The Novel Chimeric Multi-Agonist Peptide (GEP44) Reduces Energy Intake and Body Weight in Male and Female Diet-Induced Obese Mice in a Glucagon-Like Peptide-1 Receptor-Dependent Manner.

We recently reported that a novel chimeric peptide (GEP44) targeting both the glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y1- and Y2 receptor (Y1R and Y2R) reduced energy intake and body weight (BW) in diet-induced obese (DIO) rats. We hypothesized that GEP44 reduces energy intake and BW primarily through a GLP-1R dependent mechanism. To test this hypothesis, GLP-1R +/+ mice and GLP-1R null (GLP-1R -/- ) mice were fed a high fat diet for 4 months to elicit diet-induced obesity prior to undergoing a sequential 3-day vehicle period, 3-day drug treatment (5, 10, 20 or 50 nmol/kg; GEP44 vs the selective GLP-1R agonist, exendin-4) and a 3-day washout. Energy intake, BW, core temperature and activity were measured daily. GEP44 (10, 20 and 50 nmol/kg) reduced BW after 3-day treatment in DIO male GLP-1R +/+ mice by - 1.5±0.6, -1.3±0.4 and -1.9±0.4 grams, respectively ( P <0.05), with similar effects being observed in female GLP-1R +/+ mice. These effects were absent in male and female DIO GLP-1R -/- mice suggesting that GLP-1R signaling contributes to GEP44-elicited reduction of BW. Further, GEP44 decreased energy intake in both male and female DIO GLP-1R +/+ mice, but GEP44 appeared to produce more consistent effects across multiple doses in males. In GLP-1R -/- mice, the effects of GEP44 on energy intake were only observed in males and not females, suggesting that GEP44 may reduce energy intake, in part, through a GLP-1R independent mechanism in males. In addition, GEP44 reduced core temperature and activity in both male and female GLP-1R +/+ mice suggesting that it may also reduce energy expenditure. Lastly, we show that GEP44 reduced fasting blood glucose in DIO male and female mice through GLP-1R. Together, these findings support the hypothesis that the chimeric peptide, GEP44, reduces energy intake, BW, core temperature, and glucose levels in male and female DIO mice primarily through a GLP-1R dependent mechanism.

Choosing wisely: Enteral feeding tube selection, placement, and considerations before and beyond the procedure room.

When an enteral feeding tube (EFT) is placed, it is not always known how long this nutrition support intervention will be needed. As a result, the type of device the patient originally has placed may not match the function it is required to serve or the lifestyle needs of the patient throughout their enteral nutrition journey. Medicare considers an EFT a prosthetic device, as it is replacing a permanently inoperable or nonfunctioning organ. If we think about an EFT the same way we think about a prosthetic limb, one that needs to be customized to meet all of the patient's functional and lifestyle needs, we can also begin to think beyond the procedure room and carefully consider a variety of factors that impact the patient at home receiving enteral nutrition. Proper fit, function, and style is essential in order for the patient to have a positive relationship with their EFT, contributing to their successful home enteral nutrition experience. Clinicians who care for these patients in any setting and in any capacity would benefit from enhancing their understanding of available EFT options, their design components, and available methods of placement. Many home care and outpatient clinicians adopt the role of patient advocate as it relates to a patient's enteral nutrition journey, and this expanded knowledge could be used to benefit the patient by improving their overall enteral nutrition experience and ultimately their relationship with their "prosthetic."

Experimental Measurement of the Diameter of a Human Hair via Two-Color Light Diffraction.

The width of a human hair sourced from a female elementary school student was measured by light diffraction using red and blue laser pointers. The two laser sources both provided consistent estimates of the hair diameter of approximately 50 µm. The overall experiment and writing process provided a temporary respite from COVID-19 shelter-in-place requirements and deteriorating spring weather that precluded outdoor activities.

Subchondral bone structure and synovial fluid metabolism are altered in injured and contralateral limbs 7 days after non-invasive joint injury in skeletally-mature C57BL/6 mice.

