Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

An old disease, a new diagnosis; A 49 year-old man with nephrotic syndrome

Background: IgG4-related disease (IgG4-RD) is a systemic immune-mediated disease that typically manifests as fibro-inflammatory masses that can affect nearly any organ system. Case Report: We present here a case of a 49-year old man with forgotten old disease (Mikulicz disease) with membranous nephropathy (MN). Conclusions: This entity is currently included within the spectrum of IgG4-related disease. The development of renal disease shortly after the suspension of rituximab suggests another probable pathway involved. To our knowledge the transforming growth factor may be responsible for existing pattern of fibrosis in this disease. The lack of response or at least partial response to rituximab can be explained by greater involvement of regulatory T lymphocyte in the pathophysiology of this entit

Analgesic dipeptide derivatives. Part 8. 3-amino-2-hydroxy-4-[2-(o- nitrophenylthio)indol-3-yl]butanoic acid [AH(NPS)IBA]-containing dipeptide analogues of the analgesic compound H-Trp(Nps)-Lys-OMe

A series of diastereoisomeric dipeptides, analogues of the analgesic compound H-Trp(Nps)-Lys-OMe, containing 3-amino-2-hydroxy-4-[2-(o- nitrophenylthio)indol-3-yl]butanoic acid [AH(Nps)IBA] and Lys or Leu has been synthesized. These compounds were tested as aminopeptidase-M and -B (AP-M and AP-B) inhibitors and as analgesics. The AH(Nps)IBA-Leu dipeptides, independently of their stereochemistry, were poor inhibitors of AP-M and AP-B, with IC 50-values in the 10-4 mol dm-3 range, while the AH(Nps)IBA-Lys derivatives were poor AP-B inhibitors, with IC 50-values also in the 10-4 mol dm-3 range, and did not inhibit AP-M up to 10-3. All the AH(Nps)IBA-Lys derivatives induced a significant dose-related analgesic activity at 1-5 μg per mouse, which was dependent on the stereochemistry, while no analgesia was observed with the corresponding Leu-containing analogues. There is no relationship between the antinociceptive effects and the AP-M inhibitory potencies of this series of compounds, indicating that the inhibition of enkephalin-degrading AP-M is not an important factor for the mode of action of this series of analgesic dipeptides.Peer Reviewe

Analgesic dipeptide derivatives. 7. 3,7-Diamino-2-hydroxyheptanoic acid (DAHHA) containing dipeptide analogues of the analgesic compound H-Lys- Trp(Nps)-OMe

A series of diastereomeric dipeptides, analogues of the analgesic compound H-Lys-Trp(Nps)-OMe (2), containing 3,7-diamino-2-hydroxyheptanoic acid (DAHHA) and 2-[(o-nitrophenyl)sulfenyl]tryptophan [Trp(Nps)] has been synthesized. These compounds were tested as enkephalin-degrading aminopeptidases (APs), AP-M and AP-B inhibitors, and analgesics. The inhibitory potencies and the antinociceptive effects depended on the stereochemistry of the compounds. (2S,3R)-DAHHA-L-Trp(Nps)-OMe (26d) was a highly potent and selective enkephalin-degrading APs inhibitor, with an IC50 value in the 10-8 M range. Although this derivative was about 103- fold more potent than 2 against these enzymes, their antinociceptive effects were completely similar. These results indicate that the inhibitory capacity of this series of Trp(Nps)-containing dipeptides against enkephalin-degrading enzymes is not an important factor for their antinociceptive effects.The present work has been sup-ported by Comisión Interministerial de Ciencia y Tecnología (Plan Nacional Project FAR88-0298)

