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The receptor activator of nuclear factor-kappa B (RANK) and its ligand RANKL are members of the tumor necrosis factor (TNF) super-family of cytokines with a role in progestogen-associated malignancies in breast. Basic and clinical data support the participation of the cytokine pathway in metastatic disease and as poor prognosis markers. The value of RANK/RANKL as prognostic indicators in endometrial and ovarian tumors, as well as the data suggesting a potential role of RANK/RANKL in hormone dependent tumorigenesis in the endometrium, have been described. The D-CARE study could not confirm benefit in the modulation of RANKL in breast cancer.

In this case-report we describe the first reported case of early-onset fungal interface keratitis (IK) after Descemet Membrane Endothelial Keratoplasty (DMEK) successfully treated with penetrating keratoplasty (PK) during the active stage of infection. A patient with graft failure after Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) was operated on with DMEK. Donor rim culture and broth were positive for Candida albicans. Several interface infiltrates were confirmed and localized using anterior segment optical coherence tomography. Three days after diagnosis, observing clear signs of intraocular infection, the graft was removed with simultaneous washed-up of anterior chamber with fluconazole 1% followed by a PK and intrastromal corneal injections of fluconazole. A best-corrected visual acuity of 20/20 was achieved. This case highlights the importance of analysing every donor rim and broth, despite the patient doesn't show any symptoms or signs during the post-operative period. PK is a viable treatment option in early-onset interface keratitis.

Endothelial dysfunction and denudation are considered a first step in atherosclerosis. Endothelial proliferation is key for cellular repair. The effect of bazedoxifene on the vascular endothelium h...

The incidence of osteoporosis and cardiovascular disease increases with age, and there are potentially shared mechanistic associations between the two conditions. It is therefore highly relevant to understand the cardiovascular implications of osteoporosis medications. These are presented in this narrative review. Calcium supplementation could theoretically cause atheroma formation via calcium deposition, and in one study was found to be associated with myocardial infarction, but this has not been replicated. Vitamin D supplementation has been extensively investigated for cardiac benefit, but no consistent effect has been found. Despite findings in the early 21st century that menopausal hormone therapy was associated with coronary artery disease and venous thromboembolism (VTE), this therapy is now thought to be potentially safe (from a cardiac perspective) if started within the first 10 years of the menopause. Selective estrogen receptor modulators (SERMs) are associated with increased risk of VTE and may be related to fatal strokes (a subset of total strokes). Bisphosphonates could theoretically provide protection against atheroma. However, data from randomised trials and observational studies have neither robustly supported this nor consistently demonstrated the potential association with atrial fibrillation. Denosumab does not appear to be associated with cardiovascular disease and, although parathyroid hormone analogues are associated with palpitations and dizziness, no association with a defined cardiovascular pathology has been demonstrated. Finally, romosozumab has been shown to have a possible cardiovascular signal, and therefore post-market surveillance of this therapy will be vital., SCOPUS: re.j, info:eu-repo/semantics/published

Diet is a crucial variable for a healthy life. A rapidly growing number of studies in recent years support the hypothesis that the Mediterranean diet (MedDiet) has a beneficial effect on certain body systems, but the highly varied objectives and quality of these publications warrants an updated assessment. In the present review we performed a comprehensive evaluation of current evidence on the impact of the MedDiet on human health, assessing its effect on the incidence or progression of the main non-communicable diseases and their intermediate outcomes and risk factors. We scrutinised the clinical evidence from observational studies and randomised controlled trials. Cardiovascular disease was the condition with most information. The MedDiet showed a general preventive effect, which was reproduced to varying degrees for certain intermediate cardiovascular outcomes such as blood pressure, lipids, obesity, metabolic syndrome and diabetes. Benefits were also found for several types of cancer, brain function (including cognition, mood and to a lesser extent Parkinson's disease) and mortality. The quality of the published evidence was, however, generally moderate or low. In conclusion, the MedDiet shows a favourable impact on health. General adoption of a MedDiet is concordant with current policies promoting healthy and sustainable nutrition worldwide. Nonetheless, more high-quality research is needed to improve the consistency of the findings.

En la literatura científica se encuentra un gran número de controversias y resultados dispares a la hora de explicar la relación entre la hipertensión arterial y algunas variables vinculadas a la afectividad negativa, como la depresión, la ansiedad y la ira. Teniendo esto en cuenta, en la presente investigación se planteó como objetivo principal analizar medidas de ansiedad, depresión e ira en personas adultas que padecen de hipertensión arterial (HTA). A partir de un diseño de caso-control, se contrastaron dos grupos, uno conformado por personas con HTA (n = 50) y otro de control equiparado en número de casos, edad y sexo. A nivel general, el grupo de HTA mostró mayores niveles de depresión en su dimensión somática y de ira-rasgo en su dimensión de temperamento. Asimismo, las personas con HTA presentaron síntomas de irritabilidad y pérdida de energía síntomas depresivo-somáticos, además de que tendían a enojarse con facilidad o rápidamente síntomas de temperamento de ira. El abordaje de estos factores psicológicos comórbidos resulta de relevancia dado que en estudios precedentes ha demostrado aumentar la adherencia al tratamiento médico en pacientes que han sido diagnosticados con hipertensión o patologías similares. Research on the relationship between hypertension and variables linked to negative affectivity has given rise to divergent findings and differing interpretations. The main objective of this paper was therefore to shed light on the issue by analyzing measures of depression, anxiety and anger in adults suffering from hypertension (HTN). Based on a case-control design, a group of individuals suffering from HTN (n=50) was compared with a control group of the same number of cases, age and sex. In general, the HTN Group showed higher levels of depression in its somatic dimension and of trait anger in its temperament dimension. Individuals with HTN presented symptoms of irritability and loss of energy (depressive-somatic symptoms) and propensity to anger easily (temperament anger symptoms). It has been demonstrated in preceding researches that addressing these comorbid psychological factors is of importance in increase adherence to medical treatment in patients who have been diagnosed with hypertension or similar pathologies.

