An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages.

Cytosolic pathogen- and damage-associated molecular patterns are sensed by pattern recognition receptors, including members of the nucleotide-binding domain and leucine-rich repeat-containing gene family (NLR), which cause inflammasome assembly and caspase-1 activation to promote maturation and release of the inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18 and induction of pyroptosis. However, the contribution of most of the NLRs to innate immunity, host defense, and inflammasome activation and their specific agonists are still unknown. Here we describe identification and characterization of an NLRP7 inflammasome in human macrophages, which is induced in response to microbial acylated lipopeptides. Activation of NLRP7 promoted ASC-dependent caspase-1 activation, IL-1ß and IL-18 maturation, and restriction of intracellular bacterial replication, but not caspase-1-independent secretion of the proinflammatory cytokines IL-6 and tumor necrosis factor-α. Our study therefore increases our currently limited understanding of NLR activation, inflammasome assembly, and maturation of IL-1ß and IL-18 in human macrophages.

Intimate Partner Violence Experiences Among Men Living with HIV in Rural Appalachia.

There has been limited study of the syndemic link between HIV and intimate partner violence (IPV) among rural populations in the United States. We utilized the Revised Conflict Tactics Scale-2 to examine the past year prevalence, type (psychological aggression, physical assault, and sexual assault), and the impact of IPV on HIV clinical outcomes among men living with HIV in rural Appalachia. Approximately 39% of participants experienced some type of IPV in the preceding year, with 67% of those individuals experiencing more than 1 type of IPV. Approximately 77% of participants endorsing IPV exposure experienced psychological aggression. Most participants exposed to psychological aggression (70%) and/or physical assault (57%) were both victims and perpetrators, and those experiencing sexual assault reported being exclusively victims (65%). There were no significant differences in clinical outcomes including viral load and CD4 count, which may be secondary to small sample size derived from a clinic population with a high rate of virologic suppression (94%). This study demonstrates the need to assess IPV exposure in men living with HIV and further highlights the intricacies of relationship violence in these individuals.

Intracerebral Hemorrhage in a Child with Renal Artery Stenosis and COVID-19.

Pediatric intracerebral hemorrhage is a rare condition among children. We discuss the case of a 7-year-old Filipino male with generalized tonic seizures and diagnosed to have both SARS-CoV-2 infection and hypertension secondary to renal arterial stenosis. The occurrence of intracerebral hemorrhage in children, though commonly caused by arteriovenous malformations, may be secondary to an acute hypertensive episode. In this case, the presence of COVID-19 in the patient may have been contributory to the development of spontaneous intracerebral hemorrhage due to its direct endothelial effects, as well as its dysregulatory action on the renin-angiotensin-aldosterone system.

Thirty-Day Mortality and Complication Rates in Total Joint Arthroplasty After a Recent COVID-19 Diagnosis: A Retrospective Cohort in the National COVID Cohort Collaborative (N3C).

BACKGROUND: The risk of postoperative complications in patients who had a positive COVID-19 test prior to a total joint arthroplasty (TJA) is unknown. The purpose of this investigation was to study the complications and mortality associated with a recent COVID-19 diagnosis prior to TJA. METHODS: Patients undergoing primary and revision total hip arthroplasties (THAs) or total knee arthroplasties (TKAs) were identified using the National COVID Cohort Collaborative (N3C) Data Enclave. Patients were divided into a COVID-19-positive group (positive polymerase chain reaction [PCR] test, clinical diagnosis, or positive antibody test) and a COVID-19-negative group, and the time from diagnosis was noted. There was no differentiation between severity or acuity of illness available. The postoperative complications reviewed included venous thromboembolism, pneumonia, acute myocardial infarction, readmission rates, and 30-day mortality rates. RESULTS: A total of 85,047 patients who underwent elective TJA were included in this study, and 3,516 patients (4.13%) had had a recent positive COVID-19 diagnosis. Patients diagnosed with COVID-19 at 2 weeks prior to TJA were at increased risk of pneumonia (odds ratio [OR], 2.46), acute myocardial infarction (OR, 2.90), sepsis within 90 days (OR, 2.63), and 30-day mortality (OR, 10.61). CONCLUSIONS: Patients with a recent COVID-19 diagnosis prior to TJA are at greater risk of postoperative complications including 30-day mortality. Our analysis presents critical data that should be considered prior to TJA in patients recently diagnosed with COVID-19. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Activation of inflammasomes requires intracellular redistribution of the apoptotic speck-like protein containing a caspase recruitment domain.