OBJECTIVE: Post-traumatic osteoarthritis (PTOA) commonly develops after ACL injury, but early changes to the joint soon after injury are insufficiently understood. The objectives of this study were (1) evaluate the response of subchondral bone tissue modulus to joint injury and (2) identify which bone structural, material, and metabolic outcomes are local (i.e., injured joint only) or systemic (i.e., injured and contralateral-to-injured). DESIGN: Female C57Bl∖6N mice (19 weeks at injury) underwent tibial compression overload to simulate ACL injury (n = 8) or a small pre-load (n = 8). Synovial fluid was harvested at euthanasia 7 days later for metabolomic profiling. Bone outcomes included epiphyseal and SCB microarchitecture, SCB nanoindentation modulus, SCB formation rate, and osteoclast number density. RESULTS: Injury decreased epiphyseal bone volume fraction ([-5.29, -1.38%], P = 0.0016) and decreased SCB thickness for injured vs sham-injured limbs ([2.2, 31.4 µm], P = 0.017)). Epiphyseal bone loss commonly occurred for contralateral-to-injured limbs. There was not sufficient evidence to conclude that SCB modulus changes with injury. Metabolomic analyses revealed dysregulated synovial fluid metabolism with joint injury but that many metabolic pathways are shared between injured and contralateral-to-injured limbs. CONCLUSION: This study demonstrates rapid changes to bone structure and synovial fluid metabolism after injury with the potential for influencing the progression to PTOA. These changes are often evidenced in the contralateral-to-injured limb, indicating that systemic musculoskeletal responses to joint injury should not be overlooked.

Effects of long-term exercise and a high-fat diet on synovial fluid metabolomics and joint structural phenotypes in mice: an integrated network analysis.

OBJECTIVE: To explore how systemic factors that modify knee osteoarthritis risk are connected to 'whole-joint' structural changes by evaluating the effects of high-fat diet and wheel running exercise on synovial fluid (SF) metabolomics. METHODS: Male mice were fed a defined control or high-fat (60% kcal fat) diet from 6 to 52 weeks of age, and half the animals were housed with running wheels from 26 to 52 weeks of age (n = 9-13 per group). Joint tissue structure and osteoarthritis pathology were evaluated by histology and micro-computed tomography. Systemic metabolic and inflammatory changes were evaluated by body composition, glucose tolerance testing, and serum biomarkers. SF metabolites were analyzed by high performance-liquid chromatography mass spectrometry. We built correlation-based network models to evaluate the connectivity between systemic and local metabolic biomarkers and osteoarthritis structural pathology within each experimental group. RESULTS: High-fat diet caused moderate osteoarthritis, including cartilage pathology, synovitis and increased subchondral bone density. In contrast, voluntary exercise had a negligible effect on these joint structure components. 1,412 SF metabolite features were detected, with high-fat sedentary mice being the most distinct. Diet and activity uniquely altered SF metabolites attributed to amino acids, lipids, and steroids. Notably, high-fat diet increased network connections to systemic biomarkers such as interleukin-1ß and glucose intolerance. In contrast, exercise increased local joint-level network connections, especially among subchondral bone features and SF metabolites. CONCLUSION: Network mapping showed that obesity strengthened SF metabolite links to blood glucose and inflammation, whereas exercise strengthened SF metabolite links to subchondral bone structure.

Experiences of viewing self in the mirror for men and women with dementia as perceived by their caregivers: A phenomenological study.

AIM: To explore and discuss the perceptions and experiences of caregivers who rendered care to persons with dementia who viewed themselves in the mirror. BACKGROUND: Considerations must be given to caring for those with dementia due to the steady rise of adults 65 and older living with dementia. A literature review revealed limited experiential knowledge concerning aspects of mirror-viewing for persons with dementia. METHODS: This phenomenological hermeneutic study was analyzed using Ricoeur's theory of interpretation. Eighteen participants who cared for individuals with dementia in the home, and long-term care facilities took part in the study. A semi-structured interview guide with open- ended questions facilitated an open dialogue about their experiences while caring for persons with dementia when they view themselves in the mirror. Two questions guiding the study were: 1) What are caregivers' perceptions of what they see and believe when they observe dementia patients whom they care view themselves in a mirror? 2) How do the caregivers' perceptions of that experience change over time as the dementia worsens? RESULTS: The structural analysis uncovered a considerable difference between the numbers of mirrors available in the homes as compared to the long-term care facilities. Two phenomenological findings were uncovered: 1) decision to look in the mirror and 2) viewing self in the mirror. Six subsequent subthemes; mirror as a tool, wanting to look presentable, self- recognition, self-confirmation seeing another and the latent stage were revealed. CONCLUSION: A mirror assessment is needed for individuals who have dementia.