Virtual Reality is a powerful tool for the treatment of agoraphobia. However, how effective is the use of these scenarios when they do not resemble the sociocultural context? Literature suggests that the inclusion of culturally relevant elements increases the ecological validity and transferability of learning since it reduces the gap between the virtual and real context. Unfortunately, in Latin America, the development of virtual environments is incipient, and the use of generic virtual environments is commonplace. The objective of this study was to develop virtual environments that include elements that are culturally relevant to the population of the Dominican Republic. Three hundred people with symptoms of agoraphobia were interviewed. Based on the information obtained, four scenarios were designed: house, elevator, park and public transport. In each scenario, the parameters that increase anxiety levels (for example, number of people) may be controlled and modified, allowing the development of exposure levels.

To introduce a prognostic model for women’s assisted fecundity before starting the first IVF/ICSI treatment cycle. In contrast to previous predictive models, we analyze two groups of women at the extremes of prognosis. Specifically, 708 infertile women that had either a live birth (LB) event in the first autologous IVF/ICSI cycle (“high-assisted-fecundity women”, n = 458) or did not succeed in having a LB event after completing three autologous IVF/ICSI cycles (“low-assisted-fecundity women”, n = 250). The initial sample of 708 women was split into two sets in order to develop (n = 531) and internally validate (n = 177) a predictive logistic regression model using a forward-stepwise variable selection. Seven out of 32 initially selected potential predictors were included into the model: women’s age, presence of multiple female infertility factors, number of antral follicles, women’s tobacco smoking, occurrence of irregular menstrual cycles, and basal levels of prolactin and LH. The value of the c-statistic was 0.718 (asymptotic 95% CI 0.672–0.763) in the development set and 0.649 (asymptotic 95% CI: 0.560–0.738) in the validation set. The model adequately fitted the data with no significant over or underestimation of predictor effects. Women’s assisted fecundity may be predicted using a relatively small number of predictors. This approach may complement the traditional procedure of estimating cumulative and cycle-specific probabilities of LB across multiple complete IVF/ICSI cycles. In addition, it provides an easy-to-apply methodology for fertility clinics to develop and actualize their own predictive models.

The rising incidence of bone pathologies such as osteoporosis and osteoarthritis is negatively affecting the functional status of millions of patients worldwide. The genetic component of these multifactorial pathologies is far from being fully understood, but in recent years several epigenetic mechanisms involved in the pathophysiology of these bone diseases have been identified. The aim of the present study was to compare the serum expression of four miRNAs in women with hip fragility fracture (OF group), osteoarthritis requiring hip replacement (OA group) and control women (Ctrl group). Serum expression of miR-497-5p, miR-155-5p, miR-423-5p and miR-365-3p was determined in a sample of 23 OA women, 25 OF women and 52 Ctrl women. Data shown that women with bone pathologies have higher expression of miR-497 and miR-423 and lower expression of miR-155 and miR-365 than control subjects. Most importantly, miR-497 was identified as an excellent discriminator between OA group and control group (AUC: 0.89, p p = 0.002). Our data suggest that circulating miR-497 may represent a significant biomarker of OA, a promising finding that could contribute towards future early-stage diagnosis of this disease. Further studies are required to establish the role of miR-155, miR-423 and miR-365 in bone pathologies.

PURPOSE: The present study aims to ascertain whether there is a causal relationship between women’s disease conditions present at the starting time of the first intended oocyte retrieval cycle and IVF/ICSI outcomes, primarily odds of live birth in the first IVF/ICSI treatment. METHODS: This is a retrospective study of infertile healthy and diseased women that had a live birth and/or exhibited a complete first oocyte retrieval cycle. Generalized Estimating Equations (GEE) models were applied to adjust standard errors for the potential correlation among women exhibiting the same infertility etiology. Confounders to be controlled for in these GEE models were previously selected following a strict stepwise methodology. RESULTS: Compared to healthy women, diseased women exhibited lower odds of live birth (OR (95% CI) 0.704 (0.576–0.860)). Further screening analyses indicated that subclinical iodine-deficiency hypothyroidism together with autoimmune thyroiditis contributed significantly to decrease odds of live birth (OR (95% CI) 0.720 (0.608–0.853)). Another important contribution arose from practically all the remaining morbid conditions analyzed. These diseases were individually associated with lower odds of live birth, although differences were non-significant. Notwithstanding, differences became significant after merging these diseases in a single group (OR (95% CI) 0.605 (0.394–0.930)). CONCLUSION: There is a significant causal association between most diseases present at the starting time of the first intended oocyte retrieval cycle and lower odds of live birth in the first IVF/ICSI treatment.

The present study, based on a cross-sectional design, was conducted in the primary care setting with patients presenting somatic symptoms suggestive of somatoform disorders (SFD). The main aim of the study was to determine whether cognitive variables could differentiate between patients with SFD alone and those who also present depressive symptoms suggestive of depression (SFD + depression). All participants (N = 796) completed validated self-report measures to assess somatic, depressive, and/or anxiety symptoms, as well as functional impairment, quality of life (QoL), and cognitive variables (worry, rumination, metacognition, cognitive distortions, and emotion regulation). Univariate and multivariate analyses (controlled for potential sociodemographic and clinical confounders) were performed. On the univariate analysis, significant differences between the SFD and SFD + depression groups were found in sociodemographic and clinical variables, functional impairment, QoL, and cognitive variables. On the multivariate analysis, the only significative variables associated with comorbid SFD + depression were anxiety (β = 0.27; p

Background Erenumab was approved in Europe for migraine prevention in patients with ≥4 monthly migraine days (MMD). In Spain, Novartis started a personalized managed access program which allowed free access to erenumab before official reimbursement. The Headache Study Group of the Spanish Neurological Society started a registry to monitor real-world safety and efficacy, and all Spanish headache experts were invited to participate. Methods Patients fulfilled ICHD3 criteria for migraine and had ≥ 4MMD. Sociodemographic and clinical data were registered as well as MMD, headache frequency (MHD), prior and concomitant preventive treatment, medication overuse headache (MOH), migraine evolution, adverse events, and PROs: HIT6, MIDAS, and PGIC. A >50% reduction of MMD after 3 months was considered as response. Results We included 210 patients (female 86.7%, mean age 46.4 years old) from 22 hospitals from February 2019 – to – June 2020. Most patients (89.5%) suffered from chronic migraine with a mean evolution of 8.6 years. MOH was present in 70% of patients, and 17.1% had migraine with aura. Average of prior preventive treatment failure was >7 (BoNT/A had been used by 95.2%). Most patients (67,6%) started with erenumab 70mg. 61% of patients were also taking oral preventive drugs or getting simultaneous BoNT/A (27.6%). Responder rate was 37.1% and the mean reduction of MMD was -6.28 and MHD: -8.6. Regarding PROs: MIDAS: -35 p., HIT6: -11.6 p., PIGC: 4.7 p. Predictors of good response were: HIT6 score ( p =0.01), prior preventive treatment failures ( p =0.026), absence of MOH ( p =0.039), and simultaneous BoNT/A treatment ( p

