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Abstract Background A better understanding of the pathogenesis of polyarticular juvenile idiopathic arthritis (polyJIA) is needed to aide in the development of data-driven approaches to guide selection between therapeutic options. One inflammatory pathway of interest is JAK-STAT signaling. STAT3 is a transcription factor critical to the differentiation of inflammatory T helper 17 cells (Th17s). Previous studies have demonstrated increased STAT3 activation in adult patients with rheumatoid arthritis, but less is known about STAT3 activation in polyJIA. We hypothesized that Th17 cells and STAT3 activation would be increased in treatment-naïve polyJIA patients compared to pediatric controls. Methods Blood from 17 patients with polyJIA was collected at initial diagnosis and again if remission was achieved (post-treatment). Pediatric healthy controls were also collected. Peripheral blood mononuclear cells were isolated and CD4 + T cell subsets and STAT activation (phosphorylation) were evaluated using flow cytometry. Data were analyzed using Mann–Whitney U and Wilcoxon matched-pairs signed rank tests. Results Treatment-naïve polyJIA patients had increased Th17 cells (CD3 + CD4 + interleukin(IL)-17 +) compared to controls (0.15% v 0.44%, p

Purpose: Sustaining healthcare operations without adequate energy capacity creates significant challenges, especially during periods of constrained energy supply. This research develops a clinical and non-clinical activity-based hospital energy model for electrical load prioritization during periods of constrained energy supply. Design/methodology/approach: Discrete event modelling is adopted for development of the hospital energy model (HEM). The basis of the HEM is business process mapping of the hospitals clinical and non-clinical activities. The model prioritizes the electrical load demand as Priority 1, 2 and 3; with Priority 1 activities essential to the survival of patients, Priority 2 activities are critical activities that are required after one to four hours, and Priority 3 activities can run for several hours without electricity. Findings: The model was applied to a small, medium, and large hospital. The results demonstrate that Priority 2 activities have the highest energy demand, followed by Priority 1 and Priority 3 activities, respectively for all hospital sizes. For the medium and large hospitals, the top three contributors to energy demand are lighting, HVAC, and patient services. For the small hospital, it is patient services, lighting, and HVAC, respectively. Research limitations/implications: The model is specific to hospitals but can be modified for other healthcare facilities. Practical implications: The resolution of the electrical energy demand down to the business activity level, enables hospitals to evaluate current practices for optimization. It facilitates multiple energy supply scenarios, enabling hospital management to conduct feasibility studies based on available power supply options Social implications: Improved planning of capital expenditure and operational budgets and during constrained energy supply. This reduces risk to hospitals and ensures consistent quality of service. Originality/value: Current hospital energy models are limited, especially for operations management under constrained energy supply. A simple to use model is proposed to assist in planning of activities based on available supply.

Mutations in genes coding for proteasome subunits and/or proteasome assembly helpers typically cause recurring autoinflammation referred to as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) or proteasome-associated autoinflammatory syndrome (PRAAS). Patients with CANDLE/PRAAS present with mostly chronically elevated type I interferon scores that emerge as a consequence of increased proteotoxic stress by mechanisms that are not fully understood. Here, we report on five unrelated patients with CANDLE/PRAAS carrying novel inherited proteasome missense and/or nonsense variants. Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10, whereas one patient showed additive loss-of-function mutations in PSMB8. Variants in two previously not associated proteasome genes, PSMA5 and PSMC5, were found in a patient who also carried the PSMB8 founder mutation, p.T75M. All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes. Our observations expand the spectrum of PRAAS-associated genetic variants and improve a molecular diagnosis and genetic counseling of patients with sterile autoinflammation.

The formation of long-lived immune memory cells specific for pathogens is critical for the establishment of long-term immune protection against future infections. BNIP3L/NIX and BNIP3, two functionally redundant BCL2 family members required for mitophagy, undergo significant upregulation after memory B cells are formed. Deletion of Bnip3l and Bnip3 leads to mitochondrial accumulation, and increases in oxidative phosphorylation and fatty acid synthesis, resulting in the loss of memory B cells. These observations suggest that after the formation of memory B cells, mitophagy is critical for clearing superfluous mitochondria to re-shape the metabolic programs, thereby protecting the metabolic quiescence and longevity of memory B cells .

