Low lung function in Bipolar Disorder and Schizophrenia: a hidden risk.

Introduction: People with serious mental illness (SMI), such as schizophrenia and bipolar disorder, have a higher risk of premature morbidity and mortality. In the general population, impaired lung function is associated with increased morbidity and mortality. We compared lung function between people with and without serious mental illnesses using a cross-sectional study in 9 community mental health units. Methods: Subjects aged 40-70 years with a diagnosis of schizophrenia or bipolar disorder were recruited consecutively. The controls had no psychiatric diagnosis and were not receiving any psychotropics. Spirometry was performed by a trained nurse. We used the 2021 American Thoracic Society/European Respiratory Society standards for the interpretation of the spirometry results. Results: We studied 287 subjects. People with SMI (n = 169) had lower spirometry values than those without a psychiatric diagnosis (n = 118). An abnormal spirometry pattern (36.1% vs 16.9%, p < 0.001), possible restriction or non-specific (Preserved Ratio Impaired Spirometry [PRISm]) pattern (17.8% vs 7.6%, p = 0.014), and pattern of airflow obstruction or possible mixed disorder (18.3% vs 9.3%, p = 0.033) were more frequent in people with SMI. Multivariate analyses showed that the PRISm pattern was associated with abdominal circumference (odds ratio [OR] 1.05, 95%CI 1.03-1.08) and that the pattern of airflow obstruction or possible mixed disorder was associated with smoking behavior (OR 5.15, 95%CI 2.06-15.7). Conclusion: People with SMI have impaired lung function, with up to one-third of them showing an abnormal spirometry pattern. This suggests that regular monitoring of lung function and addressing modifiable risk factors, such as tobacco use and obesity, in this population is of paramount importance.

Impact of BMI on outcomes in respiratory ECMO: an ELSO registry study.

PURPOSE: The impact of body mass index (BMI) on outcomes in respiratory failure necessitating extracorporeal membrane oxygenation (ECMO) has been poorly described. We aimed to assess: (i) whether adults with class II obesity or more (BMI ≥ 35 kg/m2) have worse outcomes than lean counterparts, (ii) the form of the relationship between BMI and outcomes, (iii) whether a cutoff marking futility can be identified. METHODS: A retrospective analysis of the Extracorporeal Life Support Organization (ELSO) Registry from 1/1/2010 to 31/12/2020 was conducted. Impact of BMI ≥ 35 kg/m2 was assessed with propensity-score (PS) matching, inverse propensity-score weighted (IPSW) and multivariable models (MV), adjusting for a priori identified confounders. Primary outcome was in-hospital mortality. The form of the relationship between BMI and outcomes was studied with generalized additive models. Outcomes across World Health Organisation (WHO)-defined BMI categories were compared. RESULTS: Among 18,529 patients, BMI ≥ 35 kg/m2 was consistently associated with reduced in-hospital mortality [PS-matched: OR: 0.878(95%CI 0.798-0.966), p = 0.008; IPSW: OR: 0.899(95%CI 0.827-0.979), p = 0.014; MV: OR: 0.900(95%CI 0.834-0.971), p = 0.007] and shorter hospital length of stays. In patients with BMI ≥ 35 kg/m2, cardiovascular (17.3% versus 15.3%), renal (37% versus 30%) and device-related complications (25.7% versus 20.6%) increased, whereas pulmonary complications decreased (7.6% versus 9.3%). These findings were independent of confounders throughout PS-matched, IPSW and MV models. The relationship between BMI and outcomes was non-linear and no cutoff for futility was identified. CONCLUSION: Patients with obesity class II or more treated with ECMO for respiratory failure have lower mortality risk and shorter stays, despite increased cardiovascular, device-related, and renal complications. No upper limit of BMI indicating futility of ECMO treatment could be identified. BMI as single parameter should not be a contra-indication for respiratory ECMO.

Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme 2 (ACE2) receptor, a critical component of the kallikrein-kinin system. Its dysregulation may lead to increased vascular permeability and release of inflammatory chemokines. Interactions between the kallikrein-kinin and the coagulation system might further contribute to thromboembolic complications in COVID-19. METHODS: In this observational study, we measured plasma and tissue kallikrein hydrolytic activity, levels of kinin peptides, and myeloperoxidase (MPO)-DNA complexes as a biomarker for neutrophil extracellular traps (NETs), in bronchoalveolar lavage (BAL) fluid from patients with and without COVID-19. FINDINGS: In BAL fluid from patients with severe COVID-19 (n = 21, of which 19 were mechanically ventilated), we observed higher tissue kallikrein activity (18·2 pM [1·2-1535·0], median [range], n = 9 vs 3·8 [0·0-22·0], n = 11; p = 0·030), higher levels of the kinin peptide bradykinin-(1-5) (89·6 [0·0-2425·0], n = 21 vs 0·0 [0·0-374·0], n = 19, p = 0·001), and higher levels of MPO-DNA complexes (699·0 ng/mL [66·0-142621·0], n = 21 vs 70·5 [9·9-960·0], n = 19, p < 0·001) compared to patients without COVID-19. INTERPRETATION: Our observations support the hypothesis that dysregulation of the kallikrein-kinin system might occur in mechanically ventilated patients with severe pulmonary disease, which might help to explain the clinical presentation of patients with severe COVID-19 developing pulmonary oedema and thromboembolic complications. Therefore, targeting the kallikrein-kinin system should be further explored as a potential treatment option for patients with severe COVID-19. FUNDING: Research Foundation-Flanders (G0G4720N, 1843418N), KU Leuven COVID research fund.