Purpose: To analyze the target induced astigmatism (TIA), surgically induced astigmatism (SIA), difference vector (DV), and correction index (CI) in the correction of astigmatism with phakic lenses, and its influence on visual acuity, and to analyze the safety and efficacy indexes of the correction of high and low power astigmatism with toric phakic lenses. Design: Retrospective comparative study. Methods: The medical records of patients that were operated on at the research center during the period were analyzed. Results were divided into Low Astigmatism Group – LAG (33 eyes) and High Astigmatism Group – HAG (93 eyes) according to the implanted toric ICL lens power. Preoperative refraction and resultant postoperative refraction were analyzed by vector analysis. Visual acuity pre and postop, with and without optical correction, were compared. Results: A total of 126 eyes were studied. The average preop refraction was −5.02 D sphere with −2.61 D cylinder. The average ICL lens power implanted was −8.31 D sphere +2.77 D cylinder. Refractive remaining was −0.01 ± 0.11 D sphere −0.15 ± 0.28 D cylinder. The arithmetic average angle of error in the astigmatism correction was 1.08°. The resultant cylinder was −0.03 ± 0.12 D and −0.19 ± 0.30 D in the low and high astigmatism groups, respectively, with a mean UDVA −0.01 ± 0.10 and 0.01 ± 0.16 and CDVA −0.03 ± 0.08 and −0.01 ± 0.17 for each group. The safety and efficacy indexes for the low astigmatism group were 1.09 ± 0.16 and 1.05 ± 0.17, respectively, with 1.11 ± 0.17 and 1.06 ± 0.16 for the high astigmatism group. Conclusions: The correction of astigmatism by the implantation of toric phakic lenses of the posterior chamber is safe and effective, independently of the amount of cylinder corrected.

Background Cancer is the second leading cause of mortality worldwide. Integrating different levels of care by implementing screening programmes, extending diagnostic tools and applying therapeutic advances may increase survival. We implemented a cancer fast-track programme (CFP) to shorten the time between suspected cancer symptoms, diagnosis and therapy initiation. Patients and methods Descriptive data were collected from the 10 years since the CFP was implemented (2009-2019) at the Clinico-Malvarrosa Health Department in Valencia, Spain. General practitioners (GPs), an oncology coordinator and 11 specialists designed guidelines for GP patient referral to the CFP, including criteria for breast, digestive, gynaecological, lung, urological, dermatological, head and neck, and soft tissue cancers. Patients with enlarged lymph nodes and constitutional symptoms were also considered. On identifying patients with suspected cancer, GPs sent a case proposal to the oncology coordinator. If criteria were met, an appointment was quickly made with the patient. We analysed the timeline of each stage of the process. Results A total of 4493 suspected cancer cases were submitted to the CFP, of whom 4019 were seen by the corresponding specialist. Cancer was confirmed in 1098 (27.3%) patients: breast cancer in 33%, urological cancers in 22%, gastrointestinal cancer in 19% and lung cancer in 15%. The median time from submission to cancer testing was 11 days, and diagnosis was reached in a median of 19 days. Treatment was started at a median of 34 days from diagnosis. Conclusions The findings of this study show that the interval from GP patient referral to specialist testing, cancer diagnosis and start of therapy can be reduced. Implementation of the CFP enabled most patients to begin curative intended treatment, and required only minimal resources in our setting., Highlights • Our CFP easily connects GPs and hospital specialists. • Our CFP shortens assessment time in patients with suspected cancer, adding to quality care. • Our CFP decreases emotional stress in patients without cancer.

The aim of this study was to examine the sociodemographic and clinical differences between people with a probable diagnosis of panic disorder (PD) and those with PD and a probable comorbid diagnosis major depressive disorder (PD + MDD). We also sought to explore the potential contribution of cognitive variables to help differentiate between PD and PD + MDD. This was a subgroup analysis of 331 patients with PD symptoms who were included in the PsicAP clinical trial. All participants completed scales to evaluate panic, depression, somatization, cognitive and performance variables. A univariate analysis showed significant differences (p < .01) between the groups (PD vs PD + MDD) in clinical variables. Somatization was the best predictor of comorbid PD + MDD (β = .346; p < .01). Cognitive variables do not appear to play an essential role in predicting the presence of depressive symptoms in people with a screen positive for PD. These findings appear to support a transdiagnostic treatment approach for PD, which may be useful regardless of whether comorbid depression is present or not. PRACTITIONER POINTS: Somatic symptoms were associated with a higher probability of be in the PD + MDD group. Cognitive variables do not play a relevant role in the differentiation of both groups. A transdiagnostic approach can be useful for the treatment of PD or PD + MDD group.

INTRODUCTION: The prevalence of urinary incontinence and of other lower urinary tract symptoms increases after the menopause and affects between 38 % and 55 % of women aged over 60 years. While urinary incontinence has a profound impact on quality of life, few affected women seek care. AIM: The aim of this clinical guide is to provide an evidence-based approach to the management of urinary incontinence in postmenopausal women. MATERIALS AND METHODS: Literature review and consensus of expert opinion. SUMMARY RECOMMENDATIONS: Healthcare professionals should consider urinary incontinence a clinical priority and develop appropriate diagnostic skills. They should be able to identify and manage any relevant modifiable factors that could alleviate the condition. A wide range of treatment options is available. First-line management includes lifestyle and behavioral modification, pelvic floor exercises and bladder training. Estrogens and other pharmacological interventions are helpful in the treatment of urgency incontinence that does not respond to conservative measures. Third-line therapies (e.g. sacral neuromodulation, intravesical onabotulinum toxin-A injections and posterior tibial nerve stimulation) are useful in selected patients with refractory urge incontinence. Surgery should be considered in postmenopausal women with stress incontinence. Midurethral slings, including retropubic and transobturator approaches, are safe and effective and should be offered.

