text:
Central nervous system infections in patients with systemic lupus erythematosus: a systematic review and meta-analysis
http://orcid.org/0000-0002-0761-7092Kasra Molooghi1,
http://orcid.org/0000-0002-0766-4286Fereshte Sheybani1,
Hamidreza Naderi1,
Zahra Mirfeizi2,
Negar Morovatdar3 and
Ashkan Baradaran1
1Department of Infectious Diseases and Tropical Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
2Rheumatic Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
3Clinical Research Unit, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
Correspondence to Dr Fereshte Sheybani; fereshtesheybani{at}gmail.com
We aimed to conduct a systematic review and meta-analysis of studies on central nervous system (CNS) infections in patients with SLE, in order to describe their clinical and microbiological characteristics, and outcomes. A systematic search of PubMed/Medline and Embase electronic databases was performed (March 2021) to identify all published studies on CNS infections and their characteristics in patients with SLE. A random-effects model was adopted and findings were reported with 95% CI. Overall, 6 studies involving 17 751 patients with SLE and 209 SLE cases with CNS infection were included in our meta-analysis. The frequency rate of CNS infections in patients with SLE was 0.012 (95% CI: 0.008 to 0.018). Meningitis was the most common clinical syndrome (93.5%, n=109/114, 95% CI: 82.6% to 97.8%) and Cryptococcus neoformans (35.9%, n=55, 95% CI: 27.2% to 45.7%) and Mycobacterium tuberculosis (27.1%, n=43, 95% CI: 14.6% to 44.8%) were the most common causative pathogens. Our patient-pool showed a mean SLE Disease Activity Index (SLEDAI) score of 7.9 (95% CI: 6.1 to 9.6), while 92.4% (n=72/76, 95% CI: 83.0% to 96.8%) of cases were on oral systemic corticosteroids, with a prednisone equivalent mean daily dose of 30.9 mg/day (95% CI: 18.0 to 43.7). Our meta-analysis revealed a mortality rate of 29.0% (95% CI: 15.0% to 48.6%). Clinicians should maintain a high index of suspicion for cryptococcal and tuberculosis (TB) meningitis in patients with SLE with suspected CNS infection, particularly in those with higher SLEDAI and on higher doses of systemic corticosteroids. In conclusion, initiation of empiric antituberculous treatment for patients with SLE who are highly suspected to have CNS TB is warranted while awaiting the results of diagnostic tests. Antifungals might also be potentially useful empirically in patients with SLE who are suspected to have fungal CNS infections. However, with respect to side effects such as toxicity and high cost of antifungals, decision regarding early antifungal therapy should be guided by early and less time-consuming fungal diagnostic tests.
lupus erythematosus
http://dx.doi.org/10.1136/lupus-2021-000560
Major infections including those of the central nervous system (CNS) account for significant morbidity and mortality in patients with SLE.
What does this study add?
Our study provides relevant data for helping clinicians with the diagnostic and treatment approach to CNS infections in patients with SLE.
How might this impact on clinical practice or future developments?
Clinicians should maintain a high index of suspicion for cryptococcal and TB meningitis in patients with SLE with suspected CNS infection, particularly in those with higher SLE Disease Activity Index and on higher doses of systemic corticosteroids.
Antifungals might be potentially useful empirically in patients with SLE who are suspected to have fungal CNS infections.
However, with respect to side effects such as toxicity and high cost of antifungals, decision regarding early antifungal therapy should be guided by early and less time-consuming fungal diagnostic tests.
Empiric antituberculous treatment is warranted for patients with SLE who are highly suspected to have CNS TB while awaiting the results of diagnostic tests.
SLE is a complex autoimmune disorder characterised by chronic systemic inflammation that can affect almost any organ.1 2 It is associated with a two-fold to six-fold increase in the risk of infection and a 12-fold increase in the rate of hospitalisation due to serious infectious complications compared with the general population.3–5 Infections account for 13%–37% of hospitalisations and 15.1%–37.5% of deaths in major SLE cohorts.6–20 Patients with SLE have a five times higher risk of death due to infections than the general population.12 Factors associated with impaired immune response in patients with SLE include T cell and natural killer cell dysfunction as well as complement deficiencies.21 Furthermore, immune-modulating effects of glucocorticoids, disease-modifying antirheumatic drugs, novel biological agents and other immunosuppressive agents such as cyclophosphamide (CYC), azathioprine (AZA), mycophenolate mofetil (MMF) and methotrexate (MTX) can lead to a more intense compromise in their immune function.22
Pleuropulmonary, urinary tract and skin and soft tissue infections are the most commonly reported infectious complications in patients with SLE.13–16 23 Central nervous system (CNS) infections, although less frequent, are associated with significant morbidity and mortality in immunocompromised patients with SLE.24 25 They can mimic the symptoms of neuropsychiatric lupus or a lupus flare; however, require an entirely different management.26–28 Early diagnosis and appropriate treatment of patients with SLE with CNS infections are critical and any delays can be associated with a catastrophic outcome.27 28
Information about the clinical characteristics and outcome of CNS infections in patients with SLE are limited. Here, we conducted a descriptive systematic review and meta-analysis on observational studies that investigated CNS infections in patients with SLE, in order to report the frequency rate of CNS infections and their demographic features, clinical and microbiological characteristics and outcomes, such as morbidity and mortality.
This meta-analysis was registered in PROSPERO (UK Centre for Reviews and Dissemination, University of York, York, UK, ID number CRD42020204986) and was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-analysis of Observational Studies in Epidemiology guidelines.29 30 We systematically searched PubMed/Medline and Embase electronic databases on 1 March 2021. We used "Systemic Lupus Erythematosus" in combination with phrases such as meningitis, Central Nervous System Infection, etc, as Medical Subject Headings and text words, to identify studies on CNS infections in patients with SLE. We imposed no restrictions regarding time of publication, language, country of study or publication type to the initial search. In addition, we manually searched the references of included manuscripts for any potentially eligible articles. Full search strategy is available in online supplemental data S1.
[lupus-2021-000560supp001.pdf]
Study selection
We included observational studies that investigated CNS infections and their characteristics in patients with SLE. Two reviewers (KM and FS) independently evaluated the titles and abstracts for eligibility. KM and AB retrieved relevant full-text manuscripts and selected the studies that fulfilled the eligibility criteria. Any discrepancies between results were resolved by consensus among authors. We excluded case reports, review articles, conference abstracts and posters, while eliminating non-English articles. Furthermore, we omitted the abstracts that did not have an obtainable full manuscript and removed the studies that only reported one specific subtype of CNS infections (eg, only hospital-acquired infections, opportunistic infections, etc), populations (eg, only mortality cases, juvenile/childhood-onset subjects with SLE or febrile patients) or pathogens (such as only Mycobacterium tuberculosis, Cryptococcus neoformans, etc). When we came across two studies with partially duplicated data sets, we opted for the study that covered a larger duration and population. Full selection criteria is available in online supplemental data S2.
Two investigators (KM and AB) independently collected information regarding country and year of publication, SLE population size, study design and duration. In addition, data on frequency and characteristics of the patients with SLE with CNS infections such as gender, age, SLE duration, comorbidities, glucocorticoid use and dose, use of other immunosuppressive agents, clinical syndromes, symptoms on admission, causative pathogens, the interval between the diagnosis of SLE and CNS infection, time interval from the onset of neurological symptoms to the diagnosis of CNS infections, systemic or neurological sequelae, relapse and mortality were recorded, if available in the manuscripts. In order to evaluate disease activity and cumulative damage, we recorded SLE Disease Activity Index (SLEDAI) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index, respectively, if provided in the articles.31 32 Uncertainties were resolved by the help of a third reviewer (FS). Finally, we used the Newcastle-Ottawa Scale (NOS)33 for assessing the methodological quality of the selected observational studies (online supplemental table S1).
Comprehensive Meta-Analysis Software was used for meta-analysis. Heterogeneity between studies was assessed using the Cochran's Q test and I2 statistic. Heterogeneity was considered statistically significant if p value was <0.05 for Cochran's Q-statistics. I2 values of <40% and 40 to 70% showed minimal and moderate heterogeneity, respectively, while a value of >70% indicated substantial heterogeneity. We used the random-effects model with the weighting of the studies. OR, mean difference and standardised mean difference along with 95% CI were applied to the analysis. As the number of available studies were below 10, we did not perform meta-regression analysis due to its low reliability. In order to evaluate publication bias, funnel plots were constructed to visualise possible asymmetry when three or more studies were available.34 However, according to Sterne et al35 when there are fewer than 10 studies in the meta-analysis, test power is usually too low to distinguish chance from real asymmetry or the implications of heterogeneity from publication bias; consequently, no further mathematical tests were performed.
Study characteristics
We identified 3999 citations through the literature search and excluded 3919 irrelevant titles and abstracts after initial screening. After evaluating the full texts of 80 potentially relevant manuscripts for eligibility, 6 articles were included in the meta-analysis36–41 (figure 1). Reference lists of the selected studies were then manually reviewed; however, no additional manuscripts were added to the final analysis. We selected Jiang et al in favour of Xu et al42 due to covering a larger duration and population. Two studies (Yang et al and Jiang et al) acquired a full score on the NOS quality assessment checklist while the others received 6/9, due to not providing a control group for comparing the characteristics of patients with SLE with or without CNS infections. The selected studies were predominantly from Asian regions such as China, Korea, The Philippines and Taiwan, with only one study (Baizabal-Carvallo et al) from northern America (Mexico). All studies have reviewed the patient records/charts of an SLE database/cohort retrospectively for at least 10 years, and five studies were single-centre, whereas only Kim et al had a multicentre database. Overall, the analysis involved 17 751 patients with SLE, who fulfilled the ACR criteria.43 In order to diagnose CNS infections, all studies employed clinical criteria as well as microbiological test results with the help of a multidisciplinary expert team; however, two studies (Hung et al and Yang et al) only reported definite infections where microorganisms were isolated by cultures, stains or PCR, and two studies (Baizabal-Carvallo et al and Kim et al) reported negative or unidentified agents in a separate group called aseptic/non-infectious meningitis, while two studies (Vargas et al and Jiang et al) reported all their data in a single group, namely CNS infections. In addition, cases with neuropsychiatric syndromes, possibly produced by SLE activity which could explain the manifestations, were excluded from the original studies, except for aseptic/non-infectious meningitis cases in the study by Kim et al that were excluded from our patient pool (full criteria used by each study for the diagnosis of CNS infection is available in online supplemental data S3). The meta-analysis included 209 SLE cases with CNS infection, with a female:male ratio of 8.5:1 (187 female patients, 89.5%) and a mean age of 32.2 years (95% CI: 29.5 to 35.0, I2 73.6%). The frequency rate of CNS infections in patients with SLE was 0.012 (95% CI: 0.008 to 0.018, I2 84.8%), while mean SLEDAI score was 7.9 (95% CI: 6.1 to 9.6, I2 74.5%). The funnel plot for frequency rate was asymmetric (online supplemental figure S1), probably due to substantial heterogeneity. Details and characteristics of the SLE populations with CNS infection are available in table 1, figure 2 and online supplemental figure S2.