The Effect of Coronary Lesion Complexity and Preprocedural Revascularization on 5-Year Outcomes After TAVR.

BACKGROUND: Aortic stenosis and coronary artery disease (CAD) frequently coincide. However, the management of coexisting CAD in patients undergoing transcatheter aortic valve replacement (TAVR) remains controversial. OBJECTIVES: This study sought to determine whether the presence of CAD, its complexity, and angiography-guided percutaneous coronary intervention (PCI) are associated with outcomes after TAVR. METHODS: All patients undergoing TAVR at a tertiary referral center between 2008 and 2020 were included in a prospective observational study. Baseline SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score (SS) and, whenever applicable, a residual SS after PCI were calculated. A multivariate analysis was performed to determine the effect of CAD, stratified according to complexity, and PCI on 5-year outcomes. RESULTS: In 604 patients, the presence of CAD and its complexity were significantly associated with worse 5-year survival (SS 0: 67.9% vs SS 1-22: 56.1% vs SS >22: 53.0%; log-rank P = 0.027) and increased cardiovascular mortality (SS 0: 15.1% vs SS 1-22: 24.0% vs SS >22: 27.8%; log-rank P = 0.024) after TAVR. Having noncomplex CAD (SS 1-22) was an independent predictor for increased all-cause mortality (HR: 1.43; P = 0.046), while complex CAD (SS >22) increased cardiovascular mortality significantly (HR: 1.84; P = 0.041). Angiography-guided PCI or completeness of revascularization was not associated with different outcomes. CONCLUSIONS: The presence of CAD and its anatomical complexity in patients undergoing TAVR are associated with significantly worse 5-year outcomes. However, angiography-guided PCI did not improve outcomes, highlighting the need for further research into physiology-guided PCI.

Inequality between women and men in ICD implantation.

Background: The impact of sex on ICD implantation practice and survival remain a topic of controversy. To assess sex-specific differences in ICD implantation practice we compared clinical characteristics and survival in women and men. Methods: From a nationwide registry, all new ICD implantations performed between 01/02/2010 and 31/01/2019 in Belgian patients were analyzed retrospectively. Baseline characteristics and survival rates were compared between sexes. To identify predictors of mortality, multivariable Cox regression was performed. Results: Only 3096 (20.9%) of 14,787 ICD implantations were performed in women. Within each type of underlying cardiomyopathy, the proportion women were lower than men. The main indication in men was ischemic vs dilated cardiomyopathy in women. Women were overall younger (59.1 ± 15.1 vs 62.6 ± 13.1 years; p < 0.001) and had less comorbidities except for oncological disease. More women functioned in NYHA-class III (33.6% vs 27.9%; p < 0.001) and had a QRS > 150 ms (29.4% vs 24.3%; p < 0.001), consistent with a higher use of CRT-D devices (31.7% vs 25.1%; p < 0.001). Women had more complications, reflected by the need to more re-interventions within 1 year (4.3% vs 2.7%, p < 0.001). After correction for covariates, sex-category was not a significant predictor of mortality (p = 0.055). Conclusion: There is a significant sex-disparity in ICD implantation rates, not fully explained by epidemiological differences in the prevalence of cardiomyopathies, which could imply an undertreatment of women. Women differ from men in baseline characteristics at implantation suggesting a selection bias. Further research is necessary to evaluate if women receive equal sudden cardiac death prevention.

Predictability of cardiotoxicity: Experience of a Belgian cardio-oncology clinic.

BACKGROUND: New oncological treatments improved survival but also increased awareness of cardiovascular side-effects during and after cancer therapy. METHODS: We report the experience of the cardio-oncology clinic at a large Belgian tertiary care center and investigated the predictability of cardiotoxicity based on referring department, cardiovascular risk factors, cancer treatment and existing risk scores of the American Society of Clinical Oncologists (ASCO) and Mayo Clinic. Cardiotoxicity was defined as a 10% reduction in Left Ventricular Ejection Fraction (LVEF) compared to the baseline transthoracic echocardiography (TTE) in asymptomatic patients or 5% in symptomatic patients. RESULTS: Of the 324 patients included, 14.5% died during follow-up. Most deaths were oncological, yet 19% of deaths were attributable to cardiovascular diseases. Models based on cardiovascular risk factors alone and cardiovascular risk factors combined with cardiotoxic medication poorly predicted cardiotoxicity. Existing risk scores from ASCO and Mayo Clinic also poorly predicted cardiotoxicity. A weighed model based on the Mayo Clinic cardiotoxicity risk score was the best risk assessment tool with still a limited predictive value with an Area Under the Receiver Operating Characteristic curve of 0.654 (CI 95%: 0.601-0.715). CONCLUSION: Cardiovascular morbidity and mortality are common in cancer patients and survivors and stress the unmet need of adequate risk prediction tools for systematic screening and rigorous cardiovascular follow-up. In our outpatient cohort, cardiotoxicity risk could not be adequately predicted by cancer type, using classic cardiovascular risk factors, nor by the combination of cardiovascular risk factors and the proposed cancer treatment. Furthermore, we showed that existing cardiotoxicity risk scores are suboptimal and should thus be interpreted with caution.

