Regulation of mast cells by overlapping but distinct protein interactions of Siglec-6 and Siglec-8.

BACKGROUND: Sialic acid-binding immunoglobulin-like lectin (Siglec)-6 and Siglec-8 are closely related mast cell (MC) receptors with broad inhibitory activity, but whose functional differences are incompletely understood. METHODS: Proteomic profiling using quantitative mass spectrometry was performed on primary mouse MCs to identify proteins associated with Siglec-6 and Siglec-8. For functional characterization, each receptor was evaluated biochemically and in ex vivo and in vivo inhibition models of IgE and non-IgE-mediated MC activation in Siglec-6- or Siglec-8-expressing transgenic mice. RESULTS: Siglec-6 and Siglec-8 were found in MCs within large complexes, interacting with 66 and 86 proteins, respectively. Strikingly, Siglec-6 and Siglec-8 interacted with a large cluster of proteins involved in IgE and non-IgE-mediated MC activation, including the high affinity IgE receptor, stem cell factor (SCF) receptor KIT/CD117, IL-4 and IL-33 receptors, and intracellular kinases LYN and JAK1. Protein interaction networks revealed Siglec-6 and Siglec-8 had overlapping yet distinct MC functions, with a potentially broader regulatory role for Siglec-6. Indeed, Siglec-6 preferentially interacted with the mature form of KIT at the cell surface, and treatment with an anti-Siglec-6 antibody significantly inhibited SCF-mediated MC activation more in comparison to targeting Siglec-8. CONCLUSION: These data demonstrate a central role for Siglec-6 and Siglec-8 in controlling MC activation through interactions with multiple activating receptors and key signaling molecules. Our findings suggest that Siglec-6 has a role distinct from that of Siglec-8 in regulating MC function and represents a distinct potential therapeutic target in mast cell-driven diseases.

Microglial and neuronal fates following inhibition of CSF-1R in synucleinopathy mouse model.

Synucleinopathies are age-related neurological disorders characterized by the abnormal accumulation of α-synuclein (α-syn) in neuronal and non-neuronal cells. It has been proposed that microglial cells play an important role in synucleinopathy neuroinflammation, as well as homeostatically, such as in the clearance of α-syn aggregates in the brain. Here, we examined the effects of microglia on the pathogenesis of synucleinopathies by cell depletion in a mouse model of synucleinopathies. For this purpose, we treated non-transgenic (Non-tg) and α-synuclein transgenic (α-syn-tg) mice with pexidartinib (PLX3397), a tyrosine kinase inhibitor of colony-stimulating factor 1 receptor (CSF-1R). Neuropathological and immunoblot analysis confirmed that Iba-1 immunoreactive microglial cells were decreased by 95% following PLX3397 treatment in Non-tg and α-syn-tg mice. The level of total α-syn in the Triton X-insoluble fraction of brain homogenate was significantly decreased by microglial depletion in the α-syn-tg mice, while the level of Triton X-soluble human α-syn was not affected. Furthermore, the number of p-α-syn immunoreactive inclusions was reduced in α-syn-tg mice treated with PLX3397. Microglial depletion also ameliorated neuronal and synaptic degeneration in α-syn-tg mice, thereby resulted partially improving the motor behavioral deficit in α-syn-tg mice. Moreover, we demonstrated that microglia that survived post-PLX3397 treatment (PLX-resistant microglia) have lower expressions of CSF-1R, and microglial transcriptome analysis further elucidated that PLX-resistant microglia have unique morphology and transcriptomic signatures relative to vehicle-treated microglia of both genotypes; these include differences in definitive microglial functions such as their immune response, cell mobility, cell-cell communications, and regulation of neural homeostasis. Therefore, we suggest that microglia play a critical role in the pathogenesis of synucleinopathies, and that modulation of microglial status might be an effective therapeutic strategy for synucleinopathies.

Students' learning in theory-based simulation: A socio-material study.

