Immune cell kinetics and antibody response in COVID-19 patients with low-count monoclonal B-cell lymphocytosis.

Low-count monoclonal B-cell lymphocytosis (MBLlo ) has been associated with an underlying immunodeficiency and has recently emerged as a new risk factor for severe COVID-19. Here, we investigated the kinetics of immune cell and antibody responses in blood during COVID-19 of MBLlo versus non-MBL patients. For this study, we analyzed the kinetics of immune cells in blood of 336 COVID-19 patients (74 MBLlo and 262 non-MBL), who had not been vaccinated against SARS-CoV-2, over a period of 43 weeks since the onset of infection, using high-sensitivity flow cytometry. Plasma levels of anti-SARS-CoV-2 antibodies were measured in parallel by ELISA. Overall, early after the onset of symptoms, MBLlo COVID-19 patients showed increased neutrophil, monocyte, and particularly, plasma cell (PC) counts, whereas eosinophil, dendritic cell, basophil, and lymphocyte counts were markedly decreased in blood of a variable percentage of samples, and with a tendency toward normal levels from week +5 of infection onward. Compared with non-MBL patients, MBLlo COVID-19 patients presented higher neutrophil counts, together with decreased pre-GC B-cell, dendritic cell, and innate-like T-cell counts. Higher PC levels, together with a delayed PC peak and greater plasma levels of anti-SARS-CoV-2-specific antibodies (at week +2 to week +4) were also observed in MBLlo patients. In summary, MBLlo COVID-19 patients share immune profiles previously described for patients with severe SARS-CoV-2 infection, associated with a delayed but more pronounced PC and antibody humoral response once compared with non-MBL patients.

Predominantly Pro-Inflammatory Phenotype with Mixed M1/M2 Polarization of Peripheral Blood Classical Monocytes and Monocyte-Derived Macrophages among Patients with Excessive Ethanol Intake.

Excessive alcohol consumption impairs the immune system, induces oxidative stress, and triggers the activation of peripheral blood (PB) monocytes, thereby contributing to alcoholic liver disease (ALD). We analyzed the M1/M2 phenotypes of circulating classical monocytes and macrophage-derived monocytes (MDMs) in excessive alcohol drinkers (EADs). PB samples from 20 EADs and 22 healthy controls were collected for isolation of CD14+ monocytes and short-term culture with LPS/IFNγ, IL4/IL13, or without stimulation. These conditions were also used to polarize MDMs into M1, M2, or M0 phenotypes. Cytokine production was assessed in the blood and culture supernatants. M1/M2-related markers were analyzed using mRNA expression and surface marker detection. Additionally, the miRNA profile of CD14+ monocytes was analyzed. PB samples from EADs exhibited increased levels of pro-inflammatory cytokines. Following short-term culture, unstimulated blood samples from EADs showed higher levels of soluble TNF-α and IL-8, whereas monocytes expressed increased levels of surface TNF-α and elevated mRNA expression of pro-inflammatory cytokines and inducible nitric oxide synthase. MDMs from EADs showed higher levels of TNF-α and CD206 surface markers and increased IL-10 production. LPS/IFNγ induced higher mRNA expression of Nrf2 only in the controls. miRNA analysis revealed a distinctive miRNA profile that is potentially associated with liver carcinogenesis and ALD through inflammation and oxidative stress. This study confirms the predominantly pro-inflammatory profile of PB monocytes among EADs and suggests immune exhaustion features in MDMs.

Standardized incidence ratios and risk factors for cancer in patients with systemic sclerosis: Data from the Spanish Scleroderma Registry (RESCLE).