Validation of diagnostic nomograms based on CE-MS urinary biomarkers to detect clinically significant prostate cancer.

PURPOSE: Prostate cancer (PCa) is one of the most common cancers and one of the leading causes of death worldwide. Thus, one major issue in PCa research is to accurately distinguish between indolent and clinically significant (csPCa) to reduce overdiagnosis and overtreatment. In this study, we aim to validate the usefulness of diagnostic nomograms (DN) to detect csPCa, based on previously published urinary biomarkers. METHODS: Capillary electrophoresis/mass spectrometry was employed to validate a previously published biomarker model based on 19 urinary peptides specific for csPCa. Added value of the 19-biomarker (BM) model was assessed in diagnostic nomograms including prostate-specific antigen (PSA), PSA density and the risk calculator from the European Randomized Study of Screening. For this purpose, urine samples from 147 PCa patients were collected prior to prostate biopsy and before performing digital rectal examination (DRE). The 19-BM score was estimated via a support vector machine-based software based on the pre-defined cutoff criterion of - 0.07. DNs were subsequently developed to assess added value of integrative diagnostics. RESULTS: Independent validation of the 19-BM resulted in an 87% sensitivity and 65% specificity, with an AUC of 0.81, outperforming PSA (AUC PSA: 0.64), PSA density (AUC PSAD: 0.64) and ERSPC-3/4 risk calculator (0.67). Integration of 19-BM with the rest clinical variables into distinct DN, resulted in improved (AUC range: 0.82-0.88) but not significantly better performances over 19-BM alone. CONCLUSION: 19-BM alone or upon integration with clinical variables into DN, might be useful for detecting csPCa by decreasing the number of biopsies.

Identification of molecular pathways and protein-protein interactions in adipose tissue-derived mesenchymal stromal cells (ASCs) under physiological oxygen concentration in a diabetic rat model.

Objectives: Adipose tissue-derived mesenchymal stromal cells (ASCs) are useful in cell-based therapy. However, it is well known that diabetes mellitus (DM) alters ASCs' functionality. The majority of in vitro studies related to ASCs are developed under non-physiological oxygen conditions. Therefore, they may not reflect the full effects of DM on ASCs, in vivo. The main aim of the current study is to identify molecular pathways and underlying biological mechanisms affected by diabetes on ASCs in physiological oxygen conditions. Materials and Methods: ASCs derived from healthy (ASCs-C) and diabetic (ASCs-D) rats were expanded under standard culture conditions (21% O2) or cultured in physiological oxygen conditions (3% O2) and characterized. Differential gene expressions (DEGs) of ASCs-D with respect to ASCs-C were identified and analyzed with bioinformatic tools. Protein-protein interaction (PPI) networks, from up- and down-regulated DEGs, were also constructed. Results: The bioinformatic analysis revealed 1354 up-regulated and 859 down-regulated DEGs in ASCs-D, with 21 and 78 terms over and under-represented, respectively. Terms linked with glycosylation and ribosomes were over-represented and terms related to the activity of RNA-polymerase II and transcription regulation were under-represented. PPI network disclosed RPL11-RPS5 and KDR-VEGFA as the main interactions from up- and down-regulated DEGs, respectively. Conclusion: These results provide valuable information about gene pathways and underlying molecular mechanisms by which diabetes disturbs ASCs biology in physiological oxygen conditions. Furthermore, they reveal, molecular targets to improve the use of ASCs in autologous transplantation.

Thromboprophylaxis in COVID-19: Weight and severity adjusted intensified dosing.

Background: Venous thromboembolism (VTE) frequently occurs in hospitalized patients with coronavirus disease 2019 (COVID-19). The optimal dose of anticoagulation for thromboprophylaxis in COVID-19 is unknown. Aims: To report VTE incidence and bleeding before and after implementing a hospital-wide intensified thromboprophylactic protocol in patients with COVID-19. Methods: On March 31, 2020, we implemented an intensified thromboprophylactic protocol consisting of 50 IU anti-Xa low molecular weight heparin (LMWH)/kg once daily at the ward, twice daily at the intensive care unit (ICU). We included all patients hospitalized in a tertiary care hospital with symptomatic COVID-19 between March 7 and July 1, 2020. The primary outcome was the incidence of symptomatic or subclinical VTE and major bleeding during admission. Routine ultrasound screening for VTE was performed whenever logistically possible. Results: We included 412 patients, of which 116 were admitted to the ICU. Of 219 patients with standard a prophylactic dose of LMWH, 16 (7.3%) had VTE, 10 of which were symptomatic (4.6%). Of 193 patients with intensified thromboprophylaxis, there were no symptomatic VTE cases, three incidental deep venous thrombosis cases (1.6%), and one incidental pulmonary embolism (0.5%). The major bleeding rate was 1.2% in patients with intensified thromboprophylaxis and 7.7% when therapeutic anticoagulation was needed. Conclusion: In hospitalized patients with COVID-19, there were no additional symptomatic VTEs and a reduction in incidental deep vein thrombosis after implementing systematic thromboprophylaxis with weight-adjusted prophylactic (ward) to intermediate (ICU), but not therapeutic dosed anticoagulation. This intensified thromboprophylaxis was associated with a lower risk of major bleeding compared with therapeutic dosed anticoagulation.