BACKGROUND: Simulation-based education (SBE) is crucial to prepare nursing students prior to their clinical learning experience. Theory-based simulation learning is increasingly important for analysing how students learn. This study describes and analyses how nursing students learn through simulation in the context of palliative care communication under a socio-material approach and explores the transfer of their knowledge and skills from simulation to clinical practice. METHODS: Twenty-seven final-year nursing students in six groups participated in two simulated scenarios, followed by a debriefing and post-clinical focus groups to capture their reflections and learning. Fourteen of them joined the post-clinical focus groups after completing their clinical placements. Video recordings of the simulation, and the audio recordings from the debriefing, and post-clinical focus groups were transcribed and coded based on the human and non-human elements that were observed. These were triangulated with data collected through team participant observations, an analysis of the existing syllabi and curriculum, and a participant mapping exercise after the simulation. These various data sources illustrate how student learning and reflections took place. RESULTS: The three themes of student learning derived from the results and analysis were (1) students' expanded learning of health care communication through a socio-material approach in the context of palliative care; 2) students' discovery of the diverse and complex relations and interactions between humans and materials and (3) students' new perspectives on health care communication and the transfer of knowledge and skills through a socio-material approach in clinical practice. CONCLUSIONS: This study highlights how SBE can be further expanded using a socio-material approach to prepare students to learn beyond standardised and cognitively driven approaches and procedures. Student learning demonstrates that SBE may develop beyond high fidelity and standardisation to leave room for emergent learning and increased awareness in learning for students and teachers to optimise learning outcomes and competence.

Free tissue reconstruction in the "vessel-depleted" neck: A multi-institutional cohort study.

OBJECTIVES: Much of the literature on free tissue reconstruction in the "vessel-depleted" neck is focused on identification of vessels outside the pretreated field and data on free flap outcomes when infield microvascular anastomosis is performed remain scarce. We aim to report on free flap outcomes and recipient vessel choice in a large cohort of patients with prior radiation and neck dissection (RTND) to the ipsilateral side of vessel anastomosis. METHODS: A retrospective review was performed including patients who received head and neck free tissue transfer following prior RTND to the ipsilateral side of vessel anastomosis. Pretreatment data, free flap type, defect site, and recipient vessel choice were reported. Recipient vessel choice was stratified according to neck dissection level and prior free flap. Primary outcome was free flap survival (total failure, partial failure, success) within 30 days after surgery. RESULTS: This study included 72 free flap cases in 68 patients. Free flap success was 94.4%; one case (1.4%) resulted in total flap loss and three cases (4%) had partial flap loss. The facial (35%), external carotid (ECA) (25%), and superior thyroid arteries (16%) were the most common recipient arteries. The external jugular (EJV) (38%), facial (30%), and internal jugular veins (IJV) (15%) were the most common recipient veins. The superior thyroid artery was used less frequently with a prior level 2-3/4 neck dissection compared to a prior level 1-3/4 neck dissection (6% vs. 17%, p = 0.83). The facial artery (7% vs. 67%, p < 0.01) and vein (13% vs. 46%, p = 0.04) were used less frequently when a prior free flap with ipsilateral anastomosis was performed. The superior thyroid, ECA, IJV, and EJV were more commonly used in this subgroup. CONCLUSION: Free tissue transfer with infield microvascular anastomosis in a neck with prior RTND can be safely done with comparable outcomes to surgically naïve, non-irradiated necks.

The Addition of Chemoradiation to Adjuvant Chemotherapy is Associated With Improved Survival Following Upfront Surgical Resection for Pancreatic Cancer With Nodal Metastases.