Patient characteristics of the included studies on patients with SLE with CNS infection
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram. CNS, central nervous system; N/A, not available. Adapted from Page et al.29 For more information, visit: http://www.prisma-statement.org/.
Forest plot showing the meta-analysis results of central nervous system (CNS) infection frequency rate in patients with SLE.
Clinical syndromes
Five studies reported 109 patients with a primary diagnosis of meningitis (93.5%, n=109/114, 95% CI: 82.6% to 97.8%, I2 30.1%) and 5 cases with primary brain abscess, whereas Jiang et al did not report the clinical syndromes of their patients (table 2 and online supplemental figure S2). In addition, brain CT or MRI detected five additional cases of brain abscess among those with meningitis (10.7%, total of 10/114, 95% CI: 5.8% to 18.8%, I2 <0.1%). None of the studies reported clinical syndromes other than meningitis or brain abscess (no cases of encephalitis, subdural or epidural empyema, septic thrombophlebitis, infectious myelitis or encephalomyelitis). Funnel plot showed asymmetry for meningitis cases, however, was symmetrical in case of patients with abscess (online supplemental figure S1).
Medications, syndromes, symptoms, pathogens, mortality and morbidities of patients with SLE with CNS infection
Symptoms on admission
The most common symptoms on admission were headache (90.4%, n=192/209, 95% CI: 85.3% to 93.8%, I2 <0.1%) and fever (89.0%, n=190/209, 95% CI: 77.9% to 94.9%, I2 62.1%), followed by nausea or vomiting (53.1%, n=47/89, 4 articles, 95% CI: 34.5% to 70.9%, I2 63.5%), meningeal signs (49.4%, n=58/114, 5 articles, 95% CI: 33.0% to 65.9%, I2 65.3%), altered mental status (49.5%, n=92/186, 5 articles, 95% CI: 42.3% to 56.7%, I2 <0.1%), seizure (28.4%, n=58/209, 95% CI: 21.8% to 36.0%, I2 15.3%) and focal neurological deficits (19.5%, n=17/89, 4 articles, 95% CI: 12.5% to 29.3%, I2 <0.1), including paraparesis, hemiparesis, cranial nerve palsy, diplopia or blurred vision (online supplemental figure S2). Funnel plots are available in online supplemental figure S1.
Seventy-two out of 76 cases (92.4%, n=72/76, 4 articles, 95% CI: 83.0% to 96.8%, I2 <0.1%) were taking oral corticosteroids, with a mean daily dose of 30.9 mg/day (4 articles, 95% CI: 18.0 to 43.7, I2 94.3 %) prednisone (table 2). All six studies provided a mean daily corticosteroid dose of their subjects; however, two studies did not report the SD of their results and two major studies (Jiang et al and Yang et al) did not report the exact number of cases on corticosteroids and were consequently omitted from the analysis by the software. Other immunomodulators or immunosuppressants included CYC (24.5%, n=29/114, 5 articles, 95% CI: 13.2% to 40.9%, I2 57.3%), hydroxychloroquine (20.4%, n=20/114, 5 articles, 95% CI: 6.8% to 47.3%, I2 73.8%), AZA (15.3%, n=21/114, 5 articles, 95% CI: 4.8% to 39.5%, I2 77.6%), MMF (6.9%, n=5/114, 5 articles, 95% CI: 2.9% to 15.3%, I2 8.7) and MTX (5.6%, n=4/114, 5 articles, 95% CI: 1.8% to 16.3%, I2 29.2%). Four of 76 cases (7.6%, n=4/76, 4 articles, 95% CI: 3.2% to 17.0%, I2 <0.1%) were not taking any immunosuppressive medication, and Jiang et al did not report the exact number of cases on each individual drug (forest plots in online supplemental figure S2 and funnel plots in online supplemental figure S1).
Causative pathogens were identified in 158 of 209 patients with CNS infections (these cases will be referred to as definite CNS infections). In addition, three patients reported the co-infection of two simultaneous pathogens. Overall, bacteria were the most common microorganisms found in patients with definite CNS infections (61.3%, n=102/158, 6 articles, 95% CI: 50.0% to 71.6%, I2 35.8%), followed by fungi (36.4%, n=56/158, 6 articles, 95% CI: 27.9% to 46.0%, I2 22.6%), viruses (n=2) and parasites (n=1). C. neoformans (35.9%, n=55, 6 articles, 95% CI: 27.2% to 45.7%, I2 25.2%), M. tuberculosis (27.1%, n=43, 6 articles, 95% CI: 14.6% to 44.8%, I2 69.5%), Listeria monocytogenes (17.4%, n=24, 6 articles, 95% CI: 10.6% to 27.2%, I2 30.8%), Streptococcus pneumonia (n=6) and Nocardia asteroides (n=4) were the most common causative agents (forest plots in online supplemental figure S2 and funnel plots in online supplemental figure S1). The pathogens isolated from cases with brain abscess were C. neoformans (n=3/10), M. tuberculosis (n=2/10) and L. monocytogenes, Haemophilus influenzae, Corynebacterium bovis-Actinomyces viscosus co-infection and Aspergillus fumigatus, each in one patient (one case of unidentified pathogen).
Our pooled analysis showed an interval of 52.0 months (n=114, 5 articles, 95% CI: 40.2 to 63.7, I2 61.2%) between the diagnosis of SLE and CNS infection. Subgroup analysis showed an interval of 36.6 months (n=23, 2 articles, 95% CI: 21.0 to 52.2, I2 <0.1%) from the diagnosis of SLE to the diagnosis of CNS infection in cryptococcal meningitis (CM), and 47.7 months (n=19, 1 article, 95% CI: 25.0 to 70.4, I2 <0.1%) in CNS tuberculosis (CNS TB) (figure 3A). This interval was lower in patients with CM compared with all CNS infections (difference in means=15.1, 95% CI: −7.8 to 37.9), although not statistically significant (p=0.196).
The bar charts show mean time interval (A) from SLE diagnosis to central nervous system (CNS) infection; (B) from CNS infection symptom onset to diagnosis. TB, tuberculosis.
The time interval from the onset of symptoms to the diagnosis of CNS infections was 14.2 days (n=89, 4 articles, 95% CI: 11.1 to 17.3, I2 79.4%) for all CNS infections, 13.9 days (n=23, 2 articles, 95% CI: 9.5 to 18.3, I2 29.5%) for CM, 24.2 days (n=19, 1 article, 95% CI: 15.8 to 32.7, I2 <0.1%) for CNS TB and 6.2 days (n=13, 2 articles, 95% CI: 3.5 to 9.0, I2 87.1%) for other bacterial CNS infections (figure 3B). Our subgroup analysis showed that patients with CM had a higher interval from onset of symptoms to diagnosis of CNS infection compared with other non-TB bacterial CNS infections (difference in means 6.7 days, 95% CI: 0.3 to 13.1, I2 28.9%).
Mortality & Morbidity
Overall, 34 SLE cases with CNS infections died (mortality rate 29.0%, n=34/114, 31 meningitis cases and 3 CNS abscess cases, 5 articles, 95% CI: 15.0% to 48.6%, I2 69.8%) including 9 patients with CNS TB, 9 patients with CM and 3 patients with L. monocytogenes. The aetiological diagnosis was not mentioned in other 13 cases who succumbed to death. Of those who died, CNS infection was complicated by cryptococcaemia in 4 patients, cryptococcaemia with Salmonella enteritidis B bacteraemia in one case, and septic shock in two patients (forest plots in online supplemental figure S2 and funnel plots in online supplemental figure S1).
Among survivors, 12 cases (13.3%, n=12/76, 4 articles, 95% CI: 3.8% to 37.0%, I2 64.4) developed persistent neurological sequelae during the follow-up period. The neurological sequelae were: decreased visual acuity (n=4), unilateral abducens nerve palsy (n=4), hypoacusia (n=1), cognitive impairment (n=1), persistent partial seizures (n=1), residual facial nerve palsy (n=1), hypalgesia on the left side of the body (n=1) and residual unilateral hearing loss (n=1).
Only two cases (4.7%, n=2/76, 4 articles, 95% CI: 1.5% to 13.7%, I2 <0.1%), both diagnosed with CM, experienced a relapse of the CNS infection.
To the best of our knowledge, this is the first systematic review and meta-analysis on CNS infections in patients with SLE. Our results showed a frequency rate of 0.012 (95% CI: 0.008 to 0.018) for CNS infections in patients with SLE. Meningitis was the most common clinical syndrome (93.5%, n=109/114, 95% CI: 82.6% to 97.8%) and C. neoformans (35.9%, n=55, 95% CI: 27.2% to 45.7%) and M. tuberculosis (27.1%, n=43, 95% CI: 14.6% to 44.8%) were the most common causative pathogens among patients with definite CNS infection. Although considerable information exists about defect in humoral immunity of patients with SLE,44 encapsulated bacteria accounted for a minority of SLE cases with CNS infections. Most patients (92.4%, n=72/76, 95% CI: 83.0% to 96.8%) were on oral systemic corticosteroids, with a prednisone equivalent mean daily dose of 30.9 mg/day (95% CI: 18.0 to 43.7). The time interval between the diagnosis of SLE and CNS infection was 52.0 months (95% CI: 40.2 to 63.7) and the interval from onset of neurological symptoms to the diagnosis of CNS infection was 14.2 days (95% CI: 11.1 to 17.3). Headache (90.4%, n=192/209, 95% CI: 85.3% to 93.8%) and fever (89.0%, n=190/209, 95% CI: 77.9% to 94.9%) were the most common presenting symptoms of CNS infection among patients with SLE. Lupus Disease Activity Index indicated a mean SLEDAI score of 7.9 (95% CI: 6.1 to 9.6) in our patient pool. Moreover, our meta-analysis revealed a mortality rate of 29.0% (95% CI: 15.0% to 48.6%), a persistent neurological sequelae rate of 13.3% (95% CI: 3.8% to 37.0%) and a relapse rate of 4.7% (95% CI: 1.5% to 13.7%) in patients with SLE with CNS infection.
According to a 2014 systematic review and meta-analysis, CM accounted for the most common invasive fungal infection (IFI) in SLE cases, constituting 79.9% of fungal CNS infections and 25.8% of all IFIs.45 Another meta-analysis in 2016 reported an overall pooled prevalence of 0.005 (95% CI: 0.004 to 0.008, high heterogeneity) for CM among patients with SLE.46 Furthermore, both meta-analyses45 46 showed most patients with CM had active SLE at the time of presentation, and those on a higher daily dose of corticosteroids experienced higher mortality rates. In our meta-analysis, patients with CM had a mean SLEDAI of 5.4 (95% CI: 2.9 to 7.9) and a prednisone equivalent mean daily dose of 29.1 mg (95% CI: 22.1 to 36.0), further validating that active disease status and higher corticosteroid doses can result in an increased risk of CM. Despite the importance of considering CM in patients with SLE with suspected CNS infections, the diagnosis of CM is often missed or delayed,45 46 and fungal diagnostic tests are not requested on cerebrospinal fluid (CSF) obtained from first lumbar puncture.46 Our subgroup analysis showed that patients with CM experienced a significant delay in diagnosis compared with other non-TB bacterial CNS infections (difference in means 6.7 days, 95% CI: 0.3 to 13.1, p<0.05). Thus, it is important for physicians to maintain a high index of suspicion for CM in SLE cases with suspected CNS infection, particularly in those with moderate-to-high SLEDAI and those on high doses of systemic corticosteroids.
Although empiric antimicrobial therapy is recommended for CNS infections, empiric antifungal therapy is not a standard of care, thus, delay in treatment of CM occurs frequently until the diagnosis is confirmed. Furthermore, the unaffordability of antifungals in less developed countries further complicate this issue.45 46 While antifungals might be potentially useful empirically in patients with SLE who are suspected to have fungal CNS infections, side effects such as toxicity and high cost of antifungals make decision-making regarding empiric antifungal therapy particularly challenging. Therefore, we suggest employing fungal diagnostic tests that are less time-consuming than cultures, such as blood or CSF tests for detecting cryptococcal antigens, on the initial CSF and blood tests of these patients.
