Building a Better Defense: Expanding and Improving Natural Killer Cells for Adoptive Cell Therapy.

Natural killer (NK) cells have gained attention as a promising adoptive cell therapy platform for their potential to improve cancer treatments. NK cells offer distinct advantages over T-cells, including major histocompatibility complex class I (MHC-I)-independent tumor recognition and low risk of toxicity, even in an allogeneic setting. Despite this tremendous potential, challenges persist, such as limited in vivo persistence, reduced tumor infiltration, and low absolute NK cell numbers. This review outlines several strategies aiming to overcome these challenges. The developed strategies include optimizing NK cell expansion methods and improving NK cell antitumor responses by cytokine stimulation and genetic manipulations. Using K562 cells expressing membrane IL-15 or IL-21 with or without additional activating ligands like 4-1BBL allows "massive" NK cell expansion and makes multiple cell dosing and "off-the-shelf" efforts feasible. Further improvements in NK cell function can be reached by inducing memory-like NK cells, developing chimeric antigen receptor (CAR)-NK cells, or isolating NK-cell-based tumor-infiltrating lymphocytes (TILs). Memory-like NK cells demonstrate higher in vivo persistence and cytotoxicity, with early clinical trials demonstrating safety and promising efficacy. Recent trials using CAR-NK cells have also demonstrated a lack of any major toxicity, including cytokine release syndrome, and, yet, promising clinical activity. Recent data support that the presence of TIL-NK cells is associated with improved overall patient survival in different types of solid tumors such as head and neck, colorectal, breast, and gastric carcinomas, among the most significant. In conclusion, this review presents insights into the diverse strategies available for NK cell expansion, including the roles played by various cytokines, feeder cells, and culture material in influencing the activation phenotype, telomere length, and cytotoxic potential of expanded NK cells. Notably, genetically modified K562 cells have demonstrated significant efficacy in promoting NK cell expansion. Furthermore, culturing NK cells with IL-2 and IL-15 has been shown to improve expansion rates, while the presence of IL-12 and IL-21 has been linked to enhanced cytotoxic function. Overall, this review provides an overview of NK cell expansion methodologies, highlighting the current landscape of clinical trials and the key advancements to enhance NK-cell-based adoptive cell therapy.

B Cells and Double-Negative B Cells (CD27-IgD-) Are Related to Acute Pancreatitis Severity.

Acute pancreatitis (AP) is an increasingly frequent disease in which inflammation plays a crucial role. Fifty patients hospitalized with AP were included and peripheral blood samples were analyzed for B and T cell subpopulations at the time of hospitalization and 48 h after diagnosis. The Bedside Index of Severity in Acute Pancreatitis (BISAP) and length of hospital stay were also recorded. A healthy control (HC) group of 15 outpatients was included. AP patients showed higher neutrophil/lymphocyte (N/L) ratios and higher percentages of B cells than the HC group. The total B cell percentages were higher in patients with moderate/severe AP than in patients with mild AP. The percentages of B cells as well as the percentages of the CD27-IgD- B cell subset decreased from admission to 48 h after admission. The patients with higher BISAP scores showed lower percentages of peripheral lymphocytes but higher percentages of CD27-IgD- B cells. Higher BISAP scores, N/L ratios, and peripheral blood B cell levels emerged as predictors of hospital stay length in AP patients. Our findings underscore the importance of early markers for disease severity. Additionally, the N/L ratio along with the BISAP score and circulating B cell levels form a robust predictive model for hospital stay duration of AP patients.

Circulating Blood Lymphocytes and Acute Pancreatitis Severity: A Systematic Review.

Acute pancreatitis is an acute inflammatory process of the pancreas with high prevalence and varying degrees of severity that can be potentially life-threatening. Much is still unknown about which mechanisms determine the course and severity of acute pancreatitis. The primary objective of this review is to identify the potential association between circulating lymphocytes and the severity of acute pancreatitis. A systematic search was performed in Medline, Web of Science, Cochrane Central Register of Controlled Trials and ClinicalTrails.gov. The authors independently did the selection process as well as data extraction that was recorded into a flow diagram following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). Our initial search identified 27,783 studies which were narrowed down to 13 by applying strict inclusion and exclusion algorithms. The consistent findings across the studies indicated that peripheral blood lymphocytes are related to acute pancreatitis severity.