BACKGROUND: It is unclear whether the addition of chemoradiation (CRT) to adjuvant chemotherapy (CT) following upfront resection of pancreatic ductal adenocarcinoma (PDAC) provides any benefit. While some studies have suggested a benefit to combined modality therapy (CMT) (adjuvant CT plus CRT), it is not clear if this benefit was related to increased CT usage in patients who received CMT. We sought to clarify the use of CMT in patients who underwent upfront resection of PDAC. METHODS: Patients with non-metastatic PDAC were retrospectively identified from the linked SEER-Medicare database. Those who underwent upfront resection were identified and divided into two cohorts - patients who received adjuvant CT and patients who received adjuvant CMT. Cohorts were compared. Univariate analysis described patient characteristics. Kaplan-Meier and multivariable Cox proportional hazards modeling were used to estimate overall survival (OS). RESULTS: 3555 patients were identified; 856 (24%) received CT and 573 (16%) received CMT. The median number of CT doses was 11 for both groups. Patients who received CMT were younger, diagnosed in the earlier time frame, and had fewer comorbidities. The median OS was 21 months and 18 months for those treated with CMT and CT (P < .0001), respectively, but when stratified by nodal status, the association with improved OS in the CMT cohort was only observed in node-positive patients. On multivariable analysis, receipt of CMT and removal of >15 lymph nodes decreased the risk of death (P < .05). DISCUSSION: Receipt of CMT following upfront resection for PDAC was associated with improved survival, which was confined to node-positive patients. The role of adjuvant CMT in PDAC with nodal metastases warrants further study.

A Proactive Mobile Health Application Program for Promoting Self-Care Health Management among Older Adults in the Community: Study Protocol of a Three-Arm Randomized Controlled Trial.

BACKGROUND: The use of mobile health (mHealth) has become common in recent years and is regarded as one of the most effective interventions for developing disease-specific management skills and establishing confidence in making preventive health behavior changes and accomplishing health-related goals among community-dwelling older adults. Most mHealth designs adopt a reactive care approach whereby health care professionals do not respond until they receive abnormal assessment results from the database or a message or signal from the client. The purpose of this study is to determine the effectiveness of a proactive mobile health application program with the support of a community health-social care team for older adults dwelling in the community on improving their self-care health management. METHODS: This is a three-armed, randomized controlled trial. The study will be conducted in 7 community centers with an estimated sample size of 282 participants. The participants will be randomly assigned to mHealth with interactivity, mHealth, and control groups when they are (1) aged 60 or above, (2) complaining chiefly of pain, hypertension, or diabetes mellitus, (3) living within the service areas, and (4) smartphone users. Subjects in the mHealth with interactivity group will receive 2 main elements, the mHealth application and nurse case management supported by a social service team. The mHealth group will receive the mHealth application only. The primary outcome measure will be self-efficacy, and secondary outcomes will include self-management outcomes (pain score, blood pressure, capillary blood glucose), client outcomes (quality of life, depression), and health service utilization outcomes (institutionalization and health service utilization [general practitioner, outpatient clinic, emergency room, hospital admission]). Data will be collected before intervention, after intervention, and 3 months after intervention. DISCUSSION: The incremental benefits of adding interactivity in the mHealth program have not been confirmed. This present study will add valuable information to the knowledge gap of whether mHealth with nurse interaction supported by a health-social partnership can improve self-care management among community-dwelling older adults.

Completion of Adjuvant Chemotherapy After Upfront Surgical Resection for Pancreatic Cancer Is Uncommon Yet Associated With Improved Survival.

BACKGROUND: Multiple trials have demonstrated a survival benefit for adjuvant chemotherapy after resection of pancreatic adenocarcinoma. This study aimed to identify the rate for completion of adjuvant chemotherapy, factors associated with completion, and its impact on survival after surgical resection. METHODS: The Surveillance Epidemiology and End Results Medicare-linked data was used to identify patients who underwent upfront resection for pancreatic adenocarcinoma from 2004 to 2013. Billing codes were used to quantify receipt and completion of chemotherapy. Factors associated with completion of chemotherapy were identified using multivariable regression. Kaplan-Meier and Cox proportional-hazards modeling were used to examine survival. RESULTS: The inclusion criteria were met by 2440 patients. Of these patients, 65% received no adjuvant chemotherapy, 28% received incomplete therapy, and 7% completed chemotherapy. The factors associated with chemotherapy completion were nodal metastases and treatment at a National Cancer Institute-designated cancer center (p ≤ 0.05). Comorbidities decreased the odds of completion (p ≤ 0.05). The median overall survival (OS) was 14 months for the patients who received no adjuvant chemotherapy, 17 months for those who received incomplete adjuvant chemotherapy, and 22 months for those who completed adjuvant chemotherapy (p ≤ 0.05). More recent diagnosis, comorbidities, T stage, nodal metastases, and no adjuvant chemotherapy were associated with an increased hazard ratio for death (p ≤ 0.05). Evaluation of 15 or more nodes and completion of chemotherapy decreased the hazard ratio for death (p ≤ 0.05). CONCLUSIONS: Only 7% of the Medicare patients who underwent upfront resection for pancreatic cancer completed adjuvant chemotherapy, yet completion of adjuvant chemotherapy was associated with improved OS. Completion of adjuvant chemotherapy should be the goal after upfront resection, but neoadjuvant chemotherapy may ensure that patients receive systemic chemotherapy.

