Clustering COVID-19 ARDS patients through the first days of ICU admission. An analysis of the CIBERESUCICOVID Cohort.

BACKGROUND: Acute respiratory distress syndrome (ARDS) can be classified into sub-phenotypes according to different inflammatory/clinical status. Prognostic enrichment was achieved by grouping patients into hypoinflammatory or hyperinflammatory sub-phenotypes, even though the time of analysis may change the classification according to treatment response or disease evolution. We aimed to evaluate when patients can be clustered in more than 1 group, and how they may change the clustering of patients using data of baseline or day 3, and the prognosis of patients according to their evolution by changing or not the cluster. METHODS: Multicenter, observational prospective, and retrospective study of patients admitted due to ARDS related to COVID-19 infection in Spain. Patients were grouped according to a clustering mixed-type data algorithm (k-prototypes) using continuous and categorical readily available variables at baseline and day 3. RESULTS: Of 6205 patients, 3743 (60%) were included in the study. According to silhouette analysis, patients were grouped in two clusters. At baseline, 1402 (37%) patients were included in cluster 1 and 2341(63%) in cluster 2. On day 3, 1557(42%) patients were included in cluster 1 and 2086 (57%) in cluster 2. The patients included in cluster 2 were older and more frequently hypertensive and had a higher prevalence of shock, organ dysfunction, inflammatory biomarkers, and worst respiratory indexes at both time points. The 90-day mortality was higher in cluster 2 at both clustering processes (43.8% [n = 1025] versus 27.3% [n = 383] at baseline, and 49% [n = 1023] versus 20.6% [n = 321] on day 3). Four hundred and fifty-eight (33%) patients clustered in the first group were clustered in the second group on day 3. In contrast, 638 (27%) patients clustered in the second group were clustered in the first group on day 3. CONCLUSIONS: During the first days, patients can be clustered into two groups and the process of clustering patients may change as they continue to evolve. This means that despite a vast majority of patients remaining in the same cluster, a minority reaching 33% of patients analyzed may be re-categorized into different clusters based on their progress. Such changes can significantly impact their prognosis.

Transcription factor activity and nucleosome organization in mitosis.

Mitotic bookmarking transcription factors (BFs) maintain the capacity to bind to their targets during mitosis, despite major rearrangements of the chromatin. While they were thought to propagate gene regulatory information through mitosis by statically occupying their DNA targets, it has recently become clear that BFs are highly dynamic in mitotic cells. This represents both a technical and a conceptual challenge to study and understand the function of BFs: First, formaldehyde has been suggested to be unable to efficiently capture these transient interactions, leading to profound contradictions in the literature; and second, if BFs are not permanently bound to their targets during mitosis, it becomes unclear how they convey regulatory information to daughter cells. Here, comparing formaldehyde to alternative fixatives we clarify the nature of the chromosomal association of previously proposed BFs in embryonic stem cells: While ESRRB can be considered as a canonical BF that binds at selected regulatory regions in mitosis, SOX2 and POU5F1 (also known as OCT4) establish DNA sequence-independent interactions with the mitotic chromosomes, either throughout the chromosomal arms (SOX2) or at pericentromeric regions (POU5F1). Moreover, we show that ordered nucleosomal arrays are retained during mitosis at ESRRB bookmarked sites, whereas regions losing transcription factor binding display a profound loss of order. By maintaining nucleosome positioning during mitosis, ESRRB might ensure the rapid post-mitotic re-establishment of functional regulatory complexes at selected enhancers and promoters. Our results provide a mechanistic framework that reconciles dynamic mitotic binding with the transmission of gene regulatory information across cell division.

High IGKC-Expressing Intratumoral Plasma Cells Predict Response to Immune Checkpoint Blockade.

