratified analyses by mode of delivery and gestational age at delivery. We examined the length of stay for women and infants and estimated the gestational age at delivery. Analyses were conducted utilizing Kruskal-Wallis equality-of-populations rank tests with a significance cutoff of 0.05. RESULTS: In a California cohort of 1,722,840 women, 787,790 (45.7%) had a pre-pregnancy BMI that was considered overweight or obese. The median maternal and infant costs of each pre-pregnancy BMI strata were significantly different when compared to other strata, with underweight and normal weight women having the lowest median costs ($11,581 and $11,721, respectively) and the most obese category (BMI ≥50) having the highest costs ($15,808). When stratified by mode of delivery and gestational age at delivery, this remained true. Hospitalization costs for women and infants with severe maternal morbidity were also significantly different based on maternal BMI. COMMENT: The hospitalization costs associated with each strata of BMI were significantly different when compared to each other and when stratified by mode of delivery and prematurity. This analysis allows for a greater understanding of the health care costs associated with different maternal pre-pregnancy BMI classes.

Impact of SIV infection on mycobacterial lipid-reactive T cell responses in Bacillus Calmette-Guérin (BCG) inoculated macaques.

Background: Although BCG vaccine protects infants from tuberculosis (TB), it has limited efficacy in adults against pulmonary TB. Further, HIV coinfection significantly increases the risk of developing active TB. In the lack of defined correlates of protection in TB disease, it is essential to explore immune responses beyond conventional CD4 T cells to gain a better understanding of the mechanisms of TB immunity. Methods: Here, we evaluated unconventional lipid-reactive T cell responses in cynomolgus macaques following aerosol BCG inoculation and examined the impact of subsequent SIV infection on these responses. Immune responses to cellular lipids of M. bovis and M. tuberculosis were examined ex vivo in peripheral blood and bronchioalveolar lavage (BAL). Results: Prior to BCG inoculation, innate-like IFN-γ responses to mycobacterial lipids were observed in T cells. Aerosol BCG exposure induced an early increase in frequencies of BAL γδT cells, a dominant subset of lipid-reactive T cells, along with enhanced IL-7R and CXCR3 expression. Further, BCG exposure stimulated greater IFN-γ responses to mycobacterial lipids in peripheral blood and BAL, suggesting the induction of systemic and local Th1-type response in lipid-reactive T cells. Subsequent SIV infection resulted in a significant loss of IL-7R expression on blood and BAL γδT cells. Additionally, IFN-γ responses of mycobacterial lipid-reactive T cells in BAL fluid were significantly lower in SIV-infected macaques, while perforin production was maintained through chronic SIV infection. Conclusions: Overall, these data suggest that despite SIV-induced decline in IL-7R expression and IFN-γ production by mycobacterial lipid-reactive T cells, their cytolytic potential is maintained. A deeper understanding of anti-mycobacterial lipid-reactive T cell functions may inform novel approaches to enhance TB control in individuals with or without HIV infection.

Patient Preference and Adherence to Aminosalicylates for the Treatment of Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic inflammatory disorder that requires sustained treatment for optimal outcomes. The 5-aminosalicylate (5-ASA) class of medications are first-line for the treatment of mild-to-moderate UC but suffer from suboptimal adherence rates in real-world settings. This review summarizes the literature on adherence and patient preference to 5-ASA in patients with UC. We begin by highlighting key studies that measure real-world adherence rates, as well as some of the pitfalls associated with certain techniques. We examine the data on the consequences of non-adherence, which range from decreased quality of life and higher risk of colorectal cancer at the individual level to increased costs to the overall healthcare system. We then turn to the reasons and risk factors for non-adherence and summarize the current understanding of the barriers towards adherence. Afterwards, we describe the research on patient preferences between 5-ASA formulations and dosing regimen. Finally, we summarize the evidence regarding interventions to improve 5-ASA adherence. While adherence remains a challenge in practice, understanding the current state of the field can better inform future efforts towards increasing adherence, and thus clinical outcomes, in UC.

Blocking α4ß7 integrin delays viral rebound in SHIVSF162P3-infected macaques treated with anti-HIV broadly neutralizing antibodies.

Anti-HIV broadly neutralizing antibodies (bNAbs) may favor development of antiviral immunity by engaging the immune system during immunotherapy. Targeting integrin α4ß7 with an anti-α4ß7 monoclonal antibody (Rh-α4ß7) affects immune responses in SIV/SHIV-infected macaques. To explore the therapeutic potential of combining bNAbs with α4ß7 integrin blockade, SHIVSF162P3-infected, viremic rhesus macaques were treated with bNAbs only (VRC07-523LS and PGT128 anti-HIV antibodies) or a combination of bNAbs and Rh-α4ß7 or were left untreated as a control. Treatment with bNAbs alone decreased viremia below 200 copies/ml in all macaques, but seven of eight macaques (87.5%) in the bNAbs-only group rebounded within a median of 3 weeks (95% CI: 2 to 9). In contrast, three of six macaques treated with a combination of Rh-α4ß7 and bNAbs (50%) maintained a viremia below 200 copies/ml until the end of the follow-up period; viremia in the other three macaques rebounded within a median of 6 weeks (95% CI: 5 to 11). Thus, there was a modest delay in viral rebound in the macaques treated with the combination antibody therapy compared to bNAbs alone. Our study suggests that α4ß7 integrin blockade may prolong virologic control by bNAbs in SHIVSF162P3-infected macaques.

