Clinical Roles in the Medical Communications Centre: A Rapid Scoping Review.

In recent years, 911 call volumes have increased, and emergency medical services (EMS) are routinely stretched beyond capacity. To better match resources with patient needs, some EMS systems have integrated clinician roles into the emergency medical communications centre (MCC). Our objective was to explore the nature and scope of clinical roles in emergency MCCs. Using a rapid scoping review methodology, we searched PubMed for studies related to any clinical role employed within an emergency MCC. We accepted reviews, experimental and observational designs, as well as expert opinions. Studies reporting on dispatcher recognition and pre-arrival instructions were excluded. Title and abstract screening were conducted by a single reviewer, included studies were verified by two reviewers, and data extraction was completed in duplicate, all using Covidence review software. The level of evidence was assessed using the prehospital evidence-based practice (PEP) scale. The protocol was registered in Open Science Framework (10.17605/OSF.IO/NX4T8).  Our search yielded 1071 titles, and four were added from other sources; 44 studies were reviewed at the full-text stage and 31 were included. The included studies were published from 2002 to 2022 and represent 17 countries. Studies meeting inclusion criteria consisted of level I (n=4, 11%), II (n=13, 37%), and III (N=6, 17%) methodologies, as well as 12 other studies (34%) with qualitative or other designs. Most of the included studies reported systems that employ nurses in the MCC (n=29, 83%). Twelve (34%) studies reported on the inclusion of paramedics in the MCC, and five (14%) reported physician involvement. The roles of these clinicians chiefly consisted of triage (n=25, 71%), advice (n=20, 57%), referral to non-emergency care (n=14, 40%), and peer-to-peer consulting (n=2, 4%). Alternative dispositions (as opposed to emergency ambulance transport) for low acuity callers included self-care, as well as referral to a general practitioner, pharmacist, or other outreach programs. There is a wide range of literature reporting on clinical roles integrated within MCCs. Our findings revealed that MCC nurses, physicians, and paramedics assist substantively with triage, advice, and referrals to better match resources to patient needs, with or without the requirement for ambulance dispatch.

Adverse Health Effects Related to Shift Work Patterns and Work Schedule Tolerance in Emergency Medical Services Personnel: A Scoping Review.

Paramedicine as a profession is continually evolving in clinical practice, responsibilities, and workload. Changes over time in both population demographics and distribution have altered the demand for, and availability of, prehospital emergency medical services (EMS). These factors may also affect scheduling policies in many EMS organizations. However, there is little evidence that suggests optimal shift scheduling patterns to reduce adverse health events such as increased stress or fatigue in prehospital emergency health care providers. Our objective was to describe associations between variations in shift scheduling patterns and EMS provider health outcomes, such as fatigue, stress, sleep quality, and general mental and physiological health. We also sought to identify knowledge gaps. We performed searches of PubMed, CINAHL, Embase, and Cochrane databases for primary studies, systematic reviews, and meta-analyses published between January 2000 and December 2020. Studies reporting measurable health care outcomes in prehospital personnel with defined shift schedule patterns in land-based ambulance systems were included. Our search strategy yielded 188 studies, of which 11 met eligibility criteria (eight cross-sectional surveys, one single case report, one retrospective cohort study, one prospective cohort study, and one systematic review), with one additional study found through reference list screening, leaving 12 studies for review. All publications contained a description of shift schedule characteristics and shared similar outcomes of interest, although there was variation in comparators and assessment of outcomes. Most studies showed high rates of fatigue, stress, mental health concerns, and negative general health outcomes in paramedic shift worker populations. The case study reported improved fatigue, alertness, and sleep quality levels following a switch from a 24-hour shift pattern to an eight-hour shift. We did not complete an in-depth risk of bias assessment for any of the studies. Melnyk evidence ratings varied from IV to VI, indicating a low quality of evidence evaluating the impacts of shift schedule patterns in paramedics, with the retrospective cohort study design, ranked as IV, systematic review as a V, and prospective cohort study, case report and surveys ranked as VI. The low quality and quantity of evidence indicate the need for further research to definitively assess relationships between specific schedule patterns and health outcomes.

Interventions to Increase Retention in Mental Health Services: A Systematic Review.