Activation of caspase 1 is essential for the maturation and release of IL-1beta and IL-18 and occurs in multiprotein complexes, referred to as inflammasomes. The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is the essential adaptor protein for recruiting pro-caspase 1 into inflammasomes, and consistently gene ablation of ASC abolishes caspase 1 activation and secretion of IL-1beta and IL-18. However, distribution of endogenous ASC has not yet been examined in detail. In the present study, we demonstrated that ASC localized primarily to the nucleus in resting human monocytes/macrophages. Upon pathogen infection, ASC rapidly redistributed to the cytosol, followed by assembly of perinuclear aggregates, containing several inflammasome components, including caspase 1 and Nod-like receptors. Prevention of ASC cytosolic redistribution completely abolished pathogen-induced inflammasome activity, which affirmed that cytosolic localization of ASC is essential for inflammasome function. Thus, our study characterized a novel mechanism of inflammasome regulation in host defense.

Attachment and mental and physical health: self-compassion and mattering as mediators.

Research shows a strong link between adult attachment and mental and physical health, but little is known about the mechanisms that underlie these relationships. The present study examined self-compassion and mattering, two constructs from positive psychology literature, as potential mediators. Using survey data from a sample of 208 college students, relationships among attachment, self-compassion, mattering, and functional health were explored. Correlational analyses indicated that attachment anxiety and avoidance were strongly related to the mental health component of functional health. Mediation analyses indicated that mattering and self-compassion mediated the relationships between attachment orientation (i.e., levels of avoidance and anxiety) and mental health. These findings suggest that individuals' abilities to be kind toward themselves and their sense of belonging and being important to others are pathways through which attachment orientation relates to mental health.

The impact of discontinuing contact precautions for multidrug resistant organisms at a less than 400-bed level II teaching hospital and a community hospital: A 3-month pilot study.

BACKGROUND: The impact of discontinuing contact precautions (CPs) for patients with select multidrug-resistant organisms on bacteremia infection rates was evaluated in this quality improvement project. METHODS: The removal of use of CPs, with increased focus on standard precautions, for all patients with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE) colonization/infection was piloted via a quality improvement project over a 3-month period. RESULTS: CP was discontinued in December 2018. Comparing 3 months pre- and postchange, the overall incidence density rate decreased for hospital-onset (HO) laboratory-identified (LabID) MRSA bacteremia (0.07 vs 0.02; P = .52), whereas HO LabID VRE bacteremia rates remained the same (0.00 vs 0.00). Overall estimated financial savings, including personal protective equipment ($15,375) and staff time ($17,165), was $32,540 for the project period, with annualized estimated savings of $130,160. CONCLUSIONS: In this pilot study evaluating the discontinuance of CPs, there was no evidence of an increase in HO MRSA or VRE LabID bacteremia incidence density rates. This practice change may be safely implemented at similar health care facilities.

Perceived sources of change in trainees' self-efficacy beliefs.

Thought-listing procedures were used to examine the perceived incidence, size, direction, and bases of change in the session-level self-efficacy of therapists in training. Ninety-eight Master's-level trainees completed a cognitive assessment task immediately after each session with a client in their first practicum. Participants typically reported modest-sized, positive changes in their therapeutic self-efficacy at each session. Seven perceived sources of change in self-efficacy were identified. Some of these sources (e.g., trainees' performance evaluations, affective reactions) were consistent with general self-efficacy theory; others reflected the interpersonal performance context of therapy (e.g., perceptions of the therapeutic relationship and client behavior). Implications of the findings for training and future research on therapist development are considered. (PsycINFO Database Record (c) 2010 APA, all rights reserved).

Salmonella neck abscess in a diabetic.

Salmonella is known to cause invasive illness. However, head and neck abscesses are an unusual presentation of extra-intestinal infection with this organism. We describe a case of Salmonella neck abscess in a diabetic patient. An 18 year old diabetic male was admitted with increasing left sided neck pain and swelling approximately four weeks after gastrointestinal illness. Imaging revealed a left sided neck abscess. Surgical drainage was undertaken. Cultures grew non-typhoid Salmonella species. He was treated with intravenous antibiotics and did well clinically. Salmonella infection should be considered in the differential diagnosis of patients with immunocompromising conditions presenting with neck abscess of unclear etiology.

Measuring individual research productivity: A review and development of the integrated research productivity index.

The purpose of the present study was to investigate methods of measuring individual research productivity for counseling psychologists. Using the 60 members of the Journal of Counseling Psychology editorial board, the authors computed a comparison of 6 popular indices of productivity, revealing considerable levels of positive skewness, kurtosis, and overlap with each other. Combining the strengths of the 6 indices, the authors developed a new productivity index entitled the Integrated Research Productivity Index (IRPI). The IRPI measures individual productivity by statistically combining an individual's author-weighted publications, average times cited by other publications, and years since first publication into a comprehensive score. Productivity values and IRPI scores for 3 groups of counseling psychologists (Tyler Award recipients, Kuder Award recipients, and Division 17 Presidents) were computed to provide evidence of discriminant validity among the indices. In contrast to the other measures examined, the IRPI accounts for productivity per year and years in the field and assesses mean citation count per article as opposed to total citation count, thus yielding similar scores for Tyler (lifetime) and Kuder (early career) research award recipients. (PsycINFO Database Record (c) 2010 APA, all rights reserved).