Gut Microbiome Changes Associated with Epithelial Barrier Damage and Systemic Inflammation during Antiretroviral Therapy of Chronic SIV Infection.

Gut dysbiosis is a common feature associated with the chronic inflammation of HIV infection. Toward understanding the interplay of chronic treated HIV infection, dysbiosis, and systemic inflammation, we investigated longitudinal fecal microbiome changes and plasma inflammatory markers in the nonhuman primate model. Following simian immunodeficiency virus (SIV) infection in rhesus macaques, significant changes were observed in several members of the phylum Firmicutes along with an increase in Bacteroidetes. Viral suppression with antiretroviral therapy (ART) resulted in an early but partial recovery of compositional changes and butyrate producing genes in the gut microbiome. Over the course of chronic SIV infection and long-term ART, however, the specific loss of Faecalibacterium prausnitzii and Treponema succinifaciens significantly correlated with an increase in plasma inflammatory cytokines including IL-6, G-CSF, I-TAC, and MIG. Further, the loss of T. succinifaciens correlated with an increase in circulating biomarkers of gut epithelial barrier damage (IFABP) and microbial translocation (LBP and sCD14). As F. prausnitzii and T. succinifaciens are major short-chain fatty acid producing bacteria, their sustained loss during chronic SV-ART may contribute to gut inflammation and metabolic alterations despite effective long-term control of viremia. A better understanding of the correlations between the anti-inflammatory bacterial community and healthy gut barrier functions in the setting of long-term ART may have a major impact on the clinical management of inflammatory comorbidities in HIV-infected individuals.

Viability of acellular biologic graft for nipple-areolar complex reconstruction in a non-human primate model.

Many of the > 3.5 million breast cancer survivors in the US have undergone breast reconstruction following mastectomy. Patients report that nipple-areolar complex (NAC) reconstruction is psychologically important, yet current reconstruction techniques commonly result in inadequate shape, symmetry, and nipple projection. Our team has developed an allogeneic acellular graft for NAC reconstruction (dcl-NAC) designed to be easy to engraft, lasting, and aesthetically pleasing. Here, dcl-NAC safety and host-mediated re-cellularization was assessed in a 6-week study in rhesus macaque non-human primates (NHPs). Human-derived dcl-NACs (n = 30) were engrafted on the dorsum of two adult male NHPs with each animal's own nipples as controls (n = 4). Weight, complete blood counts, and metabolites were collected weekly. Grafts were removed at weeks 1, 3, or 6 post-engraftment for histology. The primary analysis evaluated health, re-epithelialization, and re-vascularization. Secondary analysis evaluated re-innervation. Weight, complete blood counts, and metabolites remained mostly within normal ranges. A new epidermal layer was observed to completely cover the dcl-NAC surface at week 6 (13-100% coverage, median 93.3%) with new vasculature comparable to controls at week 3 (p = 0.10). Nerves were identified in 75% of dcl-NACs (n = 9/12) at week 6. These data suggest that dcl-NAC is safe and supports host-mediated re-cellularization.

Effects of a School-Based Mindfulness Program for Young Children.

Schools are an attractive setting for implementation of mindfulness-based programs because mindfulness practices, by their very nature, align with a wide range of core educational goals. The present study investigated the effects of an 8-week (16 session) school-based mindfulness program for young children across 8 classrooms (K through 2) using a quasi-experimental delayed-intervention control group design. Results indicated that the mindfulness program was associated with significant improvements in teacher ratings of externalizing and prosocial behaviors. Program outcomes were not associated with child sex or race/ethnicity, but did vary by grade. Descriptive analyses suggest that outcomes tended to be more positive in classrooms with higher levels of teacher and student engagement. Results of the present study add to the growing knowledge base on the positive effects of school-based mindfulness programs and point to a need for more rigorous inquiry into the extent to which students and teachers are engaged with mindfulness programs both during the program itself and in their day to day functioning.

Dysregulation of IL-17/IL-22 Effector Functions in Blood and Gut Mucosal Gamma Delta T Cells Correlates With Increase in Circulating Leaky Gut and Inflammatory Markers During cART-Treated Chronic SIV Infection in Macaques.