Added value of lymphocyte subpopulations in the classification of Sjögren's syndrome.

Sjögren's Syndrome (SjS) is a chronic systemic immune-mediated inflammatory disease characterized by lymphocytic infiltration and consequent lesion of exocrine glands. SjS diagnosis and classification remains a challenge, especially at SjS onset, when patients may have milder phenotypes of the disease or uncommon presentations. New biomarkers are needed for the classification of SjS, thus, we aimed to evaluate the added-value of lymphocyte subpopulations in discriminating SjS and non-Sjögren Sicca patients. Lymphocyte subsets from 62 SjS and 63 Sicca patients were characterized by flow cytometry. The 2002 AECG and the 2016 ACR/EULAR SjS classification criteria were compared with clinical diagnosis. The added discriminative ability of joining lymphocytic populations to classification criteria was assessed by the area under the Receiver-Operating-Characteristic Curve (AUC). Considering clinical diagnosis as the gold-standard, we obtained an AUC = 0.952 (95% CI: 0.916-0.989) for AECG and an AUC = 0.921 (95% CI: 0.875-0.966) for ACR/EULAR criteria. Adding Tfh and Bm1 subsets to AECG criteria, performance increased, attaining an AUC = 0.985 (95% CI: 0.968-1.000) (p = 0.021). Th1/Breg-like CD24hiCD27+ and switched-memory B-cells maximized the AUC of ACR/EULAR criteria to 0.953 (95% CI: 0.916-0.990) (p = 0.043). Our exploratory study supports the potential use of lymphocyte subpopulations, such as unswitched memory B cells, to improve the performance of classification criteria, since their discriminative ability increases when specific subsets are added to the criteria.

Mastócitos e síndrome de ativação mastocitária: o que há de novo? / Mast cells and mast cell activation syndrome: what's new?

Os mastócitos são as principais células efetoras da resposta alérgica aguda, desempenhando também um papel importante na angiogênese, tolerância imunológica, regulação da fibrinólise, regeneração neuronal e osteoclastogênese. Localizam-se maioritariamente na pele e nas mucosas do intestino e pulmões, onde exercem uma função "sentinela". As síndromes de ativação mastocitária são caracterizadas pela ocorrência de episódios recorrentes de manifestações clínicas resultantes da libertação de mediadores mastocitários. Esta constitui-se como entidade complexa com um espectro de sintomas associados, representando um desafio diagnóstico e terapêutico. Nesta revisão, os autores pretendem apresentar uma visão geral sobre a estrutura e função dos mastócitos e sobre os critérios diagnósticos e abordagem terapêutica da síndrome de ativação mastocitária.

Mast cells are the main effector cells of acute allergic response, also playing an important role in angiogenesis, immune tolerance, regulation of fibrinolysis, neuronal regeneration, and osteoclastogenesis. They are generally located in the skin and mucous membranes of the intestines and lungs, where they perform a "sentinel" function. Mast cell activation syndrome is characterized by recurrent clinical manifestations resulting from the release of mast cell mediators. This complex entity, which involves a spectrum of associated symptoms, is a diagnostic and therapeutic challenge. In this article we overview of the structure and function of mast cells, in addition to the diagnostic criteria and therapeutic approaches to mast cell activation syndrome.

Left atrial strain is associated with distinct inflammatory and immune profile in patients with COVID-19 pneumonia.