Resistance to Immune Checkpoint Blockade (ICB) constitutes the current limiting factor for the optimal implementation of this novel therapy, which otherwise demonstrates durable responses with acceptable toxicity scores. This limitation is exacerbated by a lack of robust biomarkers. In this study, we have dissected the basal TME composition at the gene expression and cellular levels that predict response to Nivolumab and prognosis. BCR, TCR and HLA profiling were employed for further characterization of the molecular variables associated with response. The findings were validated using a single-cell RNA-seq data of metastatic melanoma patients treated with ICB, and by multispectral immunofluorescence. Finally, machine learning was employed to construct a prediction algorithm that was validated across eight metastatic melanoma cohorts treated with ICB. Using this strategy, we have unmasked a major role played by basal intratumoral Plasma cells expressing high levels of IGKC in efficacy. IGKC, differentially expressed in good responders, was also identified within the Top response-related BCR clonotypes, together with IGK variants. These results were validated at gene, cellular and protein levels; CD138+ Plasma-like and Plasma cells were more abundant in good responders and correlated with the same RNA-seq-defined fraction. Finally, we generated a 15-gene prediction model that outperformed the current reference score in eight ICB-treated metastatic melanoma cohorts. The evidenced major contribution of basal intratumoral IGKC and Plasma cells in good response and outcome in ICB in metastatic melanoma is a groundbreaking finding in the field beyond the role of T lymphocytes.

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients.

BACKGROUND: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. METHODS: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. RESULTS: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). CONCLUSIONS: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation.

Crohn's disease and Sweet's syndrome: A debut together.

The association of Sweet's syndrome and Crohn's disease is unusual, with less than 50 reported cases. We report a case in which these entities debut together.

The influence of altitude on the abundance and occurrence of species of the family Calliphoridae (Diptera) in corpses in a Mediterranean area.

A carcass is defined as a temporary resource that can support high levels of diversity compared to other resources. The level of diversity often depends on the environmental conditions in which the corpse is found. Calliphoridae (Diptera) are the most important necrophagous insects used in forensic investigations because this family is common, widespread, abundant, and usually the first to colonize a corpse. However, understanding the processes responsible for variation in calliphorid species abundance and richness along gradients in ecology remains a key challenge. In this study, we analyzed the influence of altitude on the abundance and diversity of Calliphoridae species in corpses at three different altitudes (400, 900, and 1500 m a.s.l.) in a mountainous area of southeastern Spain. The results revealed a gradient of decreasing abundance with increasing altitude. An altitudinal substitution of species was observed, with Chrysomya albiceps being found at the lowest altitude and Calliphora vicina at the highest altitude. Seasonal variation was also noted, with Ch. albiceps being the dominant species in the warmer months and C. vicina being the dominant species in winter. Our results confirm the importance of Calliphorids as seasonal, altitudinal, and environmental indicators, given the wide distribution and abundance of this family. This information is of great interest on the interpretation of data in forensic practice.

Evolutionary analysis of indeterminate cytology and risk of malignancy in a thyroid nodule unit.

OBJECTIVE: The objective of this study was to analyze the evolution in the diagnosis and management of indeterminate thyroid nodules over three time periods. METHODS: 3020 patients with thyroid nodules underwent cytological evaluation during three periods (2006-2008, 2012-2014, 2017-2019). Distribution of diagnostic cytologies, risk of malignancy, diagnostic performance indices of FNA, and cytologic-histologic correlation in indeterminate cytologies were analyzed. RESULTS: only 2.2% of cytology tests were insufficient for a diagnosis. 86.9% cytologies were benign, 1.7% malignant, and 11.4% indeterminate. Indeterminate cytology rates were 15.9% (2006-2008), 10.1% (2012-2014), and 10% (2017-2019). Surgery was performed in 13% of benign cytology, result-ing in malignant histology in 2.7%. All malignant and suspicious cytologies underwent surgery: malig-nancy confirmed in 98% and 77% of cases, respectively. All 'indeterminate with atypia' cytologies (2006-2008) and Bethesda IV (2012-2014; 2017-2019) un-derwent surgery, with malignancy confirmed in 19.6%, 43.8%, and 25.7%, respectively. In the 'inde-terminate without atypia' category (2006-2008) and Bethesda III (2012-2014; 2017-2019), diagnostic surgery was performed in 57.7%, 78.6%, and 59.4%, respectively, with malignancy confirmed in 3.3%, 20.5%, and 31.6%. The FNA sensitivity was 91.6% with a negative predictive value greater than 96% in all periods. The specificity exceeded 75% in the last two periods. CONCLUSION: Bethesda system reduces indeterminate cytologies and improves the accuracy of FNA diagnosis. We reported a higher proportion of malignancy than expected in Bethesda III, underscoring the importance of having institution-specific data to guide decision-making. However, there is a need for risk stratification tools that allow for conservative management in low-risk cases.

