Case Report: Invasive Fungal Infection and Daratumumab: A Case Series and Review of Literature.

Life expectancy of multiple myeloma (MM) patients has improved in last years due to the advent of anti-CD38 monoclonal antibodies in combination with immunomodulators and proteasome inhibitors. However, morbidity and mortality related to infections remain high and represent a major concern. This paper describes the "real life" risk of invasive fungal infections (IFI) in patients treated with daratumumab-based therapy and reviews the relevant literature. In a series of 75 patients we only observed three cases of fungal pneumonia. Unfortunately, the early signs and symptoms were not specific for fungal infection. Diagnostic imaging, microbiology and patient history, especially previous therapies, are critical in the decision to start antifungal treatment. Recognising the subgroup of MM patients with high risk of IFI can increase the rate of diagnosis, adequate treatment and MM-treatment recovery.

Acute ingestion of a high-fructose drink impairs vascular autonomic modulation and reflex control of blood pressure in first-degree relatives of diabetic patients.

First-degree relatives of diabetes patients, despite being euglycemic, presented impaired BRS and exacerbation of sympathetic modulation after ingestion of a high fructose drink when challenged to orthostatic stress. This finding alerts the importance of early autonomic dysfunction even in clinically healthy people, especially in face of a stressful situation.

Proteolysis in septic shock patients: plasma peptidomic patterns are associated with mortality.

BACKGROUND: Uncontrolled proteolysis contributes to cell injury and organ dysfunction in animal models of circulatory shock. We investigated in humans the relationship between septic shock, proteolysis, and outcome. METHODS: Intensive care patients with septic shock (n=29) or sepsis (n=6) and non-hospitalised subjects (n=9) were recruited as part of the prospective observational trial 'ShockOmics' (ClinicalTrials.gov Identifier NCT02141607). A mass spectrometry-based approach was used to analyse the plasma peptidomes and the origin of circulating peptides from proteolysis in the enrolled subjects. RESULTS: Evidence of systemic proteolysis was indicated by a larger number of circulating peptides in septic shock patients, compared with septic patients and non-hospitalised healthy subjects. The peptide count and abundance in the septic shock patients were greater in patients who died (n=6) than in survivors (n=23), suggesting an association between magnitude of proteolysis and outcome. In silico analysis of the peptide sequences and of the sites of cleavage on the proteins of origin indicated a predominant role for serine proteases, such as chymotrypsin, and matrix metalloproteases in causing the observed proteolytic degradation. CONCLUSIONS: Systemic proteolysis is a novel fundamental pathological mechanism in septic shock. Plasma peptidomics is proposed as a new tool to monitor clinical trajectory in septic shock patients. CLINICAL TRIAL REGISTRATION: NCT02141607.

Preliminary profiling of blood transcriptome in a rat model of hemorrhagic shock.

Hemorrhagic shock is a leading cause of morbidity and mortality worldwide. Significant blood loss may lead to decreased blood pressure and inadequate tissue perfusion with resultant organ failure and death, even after replacement of lost blood volume. One reason for this high acuity is that the fundamental mechanisms of shock are poorly understood. Proteomic and metabolomic approaches have been used to investigate the molecular events occurring in hemorrhagic shock but, to our knowledge, a systematic analysis of the transcriptomic profile is missing. Therefore, a pilot analysis using paired-end RNA sequencing was used to identify changes that occur in the blood transcriptome of rats subjected to hemorrhagic shock after blood reinfusion. Hemorrhagic shock was induced using a Wigger's shock model. The transcriptome of whole blood from shocked animals shows modulation of genes related to inflammation and immune response (Tlr13, Il1b, Ccl6, Lgals3), antioxidant functions (Mt2A, Mt1), tissue injury and repair pathways (Gpnmb, Trim72) and lipid mediators (Alox5ap, Ltb4r, Ptger2) compared with control animals. These findings are congruent with results obtained in hemorrhagic shock analysis by other authors using metabolomics and proteomics. The analysis of blood transcriptome may be a valuable tool to understand the biological changes occurring in hemorrhagic shock and a promising approach for the identification of novel biomarkers and therapeutic targets. Impact statement This study provides the first pilot analysis of the changes occurring in transcriptome expression of whole blood in hemorrhagic shock (HS) rats. We showed that the analysis of blood transcriptome is a useful approach to investigate pathways and functional alterations in this disease condition. This pilot study encourages the possible application of transcriptome analysis in the clinical setting, for the molecular profiling of whole blood in HS patients.

