Major adverse cardiovascular events are associated with necroptosis during severe COVID-19.

BACKGROUND: The mechanisms used by SARS-CoV-2 to induce major adverse cardiac events (MACE) are unknown. Thus, we aimed to determine if SARS-CoV-2 can induce necrotic cell death to promote MACE in patients with severe COVID-19. METHODS: This observational prospective cohort study includes experiments with hamsters and human samples from patients with severe COVID-19. Cytokines and serum biomarkers were analysed in human serum. Cardiac transcriptome analyses were performed in hamsters' hearts. RESULTS: From a cohort of 70 patients, MACE was documented in 26% (18/70). Those who developed MACE had higher Log copies/mL of SARS-CoV-2, troponin-I, and pro-BNP in serum. Also, the elevation of IP-10 and a major decrease in levels of IL-17ɑ, IL-6, and IL-1rɑ were observed. No differences were found in the ability of serum antibodies to neutralise viral spike proteins in pseudoviruses from variants of concern. In hamster models, we found a stark increase in viral titters in the hearts 4 days post-infection. The cardiac transcriptome evaluation resulted in the differential expression of ~ 9% of the total transcripts. Analysis of transcriptional changes in the effectors of necroptosis (mixed lineage kinase domain-like, MLKL) and pyroptosis (gasdermin D) showed necroptosis, but not pyroptosis, to be elevated. An active form of MLKL (phosphorylated MLKL, pMLKL) was elevated in hamster hearts and, most importantly, in the serum of MACE patients. CONCLUSION: SARS-CoV-2 identification in the systemic circulation is associated with MACE and necroptosis activity. The increased pMLKL and Troponin-I indicated the occurrence of necroptosis in the heart and suggested necroptosis effectors could serve as biomarkers and/or therapeutic targets. Trial registration Not applicable.

Early Desaturation During 6-Minute Walk Test is a Predictor of Mortality in COPD.

BACKGROUND: Oxygen desaturation during exercise is mainly observed in severe cases of chronic obstructive pulmonary disease (COPD) and is associated with a worse prognosis, but little is known about the type of desaturation that causes the greatest risk of mortality. MATERIAL AND METHODS: We studied all of the 6-min walk tests performed periodically at a tertiary hospital over a period of 12 years in patients with moderate or severe COPD. We classified patients as non-desaturators if they did not suffer a drop in oxygen saturation (SpO2 < 88%) during the test, early desaturators if the time until desaturation was < 1 min, and non-early desaturators if it was longer than 1 min. The average length of follow-up per patient was 5.6 years. RESULTS: Of the 319 patients analyzed, 126 non-desaturators, 91 non-early desaturators and 102 early desaturators were identified. The mortality analysis showed that early desaturators had a mortality of 73%, while it was 38% for non-early desaturators and 28% for non-desaturators, with a survival of 5.9 years compared to 7.5 years and 9.6 years, respectively (hazard ratio of 3.50; 95% CI 2.3-5.3; p < 0.0001). CONCLUSIONS: The early desaturation seen in patients with chronic obstructive pulmonary disease is associated with greater mortality and is likely responsible for the poor prognosis shown globally in patients who desaturate. The survival of patients with early desaturation is almost 4 years less with respect to non-desaturators, and they, thus, require closer observation.

Psychosocial impact of the COVID-19 pandemic on patients with inflammatory bowel disease in Spain. A post lockdown reflection.

OBJECTIVES: This multicenter cross-sectional study was conducted to assess the psychosocial impact of COVID-19 on patients with inflammatory bowel disease (IBD) in Spain during lockdown and the first wave of the pandemic. PATIENTS AND METHODS: A self-report questionnaire that integrated the Spanish version of the Depression, Anxiety and Stress Scale-21 items (DASS-21) and the Perceived Stress Questionnaire (PSS) was designed to gather sociodemographic data and information related to the effects of lockdown on the lives of IBD patients. Twelve IBD units invited their patients to answer the anonymous online survey between the 1st July and the 25th August 2020. RESULTS: Of the 693 survey participants with IBD, 67% were women and the mean age was 43 (SD 12). Sixty-one percent had ulcerative colitis, 36% Crohn's disease and 3% indeterminate colitis. DASS-21 scores indicate that during lockdown the estimated prevalence of depression was 11% [95% CI 8.2-13%], anxiety 20% [95% CI 17 to 23%] and stress 18% [95% CI 8.2-13%]. Multivariate analysis showed that the perceived high risk of COVID-19 infection because of having IBD and maladaptation to government measures to reduce the spread of disease doubled the risk of anxiety and stress during lockdown. CONCLUSIONS: In the short-term, lockdown during the COVID-19 pandemic seemed to have an impact on the already affected mental health of our IBD patients in Spain.