INTRODUCTION: SARS-CoV-2 infection is associated with multiple cardiac manifestations. Left atrial strain (LA-S) by speckle tracking echocardiography (STE) is a novel transthoracic echocardiography (TTE) measure of LA myocardial deformation and diastolic dysfunction, which could lead to early recognition of cardiac injury in severe COVID-19 patients with possible implications on clinical management, organ dysfunction, and mortality. Cardiac injury may occur by direct viral cytopathic effects or virus-driven immune activation, resulting in heart infiltration by inflammatory cells, despite limited and conflicting data are available on myocardial histology. PURPOSE: We aimed to explore LA-S and immune profiles in COVID-19 patients admitted to the intensive care unit (ICU) to identify distinctive features in patients with cardiac injury. METHODS: We enrolled 30 patients > 18 years with positive SARS-CoV-2 RT-PCR, admitted to ICU. Acute myocardial infarction and pulmonary embolism were exclusion criteria. On days D1, D3, and D7 after ICU admission, patients performed TTE, hemogram, cardiac (pro-BNP; troponin) and inflammatory biomarkers (ESR; ferritin; IL1ß; IL6; CRP; d-dimer; fibrinogen; PCT; adrenomedullin, ADM), and immunophenotyping by flow cytometry. RESULTS: Patient's mean age was 60.7 y, with 63% males. Hypertension was the most common risk factor (73%; with 50% of patients under ACEi or ARA), followed by obesity (40%, mean BMI = 31 kg/m2). Cardiac dysfunction was detected by STE in 73% of patients: 40% left ventricle (LV) systolic dysfunction, 60% LV diastolic dysfunction, 37% right ventricle systolic dysfunction. Mortality, hospitalization days, remdesivir use, organ dysfunction, cardiac and serum biomarkers were not different between patients with (DYS) and without cardiac dysfunction (nDYS), except for ADM (increased in nDYS group at D7). From the 77 TTE, there was a striking difference between diastolic dysfunction evaluation by classic criteria compared to STE (28.6% vs. 57.1%, p = 0.0006). Lower reservoir (Ɛ) and contraction (ƐCT) LA-S correlated with IL-6 (Ɛ, p = 0.009, r = - 0.47; ƐCT, p = 0.0002, r = - 0.63) and central memory CD4 T-cells (ƐCT, p = 0.049, r = - 0.24). Along all timepoints, DYS patients showed persistent low lymphocyte counts that recovered at D7 in nDYS patients. DYS patients had lower platelets at D3 and showed a slower recovery in platelet counts and CRP levels; the latter significantly decreased at D7 in nDYS patients (p = 0.009). Overall, patients recovered with an increasing P/F ratio, though to a lesser extent in DYS patients. DISCUSSION: Our study shows that LA-S may be a more sensitive marker for diastolic dysfunction in severe COVID-19, which could identify patients at risk for a protracted inflammatory state. A differential immune trait in DYS patients at ICU admission, with persistent lymphopenia, enriched CM T-cells, and higher IL-6 may suggest distinct inflammatory states or migration patterns in patients that develop cardiac injury.

Decreased adiponectin/leptin ratio relates to insulin resistance in adults with obesity.

Adipose tissue dysfunction is a key mechanism that leads to adiposity-based chronic disease. This study aimed to investigate the reliability of the adiponectin/leptin ratio (AdipoQ/Lep) as an adipose tissue and metabolic function biomarker in adults with obesity, without diabetes. Data were collected from a clinical trial conducted in 28 adults with obesity (mean body mass index: 35.4 ± 3.7 kg/m2) (NCT02169778). With the use of a forward stepwise multiple linear regression model to explore the relationship between AdipoQ/Lep and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), it was observed that 48.6% of HOMA-IR variance was explained by triacylglycerols, AdipoQ/Lep, and waist-to-hip ratio (P < 0.001), AdipoQ/Lep being the strongest independent predictor (Beta = -0.449, P < 0.001). A lower AdipoQ/Lep was correlated with higher body mass index (Rs = -0.490, P < 0.001), body fat mass (Rs = -0.486, P < 0.001), waist-to-height ratio (Rs = -0.290, P = 0.037), and plasma resistin (Rs = -0.365, P = 0.009). These data highlight the central role of adipocyte dysfunction in the pathogenesis of insulin resistance and emphasize that AdipoQ/Lep may be a promising early marker of insulin resistance development in adults with obesity.NEW & NOTEWORTHY Adiponectin/leptin ratio, triacylglycerols, and waist-to-hip ratio explained almost half of HOMA-IR variance in the context of obesity. This study provides evidence to support adipose tissue dysfunction as a central feature of the pathophysiology of obesity and insulin resistance. Early identification of individuals at higher risk of developing metabolic complications through adipose tissue dysfunction assessment and the staging of obesity and its transient phenotypes can contribute to improve therapeutic decision-making.

