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The aim of this article is to briefly introduce and to examine the views of the founders of the four Sunni schools of Islamic jurisprudence (namely, Abū Hanīfa Nuʻmān ibn Thābit, Mālik ibn Anas, Muhammad ibn Idrīs al-Shāfʻī, and Ahmad ibn Hanbal) and that of their renowned students and followers, regarding the legitimacy of engaging in the study of Islamic doctrinal beliefs or Kalām. Different, and often conflicting, views have been postulated on this matter. Some Sunni thinkers have condemned the pursuit of theology as an act of heresy and denounced its practitioners as apostates. Other Sunni thinkers have extolled this discipline as the noblest of sciences whose learning and teaching are, at least under certain circumstances, incumbent. This fundamental dispute regarding the legitimacy of the discipline of theology has resulted in a rather contentious and opaque scholarly environment. In addition to the inherent importance of the discipline of theology as such, the significance of this dispute is compounded by the impact that the attitude one adopts toward this discipline can have on the development of the intellectual and rational aspects of Islam. A negative attitude toward theology, for example, can hamper the application of rational elements to Islamic doctrine. Our focus in this article is on analysing the views of the leading thinkers and jurists of the Sunni school and investigating the most authoritative sources of doctrinal tradition within this major denomination of Islam. Our study leads us to conclude that the disapproving views of the preeminent Sunni figures should be construed, not as a denunciation of the discipline of theology per se, but as a refutation of certain theological principles and persuasions that are viewed as incompatible with orthodox Islamic faith. In addition to and preceding that conclusion, this article provides a survey of the literature concerning the views of Muslim scholars on the legitimacy of Kalām. After categorising these views into the two opposite camps of Kalam’s legitimacy and illegitimacy, the article then proceeds to evaluate and critically analyse them, and to resolve some of their initial incompatibilities. Contribution: The article sheds new light on the historical development of the discipline of theology within the Sunni schools of Islam. This is a little-studied and often overlooked subject that can help in attaining a better understanding of how this critical field within religious studies has emerged into its present form.

Background & Objectives: Urinary calculi are a common problem worldwide. The pattern of fluid consumption in healthy people and patients with renal calculi is not totally clear. The aim of this study was to determine the association between the amount of fluids intake and urinary calculi. Methods: In this case-control study, cases were the patients with urinary calculi admitted to Emam-Hossein Hospital, Shahroud, Iran. The controls were selected among the patients admitted to other wards of the hospital except for dialysis and ICU wards. The association between independent variables and urinary calculi was investigated using logistic regression analysis. Results: A total of 127 people (60 cases and 67 controls) participated in this study. The mean age of the participants was 44.6 years (SD = 1.7). The mean intake of tea, natural juice, alcohol free beer, and total fluid intake were higher in cases compare to controls. In participants with a negative history of urinary calculi, the total intake of fluid (P=0.021) and natural juice (P=0.006) was higher in cases. The male gender (OR=3.2), higher BMI (OR=1.2), and a positive family history of urinary calculi (OR=3.5) were associated with renal calculi in a multivariate logistic regression model, while the milk intake (OR=0.995) was a protective factor in this model. Conclusion: Milk intake is a protective factor and the male gender, higher BMI and a positive family history are the risk factors for urinary calculi.