The HIV-1 reservoirs harbor the latent proviruses that are integrated into the host genome. It is a challenging task to eradicate the proviruses in order to achieve an HIV cure. We have described a strategy for the clearance of HIV-1 infection through selective elimination of host cells harboring replication-competent HIV (SECH), by inhibition of autophagy and promotion of apoptosis during viral re-activation. HIV-1 can infect various CD4+ T cell subsets, but it is not known whether the SECH approach is equally effective in targeting HIV-1 reservoirs in these different subsets in vivo. In a humanized mouse model, we found that treatments of HIV-1 infection by suppressive antiretroviral therapy (ART) led to the establishment of latent HIV reservoirs in naïve, central memory and effector memory T cells. Moreover, SECH treatments could clear latent HIV-1 reservoirs in these different T cell subsets of humanized mice. Co-culture studies showed that T cell subsets latently infected by HIV-1, but not uninfected bystander cells, were susceptible to cell death induced by SECH treatments. Our study suggests that the SECH strategy is effective for specific targeting of latent HIV-1 reservoirs in different T cell subsets.

We conducted an observational descriptive study evaluating the effectiveness of therapeutic modification of lifestyle with adding of 1000 mg of myo-inositol and 200 mg of D-chiro inositol combination (ratio 5:1) for nutritional support in 104 women of reproductive age with polycystic ovary syndrome (classic phenotype and nonclassical phenotypes in the presence of hyperandrogenism) for 6 months. Revealed changes in anthropometric parameters (decrease in body mass index by 0.89 kg/m2; p0.05 and waist circumference by 3.0 cm; p0.05), skin status (decrease in the incidence of acne from 96.2 up to 58.6%; p0.05 and seborrhea from 34.6 to 5.8%; p0.05), hormonal profile (statistically significant change in all studied parameters; p0.05: decrease in total testosterone to 1.27 nmol/L and a free androgen index up to 4.12% under an increase in globulin binding sex hormones), carbohydrate metabolism (normalization of glucose tolerance without the development of hypoglycemia) and restoration of menstrual cycle (MC) parameters (regular MC in 76.9 %; p0.05, MC duration 33.4 days; p0.05) indicate a significant role of stage I therapy in patients with polycystic ovary syndrome and the possible benefits of 1000 mg of myo-inositol and 200 mg of D-chiro inositol combination as a nutritional support.

Mitochondrial disruption leads to the release of cytochrome c to activate caspase-9 and the downstream caspase cascade for the execution of apoptosis. However, cell death can proceed efficiently in the absence of caspase-9 following mitochondrial disruption, suggesting the existence of caspase-9-independent cell death mechanisms. Through a genome-wide siRNA library screening, we identified a network of genes that mediate caspase-9-independent cell death, through ROS production and Alox5-dependent membrane lipid peroxidation. Erk1-dependent phosphorylation of Alox5 is critical for targeting Alox5 to the nuclear membrane to mediate lipid peroxidation, resulting in nuclear translocation of cytolytic molecules to induce DNA damage and cell death. Consistently, double knockouts of caspase-9 and Alox5 in mice, but not deletion of either gene alone, led to significant T cell expansion with inhibited cell death, indicating that caspase-9- and Alox5-dependent pathways function in parallel to regulate T cell death in vivo. This unbiased whole-genome screening reveals an Erk1-Alox5-mediated pathway that promotes membrane lipid peroxidation and nuclear translocation of cytolytic molecules, leading to the execution of cell death in parallel to the caspase-9 signaling cascade.

Mitochondrial reactive oxygen species (mtROS) generated continuously under physiological conditions have recently emerged as critical players in the regulation of immune signaling pathways. In this study we have investigated the regulation of antiviral signaling by increased mtROS production in plasmacytoid dendritic cells (pDCs), which, as major producers of type I interferons (IFN), are the key coordinators of antiviral immunity. The early phase of type I IFN production in pDCs is mediated by endosomal Toll-like receptors (TLRs), whereas the late phase of IFN response can also be triggered by cytosolic retinoic acid-inducible gene-I (RIG-I), expression of which is induced upon TLR stimulation. Therefore, pDCs provide an ideal model to study the impact of elevated mtROS on the antiviral signaling pathways initiated by receptors with distinct subcellular localization. We found that elevated level of mtROS alone did not change the phenotype and the baseline cytokine profile of resting pDCs. Nevertheless increased mtROS levels in pDCs lowered the TLR9-induced secretion of pro-inflammatory mediators slightly, whereas reduced type I IFN production markedly via blocking phosphorylation of interferon regulatory factor 7 (IRF7), the key transcription factor of the TLR9 signaling pathway. The TLR9-induced expression of RIG-I in pDCs was also negatively regulated by enhanced mtROS production. On the contrary, elevated mtROS significantly augmented the RIG-I-stimulated expression of type I IFNs, as well as the expression of mitochondrial antiviral-signaling (MAVS) protein and the phosphorylation of Akt and IRF3 that are essential components of RIG-I signaling. Collectively, our data suggest that increased mtROS exert diverse immunoregulatory functions in pDCs both in the early and late phase of type I IFN responses depending on which type of viral sensing pathway is stimulated.