Association of B Cells with Idiopathic Recurrent Pregnancy Loss: A Systematic Review and Meta-Analysis.

Recurrent pregnancy loss (RPL) affects 1-2% of women and is defined as having experienced two or more failed pregnancies. In almost 50% of cases, the causes are idiopathic (IRPL), but increasing evidence has suggested an immunological cause. B cells are known to provide crucial support for a successful pregnancy outcome. However, their involvement in the mechanisms underlying IRPL is still unclear. This systematic review and meta-analysis aimed to comprehensively summarise the existing evidence regarding the levels and profiles of B cells in IRPL. An extensive computerized search in PubMed/Medline, Embase, Scopus, and Web of Science databases was performed with no imposed limits. Two reviewers independently screened all retrieved studies, extracted all the data, and assessed the methodological quality. Disagreements were resolved by a third reviewer. From a total of 1125 retrieved studies, 19 studies were included in the systematic review, and 8 studies were quantitatively analysed. We highlight a potential association between women with IRPL and increased levels of endometrial B cells. In addition, the flow cytometry technique seems to be preferred over immunohistochemistry for identifying those differences, while further studies are necessary to clarify the role of B cells as an immunological risk factor for RPL.

Intermittent energy restriction ameliorates adipose tissue-associated inflammation in adults with obesity: A randomised controlled trial.

BACKGROUND & AIMS: Although intermittent energy restriction (IER) seems to be as effective as continuous energy restriction (CER) for weight loss, there is still a need to determine the putative effect of this strategy upon the metabolic-inflammatory status. This study aimed to compare the effects of IER versus CER on cardiometabolic and inflammatory markers, over a 12-week period, in adults with obesity. METHODS: Twenty-eight Norwegian adults (20-55 years) with obesity [body mass index: 35.4 (3.7) kg/m2] from a clinical trial (NCT02169778) who completed a 12-weeks diet-induced weight loss as IER (n = 14) or CER (n = 14) were included in this study. Cardiometabolic, adipokines and inflammatory markers were evaluated at baseline and after the intervention. Plasma levels of 13 inflammatory cytokines and chemokines (IL-1ß, IFN-α2, IFN-γ, TNF-α, MCP-1, IL-6, IL-8, IL-10, IL-12, IL-17A, IL-18, IL-23, and IL-33) and 4 adipokines (adiponectin, adipsin, leptin and resistin) were measured through multiplex bead-based flow cytometric immunoassays. RESULTS: Both interventions resulted in comparable reductions in fasting glucose and insulin concentrations, lipid profile biomarkers, and adipokines. There were significant differences in HOMA-IR between interventions, with a more pronounced reduction in the IER group (-3.7 vs -1.6, P = 0.040). Inflammatory cytokines and chemokines decreased significantly in the IER group only. Differences in the relative changes of IL-1ß (-48.5 vs 58.2%, P = 0.011), IFN-γ (-53.2 vs 45.1%, P = 0.023), MCP-1 (-22.0 vs 17.4%, P = 0.023), IL-18 (-40.8 vs 10.1%, P = 0.019), IL-23 (-64.8 vs 44.0%, P = 0.011) and IL-33 (-53.4 vs 35.7%, P = 0.028) were statistically significant between groups, with improvements in the inflammatory profile in the IER group. CONCLUSIONS: Our results suggest that a 12-weeks intermittent energy restriction, in comparison to a continuous energy strategy, could be advantageous to reduce inflammation associated with obesity, and consequently improve insulin resistance, regardless of the amount of weight loss. Registered under ClinicalTrials.gov Identifier no. NCT02169778.

Characteristic Immune Dynamics in COVID-19 Patients with Cardiac Dysfunction.