Objective: The p.E148Q variant in pyrin is present in different populations at a frequency of up to 29%, and has been associated with diseases, including vasculitis and FMF. The pathogenicity of p.E148Q in FMF is unclear, even when observed in cis or in trans to a single, typically recessive, pathogenic mutation. We performed functional validation to determine whether p.E148Q increases the ability of pyrin to form an active inflammasome complex in cell lines., Methods: We interrogated the Australian Autoinflammatory Disease RegistrY (AADRY) to find candidate inheritance patterns for the p.E148Q variant in pyrin. Different pyrin variant combinations were tested in HEK293T cells stably expressing the adaptor protein apoptosis-associated speck-like (ASC), which were analysed by flow cytometry to visualize inflammasome formation, with and without stimulation by Clostridioides difficile toxin B (TcdB). Inflammasome-dependent cytokine secretion was also quantified by ELISA of supernatants from THP-1 cells transduced with lentiviral expression vectors., Results: In AADRY, we observed the p.E148Q allele in individuals with autoinflammatory diseases alone or in conjunction with other pyrin variants. Two FMF families harboured the allele p.E148Q-M694I in cis with dominant heritability. In vitro, p.E148Q pyrin could spontaneously potentiate inflammasome formation, with increased IL-1β and IL-18 secretion. p.E148Q in cis to classical FMF mutations provided significant potentiation of inflammasome formation., Conclusion: The p.E148Q variant in pyrin potentiates inflammasome activation in vitro. In cis, this effect is additive to known pathogenic FMF mutations. In some families, this increased effect could explain why FMF segregates as an apparently dominant disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: The objective was to review COVID-19 vaccine allergy advice and guidance requests received and assess the impact of advice outcome on vaccination outcome., Design: A retrospective analysis of requests for advice and guidance regarding COVID-19 vaccine allergy was completed using an electronic referral system from February 2021 to January 2022., Participants: A total of 1265 independent patient requests for advice were received from primary care. Full vaccination information was available on 1210 patients who were included in the analysis., Main Outcome Measures: We evaluated the specific outcome of request for advice (written advice versus allergy consultation), rate of vaccination, vaccination combinations, and tolerance of vaccination., Results: Of the 1210 patients included, 959 (79%) were female. Eight hundred and ninety-six (74%) requests were managed with written advice only and of these 675 (75%) patients went on to be vaccinated. Overall, 891 (74%) of the population were vaccinated with 2 or more doses.Two hundred and nineteen patient consultations were undertaken with 109 (50%) prior to the first vaccination. Forty-nine (45%) consultations prior to vaccination were undertaken due to a label of anaphylaxis to vaccination in the past. Vaccination was recommended for all patients, and 78 (72%) of these received a first dose. Eight of these patients (10%) had symptoms within 1 h of vaccine administration.One hundred and ten (50%) consultations were undertaken for adverse reactions post COVID-19 vaccination, with 84 (76%) concerning immediate symptoms. Thirty patients (27%) who had a consultation had had adrenaline administered post vaccination. One patient had biopsy confirmed Stevens Johnson Syndrome and was referred to Dermatology. All others due for further doses (107 patients) were recommended to have subsequent doses with 49 (45%) offered the same vaccine. Eighty-nine patients had a vaccine administered post adverse reaction and 79 (88%) tolerated the dose.Skin testing and challenge to polyethylene glycol were negative in the 8 patients tested., Conclusions: Over 1000 requests for advice and guidance were received during the review period, managed mainly with written advice. The overwhelming majority of requests for advice and consultations were for females, with equal distribution both pre- and post-COVID-19 vaccine administration. Vaccination was recommended in all but 1 patient (with biopsy confirmed Stevens Johnson Syndrome). Polyethylene glycol allergy was not confirmed in any patient, nor did any patient have confirmed anaphylaxis when the vaccine was administered under our supervision, suggesting that type 1 mediated hypersensitivity is uncommon even in this "high risk" population., (© 2022 The Authors.)

In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to the hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir, and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count, and the presence of co-morbidities are additional risk factors for poor outcome in this cohort., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology.)

Background: B cells play an important role in protection against viral infections, not only through the production of antibodies but also through their ability to act as antigen-presenting cells and produce cytokines., Objectives: To assess whether there is a link between low circulating B-cell counts and a predisposition to viral infections in immunocompromised individuals, we performed a retrospective cohort analysis at 2 National Health Service Clinical Immunology sites in England., Methods: Eligible patients were adults who were either diagnosed with or under investigation for an immunodeficiency and had recorded circulating B-cell counts. Information on viral infections was collected by using the departmental, hospital, and laboratory electronic information systems. A generalized linear model was used to analyze the relationship between B-cell counts and relevant indices of viral infection while controlling for patient age, diagnosis group, and T-cell and natural killer cell counts., Results: A total of 376 eligible patients were identified, 134 of whom had B-cell counts that were below the laboratory-defined refence range (<0.11 ×10 9 /L). Patients with low numbers of circulating B cells had lower pretreatment immunoglobulin levels and poorer antibody responses to vaccines ( Streptococcus pneumonia , Clostridium tetani, and Haemophilus influenzae type B ). An increased number of chronic or recurrent ( P  = .001), severe or unusual ( P  = .001), and PCR-confirmed viral infections ( P  = .04) were recorded in these patients versus in those with normal numbers of circulating B cells., Conclusion: Overall, there was a statistically significant association between low circulating B-cell counts and the incidence of clinically important viral infections in this patient cohort, even when controlling for relevant covariates. Clinicians caring for patients with immunodeficiency should be vigilant for these types of infections, particularly in patients with low peripheral B-cell counts. A prospective study will be required to confirm these findings., (© 2022 The Author(s).)

Proteasome dysfunction can lead to autoinflammatory disease associated with elevated type I interferon (IFN-αβ) and NF-κB signaling; however, the innate immune pathway driving this is currently unknown. Here, we identified protein kinase R (PKR) as an innate immune sensor for proteotoxic stress. PKR activation was observed in cellular models of decreased proteasome function and in multiple cell types from patients with proteasome-associated autoinflammatory disease (PRAAS). Furthermore, genetic deletion or small-molecule inhibition of PKR in vitro ameliorated inflammation driven by proteasome deficiency. In vivo, proteasome inhibitor-induced inflammatory gene transcription was blunted in PKR-deficient mice compared with littermate controls. PKR also acted as a rheostat for proteotoxic stress by triggering phosphorylation of eIF2α, which can prevent the translation of new proteins to restore homeostasis. Although traditionally known as a sensor of RNA, under conditions of proteasome dysfunction, PKR sensed the cytoplasmic accumulation of a known interactor, interleukin-24 (IL-24). When misfolded IL-24 egress into the cytosol was blocked by inhibition of the endoplasmic reticulum-associated degradation pathway, PKR activation and subsequent inflammatory signaling were blunted. Cytokines such as IL-24 are normally secreted from cells; therefore, cytoplasmic accumulation of IL-24 represents an internal danger-associated molecular pattern. Thus, we have identified a mechanism by which proteotoxic stress is detected, causing inflammation observed in the disease PRAAS.