OBJECTIVE: Several systematic reviews have evaluated interventions that aim to increase mental health service initiation and engagement as well as adherence to pharmacological treatment. No reviews have focused on evaluating these interventions' effects on retention in mental health services, however, which was the goal of this systematic review. METHODS: PubMed, PsycINFO, and Social Services Abstracts were searched for studies that met the inclusion criteria. All studies published prior to March 29, 2015, that compared two or more groups on any measure of retention in mental health services were included. Methodological quality was assessed for each included study. An effect size was calculated for each outcome, although a meta-analysis was not conducted because of heterogeneity across interventions. To facilitate narrative analysis, interventions were categorized by targets-the types of predictors of or barriers to mental health service use that the intervention aimed to address. RESULTS: Eleven studies met inclusion criteria. The interventions produced medium to large effects on retention outcomes. Many interventions addressed more than one target. Interventions that targeted mental health knowledge, mental health attitudes, and barriers to treatment all enhanced retention in mental health services compared with control groups. Most interventions with those targets had a large effect on retention and relatively good methodological ratings. CONCLUSIONS: The most effective retention interventions were comprehensive, addressing mental health knowledge, mental health attitudes, and barriers to treatment. The authors recommend that researchers apply relevant theories to refine these interventions and evaluate the interventions by using rigorous methodology and a range of retention outcomes, mediators, and moderators.

CD40-TRAF Signaling Upregulates CX3CL1 and TNF-α in Human Aortic Endothelial Cells but Not in Retinal Endothelial Cells.

CD40, CX3CL1 and TNF-α promote atheroma and neointima formation. CD40 and TNF-α are also central to the development of diabetic retinopathy while CX3CL1 may play a role in the pathogenesis of this retinopathy. The purpose of this study was to examine whether CD40 ligation increases CX3CL1 and TNF-α protein expression in human endothelial cells from the aorta and retina. CD154 (CD40 ligand) upregulated membrane-bound and soluble CX3CL1 in human aortic endothelial cells. CD154 triggered TNF-α production by human aortic endothelial cells. TNF Receptor Associated Factors (TRAF) are key mediators of CD40 signaling. Compared to human aortic endothelial cells that express wt CD40, cells that express CD40 with a mutation that prevents TRAF2,3 recruitment, or CD40 with a mutation that prevents TRAF6 recruitment exhibited a profound inhibition of CD154-driven upregulation of membrane bound and soluble CX3CL1 as well as of TNF-α secretion. While both CD154 and TNF-α upregulated CX3CL1 in human aortic endothelial cells, these stimuli could act independently of each other. In contrast to human aortic endothelial cells, human retinal endothelial cells did not increase membrane bound or soluble CX3CL1 expression or secrete TNF-α in response to CD154 even though CD40 ligation upregulated ICAM-1 and CCL2 in these cells. Moreover, TNF-α did not upregulate CX3CL1 in retinal endothelial cells. In conclusion, CD40 ligation increases CX3CL1 protein levels and induces TNF-α production in endothelial cells. However, endothelial cells are heterogeneous in regards to these responses. Human aortic but not retinal endothelial cells upregulated CX3CL1 and TNF-α in response to CD40 ligation, as well as upregulated CX3CL1 in response to TNF-α. These dissimilarities may contribute to differences in regulation of inflammation in large vessels versus the retina.

Blockade of CD40-TRAF2,3 or CD40-TRAF6 is sufficient to inhibit pro-inflammatory responses in non-haematopoietic cells.

