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Skin tests were carried out on 11 members in the Physiotherapy Department of Sydney Hospital using the Breville Hohensonne 2020 Impulse Lamp. As a test control, the same people were also tested with the Alpine air-cooled Sun Lamp, so that comparison could be made between the recognised first degree erythema of the person and the first degree erythema produced in test patches by the Impulse Lamp.
Hypertensive disorders of pregnancy (HDP) are significant contributors to maternal morbidity and mortality, as well as to long-term cardiovascular health, with an inequitable burden among Black individuals. While there is growing interest in the possibility that inflammatory responses are involved with HDP, work to date has primarily been cross-sectional, and immune cell profiling has focused on cell phenotyping that may not capture relevant functional properties of the immune cells. We examined whether an abnormal inflammatory cellular profile is found in the blood of Black pregnant women before the clinical onset of HDP. This nested case-control study included 27 pregnant women who later developed HDP and 73 who had a healthy pregnancy delivered at term, all of whom provided blood samples during the second trimester. Phenotype and function of immune cell populations were examined by multi-parametric flow cytometry. We observed a greater abundance of peripheral blood T cells in individuals later diagnosed with HDP. Among these were CD161+ CD4 T cells that showed increased expression of pro-inflammatory cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF). Similarly, monocytes from these individuals exhibited increased expression of pro-inflammatory cytokines. Anti-inflammatory T cells and monocytes were not altered in those with versus without a future diagnosis of HDP. We identify a pro-inflammatory cellular immune signature in pregnant individuals destined to have HDP. Immune signatures may serve as a new biomarker to identify subsets of individuals at particular risk for HDP and point to new therapeutic targets to prevent HDP.
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The cerebrospinal fluid (CSF) provides a unique glimpse into the central nervous system (CNS) compartment and offers insights into immune processes associated with both healthy immune surveillance as well as inflammatory disorders of the CNS. The latter include demyelinating disorders, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), that warrant different therapeutic approaches yet are not always straightforward to distinguish on clinical and imaging grounds alone. We established a comprehensive phenotypic landscape of the paediatric CSF immune compartment across a range of non-inflammatory and inflammatory neurological disorders, with a focus on better elucidating CNS-associated immune mechanisms potentially involved in, and discriminating between, paediatric-onset MS (MS) and other paediatric-onset suspected neuroimmune disorders, including MOGAD. CSF from paediatric patients with non-inflammatory neurological disorders is primarily composed of non-activated CD4+ T cells, with few if any B cells present. CSF from paediatric patients with acquired inflammatory demyelinating disorders is characterised by increased numbers of B cells compared to CSF of both patients with other inflammatory or non-inflammatory conditions. Certain features, including particular increased frequencies of antibody-secreting cells (ASCs) and decreased frequencies of CD14+ myeloid cells, distinguish MS from MOGAD and other acquired demyelinating syndromes. Increased CSF ASC frequencies and decreased CSF CD14+ myeloid cell frequencies help distinguish paediatric-onset MS from paediatric-onset MOGAD and other acquired demyelinating syndromes. Our findings provide insight into CNS-associated immune mechanisms that may be present early in the clinical course of MS. Stated in acknowledgements section of manuscript.