M. tuberculosis was the second most common causative pathogen in patients with SLE with CNS infection (27.1%, n=43, 95% CI: 14.6% to 44.8%). It accounted for at least 26.5% of deaths due to CNS infections in patients with SLE. Although increased rates of TB are expected in endemic regions,47 the prevalence of TB is higher in SLE cohorts than the general population,42 48–54 especially extrapulmonary forms such as meningitis.48 49 A recent meta-analysis has reported that SLE cases are at a substantially higher risk of TB compared with the general population (pooled risk ratio=6.11, 95% CI: 3.61 to 10.33, p<0.05).3 Furthermore, higher cumulative and daily doses of prednisone have been associated with an increased risk of TB in SLE.48 49 54–58 In fact, corticosteroid use is an independent risk factor for TB-related mortality in patients with SLE.59 Hydroxychloroquine, on the other hand, has shown some protective effects against major TB infections in patients with SLE (OR=0.13; 95% CI: 0.04 to 0.36),55 56 especially CNS TB.56 Novel biological agents such as antitumour necrosis (TNF) factors that are used in the treatment of SLE and other rheumatological disorders significantly increase the risk of TB reactivation in patients with SLE,60–63 and screening for and treating latent TB infection is recommended before anti-TNF treatment.60–63 In our meta-analysis, all patients with SLE were taking corticosteroids when diagnosed with CNS TB, but no cases were on anti-TNF treatment. Thus, neurotuberculosis should be considered among the most important causes of CNS infections in patients with SLE, particularly in those on higher doses of systemic corticosteroids or anti-TNFs in TB endemic regions or those with other relevant epidemiological factors (such as history of prior TB, known or possible TB exposure). Given suboptimal sensitivity and specificity of TB diagnostic tests, definitive diagnosis of CNS TB can be challenging and time consuming.64 65 Empiric antituberculous treatment should not be delayed, given the high mortality and complication rate of untreated CNS TB.66 67 Accordingly, we emphasise on the initiation of empiric antituberculous treatment for patients with SLE who are highly suspected to have CNS TB while awaiting the results of diagnostic tests.
The overall mortality rate of patients with SLE with CNS infection was 29.0% (95% CI: 15.0% to 48.6%) in our patient pool. CM and CNS TB accounted for more than half of all deaths in patients with SLE with CNS infections. Due to paucity of data in the studies that were included in our meta-analysis, we could not perform subgroup meta-analysis for risk factors of mortality and morbidity. Yang et al identified a higher CSF protein level, a higher mean dose of prednisone received within the last year and a low serum albumin level as predisposing factors for an unfavourable outcome in patients with SLE with CNS infection; defined as death within the first month, vegetative state, conscious but requiring constant supervision, severe or moderate disability, neurological impairment but independent.41 Baizabal-Carvallo et al and Hung et al proposed other risk factors for mortality in CNS infection such as septic shock and cryptococcaemia.36 37 Hydroxychloroquine has been reported as the only proven protective asset against infection-related mortality in patients with SLE.68 69 Despite the potential protective effect, almost only one-fourth of patients with SLE with CNS infection in our review were taking hydroxychloroquine (20.4%, n=20/114, 95% CI: 6.8% to 47.3%). Future research on CNS infections in patients with SLE including cohort studies should focus on identifying risk and protective factors for mortality and morbidities.
Our study had several limitations that should be mentioned. First, the included studies in our meta-analysis were mainly from Asia, therefore, the results may not be representative of patients in other regions and the recommendations may be regional in nature due to differences in comorbidities, access to care and lack of preventative approaches. Furthermore, a suboptimal standard of care in the included studies, such as a low frequency of maintenance treatment with hydroxychloroquine and high daily doses of prednisone, which are not in line with current management recommendations, could have influenced the frequency of CNS infections and the main causative agents. Other treatment strategies might lead to different circumstances regarding frequency and main pathogens. Moreover, we were not able to estimate the relative risk of CNS infections and its associated factors given the paucity of available data, including absence of adequate control groups; hence, we could only report a descriptive analysis. Finally, the included studies used different diagnostic criteria for CNS infections, which resulted in substantial heterogeneity among patients. Even though all six articles had used microbiological tests on all of their patients and included patients who were diagnosed by a multidisciplinary panel of experts based on their clinical manifestations, laboratory tests and response to treatment, the reliability of diagnosis of CNS infection without microbiological confirmation is still debatable, especially considering that reported clinical manifestations of CNS infection and CNS lupus can be similar. Importantly, cases where the aetiological agent could not be identified might lead to bias in estimating the frequency of each pathogen. Consequently, we limited our frequency analysis to cases that had a known positive microbiological result, and reported frequency percentages and proportions accordingly.
In conclusion, meningitis is the most frequent clinical syndrome in patients with SLE with CNS infections. C. neoformans, M. tuberculosis and L. monocytogenes were the most common causative pathogens while encapsulated bacteria accounted for a minority of SLE cases with CNS infections. Clinicians should maintain a high index of suspicion for CM and CNS TB in patients with SLE who present with clinical syndromes suggestive of CNS infection, especially those with moderate-to-high SLEDAI and those on higher doses of systemic corticosteroids. The high frequency of C. neoformans as a causative pathogen of CNS infections in patients with SLE suggests that antifungals might be potentially useful empirically in patients with SLE who are highly suspected to have fungal CNS infections; however, side effects such as toxicity and high cost of antifungals make such decision particularly challenging. Performing diagnostic tests that are less time-consuming than cultures, namely blood or CSF cryptococcal antigen tests could be potentially helpful in decision making regarding empiric therapy. We also suggest initiation of empiric antituberculous treatment for patients with SLE who are highly suspected to have CNS TB while awaiting the results of diagnostic tests. We emphasise on employing treatment of latent TB infection after targeted screening of patients who are starting moderate-to-high doses of prednisone and/or other high-risk immunosuppressants. Additionally, treatment regimens for patients with SLE should become optimised with maintenance therapy with hydroxychloroquine and minimisation of high-dose prednisone.
This study was approved by the Ethics Committee of Mashhad University of Medical Sciences under the project number 951021 and ethic code of IR.MUMS.fm.REC.1396.824.
Tsokos GC
. Systemic lupus erythematosus. N Engl J Med 2011;365:2110–21.doi:10.1056/NEJMra1100359pmid:http://www.ncbi.nlm.nih.gov/pubmed/22129255
Aringer M,
Costenbader K,
Daikh D, et al
. 2019 European League against Rheumatism/American College of rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis 2019;78:1151–9.doi:10.1136/annrheumdis-2018-214819pmid:http://www.ncbi.nlm.nih.gov/pubmed/31383717
Pego-Reigosa JM,
Nicholson L,
Pooley N, et al
. The risk of infections in adult patients with systemic lupus erythematosus: systematic review and meta-analysis. Rheumatology 2021;60:60–72.doi:10.1093/rheumatology/keaa478pmid:http://www.ncbi.nlm.nih.gov/pubmed/33099651
Alur S,
Mary Thabah M,
Sistla S, et al
. Occurrence, predictors and outcome of infections at three months in hospitalized patients with SLE: a prospective study from southern India. Lupus 2020;29:649–58.doi:10.1177/0961203320914739pmid:http://www.ncbi.nlm.nih.gov/pubmed/32223510
Tektonidou MG,
Wang Z,
Dasgupta A, et al
. Burden of serious infections in adults with systemic lupus erythematosus: a national population-based study, 1996-2011. Arthritis Care Res 2015;67:1078–85.doi:10.1002/acr.22575pmid:http://www.ncbi.nlm.nih.gov/pubmed/25732901
Alarcón GS,
McGwin G,
Bastian HM, et al
. Systemic lupus erythematosus in three ethnic groups. VII [correction of VIII]. Predictors of early mortality in the LUMINA cohort. LUMINA Study Group. Arthritis Rheum 2001;45:191–202.doi:10.1002/1529-0131(200104)45:2<191::AID-ANR173>3.0.CO;2-2pmid:http://www.ncbi.nlm.nih.gov/pubmed/11324784
Tselios K,
Gladman DD,
Sheane BJ, et al
. All-Cause, cause-specific and age-specific standardised mortality ratios of patients with systemic lupus erythematosus in Ontario, Canada over 43 years (1971-2013). Ann Rheum Dis 2019;78:802–6.doi:10.1136/annrheumdis-2018-214802pmid:http://www.ncbi.nlm.nih.gov/pubmed/30992296
Cervera R,
Khamashta MA,
Font J, et al
. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine 2003;82:299–308.doi:10.1097/01.md.0000091181.93122.55pmid:http://www.ncbi.nlm.nih.gov/pubmed/14530779
Fors Nieves CE,
Izmirly PM
. Mortality in systemic lupus erythematosus: an updated review. Curr Rheumatol Rep 2016;18:21. doi:10.1007/s11926-016-0571-2pmid:http://www.ncbi.nlm.nih.gov/pubmed/26984805
Lewandowski LB,
Hu J, et al
. Survival in adults and children with systemic lupus erythematosus: a systematic review and Bayesian meta-analysis of studies from 1950 to 2016. Ann Rheum Dis 2017;76:2009–16.doi:10.1136/annrheumdis-2017-211663pmid:http://www.ncbi.nlm.nih.gov/pubmed/28794077
Yurkovich M,
Vostretsova K,
Chen W, et al
. Overall and cause-specific mortality in patients with systemic lupus erythematosus: a meta-analysis of observational studies. Arthritis Care Res 2014;66:608–16.doi:10.1002/acr.22173pmid:http://www.ncbi.nlm.nih.gov/pubmed/24106157
Lee YH,
Choi SJ,
Ji JD, et al
. Overall and cause-specific mortality in systemic lupus erythematosus: an updated meta-analysis. Lupus 2016;25:727–34.doi:10.1177/0961203315627202pmid:http://www.ncbi.nlm.nih.gov/pubmed/26811368
Petri M,
Genovese M
. Incidence of and risk factors for hospitalizations in systemic lupus erythematosus: a prospective study of the Hopkins lupus cohort. J Rheumatol 1992;19:1559–65.pmid:http://www.ncbi.nlm.nih.gov/pubmed/1464868
Feldman CH,
Hiraki LT,
Winkelmayer WC, et al
. Serious infections among adult Medicaid beneficiaries with systemic lupus erythematosus and lupus nephritis. Arthritis Rheumatol 2015;67:1577–85.doi:10.1002/art.39070pmid:http://www.ncbi.nlm.nih.gov/pubmed/25772621
Goldblatt F,
Chambers S,
Rahman A, et al
. Serious infections in British patients with systemic lupus erythematosus: hospitalisations and mortality. Lupus 2009;18:682–9.doi:10.1177/0961203308101019pmid:http://www.ncbi.nlm.nih.gov/pubmed/19502263
Lee J,
Dhillon N,
Pope J
. All-Cause hospitalizations in systemic lupus erythematosus from a large Canadian referral centre. Rheumatology 2013;52:905–9.doi:10.1093/rheumatology/kes391pmid:http://www.ncbi.nlm.nih.gov/pubmed/23307831
Dhital R,
Pandey RK,
Poudel DR, et al
. All-Cause hospitalizations and mortality in systemic lupus erythematosus in the US: results from a national inpatient database. Rheumatol Int 2020;40:393–7.doi:10.1007/s00296-019-04484-5pmid:http://www.ncbi.nlm.nih.gov/pubmed/31773392
Anastasiou C,
Trupin L,
Glidden DV, et al
. Mortality among hospitalized individuals with systemic lupus erythematosus in the US between 2006 and 2016. Arthritis Care Res 2021;73:1444–50.doi:10.1002/acr.24356
Selvananda S,
Chong YY,
Thundyil RJ
. Disease activity and damage in hospitalized lupus patients: a Sabah perspective. Lupus 2020;29:344–50.doi:10.1177/0961203320904155pmid:http://www.ncbi.nlm.nih.gov/pubmed/32046576
Wu X-Y,
Yang M,
Xie Y-S, et al
. Causes of death in hospitalized patients with systemic lupus erythematosus: a 10-year multicenter nationwide Chinese cohort. Clin Rheumatol 2019;38:107–15.doi:10.1007/s10067-018-4259-zpmid:http://www.ncbi.nlm.nih.gov/pubmed/30123930
Grammatikos AP,
. Immunodeficiency and autoimmunity: lessons from systemic lupus erythematosus. Trends Mol Med 2012;18:101–8.doi:10.1016/j.molmed.2011.10.005pmid:http://www.ncbi.nlm.nih.gov/pubmed/22177735
Barber MRW,
Clarke AE
