Clinical Markers Of Disease Severity Research Articles

Vibro-tactile stimulation of the neck reduces pain in people with cervical dystonia: a proof-of-concept study.

Pain is a common non-motor symptom in patients with cervical dystonia (CD), severely impacting their quality of life. The pathophysiology of CD is incompletely understood but it involves altered processing of proprioceptive and pain signals. The purpose of this proof-of-concept study was to determine if vibro-tactile stimulation (VTS)-a non-invasive form of neuromodulation targeting the somatosensory system-can modulate neck pain in people with CD. In a multi-center study, 44 CD patients received VTS to sternocleidomastoid and/or trapezius muscles for up to 45min under 9 different stimulation conditions that either targeted a single or a pair of muscles. The primary outcome measure was a perceived pain score (PPS) rated by participants on a 100-point analogue scale. During VTS, 29/44 (66%) of participants experienced a reduction in PPS of at least 10% with 17/44 (39%) reporting a reduction in pain of 50% or higher. After VTS cessation, 57% of participants still reported a 10% or higher reduction in PPS. Effects were significant at the group level and persisted for up to 20min post-treatment. No distinct optimal stimulation profiles were identified for specific CD phenotypes. Clinical markers of disease severity or duration did not predict the degree of VTS-induced pain reduction. This proof-of-concept study demonstrates the potential of VTS as a new non-invasive therapeutic option for treating neck pain associated with CD. Further research needs to delineate optimal dosage and long-term effects.

Prevalence, stability, and clinical significance of an isolated low FEV1 spirometry pattern in children.

In adults, an isolated low FEV1 pattern (an FEV1 below the lower limit of normal with a preserved FVC and FEV1/FVC) has been associated with the risk of developing airway obstruction. Our objective was to examine the prevalence, stability, and clinical significance of an isolated low FEV1 pattern in the pediatric population. We conducted a retrospective study of spirometries from children ages 6-21 years and categorized tests into spirometry patterns according to published guidelines and recent literature. In a subgroup of tests with an isolated low FEV1 pattern, we evaluated spirometry technique. We also examined the association of having a test with an isolated low FEV1 pattern with clinical markers of disease severity in a subgroup of children with cystic fibrosis (CF). The isolated low FEV1 pattern was uncommon across the 29,979 tests included (n = 645 [2%]). In the 263 children with an isolated low FEV1 pattern who had a follow-up test performed, the most frequent spirometry pattern at last test was normal (n = 123 [47%]). A primary diagnosis of CF was associated with increased odds of having at least one test with an isolated low FEV1 pattern (OR = 8.37, 95%CI = 4.70-15.96, p < .001). The spirometry quality in a subgroup of tests with an isolated low FEV1 pattern (n = 50) was satisfactory. In the subgroup of children with CF (n = 102), those who had a test with an isolated low FEV1 pattern had higher odds of using oral antibiotics in the last 12 months than those who had a normal pattern (OR = 3.50, 95%CI = 1.15-10.63, p = .03). The isolated low FEV1 pattern can occur repeatedly over time, usually transitions to a normal pattern, is not due to a poor spirometry technique, and could be clinically relevant in children with chronic lung diseases.

Continuous age- and sex-specific reference ranges of liver enzymes in Chinese children and application in pediatric non-alcoholic fatty liver disease.

Alanine aminotransferase (ALT) is widely used to screen patients with hepatic diseases. However, the current reference ranges (< 50 U/L) were developed by laboratories and have not been validated in populations with a large number of healthy individuals. This study collected venous blood and anthropometric data from a total of 13,287 healthy children aged 3months to 18years who underwent routine physical examinations in the Department of Pediatric Healthcare. We applied the least mean square algorithm to establish age- and sex-related reference percentiles of serum levels of transaminases. For validation, we recruited 4276 children and adolescents with obesity/overweight who underwent evaluation and metabolic tests in the hospital. Using receiver operating characteristic curves, we determined age- and sex-specific upper limit percentiles of liver enzymes for fatty liver diseases. This study revealed a significant correlation between serum transaminase levels and age and sex (P < 0.01). These transaminase levels exhibited age- and sex-specific patterns. Among individuals in the non-alcoholic fatty liver disease (NAFLD) cohort, elevated ALT levels displayed a positive association with clinical markers of disease severity, including homeostatic model assessment of insulin resistance, waist-hip ratio, and serum uric acid levels (P < 0.01). According to the receiver operating characteristic curves, ALT levels at the 92.58th percentile for boys and the 92.07th percentile for girls yielded the highest accuracy and specificity. This study provides age- and sex-specific reference ranges for ALT, aspartate aminotransferase, and γ-glutamyltransferase in Chinese children and adolescents, making it the largest population study to date. Furthermore, the study establishes a precise upper limit for ALT levels, facilitating their use in NAFLD screening. Video Abstract.