The microbiome mediates epiphyseal bone loss and metabolomic changes after acute joint trauma in mice.

OBJECTIVE: To compare the early responses to joint injury in conventional and germ-free mice. DESIGN: Post-traumatic osteoarthritis (PTOA) was induced using a non-invasive anterior cruciate ligament rupture model in 20-week old germ-free (GF) and conventional C57BL/6 mice. Injury was induced in the left knees of n = 8 GF and n = 10 conventional mice. To examine the effects of injury, n = 5 GF and n = 9 conventional naïve control mice were used. Mice were euthanized 7 days post-injury, followed by synovial fluid recovery for global metabolomic profiling and analysis of epiphyseal trabecular bone by micro-computed tomography (µCT). Global metabolomic profiling assessed metabolic differences in the joint response to injury between GF and conventional mice. Magnitude of trabecular bone volume loss measured using µCT assessed early OA progression in GF and conventional mice. RESULTS: µCT found that GF mice had significantly less trabecular bone loss compared to conventional mice, indicating that the GF status was protective against early OA changes in bone structure. Global metabolomic profiling showed that conventional mice had greater variability in their metabolic response to injury, and a more distinct joint metabolome compared to their corresponding controls. Furthermore, differences in the response to injury in GF compared to conventional mice were linked to mouse metabolic pathways that regulate inflammation associated with the innate immune system. CONCLUSIONS: These results suggest that the gut microbiota promote the development of PTOA during the acute phase following joint trauma possibly through the regulation of the innate immune system.

ASPEN Consensus Recommendations for Refeeding Syndrome.

INTRODUCTION: In the spring of 2017, the American Society for Parenteral and Enteral Nutrition (ASPEN) Parenteral Nutrition Safety Committee and the Clinical Practice Committee convened an interprofessional task force to develop consensus recommendations for identifying patients with or at risk for refeeding syndrome (RS) and for avoiding and managing the condition. This report provides narrative review and consensus recommendations in hospitalized adult and pediatric populations. METHODS: Because of the variation in definitions and methods reported in the literature, a consensus process was developed. Subgroups of authors investigated specific issues through literature review. Summaries were presented to the entire group for discussion via email and teleconferences. Each section was then compiled into a master document, several revisions of which were reviewed by the committee. FINDINGS/RECOMMENDATIONS: This group proposes a new clinical definition, and criteria for stratifying risk with treatment and screening strategies. The authors propose that RS diagnostic criteria be stratified as follows: a decrease in any 1, 2, or 3 of serum phosphorus, potassium, and/or magnesium levels by 10%-20% (mild), 20%-30% (moderate), or >30% and/or organ dysfunction resulting from a decrease in any of these and/or due to thiamin deficiency (severe), occurring within 5 days of reintroduction of calories. CONCLUSIONS: These consensus recommendations are intended to provide guidance regarding recognizing risk and identifying, stratifying, avoiding and managing RS. This consensus definition is additionally intended to be used as a basis for further research into the incidence, consequences, pathophysiology, avoidance, and treatment of RS.

Ring polymer dynamics and tumbling-stretch transitions in planar mixed flows.

The properties of dilute polymer solutions are governed by the conformational dynamics of individual polymers which can be perturbed in the presence of an applied flow. Much of our understanding of dilute solutions comes from studying how flows manipulate the molecular features of polymer chains out of equilibrium, primarily focusing on linear polymer chains. Recently there has been an emerging interest in the dynamics of nonlinear architectures, particularly ring polymers, which exhibit surprising out-of-equilibrium dynamics in dilute solutions. In particular, it has been observed that hydrodynamics can couple to topology in planar elongational and shear flows, driving molecular expansion in the nonflow direction that is not observed for linear chains. In this paper, we extend our understanding of dilute ring polymer dynamics to mixed flows, which represent flow profiles intermediate between simple shear or planar elongation. We map the conformational behaviors at a number of flow geometries and strengths, demonstrating transitions between coiled, tumbling, and stretched regimes. Indeed, these observations are consistent with how linear chains respond to mixed flows. For both linear and ring polymers, we observe a marked first-order-like transition between tumbling and stretched polymers that we attribute to a dynamic energy barrier between the two states. This manifests as bimodal extension distributions in a narrow range of flow strengths and geometries, with the primary difference between rings and linear chains being the presence of molecular expansion in the vorticity direction.