Proteïna TDP-43; Esclerosi lateral amiotròfica; Demència frontotemporal Proteína TDP-43; Esclerosis lateral amiotrófica; Demencia frontotemporal TDP-43 protein; Amyotrophic lateral sclerosis; Frontotemporal dementia Cognitive impairment and behavioral changes in amyotrophic lateral sclerosis (ALS) are now recognized as part of the disease. Whether it is solely related to the extent of TDP-43 pathology is currently unclear. We aim to evaluate the influence of age, genetics, neuropathological features, and concomitant pathologies on cognitive impairment in ALS patients. We analyzed a postmortem series of 104 ALS patients and retrospectively reviewed clinical and neuropathological data. We assessed the burden and extent of concomitant pathologies, the role of APOE ε4 and mutations, and correlated these findings with cognitive status. We performed a logistic regression model to identify which pathologies are related to cognitive impairment. Cognitive decline was recorded in 38.5% of the subjects. Neuropathological features of frontotemporal lobar degeneration (FTLD) were found in 32.7%, explaining most, but not all, cases with cognitive impairment. Extent of TDP-43 pathology and the presence of hippocampal sclerosis were associated with cognitive impairment. Mutation carriers presented a higher burden of TDP-43 pathology and FTLD more frequently than sporadic cases. Most cases (89.4%) presented some degree of concomitant pathologies. The presence of concomitant pathologies was associated with older age at death. FTLD, but also Alzheimer’s disease, were the predominant underlying pathologies explaining the cognitive impairment in ALS patients. In sum, FTLD explained the presence of cognitive decline in most but not all ALS cases, while other non-FTLD related findings can influence the cognitive status, particularly in older age groups. SBE is a recipient of the Rio-Hortega post-residency grant from the Instituto de Salud Carlos III, Spain. This study was partially funded by Fundació Marató de TV3 (grant no. 20141610 to EG and no. 20143710 to RRG) and Fondo Europeo de Desarrollo Regional (FEDER) (PI15/01618 to RRG). AA is funded by Departament de Salut de la Generalitat de Catalunya, Pla estratègic de recerca i innovació en salut (PERIS) 2016–2020 (SLT002/16/00329). JG is recipient of the Instituto de Salud Carlos III-FEDER grants (PI16/01673 and PI19/00593)

Background Cognitive emotion regulation strategies (CERS) play a transdiagnostic role in emotional disorders, but the role of these strategies in coping with emotions during the coronavirus disease 2019 (COVID-19) pandemic remains poorly understood. Aims To assess the presence of emotional disorders in Spain and the association to sociodemographic characteristics and CERS during the COVID-19 outbreak. Method Cross-sectional survey administered through an online platform. Sociodemographic variables and CERS (CERQ-Short) were collected and possible diagnoses of generalized anxiety disorder (GAD, GAD-7), major depression disorder (MDD; Patient Health Questionnaire–9 [PHQ-9]), panic attacks (PA; PHQ-PD), and panic disorders (PD; PHQ-PD) were assessed. Sociodemographic risk factors and CERS association to the possible diagnosis of emotional disorders were reported with hierarchical multivariate logistic regression analyses. Results A total of 1,753 respondents completed the questionnaire in Spain. Of these, most (76.8%) were female, with a mean ( SD) age of 40.4 years (12.9). A high proportion of participants met diagnostic criteria for emotional disorders: 15.3% for GAD, 12.2% for MDD, 17.2% for PD, and 25.7% had experienced a PA. The contribution of sociodemographic variables to diagnoses of emotional disorders was modest, explaining from 3.1% to 5.7% of the variance; however, when CERS were added, the combination of sociodemographic and CERS explained from 15% to 29% of the variance. Rumination and catastrophizing were the most transdiagnostic maladaptive strategies and positive refocusing was another adaptive strategy. Discussion Although results from convenience samples should be handled with caution, the high prevalence of emotional disorders in this study suggests that the demand of mental health interventions will probably increase in Spain. Also, CERS play a clear role in the presence of these disorders. Conclusion Intervention programs should focus on training CERS in populations at high risk, focusing on the reduction of maladaptive CERS and the reinforce of other more adaptive CERS.

Objective Experimental studies suggest that lipids affect bone metabolism. We aimed to elucidate whether lipid levels are associated with bone mineral density (BMD) in a cohort of postmenopausal women. Design A cross-sectional study of participants in the Chronic Ailment Reduction after MENopause (CARMEN) cohort. Women underwent assessment of clinical and analytical parameters, including fasting lipid levels. BMD was assessed at both lumbar spine and hip. Homogeneity in the cohort was optimized by filtering out a series of confounding variables with a known impact on bone. Main outcome measures Association of BMD at lumbar spine and femoral neck with lipid levels. Results A total of 667 of the 1304 screened women were analyzed. A strong correlation was revealed between total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in univariate analysis. Multivariate analysis detected a significant positive association of HDL-C with BMD at both spine (p = 0.007) and femoral neck (p = 0.013). Other independent predictors of spine BMD were years since menopause (ysm, negatively associated), and body mass index (BMI) and estradiol, both positively associated with BMD. The other independent variables in the femoral neck were ysm and glucose (negatively associated) and BMI, estradiol, and phosphate, all positively associated with BMD. Conclusion Levels of HDL-C, but not TC, LDL-C or triglycerides, were positively associated with BMD at both the lumbar spine and femoral neck in a homogeneous cohort of postmenopausal women.

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPARγ:Peroxisome proliferator-activated receptor, NFκB: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2α:Elongation initiation factor 2α). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT1R axis (AT1R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity.