AIM: Patients with systemic sclerosis (SSc) are at increased risk of cancer, a growing cause of non-SSc-related death among these patients. We analyzed the increased cancer risk among Spanish patients with SSc using standardized incidence ratios (SIRs) and identified independent cancer risk factors in this population. MATERIAL AND METHODS: Spanish Scleroderma Registry data were analyzed to determine the demographic characteristics of patients with SSc, and logistic regression was used to identify cancer risk factors. SIRs with 95% confidence intervals (CIs) relative to the general Spanish population were calculated. RESULTS: Of 1930 patients with SSc, 206 had cancer, most commonly breast, lung, hematological, and colorectal cancers. Patients with SSc had increased risks of overall cancer (SIR 1.48, 95% CI 1.36-1.60; P < 0.001), and of lung (SIR 2.22, 95% CI 1.77-2.73; P < 0.001), breast (SIR 1.31, 95% CI 1.10-1.54; P = 0.003), and hematological (SIR 2.03, 95% CI 1.52-2.62; P < 0.001) cancers. Cancer was associated with older age at SSc onset (odds ratio [OR] 1.22, 95% CI 1.01-1.03; P < 0.001), the presence of primary biliary cholangitis (OR 2.35, 95% CI 1.18-4.68; P = 0.015) and forced vital capacity <70% (OR 1.8, 95% CI 1.24-2.70; P = 0.002). The presence of anticentromere antibodies lowered the risk of cancer (OR 0.66, 95% CI 0.45-0.97; P = 0.036). CONCLUSIONS: Spanish patients with SSc had an increased cancer risk compared with the general population. Some characteristics, including specific autoantibodies, may be related to this increased risk.

Low molecular weight heparin is useful in adult COVID-19 inpatients. Experience during the first Spanish wave: observational study

ABSTRACT BACKGROUND: The intensity of the thromboprophylaxis needed as a potential factor for preventing inpatient mortality due to coronavirus disease-19 (COVID-19) remains unclear. OBJECTIVE: To explore the association between anticoagulation intensity and COVID-19 survival. DESIGN AND SETTING: Retrospective observational study in a tertiary-level hospital in Spain. METHODS: Low-molecular-weight heparin (LMWH) status was ascertained based on prescription at admission. To control for immortal time bias, anticoagulant use was analyzed as a time-dependent variable. RESULTS: 690 patients were included (median age, 72 years). LMWH was administered to 615 patients, starting from hospital admission (89.1%). 410 (66.7%) received prophylactic-dose LMWH; 120 (19.5%), therapeutic-dose LMWH; and another 85 (13.8%) who presented respiratory failure, high D-dimer levels (> 3 mg/l) and non-worsening of inflammation markers received prophylaxis of intermediate-dose LMWH. The overall inpatient-mortality rate was 38.5%. The anticoagulant nonuser group presented higher mortality risk than each of the following groups: any LMWH users (HR 2.1; 95% CI: 1.40-3.15); the prophylactic-dose heparin group (HR 2.39; 95% CI, 1.57-3.64); and the users of heparin dose according to biomarkers (HR 6.52; 95% CI, 2.95-14.41). 3.4% of the patients experienced major hemorrhage. 2.8% of the patients developed an episode of thromboembolism. CONCLUSIONS: This observational study showed that LMWH administered at the time of admission was associated with lower mortality among unselected adult COVID-19 inpatients. The magnitude of the benefit may have been greatest for the intermediate-dose subgroup. Randomized controlled trials to assess the benefit of heparin within different therapeutic regimes for COVID-19 patients are required.

Increasing Incidence of mucormycosis in Spanish inpatients from 1997 to 2018.

BACKGROUND: Mucormycosis is a worldwide angio-invasive fungal infection that is associated with high morbidity and mortality. A few European studies have focused on the epidemiology. METHODOLOGY: A retrospective longitudinal descriptive study was performed with inpatients diagnosed with mucormycosis (ICD-9-CM, code 117.7, cases 1997-2015; and ICD-10, code B46, cases 2016-2018; along with length of hospital stay) in Spanish public hospitals between 1 January 1997 and 31 December 2018. Data were obtained from the Minimum Basic Data Set (CMBD in Spanish). PRINCIPAL FINDINGS: A total of 962 patients were recorded; 665 were men. The mean age (±SD) was 55 ± 18.8 years. The annual incidence rate increased from 0.74 to 1.24 cases per million person-years. The lethality rate was 31.3%. Renal failure (41.6%) and haematological malignancy (36.3%) were the main factors involved. CONCLUSIONS: Mucormycosis is a rare infectious disease in Spain, but it has had a significantly increased incidence in the last two decades. Being an adult male and having diabetes, neoplasm or renal failure are the main factors associated. High mortality is usually associated mainly with haematological malignancy and renal failure. CMBD studies could be an efficient tool for assessing changes in the epidemiology of mucormycosis.