Determinants of 25-hydroxyvitamin D Status in a Cutaneous Melanoma Population.

Vitamin D status is influenced by well-known determinants, but factors associated with low 25-hydroxyvitamin D levels in the cutaneous melanoma population are not well defined. The aim of this study was to confirm the well-known determinants and to assess new determinants for 25-hydroxyvitamin D levels in a cutaneous melanoma population. In a prospectively included cohort of 387 patients with cutaneous melanoma the association of 25-hydroxyvitamin D levels with sex, age, body mass index, time of blood withdrawal, Fitzpatrick phototype, vitamin D supplementation, score for intensity of lifetime sun exposure, smoking, education level, hair and skin colour, eye colour, total number of benign naevi, freckles and parameters of chronic sun damage was investigated. In addition, 25-hydroxyvitamin D levels were correlated with pathological parameters of the primary tumour and melanoma stage (8th edition of the American Joint Committee on Cancer (AJCC). Univariate and multivariate logistic regressions were performed using R software. The following factors had a significant effect on vitamin D status: body mass index, seasonal time of blood sampling, vitamin D supplementation, and a subtype of skin, and hair colour.

Value of 18F-FDG pet/CT for prognostic assessment in patients with infective endocarditis.

BACKGROUND: 18F-FDG PET/CT is a valuable diagnostic tool in infective endocarditis (IE). However, the prognostic value is unclear. This study aims to evaluate the prognostic performance of 18F-FDG PET/CT in native valve endocarditis (NVE) and prosthetic valve endocarditis (PVE). METHODS: We retrospectively included 76 patients treated for definite IE (NVE and PVE) that underwent 18F-FDG PET/CT between January 2016 and December 2018. Clinical, echocardiographic and 18F-FDG PET/CT (pathologic valvular 18F-FDG uptake, extracardiac complications (ECC)) data were collected. The primary endpoint was defined as mortality or recurrence of IE at a one-year follow-up. RESULTS: Pathologic valvular 18F-FDG uptake was detected in 32 of 57 (56.1%) patients, 30% (9/30) in NVE and 85.2% (23/27) in PVE group. Atrial fibrillation (OR 3.90, 95% CI = 1.14-16.3), prior anticoagulation treatment (OR 6.37, 95% CI = 1.89-26.7), large vegetation (≥ 10 mm) (OR 4.05, 95% CI = 1.14-16.1), perivalvular complications (OR 7.22, 95% CI = 1.68-55.1) and abscess (OR 10.9, 95% CI = 1.84-283) were associated with positive PET/CT. Extracardiac complications were found in 27 of 76 (35.5%) patients, 42.9% (18/42) in the NVE and 26.5% (9/34) in the PVE group. Pathological valvular tracer uptake (HR 1.20, 95% CI = 0.43-3.37) or extracardiac complications (HR 0.58, 95% CI = 0.21-1.62) were not associated with the occurrence of the primary endpoint. CONCLUSION: Our study could not demonstrate a prognostic value of 18F-FDG PET/CT in IE, but confirms high diagnostic performance, which may compromise prognostic significance by accelerated optimal treatment because of earlier diagnostic certainty.

Impact of sound levels on physiological and consciousness state of cardiovascular patients.

BACKGROUND: Patients treated in intensive care units (ICUs) experience life-threatening medical conditions but some external factors in ICUs do not help or even adversely affect and complicate their evolution. Among others, such factors include noise pollution due to alarms and medical clinical equipment, as well as the activities of the health care personnel themselves. AIM: This study aimed to evaluate the influence of elevated sound levels on physiological variables and the consciousness state of patients treated in a cardiovascular area in an ICU. DESIGN: A longitudinal study with several observations was carried out during 1 month in the cardiovascular area of an ICU of a third-level hospital in southern Spain. METHODS: Sound levels were monitored in different work shifts and patients' physiological data and consciousness status were recorded. Generalized additive mixed models (GAMMs) were developed to detect the variability of the sound levels together with the vital parameters of the patients in the ICU. RESULTS: Thirty-eight patients were included. The mean sound level was 54.09 dBA. The GAMM sound levels analysis showed a significant increase in sound levels from 4:30 p.m. to 8:00 p.m. (1.83 dBA; P < .001) and 8:00 p.m. to 11:30 p.m. (3.06 dBA; P < .001). An increase in heart rate (3.66 bpm; P < .001), respiratory rate (2.62 rpm; P < .001) and the Glasgow Coma Scale (0.50 units; P = .002) was detected during the 4:30 p.m.-8:30 p.m. CONCLUSIONS: Elevated sound levels in cardiovascular ICUs seem to influence positively the physiological and consciousness status of patients. Given the importance of the findings for patient safety, future intervention studies are recommended. RELEVANCE TO CLINICAL PRACTICE: The finding of this study could translate into structural changes in ICU facilities, as well as the development of clinical practice guidelines that influence the behaviour of health care professionals.