How plant composition in margins influences the assemblage of pests and predators and its effect on biocontrol in melon fields.

Many agricultural landscapes offer few resources for maintaining natural enemy populations and floral plantings have frequently been adopted to enhance biological pest control in crops. However, restored margins may harbour both pests and natural enemies. The aim was to compare the abundance of pests and natural enemies in three types of margins (unmanaged, sown herbaceous floral strips and shrubby hedgerows) as well as in adjacent melon fields. Besides, yield was compared among melon fields as way of testing the effect of the type of margin on biocontrol. The research was carried out during 2 years in twelve melon fields from four different locations in southern Spain. Arthropods were sampled periodically in margins and melon fields by visual inspections and Berlese extraction. Hedgerow and floral strips hosted higher numbers of both pests and predators than unmanaged margins. Besides, hedgerows had a similar or higher number of natural enemies than floral strips but lower number of pests. In just a few occasions, the type of margin had a significant effect on the abundance of pests and natural enemies in melon fields, but rarely there was consistency between the two growing seasons. No differences were found in yield. We hypothesised that the lack of association in the abundances of pests and natural enemies between margins and melon fields could be attributed to the overriding effects of the landscape and/or the internal population dynamics of arthropods in melon fields. Overall, shrubby hedgerows are more recommended than herbaceous floral strips.

Pattern of recurrence of early breast cancer is different according to intrinsic subtype and proliferation index.

INTRODUCTION: Recurrence risk in breast cancer varies throughout the follow-up time. We examined if these changes are related to the level of expression of the proliferation pathway and intrinsic subtypes. METHODS: Expression of estrogen and progesterone receptor, Ki-67, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR) and cytokeratin 5/6 (CK 5/6) was performed on tissue-microarrays constructed from a large and uniformly managed series of early breast cancer patients (N = 1,249). Subtype definitions by four biomarkers were as follows: luminal A (ER + and/or PR+, HER2−, Ki-67 <14), luminal B (ER + and/or PR+, HER2−, Ki-67 ≥14), HER2-enriched (any ER, any PR, HER2+, any Ki-67), triple-negative (ER−, PR−, HER2−, any Ki-67). Subtype definitions by six biomarkers were as follows: luminal A (ER + and/or PR+, HER2−, Ki-67 <14, any CK 5/6, any EGFR), luminal B (ER + and/or PR+, HER2−, Ki-67 ≥14, any CK 5/6, any EGFR), HER2-enriched (ER−, PR−, HER2+, any Ki-67, any CK 5/6, any EGFR), Luminal-HER2 (ER + and/or PR+, HER2+, any Ki-67, any CK 5/6, any EGFR), Basal-like (ER−, PR−, HER2−, any Ki-67, CK5/6+ and/or EGFR+), triple-negative nonbasal (ER−, PR−, HER2−, any Ki-67, CK 5/6−, EGFR−). Each four- or six-marker defined intrinsic subtype was divided in two groups, with Ki-67 <14% or with Ki-67 ≥14%. Recurrence hazard rate function was determined for each intrinsic subtype as a whole and according to Ki-67 value. RESULTS: Luminal A displayed a slow risk increase, reaching its maximum after three years and then remained steady. Luminal B presented most of its relapses during the first five years. HER2-enriched tumors show a peak of recurrence nearly twenty months post-surgery, with a greater risk in Ki-67 ≥14%. However a second peak occurred at 72 months but the risk magnitude was greater in Ki-67 <14%. Triple negative tumors with low proliferation rate display a smooth risk curve, but with Ki-67 ≥14% show sharp peak at nearly 18 months. CONCLUSIONS: Each intrinsic subtype has a particular pattern of relapses over time which change depending on the level of activation of the proliferation pathway assessed by Ki-67. These findings could have clinical implications both on adjuvant treatment trial design and on the recommendations concerning the surveillance of patients.

Adrenal cavernous hemangioma: is presurgical diagnosis with imaging test possible.