Genome-wide association study of asthma exacerbations despite inhaled corticosteroid use.

RATIONALE: Substantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among individuals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies. METHODS: A genome-wide association study (GWAS) of asthma exacerbations was tested in 2681 children of European descent treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed. RESULTS: 10 independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10-6). Of those, one variant at the CACNA2D3-WNT5A locus was nominally replicated in Europeans (rs67026078; p=0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found. CONCLUSIONS: The intergenic region of CACNA2D3 and WNT5A was revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response.

Efficacy of Human Papillomavirus Vaccination 4 Years After Conization for High-Grade Cervical Neoplasia.

OBJECTIVE: The aim of the study was to estimate human papillomavirus (HPV) vaccination efficacy in reducing recurrence risk within 4 years after conization for high-grade cervical neoplasia. MATERIALS AND METHODS: From January 2012 to June 2015, we performed a longitudinal, observational study (case-series study) on patients diagnosed with cervical intraepithelial neoplasia 2-3 neoplasia. Efficacy was estimated by a 95% CI of the relative risk, relative risk reduction, attributable risk, and number needed to treat. Parametric and nonparametric tests were used as appropriate to compare 160 vaccinated with 171 nonvaccinated patients. To estimate the hazard ratio of the vaccinated status, patients were subjected to multivariable analyses based on the Cox proportional hazard model. To compare recurrence-free survival, a Kaplan-Meier model and a log-rank test were applied. RESULTS: The overall recurrence was 9.4% in the nonvaccinated and 2.5% in the vaccinated group (p = .009). Vaccination was associated with a significant decrease in the relative risk (73.5%, 95% CI = 21.8%-90.9%) with a mean number needed to treat of 14 patients per relapse prevented. Although positive conization margins were related to the highest recurrence risk, not being vaccinated independently increased this risk 3.5-fold in a 4-year follow-up (p = .025). Cumulative recurrence-free rates differed significantly between both groups (log-rank test: p = .009). CONCLUSIONS: Our study corroborates the benefits of HPV vaccination, recommends a closer and longer follow-up in nonvaccinated women, and offers a 4-year prognosis for patients undergoing conization for high-grade cervical lesions.

Functional Heterologous Expression of Mature Lipase LipA from Pseudomonas aeruginosa PSA01 in Escherichia coli SHuffle and BL21 (DE3): Effect of the Expression Host on Thermal Stability and Solvent Tolerance of the Enzyme Produced.

This study aimed to express heterologously the lipase LipA from Pseudomonas aeruginosa PSA01 obtained from palm fruit residues. In previous approaches, LipA was expressed in Escherichia coli fused with its signal peptide and without its disulfide bond, displaying low activity. We cloned the mature LipA with its truncated chaperone Lif in a dual plasmid and overexpressed the enzyme in two E. coli strains: the traditional BL21 (DE3) and the SHuffle® strain, engineered to produce stable cytoplasmic disulfide bonds. We evaluated the effect of the disulfide bond on LipA stability using molecular dynamics. We expressed LipA successfully under isopropyl ß-d-1-thio-galactopyranoside (IPTG) and slow autoinducing conditions. The SHuffle LipA showed higher residual activity at 45 °C and a greater hyperactivation after incubation with ethanol than the enzyme produced by E. coli BL21 (DE3). Conversely, the latter was slightly more stable in methanol 50% and 60% (t½: 49.5 min and 9 min) than the SHuffle LipA (t½: 31.5 min and 7.4 min). The molecular dynamics simulations showed that removing the disulfide bond caused some regions of LipA to become less flexible and some others to become more flexible, significantly affecting the closing lid and partially exposing the active site at all times.

Genome-wide association study of inhaled corticosteroid response in admixed children with asthma.