Selective loss of kisspeptin signaling in oocytes causes progressive premature ovulatory failure.

STUDY QUESTION: Does direct kisspeptin signaling in the oocyte have a role in the control of follicular dynamics and ovulation? SUMMARY ANSWER: Kisspeptin signaling in the oocyte plays a relevant physiological role in the direct control of ovulation; oocyte-specific ablation of kisspeptin receptor, Gpr54, induces a state of premature ovulatory failure in mice that recapitulates some features of premature ovarian insufficiency (POI). WHAT IS KNOWN ALREADY: Kisspeptins, encoded by the Kiss1 gene, are essential for the control of ovulation and fertility, acting primarily on hypothalamic GnRH neurons to stimulate gonadotropin secretion. However, kisspeptins and their receptor, Gpr54, are also expressed in the ovary of different mammalian species, including humans, where their physiological roles remain contentious and poorly characterized. STUDY DESIGN, SIZE, DURATION: A novel mouse line with conditional ablation of Gpr54 in oocytes, named OoGpr54-/-, was generated and studied in terms of follicular and ovulatory dynamics at different age-points of postnatal maturation. A total of 59 OoGpr54-/- mice and 47 corresponding controls were analyzed. In addition, direct RNA sequencing was applied to ovarian samples from 8 OoGpr54-/- and 7 control mice at 6 months of age, and gonadotropin priming for ovulatory induction was conducted in mice (N = 7) from both genotypes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Oocyte-selective ablation of Gpr54 in the oocyte was achieved in vivo by crossing a Gdf9-driven Cre-expressing transgenic mouse line with a Gpr54 LoxP mouse line. The resulting OoGpr54-/- mouse line was subjected to phenotypic, histological, hormonal and molecular analyses at different age-points of postnatal maturation (Day 45, and 2, 4, 6 and 10-11 months of age), in order to characterize the timing of puberty, ovarian follicular dynamics and ovulation, with particular attention to identification of features reminiscent of POI. The molecular signature of ovaries from OoGpr54-/- mice was defined by direct RNA sequencing. Ovulatory responses to gonadotropin priming were also assessed in OoGpr54-/- mice. MAIN RESULTS AND THE ROLE OF CHANCE: Oocyte-specific ablation of Gpr54 caused premature ovulatory failure, with some POI-like features. OoGpr54-/- mice had preserved puberty onset, without signs of hypogonadism. However, already at 2 months of age, 40% of OoGpr54-/- females showed histological features reminiscent of ovarian failure and anovulation. Penetrance of the phenotype progressed with age, with >80% and 100% of OoGpr54-/- females displaying complete ovulatory failure by 6- and 10 months, respectively. This occurred despite unaltered hypothalamic Gpr54 expression and gonadotropin levels. Yet, OoGpr54-/- mice had decreased sex steroid levels. While the RNA signature of OoGpr54-/- ovaries was dominated by the anovulatory state, oocyte-specific ablation of Gpr54 significantly up- or downregulated of a set of 21 genes, including those encoding pituitary adenylate cyclase-activating polypeptide, Wnt-10B, matrix-metalloprotease-12, vitamin A-related factors and calcium-activated chloride channel-2, which might contribute to the POI-like state. Notably, the anovulatory state of young OoGpr54-/- mice could be rescued by gonadotropin priming. LARGE SCALE DATA: N/A. . LIMITATIONS, REASONS FOR CAUTION: Conditional ablation of Gpr54 in oocytes unambiguously caused premature ovulatory failure in mice; yet, the ultimate molecular mechanisms for such state of POI can be only inferred on the basis of RNAseq data and need further elucidation, since some of the molecular changes observed in OoGpr54-/- ovaries were secondary to the anovulatory state. Direct translation of mouse findings to human disease should be made with caution since, despite the conserved expression of Kiss1/kisspeptin and Gpr54 in rodents and humans, our mouse model does not recapitulate all features of common forms of POI. WIDER IMPLICATIONS OF THE FINDINGS: Deregulation of kisspeptin signaling in the oocyte might be an underlying, and previously unnoticed, cause for some forms of POI in women. STUDY FUNDING/COMPETING INTEREST(S): This work was primarily supported by a grant to M.P. and M.T.-S. from the FiDiPro (Finnish Distinguished Professor) Program of the Academy of Finland. Additional financial support came from grant BFU2017-83934-P (M.T.-S.; Ministerio de Economía y Competitividad, Spain; co-funded with EU funds/FEDER Program), research funds from the IVIRMA International Award in Reproductive Medicine (M.T.-S.), and EFSD Albert Renold Fellowship Programme (S.T.R.). The authors have no conflicts of interest to declare in relation to the contents of this work. TRIAL REGISTRATION NUMBER: N/A.