. Systemic lupus erythematosus and risk of infection. Expert Rev Clin Immunol 2020;16:527–38.doi:10.1080/1744666X.2020.1763793pmid:http://www.ncbi.nlm.nih.gov/pubmed/32478627
Alarcón GS
. Infections in systemic connective tissue diseases: systemic lupus erythematosus, scleroderma, and polymyositis/dermatomyositis. Infect Dis Clin North Am 2006;20:849–75.doi:10.1016/j.idc.2006.09.007pmid:http://www.ncbi.nlm.nih.gov/pubmed/17118293
Thigpen MC,
Whitney CG,
Messonnier NE, et al
. Bacterial meningitis in the United States, 1998-2007. N Engl J Med 2011;364:2016–25.doi:10.1056/NEJMoa1005384pmid:http://www.ncbi.nlm.nih.gov/pubmed/21612470
Rúa-Figueroa Íñigo,
López-Longo J,
Galindo-Izquierdo M, et al
. Incidence, associated factors and clinical impact of severe infections in a large, multicentric cohort of patients with systemic lupus erythematosus. Semin Arthritis Rheum 2017;47:38–45.doi:10.1016/j.semarthrit.2017.01.010pmid:http://www.ncbi.nlm.nih.gov/pubmed/28259425
Edwards CJ,
Lian TY,
Badsha H, et al
. Hospitalization of individuals with systemic lupus erythematosus: characteristics and predictors of outcome. Lupus 2003;12:672–6.doi:10.1191/0961203303lu452oapmid:http://www.ncbi.nlm.nih.gov/pubmed/14514129
Fang H,
Lan L,
Qu Y, et al
. Differences between central nervous system infection and neuropsychiatric systemic lupus erythematosus in patients with systemic lupus erythematosus. J Int Med Res 2018;46:485–91.doi:10.1177/0300060517722695pmid:http://www.ncbi.nlm.nih.gov/pubmed/28823196
Chen J,
Feng X,
Wang H, et al
. Discriminating infectious meningitis versus neuropsychiatric involvement in patients with systemic lupus erythematosus: a single-center experience. Clin Rheumatol 2015;34:365–9.doi:10.1007/s10067-014-2726-8pmid:http://www.ncbi.nlm.nih.gov/pubmed/24941930
Page MJ,
McKenzie JE,
Bossuyt PM, et al
. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi:10.1136/bmj.n71pmid:http://www.ncbi.nlm.nih.gov/pubmed/33782057
Stroup DF,
Berlin JA,
Morton SC, et al
. Meta-Analysis of observational studies in epidemiology: a proposal for reporting. meta-analysis of observational studies in epidemiology (moose) group. JAMA 2000;283:2008–12.doi:10.1001/jama.283.15.2008pmid:http://www.ncbi.nlm.nih.gov/pubmed/10789670
Bombardier C,
Urowitz MB, et al
. Derivation of the sledai. A disease activity index for lupus patients. Arthritis & Rheumatism 1992;35:630–40.doi:10.1002/art.1780350606
Gladman D,
Ginzler E,
Goldsmith C, et al
. The development and initial validation of the systemic lupus international collaborating Clinics/American College of rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum 1996;39:363–9.doi:10.1002/art.1780390303pmid:http://www.ncbi.nlm.nih.gov/pubmed/8607884
Wells G,
Shea B,
O'Connell D
. The Newcastle–Ottawa scale (NOS) for assessing the quality of Non-Randomized studies in meta-analysis 2000.
Schneider M, et al
. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34.doi:10.1136/bmj.315.7109.629pmid:http://www.ncbi.nlm.nih.gov/pubmed/9310563
Sutton AJ,
Ioannidis JPA, et al
. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011;343:d4002. doi:10.1136/bmj.d4002pmid:http://www.ncbi.nlm.nih.gov/pubmed/21784880
Baizabal-Carvallo JF,
Delgadillo-Márquez G,
Estañol B, et al
. Clinical characteristics and outcomes of the meningitides in systemic lupus erythematosus. Eur Neurol 2009;61:143–8.doi:10.1159/000186504pmid:http://www.ncbi.nlm.nih.gov/pubmed/19092250
Hung J-J,
Ou L-S,
Lee W-I, et al
. Central nervous system infections in patients with systemic lupus erythematosus. J Rheumatol 2005;32:40–3.pmid:http://www.ncbi.nlm.nih.gov/pubmed/15630722
Jiang M,
Shi X,
Gao X, et al
. Clinical features of central nervous system infections and experience in differential diagnosis from neuropsychiatric lupus erythematosus in a cohort of 8491 patients with systemic lupus erythematosus. Arthritis Res Ther 2019;21:189–89.doi:10.1186/s13075-019-1971-2pmid:http://www.ncbi.nlm.nih.gov/pubmed/31426834
Kim J-M,
Kim K-J,
Yoon H-S, et al
. Meningitis in Korean patients with systemic lupus erythematosus: analysis of demographics, clinical features and outcomes; experience from affiliated hospitals of the Catholic University of Korea. Lupus 2011;20:531–6.doi:10.1177/0961203310384495pmid:http://www.ncbi.nlm.nih.gov/pubmed/21282295
Vargas PJ,
King G,
Navarra SV
. Central nervous system infections in Filipino patients with systemic lupus erythematosus. Int J Rheum Dis 2009;12:234–8.doi:10.1111/j.1756-185X.2009.01416.xpmid:http://www.ncbi.nlm.nih.gov/pubmed/20374352
Yang C-D,
Wang X-D,
Ye S, et al
. Clinical features, prognostic and risk factors of central nervous system infections in patients with systemic lupus erythematosus. Clin Rheumatol 2007;26:895–901.doi:10.1007/s10067-006-0424-xpmid:http://www.ncbi.nlm.nih.gov/pubmed/17021668
Xu Y,
Xu D,
Zhang T, et al
. The prevalence and clinical characteristics of systemic lupus erythematosus with infectious brain lesions in China. Scand J Rheumatol 2012;41:466–71.doi:10.3109/03009742.2012.680607pmid:http://www.ncbi.nlm.nih.gov/pubmed/22827530
Tan EM,
Cohen AS,
Fries JF, et al
. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7.doi:10.1002/art.1780251101pmid:http://www.ncbi.nlm.nih.gov/pubmed/7138600
Sawada T,
Fujimori D,
Yamamoto Y
. Systemic lupus erythematosus and immunodeficiency. Immunol Med 2019;42:1–9.doi:10.1080/25785826.2019.1628466pmid:http://www.ncbi.nlm.nih.gov/pubmed/31204893
Wang LR,
Barber CE,
Johnson AS, et al
. Invasive fungal disease in systemic lupus erythematosus: a systematic review of disease characteristics, risk factors, and prognosis. Semin Arthritis Rheum 2014;44:325–30.doi:10.1016/j.semarthrit.2014.06.001pmid:http://www.ncbi.nlm.nih.gov/pubmed/25129259
Fang W,
Chen M,
Liu J, et al
. Cryptococcal meningitis in systemic lupus erythematosus patients: pooled analysis and systematic review. Emerg Microbes Infect 2016;5:1–7.doi:10.1038/emi.2016.93pmid:http://www.ncbi.nlm.nih.gov/pubmed/27599471
. Global tuberculosis report 2020, 2020. Available: https://www.who.int/publications/i/item/9789240013131
Xiao X,
Da G,
Xie X, et al
. Tuberculosis in patients with systemic lupus erythematosus-a 37-year longitudinal survey-based study. J Intern Med 2021;290:101-115. doi:10.1111/joim.13218pmid:http://www.ncbi.nlm.nih.gov/pubmed/33259665
Sayarlioglu M,
Inanc M,
Kamali S, et al
. Tuberculosis in Turkish patients with systemic lupus erythematosus: increased frequency of extrapulmonary localization. Lupus 2004;13:274–8.doi:10.1191/0961203303lu529xxpmid:http://www.ncbi.nlm.nih.gov/pubmed/15176665
Tam L-S,
Li EK,
Wong S-M, et al
. Risk factors and clinical features for tuberculosis among patients with systemic lupus erythematosus in Hong Kong. Scand J Rheumatol 2002;31:296–300.doi:10.1080/030097402760375205pmid:http://www.ncbi.nlm.nih.gov/pubmed/12455821
Yun JE,
Kim TH, et al
. The incidence and clinical characteristics of Mycobacterium tuberculosis infection among systemic lupus erythematosus and rheumatoid arthritis patients in Korea. Clin Exp Rheumatol 2002;20:127–32.pmid:http://www.ncbi.nlm.nih.gov/pubmed/12051389
Yang Y,
Thumboo J,
Tan BH, et al
. The risk of tuberculosis in SLE patients from an Asian tertiary hospital. Rheumatol Int 2017;37:1027–33.doi:10.1007/s00296-017-3696-3pmid:http://www.ncbi.nlm.nih.gov/pubmed/28286903
Chu AD,
Polesky AH,
Bhatia G, et al
. Active and latent tuberculosis in patients with systemic lupus erythematosus living in the United States. J Clin Rheumatol 2009;15:226–9.doi:10.1097/RHU.0b013e3181b0c85dpmid:http://www.ncbi.nlm.nih.gov/pubmed/19590444
Balbi GGM,
Machado-Ribeiro F,
Marques CDL, et al
. The interplay between tuberculosis and systemic lupus erythematosus. Curr Opin Rheumatol 2018;30:395–402.doi:10.1097/BOR.0000000000000493pmid:http://www.ncbi.nlm.nih.gov/pubmed/29438163
Ruiz-Irastorza G,
Olivares N,
Ruiz-Arruza I, et al
. Predictors of major infections in systemic lupus erythematosus. Arthritis Res Ther 2009;11:R109.doi:10.1186/ar2764pmid:http://www.ncbi.nlm.nih.gov/pubmed/19604357
Torres-González P,
Romero-Díaz J,
Cervera-Hernández ME, et al
. Tuberculosis and systemic lupus erythematosus: a case-control study in Mexico City. Clin Rheumatol 2018;37:2095–102.doi:10.1007/s10067-018-4109-zpmid:http://www.ncbi.nlm.nih.gov/pubmed/29675624
Yang S-C,
Lai Y-Y,
Huang M-C, et al
. Corticosteroid dose and the risk of opportunistic infection in a national systemic lupus erythematosus cohort. Lupus 2018;27:1819–27.doi:10.1177/0961203318792352pmid:http://www.ncbi.nlm.nih.gov/pubmed/30103646
González-Naranjo LA,
Coral-Enríquez JA,
Restrepo-Escobar M, et al
. Factors associated with active tuberculosis in Colombian patients with systemic lupus erythematosus: a case-control study. Clin Rheumatol 2021;40:181–91.doi:10.1007/s10067-020-05225-xpmid:http://www.ncbi.nlm.nih.gov/pubmed/32529420
Cheng CF,
Huang YM,
Lu CH, et al
. Prednisolone dose during treatment of tuberculosis might be a risk factor for mortality in patients with systemic lupus erythematosus: a hospital-based cohort study. Lupus 2019;28:1699–704.doi:10.1177/0961203319882759pmid:http://www.ncbi.nlm.nih.gov/pubmed/31640531
Cantini F,
Lubrano E,
Marchesoni A, et al
. Latent tuberculosis infection detection and active tuberculosis prevention in patients receiving anti-TNF therapy: an Italian nationwide survey. Int J Rheum Dis 2016;19:799–805.doi:10.1111/1756-185X.12708pmid:http://www.ncbi.nlm.nih.gov/pubmed/26172207
Nannini C,
Niccoli L, et al
. Guidance for the management of patients with latent tuberculosis infection requiring biologic therapy in rheumatology and dermatology clinical practice. Autoimmun Rev 2015;14:503–9.doi:10.1016/j.autrev.2015.01.011pmid:http://www.ncbi.nlm.nih.gov/pubmed/25617816
Shobha V,
Chandrashekara S,
Rao V, et al
. Biologics and risk of tuberculosis in autoimmune rheumatic diseases: a real-world clinical experience from India. Int J Rheum Dis 2019;22:280–7.doi:10.1111/1756-185X.13376pmid:http://www.ncbi.nlm.nih.gov/pubmed/30168281
Garziera G,
Morsch ALB,
Otesbelgue F, et al
. Latent tuberculosis infection and tuberculosis in patients with rheumatic diseases treated with anti-tumor necrosis factor agents. Clin Rheumatol 2017;36:1891–6.doi:10.1007/s10067-017-3714-6pmid:http://www.ncbi.nlm.nih.gov/pubmed/28589321
Basu Roy R,
Thee S,
Blázquez-Gamero D, et al
. Performance of immune-based and microbiological tests in children with tuberculosis meningitis in Europe: a multicentre paediatric tuberculosis network European trials Group (ptbnet) study. Eur Respir J 2020;56. doi:doi:10.1183/13993003.02004-2019. [Epub ahead of print: 02 07 2020].pmid:http://www.ncbi.nlm.nih.gov/pubmed/32299859
Bourgi K,
Fiske C,
Sterling TR
. Tuberculosis meningitis. Curr Infect Dis Rep 2017;19:39. doi:10.1007/s11908-017-0595-4pmid:http://www.ncbi.nlm.nih.gov/pubmed/28895024
Leonard JM,
Schlossberg D
. Central nervous system tuberculosis. Microbiol Spectr 2017;5:5.2.11. doi:10.1128/microbiolspec.TNMI7-0044-2017
Garg RK
. Central nervous system tuberculosis: Treatment and prognosis. In: UpToDate. Post TW. Waltham, MA: UpToDate, 2021.
Teh CL,
Wan SA,
Ling GR
. Severe infections in systemic lupus erythematosus: disease pattern and predictors of infection-related mortality. Clin Rheumatol 2018;37:2081–6.doi:10.1007/s10067-018-4102-6pmid:http://www.ncbi.nlm.nih.gov/pubmed/29667100
Mok CC,
Tse SM,
Chan KL, et al
. Effect of immunosuppressive therapies on survival of systemic lupus erythematosus: a propensity score analysis of a longitudinal cohort. Lupus 2018;27:722–7.doi:10.1177/0961203317739129pmid:http://www.ncbi.nlm.nih.gov/pubmed/29087260
Contributors FS and KM designed the outline of the study and conducted the systematic literature search. KM, FS and AB selected eligible manuscripts, extracted and evaluated the raw data and assessed the quality of the manuscripts. KM, AB and NM performed the meta-analysis. All authors aided in interpretation of the data. KM and FS wrote critical portions of the initial manuscript. All authors contributed to critical revision of the manuscript for important intellectual and scientific content. KM and FS performed the final editing and revision of the manuscript. All authors approved the final work and agreed to be accountable for all aspects of the work.
Funding This research was conducted with funding support from the vice-chancellery for research of Mashhad University of Medical Sciences (Research Project Number 951021 and ethic code of IR.MUMS.fm.REC.1396.824).