Cardiovascular risk prediction in chronic kidney disease patients

Introduction: Scores underestimate the prediction of cardiovascular risk (CVR) as they are not validated in patients with chronic kidney disease (CKD). Two of the most commonly used scores are the Framingham Risk Score (FRS-CVD) and the ASCVD (AHA/ACC 2013). The aim of this study is to evaluate the predictive ability of experiencing a cardiovascular event (CVE) via these 2 scores in the CKD population. Material and methods: Prospective, observational study of 400 prevalent patients with CKD (stages 1–4 according the KDOQI; not on dialysis). Cardiovascular risk was calculated according to the 2 scores and the predictive capacity of cardiovascular events (atherosclerotic events:myocardial infarction, ischaemic and haemorrhagic stroke, peripheral vascular disease; and non-atherosclerotic events: heart failure) was analysed. Results: Forty-nine atherosclerotic cardiovascular events occurred in 40.3 ± 6.6 months of follow-up. Most of the patients were classified as high CVR by both scores (59% by the FRS-CVD and 75% by the ASCVD). All cardiovascular events occurred in the high CVR patients and both scores (FRS-CVD log-rank 12.2, P < 0.001, HR 3.1 [95% CI: 1.3–7.1] P: 0.006 and ASCVD log-rank 8.5 P < 0.001, HR 3.2 [95% CI: 1.1–9.4] P: 0.03) were independent predictors adjusted to renal function, albuminuria and previous cardiovascular events. Conclusion: The cardiovascular risk scores (FRS-CVD and ASCVD [AHA/ACC 2013]) can estimate the probability of atherosclerotic cardiovascular events in patients with CKD regardless of renal function, albuminuria and previous cardiovascular events

Aminopeptidase inhibitory properties and analgesic activity of (2S,3R)-3,7-diamino-2-hydroxy-heptanoic acid containing tripeptide analogues of the N-terminal tripeptide of probestin

(2S,3R)-3,7-Diamino-2-hydroxy-heptanoyl-Leu-Pro-OH [(2S,3R)-DAHHA-Leu-Pro-OH, 4], analogue of the N-terminal tripeptide of probestin, has been synthesized, and tested as inhibitor of AP-B, Leu-AP, AP-M, and enkephalin-degrading APs, and as analgesic. In order to establish structure-activity relationships the dipeptide (2S,3R)-DAHHA-Pro-OH (5) and the tripeptide (2S, 3R)-DAHHA-Ala-Pro-OH (6) were also prepared. Compounds 4 and 6 were potent and selective inhibitors of enkephalin-degrading APs and showed a prolonged antinociceptive effect

Hyperuricemia is associated with progression of chronic kidney disease in patients with reduced functioning kidney mass

Background and objectives: Hyperuricemia plays a major role in the development and progression of chronic kidney disease (CKD). Many large observational studies have indicated that increased serum uric acid level predicts the development and progression of CKD in some population, however this hypothesis has not been yet studied in patients with reduced renal mass. Design, setting, participants, & measurements: Retrospective study with a cohort of 324 patients with reduced renal mass from an outpatient basis, followed during 60 (36–98) months. Demographics variables, cardiovascular factors, concomitant medications, albuminuria and uric acid levels were recorded yearly. The primary endpoint was the annual fall of estimated glomerular filtration rate (eGFR) by MDRD-4. The sample was divided into three successive groups (A1: patients with fall of eGFR lower than median, A2: greater than median, B: without fall of eGFR). Factors associated and predictors of kidney function decline were analyzed. Results: One hundred and seventy out of 324 patients suffered a fall of eGFR (group A), (median of fall −1.6 ml/min/1.73 m2/year (−3.0, −0.7)). Male gender, albuminuria > 100 mg/day and higher pulse pressure were associated to progression in our cohort (group A). Hyperuricemia was more frequent among patients with higher kidney disease progression (group A2) (33% vs 49%, p = 0.04) when comparing to lower progression (group A1). Adjusted Cox regression models showed that hyperuricemia, pulse pressure and albuminuria were independent predictors of kidney disease progression (HR 1.67 (1.06–2.63), p = 0.023; 1.02 (1.01–1.03), p = 0.001 and HR: 2.14 (1.26–3.64), p = 0.005, respectively). Kidney disease progression was higher in patients with unilateral renal atrophy or agenesis than nephrectomy (log rank: 7.433, p = 0.006). Conclusions: Hyperuricemia is independently associated with kidney disease progression in patients with reduce functioning renal mass