Editorial expression of concern: Monocytes and lymphocytes as active participants in the pathogenesis of experimental shock.

Altavilla D ，Squadrito F ，Ammendolia L ，Squadrito G ，Campo GM ，Canale P ，Ioculano M ，Musolino C ，Alonci A ，Sardella A ，Urna G ，Saitta A ，Caputi AP ... -  《-》

Characterization of cxorf21 Provides Molecular Insight Into Female-Bias Immune Response in SLE Pathogenesis.

Background: Ninety percent of systemic lupus erythematosus (SLE) patients are women. X chromosome-dosage increases susceptibility to SLE and primary Sjögren's syndrome (pSS). Chromosome X open reading frame 21 (CXorf21) escapes X-inactivation and is an SLE risk gene of previously unknown function. We undertook the present study to delineate the function of CXorf21 in the immune system as well as investigate a potential role in the sex bias of SLE and pSS. Methods: Western blot protein analysis, qPCR, BioPlex cytokine immunoassay, pHrodo™ assays, as well as in vitro CRISPR-Cas9 knockdown experiments were employed to delineate the role of CXorf21 in relevant immunocytes. Results: Expressed in monocytes and B cells, CXorf21 basal Mrna, and protein expression levels are elevated in female primary monocytes, B cells, and EBV-transformed B cells compared to male cells. We also found CXorf21 mRNA and protein expression is higher in both male and female cells from SLE patients compared to control subjects. TLR7 ligation increased CXorf21 protein expression and CXorf21 knockdown abrogated TLR7-driven increased IFNA1 mRNA expression, and reduced secretion of both TNF-alpha and IL-6 in healthy female monocytes. Similarly, we found increased pH in the lysosomes of CXorf21-deficient female monocytes. Conclusion: CXorf21 is more highly expressed in female compared to male cells and is involved in a sexually dimorphic response to TLR7 activation. In addition, CXorf21 expression regulates lysosomal pH in a sexually dimorphic manner. Thus, sexually dimorphic expression of CXorf21 skews cellular immune responses in manner consistent with expected properties of a mediator of the X chromosome dose risk in SLE and pSS.

Harris VM ，Koelsch KA ，Kurien BT ，Harley ITW ，Wren JD ，Harley JB ，Scofield RH ... -  《Frontiers in Immunology》

Alteration of gene expression profiles of peripheral mononuclear blood cells by tobacco smoke: implications for periodontal diseases.

Ryder MI ，Hyun W ，Loomer P ，Haqq C ... -  《oral microbiology and immunology》

Prophylactic use of inotropic agents for the prevention of low cardiac output syndrome and mortality in adults undergoing cardiac surgery.