Upregulation of miRNA-4776 in Influenza Virus Infected Bronchial Epithelial Cells Is Associated with Downregulation of NFKBIB and Increased Viral Survival.

Influenza A virus (IAV) infection remains a significant cause of morbidity and mortality worldwide. One key transcription factor that is activated upon IAV infection is nuclear factor Kappa B (NF-κB). NF-κB regulation involves the inhibitor proteins NF-κB inhibitor beta (NFKBIB), (also known as IκB ß), which form complexes with NF-κB to sequester it in the cytoplasm. In this study, microarray data showed differential expression of several microRNAs (miRNAs) on exposure to IAV. Target scan analysis revealed that miR-4776, miR-4514 and miR-4742 potentially target NFKBIB messenger RNA (mRNA). Time-course analysis of primary bronchial epithelial cells (HBEpCs) showed that miR-4776 expression is increased within 1 h of infection, followed by its downregulation 4 h post-exposure to IAV. NFKBIB upregulation of miR-4776 correlated with a decrease in NFKBIB expression within 1 h of infection and a subsequent increase in NFKBIB expression 4 h post-infection. In addition, miRNA ago-immunoprecipitation studies and the three prime untranslated region (3' UTR) luciferase assay confirmed that miR-4776 targets NFKBIB mRNA. Furthermore, uninfected HBEpCs transfected with miR-4776 mimic showed decreased expression of NFKBIB mRNA. Overexpression of NFKBIB protein in IAV infected cells led to lower levels of IAV. Taken together, our data suggest that miRNA-4776 modulates IAV production in infected cells through NFKBIB expression, possibly through the modulation of NF-κB.

Incidence of medically attended influenza during pandemic and post-pandemic seasons through the Influenza Incidence Surveillance Project, 2009-13.

BACKGROUND: Since the introduction of pandemic influenza A (H1N1) to the USA in 2009, the Influenza Incidence Surveillance Project has monitored the burden of influenza in the outpatient setting through population-based surveillance. METHODS: From Oct 1, 2009, to July 31, 2013, outpatient clinics representing 13 health jurisdictions in the USA reported counts of influenza-like illness (fever including cough or sore throat) and all patient visits by age. During four years, staff at 104 unique clinics (range 35-64 per year) with a combined median population of 368,559 (IQR 352,595-428,286) attended 35,663 patients with influenza-like illness and collected 13,925 respiratory specimens. Clinical data and a respiratory specimen for influenza testing by RT-PCR were collected from the first ten patients presenting with influenza-like illness each week. We calculated the incidence of visits for influenza-like illness using the size of the patient population, and the incidence attributable to influenza was extrapolated from the proportion of patients with positive tests each week. FINDINGS: The site-median peak percentage of specimens positive for influenza ranged from 58.3% to 77.8%. Children aged 2 to 17 years had the highest incidence of influenza-associated visits (range 4.2-28.0 per 1000 people by year), and adults older than 65 years had the lowest (range 0.5-3.5 per 1000 population). Influenza A H3N2, pandemic H1N1, and influenza B equally co-circulated in the first post-pandemic season, whereas H3N2 predominated for the next two seasons. Of patients for whom data was available, influenza vaccination was reported in 3289 (28.7%) of 11,459 patients with influenza-like illness, and antivirals were prescribed to 1644 (13.8%) of 11,953 patients. INTERPRETATION: Influenza incidence varied with age groups and by season after the pandemic of 2009 influenza A H1N1. High levels of influenza virus circulation, especially in young children, emphasise the need for additional efforts to increase the uptake of influenza vaccines and antivirals. FUNDING: US Centers for Disease Control and Prevention.

A report of CSF leak as a complication of nasal packing for epistaxis.

While nasal packs are effective in controlling epistaxis, some potential complications are associated with this procedure that physicians should be aware of and take measures to avoid. We report the case of an 80-year-old man who developed cerebrospinal fluid rhinorrhea several hours after he had undergone placement of nasal packing in an emergency department. He was eventually transferred to our facility, where he required a prolonged hospital stay to correct the complication. We also review the literature on various complications of nasal packing, and we emphasize the importance of carefulness when performing intranasal manipulation.

Differential splicing of the apoptosis-associated speck like protein containing a caspase recruitment domain (ASC) regulates inflammasomes.