Background: We aimed to explore immune parameters in COVID-19 patients admitted to the intensive care unit (ICU) to identify distinctive features in patients with cardiac injury. Methods: A total of 30 COVID-19 patients >18 years admitted to the ICU were studied on days D1, D3 and D7 after admission. Cardiac function was assessed using speckle-tracking echocardiography (STE). Peripheral blood immunophenotyping, cardiac (pro-BNP; troponin) and inflammatory biomarkers were simultaneously evaluated. Results: Cardiac dysfunction (DYS) was detected by STE in 73% of patients: 40% left ventricle (LV) systolic dysfunction, 60% LV diastolic dysfunction, 37% right ventricle systolic dysfunction. High-sensitivity cardiac troponin (hs-cTn) was detectable in 43.3% of the patients with a median value of 13.00 ng/L. There were no significant differences between DYS and nDYS patients regarding mortality, organ dysfunction, cardiac (including hs-cTn) or inflammatory biomarkers. Patients with DYS showed persistently lower lymphocyte counts (median 896 [661−1837] cells/µL vs. 2141 [924−3306] cells/µL, p = 0.058), activated CD3 (median 85 [66−170] cells/µL vs. 186 [142−259] cells/µL, p = 0.047) and CD4 T cells (median 33 [28−40] cells/µL vs. 63 [48−79] cells/µL, p = 0.005), and higher effector memory T cells (TEM) at baseline (CD4%: 10.9 [6.4−19.2] vs. 5.9 [4.2−12.8], p = 0.025; CD8%: 15.7 [7.9−22.8] vs. 8.1 [7.7−13.7], p = 0.035; CD8 counts: 40 cells/µL [17−61] vs. 10 cells/µL [7−17], p = 0.011) than patients without cardiac dysfunction. Conclusion: Our study suggests an association between the immunological trait and cardiac dysfunction in severe COVID-19 patients.

Pilot study in human healthy volunteers on the mechanisms underlying remote ischemic conditioning (RIC) - Targeting circulating immune cells and immune-related proteins.

Remote ischemic conditioning (RIC) is a novel promising therapy for treatment of neurological diseases, including ischemic stroke. RIC consists of short cycles of ischemia in a distant non-vital organ that may protect other organs against ischemia. Extensive experimental data and some few clinical trials support the neuroprotective role of RIC in ischemic stroke. Nevertheless, the circulating factors involved in this inter-organ communication and neuroprotection are not clarified. This pilot study in humans characterized the innate and adaptive circulating immune cell populations following RIC. This analysis has a particular focus at 24 h after RIC to avoid circadian influence. In silico functional analysis of mass spectrometry data identified 15 immune-related proteins. Our results reveal an immune response following RIC.

Brominated flame retardants effect in MCF-7 cells: Impact on vitamin D pathway.

Brominated flame retardants (BFRs) are persistent environmental pollutants, allowing a constant human exposure which carries several health risks, including the occurrence of breast cancer and vitamin D deficiency. Vitamin D inhibits cell growth and is negatively associated with breast cancer risk. The effect of BFRs in breast cancer and vitamin D pathway is still poorly understood. MCF-7 cells were treated with hexabromocyclododecane (HBCD), 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB), hexabromobenzene (HBB) and pentabromotoluene (PBT) using short and long-term exposure protocols. Viability, proliferation, migration, cell cycle and gene expression were assessed. Gene expression of hVDBP and hCYP2R1 was also evaluated in hepatocytes. Long-term exposure of MCF-7 cells to HBB increased cell proliferation and migration, consequently increasing MMP-9 expression. The vitamin D pathway was also altered by BFRs: cells appeared less prepared to activate and transport vitamin D and the signaling, action and inactivation mechanisms were diminished in the presence of BFRs. Untreated MCF-7 cells showed cell cycle arrest in phase G0/G1 in the presence of activated vitamin D. However, when MCF-7 cells were exposed to BFRs, cell cycle was arrested in phase G2/M, possibly due to DNA damage. Nonetheless, calcitriol seems to be able to mitigate the effect of some BFRs exposure, e.g. PBT.

Incidence and Risk Factors for Retinopathy of Prematurity in a Portuguese Cohort.