Purpose: NLRC4-associated autoinflammatory disease (NLRC4-AID) is an autosomal dominant condition presenting with a range of clinical manifestations which can include macrophage activation syndrome (MAS) and severe enterocolitis. We now report the first homozygous mutation in NLRC4 (c.478G > A, p.A160T) causing autoinflammatory disease with immune dysregulation and find that heterozygous carriers in the general population are at increased risk of developing ulcerative colitis., Methods: Circulating immune cells and inflammatory markers were profiled and historical clinical data interrogated. DNA was extracted and sequenced using standard procedures. Inflammasome activation assays for ASC speck formation, pyroptosis, and IL-1β/IL-18 secretion confirmed pathogenicity of the mutation in vitro. Genome-wide association of NLRC4 (A160T) with ulcerative colitis was examined using data from the IBD exomes portal., Results: A 60-year-old Brazilian female patient was evaluated for recurrent episodes of systemic inflammation from six months of age. Episodes were characterized by recurrent low-grade fever, chills, oral ulceration, uveitis, arthralgia, and abdominal pain, followed by diarrhea with mucus and variable skin rash. High doses of corticosteroids were somewhat effective in controlling disease and anti-IL-1β therapy partially controlled symptoms. While on treatment, serum IL-1β and IL-18 levels remained elevated. Genetic investigations identified a homozygous mutation in NLRC4 (A160T), inherited in a recessive fashion. Increased ASC speck formation and IL-1β/IL-18 secretion confirmed pathogenicity when NLRC4 (A160T) was analyzed in human cell lines. This allele is significantly enriched in patients with ulcerative colitis: OR 2.546 (95% 1.778-3.644), P = 0.01305., Conclusion: NLRC4 (A160T) can either cause recessively inherited autoinflammation and immune dysregulation, or function as a heterozygous risk factor for the development of ulcerative colitis., (© 2021. The Author(s).)

The SARS-CoV-2 virus causes COVID-19, an infection capable of causing severe disease and death but which can also be asymptomatic or oligosymptomatic. We investigated whether ABO blood group or secretor status was associated with COVID-19 severity. We investigated secretor status because expression of ABO glycans on secreted proteins and non-erythroid cells are controlled by a fucosyltransferase (FUT2), and inactivating FUT2 mutations result in a non-secretor phenotype which protects against some viral infections. Data combined from healthcare records and our own laboratory tests ( n  = 275) of hospitalized SARS-CoV-2 polymerase chain reaction positive patients confirmed higher than expected numbers of blood group A individuals compared to O (RR = 1.24, CI 95% [1.05, 1.47], p  = 0.0111). There was also a significant association between group A and COVID-19-related cardiovascular complications (RR = 2.56, CI 95% [1.43, 4.55], p  = 0.0011) which is independent of gender. Molecular analysis revealed that group A non-secretors are significantly less likely to be hospitalized than secretors. Testing of convalescent plasma donors, among whom the majority displayed COVID-19 symptoms and only a small minority required hospitalization, group A non-secretors were slightly over-represented. Our findings showed that group A non-secretors are not resistant to infection by SARS-CoV-2, but are more likely to experience a less severe form of associated disease., Competing Interests: The authors declare no competing financial interests., (© 2021 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: The purposes of this study are to investigate mid-term chest computed tomography (CT) findings of coronavirus disease 2019 (COVID-19) pneumonia, assess the rate of complete resolution, and determine the individuals at risk for residual abnormalities., Methods: Fifty-two cases of COVID-19 pneumonia with at least two chest CTs and mean 3-month interval between the initial and follow-up CT were enrolled in this retrospective study. Patients were categorized into two groups: complete resolution and residual disease on follow-up CT. Demographic, clinical, laboratory, and therapeutic data as well as initial and follow-up chest CT scans were compared and analyzed., Results: Thirty patients (57.7%) demonstrate complete resolution of pulmonary findings, and 22 patients (42.3%) had residual disease on follow-up CT. The mean time interval between initial and follow-up CT was 91.3 ± 17.2 and 90.6 ± 14.3 days in the complete resolution and residual groups, respectively. The most common radiologic pattern in residual disease was ground-glass opacities (54.5%), followed by mixed ground-glass and subpleural parenchymal bands (31.8%), and pure parenchymal bands (13.7%). Compared to complete resolution group, patients with residual disease had higher CT severity score on initial exam (10.3 ± 5.4 vs. 7.3 ± 4.6, P value = 0.036), longer duration of hospitalization, higher rate of intensive care unit (ICU) admission, more underlying medical conditions, higher initial WBC count, and higher occurrence rate of leukocytosis in the hospitalization time period (all P values < 0.05)., Conclusion: Extensive lung involvement on initial CT, ICU admission, long duration of hospitalization, presence of underlying medical conditions, high initial WBC count, and development of leukocytosis during the course of disease are associated with more prevalence of chronic lung sequela of COVID-19.