Hepatocyte growth factor (HGF) binds exclusively the c-Met surface receptor, and the HGF/c-Met axis regulates T cell function in autoimmune diseases. We analyzed c-Met expression on human CD4 T cells in the blood and cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS) versus non-inflammatory neurological disease (NIND), to better understand the role of CD4 T cells in MS. We recruited 34 untreated MS patients (age 28-44 years) and 13 NIND (age 34-51 years) who underwent paired blood and CSF sampling at the time of diagnosis work-up. Phenotypic and functional CD4 T cells characterization was determined by flow cytometry and bulk RNA sequencing. Adhesion and transmigration capacities were studied to further characterize the function of c-Met+ CD4 T cells. c-Met+ memory CD4 T cells were detected at higher levels in both blood (median of 1.98%) and CSF (5.88%) in MS compared to NIND (0.37% and 0.68%, respectively) (p < 0.0001). Ex vivo c-Met+ CD4 T cells exhibited higher levels of GM-CSF, interleukin (IL)-17, interferon (IFN)- γ , and double positive IL-17+IFN- γ + expression, compared with c-Met- CD4 T cells. c-Met+ CD4 T cells expressed increased levels of integrins-Itgα4β1 (VLA-4) and ItgαLβ2 (LFA-1)-compared with c-Met- CD4 T cells. Anti-Itgα4 (natalizumab) and anti-ItgαLβ2 (odulimomab) inhibited CD4 T cell transmigration with predominant inhibition of CD4 T cells expressing c-Met. These results emphasize c-Met as an immune marker of highly pro-inflammatory and migratory CD4 T lymphocytes in both the periphery and central nervous system of MS patients. ANN NEUROL 2026;99:261-273.
The emergence of SARS-CoV-2 has renewed interest in the relationship between immunity and cognition. Despite decades of work, the impact of viral exposure, mainly in the field of HIV, herpes and hepatitis infections, on distinct cognitive processes remains unclear, as most studies use global screening tools (e.g., MoCA) in isolation in each infectious context. This systematic narrative review adopts a transnosological approach, summarizing previously reported immune-cognition relationships across viral infections. Of 931 studies, 32 met inclusion criteria (N = 25,325) spanning SARS-CoV-2, HIV, herpes, hepatitis, Epstein-Barr virus, and multiple infections. Reported studies on immuno-cognitive relationships reveal several consistent findings. Elevated circulating CD14+CD16+ intermediate monocytes correlated with slower processing speed, reduced episodic memory and mental flexibility. Higher CD4+ T cells were associated with better processing speed, while reduced T cells and B cells levels together with elevated IgG predicted deficits in memory and attention. Most proinflammatory cytokines (e.g., IL-6, TNF-α, IFN-γ) were associated with impairments in overlapping cognitive domains (e.g., memory), whereas IL-10, an anti-inflammatory cytokine, consistently supported executive and memory performance.
The cerebrospinal fluid (CSF) provides a unique glimpse into the central nervous system (CNS) compartment and offers insights into immune processes associated with both healthy immune surveillance as well as inflammatory disorders of the CNS. The latter include demyelinating disorders, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), that warrant different therapeutic approaches yet are not always straightforward to distinguish on clinical and imaging grounds alone. Here, we establish a comprehensive phenotypic landscape of the pediatric CSF immune compartment across a range of non-inflammatory and inflammatory neurological disorders, with a focus on better elucidating CNS-associated immune mechanisms potentially involved in, and discriminating between, pediatric-onset MS (MS) and other pediatric-onset suspected neuroimmune disorders, including MOGAD. We find that CSF from pediatric patients with non-inflammatory neurological disorders is primarily composed of non-activated CD4+ T cells, with few if any B cells present. CSF from pediatric patients with acquired inflammatory demyelinating disorders is characterized by increased numbers of B cells compared to CSF of both patients with other inflammatory or non-inflammatory conditions. Certain features, including particular increased frequencies of antibody-secreting cells (ASCs) and decreased frequencies of CD14+ myeloid cells, distinguish MS from MOGAD and other acquired inflammatory demyelinating disorders.
The biological mechanisms underlying objective and subjective fatigue in post-COVID syndrome remain unclear. This study investigates whether immune responses during the acute phase of SARS-CoV-2 infection predict fatigue dimensions 6-9 months post-infection. We analyzed serum immune markers from 54 hospitalized patients (mean age: 58.69 ± 10.90 yrs; female: 31 %) and assessed their association with chronic fatigue using general linear mixed models. Elevated levels of IL-1RA, IFNγ, TNFα, and monocyte percentage during acute infection predicted increased physical and total fatigue. Additionally, higher TNFα levels (r = -0.40, p = .019) correlated with reduced awareness of cognitive fatigue. These findings highlight the role of acute inflammation in the persistence of post-COVID fatigue.