PURPOSE: To evaluate the incidence and risk factors for retinopathy of prematurity (ROP) in two Portuguese neonatal units with a sub-analysis of infants with a gestational age (GA) of 28 weeks or older. METHODS: This was a retrospective case series of all infants who underwent ROP screening from 2012 to 2020. Demographic, clinical, and laboratory data were collected. Univariate logistic regression was used to examine the risk factors for ROP followed by multivariate regression. RESULTS: A total of 475 infants were included with a median GA of 30 weeks (range: 23 to 36 weeks) and a median birth weight of 1,229 grams (range: 408 to 2,620 grams). ROP was diagnosed in 113 infants (23.8%) and 29 (6.1%) were treated. In the multivariate analysis, GA and hyperglycemia were significantly associated with severe ROP (P < .001). In the subgroup analysis of infants with a GA of 28 weeks or older, bronchopulmonary dysplasia, late-onset sepsis, and hyperglycemia were linked to severe ROP. CONCLUSIONS: The incidence of ROP in the cohort falls within the range of other high-income countries. Hyperglycemia overpowered all of the other risk factors. Although rare, more mature infants are also at risk for severe ROP. Infants with older GA share the same group of risk factors, but bronchopulmonary dysplasia seems to play a greater role. [J Pediatr Ophthalmol Strabismus. 2022;59(4):254-260.].

Natural Killer Cell Receptors and Endometriosis: A Systematic Review.

Endometriosis is a chronic inflammatory disorder, characterized by the presence of endometrial cells outside the uterine cavity. An increasing number of studies correlate the immune system with endometriosis, particularly NK receptors (NKR), which have been suggested to play an essential role in the pathogenesis of the disease. This systematic review aims to enlighten the role of NKR in endometriosis. A literature search was performed independently by two reviewers, to identify studies assessing the role of NKR in endometriosis. In total, 18 studies were included. Endometriosis pathogenesis seems to be marked by the overexpression of NK inhibitor receptors (KIRS), namely, CD158a+, KIR2DL1, CD94/NKG2A, PD-1, NKB1, and EB6, and inhibiting ligands such as PD-L1, HLA-E, HLA-G, and HLA-I. Concurrently, there is a decrease in NK-activating receptors and natural cytotoxicity receptors (NCRs), such as NKp46, NKp30, and NKG2D. The immune shift from NK surveillance to NK suppression is also apparent in the greater relative number of ITIM domains compared with ITAM domains in NKRs. In conclusion, NK receptor activity seems to dictate the immunocompetency of women to clear endometriotic cells from the peritoneal cavity. Future research could explore NKRs as therapeutic targets, such as that which is now well established in cancer therapy through immunotherapy.

DIGIROP efficacy for detecting treatment-requiring retinopathy of prematurity in a Portuguese cohort.

BACKGROUND/OBJECTIVES: To determine the efficacy of the DIGIROP model in detecting treatment-requiring retinopathy of prematurity (TR-ROP) in a Portuguese cohort. SUBJECTS/METHODS: Multicentre, retrospective cohort study of all consecutive preterm infants who underwent ROP screening from April 2012 to May 2019 in two neonatal units. Gestational age (GA), birth weight (BW) and sex were inserted in the DIGIROP platform. The optimal cut-off point to achieve 100% sensitivity was calculated. Area under the receiver operating characteristic curve (AUC) was calculated. RESULTS: Of the 431 infants who underwent ROP screening, 257 were eligible for DIGIROP analysis and 174 infants were excluded for having a GA outside the range 24-30 weeks imposed by the DIGIROP algorithm. Median GA was 29 weeks (range 24-30) and BW was 1060 g (range 408-2080). Twenty-tree infants (8.9%) developed TR-ROP. The highest risk obtained for TR-ROP was 0.5404 (95% CI 0.4343-0.6616) with a median achieved risk of 0.0938 (range 0.0016-0.5404). The optimal cut-off point to achieve 100% sensitivity on TR-ROP was 0.0016. The number of infants receiving ROP examinations would have been reduced from 257 to 187 infants (-27.2%) if the model was applied. CONCLUSIONS: In our cohort, of 257 infants, the optimal cut-off point to achieve 100% sensitivity for TR-ROP was 0.0016 with moderate accuracy in the AUC (0.70). The number of infants requiring screening would have decreased 27.2% if the model was applied. It is essential that algorithms continue to be tested in different populations, especially in cohorts that include both younger and older GA infants.

Correlation between hyperglycemia and glycated albumin with retinopathy of prematurity.