Nerve ultrasound in Friedreich’s Ataxia: enlarged nerves as a biomarker of disease severity

ObjectiveIn Friedreich's ataxia research, the focus is on discovering treatments and biomarkers to assess disease severity and treatment effects. Our study examines high-resolution nerve ultrasound in these patients, seeking correlations with established clinical markers of disease severity. MethodTen patients with Friedreich’s Ataxia underwent a comprehensive clinical assessment with established scales (SARA, FARS, mFARS, INCAT, ADL 0-36, IADL). Additionally, they underwent nerve conduction studies and high-resolution nerve ultrasound. Quantitative evaluation of nerve cross-sectional area, conducted at 24 nerve sites using high-resolution nerve ultrasound, was compared with data obtained from 20 healthy volunteers. ResultsAll the patients had a severe sensory axonal neuropathy. High-resolution nerve ultrasound showed significant increase, in cross sectional area, of median and ulnar nerves at the axilla and arm. The cumulative count of affected nerve sites was directly associated with clinical disability, as determined by SARA, FARS, mFARS, ADL 0-36, and INCAT score, while displaying an inverse correlation with IADL. ConclusionsOur study shows that high-resolution ultrasound reveals notable nerve abnormalities, primarily in the upper limbs of patients diagnosed with Friedreich’s Ataxia. The observed correlation between these nerve abnormalities and clinical disability scales indicates the potential use of this technique as a biomarker for evaluating disease severity and treatment effects. SignificanceNerve Ultrasound is a potential biomarker of disease severity in Friedreich’s Ataxia.

Neurofilament light chain in spinal fluid and plasma in multiple system atrophy: a prospective, longitudinal biomarker study.

There is a critical need for reliable diagnostic biomarkers as well as surrogate markers of disease progression in multiple system atrophy (MSA). Neurofilament light chain (NfL) has been reported to potentially meet those needs. We therefore sought to explore the value of NfL in plasma (NfL-p) in contrast to cerebrospinal fluid (NfL-c) as a diagnostic marker of MSA, and to assess NfL-p and NfL-c as markers of clinical disease progression. Well-characterized patients with early MSA (n = 32), Parkinson's disease (PD; n = 21), and matched controls (CON; n = 15) were enrolled in a prospective, longitudinal study of synucleinopathies with serial annual evaluations. NfL was measured using a high-sensitivity immunoassay, and findings were assessed by disease category and relationship with clinical measures of disease progression. Measurements of NfL-c were highly reproducible across immunoassay platforms (Pearson, r = 0.99), while correlation between NfL-c and -p was only moderate (r = 0.66). NfL was significantly higher in MSA compared with CON and PD; the separation was essentially perfect for NfL-c, but there was overlap, particularly with PD, for NfL-p. While clinical measures of disease severity progressively increased over time, NfL-c and -p remained at stable elevated levels within subjects across serial measurements. Neither change in NfL nor baseline NfL were significantly associated with changes in clinical markers of disease severity. These findings confirm NfL-c as a faithful diagnostic marker of MSA, while NfL-p showed less robust diagnostic value. The significant NfL elevation in MSA was found to be remarkably stable over time and was not predictive of clinical disease progression.

Interplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG.