Acute encephalopathy (AE) has been described as a severe complication of COVID-19. Inflammation has been suggested as a pathogenic mechanism, with high-dose glucocorticoids (GC) showing a beneficial effect. Here, we retrospectively analyzed the clinical and radiological features in a group of COVID-19 AE patients who received GC treatment (GT) and in a non-treated (NT) group. Thirty-six patients with COVID-19 AE (mean age 72.6 ± 11 years; 86.11% men) were evaluated for GC treatment. Twelve patients (mean age 73.6 ± 4.5 years; 66.67% men) received GC, whereas 24 patients who showed signs of spontaneous remission were not treated with GC (mean age 70.1 ± 8.6 years; 95.83% men). Differences in clinical characteristics and correlations with imaging features were explored. The GT group showed signs of vulnerability, with a longer hospitalization (p = 0.009) and AE duration (p = 0.012) and a higher hypertensive arteriopathy (HTNA) score (p = 0.022), when compared to NT group. At hospital discharge, the two groups were comparable in terms of clinical outcome (modified Rankin scale; p = 0.666) or mortality (p = 0.607). In our whole group analyses, AE severity was positively correlated with periventricular white matter hyperintensities (p = 0.011), deep enlarged perivascular spaces (p = 0.039) and HTNA score (p = 0.014). This study suggests that, despite signs of radiological vulnerability and AE severity, patients treated by high-dose GC showed similar outcome at discharge, with respect to NT patients. Imaging features of cerebral small vessel disease correlated with AE severity, supporting the hypothesis that brain structural vulnerability can impact AE in COVID-19.
Aging in multiple sclerosis (MS) leads to altered clinical manifestations, where the pathophysiology shifts towards compartmentalized inflammation that drives clinical progression independent of relapse activity. Consequently, the effectiveness of disease-modifying therapies (DMTs) diminishes in older patients, coinciding with an elevated risk of adverse events. This raises the question of whether MS therapies should be discontinued after a certain age, which is often proposed for patients over 55 years. Studies on treatment discontinuation have shown a slight increase in disease activity, yet without significant disability progression. This suggests that the decision to stop DMTs should be discussed with older patients, considering existing comorbidities. Following the cessation of therapy, meticulous monitoring is essential. L’avancée en âge modifie la présentation clinique de la sclérose en plaques (SEP). La physiopathologie évolue progressivement au profit d’une inflammation restreinte au système nerveux central entraînant une progression clinique indépendante des poussées. Cette évolution est associée à une baisse d’efficacité des traitements de la SEP, alors qu’en parallèle le risque de complications augmente. Se pose donc la question d’un arrêt des thérapies de la SEP après un certain âge, souvent proposé à 55 ans. Bien que les premières études suggèrent une légère reprise d’activité à l’arrêt des traitements, celle-ci n’est pas associée à une progression du handicap. L’arrêt du traitement chez les patients les plus âgés devrait donc être envisagé en prenant en compte les comorbidités. Par la suite, une surveillance méticuleuse est indispensable.