Introduction Dyslipidemias are common and increase the risk of cardiovascular disease. The menopause transition is associated with an atherogenic lipid profile, with an increase in the concentrations of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein B (apoB) and potentially lipoprotein (a) [Lp(a)], and a decrease in the concentration of high-density lipoprotein cholesterol (HDL-C). Aim The aim of this clinical guide is to provide an evidence-based approach to management of menopausal symptoms and dyslipidemia in postmenopausal women. The guide evaluates the effects on the lipid profile both of menopausal hormone therapy and of non-estrogen-based treatments for menopausal symptoms. Materials and methods Literature review and consensus of expert opinion. Summary recommendations Initial management depends on whether the dyslipidemia is primary or secondary. An assessment of the 10-year risk of fatal cardiovascular disease, based on the Systematic Coronary Risk Estimation (SCORE) system, should be used to set the optimal LDL-C target. Dietary changes and pharmacological management of dyslipidemias should be tailored to the type of dyslipidemia, with statins constituting the mainstay of treatment. With regard to menopausal hormone therapy, systemic estrogens induce a dose-dependent reduction in TC, LDL-C and Lp(a), as well as an increase in HDL-C concentrations; these effects are more prominent with oral administration. Transdermal rather than oral estrogens should be used in women with hypertriglyceridemia. Micronized progesterone or dydrogesterone are the preferred progestogens due to their neutral effect on the lipid profile. Tibolone may decrease TC, LDL-C, TG and Lp(a), but also HDL-C concentrations. Low-dose vaginal estrogen and ospemifene exert a favorable effect on the lipid profile, but data are scant regarding dehydroepiandrosterone (DHEA). Non-estrogen-based therapies, such as fluoxetine and citalopram, exert a more favorable effect on the lipid profile than do sertraline, paroxetine and venlafaxine. Non-oral testosterone, used for the treatment of hypoactive sexual desire disorder/dysfunction, has little or no effect on the lipid profile.

We provide an evidence base and guidance for the use of menopausal hormone therapy (MHT) for the maintenance of skeletal health and prevention of future fractures in recently menopausal women. Despite controversy over associated side effects, which has limited its use in recent decades, the potential role for MHT soon after menopause in the management of postmenopausal osteoporosis is increasingly recognized. We present a narrative review of the benefits versus risks of using MHT in the management of postmenopausal osteoporosis. Current literature suggests robust anti-fracture efficacy of MHT in patients unselected for low BMD, regardless of concomitant use with progestogens, but with limited evidence of persisting skeletal benefits following cessation of therapy. Side effects include cardiovascular events, thromboembolic disease, stroke and breast cancer, but the benefit-risk profile differs according to the use of opposed versus unopposed oestrogens, type of oestrogen/progestogen, dose and route of delivery and, for cardiovascular events, timing of MHT use. Overall, the benefit-risk profile supports MHT treatment in women who have recently (

Introduction: Globally, 985 million women are aged 50 and over, leading to increasing concerns about chronic conditions such as cardiovascular disease, osteoporosis, dementia, and cognitive decline, which can adversely affect quality of life and independent living.Aim: To evaluate the evidence from observational studies and randomized trials on the effects of the Mediterranean diet on short- and long-term menopausal health: estrogen deficiency symptoms, cardiovascular disease, osteoporosis, cognitive and mental health, breast cancer, and all-cause mortality.Materials and methods: Literature review and consensus of expert opinion.Summary recommendations: The Mediterranean diet is a non-restrictive dietary pattern common in the olive-growing areas of the Mediterranean basin. It may improve vasomotor symptoms, cardiovascular risk factors such as blood pressure, cholesterol and blood glucose levels, as well as mood and symptoms of depression. Long-term adherence may: improve cardiovascular risk and events, and death; improve bone mineral density; prevent cognitive decline; and reduce the risk of breast cancer and all-cause mortality. Sistema de Investigacion y Desarrollo (SINDE) of the Universidad Catolica de Santiago de Guayaquil, Guayaquil, Ecuador ; Vice-Rectorado de Investigacion & Postgrado (VRIP) of the Universidad Catolica de Santiago de Guayaquil, Guayaquil, Ecuador

This study explores the associations between different disability domains and the most prevalent symptoms of mental disorders in primary care patients (i.e. depression, anxiety, and somatization). A total of 1241 participants from 28 primary care centres completed self-report measures of depression, anxiety, and somatization. This same sample also completed the Sheehan Disability Scale (SDS) to assess functional impairment in work, social life, and family life domains. Associations between the symptoms and each disability domain were examined using hierarchical regression analyses. Depression emerged as the strongest predictor of all three disability domains. Somatization was associated only with the work domain, and anxiety was associated only with the family life domain. Clinical symptoms explained a greater proportion of the variance than sociodemographic variables. In primary care patients, depression, anxiety and somatizations were associated with distinct domains of disability. Early provision of effective treatments in the primary care setting may be crucial to reduce the societal burden of common mental disorders.

Evidence from different sources sustains a pro-oncogenic role of hormones, estrogens and progestogens, on the breast. The issue is of interest for young women, who are exposed to the hormonal changes imposed by the ovarian cycle and, often, take hormones with contraceptive purposes. Experimental and clinical studies show that both estrogens and progesterone are involved in mammary development during puberty and lactation, the changes being observed across mammalian species, including humans. Estrogen receptors, and more particularly the alpha isoform, participate in molecular processes of stem cells differentiation and epithelial proliferation through paracrine actions implicating growth factors. Progesterone also contributes through paracrine mechanisms involving one member of the tumor necrosis factor (TNF) family, the receptor activator of nuclear factor κB ligand (RANKL) and its receptor (RANK). Epidemiological studies have found that the length of the exposure to endogenous hormones, as determined by an early menarche or a late menopause, is a risk factor for breast cancer. Additional evidence has derived from studies with compounds modulating the estrogen or the progesterone receptors. Selective estrogen receptor modulators (SERM), like tamoxifen, have been shown to decrease the risk of breast cancer in both pre- and post-menopausal women. Aromatase inhibitors, which drastically reduce the levels of circulating estrogens, have reproduced the findings. The selective progesterone receptor modulators (SPRM) have been less investigated and issues concerning safety have arisen. These observations have interest for young women. High-risk women may consider the use of SERMs, for example, to reduce their risk. Much more common is the case of women who take hormones for contraception. The goal of the present article is twofold: i) to summarize the actual knowledge of the mechanisms implicating estrogens and progestogens on the risk for breast cancer and ii) to provide rationality for the debate about potential cancer risk of hormonal contraceptives, frequently used by premenopausal women.