PPAR-γ Gene Expression in Human Adipose Tissue Is Associated with Weight Loss After Sleeve Gastrectomy.

BACKGROUND: The peroxisome proliferator-activated receptor (PPAR)-γ plays a key role in adipose tissue differentiation and fat metabolism. However, it is unclear which factors may regulate its expression and whether obese patients have changes in adipose tissue expression of PPAR-γor potential regulators such as miR-27. Thus, our aims were to analyze PPAR-γ and miR-27 expression in adipose tissue of obese patients, and to correlate their levels with clinical variables. SUBJECTS AND METHODS: We included 43 morbidly obese subjects who underwent sleeve gastrectomy (31 of them completed 1-year follow-up) and 19 non-obese subjects. mRNA expression of PPAR-γ1 and PPAR-γ2, miR-27a, and miR-27b was measured by qPCR in visceral and subcutaneous adipose tissue. Clinical variables and serum adipokine and hormone levels were correlated with PPAR-γ and miR-27 expression. In addition, a systematic review of the literature regarding PPAR-γ expression in adipose tissue of obese patients was performed. RESULTS: We found no differences in the expression of PPAR-γ and miR-27 in adipose tissue of obese patients vs. controls. The literature review revealed discrepant results regarding PPAR-γ expression in adipose tissue of obese patients. Of note, we described a significant negative correlation between pre-operative PPAR-γ1 expression in adipose tissue of obese patients and post-operative weight loss, potentially linked with insulin resistance markers. CONCLUSION: PPAR-γ1 expression in adipose tissue is associated with weight loss after sleeve gastrectomy and may be used as a biomarker for response to surgery.

Date of Admission during COVID-19 Pandemic Impacted Patient Outcomes in Addition to the Higher Efficacy of Tocilizumab Plus High-Dose Corticosteroid Therapy Compared to Tocilizumab Alone.

BACKGROUND: The evidence for the efficacy of glucocorticoids combined with tocilizumab (TCZ) in COVID-19 comes from observational studies or subgroup analysis. Our aim was to compare outcomes between hospitalized COVID-19 patients who received high-dose corticosteroid pulse therapy and TCZ and those who received TCZ. METHODS: A retrospective single-center study was performed on consecutive hospitalized patients with severe COVID-19 between 1 March and 23 April 2020. Patients treated with either TCZ (400-600 mg, one to two doses) and methylprednisolone pulses (MPD-TCZ group) or TCZ alone were analyzed for the occurrence of a combined endpoint of death and need for invasive mechanical ventilation during admission. The independence of both treatment groups was tested using machine learning classifiers, and relevant variables that were potentially different between the groups were measured through a mean decrease accuracy algorithm. RESULTS: An earlier date of admission was significantly associated with worse outcomes regardless of treatment type. Twenty patients died (27.0%) in the TCZ group, and 33 (44.6%) died or required intubation (n = 74), whereas in the MPD-TCZ group, 15 (11.0%) patients died and 29 (21.3%) patients reached the combined endpoint (n = 136; p = 0.006 and p < 0.001, respectively). Machine learning methodology using a random forest classifier confirmed significant differences between the treatment groups. CONCLUSIONS: MPD and TCZ improved outcomes (death and invasive mechanical ventilation) among hospitalized COVID-19 patients, but confounding variables such as the date of admission during the COVID-19 pandemic should be considered in observational studies.

Adolescent Sjogren's syndrome presenting as psychosis: a case series.