Rationale and Objectives: Identifying CT predictors of mortality in nonelderly healthy patients with COVID-19 pneumonia will aid to distinguish the most vulnerable patients in this age group and thus alter the management. We aimed to evaluate the prognostic value of multiple CT features of COVID-19 pneumonia on initial presentation in nonelderly patients without underlying medical conditions., Methods: In this retrospective case-control study, thirty laboratory-confirmed COVID-19 patients with no known major underlying disease who underwent a chest CT scan and expired of pneumonia within the following 30 days after admission, were included as case group. Sixty control subjects individually matched on their age, gender, without underlying medical conditions, who received same-criteria standard care and were discharged from the hospital in 30-day follow-up were included in the control group. A conditional logistic regression model was applied., Results: Applying a univariate conditional logistic regression model, it was revealed that bilateral lung disease, anterior involvement, central extension, GGO, consolidation, air bronchograms, pleural effusion, BMI ≥ 25 kg/m² and CT severity score were the significant preliminary predictors (all p-values < 0.05). Next, by applying a multivariate conditional logistic regression model, it was determined that the CT severity score is the only statistically significant CT predictor of mortality (Odds Ratio = 1.99, Confidence Interval: 1.01-4.06, p-value < 0.05). The ROC curve analysis revealed a score of 7.5 as the cut-off point of CT severity score with the highest sensitivity (0.83) and specificity (0.87)., Conclusion: Our study demonstrates that CT severity score is a reliable predictor factor of mortality in nonelderly previously healthy individuals with COVID-19 pneumonia. Assessment of disease extension in addition to the morphological pattern is necessary for CT reports of COVID-19 patients. This may alert the clinicians to alter the management for this specific group of patients, even when they are clinically silent or have a mild presentation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS., Competing Interests: Declaration of Interests S.L.M. declares consultancy with IFM Therapeutics and Quench Bio and received funding from GlaxoSmithKline. S.L.M. and C.-H.Y. are named inventors on International Patent Application No. PCT/AU2019051201. All other authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To assess whether certain CT chest features of patients with confirmed coronavirus disease 2019 (COVID-19) may have short-term prognostic value., Materials and Methods: One hundred-twenty consecutive symptomatic patients with COVID-19 infection who had undergone chest CT were enrolled in this retrospective study. Patients were categorized into three groups: routine inward hospitalization, intensive care unit admission, and deceased based on a short-term follow-up. Detailed initial CT features and distributional evaluation were recorded., Results: The mean age in the deceased group was 70.7 years, significantly higher than the other two groups ( P < .05). Ninety-four percent (113/120) of the patients had ground-glass opacities (GGO). Peripheral and lower zone predilection was present in most patients. Subpleural sparing and pleural effusion were seen in approximately 23% (28/120) and 17% (20/120) of the patients, respectively. The combined intensive care unit group and deceased patients had significantly more consolidation, air bronchograms, crazy paving, and central involvement of the lungs compared with routinely hospitalized patients (all P < .05)., Conclusion: This study supports the previously described typical CT appearance of COVID-19 pneumonia with bilateral GGO, in peripheral distribution and lower lung zone predilection. Subpleural sparing and pleural effusion were seen approximately in one-fifth and one-sixth of the patients with COVID-19, respectively. Consolidation, air bronchograms, central lung involvement, crazy paving and pleural effusion on initial CT chest have potential prognostic values, the features more commonly observed in critically ill patients.© RSNA, 2020., Competing Interests: Disclosures of Conflicts of Interest: S.M.H.T. disclosed no relevant relationships. H.T. disclosed no relevant relationships. F.M. disclosed no relevant relationships. H.R. disclosed no relevant relationships., (2020 by the Radiological Society of North America, Inc.)

Stimulator of Interferon Genes (STING) is a critical component of host innate immune defense but can contribute to chronic autoimmune or autoinflammatory disease. Once activated, the cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS)-STING pathway induces both type I interferon (IFN) expression and nuclear factor-κB (NF-κB)-mediated cytokine production. Currently, these two signaling arms are thought to be mediated by a single upstream kinase, TANK-binding kinase 1 (TBK1). Here, using genetic and pharmacological approaches, we show that TBK1 alone is dispensable for STING-induced NF-κB responses in human and mouse immune cells, as well as in vivo. We further demonstrate that TBK1 acts redundantly with IκB kinase ε (IKKε) to drive NF-κB upon STING activation. Interestingly, we show that activation of IFN regulatory factor 3 (IRF3) is highly dependent on TBK1 kinase activity, whereas NF-κB is significantly less sensitive to TBK1/IKKε kinase inhibition. Our work redefines signaling events downstream of cGAS-STING. Our findings further suggest that cGAS-STING will need to be targeted directly to effectively ameliorate the inflammation underpinning disorders associated with STING hyperactivity., Competing Interests: Declaration of Interests S.L.M. receives funding from GlaxoSmithKline., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

The past two decades have seen an exponential increase in the number of monogenic autoinflammatory disorders described, coinciding with improved genetic sequencing techniques. This group of disorders has evolved to be heterogeneous and certainly more complex than the original four 'periodic fever syndromes' caused by innate immune over-activation. This review aims to provide an update on the classic periodic fever syndromes as well as introducing the broadening spectrum of clinical features seen in more recently described conditions., (© 2019 Royal Australasian College of Physicians.)