Congenital disorders of glycosylation (CDG) and mitochondrial disorders are multisystem disorders with overlapping symptomatology. Pathogenic variants in the PMM2 gene lead to abnormal N-linked glycosylation. This disruption in glycosylation can induce endoplasmic reticulum stress, contributing to the disease pathology. Although impaired mitochondrial dysfunction has been reported in some CDG, cellular bioenergetics has never been evaluated in detail in PMM2-CDG. This prompted us to evaluate mitochondrial function and autophagy/mitophagy in vitro in PMM2 patient-derived fibroblast lines of differing genotypes from our natural history study. We found secondary mitochondrial dysfunction in PMM2-CDG. This dysfunction was evidenced by decreased mitochondrial maximal and ATP-linked respiration, as well as decreased complex I function of the mitochondrial electron transport chain. Our study also revealed altered autophagy in PMM2-CDG patient-derived fibroblast lines. This was marked by an increased abundance of the autophagosome marker LC3-II. Additionally, changes in the abundance and glycosylation of proteins in the autophagy and mitophagy pathways further indicated dysregulation of these cellular processes. Interestingly, serum sorbitol levels (a biomarker of disease severity) and the CDG severity score showed an inverse correlation with the abundance of the autophagosome marker LC3-II. This suggests that autophagy may act as a modulator of biochemical and clinical markers of disease severity in PMM2-CDG. Overall, our research sheds light on the complex interplay between glycosylation, mitochondrial function, and autophagy/mitophagy in PMM2-CDG. Manipulating mitochondrial dysfunction and alterations in autophagy/mitophagy pathways could offer therapeutic benefits when combined with existing treatments for PMM2-CDG.

The ovarian hyperstimulation that truly matters: Admissions, severity and prevention strategies.

Ovarian hyperstimulation syndrome (OHSS) is a common but serious complication of in vitro fertilisation. Despite available strategies to reduce OHSS incidence, a small proportion of patients will develop the clinically significant disease with substantial morbidity. Efforts toward better understanding and the prevention of severe disease are required to improve patient outcomes. The aims are to: (1) formulate clinically relevant OHSS classification for inpatient settings and data collection/reporting; (2) estimate OHSS prevalence requiring hospital admission in Victoria; and (3) determine the extent of OHSS preventability with clinical strategies. This retrospective cohort study included all OHSS admissions in a tertiary referral centre, January 2016-December 2021, which included approximately 40% of all cases of hospitalisation for OHSS in the State of Victoria. Patient characteristics, treatment regimes, fertility treatment outcomes, timing classification, and clinical markers of disease severity were studied. Patients were classified as having mild, moderate, or severe OHSS with a novel inpatient classification system. Of 199 OHSS cases presenting to the tertiary institution, 107 were classified as moderate/severe, with no significant difference between age, body mass index, length of stimulation and follicle number between mild/moderate and severe groups. There were more cases of early hyperstimulation (137) compared to late (62) presentation, of which 53% were severe. The average length of stay overall was 3.1 days, and 5.2 days for severe presentations. In 15% of severe cases, an agonist trigger was used. The overall prevalence of OHSS requiring hospital admission appears to be low (approximately 0.6% of all stimulated cycles). Established risk factors may not accurately predict clinically relevant OHSS risk. Further monitoring, clinician and patient education are required to minimise the risk of significant OHSS that results in hospital admissions.

Impact of Age and Sex on COVID-19 Severity Assessed From Radiologic and Clinical Findings.

BackgroundData on the epidemiological characteristics and clinical features of COVID-19 in patients of different ages and sex are limited. Existing studies have mainly focused on the pediatric and elderly population.ObjectiveAssess whether age and sex interact with other risk factors to influence the severity of SARS-CoV-2 infection.Material and MethodsThe study sample included all consecutive patients who satisfied the inclusion criteria and who were treated from 24 February to 1 July 2020 in Dubai Mediclinic Parkview (560 cases) and Al Ain Hospital (605 cases), United Arab Emirates. We compared disease severity estimated from the radiological findings among patients of different age groups and sex. To analyze factors associated with an increased risk of severe disease, we conducted uni- and multivariate regression analyses. Specifically, age, sex, laboratory findings, and personal risk factors were used to predict moderate and severe COVID-19 with conventional machine learning methods.ResultsNeed for O2 supplementation was positively correlated with age. Intensive care was required more often for men of all ages (p < 0.01). Males were more likely to have at least moderate disease severity (p = 0.0083). These findings were aligned with the results of biochemical findings and suggest a direct correlation between older age and male sex with a severe course of the disease. In young males (18–39 years), the percentage of the lung parenchyma covered with consolidation and the density characteristics of lesions were higher than those of other age groups; however, there was no marked sex difference in middle-aged (40–64 years) and older adults (≥65 years). From the univariate analysis, the risk of the non-mild COVID-19 was significantly higher (p < 0.05) in midlife adults and older adults compared to young adults. The multivariate analysis provided similar findings.ConclusionAge and sex were important predictors of disease severity in the set of data typically collected on admission. Sexual dissimilarities reduced with age. Age disparities were more pronounced if studied with the clinical markers of disease severity than with the radiological markers. The impact of sex on the clinical markers was more evident than that of age in our study.