HIV-associated inflammation has been implicated in the premature aging and increased risk of age-associated comorbidities in cART-treated individuals. However, the immune mechanisms underlying the chronic inflammatory state of cART-suppressed HIV infection remain unclear. Here, we investigated the role of γδT cells, a group of innate IL-17 producing T lymphocytes, in the development of systemic inflammation and leaky gut phenotype during cART-suppressed SIV infection of macaques. Plasma levels of inflammatory mediators, intestinal epithelial barrier disruption (IEBD) and microbial translocation (MT) biomarkers, and Th1/Th17-type cytokine functions were longitudinally assessed in blood and gut mucosa of SIV-infected, cART-suppressed macaques. Among the various gut mucosal IL-17/IL-22-producing T lymphocyte subsets including Th17, γδT, CD161+ CD8+ T, and MAIT cells, a specific decline in the Vδ2 subset of γδT cells and impaired IL-17/IL-22 production in γδT cells significantly correlated with the subsequent increase in plasma IEBD/MT markers (IFABP, LPS-binding protein, and sCD14) and pro-inflammatory cytokines (IL-6, IL-1ß, IP10, etc.) despite continued viral suppression during long-term cART. Further, the plasma inflammatory cytokine signature during long-term cART was distinct from acute SIV infection and resembled the inflammatory cytokine profile of uninfected aging (inflammaging) macaques. Overall, our data suggest that during cART-suppressed chronic SIV infection, dysregulation of IL-17/IL-22 cytokine effector functions and decline of Vδ2 γδT cell subsets may contribute to gut epithelial barrier disruption and development of a distinct plasma inflammatory signature characteristic of inflammaging. Our results advance the current understanding of the impact of chronic HIV/SIV infection on γδT cell functions and demonstrate that in the setting of long-term cART, the loss of epithelial barrier-protective functions of Vδ2 T cells and ensuing IEBD/MT occurs before the hallmark expansion of Vδ1 subsets and skewed Vδ2/Vδ1 ratio. Thus, our work suggests that novel therapeutic approaches toward restoring IL-17/IL-22 cytokine functions of intestinal Vδ2 T cells may be beneficial in preserving gut epithelial barrier function and reducing chronic inflammation in HIV-infected individuals.

A Randomized Trial of a Multifactorial Strategy to Prevent Serious Fall Injuries.

BACKGROUND: Injuries from falls are major contributors to complications and death in older adults. Despite evidence from efficacy trials that many falls can be prevented, rates of falls resulting in injury have not declined. METHODS: We conducted a pragmatic, cluster-randomized trial to evaluate the effectiveness of a multifactorial intervention that included risk assessment and individualized plans, administered by specially trained nurses, to prevent fall injuries. A total of 86 primary care practices across 10 health care systems were randomly assigned to the intervention or to enhanced usual care (the control) (43 practices each). The participants were community-dwelling adults, 70 years of age or older, who were at increased risk for fall injuries. The primary outcome, assessed in a time-to-event analysis, was the first serious fall injury, adjudicated with the use of participant report, electronic health records, and claims data. We hypothesized that the event rate would be lower by 20% in the intervention group than in the control group. RESULTS: The demographic and baseline characteristics of the participants were similar in the intervention group (2802 participants) and the control group (2649 participants); the mean age was 80 years, and 62.0% of the participants were women. The rate of a first adjudicated serious fall injury did not differ significantly between the groups, as assessed in a time-to-first-event analysis (events per 100 person-years of follow-up, 4.9 in the intervention group and 5.3 in the control group; hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P = 0.25). The rate of a first participant-reported fall injury was 25.6 events per 100 person-years of follow-up in the intervention group and 28.6 events per 100 person-years of follow-up in the control group (hazard ratio, 0.90; 95% CI, 0.83 to 0.99; P = 0.004). The rates of hospitalization or death were similar in the two groups. CONCLUSIONS: A multifactorial intervention, administered by nurses, did not result in a significantly lower rate of a first adjudicated serious fall injury than enhanced usual care. (Funded by the Patient-Centered Outcomes Research Institute and others; STRIDE ClinicalTrials.gov number, NCT02475850.).

Once-Weekly Oral Dosing of MK-8591 Protects Male Rhesus Macaques From Intrarectal Challenge With SHIV109CP3.

BACKGROUND: MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine [EFdA]) is a novel reverse transcriptase-translocation inhibitor. METHODS: We assessed MK-8591 as preexposure prophylaxis in the rhesus macaque model of intrarectal challenge with simian/human immunodeficiency virus (SHIV). In study 1, 8 rhesus macaques received 3.9 mg/kg of MK-8591 orally on day 0 and once weekly for the next 14 weeks. Eight controls were treated with vehicle. All rhesus macaques were challenged with SHIV109CP3 on day 6 and weekly for up to 12 challenges or until infection was confirmed. The dose of MK-8591 was reduced to 1.3 and 0.43 mg/kg/week in study 2 and further to 0.1 and 0.025 mg/kg/week in study 3. In studies 2 and 3, each dose was given up to 6 times once weekly, and animals were challenged 4 times once weekly with SHIV109CP3. RESULTS: Control macaques were infected after a median of 1 challenge (range, 1-4 challenges). All treated animals in studies 1 and 2 were protected, consistent with a 41.5-fold lower risk of infection (P < .0001, by the log-rank test). In study 3, at a 0.1-mg/kg dose, 2 rhesus macaques became infected, consistent with a 7.2-fold lower risk of infection (P = .0003, by the log-rank test). The 0.025-mg/kg dose offered no protection. CONCLUSIONS: These data support MK-8591's potential as a preexposure prophylaxis agent.