BACKGROUND: Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome-wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response. OBJECTIVE: We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings. METHODS: A meta-analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10-6 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations. RESULTS: A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10-6 ). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10-3 ) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10-3 ). Additionally, the reported association of the L3MBTL4-ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified. CONCLUSIONS AND CLINICAL RELEVANCE: This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.

The COPD Comorbidome in the Light of the Degree of Dyspnea and Risk of Exacerbation.

The BODE group designed a bubble chart, analogous to the solar system, which depicts the prevalence of each disease and its association with mortality and called it a "comorbidome". Although this graph was used to represent mortality and, later, the risk of needing hospital admission, it was not applied to visualize the association between a set of comorbidities and the categories of the GOLD 2017 guidelines, neither according to the degree of dyspnea nor to the risk of exacerbation. For the purpose of knowing to which extent each comorbidity associates with each of the two conditions-most symptomatic group (groups B and D) and highest risk of exacerbation (groups C and D)-we performed a analysis based on the comorbidome. 439 patients were included. Cardiovascular comorbidity (especially cardiac and renal disease) is predominantly observed in patients with a higher degree of dyspnea, whereas bronchial asthma and stroke occur more frequently in subjects at higher risk of exacerbation. This is the first time that the comorbidome is presented based on the categories of the GOLD 2017 document, which we hope will serve as a stimulus for scientific debate.

Health Status in Patients with COPD According to GOLD 2017 Classification: Use of the COMCOLD Score in Routine Clinical Practice.

The COMCOLD score was developed to quantify the impact of comorbidities on health status in patients with chronic obstructive pulmonary disease (COPD). The objective of this study is to evaluate the association between health status in outpatients with COPD according to COMCOLD score and the GOLD 2017 groups according to symptoms (B and D vs. A and C) and exacerbations (C and D vs. A and B). 439 patients were included. The average score was 2.4 ± 3. 48% of cases had a COMCOLD score >0. The most symptomatic patients (B and D vs. A and C) had a higher score: 3 ± 3.3 vs. 1.3 ± 2.1 (p < 0.001), in contrast with the groups with a higher risk of exacerbation (C and D vs. A and B) in which there was no significant difference: 3 ± 3.5 vs. 2.2 ± 3.0 (p = 0.055). The most symptomatic patients (B and D) showed a greater prevalence of depression, peripheral artery disease and heart disease with an adjusted OR of 3.04 [CI95%: 1.36; 6.86], 2.49 [CI95%: 1.17; 5.29], and 4.41 [CI95%: 2.50; 7.75], respectively. Moreover, no relationship was found between the comorbidities defined by the COMCOLD score and the GOLD 2017 groups with the greatest risk of exacerbation (C and D). The greatest effect on health status was found in those patients with COPD belonging to the most symptomatic groups (B and D), with depression, peripheral artery disease, and heart disease being the main comorbidities involved.

A Quantile Analysis of Plateau and Driving Pressures: Effects on Mortality in Patients With Acute Respiratory Distress Syndrome Receiving Lung-Protective Ventilation.

OBJECTIVES: The driving pressure (plateau pressure minus positive end-expiratory pressure) has been suggested as the major determinant for the beneficial effects of lung-protective ventilation. We tested whether driving pressure was superior to the variables that define it in predicting outcome in patients with acute respiratory distress syndrome. DESIGN: A secondary analysis of existing data from previously reported observational studies. SETTING: A network of ICUs. PATIENTS: We studied 778 patients with moderate to severe acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed the risk of hospital death based on quantiles of tidal volume, positive end-expiratory pressure, plateau pressure, and driving pressure evaluated at 24 hours after acute respiratory distress syndrome diagnosis while ventilated with standardized lung-protective ventilation. We derived our model using individual data from 478 acute respiratory distress syndrome patients and assessed its replicability in a separate cohort of 300 acute respiratory distress syndrome patients. Tidal volume and positive end-expiratory pressure had no impact on mortality. We identified a plateau pressure cut-off value of 29 cm H2O, above which an ordinal increment was accompanied by an increment of risk of death. We identified a driving pressure cut-off value of 19 cm H2O where an ordinal increment was accompanied by an increment of risk of death. When we cross tabulated patients with plateau pressure less than 30 and plateau pressure greater than or equal to 30 with those with driving pressure less than 19 and driving pressure greater than or equal to 19, plateau pressure provided a slightly better prediction of outcome than driving pressure in both the derivation and validation cohorts (p < 0.0000001). CONCLUSIONS: Plateau pressure was slightly better than driving pressure in predicting hospital death in patients managed with lung-protective ventilation evaluated on standardized ventilator settings 24 hours after acute respiratory distress syndrome onset.