To determine the association between hyperglycemia, glycated albumin (GlyA) and retinopathy of prematurity (ROP). Prospective study of all infants under ROP screening from March 2017 to July 2019. All demographic, clinical and laboratory data were collected. Glucose was measured at birth and every 8 h for the first week and serum GlyA was evaluated at birth, 1st, 2nd and 4th weeks after birth. Reference range for GlyA was obtained. Univariate logistic regression was used to examine risk factors for ROP followed by multivariate regression. A total of 152 infants were included in the study. Median gestational age was 30 weeks and median birth weight 1240 g. Thirty-three infants (21.7%) had ROP. Hyperglycemia was present in 24 (72.7%) infants diagnosed with any ROP versus 6 (0.05%) in those without ROP. Median GlyA at birth, 1st, 2nd and 4th and respective reference ranges were 8.50% (6.00-12.65), 8.20% (5.32-11.67), 8.00% (5.32-10.00) and 7.90% (5.30-9.00) respectively. After multivariate logistic regression, hyperglycemia but not GlyA, remained a significant risk factor for ROP overpowering the other recognized risk factors (Exp (B) 28.062, 95% CI for Exp(B) 7.881-99.924 p < 0.001). In our cohort, hyperglycemia but not GlyA, remained a significant risk factor for ROP overpowering the other recognized risk factors.

Evidence for biological markers of tinnitus: A systematic review.

Subjective tinnitus is a phantom sound heard only by the affected person and may be a symptom of various diseases. Tinnitus diagnosis and monitoring is based on subjective audiometric and psychometric methods. This review aimed to synthesize evidence for tinnitus presence or its severity. We searched several electronic databases, citation searches of the included primary studies through Web of Science, and further hand searches. At least two authors performed all systematic review steps. Sixty-two records were included and were categorized according the biological variable. Evidence for possible tinnitus biomarkers come from oxidative stress, interleukins, steroids and neurotransmitters categories. We found conflicting evidence for full blood count, vitamins, lipid profile, neurotrophic factors, or inorganic ions. There was no evidence for an association between tinnitus and the remaining categories. The current review evidences that larger studies, with stricter exclusion criteria and powerful harmonized methodological design are needed. Protocol published on PROSPERO (CRD42017070998).

Corneal sub-basal nerve plexus assessment and its association with phenotypic features and lymphocyte subsets in Sjögren's Syndrome.

PURPOSE: To assess and compare corneal sub-basal nerve plexus morphology with circulating lymphocyte subsets, immunologic status and disease activity in Sjögren syndrome (SjS) patients. METHODS: Fifty-five SjS patients, 63 Sicca patients (not fulfilling SjS criteria), 18 rheumatoid arthritis (RA) patients and 20 healthy controls (HC) were included. Systemic disease activity in SjS was assessed with the ESSDAI score. Lymphocyte subpopulations were studied with flow cytometry. Corneal confocal microscopy and ImageJ software were used to characterize corneal sub-basal nerve plexus in terms of nerve density (CNFD), length (CNFL) and tortuosity (CNFT). Conventional dry eye tests were also performed. RESULTS: CNFL and CNFD were lower in SjS, Sicca and RA groups, compared to HC (p < 0.001 for both SjS and Sicca); CNFL p = 0.005, CNFD p = 0.018 in RA). CNFT was higher in SjS, followed by Sicca, RA and HC. A negative correlation was found between ESSDAI score and CNFL (r=-0.735, p = 0.012). CNFL correlated negatively with IL21+ CD8+ T cells (r=-0.279, p = 0.039) and a positively with total memory (r = 0.299, p = 0.027), unswitched memory (r = 0.281, p = 0.038) and CD24Hi CD27+ (r = 0.278, p = 0.040) B cells. CNFD showed a tendency to significance in its negative correlation with ESSDAI (r=-0.592, p = 0.071) and in its positive correlation with switched memory B cells (r = 0.644, p = 0.068). CONCLUSIONS: This is the first study aiming to correlate ocular findings with lymphocyte subsets in SjS. The associations founded between CNFL and CNFD and disease activity, IL21+ follicular T cells and some B-cell subsets suggest that corneal nerve damage may parallel systemic disease activity and inflammatory cells' dynamics.