Capacidad predictiva de las escalas de alerta temprana en los servicios de urgencias hospitalarios: revisión sistemática y metanálisis / Predictive power of early-warning scores used in hospital emergency departments: a systematic review and meta-analysis

Objetivos: Evaluar, en términos de ingreso hospitalario o en unidad de cuidados intensivos (UCI) y muerte, la capacidad predictiva de las escalas de alerta temprana en los servicios de urgencias hospitalariOs (SUH). Método: Revisión sistemática y metanálisis. Se consultaron las bases de datos Medline, Embase, Web of Science y Cochrane Library. Se incluyeron estudios observacionales y ensayos clínicos publicados entre e 1 de enero de 1950 y 12 de junio de 2020 en los que se empleara una escala de alerta temprana en los SUH. Las variables de resultadosprincipales fueron mortalidad (24 horas, 48 horas y más de 72 horas) e ingreso hospitalario y en UCI. Resultados: Se seleccionaron 9 estudios en la revisión sistemática, 4 se incluyeron en el metanálisis (165.580 pacientes). Hubo heterogeneidad en las escalas empleadas, siendo la escala NEWS la más utilizada. El uso de la escala NEWS mostró una buena capacidad predictiva para la mortalidad a las 24 horas [AUROC 0,88 (IC 95% 0,87-0,89);p < 0,001; I2 = 0%], a las 48 horas [AUROC 0,86 (IC 95% 0,84-0,88); p < 0,001; I2 = 49,3%] e intrahospitalaria [AUROC: 0,77 (IC 95% 0,74-0,80); p < 0,001; I2 = 96,2%]. Para el ingreso hospitalario y en UCI, NEWS mostró una capacidad predictiva adecuada. Conclusiones: El uso de las escalas de alerta temprana en los SUH muestra una capacidad predictiva buena en términos de mortalidad temprana e intrahospitalaria. (AU)

Objectives: To assess the predictive power of scores used in hospital emergency departments (EDs) to give early warning of risk for mortality and hospital ward or intensive care unit (ICU) admission. Material and methods: Systematic review and meta-analysis. We searched MEDLINE, Embase, the Web of Science, and the Cochrane Library. Observational studies and clinical trials published between January 1, 1950, and June 12, 2020 that used early-warning scores in hospital EDs were included. The main outcomes were mortality (at 24, 48, and more than 72 hours), hospital admission, and ICU admission. Results: Nine studies entered into the systematic review; 4 of them, with 165 580 patients, were included in the meta-analysis. The studies were heterogeneous with respect to the scores used. The one used most often was the National Early Warning Score (NEWS). The meta-analysis of studies using the NEWS scale showed that it had good predictive power for mortality: the area under the curve (AUC) of the receiver operating characteristic was 0.88 (95%, CI, 0.87-0.89; P .001, I2 = 0%) at 24 hours and 0.86 (0.84-0.88; P .001; I2 = 49.3%) at 48 hours. The AUC for inhospital mortality was 0.77 (95% CI, 0.74-0.80; P .001; I2 = 96.2%). The NEWS score had adequate power for predicting risk of hospital ward and ICU admission. Conclusion: Early warning scores used in hospital EDs are able to predict risk of early and in-hospital mortality. (AU)

Predictive power of early-warning scores used in hospital emergency departments: a systematic review and meta-analysis. / Capacidad predictiva de las escalas de alerta temprana en los servicios de urgencias hospitalarios: revisión sistemática y metanálisis.

OBJECTIVES: To assess the predictive power of scores used in hospital emergency departments (EDs) to give early warning of risk for mortality and hospital ward or intensive care unit (ICU) admission. MATERIAL AND METHODS: Systematic review and meta-analysis. We searched MEDLINE, Embase, the Web of Science, and the Cochrane Library. Observational studies and clinical trials published between January 1, 1950, and June 12, 2020 that used early-warning scores in hospital EDs were included. The main outcomes were mortality (at 24, 48, and more than 72 hours), hospital admission, and ICU admission. RESULTS: Nine studies entered into the systematic review; 4 of them, with 165 580 patients, were included in the meta-analysis. The studies were heterogeneous with respect to the scores used. The one used most often was the National Early Warning Score (NEWS). The meta-analysis of studies using the NEWS scale showed that it had good predictive power for mortality: the area under the curve (AUC) of the receiver operating characteristic was 0.88 (95%, CI, 0.87-0.89; P .001, I2 = 0%) at 24 hours and 0.86 (0.84-0.88; P .001; I2 = 49.3%) at 48 hours. The AUC for inhospital mortality was 0.77 (95% CI, 0.74-0.80; P .001; I2 = 96.2%). The NEWS score had adequate power for predicting risk of hospital ward and ICU admission. CONCLUSION: Early warning scores used in hospital EDs are able to predict risk of early and in-hospital mortality.