Age, PaO2/FIO2, and Plateau Pressure Score: A Proposal for a Simple Outcome Score in Patients With the Acute Respiratory Distress Syndrome.

OBJECTIVES: Although there is general agreement on the characteristic features of the acute respiratory distress syndrome, we lack a scoring system that predicts acute respiratory distress syndrome outcome with high probability. Our objective was to develop an outcome score that clinicians could easily calculate at the bedside to predict the risk of death of acute respiratory distress syndrome patients 24 hours after diagnosis. DESIGN: A prospective, multicenter, observational, descriptive, and validation study. SETTING: A network of multidisciplinary ICUs. PATIENTS: Six-hundred patients meeting Berlin criteria for moderate and severe acute respiratory distress syndrome enrolled in two independent cohorts treated with lung-protective ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Using individual demographic, pulmonary, and systemic data at 24 hours after acute respiratory distress syndrome diagnosis, we derived our prediction score in 300 acute respiratory distress syndrome patients based on stratification of variable values into tertiles, and validated in an independent cohort of 300 acute respiratory distress syndrome patients. Primary outcome was in-hospital mortality. We found that a 9-point score based on patient's age, PaO2/FIO2 ratio, and plateau pressure at 24 hours after acute respiratory distress syndrome diagnosis was associated with death. Patients with a score greater than 7 had a mortality of 83.3% (relative risk, 5.7; 95% CI, 3.0-11.0), whereas patients with scores less than 5 had a mortality of 14.5% (p < 0.0000001). We confirmed the predictive validity of the score in a validation cohort. CONCLUSIONS: A simple 9-point score based on the values of age, PaO2/FIO2 ratio, and plateau pressure calculated at 24 hours on protective ventilation after acute respiratory distress syndrome diagnosis could be used in real time for rating prognosis of acute respiratory distress syndrome patients with high probability.

A clinical classification of the acute respiratory distress syndrome for predicting outcome and guiding medical therapy*.

OBJECTIVE: Current in-hospital mortality of the acute respiratory distress syndrome (ARDS) is above 40%. ARDS outcome depends on the lung injury severity within the first 24 hours of ARDS onset. We investigated whether two widely accepted cutoff values of PaO2/FIO2 and positive end-expiratory pressure (PEEP) would identify subsets of patients with ARDS for predicting outcome and guiding therapy. DESIGN: A 16-month (September 2008 to January 2010) prospective, multicenter, observational study. SETTING: Seventeen multidisciplinary ICUs in Spain. PATIENTS: We studied 300 consecutive, mechanically ventilated patients meeting American-European Consensus Conference criteria for ARDS (PaO2/FIO2 ≤ 200 mm Hg) on PEEP greater than or equal to 5 cm H2O, and followed up until hospital discharge. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Based on threshold values for PaO2/FIO2 (150 mm Hg) and PEEP (10 cm H2O) at ARDS onset and at 24 hours, we assigned patients to four categories: group I (PaO2/FIO2 ≥ 150 on PEEP < 10), group II (PaO2/FIO2 ≥ 150 on PEEP ≥ 10), group III (PaO2/FIO2 < 150 on PEEP < 10), and group IV (PaO2/FIO2 < 150 on PEEP ≥ 10). The primary outcome was all-cause in-hospital mortality. Overall hospital mortality was 46.3%. Although at study entry, patients with PaO2/FIO2 less than 150 had a higher mortality than patients with a PaO2/FIO2 greater than or equal to 150 (p = 0.044), there was minimal variability in mortality among the four groups (p = 0.186). However, classification of patients in each group changed markedly after 24 hours of usual care. Group categorization at 24 hours provided a strong association with in-hospital mortality (p < 0.00001): group I had the lowest mortality (23.1%), whereas group IV had the highest mortality (60.3%). CONCLUSIONS: The degree of lung dysfunction established by a PaO2/FIO2 of 150 mm Hg and a PEEP of 10 cm H2O demonstrated that ARDS is not a homogeneous disorder. Rather, it is a series of four subsets that should be considered for enrollment in clinical trials and for guiding therapy. A major contribution of our study is the distinction between survival after 24 hours of care versus survival at the time of ARDS onset.