Background The Patient Health Questionnaire-4 (PHQ-4) is an ultra-brief self-report consisting of a 2-item depression scale (PHQ-2) and a 2-item anxiety scale (GAD-2). The aim of the present study is to determine the psychometric properties of a computerized version of the PHQ-4 used to detect emotional disorders (anxiety and depression) in the primary care setting. Method A total of 1052 patients with suspected anxiety, depression, or somatic symptoms were recruited from 28 primary care centres participating in the PsicAP trial and completed the full version of the computerized PHQ. In addition, 178 of these patients also underwent in clinical interviews as a gold standard. Results Confirmatory factor analyses showed very good fit indices for a two-factor solution. This model was structurally invariant among the various age and gender groups and internal consistency was acceptable (PHQ-4; α = .83, PHQ-2; α = .86, and GAD-2; α = .76). The best cut-off points to obtain high sensitivity values was 3, on both the PHQ-2 (major depressive disorder) and the GAD-2 (generalized anxiety disorder). The criterion validity (sensitivity and specificity) for the PHQ-2 were .90 and .61 and for the GAD-2, .88 and 0.61. Limitations The study was not designed as a prevalence study. Therefore, does not contain information on patients whose general practitioners do not consider them to suffer emotional disorders. Conclusion This is the first study to provide evidence for the reliability and validity of a computerized version of the PHQ-4. This computerized tool can be used to detect depression and anxiety in a primary care setting.

Introduction Postmenopausal osteoporosis is a highly prevalent disease. Prevention through lifestyle measures includes an adequate calcium intake. Despite the guidance provided by scientific societies and governmental bodies worldwide, many issues remain unresolved. Aims To provide evidence regarding the impact of calcium intake on the prevention of postmenopausal osteoporosis and critically appraise current guidelines. Materials and methods Literature review and consensus of expert opinion. Results and conclusion The recommended daily intake of calcium varies between 700 and 1200 mg of elemental calcium, depending on the endorsing source. Although calcium can be derived either from the diet or supplements, the former source is preferred. Intake below the recommended amount may increase fragility fracture risk; however, there is no consistent evidence that calcium supplementation at, or above, recommended levels reduces risk. The addition of vitamin D may minimally reduce fractures, mainly among institutionalised people. Excessive intake of calcium, defined as higher than 2000 mg/day, can be potentially harmful. Some studies demonstrated harm even at lower dosages. An increased risk for cardiovascular events, urolithiasis and even fractures has been found in association with excessive calcium intake, but this issue remains unresolved. In conclusion, an adequate intake of calcium is recommended for general bone health. Excessive calcium intake seems of no benefit, and could possibly be harmful.

The association between steroid hormones and cancer has been a primary research focus for many years. Reproductive hormones are of particular interest given the fact that several highly prevalent c...

Background: The COVID-19 pandemic has disrupted many aspects of clinical practice in oncology, particularly in making timely cancer diagnosis. Our public health system has been concerned about potential delays leading to a higher proportion of patients with advanced stages. Our cancer diagnosis fast-track program (CFP) in the Clinic-Malvarrosa Health department in Valencia (Spain) is connecting primary care (PC) with different specialists to speed cancer diagnosis and treatment upon well founded suspicion. A 10-year evaluation of our CFP has recently been published. The aim of this analysis was to investigate the impact of the COVID-19 pandemic on the CFP. Methods: We analysed the programme flow during the state of emergency starting on March 16, 2020 for one year. Results: During that year, 975 suspected cancer cases were submitted to the CFP. The submissions only decreased during the times of highest COVID-19 incidence and stricter lockdown (March, April and October 2020). However, referrals were slightly higher than in the two previous years (average 877). Of those 975 patients, 817 were seen by the corresponding specialist. A cancer diagnosis was confirmed in 197 (24.1%) with 33% urological, 23% breast, 16% gastrointestinal and 9% lung cancer. Median time from referral to the specialist visit was 13 (interquartile range, 8 to 22 days) days and a diagnosis was reached in a median of 18 days (interquartile range, 10 to 30 days). In cancer patients, treatment was started in around 30 days (interquartile range, 13.5 to 51 days) from the time of diagnosis. Sixty-one percent of cancers were found in an early stage, 20% in a locally advanced stage, and 19% in an advanced stage. These intervals and proportions were similar to the previous years. Conclusions: Our programme has proven to be a reliable tool to help PC physicians referring patients with cancer suspicion cancer, maintaining its normal flow and efficacy despite the current pandemic. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Endometriosis is a chronic inflammatory disease that has been associated with an increased risk of ovarian cancer, especially epithelial tumors. Transvaginal ultrasound is a first-line diagnostic method for the assessment of endometriosis, and of endometriomas, the ovarian cystic form of endometriosis. Endometriomas usually have typical ultrasound features that allow them to be easily diagnosed. When atypical images are observed, such as solid areas with vascular flow, their malignancy should be ruled out, especially in peri-menopausal women. Early diagnosis of these tumors is essential because immediate surgical treatment is crucial for prognosis. Malignant neoplasms associated with endometriomas are, in the vast majority of cases, clear cell and endometrioid adenocarcinomas. In some cases seromucinous tumors have been described, but mainly in their borderline stage. A case is presented in which a patient developed an invasive seromucinous ovarian neoplasm on an endometrioma.

Key Clinical Message In young patients with T1D, neurological manifestations of cerebral hypertension should suggest the possibility of a cerebral venous sinus thrombosis (CVST). In these patients an inherited prothrombotic risk factor, including factor V Leiden G1691A gene mutation, should be considered during an event of thrombosis. Improving the glycemic control is the first factor that should be controlled in a patient who carries a genetic prothrombotic risk factor. Anticoagulant treatment should be started as son as CVST has been diagnosed. Long‐term antithrombotic treatment with tinzaparin 175 IU/kg/day, a low‐molecular weight heparin (LMWH), could be reliable and well tolerated, although an indefinite special follow‐up, including neurological controls, is advisable even in asymptomatic patients.