To assess the long-term efficacy and safety of treatments for cystoid macular edema in birdshot retinochoroïditis. Observational retrospective study of 142 HLA-A29-positive patients with cystoid macular edema; the main outcome was the optical coherence tomography intraretinal cysts resolution. During the mean follow-up of 75 months (12-178), 61.3% of patients were successfully treated using 1 to 3 treatment steps, while the others needed more steps. At 6 months, there were no significant effects on ME for anti-TNF (tumor necrosis factor) and IVIg (immunoglobulin) in contrast to antimetabolites (OR 1.98), systemic GCS (glucocorticosteroids), CsA (cyclosporine A) and tocilizumab (odds ratio closed to 2.7), intraocular injected GCS (odds ratio of 4.2), and interferon (odds ratio of 4.4). The percentages of therapeutic success trend to decrease from the initial three treatment steps to the subsequent treatment steps, for systemic GCS (84% to 70%), for anti-TNF (42% to 33%), and for CsA (71% to 33%); the success percentages did not decrease for injected GCS (83% to 89%). Macular edema recurrence occurred with the highest percentage for injected GCS (86.8%, P = 0.01) and the lowest for tocilizumab (10.5%, P = 0.001). Interferons-α and tocilizumab were associated with the lowest prednisone daily doses. The classical uveitic cystoid macular edema therapeutic algorithm could be adapted to birdshot retinochoroïditis.
Cognitive symptoms persisting beyond the acute phase of COVID-19 infection are commonly described for up to 2 years after infection. The relationship between cognitive performance, in particular episodic memory processes observed chronically after infection, and cytokine levels in the acute phase of COVID-19 has not yet been identified in humans. To determine whether the levels of cytokines IL1β, IL-6 and TNFα secreted in the acute phase of SARS-CoV-2 infection are associated and predict verbal and visuospatial episodic memory performance in humans 6 to 9 months and 12 to 15 months post-infection. The associations and predictive value of the concentration of cytokines measured in acute phase (IL-1β, IL-6, TNFα) from plasma samples of N = 33 hospitalized COVID-19 patients (mean age 61 years, 39-78, 65% in intensive care) in relation to their verbal and visuospatial episodic memory performance measured at 6-9 months and 12-15 months post-infection were analyzed. To do this, we used Spearman correlations and generalised linear mixed models. IL-1β levels were associated with verbal episodic memory total recall scores 6-9 months post-infection. At 12-15 months post-infection IL-6 predicted verbal episodic memory score. This study demonstrated that the severity of inflammatory reaction at acute phase of SARS-CoV-2 infection predicts verbal episodic memory performance in the long-term post-infection.
The diagnosis of neurosyphilis (NS) lacks a true 'gold standard', making the diagnosis challenging while consequences of a misdiagnosis are potentially severe. The aim of this study was to evaluate the diagnostic performance of measuring an antibody index (AI) for the intrathecal synthesis of specific anti-Treponema pallidum (T. pallidum) IgG for the diagnosis of NS. Specific anti-T. pallidum IgG were measured simultaneously in paired cerebrospinal fluid (CSF)-serum samples collected retrospectively and prospectively between 2007 and 2022, from patients suspected of NS, in Switzerland. An AI was calculated to account for blood-brain barrier integrity. Area under the receiver operating characteristic curve, sensitivity/specificity and positive/negative predictive values of AI test were estimated. Two NS definitions were used: NS1 included patients with NS suspicion presenting with neurological symptoms and/or acute neurosensory signs, and positive T. Pallidum Hemagglutinations Assay (TPHA)/T. pallidum particle agglutination assay (TPPA) serology and CSF-TPHA/TPPA ≥320, and either CSF-leucocytes >5 cells/mm3 and/or CSF-protein >0.45 g/L and/or a reactive CSF-venereal disease research laboratory (VDRL)/rapid plasma reagin (RPR) test. NS2 included patients with suspected NS presenting with acute ocular and/or otologic symptoms, and positive TPHA/TPPA serology, and a favourable response to NS treatment. Controls were patients diagnosed with any other central nervous system (CNS) pathologies and with positive TPHA/TPPA serology. The study included 71 NS (43 NS1 and 28 NS2) and 110 controls. With a threshold of ≥1.7, sensitivity and specificity of the specific AI test were 90.7% (CI 77.7 to 97.4) and 100% (CI 96.7 to 100.0), respectively, for NS1 and 14.3% (CI 4 to 32.7) and 100% (CI 96.7 to 100.0) for NS2. In patients suspected of NS with a CNS involvement (NS1 group), NS could be confirmed by the positivity of this specific AI. Measurement of an intrathecal synthesis index of specific anti-T. pallidum IgG in patients with CSF inflammatory signs appears to be a valuable diagnostic test. However, in otic or ocular syphilis, presenting few CSF abnormalities, AI is not sufficient alone to confirm NS diagnosis. Swiss Association of Research Ethics Committees number 2019-00232.