Effectiveness of a community-based self-care promoting program for community-dwelling older adults: a randomized controlled trial.

BACKGROUND: The existing health care system tends to be focused on acute diseases or patients with high levels of need and is not ideal for meeting the challenges of an ageing population. This study introduced a community-based self-care promoting program for community-dwelling older adults, and tested its effects on maintaining health. OBJECTIVES: To determine whether the program can increase self-efficacy, quality of life (QoL), basic and instrumental activities of daily living, and medication adherence, while reducing health service utilization for community-dwelling older adults. METHODS: Researchers randomly assigned 457 older adults to receive the intervention (n = 230) or be controls (n = 227). The intervention included assessment and education of self-care and health-promoting behaviors, co-produced care planning and self-efficacy enhancing components supported by a health-social partnership. The control group received placebo social calls. The outcomes were measured at pre-intervention (T1) and three months post-intervention (T2). RESULTS: Analysis showed that the intervention group had a significantly higher score in self-efficacy (P = 0.049), activities of daily living (ADL) (P = 0.012), instrumental activities of daily living (IADL) (P = 0.021) and the physical components of QoL (P < 0.001) at T2 than at T1. The program also significantly improved the mental component of QoL (P < 0.001) and medication adherence (P < 0.001), as well as reducing the total number of health service attendances compared to the control group (P = 0.016). CONCLUSION: The program can help enhance the self-efficacy of community-dwelling older adults towards self-care, which may in turn enable them to maintain optimal well-being while remaining in the community.

Mapping transcription factor interactome networks using HaloTag protein arrays.

Protein microarrays enable investigation of diverse biochemical properties for thousands of proteins in a single experiment, an unparalleled capacity. Using a high-density system called HaloTag nucleic acid programmable protein array (HaloTag-NAPPA), we created high-density protein arrays comprising 12,000 Arabidopsis ORFs. We used these arrays to query protein-protein interactions for a set of 38 transcription factors and transcriptional regulators (TFs) that function in diverse plant hormone regulatory pathways. The resulting transcription factor interactome network, TF-NAPPA, contains thousands of novel interactions. Validation in a benchmarked in vitro pull-down assay revealed that a random subset of TF-NAPPA validated at the same rate of 64% as a positive reference set of literature-curated interactions. Moreover, using a bimolecular fluorescence complementation (BiFC) assay, we confirmed in planta several interactions of biological interest and determined the interaction localizations for seven pairs. The application of HaloTag-NAPPA technology to plant hormone signaling pathways allowed the identification of many novel transcription factor-protein interactions and led to the development of a proteome-wide plant hormone TF interactome network.

Opioid prescribing patterns among postpartum women.