Characterization of synovial fluid metabolomic phenotypes of cartilage morphological changes associated with osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is a multifactorial disease with etiological heterogeneity. The objective of this study was to classify OA subgroups by generating metabolomic phenotypes from human synovial fluid. DESIGN: Post mortem synovial fluids (n = 75) were analyzed by high performance-liquid chromatography mass spectrometry (LC-MS) to measure changes in the global metabolome. Comparisons of healthy (grade 0), early OA (grades I-II), and late OA (grades III-IV) donor populations were considered to reveal phenotypes throughout disease progression. RESULTS: Global metabolomic profiles in synovial fluid were distinct between healthy, early OA, and late OA donors. Pathways differentially activated among these groups included structural deterioration, glycerophospholipid metabolism, inflammation, central energy metabolism, oxidative stress, and vitamin metabolism. Within disease states (early and late OA), subgroups of donors revealed distinct phenotypes. Synovial fluid metabolomic phenotypes exhibited increased inflammation (early and late OA), oxidative stress (late OA), or structural deterioration (early and late OA) in the synovial fluid. CONCLUSION: These results revealed distinct metabolic phenotypes in human synovial fluid, provide insight into pathogenesis, represent novel biomarkers, and can move toward developing personalized interventions for subgroups of OA patients.

Effects of early life stress on cocaine conditioning and AMPA receptor composition are sex-specific and driven by TNF.

Exposure to early life adversity can predispose adolescents to the formation of substance abuse disorders. In rodents, early stressors such as repeated maternal separation (MS) impact AMPAR activity in the prefrontal cortex (PFC) and nucleus accumbens (NAc), regions involved in drug-cue association after cocaine-induced conditioned place preference (CPP). Notably, previous reports suggest that the pro-inflammatory cytokine tumor necrosis factor (TNF) regulates AMPAR subunit composition; increased TNF levels are reported to reduce GluA2-positive AMPARs. Since MS can elevate adolescent TNF levels, the stressor may therefore alter AMPAR subunit composition via neuroimmune signaling, thereby affecting cocaine-induced CPP. We tested the specific role of soluble TNF in MS-induced GluA2 loss and cocaine-induced CPP with biologic disruption of TNF signaling. TNF gene and protein expression were elevated in both PFC and NAc of MS males, but not females. GluA2 expression was reduced in both regions in only male MS rats, and systemic treatment with either ibudilast - a phosphodiesterase inhibitor, or XPro1595 - a blood-brain barrier-permeable blocker of soluble TNF - reversed such loss. MS males also formed greater preference for a cocaine-paired environment, the expression of which returned to control levels after XPro1595 administration. These data suggest a sex-specific mechanistic link between TNF signaling and changes in GluA2 expression and drug-cue conditioning, thereby providing further evidence for a role of MS and neuro-immune activity in cortical and striatal AMPAR changes. Moreover, manipulation of the TNF signaling pathway represents a novel approach for influencing response to reinforcing effects of drug use.

Inhibition of early response genes prevents changes in global joint metabolomic profiles in mouse post-traumatic osteoarthritis.

OBJECTIVE: Although joint injury itself damages joint tissues, a substantial amount of secondary damage is mediated by the cellular responses to the injury. Cellular responses include the production and activation of proteases (MMPs, ADAMTSs, Cathepsins), and the production of inflammatory cytokines. The trajectory of cellular responses is driven by the transcriptional activation of early response genes, which requires Cdk9-dependent RNA Polymerase II phosphorylation. Our objective was to determine whether inhibition of cdk9-dependent early response gene activation affects changes in the joint metabolome. DESIGN: To model post-traumatic osteoarthritis, we subjected mice to non-invasive Anterior Cruciate Ligament (ACL)-rupture joint injury. Following injury, mice were treated with flavopiridol - a potent and selective inhibitor of Cdk9 kinase activity - to inhibit Cdk9-dependent transcriptional activation, or vehicle control. Global joint metabolomics were analyzed 1 h after injury. RESULTS: We found that injury induced metabolomic changes, including increases in Vitamin D3 metabolism, anandamide, and others. Inhibition of primary response gene activation immediately after injury largely prevented the global changes in the metabolomics profiles. Cluster analysis of joint metabolomes identified groups of injury-induced and drug-responsive metabolites. CONCLUSIONS: Metabolomic profiling provides an instantaneous snapshot of biochemical activity representing cellular responses. We identified two sets of metabolites that change acutely after joint injury: those that require transcription of primary response genes, and those that do not. These data demonstrate the potential for inhibition of early response genes to alter the trajectory of cell-mediated degenerative changes following joint injury, which may offer novel targets for cell-mediated secondary joint damage.