Comprehensive proteomics profiling reveals molecular pathways that are differentially regulated in hypertrophic cardiomyopathy and correlate with clinical markers of disease severity

Abstract Background Hypertrophic cardiomyopathy (HCM) is caused by mutations in the genes coding for proteins essential in normal myocardial contraction. However, it remains unclear through which molecular pathways gene mutations mediate the development and progression of HCM. Purpose To determine protein biomarkers and molecular pathways that are differentially regulated in HCM and correlated with disease severity. Methods We conducted a multicenter case-control study of cases with HCM and controls with hypertensive left ventricular hypertrophy. We carried out plasma proteomics profiling of 1681 proteins using the SOMAscan assay. We performed a sparse partial least squares discriminant analysis to develop a proteomics-based discrimination model with data from 1 institution (i.e., the training set). We tested the discriminative ability in independent samples from the other institutions (i.e., the test set). We executed pathway analysis using significantly dysregulated proteins with Bonferroni-corrected p&amp;lt;0.05. Pathways with false discovery rate (FDR) &amp;lt;0.05 and dysregulation of ≥5 member proteins were declared positive. In HCM, we also identified proteins with significant correlation with clinical markers of disease severity (e.g., New York Heart Association [NYHA] class, left atrial diameter) and performed pathway analysis. Results The study included 266 cases and 167 controls (n=308 in the training set; n=125 in the test set). Using the proteomics-based model derived from the training set, the area under the receiver-operating-characteristic curve was 0.89 (95% confidence interval [CI] 0.83–0.94, p&amp;lt;0.001) in the test set (Figure). The sensitivity was 0.84 (95% CI 0.76–0.92) and the specificity was 0.78 (95% CI 0.66–0.90). A total of 508 proteins were significantly associated with the disease status. As shown in the Table, pathway analysis revealed that the Ras-MAPK pathway, along with its upstream and downstream (e.g., Rap1, PI3K-Akt) pathways, was upregulated in HCM (FDR &amp;lt;0.001). Pathways involved in inflammation and fibrosis – e.g., the TGF-β pathway – were also found to be upregulated in HCM. In patients with HCM, 207 out of the 1681 proteins were significantly correlated with NYHA functional class. This number is more than twice as large as what would be expected by chance (i.e., 84 proteins at α=0.05 level). Pathway analysis of these 207 proteins showed upregulation of the Ras-MAPK and related pathways – e.g., PI3K-Akt, Rap1, and TNF. Similarly, 264 of the 1681 proteins were correlated with left atrial diameter in HCM. Pathway analysis of the 264 proteins revealed upregulation of the MAPK and the PI3K-Akt pathways. Conclusions This multicenter case-control study with independent validation serves as the largest-scale investigation with the most comprehensive proteomics profiling in HCM, exhibiting both novel (e.g., Ras-MAPK) and known (e.g., TGF-β) pathways that are differentially regulated in HCM and correlated with disease severity. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute of Health and American Heart Association Figure 1. ROC curveTable 1. Differentially regulated pathways

Gene signature and immune cell profiling by high-dimensional, single-cell analysis in COVID-19 patients, presenting Low T3 syndrome and coexistent hematological malignancies

