Developing a personalized remote patient monitoring algorithm: a proof-of-concept in heart failure

Aims Non-invasive remote patient monitoring is an increasingly popular technique to aid clinicians in the early detection of worsening heart failure (HF) alongside regular follow-ups. However, previous studies have shown mixed results in the performance of such systems. Therefore, we developed and evaluated a personalized monitoring algorithm aimed at increasing positive-predictive-value (PPV) (i.e. alarm quality) and compared performance with simple rule-of-thumb and moving average convergence-divergence algorithms (MACD). Methods and results In this proof-of-concept study, the developed algorithm was applied to retrospective data of daily bodyweight, heart rate, and systolic blood pressure of 74 HF-patients with a median observation period of 327 days (IQR: 183 days), during which 31 patients experienced 64 clinical worsening HF episodes. The algorithm combined information on both the monitored patients and a group of stable HF patients, and is increasingly personalized over time, using linear mixed-effect modelling and statistical process control charts. Optimized on alarm quality, heart rate showed the highest PPV (Personalized: 92%, MACD: 2%, Rule-of-thumb: 7%) with an F1 score of (Personalized: 28%, MACD: 6%, Rule-of-thumb: 8%). Bodyweight demonstrated the lowest PPV (Personalized: 16%, MACD: 0%, Rule-of-thumb: 6%) and F1 score (Personalized: 10%, MACD: 3%, Rule-of-thumb: 7%) overall compared methods. Conclusion The personalized algorithm with flexible patient-tailored thresholds led to higher PPV, and performance was more sensitive compared to common simple monitoring methods (rule-of-thumb and MACD). However, many episodes of worsening HF remained undetected. Heart rate and systolic blood pressure monitoring outperformed bodyweight in predicting worsening HF. The algorithm source code is publicly available for future validation and improvement

Lipoproteins attenuate TLR2 and TLR4 activation by bacteria and bacterial ligands with differences in affinity and kinetics

BACKGROUND: The small intestine is a specialized compartment were close interactions take place between host, microbes, food antigens and dietary fatty acids. Dietary fats get absorbed by epithelial cells and processed into a range of lipoprotein particles after which they are basolaterally secreted and collected in the lymphatics. In contrast to the colon, the small intestine is covered only by a thin mucus coat that allows for intimate interactions between host-cells and microbes. Lipoproteins have long been recognized as protective factors in infectious diseases via the neutralization of bacterial toxins like lipopolysaccharides. Much less attention has been given to the potential role of lipoproteins as factors contributing to the maintenance of small intestinal immune homeostasis via modulating bacteria-induced immune responses. RESULTS: Lipoproteins VLDL, LDL and HDL were found to neutralize TLR responses towards specific TLR-ligands or a selection of gram-negative and gram-positive bacteria. Attenuation of TLR2 activity was acute and only slightly improved by longer pre-incubation times of ligands and lipoproteins with no differences between bacterial-lipopeptides or bacteria. In contrast, attenuation of TLR4 responses was only observed after extensive preincubation of lipoproteins and LPS. Preincubation of bacteria and lipoproteins led only to a modest attenuation of TLR4 activity. Moreover, compared to TLR2, TLR4 activity could only be attenuated by lipoproteins over a small ligand dose range. CONCLUSIONS: These results demonstrate the ability of lipoproteins VLDL, LDL and HDL to inhibit TLR responses towards bacterial-ligands and bacteria. Presence of lipoproteins was found to modulate the MAMP-induced cytokine release by primary human monocytes measured as changes in the release of IL-6, TNFα, GM-CSF and IFNγ. Using TLR2 and TLR4-reporter cells, lipoproteins were found to inhibit TLR responses with differences in affinity and kinetics. These data establish a role for lipoproteins as immunoregulatory molecules, attenuating TLR-responses and thereby positively contributing to mucosal homeostasis

Lipoproteins attenuate TLR2 and TLR4 activation by bacteria and bacterial ligands with differences in affinity and kinetics