Fluctuating Physical Function and Health: Their Role at the End of Life.

BACKGROUND: Our recent research suggests that a fluctuating trajectory, previously thought to be the experience of those dying with heart failure or chronic lung disease, may not accurately characterize the end of life for these patients. OBJECTIVE: We sought to further examine health and function to investigate whether other measures or a different time frame captures the purported exacerbation/recovery trajectory associated with these diseases. DESIGN: Function and health data were collected prospectively at six-month intervals for 17 years during the Heath, Aging and Body Composition Study. SUBJECTS AND MEASURES: We analyzed self-reported mobility, health status, and health care utilization for 1410 decedents, defining high fluctuations as transitions in two or more adjacent assessment pairs during the last three years of life. RESULTS: Among decedents, only 207 (14.7%) reported two or more changes in mobility during the last three years of life; and 586 (41.6%) reported more than two transitions in self-reported health during the period. This fluctuation was not associated with any clinical condition in the three years before death, but decedents with chronic heart failure or chronic lung disease reported significantly more changes in mobility (odds ratio = 1.15, p = 0.025) for a longer follow-up period. Decedents with heart failure were also more likely to report hospital stays in the last three years of life. CONCLUSIONS: Fluctuations in mobility and self-reported health do not differ by clinical condition in the three years before death, but people dying with chronic heart failure or chronic lung disease are more frequently hospitalized during this period and experience more unstable mobility for a longer period of observation.

Head and Neck Cancer Tumor Seeding at the Percutaneous Endoscopic Gastrostomy Site.

The National Institutes of Health National Cancer Institute estimates that over 13,000 new cases of head and neck cancer (HNC) will be diagnosed in 2017. Patients with HNC often require enteral nutrition (EN) via gastrostomy tube to provide nutrition support and hydration because of tumor obstruction of the oropharynx and/or cumulative effects of chemoradiation therapy. The percutaneous endoscopic gastrostomy (PEG) tube has become the preferred technique for EN access because placement is considered a minimally invasive procedure. There are 3 methods of PEG placement: Gauderer-Ponsky "pull," Sachs-Vine "push," and Russell "push" method. The Gauderer-Ponsky "pull" method has become the preferred method of PEG placement. It has been previously reported that the rate of stomal metastasis can be 0.5%-1% of those undergone the Gauderer-Ponsky "pull" method that is consistent with HNC morphology. Other researchers believe the rate may be as high as 0.5%-3%. This article reviews the 3 methods of PEG placement, as well as all potential complications, including metastatic seeding at the PEG site. In addition, 1 additional case of tumor seeding at the PEG site will be reviewed. Consideration for avoidance of the Gauderer-Ponsky pull method of PEG placement or other methods of feeding tube placement where the gastrostomy tube has to pass through the oral cavity before exiting the abdominal wall in patients with squamous cell carcinoma of the head and neck should be considered.

Mobility Trajectories at the End of Life: Comparing Clinical Condition and Latent Class Approaches.

OBJECTIVES: To assess mobility disability trajectories before death in a large sample of very old adults using two analytical approaches to determine how well they corresponded. DESIGN: Decedent sample from the Health, Aging and Body Composition (Health ABC) Study. Data were collected between 1997 and 2015. SETTING: Pittsburgh, Pennsylvania, and Memphis, Tennessee. PARTICIPANTS: Individuals randomly selected from well-functioning white Medicare beneficiaries and all black community residents meeting age criteria (70-79) (N = 3,075). MEASUREMENTS: Participants were interviewed in person or by phone at least every six months throughout the study. Of the 1,991 participants who died by the end of the study, 1,410 had been interviewed for 3 years before death, including an interview 6 months before dying. We analyzed self-reported mobility collected prospectively at 6-month intervals during the last 3 years of life. We derived trajectories in two ways: by averaging decline within decedent groups prespecified according to clinical conditions and by estimating trajectory models using maximum-likelihood semiparametric modeling. RESULTS: Ninety-eight percent of decedents were classified according to 4 prespecified clinical conditions (sudden death, terminal, organ failure, frailty), which produced groups with different characteristics. Five disability trajectories were identified: late decline, progressive disability, moderate disability, early decline, and persistent disability. Disability trajectory and clinical condition grouping confirmed previous research but were only marginally related. CONCLUSION: Derived disability trajectories and grouping according to clinical condition provide useful information about different facets of the end-of-life experience. The lack of fit between them suggests a need for greater attention to heterogeneity in disability in the period before death.