BACKGROUND: Women commonly receive opioid prescriptions following hospitalization. The rise of the opioid epidemic in the United States underscores the importance of a better understanding of prescribing patterns. Although delivery is the most frequent reason for hospitalization in the United States, there is inadequate knowledge regarding opioid prescribing at postpartum hospital discharge. OBJECTIVE: We sought to describe opioid prescribing patterns at the time of discharge following delivery in a large, diverse cohort, and to describe the relationship of these patterns with objective and subjective measures of pain prior to discharge. STUDY DESIGN: This is a retrospective cohort study of all deliveries at a single, high-volume tertiary care center over a 1-year period. Women were excluded from analysis if they had evidence of recent opioid use, or their labor, delivery, or postpartum course was notable for rare, nonroutine events anticipated to increase pain. Medical records were queried for demographic and clinical data, including whether an opioid prescription was provided at discharge, and if so, details of that prescription. The primary outcome was amount of opioid morphine milligram equivalents prescribed at discharge, described separately for women after vaginal and cesarean deliveries. Among women who received a prescription, we additionally assessed associations between prescription quantity and subjective (patient-reported pain score) and objective (inpatient opioid requirement during the final 24 hours of hospitalization) assessments of pain. Descriptive and bivariable analyses were performed. RESULTS: Of the total 12,611 women, 12,326 were eligible for inclusion. Of 9038 women postvaginal delivery and 3288 women postcesarean delivery, 30.4% and 86.7% received an opioid prescription at discharge, respectively. Of women receiving discharge opioid prescriptions, median morphine milligram equivalents received was 200 (interquartile range: 120-300) following vaginal and 300 (interquartile range: 200-300) following cesarean delivery. Nearly half (45.7%) of women postvaginal delivery and 18.5% of women postcesarean delivery who received an opioid prescription used 0 morphine milligram equivalent during the final hospital day. Similarly, 26.5% and 18.5% of women after vaginal and cesarean delivery, respectively, reported a pain score of 0 of 10 prior to discharge. Regardless of delivery mode, the amount of opioids prescribed did not differ between those who reported a pain score of 0 of 10 and those who reported a pain score of >0 of 10 immediately prior to discharge. Similarly, for women who underwent cesarean delivery, the morphine milligram equivalents prescribed did not differ between those who used 0 morphine milligram equivalents and those who used >0 in the 24 hours prior to hospital discharge. CONCLUSION: Postpartum women are commonly prescribed opioids at the time of postpartum hospital discharge. There is a wide range of morphine milligram equivalents prescribed at hospital discharge following delivery, highlighting a lack of standardization. Furthermore, regardless of objective and subjective measures of pain prior to discharge, women received similar amounts of prescription morphine milligram equivalents following either vaginal or cesarean deliveries.

The effect of complex interventions on supporting self-care among community-dwelling older adults: a systematic review and meta-analysis.

Background: self-care is critical to enable community-dwelling older adults to live independently. Complex interventions have emerged as a strategy to support self-care, but their effectiveness is unknown. Our objective was to review systematically their effectiveness on both positive (increased scores in self-rated health, Activities of Daily Living, Instrumental Activities of Daily Living, quality of life) and negative aspects (increased incidence of falls, fear of falling, hospital and nursing home admission, increased depression score), and to determine which intervention components explain the observed effects. Methods: CINAHL, MEDLINE, British Nursing Index, PsycInfo and Cochrane CENTRAL were searched from January 2006 to October 2016. Randomised controlled trials providing at least two of these components: individual assessment, care planning or provision of information were reviewed. Outcomes were pooled by random-effects meta-analysis. Results: twenty-two trials with 14,364 participants were included with a low risk of bias. Pooled effects showed significant benefits on positive aspects including self-rated health [standardised mean difference (SMD) 0.09, 95% confidence interval (CI) 0.01-0.17] and the mental subscale of quality of life (SMD 0.44, 95% CI 0.09-0.80) as well as on the negative aspect of incidence of falls [odds ratio (OR) 0.60, 95% CI 0.46-0.79]. There was no significant improvement in ADL, IADL, overall quality of life, fear of falling, reduction in health service utilisation or depression levels. Meta-regression and subgroup analysis did not identify any specific component or characteristic in complex interventions which explained these effects. Conclusion: based on current evidence, supporting self-care in community-dwelling older adults using complex interventions effectively increases self-rated health, reduces the occurrence of falls and improves the mental subscale of quality of life.

Assessing quality of life using WHOQOL-BREF: a cross-sectional study on the association between quality of life and neighborhood environmental satisfaction, and the mediating effect of health-related behaviors.