Inflammasomes are signaling hubs that activate inflammatory caspases to drive cytokine maturation and cell lysis. Inflammasome activation by Salmonella Typhimurium infection or Salmonella-derived molecules is extensively studied in murine myeloid cells. Salmonella-induced inflammasome signaling in human innate immune cells, is however, poorly characterized. Here, we show that Salmonella mutation to inactivate the Salmonella pathogenicity island-2 type III secretion system (SPI2 T3SS) potentiates S. Typhimurium-induced inflammasome responses from primary human macrophages, resulting in strong IL-1β production and macrophage death. Inactivation of the SPI1 T3SS diminished human macrophage responses to WT and ΔSPI2 Salmonella. Salmonella ΔSPI2 elicited a mixed inflammasome response from human myeloid cells, in which NLR family CARD-domain containing protein 4 (NLRC4) and NLR family PYRIN-domain containing protein 3 (NLRP3) perform somewhat redundant functions in generating IL-1β and inducing pyroptosis. Our data suggest that Salmonella employs the SPI2 T3SS to subvert SPI1-induced NLRP3 and NLRC4 inflammasome responses in human primary macrophages, in a species-specific immune evasion mechanism., (©2018 Society for Leukocyte Biology.)

Background: Monogenic autoinflammatory disorders are characterized by dysregulation of the innate immune system, for example by gain-of-function mutations in inflammasome-forming proteins, such as NOD-like receptor family CARD-containing 4 protein (NLRC4)., Objective: Here we investigate the mechanism by which a novel mutation in the leucine-rich repeat (LRR) domain of NLRC4 (c.G1965C, p.W655C) contributes to autoinflammatory disease., Methods: We studied 2 unrelated patients with early-onset macrophage activation syndrome harboring the same de novo mutation in NLRC4. In vitro inflammasome complex formation was quantified by using flow cytometric analysis of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 techniques and lentiviral transduction were used to generate THP-1 cells with either wild-type or mutant NLRC4 cDNA. Cell death and release of IL-1β/IL-18 were quantified by using flow cytometry and ELISA, respectively., Results: The p.W655C NLRC4 mutation caused increased ASC speck formation, caspase-1-dependent cell death, and IL-1β/IL-18 production. ASC contributed to p.W655C NLRC4-mediated cytokine release but not cell death. Mutation of p.W655 activated the NLRC4 inflammasome complex by engaging with 2 interfaces on the opposing LRR domain of the oligomer. One key set of residues (p.D1010, p.D1011, p.L1012, and p.I1015) participated in LRR-LRR oligomerization when triggered by mutant NLRC4 or type 3 secretion system effector (PrgI) stimulation of the NLRC4 inflammasome complex., Conclusion: This is the first report of a mutation in the LRR domain of NLRC4 causing autoinflammatory disease. c.G1965C/p.W655C NLRC4 increased inflammasome activation in vitro. Data generated from various NLRC4 mutations provides evidence that the LRR-LRR interface has an important and previously unrecognized role in oligomerization of the NLRC4 inflammasome complex., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Monogenic autoinflammatory disorders are an increasingly heterogeneous group of conditions characterised by innate immune dysregulation. Improved genetic sequencing in recent years has led not only to the discovery of a plethora of conditions considered to be 'autoinflammatory', but also the broadening of the clinical and immunological phenotypic spectra seen in these disorders. This review outlines the classification strategies that have been employed for monogenic autoinflammatory disorders to date, including the primary innate immune pathway or the dominant cytokine implicated in disease pathogenesis, and highlights some of the advantages of these models. Furthermore, the use of the term 'autoinflammatory' is discussed in relation to disorders that cross the innate and adaptive immune divide. The utilisation of next-generation sequencing (NGS) in this population is examined, as are potential in vivo and in vitro methods of modelling to determine pathogenicity of novel genetic findings. Finally, areas where our understanding can be improved are highlighted, such as phenotypic variability and genotype-phenotype correlations, with the aim of identifying areas of future research., (© 2018 The Author(s).)