OBJETIVO: Evaluar, en términos de ingreso hospitalario o en unidad de cuidados intensivos (UCI) y muerte, la capacidad predictiva de las escalas de alerta temprana en los servicios de urgencias hospitalarios (SUH). METODO: Revisión sistemática y metanálisis. Se consultaron las bases de datos Medline, Embase, Web of Science y Cochrane Library. Se incluyeron estudios observacionales y ensayos clínicos publicados entre e 1 de enero de 1950 y 12 de junio de 2020 en los que se empleara una escala de alerta temprana en los SUH. Las variables de resultados principales fueron mortalidad (24 horas, 48 horas y más de 72 horas) e ingreso hospitalario y en UCI. RESULTADOS: Se seleccionaron 9 estudios en la revisión sistemática, 4 se incluyeron en el metanálisis (165.580 pacientes). Hubo heterogeneidad en las escalas empleadas, siendo la escala NEWS la más utilizada. El uso de la escala NEWS mostró una buena capacidad predictiva para la mortalidad a las 24 horas [AUROC 0,88 (IC 95% 0,87-0,89); p 0,001; I2 = 0%], a las 48 horas [AUROC 0,86 (IC 95% 0,84-0,88); p 0,001; I2 = 49,3%] e intrahospitalaria [AUROC: 0,77 (IC 95% 0,74-0,80); p 0,001; I2 = 96,2%]. Para el ingreso hospitalario y en UCI, NEWS mostró una capacidad predictiva adecuada. CONCLUSIONES: El uso de las escalas de alerta temprana en los SUH muestra una capacidad predictiva buena en términos de mortalidad temprana e intrahospitalaria.

Molecular diagnosis of polycystic ovary syndrome in obese and non-obese women by targeted plasma miRNA profiling.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is diagnosed based on the clinical signs, but its presentation is heterogeneous and potentially confounded by concurrent conditions, such as obesity and insulin resistance. miRNA have recently emerged as putative pathophysiological and diagnostic factors in PCOS. However, no reliable miRNA-based method for molecular diagnosis of PCOS has been reported. The aim of this study was to develop a tool for accurate diagnosis of PCOS by targeted miRNA profiling of plasma samples, defined on the basis of unbiased biomarker-finding analyses and biostatistical tools. METHODS: A case-control PCOS cohort was cross-sectionally studied, including 170 women classified into four groups: non-PCOS/lean, non-PCOS/obese, PCOS/lean, and PCOS/obese women. High-throughput miRNA analyses were performed in plasma, using NanoString technology and a 800 human miRNA panel, followed by targeted quantitative real-timePCR validation. Statistics were applied to define optimal normalization methods, identify deregulated biomarker miRNAs, and build classification algorithms, considering PCOS and obesity as major categories. RESULTS: The geometric mean of circulating hsa-miR-103a-3p, hsa-miR-125a-5p, and hsa-miR-1976, selected among 125 unchanged miRNAs, was defined as optimal reference for internal normalization (named mR3-method). Ten miRNAs were identified and validated after mR3-normalization as differentially expressed across the groups. Multinomial least absolute shrinkage and selection operator regression and decision-tree models were built to reliably discriminate PCOS vs non-PCOS, either in obese or non-obese women, using subsets of these miRNAs as performers. CONCLUSIONS: We define herein a robust method for molecular classification of PCOS based on unbiased identification of miRNA biomarkers and decision-tree protocols. This method allows not only reliable diagnosis of non-obese women with PCOS but also discrimination between PCOS and obesity. CAPSULE: We define a novel protocol, based on plasma miRNA profiling, for molecular diagnosis of PCOS. This tool not only allows proper discrimination of the condition in non-obese women but also permits distinction between PCOS and obesity, which often display overlapping clinical presentations.

Assessment of Subclinical Psychotic Symptoms in Patients with Rheumatoid Arthritis and Spondyloarthritis.

Inflammatory and autoimmune processes have been associated with the onset of depressive and psychotic symptoms. Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are rheumatic diseases with an inflammatory etiology. A high prevalence of depressive and anxiety-related comorbidity has been reported for both diseases, with no evidence of a greater prevalence of psychosis. The objective of the present study was to evaluate for the first time subclinical psychotic symptoms in patients with RA and SpA. This is a cross-sectional, single-center study including RA and SpA patients, as well as healthy controls. Abnormal psychotic experiences (positive, negative, and depressive symptoms) were evaluated using the Community Assessment of Psychic Experiences (CAPE-42). Functional capacity was evaluated using the Short-Form Health Survey SF-12. We compared the CAPE and SF-12 scores between the three groups. We recruited 385 individuals: 218 with RA, 100 with SpA, and 67 healthy controls. According to the CAPE scale, the frequency of subclinical psychotic symptoms was greater in patients than in healthy controls (RA, 1.90 vs. 1.63, p < 0.001; SpA, 1.88 vs. 1.63, p = 0.001). Distress was also greater in patients than in controls owing to the presence of symptoms. No differences were observed between the three groups for the mental dimension scores in the SF-12 Health Survey (43.75 in RA, 45.54 in SpA, and 43.19 in healthy controls). Our findings point to a greater prevalence of subclinical psychotic symptoms in patients with RA and patients with SpA than in the general population. The results suggest an association between inflammation and depression/subclinical psychotic symptoms.

In1-Ghrelin Splicing Variant as a Key Element in the Pathophysiological Association Between Obesity and Prostate Cancer.