BACKGROUND: Quality of life (QOL) is an important component in assessing people's health. Environmental quality can influence people's QOL in the physical health, psychological, social relationships and environment domains. QOL in the four domains, overall QOL and general heath of residents living in the Kowloon Peninsula of Hong Kong were assessed. The association between satisfaction with the neighborhood environment and QOL, and health-related behaviors which mediated the effect were investigated. METHODS: A sample of 317 residents completed a questionnaire which comprised the WHOQOL-BREF (Hong Kong version) to assess QOL, the International Physical Activity Questionnaire (IPAQ) to study physical activities, and questions on satisfaction with the neighborhood environment, health-related behaviors and socio-demographics. One-way ANOVA and linear regression were used to study the associations between environmental satisfaction and QOL in the four domains, overall QOL and general health, followed by assessing the relationships between environmental satisfaction and the potential health-related behavior mediators with regression tests. Mediation analysis was conducted using multiple linear regressions to study the effects of environmental satisfaction on QOL in the four domains, overall QOL and general health, as well as the potential mediating roles played by various health-related behaviors. A P-value of < 0.05 was considered as statistically significant. RESULTS: The residents had a relatively higher physical health mean score of 70.83 ± 12.69, and a lower environmental mean score of 61.98 ± 13.76. Moderate satisfaction with the neighborhood environment had a significant relationship with QOL in the psychological domain (ß = 0.170, P = 0.006), however, this effect was partially mediated by the non-smoking behavior of the residents (ß = 0.143, P = 0.022). CONCLUSIONS: Our residents had lower QOL in the physical health and psychological domains but similar QOL in the social relationships and environmental domains compared to other countries. Only QOL in the psychological domain could be predicted by the satisfaction with the neighborhood environment, and non-smoking status was a partial mediator of the effect of moderate environmental satisfaction on QOL in the psychological domain. Refrain from smoking seems to be able to lower the influence of neighborhood environment on people's QOL in the psychological domain to a certain extent.

Anti-PD-L1 peptide improves survival in sepsis.

BACKGROUND: Sepsis remains a leading cause of death in most intensive care units. Many deaths in sepsis are due to nosocomial infections in patients who have entered the immunosuppressive phase of the disorder. One cause of immunosuppression in sepsis is T-cell exhaustion mediated by programmed cell death-1 (PD-1) interaction with its ligand (PD-L1). Studies demonstrated that blocking the interaction of PD-1 with PD-L1 with knockout mice or inhibitory antibodies reversed T-cell dysfunction and improved sepsis survival. This study assessed the efficacy of a novel short-acting peptide (compound 8) that inhibits PD-1:PD-L1 signaling in a clinically relevant second-hit fungal sepsis model. METHODS: Mice underwent cecal ligation and puncture to induce peritonitis. Three days later, mice received intravenous injection of Candida albicans. Forty-eight hours after Candida infection, mice were treated with compound 8 or inactive peptide. The effect of Candida infection on expression of coinhibitory molecules, PD-1, and PD-L1 were quantitated by flow cytometry on CD4+ cells, CD8+ cells, natural killer (NK) cells, and natural killer T-cells (NKT). The effect of compound 8 on survival was also examined. RESULTS: Four days after fungal infection, PD-1 and PD-L1 expressions were markedly increased on CD4+, NK, and NKT cells in septic versus sham-operated mice (%PD-1 on CD4+, 11.9% versus 2.8%; and %PD-L1 on NKT, 14.8% versus 0.5%). Compared with control, compound 8 caused a 2-fold increase in survival from 30% to 60%, P < 0.05. CONCLUSIONS: Compound 8 significantly improved survival in a clinically relevant immunosuppressive model of sepsis. These results support immunoadjuvant therapy targeting T-cell exhaustion in this lethal disease.

Interplay between ethylene, ETP1/ETP2 F-box proteins, and degradation of EIN2 triggers ethylene responses in Arabidopsis.

