Regulatory T-cell dysfunctions are associated with increase in tumor necrosis factor α in autoimmune hemolytic anemia and participate in Th17 polarization.

Warm autoimmune hemolytic anemia (wAIHA) is a rare acquired autoimmune disease mediated by antibodies targeting red blood cells. The involvement of CD4 T-helper cells has been scarcely explored, with most findings extrapolated from animal models. Here, we performed quantification of both effector T lymphocytes (Teff) and regulatory T cells (Treg), associated with functional and transcriptomic analyses of Treg in human wAIHA. We observed a shift of Teff toward a Th17 polarization concordant with an increase in serum interleukin-17 concentration that correlates with red blood cell destruction parameters, namely lactate dehydrogenase and bilirubin levels. A decrease in circulating Treg, notably effector Treg, associated with a functional deficiency, as represented by their decrease capability to inhibit Teff proliferation, were also observed. Treg deficiency was associated with a reduced expression of Foxp3, the master transcription factor known to maintain the Treg phenotype stability and suppressive functions. Transcriptomic profiling of Treg revealed activation of the tumor necrosis facto (TNF)-α pathway, which was linked to increased serum TNF-α concentrations that were twice as high as in controls. Treg transcriptomic profiling also suggested that post-translational mechanisms possibly accounted for Foxp3 downregulation and Treg dysfunctions. Since TNF-α participates in the rupture of immune tolerance during wAIHA, its inhibition could be of interest. To this end, the effects of fostamatinib, a SYK inhibitor, were investigated in vitro, and we showed that besides the inhibition of erythrocyte phagocytosis by monocytes, fostamatinib is also able to dampen TNF-α production, thus appearing as a promising multitargeting therapy in wAIHA (clinicaltrials gov. Identifier: NCT02158195).

Surgery, Tissue Plasminogen Activator, Antiangiogenic Agents, and Age-Related Macular Degeneration Study: A Randomized Controlled Trial for Submacular Hemorrhage Secondary to Age-Related Macular Degeneration.

PURPOSE: To compare the efficacy and the safety of submacular hemorrhage (SMH) management using either surgical pars plana vitrectomy (PPV) or pneumatic displacement (PD) with tissue plasminogen activator (tPA) and vascular endothelial growth factor (VEGF) inhibitor added to each arm. DESIGN: Randomized, open-label, multicenter superiority study. PARTICIPANTS: Ninety patients with neovascular age-related macular degeneration (nAMD) 50 years of age or older with recent SMH (≤ 14 days) of more than 2 optic disc areas and predominantly overlying the retinal pigment epithelium. METHODS: Patients were assigned randomly to surgery (PPV, subretinal tPA [maximum, 0.5 ml/50 µg], and 20% sulfur hexafluoride [SF6] tamponade) or PD (0.05 ml intravitreal tPA [50 µg] and 0.3 ml intravitreal pure SF6). Both groups were asked to maintain a head upright position with the face forward at 45° for 3 days after intervention and received 0.5 mg intravitreal ranibizumab at the end of the intervention, at months 1 and 2, as the loading phase, and then on a pro re nata regimen during a 6-month follow-up. MAIN OUTCOME MEASURES: The primary efficacy endpoint was mean best-corrected visual acuity (VA) change at month 3. The secondary endpoints were mean VA change at month 6, 25-item National Eye Institute Visual Function Questionnaire composite score value at months 3 and 6, number of anti-VEGF injections, and complications during the 6-month follow-up. RESULTS: Of the 90 patients randomized, 78 patients (86.7%) completed the 3-month efficacy endpoint visit. The mean VA change from baseline to month 3 in the surgery group (+16.8 letters [95% confidence interval (CI), 8.7-24.9 letters]) was not significantly superior to that in the PD group (+16.4 letters [95% CI, 7.1-25.7 letters]; adjusted difference ß, 1.9 [-11.0; 14.9]; P = 0.767). Both groups achieved similar secondary outcomes at month 6. No unexpected ocular safety concerns were observed in either group. CONCLUSIONS: Surgery did not yield superior visual gain nor additional benefit for SMH secondary to nAMD compared with PD at 3 months, with intravitreal anti-VEGF added to each arm. Both treatment strategies lead to a clinical improvement of VA without safety concerns for SMH over 6 months. Both design and results of the trial cannot be used to establish equivalence between treatments. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Efficacy of repetitive transcranial magnetic stimulation (rTMS) for reducing consumption in patients with alcohol use disorders (ALCOSTIM): study protocol for a randomized controlled trial.