CONTEXT: Recent studies emphasize the importance of considering the metabolic status to develop personalized medicine approaches. This is especially relevant in prostate cancer (PCa), wherein the diagnostic capability of prostate-specific antigen (PSA) dramatically drops when considering patients with PSA levels ranging from 3 to 10 ng/mL, the so-called grey zone. Hence, additional noninvasive diagnostic and/or prognostic PCa biomarkers are urgently needed, especially in the metabolic-status context. OBJECTIVE: To assess the potential relation of urine In1-ghrelin (a ghrelin-splicing variant) levels with metabolic-related/pathological conditions (eg, obesity, diabetes, body mass index, insulin and glucose levels) and to define its potential clinical value in PCa (diagnostic/prognostic capacity) and relationship with PCa risk in patients with PSA in the grey zone. METHODS: Urine In1-ghrelin levels were measured by radioimmunoassay in a clinically, metabolically, pathologically well-characterized cohort of patients without (n = 397) and with (n = 213) PCa with PSA in the grey zone. RESULTS: Key obesity-related factors associated with PCa risk (BMI, diabetes, glucose and insulin levels) were strongly correlated to In1-ghrelin levels. Importantly, In1-ghrelin levels were higher in PCa patients compared to control patients with suspect of PCa but negative biopsy). Moreover, high In1-ghrelin levels were associated with increased PCa risk and linked to PCa aggressiveness (eg, tumor stage, lymphovascular invasion). In1-ghrelin levels added significant diagnostic value to a clinical model consisting of age, suspicious digital rectal exam, previous biopsy, and PSA levels. Furthermore, a multivariate model consisting of clinical and metabolic variables, including In1-ghrelin levels, showed high specificity and sensitivity to diagnose PCa (area under the receiver operating characteristic curve = 0.740). CONCLUSIONS: Urine In1-ghrelin levels are associated with obesity-related factors and PCa risk and aggressiveness and could represent a novel and valuable noninvasive PCa biomarker, as well as a potential link in the pathophysiological relationship between obesity and PCa.

Venous Thromboembolism in Patients Discharged after COVID-19 Hospitalization.

BACKGROUND: Venous thromboembolism (VTE) is a frequent complication of COVID-19, so that the importance of adequate in-hospital thromboprophylaxis in patients hospitalized with COVID-19 is well established. However, the incidence of VTE after discharge and whether postdischarge thromboprophylaxis is beneficial and safe are unclear. In this prospective observational single-center study, we report the incidence of VTE 6 weeks after hospitalization and the use of postdischarge thromboprophylaxis. METHODS: Patients hospitalized with confirmed COVID-19 were invited to a multidisciplinary follow-up clinic 6 weeks after discharge. D-dimer and C-reactive protein were measured, and all patients were screened for deep vein thrombosis with venous duplex-ultrasound. Additionally, selected high-risk patients received computed tomography pulmonary angiogram or ventilation-perfusion (V/Q) scan to screen for incidental pulmonary embolism. RESULTS: Of 485 consecutive patients hospitalized from March through June 2020, 146 patients were analyzed, of which 39% had been admitted to the intensive care unit (ICU). Postdischarge thromboprophylaxis was prescribed in 28% of patients, but was used more frequently after ICU stay (61%) and in patients with higher maximal D-dimer and C-reactive protein levels during hospitalization. Six weeks after discharge, elevated D-dimer values were present in 32% of ward and 42% of ICU patients. Only one asymptomatic deep vein thrombosis (0.7%) and one symptomatic pulmonary embolism (0.7%) were diagnosed with systematic screening. No bleedings were reported. CONCLUSION: In patients who had been hospitalized with COVID-19, systematic screening for VTE 6 weeks after discharge revealed a low incidence of VTE. A strategy of selectively providing postdischarge thromboprophylaxis in high-risk patients seems safe and potentially effective.

Reduction in Circulating Advanced Glycation End Products by Mediterranean Diet Is Associated with Increased Likelihood of Type 2 Diabetes Remission in Patients with Coronary Heart Disease: From the Cordioprev Study.

SCOPE: It is hypothesized that decreased advanced glycation end products (AGEs) levels could affect type 2 diabetes mellitus (T2DM) remission in newly diagnosed patients through the consumption of two healthy diets. METHODS AND RESULTS: Patients from CORDIOPREV study, all with previous cardiovascular events, with T2DM at the beginning of the study are included. Patients are randomized to a Mediterranean or a low-fat diet for five years. No different diabetes remission rates are found among diets. Serum methylglioxal (MG) and carboximethyllysine (CML), levels dietary AGE, as well as gene expression of AGER1 and RAGE are measured. Serum MG decreases only after the consumption of the Mediterranean diet. Moreover, a COX regression analysis shows that each SD decrease in the MG, occurring after the Mediterranean diet, increases the probability of T2DM remission with HR:2.56(1.02-6.25) and p = 0.046 and each SD increase in disposition index at baseline increases the probability of remission with HR:1.94(1.32-2.87) and p = 0.001. CONCLUSIONS: It is demonstrated that the reduction of serum AGEs levels and the modulation of its metabolism, occurring after the consumption of a Mediterranean diet, might be involved in the molecular mechanism underlying the T2DM remission of newly diagnosed patients with coronary heart disease.