BackgroundLow T3 syndrome is frequent in patients admitted to intensive care units for critical illness and pneumonia. It has been reported also in patients with COVID-19, Hodgkin disease and chronic lymphocytic leukemia. We analyzed the clinical relevance of Low T3 syndrome in COVID-19 patients and, in particular, in those with associated hematological malignancies.MethodsSixty-two consecutive patients, hospitalized during the first wave of SARS-CoV-2 outbreak in Sant’Andrea University Hospital in Rome, were subdivided in 38 patients (Group A), showing low levels of FT3, and in 24 patients (Group B), with normal FT3 serum values. During the acute phase of the disease, we measured serum, radiologic and clinical disease severity markers and scores, in search of possible correlations with FT3 serum values. In addition, in 6 COVID-19 patients, 4 with Low T3 syndrome, including 2 with a hematological malignancy, and 2 with normal FT3 values, we performed, high-dimensional single-cell analysis by mass cytometry, multiplex cytokine assay and gene expression profiling in peripheral blood mononuclear cells (PBMC).ResultsLow FT3 serum values were correlated with increased Absolute Neutrophil Count, NLR and dNLR ratios and with reduced total count of CD3+, CD4+ and CD8+ T cells. Low FT3 values correlated also with increased levels of inflammation, tissue damage and coagulation serum markers as well as with SOFA, LIPI and TSS scores. The CyTOF analysis demonstrated reduction of the effector memory and terminal effector subtypes of the CD4+ T lymphocytes. Multiplex cytokine assay indicates that mainly IL-6, IP-10 and MCAF changes are associated with FT3 serum levels, particularly in patients with coexistent hematological malignancies. Gene expression analysis using Nanostring identified four genes differently expressed involved in host immune response, namely CD38, CD79B, IFIT3 and NLRP3.ConclusionsOur study demonstrates that low FT3 serum levels are associated with severe COVID-19. Our multi-omics approach suggests that T3 is involved in the immune response in COVID-19 and coexistent hematological malignancy and new possible T3 target genes in these patients have been identified.

Weight loss is correlated with disease severity in Spinocerebellar ataxia type 2: a cross-sectional cohort study

ABSTRACT Background Body weight changes occur frequently during advanced stages of Spinocerebellar Ataxia type 2 (SCA2), nevertheless limited information exists on biomarkers of nutritional status of these patients. Objective. To assess changes in surrogate nutritional markers of SCA2 patients; to explore their associations with expanded CAG repeats and disease severity. Methods One-hundred-thirteen SCA2 patients and 50 healthy controls underwent a comprehensive anthropometrical and biochemical assessment protocol of the nutritional status. Neurological and genotype assessments were also performed. Results A decrease in weight, body mass index (BMI), cutaneous skinfold thickness, fat mass, arm muscle circumference, calf circumference and skeletal muscle mass was observed in SCA2 patients compared to the controls. The total/HDL cholesterol ratio was significantly reduced in patients. BMI was correlated with the age at onset. Overall, anthropometric measures were correlated with clinical markers of disease severity and were more evident in severe and moderate cases. Conclusions Using anthropometric measures in the assessment of the nutritional status of SCA2 patients might provide hints about pathophysiological mechanisms that underlie metabolic abnormalities in SCA2. Anthropometric are close related with disease severity and progression, and trigger preventive therapies aimed to ameliorate weight loss and wasting in these patients.

Observational Study of Chlorpromazine in Hospitalized Patients with COVID-19.

IntroductionChlorpromazine has been suggested as being potentially useful in patients with coronavirus disease 2019 (COVID-19) on the grounds of its potential antiviral and anti-inflammatory effects.ObjectiveThe aim of this study was to examine the association between chlorpromazine use and mortality among adult patients hospitalized for COVID-19.MethodsWe conducted an observational, multicenter, retrospective study at Assistance Publique-Hôpitaux de Paris (AP-HP) Greater Paris University hospitals. Study baseline was defined as the date of first prescription of chlorpromazine during hospitalization for COVID-19. The primary endpoint was death. Among patients who had not been hospitalized in intensive care units (ICUs), we compared this endpoint between those who received chlorpromazine and those who did not, in time-to-event analyses adjusted for patient characteristics, clinical markers of disease severity, and other psychotropic medications. The primary analysis used a Cox regression model with inverse probability weighting. Multiple sensitivity analyses were performed.ResultsOf the 14,340 adult inpatients hospitalized outside ICUs for COVID-19, 55 patients (0.4%) received chlorpromazine. Over a mean follow-up of 14.3 days (standard deviation [SD] 18.2), death occurred in 13 patients (23.6%) who received chlorpromazine and 1289 patients (9.0%) who did not. In the primary analysis, there was no significant association between chlorpromazine use and mortality (hazard ratio [HR] 2.01, 95% confidence interval [CI] 0.75–5.40; p = 0.163). Sensitivity analyses included a Cox regression in a 1:5 ratio matched analytic sample that showed a similar result (HR 1.67, 95% CI 0.91–3.06; p = 0.100) and a multivariable Cox regression that indicated a significant positive association (HR 3.10, 95% CI 1.31–7.34; p = 0.010).ConclusionOur results suggest that chlorpromazine prescribed at a mean daily dose of 70.8 mg (SD 65.3) was not associated with reduced mortality.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40261-021-01001-0.