Common variants of NFE2L2 gene predisposes to acute respiratory distress syndrome in patients with severe sepsis.

INTRODUCTION: The purpose of this study was to investigate whether common variants across the nuclear factor erythroid 2-like 2 (NFE2L2) gene contribute to the development of the acute respiratory distress syndrome (ARDS) in patients with severe sepsis. NFE2L2 is involved in the response to oxidative stress, and it has been shown to be associated with the development of ARDS in trauma patients. METHODS: We performed a case-control study of 321 patients fulfilling international criteria for severe sepsis and ARDS who were admitted to a Spanish network of post-surgical and critical care units, as well as 871 population-based controls. Six tagging single-nucleotide polymorphisms (SNPs) of NFE2L2 were genotyped, and, after further imputation of additional 34 SNPs, association testing with ARDS susceptibility was conducted using logistic regression analysis. RESULTS: After multiple testing adjustments, our analysis revealed 10 non-coding SNPs in tight linkage disequilibrium (0.75 ≤ r (2) ≤ 1) that were associated with ARDS susceptibility as a single association signal. One of those SNPs (rs672961) was previously associated with trauma-induced ARDS and modified the promoter activity of the NFE2L2 gene, showing an odds ratio of 1.93 per T allele (95 % confidence interval, 1.17-3.18; p = 0.0089). CONCLUSIONS: Our findings support the involvement of NFE2L2 gene variants in ARDS susceptibility and reinforce further exploration of the role of oxidant stress response as a risk factor for ARDS in critically ill patients.

Does the new staging system proposed for mycosis fungoides and Sézary syndrome provide reliable agreement for T1 and T2 disease?

BACKGROUND: Patch or plaque stages in mycosis fungoides (MF) have different prognoses. The recent staging system proposed for MF discriminates between patches and plaques based upon clinical features. OBJECTIVE: To estimate interdermatologist agreement on the morphological evaluation of MF lesions. METHODS: Twenty-four patients with MF were enrolled. Two dermatologists evaluated every lesion face to face and independently with respect to the patch-plaque status. Cohen's κ was used to determine the rate of agreement. RESULTS: Agreement was 67% with respect to the patch or plaque status [95% confidence interval (CI) = 49-85%; p < 0.001]. Current systemic treatment (56%; p = 0.01) was associated with lower agreement. Younger age at diagnosis [odds ratio (OR) 1.03 (95% CI 1.02-1.05)], younger age at enrolment [OR 1.03 (95% CI 1.02-1.04)] and time on systemic treatment [OR 1.02 (95% CI 1.01-1.04)] were independent risk factors for disagreement (p < 0.001). CONCLUSION: The new system for MF staging carries a significant risk of disagreement regarding patch and plaque subsets.

Molecular characterization and descriptive analysis of carbapenemase-producing Gram-negative rod infections in Bogota, Colombia.