BACKGROUND: Neurological involvement has been reported in up to 80% of adults with Primary Sjogren's syndrome (pSS) with psychiatric abnormalities including anxiety, depression, and cognitive dysfunction being common. Psychosis due to pSS has been reported in adult patients but has never been previously reported in the adolescent/pediatric literature. Here we describe for the first time four cases of adolescent Sjogren's syndrome that presented with psychotic symptoms. Rituximab treatment was followed by improvement of psychiatric symptoms in all patients. CASE PRESENTATION: 1: 16 year old female without significant past medical history presented to the emergency department with 4 days of abnormal behavior, tremors, insomnia, polyphagia, polyuria, and suicidal ideation. 2: 16 year old female with a 4 year history of severe anxiety, OCD, and tic disorder treated with fluoxetine with partial benefit presented with an abrupt and severe worsening of anxiety, OCD and new auditory hallucinations. 3: 19 year old female without significant past medical history presented with a 3 day history of progressively altered behavior, incoherent speech, insomnia, headache, and tangential thoughts. 4: 17 year old female without significant past medical history presented with new onset suicidal ideation, paranoia, confusion, and emotional lability. CONCLUSION: Psychosis is more common in autoimmune disease than previously known. To our knowledge, the four teenage women described above are the first reported patients with adolescent pSS manifesting as psychosis. pSS should be considered in the differential diagnosis of young patients with new psychiatric disorders, even in the absence of sicca symptoms. Psychiatric symptoms improved with rituximab infusions in all 4 of our patients, which suggests rituximab may be an effective treatment option that should be considered early after the diagnosis of pSS-associated psychiatric disturbance.

Clinical and MRI phenotype of children with MOG antibodies.

OBJECTIVE: To investigate the clinical and magnetic resonance imaging (MRI) features of anti-myelin oligodendrocyte glycoprotein (MOG) antibody-seropositive pediatric demyelinating syndromes. METHODS: Serum samples collected from 74 children with suspected demyelinating disorders whom were being followed at Massachusetts General Hospital were incubated with control green fluorescent protein (GFP)- and MOG-GFP-transfected Jurkat cell clones. The binding ratios were calculated using flow cytometry. Using statistical analyses, we compared the demographic, clinical and radiological features in our seropositive and seronegative patients. RESULTS: We found that 13 out of 74 (17.5%) patients were seropositive for MOG. The MOG-seropositive patients were younger than the seronegative patients (p = 0.049). No single disease category predominated among the seropositive patients, nor was one group more likely to have a polyphasic course. There were two out of four neuromyelitis optica (NMO) patients who had MOG antibodies; both were seronegative for aquaporin -4 (AQP4) antibodies. One had monophasic disease and the other had frequent relapses. There was a bimodal distribution of the MOG-seropositive patients by age at onset, with a distinct younger group (4-8 years) having a high prevalence of encephalopathy and an older group (13-18 years), whom presented almost exclusively with optic neuritis. MRI analysis demonstrated the absence of corpus callosum lesions in the seropositive patients (p = 0.012). The annualized relapse rate (ARR) and the Expanded Disability Status Scale (EDSS) results at 2 years did not differ between the seropositive and seronegative patients. CONCLUSION: MOG antibodies are found across a variety of pediatric demyelinating syndromes having some distinct clinical and MRI features.

Socioeconomic status and its association with the risk of developing hip fractures: a region-wide ecological study.

PURPOSE: To determine the association between socioeconomic deprivation (SES) and hip fracture risk. METHODS: Retrospective cohort study using a population-based database (primary care records) of over 5 million people. Eligibility: all living subjects registered during the period 2009-2012 and resident in an urban area. MEASURES: a validated SES composite index (proportion of unemployed, temporary workers, manual workers, low educational attainment and low educational attainment among youngsters) estimated for each area based on census data. OUTCOME: incident hip fracture rates as coded in medical records using ICD-10 codes. STATISTICS: zero-inflated Poisson models fitted to study the association between SES quintiles and hip fracture risk, adjusted for age, sex, obesity, smoking and alcohol consumption. RESULTS: Compared to the most deprived, wealthy areas had a higher hip fracture incidence (age- and sex-adjusted incidence 38.57 (37.14-40.00) compared to 34.33 (32.90-35.76) per 10,000 person-years). Similarly, most deprived areas had a crude and age- and sex-adjusted lower risk of hip fracture, RR of 0.71 (0.65-0.78) and RR of 0.90 (0.85-0.95), respectively, compared to wealthiest areas. The association was attenuated and no longer significant after adjustment for obesity: RR 0.96 (0.90-1.01). Further adjustment for smoking and high alcohol consumption did not make a difference. CONCLUSION: Wealthiest areas have an almost 30% increased risk of hip fracture compared to the most deprived. Differences in age-sex composition and a higher prevalence of obesity in deprived areas could explain this higher risk.