As the burden of cardiovascular disease grows, so does the number of cardiac surgeries. Surgery is increasingly performed on older people with comorbidities who are at higher risk of developing perioperative complications such as low cardiac output state (LCOS). Surgery-associated LCOS represents a serious pathology responsible for substantial morbidity and mortality. Prevention of LCOS is a critical and worthwhile aim to further improve the outcome and effectiveness of cardiac surgery. However, guidelines consistently report a lack of evidence for pharmacological LCOS prophylaxis. To assess the benefits and harms of the prophylactic use of any inotropic agent to prevent low cardiac output and associated morbidity and mortality in adults undergoing cardiac surgery. We identified trials (without language restrictions) via systematic searches of CENTRAL, MEDLINE, Embase, and CPCI-S Web of Science in October 2022. We checked reference lists from primary studies and review articles for additional references. We also searched two registers of ongoing trials. We included randomised controlled trials (RCTs) enrolling adults who underwent cardiac surgery and were prophylactically treated with one or multiple inotropic agent(s) in comparison to any type of control (i.e. standard cardiac care, placebo, other inotropic agents). We used established methodological procedures according to Cochrane standards. Two review authors independently extracted data and assessed risk of bias according to a pre-defined protocol. On request, we obtained a reply and additional information from only one of the included study authors. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of evidence from the studies that contributed data to the meta-analyses for the pre-specified outcomes. Based on the identified studies, there were seven comparison groups: amrinone versus placebo, dopamine versus placebo, milrinone versus placebo, levosimendan versus dobutamine, levosimendan versus milrinone, levosimendan versus standard cardiac care, and levosimendan versus placebo. We identified 29 eligible studies, including 3307 individuals, and four ongoing studies. In general, confidence in the results of the analysed studies was reduced due to relevant study limitations, imprecision, or inconsistency. Domains of concern encompassed inadequate methods of sequence generation and lack of blinding. The majority of trials were small, with only a few included participants, and investigated the prophylactic use of levosimendan. Our meta-analyses showed that levosimendan as compared to placebo may reduce the risk of LCOS (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.25 to 0.74; I2 = 66%; 1724 participants, 6 studies; GRADE: low) and probably reduces all-cause mortality (RR 0.65, 95% CI 0.43 to 0.97; I2 = 11%; 2347 participants, 14 studies; GRADE: moderate). This translates into a number needed to treat for an additional beneficial outcome (NNTB) of 8 to prevent one event of LCOS post surgery and of 44 to prevent one death at 30 days. Subgroup analyses revealed that the beneficial effects of levosimendan were predominantly observed in preoperative drug administration. Our meta-analyses further indicated that levosimendan as compared to placebo may shorten the length of intensive care unit (ICU) stay (mean difference -1.00 days, 95% CI -1.63 to -0.37; 572 participants, 7 studies; GRADE: very low) and the duration of mechanical ventilation (mean difference -8.03 hours, 95% CI -13.17 to -2.90; 572 participants, 7 studies; GRADE: very low) but the evidence is very uncertain. The risk of adverse events did not clearly differ between levosimendan and placebo groups (cardiogenic shock: RR 0.65, 95% CI 0.40 to 1.05; I2 = 0%; 1212 participants, 3 studies; GRADE: high; atrial fibrillation: RR 1.02, 95% CI 0.82 to 1.27; I2 = 60%; 1934 participants, 11 studies; GRADE: very low; perioperative myocardial infarction: RR 0.89, 95% CI 0.61 to 1.31; I2 = 13%; 1838 participants, 8 studies; GRADE: moderate; non-embolic stroke or transient ischaemic attack: RR 0.89, 95% CI 0.58 to 1.38; I2 = 0%; 1786 participants, 8 studies; GRADE: moderate). However, levosimendan as compared to placebo might reduce the number of participants requiring mechanical circulatory support (RR 0.47, 95% CI 0.24 to 0.91; I2 = 74%; 1881 participants, 10 studies; GRADE: low). There was no conclusive evidence on the effect of levosimendan compared to standard cardiac care on LCOS (RR 0.49, 95% CI 0.14 to 1.73; I2 = 59%; 208 participants, 3 studies; GRADE: very low), all-cause mortality (RR 0.37, 95% CI 0.13 to 1.04; I2 = 0%; 208 participants, 3 studies; GRADE: low), adverse events (cardiogenic shock: RR 0.62, 95% CI 0.22 to 1.81; 128 participants, 1 study; GRADE: very low; atrial fibrillation: RR 0.40, 95% CI 0.11 to 1.41; I2 = 60%; 188 participants, 2 studies; GRADE: very low; perioperative myocardial infarction: RR 0.62, 95% CI 0.22 to 1.81; 128 participants, 1 study; GRADE: very low; non-embolic stroke or transient ischaemic attack: RR 0.56, 95% CI 0.27 to 1.18; 128 participants, 1 study; GRADE: very low), length of ICU stay (mean difference 0.33 days, 95% CI -1.16 to 1.83; 80 participants, 2 studies; GRADE: very low), the duration of mechanical ventilation (mean difference -3.40 hours, 95% CI -11.50 to 4.70; 128 participants, 1 study; GRADE: very low), and the number of participants requiring mechanical circulatory support (RR 0.88, 95% CI 0.50 to 1.55; I2 = 0%; 208 participants, 3 studies; GRADE: low). Prophylactic treatment with levosimendan may reduce the incidence of LCOS and probably reduces associated mortality in adult patients undergoing cardiac surgery when compared to placebo only. Conclusions on the benefits and harms of other inotropic agents cannot be drawn due to limited study data. Given the limited evidence available, there is an unmet need for large-scale, well-designed randomised trials. Future studies of levosimendan ought to be designed to derive potential benefit in specific patient groups and surgery types, and the optimal administration protocol.

Gayatri D ，Tongers J ，Efremov L ，Mikolajczyk R ，Sedding D ，Schumann J ... -  《Cochrane Database of Systematic Reviews》

Repetitive transcranial magnetic stimulation for post-traumatic stress disorder in adults.