BACKGROUND: The small intestine is a specialized compartment were close interactions take place between host, microbes, food antigens and dietary fatty acids. Dietary fats get absorbed by epithelial cells and processed into a range of lipoprotein particles after which they are basolaterally secreted and collected in the lymphatics. In contrast to the colon, the small intestine is covered only by a thin mucus coat that allows for intimate interactions between host-cells and microbes. Lipoproteins have long been recognized as protective factors in infectious diseases via the neutralization of bacterial toxins like lipopolysaccharides. Much less attention has been given to the potential role of lipoproteins as factors contributing to the maintenance of small intestinal immune homeostasis via modulating bacteria-induced immune responses. RESULTS: Lipoproteins VLDL, LDL and HDL were found to neutralize TLR responses towards specific TLR-ligands or a selection of gram-negative and gram-positive bacteria. Attenuation of TLR2 activity was acute and only slightly improved by longer pre-incubation times of ligands and lipoproteins with no differences between bacterial-lipopeptides or bacteria. In contrast, attenuation of TLR4 responses was only observed after extensive preincubation of lipoproteins and LPS. Preincubation of bacteria and lipoproteins led only to a modest attenuation of TLR4 activity. Moreover, compared to TLR2, TLR4 activity could only be attenuated by lipoproteins over a small ligand dose range. CONCLUSIONS: These results demonstrate the ability of lipoproteins VLDL, LDL and HDL to inhibit TLR responses towards bacterial-ligands and bacteria. Presence of lipoproteins was found to modulate the MAMP-induced cytokine release by primary human monocytes measured as changes in the release of IL-6, TNFα, GM-CSF and IFNγ. Using TLR2 and TLR4-reporter cells, lipoproteins were found to inhibit TLR responses with differences in affinity and kinetics. These data establish a role for lipoproteins as immunoregulatory molecules, attenuating TLR-responses and thereby positively contributing to mucosal homeostasis

A Mathematical Model to Evaluate Control Strategies for Mechanical Circulatory Support

Continuous flow ventricular assist devices (VADs) for mechanical circulatory support (MCS) are generally smaller and believed to be more reliable than pulsatile VADs. However, regarding continuous flow, there are concerns about the decreased pulsatility and ventricular unloading. Moreover, pulsatile VADs offer a wider range in control strategies. For this reason, we used a computer model to evaluate whether pulsatile operation of a continuous flow VAD would be more beneficial than the standard constant pump speed. The computer model describes the left and right ventricle with one-fiber heart contraction models, and the systemic, pulmonary, and coronary circulation with lumped parameter hemodynamical models, while the heart rate is regulated with a baroreflex model. With this computer model, both normal and heart failure hemo-dynamics were simulated. A HeartMate II left ventricular assist device model was connected to this model, and both constant speed and pulsatile support were simulated. Pulsatile support did not solve the decreased pulsatility issue, but it did improve perfusion ( cardiac index and coronary flow) and unloading ( stroke work and heart rate) compared with constant speed. Also, pulsatile support would be beneficial for developing control strategies, as it offers more options to adjust assist device settings to the patient's needs. Because the mathematical model used in this study can simulate different assist device settings, it can play a valuable role in developing mechanical circulatory support control strategie

Extracellular Vesicles Modulate Host-Microbe Responses by Altering TLR2 Activity and Phagocytosis

<div><p>Oral delivery of Gram positive bacteria, often derived from the genera Lactobacillus or Bifidobacterium, can modulate immune function. Although the exact mechanisms remain unclear, immunomodulatory effects may be elicited through the direct interaction of these bacteria with the intestinal epithelium or resident dendritic cell (DC) populations. We analyzed the immune activation properties of Lactobacilli and Bifidobacterium species and made the surprising observation that cellular responses in vitro were differentially influenced by the presence of serum, specifically the extracellular vesicle (EV) fraction. In contrast to the tested Lactobacilli species, tested Bifidobacterium species induce TLR2/6 activity which is inhibited by the presence of EVs. Using specific TLR ligands, EVs were found to enhance cellular TLR2/1 and TLR4 responses while TLR2/6 responses were suppressed. No effect could be observed on cellular TLR5 responses. We determined that EVs play a role in bacterial aggregation, suggesting that EVs interact with bacterial surfaces. EVs were found to slightly enhance DC phagocytosis of <i>Bifidobacterium breve</i> whereas phagocytosis of <i>Lactobacillus rhamnosus</i> was virtually absent upon serum EV depletion. DC uptake of a non-microbial substance (dextran) was not affected by the different serum fractions suggesting that EVs do not interfere with DC phagocytic capacity but rather modify the DC-microbe interaction. Depending on the microbe, combined effects of EVs on TLR activity and phagocytosis result in a differential proinflammatory DC cytokine release. Overall, these data suggest that EVs play a yet unrecognized role in host-microbe responses, not by interfering in recipient cellular responses but via attachment to, or scavenging of, microbe-associated molecular patterns. EVs can be found in any tissue or bodily fluid, therefore insights into EV-microbe interactions are important in understanding the mechanism of action of potential probiotics and gut immune homeostasis.</p></div