This study represented a translational study that first compared gene expression of B cells of BM from ovariectomized and control mice, and then analyzed some of the differentially expressed genes in women. Results showed novel genetic associations with bone phenotypes and points to the CD80 gene as relevant in postmenopausal bone loss. Osteoporosis is a multifactorial disease with a strong genetic component. However, to date, research into osteoporosis has only been able to explain a small part of its heritability. Moreover, several components of the immune system are involved in the regulation of bone metabolism. Among them, B cells occupy a prominent place. The study consisted of two stages. In the first, gene expression in bone marrow B cells is compared between ovariectomized and SHAM control mice using microarrays. In the second, we studied the association of polymorphisms in some differentially expressed genes (DEG) in a cohort of postmenopausal women. The present study has found 2791 DEG (false discovery rate (FDR)

Background In natalizumab-treated relapsing-remitting MS (RRMS) patients, various extended interval dosing strategies are under evaluation to minimize severe treatment-associated side effects, mainly progressive multifocal leukoencephalopathy development. Up to now, it has not been presented any approach, even in form of assay design, to determine the optimal percentage of CD49d receptor occupancy (RO) associated with a favorable clinical, radiological, and immunological response. Methods A multiparametric quantitative flow cytometry method was settled to measure CD49d RO on peripheral blood lymphocytes. The analytical protocol was tested in a 6-month follow-up from 19 RRMS patients treated with the natalizumab standard dosing of every 4 weeks or an extended-interval dosing of every 6 weeks. Results Extended natalizumab dose schedule promoted an increase of CD49d molecules per cell surface and a reduction of CD49d RO levels. The reduction observed on CD49d RO was not only depending on dose schedule but also on individual parameters such as body mass. Interestingly, individual clinical outcome was apparently the same between the different dose schedules or even better with the extended interval dosing. Conclusions Following up CD49d RO levels with a well-regulated monitoring work scheme is crucial to further identify over-/under-treated patients and to define a safe, personalized natalizumab regimen. © 2017 International Clinical Cytometry Society

Simoncini, Tommaso/0000-0002-2971-0079; Chung, Hsin-Fang/0000-0003-3261-5942; Mishra, Gita/0000-0001-9610-5904 WOS:000468709100014 PubMed ID: 31027683 Introduction: While the associations of genetic, reproductive and environmental factors with the timing of natural menopause have been extensively investigated, few epidemiological studies have specifically examined their association with premature (< 40 years) or early natural menopause (40-45 years). Aim: The aim of this position statement is to provide evidence on the predictors of premature and early natural menopause, as well as recommendations for the management of premature and early menopause and future research. Materials and methods: Literature review and consensus of expert opinion. Results and conclusions: Strong genetic predictors of premature and early menopause include a family history of premature or early menopause, being a child of a multiple pregnancy and some specific genetic variants. Women with early menarche and nulliparity or low parity are also at a higher risk of experiencing premature or early menopause. Cigarette smoking (with a strong dose-response effect) and being underweight have been consistently associated with premature and early menopause. Current guidelines for the management of premature and early menopause mainly focus on early initiation of hormone therapy (HT) and continued treatment until the woman reaches the average age at menopause (50-52 years). We suggest that clinicians and health professionals consider the age at menopause of the relevant region or ethnic group as part of the assessment for the timing of HT cessation. In addition, there should be early monitoring of women with a family history of early menopause, who are a child of a multiple pregnancy, or who have had early menarche (especially those who have had no children). As part of preventive health strategies, women should be encouraged to quit smoking (preferably before the age of 30 years) and maintain optimal weight in order to reduce their risk of premature or early menopause.

Here, we describe a protocol for the implementation of a heterologous mouse model in which progression of endometriosis can be assessed in real time through noninvasive monitoring of fluorescence emitted by implanted ectopic human endometrial tissue. For this purpose, biopsies of human endometrium are obtained from donor women ongoing oocyte donation. Human endometrial fragments are cultured in the presence of adenoviruses engineered to express cDNA for the reporter fluorescent protein mCherry. Upon visualization, labeled tissues with an optimal rate of fluorescence after infection are subsequently chosen for the implantation in recipient mice. One week prior to the implantation surgery, recipient mice are oophorectomized, and estradiol pellets are placed subcutaneously to sustain the survival and growth of lesions. On the day of surgery mice are anesthetized, and peritoneal cavity accessed through a small (1.5 cm) incision by the linea-alba. Fluorescently labeled implants are tweezed, briefly soaked in glue and attached to the peritoneal layer. Incisions are sutured, and animals left to recover for a couple of days. Fluorescence emitted by endometriotic implants is usually non-invasively monitored every 3 days for 4 weeks with an in vivo imaging system. Variations in the size of endometriotic implants can be estimated in real time by quantification of the mCherry signal and normalization against the initial time-point showing maximal fluorescence intensity. Traditional preclinical rodents of models of endometriosis do not allow non-invasive monitoring of lesion in real time but rather allow evaluation of the effects of drugs assayed at the end point. This protocol allows one to track lesions in real time and is more useful to explore the therapeutic potential of drugs in preclinical models of endometriosis. The main limitation of the model thus generated is that non-invasive monitoring is not possible over long periods of time due to the episomal expression of Ad-virus.

Osteoporosis is a noncommunicable disease with increasing incidence at a global level. The burden of the disease particularly concerns women. A drastic and rapid decline in the circulating levels of estrogens, a key regulator of bone metabolism, is responsible for the increase in bone loss after menopause. Cells with a role in bone metabolism, osteoblasts, osteoclasts and osteocytes, have estrogen receptors. The fall in estrogens increases the differentiation of osteoclasts from progenitors in the bone marrow. A significant expansion in the resorption process follows.

Peripheral blood biomarkers able to predict disease activity in multiple sclerosis (MS) patients have not been identified yet. Here, we analyzed the immune phenotype of T lymphocyte subpopulations in peripheral blood samples from 66 RRMS patients under DMF (n=22) or fingolimod (n=44) treatment, by flow cytometry. A correlation study between the percentage and absolute cell number of each lymphocyte subpopulation with the presence of relapses or new MRI lesions during 12-month follow-up was performed. Patients who had undergone relapses showed at baseline higher percentage of Th1CM cells (relapsed: 11.60±4.17%vs. nonrelapsed: 9.25±3.17%, p<0.05) and Th1Th17CM cells (relapsed: 15.65±6.15%vs. nonrelapsed: 10.14±4.05%, p<0.01) before initiating DMF or fingolimod treatment. Kaplan-Meier analysis revealed that patients with Th1Th17CM (CD4+CCR7+CD45RA-CCR6+CXCR3+) cells>11.48% had a 50% relapse-free survival compared to patients with Th1Th17CMcells<11.48% whose relapse-free survival was 88% (p=0.013, log-rank test). Additionally, a high percentage of Th1Th17CM cells was also found in patients with MRI activity (MRI activity: 14.02±5.87%vs. no MRI activity: 9.82±4.06%, p<0.01). Our results suggest that the percentage of Th1Th17CM lymphocytes at baseline is a predictive biomarker of activity during the first 12 months of treatment, regardless of the treatment.