Intra-alveolar neutrophil-derived microvesicles are associated with disease severity in COPD.

Despite advances in the pathophysiology of chronic obstructive pulmonary disease (COPD), there is a distinct lack of biochemical markers to aid clinical management. Microvesicles (MVs) have been implicated in the pathophysiology of inflammatory diseases including COPD, but their association to COPD disease severity remains unknown. We analyzed different MV populations in plasma and bronchoalveolar lavage fluid (BALF) taken from 62 patients with mild to very severe COPD (51% male; mean age: 65.9 yr). These patients underwent comprehensive clinical evaluation (symptom scores, lung function, and exercise testing), and the capacity of MVs to be clinical markers of disease severity was assessed. We successfully identified various MV subtype populations within BALF [leukocyte, polymorphonuclear leukocyte (PMN; i.e., neutrophil), monocyte, epithelial, and platelet MVs] and plasma (leukocyte, PMN, monocyte, and endothelial MVs) and compared each MV population to disease severity. BALF neutrophil MVs were the only population to significantly correlate with the clinical evaluation scores including forced expiratory volume in 1 s, modified Medical Research Council dyspnea score, 6-min walk test, hyperinflation, and gas transfer. BALF neutrophil MVs, but not neutrophil cell numbers, also strongly correlated with BODE index. We have undertaken, for the first time, a comprehensive evaluation of MV profiles within BALF/plasma of COPD patients. We demonstrate that BALF levels of neutrophil-derived MVs are unique in correlating with a number of key functional and clinically relevant disease severity indexes. Our results show the potential of BALF neutrophil MVs for a COPD biomarker that tightly links a key pathophysiological mechanism of COPD (intra-alveolar neutrophil activation) with clinical severity/outcome.

Radiographic imaging, densitometry and disease severity in Autosomal dominant osteopetrosis type 2.

To characterize relationships between quantitative computed tomography bone mineral density measurements and other qualitative and quantitative imaging measures, as well as clinical metrics, in patients with autosomal dominant osteopetrosis type 2 (ADO2). Clinical and radiologic parameters of 9 adults and 3 children with autosomal dominant osteopetrosis type 2 were assessed including lumbar spine quantitative computed tomography (QCT), radiographic skeletal survey (skull base thickening; Erlenmeyer flask deformity; endobone pattern; and spine density pattern (endplate sclerosis, "anvil" appearance, or diffuse sclerosis)), dual-energy x-ray absorptiometry (DXA), tibial peripheral quantitative computed tomography (pQCT) volumetric bone mineral density (vBMD), bone turnover markers, and bone marrow failure or visual impairment. The skeletal parameter most divergent from normal was lumbar spine QCT Z-score (+ 3.6 to + 38.7). Lumbar QCT Z-score correlated positively with pQCT tibial diaphysis vBMD (Pearson correlation r = 0.73, p = 0.02) and pQCT tibial metaphysis vBMD (r = 0.87, p < 0.01). A trend towards positive lumbar QCT Z-score correlation with serum P1NP/CTX ratio (r = 0.54, p = 0.10) and lumbar DXA Z-score (r = 0.55, p = 0.10) were observed. Bone marrow failure and vision impairment occurred in those with most severe quantitative and qualitative measures, while those with less severe radiographic features had the lowest QCT Z-scores. Lumbar spine QCT provided the most extreme skeletal assessment in ADO2, which correlated positively with other radiologic and clinical markers of disease severity. Given the quantification of trabecular bone and greater variation from normal with wider range of values, lumbar QCT Z-scores may be useful to determine or detect impact of future treatments.

Robust T Cell Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19

SARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19. Here, we systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in unexposed individuals, exposed family members, and individuals with acute or convalescent COVID-19. Acute-phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent-phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype. Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative exposed family members and convalescent individuals with a history of asymptomatic and mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits broadly directed and functionally replete memory T cell responses, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19.