text:
Q: UIBarButtonItem with style UIBarButtonItemStylePlain and with both text and image I'm trying to generate an UIBarButtonItem with style:UIBarButtonItemStlyePlain, and also with both text and image.
The best solutions I found in this site (this one for example) didn't let me set the style as Plain. In fact, this solution only makes a buttonitem with no stlye, but with both text and image.
That's a good progress to solve what I want, but is there a way to add programmatically that plain stlye?

A: You could create a UIBarButtonItem with a custom view that has both an image and label.  You can ask the system for the UIBarButtonItemStlyePlain style properties using UIAppearance protocols.
Example:
UIColor *textColor = [[UIBarButtonItem appearance] titleTextAttributesForState:UIControlStateNormal][UITextAttributeTextColor];

redpajama_set_name: RedPajamaStackExchange


120V For Use in US, Canada, Mexico, and other countries with 110-120V electrical systems. NOT FOR USE IN EUROPE, ASIA, AFRICA, OCEANIA.
TheraBulb's complete therapeutic infrared lighting solution includes our custom designed lamp made from medical grade plastic with a heavy duty ceramic light socket.
The TheraBulb lamp is designed to be used with and comes paired with the TheraBulb 150 Watt NIR-A Near Infrared Bulb.
The TheraBulb Lamp is only compatible with TheraBulb 150 - original or silicone coated bulbs. Higher wattage / heat bulbs may damage lamp.
TheraBulb uses a thicker that typical coating on the outside surface that is both reflective and protective resulting in a bulb that more efficiently directs the release of infrared light safely through the top of the bulb. These marks may be more apparent when the bulb is on, but in no way negatively impacts the performance or life of the bulb.
Instructions and precautions are emailed upon purchase and included in the product box.


Our Clover Lace Gown is simply divine, with intricate lace detailing and a beautifully feminine silhouette, and is one of our favourites to date! We imagine it being worn in a gorgeous Parisienne garden for a picnic… but even if you're simply strolling through the local farmer's market, this heavenly dress will bring an indescribable romanticism into your life, and you'll be turning heads all the way.
Our model is wearing a size small. She is 5'10" (178cm) tall and has a 60cm waist.
Our studio model is wearing a size small. She is 5'7″ (176cm) tall and has a 61cm waist.


text:
Tropical Storm Iselle Damage Survey
By Scott Stransky | August 18, 2014
Early on the morning of August 8, 2014, Tropical Storm Iselle made landfall on the Big Island of Hawaii,near the small town of Pahala with 60 mph sustained winds. Iselle was the first tropical cyclone landfall on the Big Island since 1958, and just a few hours prior to landfall, it was still a hurricane. Six days later, I toured the parts of the island that were impacted by the storm. Interestingly, the town of Pahala itself was effectively untouched by Iselle's winds. However, several subdivisions about 40-50 miles north of Pahala, including Hawaiian Paradise Park and Hawaiian Beaches, did experience wind damage. Additionally, the storm devastated the island's papaya crop.
Driving through the areas of the island impacted by the storm, starting in Hawaiian Paradise Park (located just southeast of Hilo,the Big Island's largest community), the most obvious damage was to trees. Numerous trees were down, taking power lines with them. Many people were still without power. Utility crews were busy repairing the lines. In some cases, though, the wind itself was strong enough to destroy a telephone pole.
Here I am surveying a damaged telephone pole
Most residential structures in the subdivisions were single walled wood construction, with tofu block foundations, and metal roofs. The small minority of homes with shingle roofs did lose a few shingles. Other homes were covered in blue tarps, so it was difficult to determine the extent of their damage or even what their roofs were constructed from. One home in the middle of Hawaiian Paradise Park, several miles inland from the water, lost most of its roof (this home was in an area with many downed trees and power lines, so there was likely a localized wind effect):
Severe roof damage to a home in the middle of Hawaiian Paradise Park, several miles inland
A bit south and east of Hawaiian Paradise Park is another subdivision: Hawaiian Beaches. Similarly to Hawaiian Paradise Park,there were many trees and power lines down. Many roads through the subdivision were still blocked off by downed trees and debris.
This house, directly across the street from the ocean, lost part of its roof
After surveying those two subdivisions, it made sense to see what happened in Pahala, the closest town to the storm's landfall.Driving around Pahala, there was no visible damage. Almost all the construction in Pahala was single wall wood frame, so they were quite lucky to have come out of the storm cleanly.
Finally, this would not be a good report about a damage survey in Hawaii without the obligatory steaming volcano photo.
The Caldera of Kilauea, the most active of the five volcanoes that form the island of Hawaiʻi
Iselle reminds us that Hawaii is not immune to tropical cyclones and that each of the Hawaiian Islands is at risk.

redpajama_set_name: RedPajamaCommonCrawl


Many veteran ISPA EXPO attendees may have enjoyed Bill Evans' helpful demonstration on building pillowtop mattresses, as in the video below. He shows you how to create an excellent mitered-corner pillow top bed with some great sewing systems from Porter International.
In 2010, Porter International will be demonstrating the fastest way to assemble a pillowtop with ruffled corners. Now you can have perfectly ruffled corners without precise marking and sewing or time-consuming build-up methods. One snug of the Cinch-Loc cord and you've got perfectly placed ruffled corners.
Cinch-Loc™ pillow top system* is the fastest way to build a pillow top bed - see for yourself at Booth 2625, in Charlotte.
Miter corners or Ruffle corners?
GSG wants to know what you like.
why doesn't this video ever work. I hope the machine works.
I have followed their Help instructions and it appears to work in my browser. Hopefully, you can now view it properly as well.