OBJECTIVE: To describe a case of adrenal cavernous hemangioma in a 67 year old man who presented left lumbar pain. METHODS: Abdominal ultrasound, contrast enhanced ultrasound of the lesion, abdominal-pelvic CT scan, and then left adrenalectomy and pathology were performed RESULTS: Imaging studies showed a large solid-cystic mass with 12 × 11 cm diameters in the left adrenal gland, well defined, with calcifications, which showed peripheral arterial globular contrast enhancement on CT and ultrasound. The lesion displaced neighboring structures without other findings in the abdominopelvic study. The pathology report after adrenalectomy was: cavernous hemangioma with calcifications, ossifications and necrosis. CONCLUSIONS: Cavernous hemangioma is a rare cause of adrenal mass. The globular peripheral contrast uptake and gradual filling of the lesion on dynamic imaging studies (Ultrasound or CT) and phlebolith type calcifications suggest the diagnosis of typical angioma. However, the presence of thrombosis, necrosis and calcifications in large lesions confer an unusual dynamic behavior and force pathology for definitive diagnosis.

Effects of Managed and Unmanaged Floral Margins on Pollination Services and Production in Melon Crops.

Melon is among the most consumed fruits in the world, being a crop that depends almost entirely on insects for its reproduction, which is why it is especially sensitive to declining pollination services. Restoration and maintenance of hedgerows and agricultural borders around crops are generally carried out by sowing flowering herbaceous plants or establishing shrubby species; however, a cost-effective and lower-maintenance alternative for farmers could be as simple as allowing vegetation to regenerate naturally without any management actions. This work aimed to test the effects of three different types of margins (managed herbaceous, managed shrubby, and unmanaged herbaceous) on the overall abundance and richness of wild pollinators in melon crops. The work was performed in three localities in southern Spain over two years. Pollinators were monitored visually using 1 × 1 m sampling squares and pan traps within melon fields. Moreover, crop yield was estimated by measuring fruit weight and the number of seeds. In general, higher abundances of pollinators were observed in melon fields during the second year. In addition, the abundances of Syrphidae, Andrenidae, Apidae (excl. Apis mellifera), and pollinators other than bees, belonging to the orders Diptera, Coleoptera, Hymenoptera, and Lepidoptera, showed higher values in melon fields with shrubby margins than in fields with herbaceous margins (managed or unmanaged). However, no effect of floral margins on the yield of melon crops was found.

Key Factors Associated With Pulmonary Sequelae in the Follow-Up of Critically Ill COVID-19 Patients.

INTRODUCTION: Critical COVID-19 survivors have a high risk of respiratory sequelae. Therefore, we aimed to identify key factors associated with altered lung function and CT scan abnormalities at a follow-up visit in a cohort of critical COVID-19 survivors. METHODS: Multicenter ambispective observational study in 52 Spanish intensive care units. Up to 1327 PCR-confirmed critical COVID-19 patients had sociodemographic, anthropometric, comorbidity and lifestyle characteristics collected at hospital admission; clinical and biological parameters throughout hospital stay; and, lung function and CT scan at a follow-up visit. RESULTS: The median [p25-p75] time from discharge to follow-up was 3.57 [2.77-4.92] months. Median age was 60 [53-67] years, 27.8% women. The mean (SD) percentage of predicted diffusing lung capacity for carbon monoxide (DLCO) at follow-up was 72.02 (18.33)% predicted, with 66% of patients having DLCO<80% and 24% having DLCO<60%. CT scan showed persistent pulmonary infiltrates, fibrotic lesions, and emphysema in 33%, 25% and 6% of patients, respectively. Key variables associated with DLCO<60% were chronic lung disease (CLD) (OR: 1.86 (1.18-2.92)), duration of invasive mechanical ventilation (IMV) (OR: 1.56 (1.37-1.77)), age (OR [per-1-SD] (95%CI): 1.39 (1.18-1.63)), urea (OR: 1.16 (0.97-1.39)) and estimated glomerular filtration rate at ICU admission (OR: 0.88 (0.73-1.06)). Bacterial pneumonia (1.62 (1.11-2.35)) and duration of ventilation (NIMV (1.23 (1.06-1.42), IMV (1.21 (1.01-1.45)) and prone positioning (1.17 (0.98-1.39)) were associated with fibrotic lesions. CONCLUSION: Age and CLD, reflecting patients' baseline vulnerability, and markers of COVID-19 severity, such as duration of IMV and renal failure, were key factors associated with impaired DLCO and CT abnormalities.