Inhibition of the CD40-CD154 pathway controls inflammatory disorders. Unfortunately, administration of anti-CD154 monoclonal antibodies causes thromboembolism. Blockade of signalling downstream of CD40 may represent an approach to treat CD40-driven inflammatory disorders. Blocking tumour necrosis factor receptor-associated factor 6 (TRAF6) signalling downstream of CD40 in MHC II(+) cells diminishes inflammation. However, CD40-TRAF6 blockade may cause immunosuppression. We examined the role of CD40-TRAF2,3 and CD40-TRAF6 signalling in the development of pro-inflammatory responses in human non-haematopoietic and monocytic cells. Human aortic endothelial cells, aortic smooth muscle cells, renal proximal tubule epithelial cells, renal mesangial cells and monocytic cells were transduced with retroviral vectors that encode wild-type CD40, CD40 with a mutation that prevents TRAF2,3 recruitment (ΔT2,3), TRAF6 recruitment (ΔT6) or both TRAF2,3 plus TRAF6 recruitment (ΔT2,3,6). Non-haematopoietic cells that expressed CD40 ΔT2,3 exhibited marked inhibition in CD154-induced up-regulation of vascular cell adhesion molecule 1, intercellular adhesion molecule 1 (ICAM-1), monocyte chemotactic protein 1 (MCP-1), tissue factor and matrix metalloproteinase 9. Similar results were obtained with cells that expressed CD40 ΔT6. Although both mutations impaired ICAM-1 up-regulation in monocytic cells, only expression of CD40 ΔT6 reduced MCP-1 and tissue factor up-regulation in these cells. Treatment of endothelial and smooth muscle cells with cell-permeable peptides that block CD40-TRAF2,3 or CD40-TRAF6 signalling impaired pro-inflammatory responses. In contrast, while the CD40-TRAF2,3 blocking peptide did not reduce CD154-induced dendritic cell maturation, the CD40-TRAF6 blocking peptide impaired this response. Hence, preventing CD40-TRAF2,3 or CD40-TRAF6 interaction inhibits pro-inflammatory responses in human non-haematopoietic cells. In contrast to inhibition of CD40-TRAF6 signalling, inhibition of CD40-TRAF2,3 signalling did not impair dendritic cell maturation. Blocking CD40-TRAF2,3 signalling may control CD40-CD154-dependent inflammatory disorders.

CD40 promotes the development of early diabetic retinopathy in mice.

AIMS/HYPOTHESIS: Microangiopathy is a leading complication of diabetes that commonly affects the retina. Degenerate capillaries are a central feature of diabetic retinopathy. An inflammatory process has been linked to the development of diabetic retinopathy but its regulation is incompletely understood. Cluster of differentiation (CD) 40 is a member of the TNF receptor superfamily that promotes the development of certain inflammatory disorders. The role of CD40 in diabetic microangiopathy is unknown. METHODS: B6 and Cd40−/− mice were administered streptozotocin to induce diabetes. Leucostasis was assessed using fluorescein isothiocyanate-conjugated concanavalin A. Retinal Icam1 and Cd40 mRNA levels were examined using real-time PCR. Protein nitration was assessed by immunohistochemistry. Histopathology was examined in the retinal vasculature. CD40 expression was assessed by flow cytometry and immunohistochemistry. Intercellular adhesion molecule 1 (ICAM-1) and nitric oxide synthase 2 (NOS2) were examined by immunoblot and/or flow cytometry. Nitric oxide production was examined by immunoblot and Griess reaction. RESULTS: In mouse models of diabetes, Cd40−/− mice exhibited reduced retinal leucostasis and did not develop capillary degeneration in comparison with B6 mice. Diabetic Cd40−/− mice had diminished ICAM-1 upregulation and decreased protein nitration. Cd40 mRNA levels were increased in the retinas of diabetic B6 mice compared with non-diabetic controls. CD40 expression increased in retinal Müller cells, endothelial cells and microglia of diabetic animals. CD40 stimulation upregulated ICAM-1 in retinal endothelial cells and Müller cells. CD40 ligation upregulated NOS2 and nitric oxide production by Müller cells. CONCLUSIONS/INTERPRETATION: CD40-deficient mice were protected fromthe development of diabetic retinopathy. These mice exhibited diminished inflammatory responses linked to diabetic retinopathy. CD40 stimulation of retinal cells triggered these pro-inflammatory responses.

Impact of family caregiving by youth on their psychological well-being: a latent trait analysis.

Secondary data analyses were conducted on a survey dataset from 1,281 middle school students to analyze the impact of family caregiving on self-reports of psychological well-being using the Multiple Indicators, Multiple Causes (MIMIC) model. Factor analysis resulted in four latent factors underlying psychological functioning, and the MIMIC model revealed significant caregiver effects on three factors: anxiety/depression, engaged coping, and disengaged coping, but not life satisfaction. Youth caregivers, especially those living with the care recipient, reported significantly higher anxiety/depression and a greater use of both coping styles compared to non-caregivers. Caregiving has a negative influence on the emotional well-being of youth with dual student-caregiver roles. The utilization of more coping strategies may reflect needing to try many approaches to school/family stressors because supports and experience are limited. Research to clarify how caregiving mediates the behavioral health and academic success of youth and also impacts care recipients and the family is warranted.