Lack of Consensus Across Clinical Guidelines Regarding the Role of Psychosocial Factors Within Low Back Pain Care: A Systematic Review

It is widely accepted that psychosocial prognostic factors should be addressed by clinicians in their assessment and management of patient suffering from low back pain (LBP). On the other hand, an overview is missing how these factors are addressed in clinical LBP guidelines. Therefore, our objective was to summarize and compare recommendations regarding the assessment and management of psychosocial prognostic factors for LBP chronicity, as reported in clinical LBP guidelines. We performed a systematic search of clinical LBP guidelines (PROSPERO registration number 154730). This search consisted of a combination of previously published systematic review articles and a new systematic search in medical or guideline-related databases. From the included guidelines, we extracted recommendations regarding the assessment and management of LBP which addressed psychosocial prognostic factors (ie, psychological factors ["yellow flags"], perceptions about the relationship between work and health, ["blue flags"], system or contextual obstacles ["black flags") and psychiatric symptoms ["orange flags"]). In addition, we evaluated the level or quality of evidence of these recommendations. In total, we included 15 guidelines. Psychosocial prognostic factors were addressed in 13 of 15 guidelines regarding their assessment and in 14 of 15 guidelines regarding their management. Recommendations addressing psychosocial factors almost exclusively concerned "yellow" or "black flags," and varied widely across guidelines. The supporting evidence was generally of very low quality. We conclude that in general, clinical LBP guidelines do not provide clinicians with clear instructions about how to incorporate psychosocial factors in LBP care and should be optimized in this respect. More specifically, clinical guidelines vary widely in whether and how they address psychosocial factors, and recommendations regarding these factors generally require better evidence support. This emphasizes a need for a stronger evidence-base underlying the role of psychosocial risk factors within LBP care, and a need for uniformity in methodology and terminology across guidelines. PERSPECTIVE: This systematic review summarized clinical guidelines on low back pain (LBP) on how they addressed the identification and management of psychosocial factors. This review revealed a large amount of variety across guidelines in whether and how psychosocial factors were addressed. Moreover, recommendations generally lacked details and were based on low quality evidence

<i>B. breve</i> but not <i>L. rhamnosus</i> ligate DC-expressed TLR2.

<p>1×10⁵ DCs were co-incubated with 1×10⁶<i>B. breve</i> NutRes 200 or <i>L. rhamnosus</i> NutRes 1 at 37°C in medium, HS, HS-D or HS-EVs. TLR2 activity was inhibited by preincubating cells with a specific anti TLR2 antibody or isotype control. After 16H, supernatants were collected and analyzed for IL-6 and TNFα release. Relative cytokine levels were calculated according to the ratio between responses at serum-free medium and serum fraction supplemented medium. (A) Blocking TLR2 significantly inhibited DC IL-6 release after ligation by B. breve but not L. rhamnosus irrespective of the serum fractions. (B) Blocking TLR2 significantly inhibited DC TNFα release after ligation of B. breve in the presence of medium and HS-D but not intact HS or HS-EVs. DC TNFα release in response to ligation of L. rhamnosus was not affected. Data are represented as mean ± SEM n = 4 (^***P<0.001)(^**P<0.01)(^*P<0.05).</p

EV mediated bacterial aggregation.

<p>Picture A and C respectively represent a typical example of <i>L. rhamnosus</i> NutRes 1 and <i>B. breve</i> Nutres 200 co-incubated with medium, medium with ExoQuick or medium depleted for EVs. Picture B and D respectively represent a typical example of <i>L. rhamnosus</i> NutRes 1 and <i>B. breve</i> Nutres 200 co-incubated with HS or HS-EVs.</p

EVs induce bacterial aggregation.

<p><i>B. breve</i> NutRes 200 and <i>L. rhamnosus</i> NutRes 1 were seeded in flat-bottom 96-wells plates at 2.5×10⁶ bacteria/well in medium, medium with ExoQuick (EQ)(control), HS, HS-D or HS-EV and incubated at 37°C. After 16H cultures were analyzed for aggregation using microscopy and pictures were taken. Pictures were digitally processed and analyzed using ImageJ software, calculating the area covered by objects. Intact serum as well as HS-EVs induced bacterial aggregation, reducing the area covered by objects by approximately 50%. Aggregation was not observed upon EV depletion. No differences between strains could be observed.</p