Comparing paediatric- and adult-onset linear morphoea in a large tertiary-referral scleroderma centre.

Linear morphoea is a severe morphoea subtype associated with extracutaneous manifestations, potentially permanent disfigurement and functional impairment. Linear morphoea is more prevalent in paediatric patients, and knowledge of disease in adults is limited. The objective of this study was to compare paediatric- and adult-onset linear morphoea, in an exclusively adult population. This was a retrospective cohort study of adult patients with linear morphoea seen over a 3-year period at a single-site adult tertiary-referral Connective Tissue Disease centre. Clinical markers of disease severity and course, including anatomical distribution, extracutaneous manifestations, cutaneous symptoms, associated autoimmunity, inflammatory blood parameters, Dermatology Life Quality Index scores, treatment requirements and modified Localised Scleroderma Activity Tool were assessed and compared in paediatric- and adult-onset linear morphoea. Of 298 patients with morphoea seen during the study period, 135 had linear morphoea and 133 were included in the study. Most were female (78.9%), the mean age was 36.5 years and almost half (43.6%) had adult-onset disease. Disease was similarly severe between groups with regard to anatomical distribution, cutaneous symptoms (n = 89, 66.9%), extracutaneous manifestations (n = 76, 57.1%), antinuclear antibody-positivity (n = 40, 40.4%), raised erythrocyte sedimentation rate (n = 27, 25.0%) and associated autoimmune diagnoses (n = 15, 11.3%). Prescribed treatments were similar between groups; 73.7% receiving methotrexate and almost one-third (32.3%) requiring more than one steroid-sparing agent. Those with paediatric-onset had more disease-related damage, with a mean modified Localised Scleroderma Skin Damage Index score of 19.5 (95% confidence interval: 17.0-22.0) versus 8.1 (95% confidence interval: 4.4-11.8; p < 0.001). Significantly more patients with adult-onset linear morphoea had quiescent disease (p = 0.0332), and even after correcting for disease duration, paediatric-onset patients still had 2.6 times greater odds of active disease (odds ratio = 2.59, 95% confidence interval: 0.9-7.6; p = 0.083). Linear morphoea in adults can be a severe disease with extracutaneous, autoimmune and systemic features. Adults with paediatric-onset disease appear to have more severe cumulative damage, greater functional impairment and ongoing disease activity. This patient subgroup may require particularly close monitoring and more aggressive therapy.

EARLY CLINICAL MARKERS OF SEVERITY OF ACUTE NECROTIC PANCREATITIS

Summary. Acute necrotic pancreatitis carries enough difficulty in diagnosis and treatment. Destructive forms with retroperitoneal tissue damage cause lethality up to 70 %.&#x0D; The aim was to establish early clinical markers of disease severity.&#x0D; Material and methods. The results of surgical treatment of 120 patients with acute pancreatitis were analyzed. Patients were divided into groups: first group – 40 patients without parapancreatitis; second group — 80 patients with parapancreatitis. Peripheral blood reaction, main biochemical indicators, blood electrolytes, general condition by integral scales were evaluated in this groups.&#x0D; Results and discussion. On the admission day, the levels of erythrocytes and hemoglobin in patients in both groups were within normal limits. All patients had leukocytosis. All subjects had high LII rates. In the dynamics of treatment leukocytosis significantly decreased in the second group. Changes in clinical blood tests, urinalysis, ALT, AST, bilirubin, urea, creatinine were not significant.&#x0D; Conclusions. Postoperative mortality was 27.2 %. 67 % of patients had parapancreatitis. It was revealed, that reliable early markers of severity of acute necrotizing pancreatitis are: level of WBC, leucocyte intoxication index, intoxication indicator, organism`s resistance index, reactive neutrophilic response, C-reactive protein and level of calcium. It was proved, that evaluation of patient`s condition by scales ASSES, SAPS II and Ranson objectively reflects the patient`s condition during the course of treatment.

Scleral pits represent degeneration around the posterior ciliary arteries and are signs of disease severity in choroideremia.