In this study, the genetic differences and clinical impact of the carbapenemase-encoding genes among the community and healthcare-acquired infections were assessed. This retrospective, multicenter cohort study was conducted in Colombia and included patients infected with carbapenem-resistant Gram-negative rods between 2017 and 2021. Carbapenem resistance was identified by Vitek, and carbapenemase-encoding genes were identified by whole-genome sequencing (WGS) to classify the alleles and sequence types (STs). Descriptive statistics were used to determine the association of any pathogen or gene with clinical outcomes. A total of 248 patients were included, of which only 0.8% (2/248) had community-acquired infections. Regarding the identified bacteria, the most prevalent pathogens were Pseudomonas aeruginosa and Klebsiella pneumoniae. In the WGS analysis, 228 isolates passed all the quality criteria and were analyzed. The principal carbapenemase-encoding gene was blaKPC, specifically blaKPC-2 [38.6% (88/228)] and blaKPC-3 [36.4% (83/228)]. These were frequently detected in co-concurrence with blaVIM-2 and blaNDM-1 in healthcare-acquired infections. Notably, the only identified allele among community-acquired infections was blaKPC-3 [50.0% (1/2)]. In reference to the STs, 78 were identified, of which Pseudomonas aeruginosa ST111 was mainly related to blaKPC-3. Klebsiella pneumoniae ST512, ST258, ST14, and ST1082 were exclusively associated with blaKPC-3. Finally, no particular carbapenemase-encoding gene was associated with worse clinical outcomes. The most identified genes in carbapenemase-producing Gram-negative rods were blaKPC-2 and blaKPC-3, both related to gene co-occurrence and diverse STs in the healthcare environment. Patients had several systemic complications and poor clinical outcomes that were not associated with a particular gene.IMPORTANCEAntimicrobial resistance is a pandemic and a worldwide public health problem, especially carbapenem resistance in low- and middle-income countries. Limited data regarding the molecular characteristics and clinical outcomes of patients infected with these bacteria are available. Thus, our study described the carbapenemase-encoding genes among community- and healthcare-acquired infections. Notably, the co-occurrence of carbapenemase-encoding genes was frequently identified. We also found 78 distinct sequence types, of which two were novel Pseudomonas aeruginosa, which could represent challenges in treating these infections. Our study shows that in low and middle-income countries, such as Colombia, the burden of carbapenem resistance in Gram-negative rods is a concern for public health, and regardless of the allele, these infections are associated with poor clinical outcomes. Thus, studies assessing local epidemiology, prevention strategies (including trials), and underpinning genetic mechanisms are urgently needed, especially in low and middle-income countries.

Comparative study of weekly and three-weekly neoadjuvant carboplatin in triple-negative breast cancer: retrospective analysis in real-world settings.

PURPOSE: Tri-weekly carboplatin is an established neoadjuvant treatment for triple-negative breast cancer, enhancing pathological complete response (pCR) and overall survival. This study explores if weekly carboplatin provides lower toxicity and comparable pCR rates. METHODS/PATIENTS: A retrospective multicenter study (January 2021 to March 2023) compares outcomes of weekly and tri-weekly carboplatin. RESULTS: Among 104 participants, 60% received weekly and 40% tri-weekly treatments. Weekly administration had fewer discontinuations (56.5 vs. 70.7%, p = 0.154). Both schedules exhibited similar overall toxicity (p = 0.087), with slightly higher grade 3-4 toxicity in the tri-weekly group (56.1 vs. 48.4%, p = 0.126). Hematological toxicity was comparable, but the weekly group experienced more diarrhea (p = 0.432) and asthenia (p = 0.012). Weekly treatment correlated with more frequent breast-conserving surgeries (p = 0.004). pCR rates were 50% with weekly and 61% with tri-weekly regimens (p = 0.186). CONCLUSIONS: Weekly carboplatin exhibited comparable toxicity, a trend toward fewer interruptions, and similar pCR rates. Prospective studies are essential for validating these findings.

Improving the Gleason grading accuracy of transrectal ultrasound-guided biopsy.

BACKGROUND: Transrectal ultrasound (TRUS)-guided prostate biopsy is the technique of choice for the assessment of clinical suspicion of prostate cancer (PC) based on abnormal digital rectal examination (DRE) and/or elevated or rising levels of prostate-specific antigen (PSA). PURPOSE: To identify factors involved in TRUS-guided prostate biopsy, which can be modified by radiologists in order to improve Gleason score (GS) accuracy, and to assess the influence of clinical variables. MATERIAL AND METHODS: We carried out a retrospective review of the records of 185 patients with PC treated surgically at our hospital between 2005 and 2008. Biopsy schemes were classified according to the number of cores (≤7, 8-9, 10-11, 12-15) and the needle length (11, 16, 20 mm). Clinical characteristics - age, family history of PC, DRE, PSA levels, and sonographic data - and prostatectomy GS (pGS) were collected. RESULTS: Non-random concordance between biopsy Gleason score (bGS) and pGS was obtained for 36% of patients (P < 0.001). Under- and over-staging were 30% and 4%, respectively. Concordance was correlated with the core number (45% for ≤7, 54% for 8-9, 85% for 10-11, and 80% for 12-15; P < 0.001), but not with the needle length. The concordance rate showed a seven-fold increase when 10-11 cores were obtained (95% CI, 2-18; P < 0.001) compared to those cases in which the core number obtained was ≤7. Among clinical variables, only PSA correlated with concordance, showing an inverse relationship. CONCLUSION: The Gleason correlation values were not improved when 12 or more cores were collected. These values reached a plateau beyond that number of samples. Therefore, when determining treatment strategies, physicians must consider the biopsy scheme used since it has proven to be a predictor of the accuracy of the PC grading system.