The gaseous plant hormone ethylene can trigger myriad physiological and morphological responses in plants. While many ethylene signaling pathway components have been identified and characterized, little is known about the function of the integral membrane protein ETHYLENE-INSENSITIVE2 (EIN2), a central regulator of all ethylene responses. Here, we demonstrate that Arabidopsis thaliana EIN2 is a protein with a short half-life that undergoes rapid proteasome-mediated protein turnover. Moreover, EIN2 protein accumulation is positively regulated by ethylene. We identified two F-box proteins, EIN2 TARGETING PROTEIN1 (ETP1) and EIN2 TARGETING PROTEIN2 (ETP2), that interact with the EIN2 C-terminal domain (EIN2-CEND), which is highly conserved and sufficient to activate most ethylene responses. Overexpression of ETP1 or ETP2 disrupts EIN2 protein accumulation, and these plants manifest a strong ethylene-insensitive phenotype. Furthermore, knocking down the levels of both ETP1 and ETP2 mRNAs using an artificial microRNA (amiRNA) leads to accumulation of EIN2 protein, resulting in plants that display constitutive ethylene response phenotypes. Finally, ethylene down-regulates ETP1 and ETP2 proteins, impairing their ability to interact with EIN2. Thus, these studies reveal that a complex interplay between ethylene, the regulation of ETP1/ETP2 F-box proteins, and subsequent targeting and degradation of EIN2 is essential for triggering ethylene responses in plants.

T cells from patients with Candida sepsis display a suppressive immunophenotype.

BACKGROUND: Despite appropriate therapy, Candida bloodstream infections are associated with a mortality rate of approximately 40%. In animal models, impaired immunity due to T cell exhaustion has been implicated in fungal sepsis mortality. The purpose of this study was to determine potential mechanisms of fungal-induced immunosuppression via immunophenotyping of circulating T lymphocytes from patients with microbiologically documented Candida bloodstream infections. METHODS: Patients with blood cultures positive for any Candida species were studied. Non-septic critically ill patients with no evidence of bacterial or fungal infection were controls. T cells were analyzed via flow cytometry for cellular activation and for expression of positive and negative co-stimulatory molecules. Both the percentages of cells expressing particular immunophenotypic markers as well as the geometric mean fluorescence intensity (GMFI), a measure of expression of the number of receptors or ligands per cell, were quantitated. RESULTS: Twenty-seven patients with Candida bloodstream infections and 16 control patients were studied. Compared to control patients, CD8 T cells from patients with Candidemia had evidence of cellular activation as indicated by increased CD69 expression while CD4 T cells had decreased expression of the major positive co-stimulatory molecule CD28. CD4 and CD8 T cells from patients with Candidemia expressed markers typical of T cell exhaustion as indicated by either increased percentages of or increased MFI for programmed cell death 1 (PD-1) or its ligand (PD-L1). CONCLUSIONS: Circulating immune effector cells from patients with Candidemia display an immunophenotype consistent with immunosuppression as evidenced by T cell exhaustion and concomitant downregulation of positive co-stimulatory molecules. These findings may help explain why patients with fungal sepsis have a high mortality despite appropriate antifungal therapy. Development of immunoadjuvants that reverse T cell exhaustion and boost host immunity may offer one way to improve outcome in this highly lethal disorder.

Health-social partnership intervention programme for community-dwelling older adults: a research protocol for a randomized controlled trial.

AIM: This paper aims to describe the research protocol that will be used to determine the effectiveness of a health-social partnership intervention programme among community-dwelling older adults. BACKGROUND: Ageing in place is a preferred option for overcoming challenges of the increasing prevalence of chronic diseases and the risk for hospitalization associated with the ageing population. Nevertheless, our knowledge of how to implement this concept is limited. The integrated efforts of health and social services may help to enable older adults to live with a sense of control over their daily life and to be independent to the fullest extent possible in the community. DESIGN: This is a randomized, controlled trial. METHODS: Participants are community-dwelling older adults referred from a community centre. Sample size calculation was based on power analysis. The intervention group will receive the programme with the standard protocols guided by a comprehensive assessment-intervention-evaluation framework. Home visits and telephones follow-up will be employed as means of conducting the interventions and monitoring their progress. The customary care group will receive placebo social calls. The duration of the interventions will be 3 months. The study was funded by the School of Nursing in Hong Kong. Research Ethics Committee approval was obtained in September 2014. DISCUSSION: The results of this research are expected to enable older adults to stay in the community with optimal health and well-being. Health and social sciences are integrated into the practice in this research protocol. The scarce literature on this topic means that this study can also provide an opportunity to bridge the caring gap among older adults.

Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis.

INTRODUCTION: A major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients. METHODS: Blood was obtained from 43 septic and 15 non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma (IFN-γ) and interleukin-2 (IL-2) production were quantitated by flow cytometry. RESULTS: Lymphocytes from septic patients produced decreased IFN-γ and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients (P<0.05). Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients (P<0.01). CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-γ, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-γ and IL-2 production in septic patients; (P<0.01). The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis (P<0.01). CONCLUSIONS: In vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1/anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality.

Poor Dental Health as a Risk Factor for Alveolar Ridge Malignancies.

OBJECTIVE: To determine the association between poor dental health and risk of oral cavity squamous cell cancer (OCSCC) at individual tumor subsites. STUDY DESIGN: Case-control and cross-sectional METHODS: A case-control study was performed using a population-based cohort in North Carolina (Carolina Head and Neck Cancer Epidemiology Study [CHANCE]). A secondary cross-sectional analysis was performed with an institutional cohort (WashU/Siteman). Cases were adults with primary OCSCC and an identifiable tumor subsite. In the CHANCE cohort, controls were adults without head and neck cancer. In the Washington University/Siteman cohort, patients with tongue cancer served as the comparator group. We used number of missing teeth (categorized 0-6, 7-24, 25-28) as a surrogate for poor dental health, which was self-reported in CHANCE and measured on a pretreatment computed tomography scan in the WashU/Siteman study. Adjusted odds ratios (aORs) for missing teeth were estimated for each tumor subsite using binomial logistic regression models. RESULTS: Near complete tooth loss (25-28 teeth) was associated with a 3.5-fold increased risk of alveolar ridge malignancy (aOR: 3.51; 95% confidence interval [CI]: 1.14-11.01, P = .03) in the CHANCE study. This association was confirmed in our cross-sectional analysis (WashU/Siteman study) where missing 25-28 teeth was associated with an increased risk of alveolar ridge compared to tongue cancer (aOR: 4.60; 95% CI: 1.97-11.10, P = .001). CONCLUSIONS: This study suggests an association between poor dental health and risk of alveolar ridge cancer independent of smoking, alcohol use, age, race, and sex. Future prospective and translational studies are needed to confirm this association and elucidate the mechanism of dental disease in alveolar ridge malignancies.

Prevention of lymphocyte apoptosis in septic mice with cancer increases mortality.

Lymphocyte apoptosis is thought to have a major role in the pathophysiology of sepsis. However, there is a disconnect between animal models of sepsis and patients with the disease, because the former use subjects that were healthy prior to the onset of infection while most patients have underlying comorbidities. The purpose of this study was to determine whether lymphocyte apoptosis prevention is effective in preventing mortality in septic mice with preexisting cancer. Mice with lymphocyte Bcl-2 overexpression (Bcl-2-Ig) and wild type (WT) mice were injected with a transplantable pancreatic adenocarcinoma cell line. Three weeks later, after development of palpable tumors, all animals received an intratracheal injection of Pseudomonas aeruginosa. Despite having decreased sepsis-induced T and B lymphocyte apoptosis, Bcl-2-Ig mice had markedly increased mortality compared with WT mice following P. aeruginosa pneumonia (85 versus 44% 7-d mortality; p = 0.004). The worsened survival in Bcl-2-Ig mice was associated with increases in Th1 cytokines TNF-α and IFN-γ in bronchoalveolar lavage fluid and decreased production of the Th2 cytokine IL-10 in stimulated splenocytes. There were no differences in tumor size or pulmonary pathology between Bcl-2-Ig and WT mice. To verify that the mortality difference was not specific to Bcl-2 overexpression, similar experiments were performed in Bim(-/-) mice. Septic Bim(-/-) mice with cancer also had increased mortality compared with septic WT mice with cancer. These data demonstrate that, despite overwhelming evidence that prevention of lymphocyte apoptosis is beneficial in septic hosts without comorbidities, the same strategy worsens survival in mice with cancer that are given pneumonia.