HIV infection is strongly associated with hip fracture risk, independently of age, gender, and comorbidities: a population-based cohort study.

HIV infection and antiretroviral therapies have detrimental effects on bone metabolism, but data on their impact on fracture risk are controversial. We conducted a population-based cohort study to explore the association between clinical diagnosis of HIV infection and hip and major osteoporotic fracture risk. Data were obtained from the SIDIAP(Q) database, which contains clinical information for >2 million patients in Catalonia, Spain (30% of the population). We screened the database to identify participants with a clinical diagnosis of HIV infection, and ascertained incident hip and osteoporotic major fractures in the population aged 40 years or older in 2007 to 2009. In addition, data on incident fractures involving hospital admission were obtained from the Hospital Admissions database. Cox regression models were used to estimate hazard ratios (HRs) for the HIV-infected versus uninfected participants. Models were adjusted for age, sex, body mass index, smoking status, alcohol drinking, oral glucocorticoid use, and comorbid conditions (Charlson index). Among 1,118,156 eligible participants, we identified 2489 (0.22%) subjects with a diagnosis of HIV/AIDS. Age- and sex-adjusted HR for HIV/AIDS were 6.2 (95% confidence interval [CI] 3.5-10.9; p < 0.001) and 2.7 (2.01-3.5; p < 0.001) for hip and major fractures, respectively; this remained significant after adjustment for all mentioned potential confounders: HR 4.7 (2.4-9.5; p < 0.001) and 1.8 (1.2-2.5; p = 0.002). After stratifying by age, the association between HIV infection and major fractures was attenuated for those aged <59 years (adjusted HR 1.35 [0.88-2.07], p = 0.17) but appeared stronger in older patients (adjusted HR 2.11 [1.05-4.22], p = 0.035). We report a strong association between HIV infection and hip fracture incidence, with an almost fivefold increased risk in the HIV infected, independent of sex, age, smoking, alcohol drinking, and comorbidities. Similarly, we demonstrate a 75% higher risk of all clinical fractures and a 60% increase in risk of non-hip clinical fractures among patients with a diagnosis of HIV infection.

Observational study of treatment compliance in women initiating antiresorptive therapy with or without calcium and vitamin D supplements in Spain.

OBJECTIVE: The aims of this study were to evaluate the compliance with antiresorptive therapy (ART) and supplements in Spain and to analyze the validity of the different treatment compliance assessment methods. METHODS: A cross-sectional study with retrospective data collection was carried out in women starting ART, evaluating indirect objective compliance, self-reported compliance, and the Morisky-Green questionnaire. RESULTS: A total of 480 women with a mean (SD) age of 65.8 (9.2) years were studied. Of these women, 62.9% received calcium and/or vitamin D supplements in addition to ART. According to the objective compliance method, 76.9% of the women were compliers (≥80%) with bisphosphonates; 69.4%, with selective estrogen receptor modulators; and 61.8%, with supplements (P < 0.01). Using the self-reported compliance, we identified 91% compliers with antiresorptive drugs and 75% with supplements. Using the Morisky-Green test, we classified 60.8% of the women as compliers with antiresorptive drugs and 48.4% with supplements. Combining the objective and self-reported compliance, 29.5% of the women did not adequately comply with ART and 56% with the drug supplements. CONCLUSIONS: With all three compliance measures, supplements were the treatment yielding the lowest percentage of compliers. Bisphosphonates constituted the treatment offering the best objective compliance: 38.2% of the women with drug supplements and between 23.1% and 30.6% of the women with ART failed to exceed the theoretical value of 80% regarded as representing good compliance.