Toll-like receptor polymorphisms and cerebral malaria: TLR2 Δ22 polymorphism is associated with protection from cerebral malaria in a case control study.

BACKGROUND: In malaria endemic areas, host genetics influence whether a Plasmodium falciparum-infected child develops uncomplicated or severe malaria. TLR2 has been identified as a receptor for P. falciparum-derived glycosylphosphatidylinositol (GPI), and polymorphisms within the TLR2 gene may affect disease pathogenesis. There are two common polymorphisms in the 5' un-translated region (UTR) of TLR2, a 22 base pair deletion in the first unstranslated exon (Δ22), and a GT dinucleotide repeat in the second intron (GTn). METHODS: These polymorphisms were examined in a Ugandan case control study on children with either cerebral malaria or uncomplicated malaria. Serum cytokine levels were analysed by ELISA, according to genotype and disease status. In vitro TLR2 expression was measured according to genotype. RESULTS: Both Δ22 and GTn polymorphisms were highly frequent, but only Δ22 heterozygosity was associated with protection from cerebral malaria (OR 0.34, 95% confidence intervals 0.16, 0.73). In vitro, heterozygosity for Δ22 was associated with reduced pam3cys inducible TLR2 expression in human monocyte derived macrophages. In uncomplicated malaria patients, Δ22 homozygosity was associated with elevated serum IL-6 (p = 0.04), and long GT repeat alleles were associated with elevated TNF (p = 0.007). CONCLUSION: Reduced inducible TLR2 expression may lead to attenuated pro-inflammatory responses, a potential mechanism of protection from cerebral malaria present in individuals heterozygous for the TLR2 Δ22 polymorphism.

TLR9 polymorphisms are associated with altered IFN-gamma levels in children with cerebral malaria.

Toll-like receptor (TLR) polymorphisms have been associated with disease severity in malaria infection, but mechanisms for this association have not been characterized. The TLR2, 4, and 9 single nucleotide polymorphism (SNP) frequencies and serum interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) levels were assessed in Ugandan children with cerebral malaria (CM, N = 65) and uncomplicated malaria (UM, N = 52). The TLR9 C allele at -1237 and G allele at 1174 were strongly linked, and among children with CM, those with the C allele at -1237 or the G allele at 1174 had higher levels of IFN-gamma than those without these alleles (P = 0.03 and 0.008, respectively). The TLR9 SNPs were not associated with altered IFN-gamma levels in children with UM or altered TNF-alpha levels in either group. We present the first human data that TLR SNPs are associated with altered cytokine production in parasitic infection.

Toll-like receptor polymorphisms in malaria-endemic populations.

BACKGROUND: Toll-like receptors (TLR) and related downstream signaling pathways of innate immunity have been implicated in the pathogenesis of Plasmodium falciparum malaria. Because of their potential role in malaria pathogenesis, polymorphisms in these genes may be under selective pressure in populations where this infectious disease is endemic. METHODS: A post-PCR Ligation Detection Reaction-Fluorescent Microsphere Assay (LDR-FMA) was developed to determine the frequencies of TLR2, TLR4, TLR9, MyD88-Adaptor Like Protein (MAL) single nucleotide polymorphisms (SNPs), and TLR2 length polymorphisms in 170 residents of two regions of Kenya where malaria transmission is stable and high (holoendemic) or episodic and low, 346 residents of a malaria holoendemic region of Papua New Guinea, and 261 residents of North America of self-identified ethnicity. RESULTS: The difference in historical malaria exposure between the two Kenyan sites has significantly increased the frequency of malaria protective alleles glucose-6-phoshpate dehydrogenase (G6PD) and Hemoglobin S (HbS) in the holoendemic site compared to the episodic transmission site. However, this study detected no such difference in the TLR2, TLR4, TLR9, and MAL allele frequencies between the two study sites. All polymorphisms were in Hardy Weinberg Equilibrium in the Kenyan and Papua New Guinean populations. TLR9 SNPs and length polymorphisms within the TLR2 5' untranslated region were the only mutant alleles present at a frequency greater than 10% in all populations. CONCLUSION: Similar frequencies of TLR2, TLR4, TLR9, and MAL genetic polymorphisms in populations with different histories of malaria exposure suggest that these innate immune pathways have not been under strong selective pressure by malaria. Genotype frequencies are consistent with Hardy-Weinberg Equilibrium and the Neutral Theory, suggesting that genetic drift has influenced allele frequencies to a greater extent than selective pressure from malaria or any other infectious agents in these populations.