text:
Darwin's Tree Morphs into a Network, with Implications for Intelligent Design
June 1, 2021, 12:41 PM
Image credit: Brian Gage.
Could the new genomics start a scientific revolution that traps Darwin in its web? His iconic "tree of life" is morphing into a network, thanks to a flood of new data showing that lateral gene transfer (LGT) is ubiquitous. If the opinions of some geneticists take root, phylogenetic studies may become relics of the last paradigm. The implications for evolutionary theory are enormous.
Ever since Darwin sketched a branching tree in his notes, the "tree of life" icon has become a fixture in the minds of biologists and students. It seems intuitively obvious: since individuals are descended from parents and grandparents, each species has a genetic lineage. According to Darwin's thinking, these lineages connect back in time due to the repeated "origin of species" by natural selection. Each species would have originated at one of these branching points. If followed far back enough, all the bifurcating twigs and branches would connect in a tree-like pattern of universal common descent. Implicit in this picture is the assumption that branches do not re-connect; once bifurcated, they share the traits of the common ancestor but evolve thereon in their own direction.
A Profound Rethink
Writing in Current Biology, Cédric Blais and John M. Archibald look back at the modern genomics revolution and the profound rethink it is causing about "biology's unifying metaphor," the tree of life.
Some twenty years ago, the foundations of the tree of life were shaken by the realization that prokaryotic genomes are comprised of genes with different evolutionary histories…. [W]ith Charles Darwin's On the Origin of Species and Ernst Haeckel's vivid depictions of evolutionary trees, the tree of life took root as biology's unifying metaphor. Molecular phylogenetics emerged in the 1960s and 1970s and followed Darwin's template: the branches of life's tree diverged and never merged (Box 1). Comparative genomics was expected to solidify this view of evolution, but the genomes of bacteria and archaea were found to be mosaic in nature, having acquired genes from both closely and distantly related taxa by lateral (or horizontal) gene transfer. This realization unsettled the primacy of vertical descent in the history of life and its use in the taxonomic classification of organisms. It ushered in a heated debate over how best to depict the relationships between organisms in nature. Should the tree of life be abandoned, and could it be suitably replaced by a network of life? Or was lateral gene transfer largely inconsequential, mere noise that could and should be filtered out, with the remaining signal thus revealing life's true tree? [Emphasis added.]
Think of how profound a scientific revolution is at hand, when "biology's unifying metaphor" is being questioned. Some geneticists are standing with an axe in hand at the base of the iconic tree. Blais and Archibald point out that the exponential rise in genome sequencing, particularly of microbes, has led to this major reconsideration. It wouldn't be happening without big data forcing it. Look at the long-accepted concepts that are at risk:
The existence of a single phylogenetic tree
Carl Woese's concept of three domains (bacteria, archaea, eukarya)
Molecular phylogenetic practice
Universal common ancestry
Taking Sides
As in any revolution, people take sides. Radicals on one end of the spectrum are happy to cut down the old tree and replace it with a modern network. Radicals on the other side want to save the tree, like conservationists sitting in the branches to stop the chainsaws. Then there is middle ground where peacemakers think both concepts can coexist, and everybody will be happy. Every scientist, though, must be united about the facts. Blais and Archibald describe the party politics without taking sides, but they point out that LGT is real and cannot be ignored:
The primacy of the tree of life must be qualified by the recognition that it represents only a fraction of evolutionary history and that networks capture bona fide evolutionary dynamics that are incompatible with it. Networks now encompass far more entities and processes than were first considered when discussing the tree and the network of life. Even though the tree of life survives, it is now clear that vertical and reticulate lineages co-exist within gene exchange communities of varied topologies.
And yet think of how the tree picture changes if twigs interconnect. The tree morphs into a network of interconnecting nodes. There's no necessary vertical component to a network diagram; it can be rotated at will and the connections remain. If LGT is indeed rampant throughout life, as appears beyond doubt, the universal tree of life concept becomes a matter of philosophical preference, not empirical demonstration.
How do organisms share genetic information? For prokaryotes, it's simple: they routinely share plasmids (this is how antibiotic resistance genes can travel from species to species). This phenomenon gave rise to the "quasispecies" concept, where individuals within a species may not have the entire repertoire of genes but can get them from other members when under stress. For higher organisms, other methods of information transfer include phages and mobile genetic elements ("jumping genes" or transposons), hybridization, and introgression. Microbiologists are studying nanoscopic channels that appear to connect cells, through which information can travel. If so, cells become less like individual buildings and more like commercial plazas with walkways between them.
A Hindrance to Scientific Advance
The old tree concept can hinder scientific progress, the authors say.
[L]ateral gene transfer does not respect species boundaries and is enabled by mobile genetic elements and their vehicles not included in the tree of life, such as viruses, gene transfer agents, plasmids and transposons… Moreover, even though it allows for lateral connections, the tree of life recognizes only one 'right' way of grouping existing taxa: vertical descent. It is thus ill-equipped to study species groupings reflective of the complex gene-transfer dynamics that exist in the microbial world. Networks, on the other hand, are not restricted by a tree structure and can be used to shine new light on evolutionary questions. Indeed, recent studies have found that networks can outperform trees when faced with complex or ambiguous phylogenetic scenarios,
"Evolutionary questions" in the new paradigm, if they are not vertical, can hardly be called evolutionary in the Darwinian sense. The question now becomes whether the boundaries of the nested hierarchies by which organisms have been classified are as impenetrable as previously believed. The implications of network thinking have yet to be fully explored, but the prospects are as exciting as they are revolutionary.
Implications for Intelligent Design
If the network concept continues to supplant or supplement the old tree concept, here are some research questions that design advocates might consider.
The primacy of information over ancestry.
The ability of LGT to prime a migrating organism for a new environment.
Adaptation in light of LGT rather than ancestry.
How networking provides resilience.
New explanations for "convergent evolution" — sharing instead of ancestry.
Expanded taxonomical principles that include LGT.
Limits to information sharing that preserve species identity.
Interpreting the fossil record in light of network genomics.
Replacing phylogenetic trees with network diagrams.
The essay by Blais and Archibald, "The past, present and future of the tree of life," is worth reading. We may be on the verge of a major scientific revolution in biology. It appears that the new genomics will be more compatible with design than Darwin's model ever was.
Discovery Institute is co-sponsoring an event this week in Texas, the "Conference on Engineering in Living Systems" (CELS). Participants will likely be discussing some of the concepts coming to light in the new genomics, and how they intersect with engineering principles evident in life. What's more engineered than a network?
archaeabacteriaBig DatabiologyCarl WoeseCédric BlaisCELS 2021Conference on Engineering in Living SystemsCurrent BiologyDarwinian theoryEngineeringeukaryagenomicshybridizationintelligent designintrogressionJohn M. Archibaldjumping geneslateral gene transferLGTnatural selectionnetworkOrigin of SpeciestaxonomyTexastransposonsTree of Life


Optic neuropathies blind through the progressive degeneration of the retina and optic nerve. As with other diseases of the central nervous system, optic neuropathies involve complex interactions between glial cells and retinal neurons and their axons. These interactions comprise a broad inflammatory response that includes both protective mechanisms and cascades that contribute to programmed degeneration. Our laboratory focuses on neuronal-glial interactions in glaucoma, an optic neuropathy that is blinding some 80 million people worldwide. In glaucoma, sensitivity to pressure in the eye causes the slow retraction of the axons in the optic nerve, which arise from the roughly 1.5 million retinal ganglion cells that collect the light signals used for vision. We utilize both in vivo and in vitro models to isolate the inflammatory signals from microglia and astrocyte glia in the retina and optic nerve that contribute to ganglion cell death. We also focus on the molecular mechanisms intrinsic to ganglion cells and their axons that mediate their sensitivity to ocular pressure and could represent novel therapeutic targets.
Students working in our laboratory will receive training in many modern techniques in neuroscience, including primary neuronal cell culture, digital microscopy, quantitative real-time PCR, immunocytochemistry and ELISA. Students are also expected to participate in journal club and laboratory meetings on a regular basis.


MASSENET, J[ules]. Esclarmonde: Opéra Romanesque en quatre actes et huit tableaux. Paris: G. Hartmann, . Quarto, contemporary half red straight-grain morocco. $3800.
First edition, association copy of the piano-vocal score, inscribed by Massenet to the great French bass Joseph Tagliafico "a l'ami Tagliafico, souvenir de son bien affectionne, J. Massenet," with a musical quotation from the prologue ("O divine Esclarmonde…"), dated Paris, October 1889. With lovely art nouveau color illustrations, including vignette title page, by E. Grasset.
"On 15 May 1889, Esclarmonde opened at the Opéra-Comique in the Place du Chatelet with Sibyl Sanderson in the title role. Billed as opéra romanesque, it did quite well, with ninety-one performances by the end of 1889 and ten more the following year, before it closed its run" (Irvine, 164). In Esclarmonde, Massenet, the predominant French opera composer of his generation, departs from his characteristic elegance in favor of a more Wagnerian intensity. The opera prompted one contemporary critic to write: "never yet, I believe, has anyone produced so accurate and detailed a musical description of la manifestation physique des tendresses humaines" (Irvine, 166). With front wrapper bound in.
Front inner paper hinge splitting, contemporary binding sound and attractive. An extremely good association copy.


text:
Vincent Laron Sanford III (Lexington, Kentucky, ) es un jugador de baloncesto estadounidense que actualmente se encuetra sin equipo. Con 1,91 metros de estatura, juega en la posición de escolta.

Trayectoria deportiva

Es un ala-pívot formado a caballo entre  Georgetown Hoyas y Dayton Flyers y tras no ser drafteado en 2012, daría el salto al baloncesto europeo, en concreto a Islandia en las filas del Thor Thorl primero y después jugaría en Alemania, en el s.Oliver Würzburg. En la temporada 2016-17, alternaría el primer equipo de la BBL con el filial de la BBL-2 alemana.

En 2017 firmaría con el Olympique d'Antibes para jugar en la Pro A francesa.