Objective: Autoantibodies recognizing specificity protein 4 (Sp4) were recently discovered in adults with idiopathic inflammatory myopathies (IIM). Anti‐Sp4 autoantibodies co‐occurred in patients with anti–transcription intermediary factor 1 (anti‐TIF1) autoantibody‐positive dermatomyositis (DM) and were associated with a reduced risk of cancer. In the present study, the prevalence and clinical features associated with anti‐Sp4 autoantibodies in juvenile‐onset IIM were investigated. Methods: Serum samples from 336 patients with juvenile myositis in a cross‐sectional cohort and 91 healthy controls were screened for anti‐Sp4 autoantibodies using enzyme‐linked immunosorbent assay. Clinical characteristics, outcomes, and HLA alleles of those with and those without anti‐Sp4 autoantibodies were compared. Results: Anti‐Sp4 autoantibodies were present in 23 patients (7%) with juvenile myositis and were not present in any of the controls. Anti‐Sp4 autoantibodies were found among each clinical myositis subgroup. The frequency of TIF1 autoantibody positivity was significantly higher among those with anti‐Sp4 autoantibodies (21 [91%] versus 92 [30%], P < 0.001). In the anti‐TIF1 autoantibody–positive subgroup, Raynaud's phenomenon (8 [38%] versus 2 [2%], P < 0.001) was more common and peak aspartate aminotransferase was significantly lower in those with anti‐Sp4 autoantibodies. None of the patients with anti‐Sp4 autoantibodies required a wheelchair. Among White patients, DQA1*04 and DRB1*08 were associated with anti‐Sp4 autoantibodies. Conclusion: Anti‐Sp4 autoantibodies were found in patients with juvenile‐onset IIM, predominantly those with coexisting anti‐TIF1 autoantibodies. Patients with anti‐Sp4 autoantibodies represent a phenotypic subset of anti‐TIF1 autoantibody–positive myositis characterized by frequent Raynaud's phenomenon and less pronounced muscle involvement, similar to adults with these autoantibodies. Novel immunogenetic risk factors for White patients with IIM were identified among juveniles with anti‐Sp4 autoantibodies. [ABSTRACT FROM AUTHOR]

This profile describes the University of Hartford's new Master of Education degree program in Aural Habilitation and Education of Hearing-Impaired Children. The Aural Habilitation and Education graduate program was conceptualized as a model partnership between Capitol Region Education Council (CREC) Soundbridge, the largest public provider of services to children who are deaf or hard of hearing and their families in Connecticut, and the University of Hartford, "a private university with a public purpose." The program was specifically created to address the nationally recognized need to increase the quality and quantity of professionals in auditory-based deaf education who are prepared to work with advanced hearing technology to promote the listening and spoken language development of children who are deaf or hard of hearing. As a result of 9 years of sustained effort, planning, and approvals, the program was launched in July 2007. (Contains 1 table.)