Is there a chronic sleep stage-dependent linear and nonlinear cardiac autonomic impairment in obstructive sleep apnea?

RATIONALE: Obstructive sleep apnea (OSA) is a respiratory disorder that has the potential to negatively impact heart rate variability (HRV) during the sleep cycle. However, it is uncertain whether there is a chronic sleep stage-dependent linear and nonlinear cardiac autonomic impairment in OSA. The aim of this study was to perform HRV analysis in apnea-free samples as well as during stage 2 and rapid eye movement (REM) sleep in mild and moderate OSA (MiOSA and MOSA, respectively) subjects as well as health controls (NonOSA). METHODS: This study included 20 MiOSA (37 ± 14 years), 20 MOSA (39 ± 8 years), and 18 NonOSA (36 ± 8 years) subjects. Subjects underwent in-laboratory overnight polysomnography with electrocardiography recording. HRV indices were obtained by analyzing the R-R intervals (RRis) in 5-min apnea-free samples by the linear frequency domain [low frequency (LF), high frequency (HF) and LF/HF], Poincaré plot [standard deviation (SD1) and (SD2)], recurrence plot [mean line length (Lmean)], recurrence rate (REC), determinism (DET), and Shannon entropy (ShanEn). RESULTS: The MOSA group presented with higher LF, LF/HF, and DET indices compared to NonOSA as well as a lower parasympathetic index (HF), suggesting sympathetic hyperactivity in MOSA subjects. Interestingly, MiOSA subjects failed to show the expected linear HRV difference between sleep stages, as observed in NonOSA, which may represent an early onset of autonomic impairment at this stage of OSA. CONCLUSION: In OSA patients, there is a chronic sleep stage-dependent impairment of linear and nonlinear cardiac autonomic modulation. Interestingly, this impairment may be identifiable during the early stages of the disease.

Cardiac output is not a significant source of low frequency mean arterial pressure variability.

Spontaneous mean arterial pressure (MAP) variability may be mainly due to fluctuations in cardiac output (CO) and total peripheral resistance (TPR). While high frequency (HF ∼ 0.25 Hz) oscillations in MAP are ultimately driven by respiration, the source of low frequency (LF ∼ 0.1 Hz) fluctuations has not been fully elucidated. It is known that CO buffers these oscillations, but there is no evidence on its potential role in also generating them. The main goal was to determine whether CO is a source of LF variability in MAP. Six dogs were chronically instrumented to obtain beat-to-beat measurements of CO and MAP while the dogs were fully awake and at rest. A causal dynamic model was identified to relate the fluctuations in CO to MAP. The model was then used to predict the MAP fluctuations from the CO fluctuations. The CO fluctuations were able to predict about 70% of the MAP oscillations in the HF band but showed no predictive value in the LF band. Hence, respiration induces CO fluctuations in the HF band that, in turn, cause MAP oscillations, while TPR fluctuations appear to be the dominant mediator of LF fluctuations of MAP. CO is not a significant source of these oscillations, and it may only be responsible for dampening them, likely through the baroreflex.

Interferences between baroreflex and respiration. Evaluation by symbolic analysis and conditional entropy.

BACKGROUND: The baroreflex is one of the most important short-term cardiovascular autonomic control mechanisms. Its interactions with other reflexes, mainly cardiopulmonary reflexes, are of paramount importance in controlling heart rate. OBJECTIVES: This study assesses the coupling between baroreflex and respiration during a progressive bicycle mild dynamical exercise. METHODS: The coupling was assessed by symbolic analysis and conditional entropy. RESULTS: Findings suggested the close relationship between the baroreflex sequences and the phase of respiratory signal and, thus, the interference between baroreflex and cardiopulmonary reflexes. CONCLUSIONS: Indexes describing baroreflex based on spontaneous variability are strongly affected by cardiopulmonary influences.

Sleep staging classification based on HRV: time-variant analysis.

An algorithm to evaluate the sleep macrostructure based on heart rate fluctuations from ECG signal is presented. This algorithm is an attempt to evaluate the sleep quality out of sleep centers. The algorithm is made up by a) a time-variant autoregressive model used as feature extractor and b) a hidden Markov model used as classifier. Characteristics coming from the joint probability of HRV features were used to fed the HMM. 17 full polysomnography recordings from healthy subjects were used in the current analysis. When compared to Wake-NREM-REM given by experts, the automatic classifier achieved a total accuracy of 78.21+/-6.44% and a kappa index of 0.41+/-.1085 using two features and a total accuracy of 79.43+/-8.83% and kappa index of 0.42+/-.1493 using three features.