BACKGROUND: The apoptotic speck-like protein containing a caspase recruitment domain (ASC) is the essential adaptor protein for caspase 1 mediated interleukin (IL)-1beta and IL-18 processing in inflammasomes. It bridges activated Nod like receptors (NLRs), which are a family of cytosolic pattern recognition receptors of the innate immune system, with caspase 1, resulting in caspase 1 activation and subsequent processing of caspase 1 substrates. Hence, macrophages from ASC deficient mice are impaired in their ability to produce bioactive IL-1beta. Furthermore, we recently showed that ASC translocates from the nucleus to the cytosol in response to inflammatory stimulation in order to promote an inflammasome response, which triggers IL-1beta processing and secretion. However, the precise regulation of inflammasomes at the level of ASC is still not completely understood. In this study we identified and characterized three novel ASC isoforms for their ability to function as an inflammasome adaptor. METHODS: To establish the ability of ASC and ASC isoforms as functional inflammasome adaptors, IL-1beta processing and secretion was investigated by ELISA in inflammasome reconstitution assays, stable expression in THP-1 and J774A1 cells, and by restoring the lack of endogenous ASC in mouse RAW264.7 macrophages. In addition, the localization of ASC and ASC isoforms was determined by immunofluorescence staining. RESULTS: The three novel ASC isoforms, ASC-b, ASC-c and ASC-d display unique and distinct capabilities to each other and to full length ASC in respect to their function as an inflammasome adaptor, with one of the isoforms even showing an inhibitory effect. Consistently, only the activating isoforms of ASC, ASC and ASC-b, co-localized with NLRP3 and caspase 1, while the inhibitory isoform ASC-c, co-localized only with caspase 1, but not with NLRP3. ASC-d did not co-localize with NLRP3 or with caspase 1 and consistently lacked the ability to function as an inflammasome adaptor and its precise function and relation to ASC will need further investigation. CONCLUSIONS: Alternative splicing and potentially other editing mechanisms generate ASC isoforms with distinct abilities to function as inflammasome adaptor, which is potentially utilized to regulate inflammasomes during the inflammatory host response.

A Shope Fibroma virus PYRIN-only protein modulates the host immune response.

PYRIN domain (PYD) proteins have recently emerged as important signaling molecules involved in the development of innate immunity to intracellular pathogens through activation of inflammatory mediator pathways. ASC is the central adaptor protein, which links pathogen recognition by PYD-containing pathogen recognition receptors to the activation of downstream effectors, including activation of Caspase-1 and NF-kappaB. The cellular PYD-only protein 1 (cPOP1) can block the recruitment of ASC to activated PAN receptors and thereby functions as an endogenous inhibitor of the PYD-mediated signal transduction pathway. Here we describe the identification and characterization of a Shope Fibroma homolog to cPOP1. Like cPOP1, a Shope Fibroma virus-encoded POP (vPOP), co-localizes and directly associates with ASC and inhibits PYD-mediated signal transduction. Poxviruses are known to encode immune evasive proteins to promote host cell infection and suppression of the host immune response. Poxvirus-encoded vPOPs represent a novel class of immune evasive proteins and impair the host response by blocking Cryopyrin and ASC inflammasome-mediated activation of pro-Caspase-1 and subsequent processing of pro-interleukin (IL)-1beta, and expression of vPOPs causes activation of NF-kappaB.

Cellular pyrin domain-only protein 2 is a candidate regulator of inflammasome activation.

Pyrin domain (PYD) proteins have recently emerged as important signaling molecules involved in the development of innate immunity against intracellular pathogens through activation of inflammatory mediator pathways. ASC is the central adaptor protein, which links pathogen recognition by PYD-containing pathogen recognition receptors, known as PYD-Nod-like receptors (NLR), PAN, PYPAF, NALP, Nod, and Caterpiller proteins, to the activation of downstream effectors, including activation of caspase-1 and NF-kappaB. Activation of these effectors occurs when specific protein complexes, known as inflammasomes, are formed. PYD signal transduction leads to inflammasome assembly and activation of specific effector proteins. It is modulated by a cellular PYD-only protein (cPOP1), which binds to ASC and interferes with the recruitment of ASC to activated PYD-NLRs. Here we describe the identification and characterization of a second cellular POP (cPOP2), which shows highest homology to the PYD of PAN1. cPOP2 binds to ASC and PAN1, thereby blocking formation of cryopyrin and PAN1-containing inflammasomes, activation of caspase-1, and subsequent processing and secretion of bioactive interleukin-1beta. Existence of a second cPOP provides additional insights into inflammasome formation and suggests that POPs might be a common regulatory mechanism to "fine-tune" the activity of specific PYD-NLR family protein-containing inflammasomes.