BACKGROUND: The number of people with an alcohol use disorder (AUD) was recently estimated to be 63.5 million worldwide. The global burden of disease and injury attributable to alcohol is considerable: about 3 million deaths, namely one in 20, were caused by alcohol in 2015. At the same time, AUD remains seriously undertreated. In this context, alternative or adjunctive therapies such as brain stimulation could play an important role. The early results of studies using repetitive transcranial magnetic stimulation (rTMS) suggest that stimulations delivered to the dorsolateral prefrontal cortex significantly reduce cravings and improve decision-making processes in various addictive disorders. We therefore hypothesize that rTMS could lead to a decrease in alcohol consumption in patients with AUD. METHODS/DESIGN: We report the protocol of a randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy of rTMS on alcohol reduction in individuals diagnosed with AUD. The study will be conducted in 2 centers in France. Altogether, 144 subjects older than 18 years and diagnosed with AUD will be randomized to receive 5 consecutive twice-daily sessions of either active or sham rTMS (10 Hz over the right DLPFC, 2000 pulses per day). The main outcomes of the study will be changes in alcohol consumption within the 4 weeks after the rTMS sessions. Secondary outcome measures will include changes in alcohol consumption within the 24 weeks, alcohol cravings, clinical and biological improvements, effects on mood and quality of life, and cognitive and safety assessments, and, for smokers, an assessment of the effects of rTMS on tobacco consumption. DISCUSSION: Several studies have observed a beneficial effect of rTMS on substance use disorders by reducing craving, impulsivity, and risk-taking behavior and suggest that rTMS may be a promising treatment in addiction. However, to date, no studies have included sufficiently large samples and sufficient follow-up to confirm this hypothesis. The results from this large randomized controlled trial will give a better overview of the therapeutic potential of rTMS in AUD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04773691. Registered on 26 February 2021 https://clinicaltrials.gov/ct2/show/NCT04773691?term=trojak&draw=2&rank=5 .

Mucosal-associated invariant T cells in Giant Cell Arteritis.

This study aimed to assess the implication of mucosal-associated invariant T (MAIT) cells in GCA. Blood samples were obtained from 34 GCA patients (before and after 3 months of treatment with glucocorticoids (GC) alone) and compared with 20 controls aged >50 years. MAIT cells, defined by a CD3+CD4-TCRγδ-TCRVα7.2+CD161+ phenotype, were analyzed by flow cytometry. After sorting, we assessed the ability of MAIT cells to proliferate and produce cytokines after stimulation with anti CD3/CD28 microbeads or IL-12 and IL-18. MAIT were stained in temporal artery biopsies (TAB) by confocal microscopy. MAIT cells were found in the arterial wall of positive TABs but was absent in negative TAB. MAIT frequency among total αß-T cells was similar in the blood of patients and controls (0.52 vs. 0.57%; P = 0.43) and not modified after GC treatment (P = 0.82). Expression of IFN-γ was increased in MAIT cells from GCA patients compared to controls (44.49 vs. 32.9%; P = 0.029), and not modified after 3 months of GC therapy (P = 0.82). When they were stimulated with IL-12 and IL-18, MAIT from GCA patients produced very high levels of IFN-γ and displayed a stronger proliferation compared with MAIT from controls (proliferation index 3.39 vs. 1.4; P = 0.032). In GCA, the functional characteristics of MAIT cells are modified toward a pro-inflammatory phenotype and a stronger proliferation capability in response to IL-12 and IL-18, suggesting that MAIT might play a role in GCA pathogenesis. Our results support the use of treatments targeting IL-12/IL-18 to inhibit the IFN-γ pathway in GCA.

Impact of lockdown on patients with congestive heart failure during the coronavirus disease 2019 pandemic.

AIMS: Cardiovascular co-morbidities like congestive heart failure (CHF) alter the course of coronavirus disease 2019. Factors associated with the outbreak and lockdown can exacerbate CHF. METHODS AND RESULTS: We analysed the answers of 124 randomly selected CHF outpatients (mean age 71.0 ± 14.0 years, 60.5% male) interviewed by phone during the sixth and seventh weeks of the lockdown. Most patients were treated for New York Heart Association class II (38.7%) and reduced ejection fraction HF (70.2%). Psychological distress (Kessler 6 score ≥ 5) was common (18.5%), and 21.8% felt worse than before the lockdown. Few patients (n = 10) adjusted their intake of HF medications, always on medical prescription. Decreased physical activity was common (41.9%) and more frequent in women (P = 0.025) and urban dwellers (P = 0.009). Almost half of respondents (46.0%) declared increased screen time, but only few declared more alcohol intake (4.0%). Weight gain was common (27.4%), and 44.4% of current smokers increased tobacco consumption. Adherence to recommended salt or fluid intake restrictions was reduced in 14.5%. Increase in HF symptoms was commonly reported (21.8%) and tended to be higher in women than in men (P = 0.074). Of the 23 patients who had a phone teleconsultation during the pandemic, 16 had initially planned an in-person consultation that they switched for teleconsultation. CONCLUSIONS: During the lockdown, psychological distress and decreased well-being were common in CHF outpatients, and there was an increase in unhealthy lifestyle behaviours. These changes may negatively impact short-term and long-term prognoses. Medication adherence was maintained, and limitations in access to care were partly counterbalanced by use of telehealth.

Screening for Retinopathy of Prematurity: Insight into Optimizing Screening.