Our objective was to evaluate the individual and combined prognostic attributes of baseline serum and CSF measurements of Neurofilament light chain (sNfL, cNfL) and glial fibrillary acidic protein (sGFAP, cGFAP) on long term clinical outcomes in MS. In this retrospective single center study, patients with serum and CSF stored at first MS presentation and > 15-years of follow-up were analyzed. NfL and GFAP were quantified from cryopreserved samples using a digital immunoassay and analyzed as predictors of confirmed disability worsening (CDW). Sixty patients (70% female) underwent baseline tandem CSF and serum sampling and were followed for a mean of 17.8 years (SD 2.5). 32 developed CDW. By logistic regression, while sNfL cNfL and cGFAP showed prognostic merit (AUC 0.72, 0.70, 0.62 respectively), sGFAP did not (AUC 0.5). The combination of cNfL and cGFAP improved CDW prediction compared to either measure considered in isolation (AUC 0.72). The optimal predictive cut-off for CDW (Youden's index) for cNfL was 596 pg/mL and for cGFAP was 8160 pg/mL. Kaplan-Meier analysis of the cutoff-defined 'high-high' and 'low-low' combined cNfL and cGFAP groupings improved prediction of CDW compared to either marker individually (Hazard ratio 4.5 (95% CI 2.7-18.3), Logrank P < 0.0001). Cox Proportional Hazards regression demonstrated that high baseline cNfL and cGFAP were independently prognostic of subsequent CDW after adjusting for baseline age, sex, EDSS score and subsequent treatment exposure. Each unit increase in Ln(cNfL) and Ln(cGFAP) was respectively associated with an additional hazard of 2.36 (95% CI 1.12-5.52) and 2.26 (95% CI 1.03-5.21). CSF NfL and GFAP are independently prognostic of long-term clinical worsening in MS, and may represent a complementary pairing.
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This study evaluates the impact of high risk of obstructive sleep apnea (OSA) on coronavirus disease 2019 (COVID-19) acute encephalopathy (AE). Between 3/1/2020 and 11/1/2021, 97 consecutive patients were evaluated at the Geneva University Hospitals with a neurological diagnosis of COVID-19 AE. They were divided in two groups depending on the presence or absence of high risk for OSA based on the modified NOSAS score (mNOSAS, respectively ≥ 8 and < 8). We compared patients' characteristics (clinical, biological, brain MRI, EEG, pulmonary CT). The severity of COVID-19 AE relied on the RASS and CAM scores. Most COVID-19 AE patients presented with a high mNOSAS, suggesting high risk of OSA (> 80%). Patients with a high mNOSAS had a more severe form of COVID-19 AE (84.8% versus 27.8%), longer mean duration of COVID-19 AE (27.9 versus 16.9 days), higher mRS at discharge (≥ 3 in 58.2% versus 16.7%), and increased prevalence of brain vessels enhancement (98.1% versus 20.0%). High risk of OSA was associated with a 14 fold increased risk of developing a severe COVID-19 AE (OR = 14.52). These observations suggest an association between high risk of OSA and COVID-19 AE severity. High risk of OSA could be a predisposing factor leading to severe COVID-19 AE and consecutive long-term sequalae.