Life Cycle and Biometric Study of Hydrotaea capensis (Wiedemann, 1818) (Diptera, Muscidae), a Species of Forensic Interest.

One of the most important and perhaps most used applications of forensic entomology concerns the estimation of the minimum post-mortem interval (minPMI), defined as the time interval between death and the actual finding of a corpse. Some Diptera species are critical in these studies because they are the first ones capable of detecting and finding a corpse and are selectively attracted by its decomposing status. Thus, the knowledge of the micromorphology of their preimaginal stages and of their life cycles within a time frame constitutes solid indicators for estimating the minPMI. Hydrotaea capensis is a Muscidae of forensic interest usually considered as a late colonizer of corpses. It is widely distributed, living mainly in warm regions, and present in a wide variety of habitats. In this study, the H. capensis life cycle was studied at four constant temperatures, 18°, 20°, 25° and 30 °C, by recording the duration of its different developmental stages, including the length reached in each larval stage, as well as some biometric characteristics of the emerged adults. Significant differences were observed in the average time of development of most larval stages, with a longer duration at low temperatures, and in the length of each larval stage depending on the temperature, but, in this case, without a clear pattern. Moreover, significant differences were found in some alar features, pointing to them as a relevant indicator to be considered. The data provided will assist forensic entomologists to make more accurate minPMI estimations in cases where H. capensis is present.

Density thresholds and the incorporation of biocontrol into decision-making to enhance the control of Cacopsylla pyri in pear (cv. Ercolini) orchards.

BACKGROUND: Economic injury level (EIL) and economic threshold (ET) are customary tools for integrated pest management. Cacopsylla pyri L. is a major pest in pear orchards. The aim of this work was to establish EIL and ET for the optimization of the use of insecticides to control this psyllid, considering biocontrol and two spraying strategies (low-toxicity versus broad spectrum chemicals). This research was conducted over 4 years in five commercial pear, cv. Ercolini, orchards in south-eastern Spain. RESULTS: Psyllids and ant populations were followed using periodic sampling, and the russet on fruits was quantified. The effect of spray intensity and ant exclusion on psyllid abundance and yield were also tested: both had a significant effect on the cumulative number of C. pyri (CNP), yield and fruit weight. Yield was found to be negatively correlated with CNP. The russet index (RI) increased in a sigmoidal fashion as a function of CNP, being significantly higher with than without ant exclusion. The commercial categorization of fruits was explained satisfactorily as a function of CNP and the cumulative number of ants (CNA). The quantitative EIL was established at a CNP of 427.2 for spraying with paraffinic oil and 425.7 for abamectin. As for the cosmetic EIL, when CNA was zero, this EIL was 24.2, at a CNP of 16.6 for spraying with paraffinic oil or abamectin. CONCLUSIONS: The use of products of low toxicity, for the conservation of ants, is expected to increase ET and, thus, reduce the intensity of spraying. © 2021 Society of Chemical Industry.

Clinical and pathological features of Merkel cell carcinoma: A 4-year follow-up observational retrospective study in Spain.

BACKGROUND: Merkel cell carcinoma (MCC) is a malignant skin cancer with a 5-year survival rate of approximately 50%. Knowledge of MCC has increased in recent years mostly due to improved diagnosis techniques. In Spain there is lack of information regarding the incidence and tumour characteristics, and the treatment approaches are not standardised. The objective of this study was to provide information of the clinical and epidemiological characteristics of MCC patients in Spain. METHODS: Retrospective, observational study involving 192 patients from 25 Spanish hospitals. Evaluated variables included overall survival and incidence rate of Merkel cell polyomavirus, in patients diagnosed from 2012 to 2016. RESULTS: The Spanish incidence rate was estimated 0.32/100,000 inhabitants/year, with variations according to geographical regions, being slightly higher in areas with greater sunlight exposure. In total, 61.5% of tumours showed expansive growth (progressive growth of the tumour), 78.6% showed localisation in UV-exposed skin. 97.4% of patients were diagnosed by excisional biopsy. Surgery was the first line treatment in 96.6% of patients, radiotherapy in 24.6%, and chemotherapy in 6.3%. These treatments were not mutually exclusive. Median overall survival was 38.3 months (78.4% at 12 months and 60% at 24 months). MCPyV was present in 33.8% of patients. CONCLUSION: The incidence of MCC in Spain is one of the highest in Europe, with a slight predominance in men. The sample has shown that a biopsy is available for diagnosis in most cases. Moreover, the treatment is surgical when the tumour is localized and is associated with lymphadenectomy, and/or it is radiotherapy if widespread.