PURPOSE: To determine the factors influencing the time from preterm birth and retinopathy of prematurity (ROP) detection to optimize the timing of the initial screening. METHODS: This multicenter retrospective study enrolled preterm infants born before 32 weeks of gestational age (GA) and/or weighing less than 1,500 g between January 1, 2011, and December 31, 2015. ROP screening was performed using fundus photography with a wide-field camera. Population and follow-up characteristics were recorded. RESULTS: Among the 1,266 preterm infants observed, 795 were retained for analysis. One hundred seventy-four (21.6%) cases of ROP were detected with the first examination performed at 32.3 ± 1.6 weeks of postmenstrual age (PMA) and 5.4 ± 1.0 weeks of postnatal age (PNA). The first signs of ROP were detected at 34.0 ± 1.9 weeks of PMA and 7.2 ± 1.8 weeks of PNA, respectively. In the multivariate analysis, an older GA, a longer duration of mechanical ventilation, and a lower birth weight were correlated with a longer time between preterm birth and ROP detection (p < 0.0001, p < 0.0001, and p = 0.0359, respectively). CONCLUSION: The first examination for ROP screening should be individualized to fit the first screening examination as closely as possible to the first signs of ROP in order to avoid unnecessary examinations without missing ROP.

Cerebral Infarct Topography and Early Outcome after Surgery for Symptomatic Carotid Stenosis: A Multicentre Study.

INTRODUCTION: Although carotid stenosis can cause both territorial and border-zone (BZ) cerebral infarcts (CI), the influence of CI topography on postoperative complications after surgery remains unclear. We compared early outcomes after endarterectomy on the basis of CI location: territorial (T group) or BZ group. MATERIAL AND METHODS: During the period between 2009 and 2013, ischaemic stroke patients who had undergone surgery for symptomatic carotid stenosis were identified from prospective databases from 3 French centres. The outcome was the identification of a combined stroke/death rate 30 days after endarterectomy. RESULTS: Two hundred and eighty-nine patients were included, 216 (74.7%) in the T group and 73 (25.3%) in the BZ group. The mean degree of stenosis was comparable in the 2 groups (78 ± 12% in the T group vs. 80 ± 12% in the BZ group, p = 0.105), with, however, more sub-occlusions (stenosis >90%) in the BZ group (38.4 vs. 23.1%, p = 0.012). The mean time between the time CI developed and the time surgery was performed was 19.6 ± 24.8 days, with a majority of patients being operated upon within 2 weeks following the formation of CI (66.7% in the T group vs. 60.3% in the BZ group, p = 0.322). The combined endpoint was significantly more frequent in the BZ group (9.6 vs. 1.9%, p = 0.003), with 4 ischaemic strokes and 3 deaths. In multivariate analysis, BZ CI was an independent predictor of postoperative stroke or death at 30 days (HR 4.91-95% CI [1.3-18.9], p = 0.020). CONCLUSION: BZ infarcts carry a greater risk of postoperative complications after carotid surgery, thus suggesting that topography of the CI should be considered in the decision-making process regarding surgery.

Efficacy of transcranial direct current stimulation (tDCS) in reducing consumption in patients with alcohol use disorders: study protocol for a randomized controlled trial.

BACKGROUND: Approximately 15 million persons in the European Union and 10 million persons in the USA are alcohol-dependent. The global burden of disease and injury attributable to alcohol is considerable: worldwide, approximately one in 25 deaths in 2004 was caused by alcohol. At the same time, alcohol use disorders remain seriously undertreated. In this context, alternative or adjunctive therapies such as brain stimulation may play a prominent role. The early results of studies using transcranial direct current stimulation found that stimulations delivered to the dorsolateral prefrontal cortex result in a significant reduction of craving and an improvement of the decision-making processes in various additive disorders. We, therefore, hypothesize that transcranial direct current stimulation can lead to a decrease in alcohol consumption in patients suffering from alcohol use disorders. METHODS/DESIGN: We report the protocol of a randomized, double-blind, placebo-controlled, parallel-group trial, to evaluate the efficacy of transcranial direct current stimulation on alcohol reduction in patients with an alcohol use disorder. The study will be conducted in 14 centers in France and Monaco. Altogether, 340 subjects over 18 years of age and diagnosed with an alcohol use disorder will be randomized to receive five consecutive twice-daily sessions of either active or placebo transcranial direct current stimulation. One session consists in delivering a current flow continuously (anode F4; cathode F3) twice for 13 minutes, with treatments separated by a rest interval of 20 min. Efficacy will be evaluated using the change from baseline (alcohol consumption during the 4 weeks before randomization) to 24 weeks in the total alcohol consumption and number of heavy drinking days. Secondary outcome measures will include alcohol craving, clinical and biological improvements, and the effects on mood and quality of life, as well as cognitive and safety assessments, and, for smokers, an assessment of the effects of transcranial direct current stimulation on tobacco consumption. DISCUSSION: Several studies have reported a beneficial effect of transcranial direct current stimulation on substance use disorders by reducing craving, impulsivity, and risk-taking behavior, and suggest that transcranial direct current stimulation may be a promising treatment in addiction. However, to date, no studies have included sufficiently large samples and sufficient follow-up to confirm the hypothesis. Results from this large randomized controlled trial will give a better overview of the therapeutic potential of transcranial direct current stimulation in alcohol use disorders. TRIAL REGISTRATION: Clinical Trials Gov, NCT02505126 (registration date: July 15 2015).