In vivo and in vitro regulation of type I IFN synthesis by synergistic effects of CD40 and type II IFN.

During cognate interaction with CD40 ligand (CD154)-expressing T cells, Ag-presenting accessory cells are activated for increased cytokine synthetic and costimulatory function. We examined whether CD40 modulates in vivo innate immune function over time, hypothesizing that distinct cytokine responses evolve to delayed microbial exposure. C3H/HeN mice pretreated with activating anti-CD40 Ab (FGK45) produced 10-fold more serum IFN-gamma and IL-12 p70 to delayed, but not synchronous, challenge with LPS. A novel finding was that LPS-induced IFN-alpha increased by 20-fold in mice pretreated for 24 h, but not 6 h or less, with anti-CD40. Anti-CD40-pretreated C57BL/6 RAG-2(-/-) mice similarly increased IFN-alpha responses to delayed LPS challenge, confirming mediation by innate immunity. Type I IFNR- and IFN-gamma-deficient mice treated with anti-CD40 failed to expand serum IFN-alpha responses to LPS challenge. Combined pretreatment with anti-CD40 and anti-IFN-gamma mAb showed that IFN-gamma produced after anti-CD40 pretreatment, but before LPS challenge, was necessary for IFN-alpha synthetic enhancement. Anti-CD40 also increased polyinosinic-polycytidylic acid (poly(I:C))-inducible IFN-alpha by 5-fold in an IFN-gamma-dependent fashion, but did not significantly increase IFN-alpha production to CpG or Pam(3)Cys challenges. Poly(IC)-stimulated splenocytes from anti-CD40-pretreated mice produced 4-fold more IFN-alpha than controls and production associated with CD11c(+) cells. Finally, rIFN-gamma and anti-CD40 combined synergistically to increase poly(IC)-inducible IFN-alpha synthetic capacity in bone marrow dendritic cells. We conclude that innate immune production of IFN-alpha is cooperatively regulated by CD40 and IFN-gamma acting on dendritic cells, suggesting a unique mechanism by which innate immune function evolves in response to specific adaptive immune signals.

Distinct modulatory effects of LPS and CpG on IL-18-dependent IFN-gamma synthesis.

Innate cellular production of IFN-gamma is suppressed after repeated exposure to LPS, whereas CpG-containing DNA potentiates IFN-gamma production. We compared the modulatory effects of LPS and CpG on specific cellular and cytokine responses necessary for NK-cell dependent IFN-gamma synthesis. C3H/HeN mice pretreated with LPS for 2 days generated 5-fold less circulating IL-12 p70 and IFN-gamma in response to subsequent LPS challenge than did challenged control mice. In contrast, CpG-pretreated mice produced 10-fold more circulating IFN-gamma without similar changes in IL-12 p70 levels, but with 10-fold increases in serum IL-18 relative to LPS-challenged control or endotoxin-tolerant mice. The role of IL-18 in CpG-induced immune potentiation was studied in splenocyte cultures from control, LPS-conditioned, or CpG-conditioned mice. These cultures produced similar amounts of IFN-gamma in response to rIL-12 and rIL-18. However, only CpG-conditioned cells produced IFN-gamma when cultured with LPS or CpG, and production was ablated in the presence of anti-IL-18R Ab. Anti-IL-18R Ab also reduced in vivo IFN-gamma production by >2-fold in CpG-pretreated mice. Finally, combined pretreatment of mice with LPS and CpG suppressed the production of circulating IFN-gamma, IL-12 p70, and IL-18 after subsequent LPS challenge. We conclude that CpG potentiates innate IFN-gamma production from NK cells by increasing IL-18 availability, but that the suppressive effects of LPS on innate cellular immunity dominate during combined LPS and CpG pretreatment. Multiple Toll-like receptor engagement in vivo during infection can result in functional polarization of innate immunity dominated by a specific Toll-like receptor response.