Prognostic implications of comorbidity patterns in critically ill COVID-19 patients: A multicenter, observational study.

Background: The clinical heterogeneity of COVID-19 suggests the existence of different phenotypes with prognostic implications. We aimed to analyze comorbidity patterns in critically ill COVID-19 patients and assess their impact on in-hospital outcomes, response to treatment and sequelae. Methods: Multicenter prospective/retrospective observational study in intensive care units of 55 Spanish hospitals. 5866 PCR-confirmed COVID-19 patients had comorbidities recorded at hospital admission; clinical and biological parameters, in-hospital procedures and complications throughout the stay; and, clinical complications, persistent symptoms and sequelae at 3 and 6 months. Findings: Latent class analysis identified 3 phenotypes using training and test subcohorts: low-morbidity (n=3385; 58%), younger and with few comorbidities; high-morbidity (n=2074; 35%), with high comorbid burden; and renal-morbidity (n=407; 7%), with chronic kidney disease (CKD), high comorbidity burden and the worst oxygenation profile. Renal-morbidity and high-morbidity had more in-hospital complications and higher mortality risk than low-morbidity (adjusted HR (95% CI): 1.57 (1.34-1.84) and 1.16 (1.05-1.28), respectively). Corticosteroids, but not tocilizumab, were associated with lower mortality risk (HR (95% CI) 0.76 (0.63-0.93)), especially in renal-morbidity and high-morbidity. Renal-morbidity and high-morbidity showed the worst lung function throughout the follow-up, with renal-morbidity having the highest risk of infectious complications (6%), emergency visits (29%) or hospital readmissions (14%) at 6 months (p<0.01). Interpretation: Comorbidity-based phenotypes were identified and associated with different expression of in-hospital complications, mortality, treatment response, and sequelae, with CKD playing a major role. This could help clinicians in day-to-day decision making including the management of post-discharge COVID-19 sequelae. Funding: ISCIII, UNESPA, CIBERES, FEDER, ESF.

Major candidate variables to guide personalised treatment with steroids in critically ill patients with COVID-19: CIBERESUCICOVID study.

PURPOSE: Although there is evidence supporting the benefits of corticosteroids in patients affected with severe coronavirus disease 2019 (COVID-19), there is little information related to their potential benefits or harm in some subgroups of patients admitted to the intensive care unit (ICU) with COVID-19. We aim to investigate to find candidate variables to guide personalized treatment with steroids in critically ill patients with COVID-19. METHODS: Multicentre, observational cohort study including consecutive COVID-19 patients admitted to 55 Spanish ICUs. The primary outcome was 90-day mortality. Subsequent analyses in clinically relevant subgroups by age, ICU baseline illness severity, organ damage, laboratory findings and mechanical ventilation were performed. High doses of corticosteroids (≥ 12 mg/day equivalent dexamethasone dose), early administration of corticosteroid treatment (< 7 days since symptom onset) and long term of corticosteroids (≥ 10 days) were also investigated. RESULTS: Between February 2020 and October 2021, 4226 patients were included. Of these, 3592 (85%) patients had received systemic corticosteroids during hospitalisation. In the propensity-adjusted multivariable analysis, the use of corticosteroids was protective for 90-day mortality in the overall population (HR 0.77 [0.65-0.92], p = 0.003) and in-hospital mortality (SHR 0.70 [0.58-0.84], p < 0.001). Significant effect modification was found after adjustment for covariates using propensity score for age (p = 0.001 interaction term), Sequential Organ Failure Assessment (SOFA) score (p = 0.014 interaction term), and mechanical ventilation (p = 0.001 interaction term). We observed a beneficial effect of corticosteroids on 90-day mortality in various patient subgroups, including those patients aged ≥ 60 years; those with higher baseline severity; and those receiving invasive mechanical ventilation at ICU admission. Early administration was associated with a higher risk of 90-day mortality in the overall population (HR 1.32 [1.14-1.53], p < 0.001). Long-term use was associated with a lower risk of 90-day mortality in the overall population (HR 0.71 [0.61-0.82], p < 0.001). No effect was found regarding the dosage of corticosteroids. Moreover, the use of corticosteroids was associated with an increased risk of nosocomial bacterial pneumonia and hyperglycaemia. CONCLUSION: Corticosteroid in ICU-admitted patients with COVID-19 may be administered based on age, severity, baseline inflammation, and invasive mechanical ventilation. Early administration since symptom onset may prove harmful.