Can Achilles tendinosis be treated effectively with lidocaine and glucose infiltrations, and if so, is the effect lasting? A longitudinal, observational on 27 consecutive patients.

OBJECTIVE: Our aim was to add to the small but growing body of evidence on the effectiveness of ultrasound-guided Achilles intratendinous hyperosmolar dextrose prolotherapy and introduce a novel, preceding step of paratenon hydrodissection with lidocaine in patients with chronic Achilles tendinosis resistant to rehabilitation therapy. METHODS: We conducted a longitudinal, observational study on 27 consecutive patients diagnosed with Achilles tendinosis, in whom conservative treatment, ie, physiotherapy or shock wave therapy, had failed. A 2% lidocaine paratenon anesthesia and hydrodissection was followed by ultrasound-guided, intratendinous injections of 25% glucose every 5 weeks. Visual analogue scales (VAS) were used for pain assessment at rest, for activities of daily living, and after moderate exercise at the begining and at the end of the treatment. Moreover, tendon thickness and vascularisation were recorded at baseline and final treatment consultation. Effectiveness was estimated from scoring and relative pain reduction using a 95% CI. The non-parametric Wilcoxon test and a general linear model for repeated measures were applied. Statistical significance was established as p < 0.05. RESULTS: A median of 5 (1-11) injection consultations per patient were required. Pain scores decreased significantly in all three conditions (p < 0.001). Relative reductions were 75% in pain at rest (95% CI;61-93%), 69% in pain with daily living activities (95% CI; 55-83%), and 70% in pain after moderate exercise (95% CI; 57-84%). Tendon neo-vascularisation was significantly reduced (p < 0.001). We did not observe significant changes in tendon thickness (p = 0.083). CONCLUSIONS: Achilles tendinosis treatment with paratenon lidocaine hydrodissection and subsequent prolotherapy with hyperosmolar glucose solution is safe, effective, inexpensive, and virtually painless with results maintained over time.

Necroptosis Drives Major Adverse Cardiovascular Events During Severe COVID-19.

Background The mechanisms used by SARS-CoV-2 to induce major adverse cardiac events (MACE) are unknown. Thus, we aimed to determine if SARS-CoV-2 can infect the heart to kill cardiomyocytes and induce MACE in patients with severe COVID-19. Methods This observational prospective cohort study includes experiments with hamsters and human samples from patients with severe COVID-19. Cytokines and serum biomarkers were analyzed in human serum. Cardiac transcriptome analyses were performed in hamsters' hearts. Results From a cohort of 70 patients, MACE was documented in 26% (18/70). Those who developed MACE had higher Log copies/mL of SARS-CoV-2, troponin-I, and pro-BNP in serum. Also, the elevation of IP-10 and a major decrease in levels of IL-17ɑ, IL-6, and IL-1rɑ were observed. No differences were found in the ability of serum antibodies to neutralize viral spike proteins in pseudoviruses from variants of concern. In hamster models, we found a stark increase in viral titers in the hearts 4 days post-infection. The cardiac transcriptome evaluation resulted in the differential expression of ~ 9% of the total transcripts. Analysis of transcriptional changes of the effectors of necroptosis (mixed lineage kinase domain-like, MLKL) and pyroptosis (gasdermin D) showed necroptosis, but not pyroptosis, to be elevated. Active form of MLKL (phosphorylated MLKL, pMLKL) was elevated in hamster hearts and, most importantly, in the serum of MACE patients. Conclusion SARS-CoV-2 can reach the heart during severe COVID-19 and induce necroptosis in the heart of patients with MACE. Thus, pMLKL could be used as a biomarker of cardiac damage and a therapeutic target. Trial registration: Not applicable.