Purpose: Sustaining healthcare operations without adequate energy capacity creates significant challenges, especially during periods of constrained energy supply. This research develops a clinical and non-clinical activity-based hospital energy model for electrical load prioritization during periods of constrained energy supply. Design/methodology/approach: Discrete event modelling is adopted for development of the hospital energy model (HEM). The building block of the HEM is business process mapping of a hospitals clinical and non-clinical activities. The model prioritizes the electrical load demand as Priority 1, 2 and 3; Priority 1 activities are essential to the survival of patients, Priority 2 activities are critical activities that are required after one to four hours, and Priority 3 activities can run for several hours without electricity. Findings: The model was applied to small, medium, and large hospitals. The results demonstrate that Priority 2 activities have the highest energy demand, followed by Priority 1 and Priority 3 activities, respectively for all hospital sizes. For the medium and large hospitals, the top three contributors to energy demand are lighting, HVAC, and patient services. For the small hospital, it is patient services, lighting, and HVAC. Research limitations/implications: The model is specific to hospitals but can be modified for other healthcare facilities. Practical implications: The resolution of the electrical energy demand down to the business activity level enables hospitals to evaluate current practices for optimization. It facilitates multiple energy supply scenarios, enabling hospital management to conduct feasibility studies based on available power supply options. Social implications: Improved planning of capital expenditure and operational budgets. Improved operations during periods of constrained energy supply, which reduces the risk to hospitals and ensures consistent quality of service. Originality/value: Current hospital energy models are limited, especially for operations management under constrained energy supply. A simple to use model is proposed to assist in planning of activities based on available supply. [ABSTRACT FROM AUTHOR]

The reservoirs of the HIV display cellular properties resembling long‐lived immune memory cells that could be exploited for viral clearance. Our interest in developing a cure for HIV stems from the studies of immunologic memory against infections. We and others have found that long‐lived immune memory cells employ prosurvival autophagy and antiapoptotic mechanisms to protect their longevity. Here, we describe the rationale for the development of an approach to clear HIV‐1 by selective elimination of host cells harboring replication‐competent HIV (SECH). While reactivation of HIV‐1 in the host cells with latency reversing agents (LRAs) induces viral gene expression leading to cell death, LRAs also simultaneously up‐regulate prosurvival antiapoptotic molecules and autophagy. Mechanistically, transcription factors that promote HIV‐1 LTR‐directed gene expression, such as NF‐κB, AP‐1, and Hif‐1α, can also enhance the expression of cellular genes essential for cell survival and metabolic regulation, including Bcl‐xL, Mcl‐1, and autophagy genes. In the SECH approach, we inhibit the prosurvival antiapoptotic molecules and autophagy induced by LRAs, thereby allowing maximum killing of host cells by the induced HIV‐1 proteins. SECH treatments cleared HIV‐1 infections in humanized mice in vivo and in HIV‐1 patient PBMCs ex vivo. SECH also cleared infections by the SIV in rhesus macaque PBMCs ex vivo. Research efforts are underway to improve the efficacy and safety of SECH and to facilitate the development of SECH as a therapeutic approach for treating people with HIV. [ABSTRACT FROM AUTHOR]

Mitochondrial disruption leads to the release of cytochrome c to activate caspase-9 and the downstream caspase cascade for the execution of apoptosis. However, cell death can proceed efficiently in the absence of caspase-9 following mitochondrial disruption, suggesting the existence of caspase-9-independent cell death mechanisms. Through a genome-wide siRNA library screening, we identified a network of genes that mediate caspase-9-independent cell death, through ROS production and Alox5-dependent membrane lipid peroxidation. Erk1-dependent phosphorylation of Alox5 is critical for targeting Alox5 to the nuclear membrane to mediate lipid peroxidation, resulting in nuclear translocation of cytolytic molecules to induce DNA damage and cell death. Consistently, double knockouts of caspase-9 and Alox5 in mice, but not deletion of either gene alone, led to significant T cell expansion with inhibited cell death, indicating that caspase-9- and Alox5-dependent pathways function in parallel to regulate T cell death in vivo. This unbiased whole-genome screening reveals an Erk1-Alox5-mediated pathway that promotes membrane lipid peroxidation and nuclear translocation of cytolytic molecules, leading to the execution of cell death in parallel to the caspase-9 signaling cascade. [ABSTRACT FROM AUTHOR]

Our innate immune system distinguishes microbes from self by detecting conserved pathogen-associated molecular patterns (1). However, these are produced by all microbes, regardless of their pathogenic potential. To distinguish virulent [...]