Dopamine receptor 2 agonists (D2-ags) have been shown to reduce the size of tumors by targeting aberrant angiogenesis in pathological tissue. Because of this, the use of a D2-ag was inferred for endometriosis treatment. When assayed in mouse models however, D2-ags have been shown to cause a shift of the immature vessels towards a more mature phenotype but not a significant reduction in the amount of vascularization and size of lesions. These has raised concerns on whether the antiangiogenic effects of these compounds confer a therapeutic value for endometriosis. In the belief that antiangiogenic effects of D2-ags in endometriosis were masked due to non-optimal timing of pharmacological interventions, herein we aimed to reassess the antiangiogenic therapeutic potential of D2-ags in vivo by administering compounds at a timeframe in which vessels in the lesions are expected to be more sensitive to antiangiogenic stimuli. To prove our point, immunodeficient (NU/NU) mice were given a D2-ag (cabergoline), anti-VEGF (CBO-P11) or vehicle (saline) compounds (n = 8 per group) starting 5 days after implantation of a fluorescently labeled human lesion. The effects on the size of the implants was estimated by monitoring the extent of fluorescence emitted by the lesion during the three-week treatment period. Subsequently mice were sacrificed and lesions excised and fixed for quantitative immunohistochemical/immunofluorescent analysis of angiogenic parameters. Lesion size, vascular density and innervation were comparable in D2-ag and anti-VEGF groups and significantly decreased when compared to control. These data suggest that D2-ags are as powerful as standard antiangiogenic compounds in interfering with angiogenesis and lesion size. Our preliminary study opens the way to further exploration of the mechanisms beneath the antiangiogenic effects of D2-ags for endometriosis treatment in humans.

Physical inactivity not only places women's health at risk during menopause, but also increases menopausal problems. Abundant evidence links habitual physical exercise (PE) to a better status on numerous health indicators and better quality of life and to the prevention and treatment of the ailments that typically occur from mid-life onwards. We can infer that PE is something more than a lifestyle: it constitutes a form of therapy in itself. A panel of experts from various Spanish scientific societies related to PE and menopause (Spanish Menopause Society, Spanish Cardiology Society, Spanish Federation of Sports Medicine) met to reach a consensus on these issues and to decide the optimal timing of and methods of exercise, based on the best evidence available.

The aims of this study were to explore intestinal microbial composition and functionality in primary Sj&ouml, gren&rsquo, s syndrome (pSS) and to relate these findings to inflammation, permeability and the transcription factor Forkhead box protein P3 (FOXP3) gene expression in peripheral blood. The study included 19 pSS patients and 19 healthy controls matched for age, sex, and body mass index. Fecal bacterial DNA was extracted and analyzed by 16S rRNA sequencing using an Ion S5 platform followed by a bioinformatics analysis using Quantitative Insights into Microbial Ecology (QIIME II) and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Our data suggest that the gut microbiota of pSS patients differs at both the taxonomic and functional levels with respect to healthy controls. The gut microbiota profile of our pSS patients was characterized by a lower diversity and richness and with Bacteroidetes dominating at the phylum level. The pSS patients had less beneficial or commensal butyrate-producing bacteria and a higher proportion of opportunistic pathogens with proinflammatory activity, which may impair intestinal barrier function and therefore contribute to inflammatory processes associated with pSS by increasing the production of proinflammatory cytokines and decreasing the release of the anti-inflammatory cytokine IL-10 and the peripheral FOXP3 mRNA expression, implicated in the development and function of regulatory T cells (Treg) cells. Further studies are needed to better understand the real impact of dysbiosis on the course of pSS and to conceive preventive or therapeutic strategies to counteract microbiome-driven inflammation.

The rates of metabolic syndrome are increasing in parallel with the increasing prevalence of obesity, primarily due to its concomitant insulin resistance. This is particularly concerning for women, as the years around menopause are accompanied by an increase in visceral obesity, a strong determinant of insulin resistance. A fall in estrogens and increase in the androgen/estrogen ratio is attributed a determining role in this process, which has been confirmed in other physiological models, such as polycystic ovary syndrome. A healthy lifestyle, with special emphasis on nutrition, has been recommended as a first-line strategy in consensuses and guidelines. A consistent body of evidence has accumulated suggesting that the Mediterranean diet, with olive oil as a vital component, has both health benefits and acceptable adherence. Herein, we provide an updated overview of current knowledge on the benefits of olive oil most relevant to menopause-associated metabolic syndrome, including an analysis of the components with the greatest health impact, their effect on basic mechanisms of disease, and the state of the art regarding their action on the main features of metabolic syndrome.

A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11b(mid) regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-alpha was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2 - and TMPRSS2 - which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.

Background The Generalized Anxiety Disorder 7-item scale (GAD-7) is commonly used by clinicians and researchers to screen for anxiety disorders and to monitor anxiety symptoms in primary care. However, findings regarding its factor structure are mixed, with most studies reporting a best-fitting for a one-factor structure, whereas others indicate a two-factor model. To be valid for comparisons, the GAD-7 should measure the same latent construct with the same structure across groups and over time. We aimed to examine the best-fit factor structure model of the GAD-7 among primary care patients and to evaluate its measurement invariance. Methods A total of 1255 patients completed the computerized version of GAD-7 and a subsample of 238 cases was assessed at the 3-month follow-up. A confirmatory factor analysis (CFA) was performed and analyses of multiple-group invariance were also conducted to determine the extent to which the factor structure was comparable across various sociodemographic groups and over time. Results The results showed that both a one- and two-factor structure (representing somatic and cognitive-affective components) were invariant across sociodemographic groups and over time. The two-factor structure provided the best model fit. Limitations Results cannot be generalized to all primary care patients, as only patients whose general practitioners consider them to suffer emotional disorders were included. Conclusions Our study supports the reliability and validity of the one- and two-factor model of the GAD-7, both for screening purposes and for monitoring response to treatment.