Referencias

Enlaces externos
German League Profile
Eurobasket.com Profile
Dayton Flyers bio

Baloncestistas de Kentucky
Baloncestistas de los Georgetown Hoyas
Baloncestistas de los Dayton Flyers
Baloncestistas del s.Oliver Baskets
Baloncestistas del Olympique Antibes
Baloncestistas del Élan Sportif Chalonnais
Baloncestistas del CSP Limoges
Baloncestistas del Pau Orthez
Baloncestistas del Victoria Libertas Pesaro
Baloncestistas del TG Würzburg

redpajama_set_name: RedPajamaWikipedia


text:
Drama at the Dam
October 23, 2013 • Nigeria
Building the dam at Egbe Hospital has taken the hands of many volunteers.
The dam at Egbe Hospital has been under repair for more than a year. This past summer, the staff watched as it was slowly destroyed by a sinkhole and heavy rain. Through prayer and quick thinking, they were able to salvage part of their hard work.
Abby Anderson and her husband, Mark, moved to Nigeria in 2011 to manage the construction portion of the revitalization of Egbe Hospital, a rural teaching hospital in southwest Nigeria.
The drama at the dam at Egbe Hospital in Nigeria started back in June when William, the construction foreman, left for one of his recovery breaks. Our intern Luke called Mark because there was a "sinkhole" at the dam. Mark rushed out to evaluate, and indeed the earthen dam had a growing sinkhole. The pipe was opened to drain the dam and the water pump was set up, but the sinkhole continued. The hole got larger by the minute.
The pipe running through the dam wall had collapsed, which meant we now had a hole penetrating both the earthen dam and the concrete dam wall in which the water was rushing through along with the clay of the earthen dam. I remember sitting out there with Mark and the interns, Luke and Jeremy, watching the hole grow in silence. We were in shock over what was happening. All that work and effort was just sinking away. Since we arrived, we have been on severe water restrictions. The dam was supposed to help us meet water needs for the hospital and school.
As Will watched the dam slowly destroyed by a sinkhole and rain, he got the idea to fill bags with sand and put them around the dam.
Everyone agreed not to tell Will until his break was over so that he wouldn't immediately rush home to fix it. Then we all agreed that we needed some serious prayer! So we prayed.
When Will finally came home and saw it, he too joined in the grieving process. Why was this happening? We continued to attempt to drain the dam in order to start the repair work; however, torrential rainfalls ensued. Rain was filling the dam to overflowing with runoff coming into the dam in all directions. All taps were open and the water pump was running 24/7 in attempt to drain the water. But the dam couldn't drain fast enough, and again the sinkhole began to expand.
Thinking quickly, Will started filling cement bags with sand and throwing them down into the sink hole until a sandbag wall was built in front of the original wall. This would keep us from losing more of the earthen dam.
And now we waited … and prayed some more! The rains kept falling. For two weeks straight it rained, but the sand bags held. When the rain finally stopped, it took a week to empty the reservoir completely in order for work to repair the hole and pipe to start.
After some hard work, the dam is complete again. Please pray with the team at Egbe that it will continue to hold.
A new and stronger pipe was installed, and the now large hole around the pipe was patched thoroughly and carefully. The filling of the sinkhole was painstakingly slow as they compacted each individual layer of dirt/clay in it. Finally everything was repaired and patched, and the wall was deemed worthy. The reservoir was allowed to slowly fill up again.
Today we are rejoicing. The dam has been completed (again!), and we are covering it in prayers for protection. We are also praying for the pipe to arrive. It is now months past due its arrival in Egbe. The new reservoir and filter beds cannot be used by the hospital until the pipe has been laid to transport the water to the compound.
Franklin Graham Meets with Iraqi Believers as Homes Are Restored
Christian families are encouraged by the help they're receiving as they return home... ▶
New Building Will Help Church Shine the Light of Jesus in Southwestern Alaska
Samaritan's Purse recently completed its 29th building project in Alaska with a new... ▶
Grants Help Texas Churches Recover After Harvey
Many pastors and congregations across southeast Texas faced personal crises at home and... ▶
Samaritan's Purse helps to build communities by constructing houses, schools, hospitals, and churches. Our projects provide shelter for families who lost everything in disasters, education opportunities to help break the cycle of poverty, facilities for physical and spiritual healing, and places to build up the body of Christ.


text:
Other Ride Construction
Thorpe Park | Derren Brown's Ghost Train | VR Attraction
Thread starter pitchnoir
Nitefly
I didn't like the addition of actors and the whole 'remember the code' section in recent years - but I still like the iteration I've been on (v2 with the demon scene), even if the headsets were very low quality and disappointing.
I love it conceptually (as a low burn, confusing chiller - particularly think it's clever that people get different videos) but ultimately, it's just not the ride people were hoping for and for most I can see how it lacks re-ridability because of its fiendishly slow queues.
The solutions from my perspective are:
- better headsets
- better ops, however achieved
- less 'am-dram' (actors)
Rollercoaster David
I mean the answer is obvious to me given Thorpe's love of celebs and IP.
Turn it in to Francis Bourgeois' super fun train time. He already has a show on channel 4 and is all over tiktok and the other socials. Seems like the perfect celeb endorsement
Joelpagett
The whole concept of DBGT is flawed. From the VR which was in it's infancy (I would still say it is) to the mid-journey 'scare zone' - the whole thing is a massive waste of time and money. I understand what they were trying to achieve, but it could have been executed without the VR to much greater effect.
I've ridden it 5 or so times over the years and the most unnerving thing about it is when a member of staff walks down the train and strokes your leg!
I believe I read somewhere (don't quote me) that the maintenance team had to start working on it at 6:30am to get it open for 12pm as they had to test all the headsets. The thing must hemorrhage cash.
I would go as far to say it was the biggest failure in the Merlin portfolio as far as IP acquisition and implementation.
It has been a colossal waste of resources from the moment it opened. The problem is it cost so much money they can't just close it, so you know whatever is coming 'down the line' is going to be just as terrible as there isn't going to be the CAPEX to fix the glaring issues with it.
Reactions: holtjammy16
CSLKennyNI
Has the VR hardware ever been updated/renewed since opening in 2016? Because if not yikes that alone must be a nightmare and already feel quite outdated. With such fast developing tech you need to keep on top of it (or better have waited in the first place a bit to use it until the quality was further developed).
CSLKennyNI said:
They updated the film slightly the year after it opened to tie in with the Rise of the Demon theme - but I don't think the physical headsets have been updated. It seemed pretty poor quality when I rode it in October, so I would say the headsets hadn't been updated.
I like being proved wrong however if anyone knows otherwise!
I'll never understand why they built something which relies on tech that was destined to be outdated by the end of the first season.
Decent hardware is never going to go out of style.You can leave it in a park for decades and it will still be popular.
If you order a B&M invert, hyper or looper, apart from minor tweaks, you're going to get the same thing you would have got if you'd ordered it in the '90s. Those rides built in the '90s are still major, popular attractions with loads of reride value.
VR is crap. It just is. It's sold as this "immersive" (f**k that word) experience, but you can never get away from the knowledge and feeling that you've got a heavy contraption strapped to your face and you're looking at a screen with (usually) cheap, crappy graphics.
You can shove VR on coasters as a gimmick, and it doesn't matter if it's sh**e since it's a temporary curiosity, but why the hell would any park build a whole, extremely expensive attraction around it when, for less money, they could've built something with way more longevity?
Did the ride bring people into the park when it opened? Probably. Is it bringing people in now? Doubtful. Will it be bringing people into the park for years to come? Absolutely f**king not.
Reactions: ThrillsExpress, Pokemaniac, Dar and 6 others
Heth
Using the example I did earlier, physical sets are much more immersive. Pirates of the Caribbean opened in 1967 in Dosneylamd and feels less date than this ride opened in 2016.
Heth said:
Agree. Look at Gruffalo at Chessington which is a rebranded Bubbleworks, over 30 years old and still one of the most popular rides in the park.
I don't even enjoy rides with 3D glasses tbh.
AidanCKY
I think VR is great for people at home, who are "into" it and looking after the equipment, playing games they specifically like etc.
For a theme park its just the worst idea, attaching a fragile expensive bit of kit to people of all shapes and sizes and then relying on it entirely to make something fun.
Merlin must have gotten a really good deal on the ride or something cos I dont see why they built it otherwise.
Reactions: Serena and gavin
In the context of a 'dark ride', I don't necessarily think that VR is as bad an idea as it is on something like a rollercoaster. That said, it would have to be a well-thought-out concept with expensive VR goggles and graphics to stand a good chance.
For me, what makes the Derren Brown experience poor is jumping from VR into a 'scare maze' style experience. Going from virtual reality to reality. The contrast is too stark and it becomes so unbelievable that as good as some of the theming is, I'm just not immersed. It becomes quite awkward and cringeworthy and too stop/start. It was poorly conceived and executed.
Reactions: Yoris Kerkhoff and Howie
toofpikk
Maybe thorpe will turn it into a nice steampunk restuarant and finally have a food option that won't give you food poisoning or taste like cardboard and dog sh**.
Reactions: Hixee and JoshC.


What Is Your Plan Of Action If Your Hotel Is On Fire?
"Best Response Practices for Fire Alarms & Fires"
Give your hotel management the pertinent fire procedures needed in case of a fire alarm or an actual fire.
Success! We've sent it to your email!
Ready to train your staff?
WHAT IS HOTEL FIRE SAFETY?
As the creator of High-Rise Staged Evacuation, NFPA's "Traditional Response" to fire alarms and fire, we share expert insight for hotels' best preparation plans & offer online fire safety training for your entire hotel staff. Our Response To Fire Alarms and Fire Procedures for high-rise office buildings and high-rise hotels have been adopted by the National Fire Protection Association and most fire departments worldwide.
Hotel Fire Safety is an online educational resource for hotel management to protect themselves, their staff, and hotel guest from the dangers of fire. Our online courses will train everyone on your staff from kitchen personnel to doorman/security to chief engineers. We also provide pertinent fire safety resources with online videos & downloadable PDFs for your hotel managers.
We also have response procedures for mid-rise buildings with special concerns, and have hundreds of clients including major oil & energy companies. Some of the tallest world-renown office buildings have been certified by our training practices.
Hotel Fire Safety is the online fire safety resource for hotels across America.


text:
Men's Basketball vs. NYU
On Friday, the Carnegie Mellon University Men's Basketball Team traveled to New York City to take on the New York University Violets. The first half...
Kobe Bryant dies in fatal crash
Last week, retired NBA star Kobe Bryant died in a helicopter crash at the age of 41. Bryant's daughter Gianna, age 13, also died in the crash. The tragedy...
Penalty shouts: MLB Hall of Fame
This is Penalty Shouts, The Tartan's sports column inspired by the The New Yorker's column Daily Shouts. This satire-fueled column will focus on anything...
Innovation in sports technology
These days, we often take the accessibility of sports broadcasts for granted. As such, it's rather rare for the vast majority of the spectators to be...


text:
OZZY DIDN'T MEAN TO HURT THAT POOR BAT
Q: Did singer Ozzy Osbourne really bite off the head of a bat at a concert?
When did this happen? -- K.G., Newport News
A: Yes. Rock singer Ozzy Osbourne did bite the head off a bat during one of his outrageous concerts many years ago, but he claims it was an accident.
The incident happened Jan. 20, 1982 at the Veterans Auditorium in Des Moines, Ill. A fan of Osbourne's threw a bat onstage during the concert performance. Mistaking it for a rubber toy, Osbourne picked up the animal and bit off its head as part of the show. He sought medical treatment and received a rabies vaccine and tetanus shot.
Osbourne was criticized by Humane Societies around the country and his concerts were monitored for further cases of animal abuse.
Ozzy Osbourne is currently the star of the MTV show, "The Osbournes" that shows the real-life at-home shenanigans of Osbourne, his wife Sharon and his two teen-age children, Kelly and Jack. Cameras follow the family members 24/7 as they go about their sometimes mundane, but off-the wall lives. The show has even been spoofed in a Saturday Night Live sketch.