Objectives: Our goal was to optimize infection control of paired environmental control interventions within hospitals to reduce methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Enterobacteriaceae (CRE), and vancomycin-resistant Enterococci (VRE). Background: The most widely used infection control interventions are deployment of handwashing (HW) stations, control of relative humidity (RH), and negative pressure (NP) treatment rooms. Direct costs of multidrug-resistant organism (MDRO) infections are typically not included in the design of such interventions. Methods: We examined the effectiveness of pairing HW with RH and HW with NP. We used the following three data sets: A meta-analysis of progression rates from uncolonized to colonized to infected, 6 years of MDRO treatment costs from 400 hospitals, and 8 years of MDRO incidence rates at nine army hospitals. We used these data as inputs into an Infection De-Escalation Model with varying budgets to obtain optimal intervention designs. We then computed the infection and prevention rates and cost savings resulting from these designs. Results: The average direct cost of an MDRO infection was $3,289, $1,535, and $1,067 for MRSA, CRE, and VRE. The mean annual incidence rates per facility were 0.39%, 0.034%, and 0.011% for MRSA, CRE, and VRE. After applying the cost-minimizing intervention pair to each scenario, the percentage reductions in infections (and annual direct cost savings) in large, community, and small acute care hospitals were 69% ($1.5 million), 73% ($631K), 60% ($118K) for MRSA, 52% ($460.5K), 58% ($203K), 50% ($37K) for CRE, and 0%, 0%, and 50% ($12.8K) for VRE. Conclusion: The application of this Infection De-Escalation Model can guide cost-effective decision making in hospital built environment design to improve control of MDRO infections. [ABSTRACT FROM AUTHOR]

Recent advances in techniques to differentiate human induced pluripotent stem cells (hiPSCs) hold the promise of an unlimited supply of human derived cardiac cells from both healthy and disease populations. That promise has been tempered by the observation that hiPSC-derived cardiomyocytes (hiPSC-CMs) typically retain a fetal-like phenotype, raising concern about the translatability of the in vitro data obtained to drug safety, discovery, and development studies. The Biowire II platform was used to generate 3D engineered cardiac tissues (ECTs) from hiPSC-CMs and cardiac fibroblasts. Long term electrical stimulation was employed to obtain ECTs that possess a phenotype like that of adult human myocardium including a lack of spontaneous beating, the presence of a positive force-frequency response from 1 to 4 Hz and prominent postrest potentiation. Pharmacology studies were performed in the ECTs to confirm the presence and functionality of pathways that modulate cardiac contractility in humans. Canonical responses were observed for compounds that act via the β-adrenergic/cAMP-mediated pathway, eg, isoproterenol and milrinone; the L-type calcium channel, eg, FPL64176 and nifedipine; and indirectly effect intracellular Ca2+ concentrations, eg, digoxin. Expected positive inotropic responses were observed for compounds that modulate proteins of the cardiac sarcomere, eg, omecamtiv mecarbil and levosimendan. ECTs generated in the Biowire II platform display adult-like properties and have canonical responses to cardiotherapeutic and cardiotoxic agents that affect contractility in humans via a variety of mechanisms. These data demonstrate that this human-based model can be used to assess the effects of novel compounds on contractility early in the drug discovery and development process. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study is to determine the optimal allocation of budgets for pairs of alterations that reduce pathogenic bacterial transmission. Three alterations of the built environment are examined: handwashing stations (HW), relative humidity control (RH), and negatively pressured treatment rooms (NP). These interventions were evaluated to minimize total cost of healthcare-associated infections (HAIs), including medical and litigation costs. Background: HAIs are largely preventable but are difficult to control because of their multiple mechanisms of transmission. Moreover, the costs of HAIs and resulting mortality are increasing with the latest estimates at US$9.8 billion annually. Method: Using 6 years of longitudinal multidrug-resistant infection data, we simulated the transmission of pathogenic bacteria and the infection control efforts of the three alterations using Chamchod and Ruan's model. We determined the optimal budget allocations among the alterations by representing them under Karush–Kuhn–Tucker conditions for this nonlinear optimization problem. Results: We examined 24 scenarios using three virulence levels across three facility sizes with varying budget levels. We found that in general, most of the budget is allocated to the NP or RH alterations in each intervention. At lower budgets, however, it was necessary to use the lower cost alterations, HW or RH. Conclusions: Mathematical optimization offers healthcare enterprise executives and engineers a tool to assist with the design of safer healthcare facilities within a fiscally constrained environment. Herein, models were developed for the optimal allocation of funds between HW, RH, and negatively pressured treatment rooms (NP) to best reduce HAIs. Specific strategies vary by facility size and virulence. [ABSTRACT FROM AUTHOR]