Three Year Functional Trajectories Among Old Age Survivors and Decedents: Dying Eliminates a Racial Disparity.

BACKGROUND: Long-term trajectories of disability comparing decedents and survivors and differences by race have not been assessed. OBJECTIVE: To examine self-reported difficulty in walking a quarter mile and the need for assistance with activities of daily living (ADL) beginning 3 years before death among decedents and age- and gender-matched survivors. DESIGN: A case-control sample drawn from the Health, Aging and Body Composition Study (Health ABC). Data were collected between 1997 and 2015. PARTICIPANTS: Of the 1991 participants who died by the end of the study, 1410 were interviewed for 3 years prior to death, including an interview 6 months before dying. Of these, 1379 decedents were successfully matched by age and gender with 1379 survivors and tracked over the same 3-year period. MAIN MEASURES: Self-reported difficulty walking a quarter mile and the ability to perform activities of daily living without assistance (bathing, dressing, transferring). KEY RESULTS: Decedents (mean age at death, 84) increased in mobility disability from 44.1% 3 years before death to 69.4% 6 months before death and in ADL disability from 32.9% to 58.4%. Among survivors, mobility disability increased from 31.4% to 40.7% and ADL disability from 17.4% to 31.4%. The proportion of decedents and survivors with mobility disability differed significantly in adjusted models at all assessment points (p < 0.0001). African-American survivors were significantly more disabled than White survivors at all points (p < 0.0001), but trajectories of disability among decedents did not differ by race in the last 18 months of life (p = 0.35). CONCLUSIONS: Trajectories of self-reported disability differ between survivors and decedents. Older adults who died were more disabled 3 years before death and also had a greater risk of increasing disability over each subsequent 6-month assessment. The gap in disability between African Americans and Whites was erased in the final 1 to 1.5 years before death.

Are Preferences for Aggressive Medical Treatment Associated with Healthcare Utilization in the Very Old?

Objectives: To examine the relationship between end-of-life (EOL) treatment preferences and recent hospitalization or emergency department (ED) care in the very old. Design: Quarterly telephone follow-up of participants in the EOL in the Very Old cohort. Setting: The EOL in the Very Old Age cohort drew from 1403 participants in the Health, Aging, and Body Composition (Health ABC) study who were alive in year 15 of follow-up. 87.5% (n = 1227) were successfully recontacted and enrolled. Participants: Preferences for treatment at the EOL and reported hospital and ED use were examined for 1118 participants (18% involving proxy reports) over 6 months, 1021 (16% with proxy reports) over 12 months, and 945 (23% with proxy reports) over 18 months in 6-month intervals. Measurements: Preferences for eight EOL treatments, elicited once each year; hospitalization and ED use reported every six months. Results: Preferences for more aggressive treatment (endorsing ≥5 of 8 options) were not significantly associated with inpatient or ED treatment. Inpatient and ED treatment were not associated with changes in preferences for aggressive EOL treatment over 12 months. Conclusion: Alternative measures that tap attitudes toward routine care, rather than EOL treatment preferences, may be more highly associated with healthcare utilization.

Factors Associated with Family Reports of Pain, Dyspnea, and Depression in the Last Year of Life.