Background: Mutations in the gene encoding stimulator of interferon genes (STING) underlie a type I interferon (IFN) associated disease, STING-associated vasculopathy with onset in infancy (SAVI). Patients suffer cutaneous vasculopathy and interstitial lung disease, but are not known to suffer life-threatening infection., Case: We describe a child who presented with Pneumocystis jirovecii pneumonia in early life, from which he recovered. He went on to suffer failure to thrive, developmental delay, livedo reticularis, and vesicular rash, but without cutaneous vasculitis, and with normal C-reactive protein and erythrocyte sedimentation rates. At 3 years of age, he developed life-threatening pulmonary hypertension., Methods: Whole genome sequencing (WGS) was performed using the Illumina HiSeqX10 platform and the Seave platform was used for bioinformatic analysis. mRNA expression of IFN-stimulated genes and inflammatory cytokines from peripheral blood mononuclear cells was determined by quantitative polymerase chain reaction. Luciferase assay was used to model IFNβ and NF-κB activity in vitro ., Results: WGS revealed a de novo mutation p.Arg284Ser in STING at an amino acid previously associated with SAVI. Although this mutation did not fall in the dimerization domain (DD), mRNA analysis revealed constitutive IFN-gene activation consistent with an interferonopathy, which correlated to STING activation in vitro . The patient was treated with corticosteroids and the JAK inhibitor Ruxolitinib, resulting in a rapid improvement of pulmonary hypertension, general well-being, and resolution of the IFN gene signature. However, he did go on to evolve a nasal septal erosion suggesting incomplete control of disease., Conclusion: This case provides molecular evidence to support the p.Arg284Ser variant in STING exerting pathogenicity through a gain-of-function mechanism. The lack of cutaneous vasculitis or elevated systemic inflammatory markers, and the occurrence of an opportunistic infection are notable, and raise the possibility that variants outside the STING DD may potentially manifest with an atypical SAVI phenotype. Nevertheless, there was an objective clinical improvement in response to JAK inhibition.

Objective: Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND) is a recently described monogenic autoinflammatory disease. The causal p.S242R MEFV mutation disrupts a binding motif of the regulatory 14-3-3 proteins within pyrin. Here, we investigate a family with clinical features consistent with PAAND in whom the novel p.E244K MEFV mutation, located in the +2 site of the 14-3-3 binding motif in pyrin, has been found., Methods: Multiplex cytokine analyses were performed on p.E244K patient and control serum. Peripheral blood mononuclear cells were stimulated ex vivo with lipopolysaccharide (LPS). In vitro, inflammasome complex formation was evaluated by flow cytometry of Apoptosis-associated Speck-like protein containing a Caspase recruitment domain (ASC) specks. Interleukin-1β (IL-1β) and IL-18 production was quantified by ELISA. The ability of the p.E244K pyrin mutation to interact with 14-3-3 was assessed by immunoprecipitation., Results: PAAND p.E244K patient serum displayed a different cytokine profile compared with patients with Familial Mediterranean Fever (FMF). In overexpression models, p.E244K pyrin was associated with decreased 14-3-3 binding and increased ASC speck formation. THP-1 monocytes expressing PAAND pyrin mutations demonstrated spontaneous caspase-1-dependent IL-1β and IL-18 secretion, as well as cell death, which were significantly greater than those of wild-type and the FMF-associated mutation p.M694V., Conclusion: In PAAND, disruption of the +2 position of a 14-3-3 binding motif in pyrin results in its constitutive activation, with spontaneous production of IL-1β and IL-18, associated with inflammatory cell death. The altered serum cytokine profile may explain the different clinical features exhibited by PAAND patients compared with those with FMF., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Cell surface innate immune receptors can directly detect a variety of extracellular pathogens to which cytoplasmic innate immune sensors are rarely exposed. Instead, within the cytoplasm, the environment is rife with cellular machinery and signaling pathways that are indirectly perturbed by pathogenic microbes to activate intracellular sensors, such as pyrin, NLRP1, NLRP3, or NLRC4. Therefore, subtle changes in key intracellular processes such as phosphorylation, ubiquitination, and other pathways leading to posttranslational protein modification are key determinants of innate immune recognition in the cytoplasm. This concept is critical to establish the "guard hypothesis" whereby otherwise homeostatic pathways that keep innate immune sensors at bay are released in response to alterations in their posttranslational modification status. Originally identified in plants, evidence that a similar guardlike mechanism exists in humans has recently been identified, whereby a mutation that prevents phosphorylation of the innate immune sensor pyrin triggers a dominantly inherited autoinflammatory disease. It is also noteworthy that even when a cytoplasmic innate immune sensor has a direct ligand, such as bacterial peptidoglycan (NOD1 or NOD2), RNA (RIG-I or MDA5), or DNA (cGAS or IFI16), it can still be influenced by posttranslational modification to dramatically alter its response. Therefore, due to their existence in the cytoplasmic milieu, posttranslational modification is a key determinant of intracellular innate immune receptor functionality., (Copyright © 2017 the American Physiological Society.)