The estimated lifetime prevalence of post-traumatic stress disorder (PTSD) in adults worldwide has been estimated at 3.9%. PTSD appears to contribute to alterations in neuronal network connectivity patterns. Current pharmacological and psychotherapeutic treatments for PTSD are associated with inadequate symptom improvement and high dropout rates. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive therapy involving induction of electrical currents in cortical brain tissue, may be an important treatment option for PTSD to improve remission rates and for people who cannot tolerate existing treatments. To assess the effects of repetitive transcranial magnetic stimulation (rTMS) on post-traumatic stress disorder (PTSD) in adults. We searched the Cochrane Common Mental Disorders Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and two clinical trials registers. We checked reference lists of relevant articles. The most recent search was January 2023. We included randomized controlled trials (RCTs) assessing the efficacy and safety of rTMS versus sham rTMS for PTSD in adults from any treatment setting, including veterans. Eligible trials employed at least five rTMS treatment sessions with both active and sham conditions. We included trials with combination interventions, where a pharmacological agent or psychotherapy was combined with rTMS for both intervention and control groups. We included studies meeting the above criteria regardless of whether they reported any of our outcomes of interest. Two review authors independently extracted data and assessed the risk of bias in accordance with Cochrane standards. Primary outcomes were PTSD severity immediately after treatment and serious adverse events during active treatment. Secondary outcomes were PTSD remission, PTSD response, PTSD severity at two follow-up time points after treatment, dropouts, and depression and anxiety severity immediately after treatment. We included 13 RCTs in the review (12 published; 1 unpublished dissertation), with 577 participants. Eight studies included stand-alone rTMS treatment, four combined rTMS with an evidence-based psychotherapeutic treatment, and one investigated rTMS as an adjunctive to treatment-as-usual. Five studies were conducted in the USA, and some predominantly included white, male veterans. Active rTMS probably makes little to no difference to PTSD severity immediately following treatment (standardized mean difference (SMD) -0.14, 95% confidence interval (CI) -0.54 to 0.27; 3 studies, 99 participants; moderate-certainty evidence). We downgraded the certainty of evidence by one level for imprecision (sample size insufficient to detect a difference of medium effect size). We deemed one study as having a low risk of bias and the remaining two as having 'some concerns' for risk of bias. A sensitivity analysis of change-from-baseline scores enabled inclusion of a greater number of studies (6 studies, 252 participants). This analysis yielded a similar outcome to our main analysis but also indicated significant heterogeneity in efficacy across studies, including two studies with a high risk of bias. Reported rates of serious adverse events were low, with seven reported (active rTMS: 6; sham rTMS: 1). The evidence is very uncertain about the effect of active rTMS on serious adverse events (odds ratio (OR) 5.26, 95% CI 0.26 to 107.81; 5 studies, 251 participants; very low-certainty evidence [Active rTMS: 23/1000, sham rTMS: 4/1000]). We downgraded the evidence by one level for risk of bias and two levels for imprecision. We rated four of five studies as having a high risk of bias, and the fifth as 'some concerns' for bias. We were unable to assess PTSD remission immediately after treatment as none of the included studies reported this outcome. Based on moderate-certainty evidence, our review suggests that active rTMS probably makes little to no difference to PTSD severity immediately following treatment compared to sham stimulation. However, significant heterogeneity in efficacy was detected when we included a larger number of studies in sensitivity analysis. We observed considerable variety in participant and protocol characteristics across studies included in this review. For example, studies tended to be weighted towards inclusion of either male veterans or female civilians. Studies varied greatly in terms of the proportion of the sample with comorbid depression. Study protocols differed in treatment design and stimulation parameters (e.g. session number/duration, treatment course length, stimulation intensity/frequency, location of stimulation). These differences may affect efficacy, particularly when considering interactions with participant factors. Reported rates of serious adverse events were very low (< 1%) across active and sham conditions. It is uncertain whether rTMS increases the risk of serious adverse event occurrence, as our certainty of evidence was very low. Studies frequently lacked clear definitions for serious adverse events, as well as detail on tracking/assessment of data and information on the safety population. Increased reporting on these elements would likely aid the advancement of both research and clinical recommendations of rTMS for PTSD. Currently, there is insufficient evidence to meta-analyze PTSD remission, PTSD treatment response, and PTSD severity at different periods post-treatment. Further research into these outcomes could inform the clinical use of rTMS. Additionally, the relatively large contribution of data from trials that focused on white male veterans may limit the generalizability of our conclusions. This could be addressed by prioritizing recruitment of more diverse participant samples.

Brown R ，Cherian K ，Jones K ，Wickham R ，Gomez R ，Sahlem G ... -  《Cochrane Database of Systematic Reviews》