Despite the widespread use of glucocorticoids in inflammatory and autoimmune disorders, there is uncertainty about the safe cessation of long-term systemic treatment, as data from prospective trials are largely missing. Due to potential disease relapse or glucocorticoid-induced hypocortisolism, the drug is often tapered to sub-physiological doses rather than stopped when the underlying disease is clinically stable, increasing the cumulative drug exposure. Conversely, the duration of exposure to glucocorticoids should be minimized to lower the risk of side effects. We designed a multicenter, randomized, triple-blinded, placebo-controlled trial to test the clinical noninferiority of abrupt glucocorticoid stop compared to tapering after ≥28 treatment days with ≥420 mg cumulative and ≥7.5 mg mean daily prednisone-equivalent dose. 573 adult patients treated systemically for various disorders will be included after their underlying disease has been stabilized. Prednisone in tapering doses or matching placebo is administered over 4 weeks. A 250 mg ACTH-test, the result of which will be revealed a posteriori, is performed at study inclusion; all patients are instructed on glucocorticoid stress cover dosing. Follow-up is for 6 months. The composite primary outcome measure is time to hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis. Secondary outcomes include the individual components of the primary outcome, cumulative glucocorticoid doses, signs and symptoms of hypocortisolism, and the performance of the ACTH test in predicting the clinical outcome. Cox proportional hazard, linear, and logistic regression models will be used for statistical analysis. This trial aims to demonstrate the clinical noninferiority and safety of abrupt treatment cessation after ≥28 days of systemic glucocorticoid therapy in patients with stabilized underlying disease. ClinicalTrials.gov Identifier: NCT03153527; EUDRA-CT: 2020-005601-48 https://clinicaltrials.gov/ct2/show/NCT03153527?term=NCT03153527&draw=2&rank=1.
The classic Coffee Brewing Control Chart (BCC) was originally developed in the 1950s. It relates coffee quality to brew strength and extraction yield, and it is still widely used today by coffee industry professionals around the world to provide guidance on the brewing of coffee. Despite its popularity, recent experimental studies have revealed that sensory attributes and consumer preferences actually follow much more complicated trends than those indicated by the classic BCC. Here, we present a methodology to synthesize the results of these recent studies on drip-brewed coffee to generate new versions of the BCC: a new Sensory BCC that displays a broad array of statistically significant sensory attributes across typical total dissolved solids and percent extraction ranges, a new Consumer BCC that highlights the existence of two preference clusters with different likes and dislikes across those ranges, a new Sensory and Consumer BCC that combines both sensory descriptive and consumer preferences on the same chart, and a more streamlined BCC that omits consumer preferences and focuses on the overarching sensory descriptive trends. The new BCCs provide more accurate insight on how best to brew coffee to achieve desired sensory profiles. PRACTICAL APPLICATION: Through the manipulation of yield and extraction parameters, the new Sensory and Consumer Coffee Brewing Control Chart presented here can be used by brewers of drip coffee to design coffees with specific sensory profiles and match the preferences of different consumer types.
Background and Objectives: Vaccination has been critical to managing the COVID-19 pandemic. Autoimmunity of the nervous system, especially among a select set of high-risk groups, can be triggered or enhanced by the contents of vaccines. Here, we report a case series of acute peripheral neuropathies following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report on 11 patients (range: 30-90 years old) who presented at our center between January 2021 and February 2022. Methods: We obtained the patients' history and performed clinical neurological examination and electromyoneurography on all subjects. If necessary, magnetic resonance imaging and laboratory testing, including cerebrospinal fluid analysis and specific antibody testing, were performed. Results: Patients presented with peripheral neuropathies of acute onset between 1 and 40 days after vaccination with different types of COVID-19 vaccines. Most cases (9/11) resolved with a rapid, complete or partial recovery. Conclusions: We found acute peripheral neuropathies in a set of individuals after they received vaccines against SARS-CoV-2. Albeit our observation shows that during extensive vaccination programs, negative side effects on the peripheral nervous system might occur, most of them showed benign clinical evolution. Thus, potential side effects should not hinder the prescription of vaccines. More extensive studies are needed to elucidate populations at risk of developing peripheral neuropathies and mechanisms of autoimmune response in the nervous system.