Background and Objective: Asthma deaths in Australia are associated with illicit substance abuse, mental health problems and social issues. However, a large proportion of these deaths occurs out of hospital and is difficult to avert by the time the individuals seek medical attention. We hypothesized that these characteristics may also increase the risk for a patient to require intensive care admission when they present to emergency departments., Methods: We studied consecutive patients admitted to a tertiary metropolitan hospital with a primary diagnosis of asthma between January 2010 and January 2014. Clinical and demographical data were obtained from chart review. The patient's postcode was used as a surrogate for socioeconomic status., Results: There were 482 asthma patients admitted during the study period, of which 39 required intensive care. Ten patients admitted to intensive care (26%) used illicit drugs compared with 29 (7%) of those admitted to the ward (adjusted odds ratio: 3.6, P = 0.012). For illicit users, nonadherence to preventer therapy was associated with an even higher risk of intensive care unit admission. Socioeconomic index was lower in the group requiring intensive care admission. The frequency of psychiatric diagnoses was similar in both groups., Conclusion: Among patients admitted to hospital for asthma, illicit substance abuse is a strong independent risk factor for intensive care requirement. Preventer therapy nonadherence further increases this risk. Lower socioeconomic status is also associated with increased risk. These historical features should be actively sought on admission and may serve as useful 'red flags' to prompt consideration of intensive monitoring., (© 2016 Asian Pacific Society of Respirology.)

Introduction and Hypothesis: To compare complications and outcomes of complete supine percutaneous nephrolithotomy (csPCNL) with ultrasound guided and fluoroscopically guided procedure., Materials and Methods: In this randomized clinical trial study from January 2009 to September 2010, 26 of 51 patients with renal stones underwent csPCNL with ultrasonographic guidance in all steps of the procedure (group A), and the other 25 patients underwent standard fluoroscopically guided csPCNL (group B). All of the patients underwent PCNL in the complete supine position. Statistical analysis was performed with SPSS16 software., Results: Mean BMI was 28.14 in group A and 26.31 in group B (p=0.30). The mean stone burden was 26.48 and 30.44 in groups A and B, respectively (p=0.20). The stone free rate was 88.5% in group A and 75.5% in group B, that was no significant (p=0.16). Overall 2 patients (7.7%) in group A and 6 patients (24%) in group B had complications (p=0.11). Mean operative time in group A was 88.46 minutes, and in group B it was 79.58 minutes (p=0.39). Mean hospital stay was 69.70 and 61.79 hours in group A and B, respectively (p=0.22). There was no visceral injury in groups., Conclusions: This randomized study showed that totally ultrasonic had the same outcomes of fluoroscopically csPCNL. Ultrasonography can be an alternative rather than fluoroscopy in PCNL. We believe that more randomized studies are needed to allow endourologists to use sonography rather than fluoroscopy in order to avoid exposition to radiation., Competing Interests: Conflicts of Interest: None declared., (Copyright© by the International Brazilian Journal of Urology.)

It has long been a common goal for both medical educators and ethicists to develop effective methods or programs for medical ethics education. The current lecture-based courses of medical ethics programs in medical schools are demonstrated as insufficient models for training "good doctors''. In this study, we introduce an innovative program for medical ethics education in an extra-curricular student-based design named Students' Medical Ethics Rounds (SMER). In SMER, a combination of educational methods, including theater-based case presentation, large group discussion, expert opinions, role playing and role modeling were employed. The pretest-posttest experimental design was used to assess the impact of interventions on the participants' knowledge and attitude regarding selected ethical topics. A total of 335 students participated in this study and 86.57% of them filled the pretest and posttest forms. We observed significant improvements in the knowledge (P < 0.0500) and attitude (P < 0.0001) of participants. Interestingly, 89.8% of participants declared that their confidence regarding how to deal with the ethical problems outlined in the sessions was increased. All of the applied educational methods were reported as helpful. We found that SMER might be an effective method of teaching medical ethics. We highly recommend the investigation of the advantages of SMER in larger studies and interdisciplinary settings.

Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1β (IL-1β). Mutations in the B30.2/SPRY domain cause pathogen-independent activation of pyrin and are responsible for the autoinflammatory disease familial Mediterranean fever (FMF). We studied a family with a dominantly inherited autoinflammatory disease, distinct from FMF, characterized by childhood-onset recurrent episodes of neutrophilic dermatosis, fever, elevated acute-phase reactants, arthralgia, and myalgia/myositis. The disease was caused by a mutation in MEFV, the gene encoding pyrin (S242R). The mutation results in the loss of a 14-3-3 binding motif at phosphorylated S242, which was not perturbed by FMF mutations in the B30.2/SPRY domain. However, loss of both S242 phosphorylation and 14-3-3 binding was observed for bacterial effectors that activate the pyrin inflammasome, such as Clostridium difficile toxin B (TcdB). The S242R mutation thus recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1β production. Successful therapy targeting IL-1β has been initiated in one patient, resolving pyrin-associated autoinflammation with neutrophilic dermatosis. This disease provides evidence that a guard-like mechanism of pyrin regulation, originally identified for Nod-like receptors in plant innate immunity, also exists in humans., (Copyright © 2016, American Association for the Advancement of Science.)