Risk factors for osteoporosis and fractures in postmenopausal women between 50 and 65 years of age in a primary care setting in Spain: a questionnaire.

INTRODUCTION: Osteoporosis (OP) is a major, highly prevalent health problem and osteoporosis-related fractures account for high morbidity and mortality. Therefore, prevention and early detection of osteoporosis should strive to substantially reduce this risk of fracture. OBJECTIVE: The present observational, descriptive, cross-sectional study sought to assess the prevalence of risk factors for osteoporosis and fractures in a large sample of postmenopausal women aged 50 to 65 years attending Primary Care facilities in Spain. METHODS: We recruited 4,960 women, at 96 Primary Care centers. Demographic and anthropometrical data, as well as information regarding risk factors for OP were collected using a questionnaire. RESULTS: the prevalence rates for the major osteoporosis risk factors in our population were: low calcium intake, 43%; benzodiazepine use, 35.1%, and height loss, 30.1%. Other relatively prevalent factors include: having suffered at least one fall during the preceding year; positive family history of falls (particularly on the mother's side), smoking, kyphosis, presence of any disease affecting bone metabolism, personal history of falls, and inability to rise from a chair without using one's arms. The least frequent factors were weight loss of greater than 10% over the preceding 10 years and problems in sensory perception that affect patient's ability to walk. CONCLUSIONS: The main risk factors for osteoporosis in women 50-65 years of age are low calcium intake, use of benzodiazepines, and observed loss of height. Our results may help physicians to identify groups at risk for OP and fractures at early stages and consequently, optimize prevention and early diagnosis of osteoporosis in postmenopausal women.

Analysis of the value of the ICIQ-UI SF questionnaire and stress test in the differential diagnosis of the type of urinary incontinence.

AIMS: Presently, there is no simple, universally accepted instrument for the initial diagnosis of urinary incontinence (UI), which is why physicians find it so difficult to integrate the diagnosis into their daily clinical practice. The objective of this study is to analyze the true value of the ICIQ-UI SF questionnaire (ICIQ), the stress test, and the combination of both for the diagnosis as to the type of UI. METHODS: Cross-sectional study performed in 116 women consulting for UI symptoms in two specialized health care centers. The subjects completed the ICIQ and underwent a stress test and urodynamic testing which was used for the reference diagnosis. Sensitivity, specificity, positive and negative predictive values, and the statistical "likelihood ratio (LR)" were assessed. RESULTS: According to the ICIQ, 45 women (38.8%) suffered from Stress UI (SUI); 19 (16.4%), Urgency UI (UUI), and 49 (42.2%), Mixed UI (MUI). According to the stress test, 75 (64.7%) presented SUI. According to the combination of both tests, the diagnosis was SUI in 35 (30.2%), UUI in 17 (14.7%), and MUI in 37 (31.9%). Regarding urodynamic testing, observations were as follows: USI in 45 subjects (38.8%), detrusor overactivity (DO) in 25 (21.6%), and combination of both (MUI) in 30 (25.9%). The combination of ICIQ-UI SF plus stress test showed good specificity and negative predictive value, and the best LR coefficients obtained were: 3.11 (USI); 6.64 (UUI); 2.64 (MUI), and 3.77 ("all" SUI). CONCLUSIONS: The combined use of the ICIQ plus stress test will aid in characterizing the type of UI at a basic health care level, favoring the prescription of the most appropriate treatment for each case.

Evaluation of calcaneal quantitative ultrasound in a primary care setting as a screening tool for osteoporosis in postmenopausal women.

Screening of osteoporosis by quantitative ultrasound (QUS) has become widely available in Europe, but no clear strategies for its clinical use have been established. The aim of this study was to validate the use of QUS in a cross-sectional study carried out in three primary care centers. Measurements of calcaneal QUS and bone mineral density (BMD) at proximal femur were obtained by dual-energy X-ray absorptiometry (DXA). Osteoporosis was diagnosed by DXA T-score