text:
package org.apache.cordova.test;

import java.util.concurrent.ExecutorService;

import org.apache.cordova.CordovaInterface;
import org.apache.cordova.CordovaPlugin;

import android.app.Activity;
import android.content.Context;
import android.content.Intent;
import android.os.Bundle;

public class CordovaDriverAction extends Activity implements CordovaInterface {
    /** Called when the activity is first created. */
    @Override
    public void onCreate(Bundle savedInstanceState) {
        super.onCreate(savedInstanceState);
    }

    public void startActivityForResult(CordovaPlugin command, Intent intent,
            int requestCode) {
        // TODO Auto-generated method stub

    }

    public void setActivityResultCallback(CordovaPlugin plugin) {
        // TODO Auto-generated method stub

    }

    public Activity getActivity() {
        // TODO Auto-generated method stub
        return null;
    }

    @Deprecated
    public Context getContext() {
        // TODO Auto-generated method stub
        return null;
    }

    @Deprecated
    public void cancelLoadUrl() {
        // TODO Auto-generated method stub

    }

    public Object onMessage(String id, Object data) {
        // TODO Auto-generated method stub
        return null;
    }

    public ExecutorService getThreadPool() {
        // TODO Auto-generated method stub
        return null;
    }

}

redpajama_set_name: RedPajamaGithub


"Your checking account tells your story," says Suzanne Evans. That's a scary thought, and if it's true, I'm in deep do-do.
Action expert Suzanne Evans, business-building and wealth coach for women, joins me live online on YAK Wednesday, August 1st, 11am EDT, telling how she went from zero to millionaire in three years and has coached private clients to total revenues exceeding $8 million via live events, virtual coaching programs and high-end VIP coaching.
To free yourself financially, she says, you have to take 100% responsibility for everything you are experiencing and then make a different choice; responsibility breeds authority.
Plus, our own lovable Colin Lively joins us for a little CLZ, and maybe he too will share some tips on success.
PreviousShame On You, Ralph Lauren!
I pray that God will grace that program and make a memorable day and the atmosphere will be very friendly in Jesus name Amen.
Hi Devin, I'll put that on the list of questions. Thanks!
This is going to be a informative show. I have a question, please. I would be curious to know if one could apply her 15-minute formula to one's personal financial goals, not only at the business level. Thank you.


The main responsibility or task of a private investigator would be to conduct surveillance and collect data from their target. It is often unavoidable that the private investigator has to carry out info gathering from the target individual himself or herself or to the acquaintances or relatives of the target individual. However in order to keep away from detection from the target person the private investigator need to conduct his or her interview inside the most discreet manner. Bringing out a pen and paper or the use of conventional audio recorders would right away spark suspicion this strategy of data gathering would not be effective and thus it would only create danger to the safety of the private investigator or private detective.
Simply because of the must conduct and collect audio data, although avoiding detection, was the reason that the pen recorder was developed. The pen voice recorder is in fact a recorder which is disguised as a pen, which would allow the private detectives to conduct their investigation in a discreet manner. The Pen Recorder might be on a stand-by and activated to a record state with the subtle movement of the clip, which of course wouldn't spark any suspicion and it is possible to readily turn it back to stand by as a way to avoid recording any unnecessary conversations.
Among the ideal functions of the Pen Recorder is that it has a voice activation property, which would permit the pen to record as soon as it "hears" a sound. This voice activation property would enable private investigators and private detectives to collect data in a particular location even with no being inside the very same location as the target individual. The distinct recordings are readily played back and listened to through the supplied earpiece and by way of a PC playback.


text:
Lisa Miller: The world we're leaving our kids
It may be time for baby boomers to give up the mantle and see if the next generations can do better.
By Lisa Miller
The world we baby boomers are leaving our kids
The recent Ken Burns-Lynn Novick series "The Vietnam War" has vividly brought back a time of both hope and turmoil for people my age. I am firmly rooted in the baby boomer generation, and the series brings back memories of the political upheaval, dissent, and generational discord that defined that era.
People parade up and down the streets of the Haight-Ashbury district in San Francisco on April 3, 1967, to resist the Vietnam War and 1960s American orthodoxy. Associated Press/Robert W. Klein
I am a child of the 1960s. Our generation writhed under the traditional value system of our parents. We sought change at all levels. Our generation was activist in nature — the social justice, feminist, and civil rights movements swelled with willing boomer recruits.
We are the generation that brought down a powerful president fighting an unpopular war.
We are the generation that ushered in environmental awareness with the first Earth Day in 1970 (fearing world overpopulation, I was convinced that I would never have children). We created the environmental ethic that is now embraced by younger generations.
And let's not forget rock 'n' roll! While the roots of rock began in the '50s, the music of our generation exploded in the '60s and created our cultural identity — fast, loud, edgy (sometimes obscene), inventive, and politically tinged. My rock credentials at the time included attending Monterey Pop (the first big rock festival) and booking one of the Grateful Dead's earliest concerts at my high school.
We were idealistic, change oriented, and suspicious of wealth and consumerism. What happened?!?
Baby boomers were fortunate to be raised in an economy of opportunity and expansion. Despite our early rejection of middle-class values, we accumulated great wealth that, with the huge size of our cohort, contributed to a giant burst of consumerism. As we got older, prosperity trumped environmentalism — we demanded bigger and more numerous cars, televisions and houses (all with air conditioning, of course).
This wealth also fed an ethic of privilege and greed that created fertile conditions for high-risk financial asset maneuvers and wildly accelerating real estate bubbles. The Great Recession happened on our watch, a 10-year economic slump that compromised our children's future earnings — the Gen X and Millennial generations are the first to earn less than their parents.
Our baby boomer presidents got us into endless wars that continue today — starting with Clinton's bombing of Iraq that Bush expanded into full-fledged war and Obama (on the cusp between boomer and Gen X) continued. Who knows what the current baby boomer president will get us into?
The "off-budget" wars helped fuel a phenomenal increase in national debt. The debt ballooned while boomers in Congress (a majority since the beginning of the George W. Bush administration) went on to cut taxes, underfunded Social Security and Medicare, and approved a new expensive Medicare prescription drug benefit.
Civil rights, gay rights, and racial equality may have improved over the years, but our recent experiences with police shootings and protests have revealed a disturbing undercurrent of racial tension that persists. Moreover, women's reproductive health care is under renewed assault.
And, despite our lofty intentions, environmental degradation continues apace under our watch. Climate change (I'm a believer) may be the single greatest challenge to our children's generation.
What can be done? Boomers need to be honest that we've had it good and we must set a better table for our children and grandchildren.
We need to share in the pain of shoring up Social Security and Medicare. Did we pay for those benefits with taxes? Yes, but not enough for our large, long-living cohort. Solutions, mostly unpopular, include more taxes (gulp!), a modest reduction in benefits, or means testing before receiving benefits. Some even suggest privatizing Medicare, but I'm not willing to go there yet.
And while we're talking about debt, we need to reinvest in the higher education system that we benefitted from in our youth. While on our watch, college costs more than doubled between 1982 and 2012. We cannot continue saddling our descendants with phenomenal student loan debts to get the education that is obligatory for 21st century jobs.
Finally, Trump administration efforts to the contrary, we need to reduce carbon emissions and promote cleaner energy sources. Climate change used to be a bipartisan issue — in 1988, George H.W. Bush pledged to "fight the greenhouse effect with the White House effect." But then the power and money of the fossil fuel industry stepped in and he later declared "the American way of life is not up for negotiation."
That phrase seems to sum it all up for the boomer generation.
If I'm honest with myself, boomers have had ample opportunity to address many of the above solutions. At this point, I think the best solution is to get out of the way. We need to vote out the entitled boomers and vote in younger generations with the guts to make the tough choices.
Lisa Miller, of Somerville, is a former legislator who served on the Health and Human Services and Appropriations and Financial Affairs committees.
Browse more in Opinion
Central Maine Opinion
Enter your email and each Sunday we'll send you our opinion section picks of the week.
A new Opinion feature that aims to build community and entertain.
Read now »


text:
63 Percent of Employees Say This Benefit Matters Even More Than Their Salary
A new survey found that most employees value paid time off more than getting a plump paycheck.
By Brenda BarbosaFounder, www.brendabarbosa.com@writerinflorida
StockSnap
Though Americans are notorious for skipping vacations, a new study shows an overwhelming majority of employees believe companies should offer paid time off as part of their benefits package. In fact, employees said, they'd turn down a job if paid time off weren't offered.
According to a survey by TSheets, a time-tracking and scheduling software company, 88 percent of the 400 respondents surveyed said employers should offer paid time off, while 63 percent said they would decline a job offer from a company that didn't.
Ironically, while most employees said they valued paid time off, many admit to not using it. A whopping 70 percent of workers who received paid time off in 2016 did not use up all their days, with 26 percent of them saying they left 10 or more unused days on the table at year's end.
So even though employees don't use up all their allotted time, most say they like knowing it's there--just in case.
"I have kids, and sometimes you just don't know when one of them wakes up with a fever," said Maggie Giles, a graphic designer in Fort Lauderdale, Florida. "It's nice to know I won't be docked for the day if I have to tend to a sick child."
Giles's family situation is not unlike that of many families across the country. And it could be one reason why more companies are moving toward a paid time off model where all days come out of one bucket, as compared to the traditional model of categorizing time based on sick days, vacation days, and personal days.
As The Washington Post reports:
One of the biggest pluses about [paid time off] for small-business owners is eliminating the administrative chore of tracking how many sick days versus vacation days their employees have used. That can be particularly helpful in the growing number of states, counties, and cities where employers are required to allow staffers to accrue sick time, usually up to 40 hours a year, depending on how many hours they work. With [paid time off], there's no need to track hours worked or accrued.
Many business owners don't want to have to police their employees to find out whether or not they're actually sick. As The Washington Post reports, "Some companies even offer unlimited [paid time off], particularly in places where staff members are not on set schedules." That means workers can "take as many days off as needed for whatever reason."
Carol O'Kelley is the CEO of Salesfusion, an Atlanta-based marketing software manufacturer that offers unlimited paid time off. She tells The Washington Post, "Employees are much more comfortable if they need to be out with a sick child or need to be at an appointment."
"That has relieved a lot of unnecessary pressure and burdens on employees and managers," she adds.
Business owners all over are tuning into the trend.
Paid time off is a sound business investment.
Almost from the beginning, Geeta Nadkarni, founder and CEO of Baby Got Booked (and a fellow Inc.com columnist), offered her full-time employees paid time off. It's a tool she uses to attract top talent.
Between paid time off and national holidays, Nadkarni says her employees get about 18 days off a year. She doesn't care how they use the time, as long as they use it, she says. In her mind, Nadkarni sees offering paid time off as an investment in her business. It's a way to keep her team fresh and energized.
"You shouldn't have to get sick to be able to take time off," Nadkarni says. "I look at it like my internet bill, or any other bill. This is my creativity bill. I can always switch my internet provider. But can I switch my team? Hell no."
Still, she asks employees to schedule their time off in advance so it doesn't create gaps in workflow, or lead to someone unknowingly calling or texting a team member on their day off.
"Ideally, they let us know ahead of time," Nadkarni said. "We won't text you, call you, or bug you. It's really a vacation for your brain."
Published on: Jul 19, 2017