Background: Autoantibodies directed to centromere protein F were first reported in 1993 and their association with malignancy has been well documented., Case: We present the case of a 48-year-old Caucasian female with a BRCA1 gene mutation associated with bilateral breast cancer. Antinuclear autoantibody immunofluorescence performed for workup of possible inflammatory arthropathy showed a high titre cell cycle related nuclear speckled pattern, with subsequent confirmation by addressable laser bead immunoassay of the target antigen as an immunodominant epitope at the C-terminus of centromere protein F., Conclusion: Here we review the current literature on centromere protein F, its association with breast cancer and present the first case of this antibody being identified in a person with a BRCA1 gene mutation.

Rapid advances in genetics are providing unprecedented insight into functions of the innate immune system with identification of the mutations that cause monogenic autoinflammatory disease. Cytokine antagonism is profoundly effective in a subset of these conditions, particularly those associated with increased interleukin-1 (IL-1) activity, the inflammasomopathies. These include syndromes where the production of IL-1 is increased by mutation of innate immune sensors such as NLRP3, upstream signalling molecules such as PSTPIP1 and receptors or downstream signalling molecules, such as IL-1Ra. Another example of this is interferon (IFN) and the interferonopathies, with mutations in the sensors STING and MDA5, the upstream signalling regulator AP1S3, and a downstream inhibitor of IFN signalling, ISG15. We propose that this can be extended to cytokines such as IL-36, with mutations in IL-36Ra, and IL-10, with mutations in IL-10RA and IL-10RB, however mutations in sensors or upstream signalling molecules are yet to be described in these instances. Additionally, autoinflammatory diseases can be caused by multiple cytokines, for example with the activation of NF-κB/Rel, for which we propose the term Relopathies. This nosology is limited in that some cytokine pathways may be degenerate in their generation or execution, however provides insight into likely autoinflammatory disease candidates and the cytokines with which newly identified mutations may be associated, and therefore targeted., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To study a perceived relationship of urinary incontinence with self-reported depression among middle-aged women, and to outline whether hormone therapy, selective serotonin reuptake inhibitors, or serotonin norepinephrine reuptake inhibitors influence the prevalence of urinary incontinence., Design: A population-based cross-sectional study of 6,642 women from the Lund area, Sweden, aged 50 to 64 years, who answered questions on urinary incontinence. We obtained information on urinary incontinence, self-reported depression, and medication by questionnaire and personal interviews between December 1995 and February 2000., Results: Thirty-one percent of the women reported urinary incontinence of various severities and 52% reported episodes of depression. Urinary incontinence and self-reported depression were significantly associated [odds ratio (OR) 1.37; 95% CI, 1.23-1.52; P < 0.001]. Among women with self-reported depression, the use of serotonergic antidepressants was statistically associated with urinary incontinence (OR 1.78; 95% CI, 1.33-2.38; P < 0.001). Among women not reporting depression, hormone therapy was significantly associated with urinary incontinence (OR 1.45; 95% CI, 1.22-1.70; P < 0.001). After adjustment for other potential risk factors, serotonergic antidepressants and hormone therapy use were no longer associated with urinary incontinence in women with self-reported depression. However, among women not reporting depression, hormone therapy was still significantly more common in women with urinary incontinence., Conclusions: Urinary incontinence and self-reported depression seemed to be associated in middle-aged women. Use of serotonergic antidepressants or hormone therapy does not seem to be associated with a lower prevalence of urinary incontinence.

Purpose: To examine the pathologic changes in the retina of apolipoprotein E (apoE)-deficient mice fed a high-cholesterol diet., Methods: ApoE-deficient mice (ApoE) were maintained on either regular mouse chow (ApoE-R) or a high-cholesterol diet (ApoE-C) for 25 weeks. Age-matched control C57BL/6J mice (C57) were also maintained on either regular mouse chow (C57-R) or a cholesterol-containing diet (C57-C). Retinal function was assessed by dark-adapted electroretinography (ERG). The eyes were embedded, sectioned, and analyzed by histologic and immunohistochemical methods, as well as by light and transmission electron microscopy., Results: After the 25-week feeding period, ERG tracings of ApoE-C mice revealed significant increases of a- and b-wave implicit times when compared with the C57-R group of mice. In addition, there were reductions in oscillatory potential (OP) amplitudes in the ApoE-C group. However, a- and b-wave amplitudes appeared to be unchanged among the four groups of mice. Light microscopic examination of the retinas showed that compared with control C57-R mice, ApoE-C mice had significantly lower cell numbers in the inner and outer nuclear layers (85.1% +/- 4.6%, P < 0.05 and 81.4% +/- 3.7%, P < 0.01 of C57-R controls, respectively). Transmission electron microscopy of apoE-deficient mice revealed cells of the inner nuclear layer with condensation of nuclear chromatin and perinuclear vacuolization in focal areas. Bruch's membrane was also found to be thicker, and its elastic lamina appeared disorganized and discontinuous. Immunohistochemistry demonstrated diminished or no immunoreactivity for carbonic anhydrase II and calretinin in the retinal layers of apoE-deficient mice., Conclusions: Overall, there were increasing abnormalities of retinal function and cellular morphology among the four groups of mice in the order of C57-R < C57-C < ApoE-R < ApoE-C. These findings suggest that apoE and/or cholesterol play an important role in retinal function.