Choroideremia is an X-linked recessive condition characterized by progressive chorioretinal degeneration. Recently, peculiar scleral ectasias, termed scleral "pits" and "tunnels," have been described as a novel finding in patients with choroideremia, but little is known regarding their etiology or their evolution over time. This is a retrospective chart review of consecutive patients with molecularly-confirmed choroideremia and related female carriers seen at a university-based tertiary referral center from January 2010 to July 2016. Multimodal imaging was evaluated for the evolution of scleral pits on fundus photography and scleral tunnels on optical coherence tomography (OCT). The presence of scleral pits and tunnels was correlated with markers of disease severity including age, visual acuity, and severity of visual field loss. Thirty patients (21 affected males, 9 female carriers) were included in the study. Scleral pits were seen in 38.1% (8/21) of affected males and found to occur at insertion sites of the posterior ciliary arteries. Those with scleral pits were older, had poorer visual acuity, and more severe visual field loss than those without (p ≤ 0.05). Scleral tunnels were common (68.4%, 13/19 affected males with available OCT imaging), but no statistically-significant associations with disease severity were seen. The development of new scleral pits and tunnels was observed on longitudinal imaging in 4 and 2 affected males, respectively. No scleral pits or tunnels were visualized in any female carriers. Scleral pits represent degeneration around the posterior ciliary arteries and may be useful as clinical markers of disease severity in choroideremia.

Correlation between systemic inflammatory response and quality of life in patients with chronic rhinosinusitis.

Local sinonasal inflammation resulting from altered T-cell immune signaling is a contributor to the pathogenesis of chronic rhinosinusitis (CRS). CRS patients experience negative impacts on quality of life (QOL) and suffer from comorbidities linked to systemic inflammation. However, systemic inflammatory profiling to evaluate the association between systemic inflammation and QOL in CRS has not been performed. Our objectives were to compare local and systemic inflammatory gene expression in patients with CRS to determine if systemic markers of inflammation associate with disease severity and disease-specific QOL. A prospective observational study was conducted comparing 16 patients with CRS to 10 controls. Inflammatory gene expression in the anterior ethmoid tissues and peripheral blood of patients was measured using multiplex gene expression analysis and correlated to disease severity (computed tomography and nasal endoscopy) and disease-specific QOL (22-item Sino-Nasal Outcome Test [SNOT-22] and Rhinosinusitis Disability Index) using linear regression analyses. Patients with CRS showed significant increases in the expression of ctla4 and jak1 in sinonasal tissue and blood (p<0.05), whereas the gene expression of hla-dqa1, hla-dqb1, and dusp4 was significantly decreased in patients with CRS compared to controls (p<0.05). Soluble and local ctla4 and jak1 showed a significant positive correlation with clinical markers of disease severity and disease-specific QOL (p<0.05). Local and systemic gene expression involved in T-cell immune signaling was found to be significantly altered in the blood and sinonasal tissues of patients with CRS compared to controls and significantly correlated to disease severity and QOL in patients with CRS.

Clinical associations between acetylcholine levels and cholinesterase activity in saliva and gingival crevicular fluid and periodontal diseases.

The oral mucosa possesses a non-neuronal cholinergic system. This study aimed to determine clinical evidence for a role of cholinergic mechanisms in the pathogenesis of periodontal diseases. Fifty healthy participants, 52 patients with gingivitis and 49 with periodontitis were recruited. Full periodontal parameters were recorded and saliva and gingival crevicular fluid (GCF) collected. Levels of acetylcholine and inflammatory mediators were quantified using commercially available assay kits. Acetylcholinesterase and butyrylcholinesterase activities were measured using a published biochemical assay. Acetylcholine levels are significantly elevated in saliva and GCF, whereas GCF levels of butyrylcholinesterase activity are significantly decreased, in patients with periodontal diseases. Acetylcholine levels in saliva and GCF correlated positively with clinical markers of disease severity and with increased levels of IL-17A and IL-17F. In contrast, butyrylcholinesterase activity levels in GCF showed significant negative correlations with clinical markers of disease severity and IL-17A and IL-17F levels. None of the findings were due to smoking. Elevated acetylcholine levels and reduced butyrylcholinesterase activity are clinically associated with periodontal diseases and elevated levels of IL-17A and IL-17F. Therefore, non-neuronal cholinergic mechanisms may influence IL-17 biology and the aetiopathogenesis of periodontal diseases and therefore are possible therapeutic targets.