Methodology of a Large Multicenter Observational Study of Patients with COVID-19 in Spanish Intensive Care Units.

INTRODUCTION: The COVID-19 pandemic created tremendous challenges for health-care systems. Intensive care units (ICU) were hit with a large volume of patients requiring ICU admission, mechanical ventilation, and other organ support with very high mortality. The Centro de Investigación Biomédica en Red-Enfermedades Respiratorias (CIBERES), a network of Spanish researchers to investigate in respiratory disease, commissioned the current proposal in response to the Instituto de Salud Carlos III (ISCIII) call. METHODS: CIBERESUCICOVID is a multicenter, observational, prospective/retrospective cohort study of patients with COVID-19 admitted to Spanish ICUs. Several work packages were created, including study population and ICU data collection, follow-up, biomarkers and miRNAs, data management and quality. RESULTS: This study included 6102 consecutive patients admitted to 55 ICUs homogeneously distributed throughout Spain and the collection of blood samples from more than 1000 patients. We enrolled a large population of COVID-19 ICU-admitted patients including baseline characteristics, ICU and MV data, treatments complications, and outcomes. The in-hospital mortality was 31%, and 76% of patients required invasive mechanical ventilation. A 3-6 month and 1 year follow-up was performed. Few deaths after 1 year discharge were registered. Low anti-SARS-CoV-2 S antibody levels predict mortality in critical COVID-19. These antibodies contribute to prevent systemic dissemination of SARS-CoV-2. The severity of COVID-19 impacts the circulating miRNA profile. Plasma miRNA profiling emerges as a useful tool for risk-based patient stratification in critically ill COVID-19 patients. CONCLUSIONS: We present the methodology used in a large multicenter study sponsored by ISCIII to determine the short- and long-term outcomes in patients with COVID-19 admitted to more than 50 Spanish ICUs.

Outcome of small invasive breast cancer with no axillary lymph node involvement.

The prognosis and need or not for adjuvant therapy in patients with small breast tumors (≤1cm N0) is the subject of controversy as regards the clinical benefit obtained, toxicity, and the economical costs generated. A retrospective analysis was made of 238 patients with early-stage breast cancer (pT1≤1 cm N0M0) diagnosed between January 1993 and May 2008. As regards the systemic adjuvant treatments provided, (a) 122 (51%) received no treatment, (b) 102 (43%) received hormone therapy, (c) 9 (4%) chemotherapy, and (d) 5 (2%) received both hormone therapy and chemotherapy. An analysis was made of disease-free survival (DFS) and breast cancer-specific survival in our series of patients, and of their correlation to clinicopathological factors (age, tumor size, histological grade, estrogen receptor (ER) expression, HER-2 overexpression, and systemic adjuvant therapy). The median follow-up of this cohort was 63months (range 5-145). Some type of relapse was recorded in 4.2% of the patients (six patients presented local recurrence in all cases subjected to rescue treatment with surgery and/or radiotherapy, three patients developed distant metastases, and one patient presented a resected local recurrence followed by systemic relapse). The 5year DFS was 96%, and the 5year breast cancer-specific survival was 99.6%. A univariate analysis was made of the clinicopathological variables and their association to DFS. None of the variables was seen to be significantly correlated to shorter DSF except for an association between HER-2 overexpression and poor outcome borderline significance (p=0.07). The prognosis of our pT1≤1cm N0M0 tumors was excellent, although the absence of systemic adjuvant therapy in one-half of the patients.