BACKGROUND: Pain, dyspnea, and depression are highly troubling near the end of life. OBJECTIVE: To characterize factors associated with clinically significant pain and the presence of dyspnea and depression during the last year of life in a nationally representative sample. DESIGN: Retrospective cohort study. SETTING: Health and Retirement Study, a national sample of community-dwelling US residents aged 51 and older. PARTICIPANTS: Family respondents of 8254 decedents who died between 1998 and 2012. MEASUREMENTS: Clinically significant pain often during the last year of life; dyspnea and depression for at least one month during the last year of life. RESULTS: Life support was associated with dyspnea (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.42-2.06) and depression (OR 1.20, CI 1.04-1.39), treatment for cancer with pain (OR 1.65, CI 1.41-1.92), and oxygen for a lung condition with dyspnea (OR 14.78, CI 11.28-19.38). More diagnoses were associated with dyspnea (OR 1.24, CI 1.17-1.30) and depression (OR 1.14, CI 1.08-1.21). More activities of daily living (ADL) dependencies were associated with clinically significant pain (OR 1.06, CI 1.03-1.09), dyspnea (OR 1.06, CI 1.02-1.10), and depression (OR 1.10, CI 1.07-1.12), and more instrumental activities of daily living (IADL) dependencies with depression (OR 1.12, CI 1.08-1.18). Worse self-rated health was associated with pain (OR 0.83, CI 0.77-0.88), dyspnea (OR 0.89, CI 0.84-0.95), and depression (OR 0.83, CI 0.78-0.89). Arthritis was associated with clinically significant pain (OR 2.24, CI 1.91-2.63). CONCLUSIONS: Factors associated with common, burdensome symptoms in a national sample suggest clinical and population strategies for targeting symptom assessment and management.

Symptom Burden and End-of-Life Treatment Preferences in the Very Old.

CONTEXT: End-of-life (EOL) treatment preferences among the very old (age 85+) may differ from preferences in younger aged populations because of high levels of symptom burden and disability and high risk of mortality. It is unclear if symptom burden or level of disability is more important for such preferences. OBJECTIVES: To investigate whether distress from daily symptom burden was an independent correlate of EOL treatment preferences over two years of follow-up in people with median age 86 (participants) and 88 (reported by proxies) at baseline. METHODS: The End of Life in Very Old Age is an ancillary study to the Health, Aging and Body Composition study. At baseline in Year 15 of Health, Aging and Body Composition, 1038 participants and 189 proxies reported levels of symptom distress every quarter, as well as 0-8 EOL treatment preferences elicited once each year. RESULTS: At baseline, the mean (SD) count of EOL treatment preferences was 4.2 (2.1) in participants, and 2.9 (2.3) in proxies. EOL treatment preference was not associated with symptom distress. By contrast, black race, male gender, and reported ease walking a quarter mile were independently associated with more aggressive EOL treatment preferences. CONCLUSION: Preferences for more aggressive EOL treatment were not related to daily symptom distress but were significantly more likely to be endorsed among those with better mobility, suggesting that disability is an independent predictor of EOL treatment preferences in the very old.

Oral Immunization with a Recombinant Lactococcus lactis-Expressing HIV-1 Antigen on Group A Streptococcus Pilus Induces Strong Mucosal Immunity in the Gut.

The induction of a potent humoral and cellular immune response in mucosal tissue is important for the development of an effective HIV vaccine. Most of the current HIV vaccines under development use the i.m. route for immunization, which is relatively poor in generating potent and long-lived mucosal immune responses. In this article, we explore the ability of an oral vaccination with a probiotic organism, Lactococcus lactis, to elicit HIV-specific immune responses in the mucosal and systemic compartments of BALB/c mice. We expressed the HIV-1 Gag-p24 on the tip of the T3 pilus of Streptococcus pyogenes as a fusion to the Cpa protein (LL-Gag). After four monthly LL-Gag oral immunizations, we observed strong Gag-specific IgG and IgA responses in serum, feces, and vaginal secretions. However, the Gag-specific CD8 T cell responses in the blood were at or below our detection limit. After an i.m. modified vaccinia Ankara/Gag boost, we observed robust Gag-specific CD8 T cell responses both in systemic and in mucosal tissues, including intraepithelial and lamina propria lymphocytes of the small intestine, Peyer's patches, and mesenteric lymph nodes. Consistent with strong immunogenicity, the LL-Gag induced activation of CD11c(+) CD11b(+) dendritic cells in the Peyer's patches after oral immunization. Our results demonstrate that oral immunization with L. lactis expressing an Ag on the tip of the group A Streptococcus pilus serves as an excellent vaccine platform to induce strong mucosal humoral and cellular immunity against HIV.