Haemodialysis and peritoneal dialysis patients admitted to intensive care units.

Hutchison and colleagues report a 10-year experience of dialysis patients admitted to intensive care units (ICUs) in the UK excluding Scotland. Their study is the largest published so far and raises issues of interest to both ICU physicians and nephrologists. Overall, the dialysis patients, although sicker on admission and having pre-existing co-morbidities, do as well as other ICU patients. Their clinical progress after leaving the ICU, however, is less good than for other ICU patients, raising the possibility that the patients might be leaving too early, or perhaps that dialysis patients should be discharged to a high-dependency unit rather than go direct to a renal ward. All in all, the paper by Hutchison and colleagues provides a useful foundation for planning the critical care management of dialysis patients in the UK and elsewhere

P2X7 receptor and Sepsis-Induced Acute Kidney Injury

Acute kidney injury (AKI) is a common clinical problem within the intensive care unit. Sepsis is implicated in half the cases of AKI; in those patients requiring acute renal replacement therapy there is an associated mortality of 50%. However, other than maintenance of an adequate circulation, no specific therapy exists for septic AKI. This is in large part related to a poor understanding of the underlying pathophysiology.. I used a 72 hr clinically relevant, fluid-resuscitated rat model of sepsis and recovery to undertake a detailed temporal characterization of the pathophysiology of septic AKI and relevant biomarkers of kidney injury and dysfunction, and to assess the impact of targeted treatments. As with human studies, renal histology demonstrated minimal tissue injury or early inflammatory cell infiltration, however renal recovery was associated with a marked increase in renal macrophage infiltration. A panel of 8 renal biomarkers revealed that urine NGAL was the most sensitive marker, having risen by 3 hours’ post-insult and elevated for 24hrs. Renal blood flow was maintained over the first 24 hrs, however a fall in renal cortical oxygenation occurred despite similar renal oxygen delivery and utilization at 24 hrs. Though electron microscopy showed normal mitochondrial structure, I found an increased expression of mitochondrial uncoupling protein-2 (UCP-2); this may further uncouple mitochondrial respiration. Multiphoton imaging of live healthy kidney slices incubated in either sham or septic serum showed a rise in tubular reactive oxygen species (ROS) and falls in NADH and mitochondrial membrane potential in the septic serum group, findings that are consistent with uncoupling. Pre-incubation with the ROS scavenger, 4-OHTEMPO, prevented these effects. The NLRP3 inflammasome plays an important role in pro-inflammatory cytokine production. A NLRP3 inflammasome inhibitor, P2X7 antagonist, prevented LPS-induced IL-1β production by peripheral blood monocytes in vitro, however this was related in part to its diluent vehicle, dimethyl sulfoxide (DMSO). In the kidney, proximal tubular P2X7 and caspase-1 expression was seen both in vivo and ex vivo during sepsis. DMSO/P2X7 antagonist treatment after the onset of sepsis was associated with reduced renal IL-1β expression and improvements in tachycardia, stroke volume, albumin and lactate however effects on renal function were inconclusive. Further studies targeting the NLRP3 inflammasome in sepsis are warranted

Deep unsupervised clustering with Gaussian mixture variational autoencoders

We study a variant of the variational autoencoder model with a Gaussian mixture as a prior distribution, with the goal of performing unsupervised clustering through deep generative models. We observe that the standard variational approach in these models is unsuited for unsupervised clustering, and mitigate this problem by leveraging a principled information-theoretic regularisation term known as consistency violation. Adding this term to the standard variational optimisation objective yields networks with both meaningful internal representations and well-defined clusters. We demonstrate the performance of this scheme on synthetic data, MNIST and SVHN, showing that the obtained clusters are distinct, interpretable and result in achieving higher performance on unsupervised clustering classification than previous approaches

Tocilizumab in COVID-19: a meta-analysis, trial sequential analysis, and meta-regression of randomized-controlled trials

PURPOSE: Interleukin-6 (IL-6) levels discriminate between patients with mild and severe COVID-19, making IL-6 inhibition an attractive therapeutic strategy. We conducted a systematic review, meta-analysis, trial sequential analysis (TSA), and meta-regression of randomized-controlled trials to ascertain the benefit of IL-6 blockade with tocilizumab for COVID-19. METHODS: We included randomized-controlled trials (RCTs) allocating patients with COVID-19 to tocilizumab. Our control group included standard care or placebo. Trials co-administering other pharmacological interventions for COVID-19 were not excluded. Primary outcome was 28–30 day mortality. Secondary outcomes included progression-to-severe disease defined as need for mechanical ventilation, intensive-care unit (ICU) admission, or a composite. RESULTS: We identified 10 RCTs using tocilizumab, 9 of which reported primary outcome data (mortality), recruiting 6493 patients with 3358 (52.2%) allocated to tocilizumab. Tocilizumab may be associated with an improvement in mortality (24.4% vs. 29.0%; OR 0.87 [0.74–1.01]; p = 0.07; I2 = 10%; TSA adjusted CI 0.66–1.14). Meta-regression suggested a relationship between treatment effect and mortality risk, with benefit at higher levels of risk (logOR vs %risk beta = −0.018 [−0.037 to −0.002]; p = 0.07). Tocilizumab did reduce the need for mechanical ventilation and was associated with a benefit in the composite secondary outcome but did not reduce ICU admission. CONCLUSIONS: For hospitalized COVID-19 patients, there is some evidence that tocilizumab use may be associated with a short-term mortality benefit, but further high-quality data are required. Its benefits may also lie in reducing the need for mechanical ventilation

COVID-19 and non-COVID ARDS patients demonstrate a distinct response to low dose steroids- A retrospective observational study

Patients with COVID-19 ARDS have distinct physiological and immunological phenotypes compared to patients with non-COVID ARDS. Patients with COVID-19 ARDS (n = 32) had a significant improvement in PaO2: FiO2 ratio (p = 0.046) following low-dose steroid treatment, unlike patients with non-COVID ARDS (n = 16) (p = 0.529). Patients with COVID-19 ARDS had a greater fall in CRP compared to patients with non-COVID ARDS, albeit not statistically significant (p = 0.07). Our novel findings highlight differences in the underlying physiological and immunological phenotypes between COVID-19 and non-COVID ARDS, with implications for future ARDS studies

Convalescent plasma for COVID-19: a meta-analysis, trial sequential analysis, and meta-regression

Background: SARS-CoV-2-specific antibodies, particularly those preventing interaction between the viral spike receptor-binding domain and the host angiotensin-converting enzyme 2 receptor, may prevent viral entry into host cells and disease progression. / Objective: We performed a systematic review, meta-analysis, trials sequential analysis (TSA) and meta-regression of randomized control trials (RCTs) to evaluate the benefit of convalescent plasma for COVID-19. The primary outcome was 28-30-day mortality. Secondary outcomes included need for mechanical ventilation and intensive care (ICU) admission. / Data sources: PubMed, Embase, MedRxiv, and the Cochrane library on 2nd July 2021. / Results: Seventeen RCTs were identified recruiting 15,587 patients with 8027 (51.5%) allocated to receive convalescent plasma. Convalescent plasma use was not associated with a mortality benefit (24.7% vs. 25.5%; OR 0.94 (0.85 – 1.04); p = 0.23; I2 = 4%; TSA adjusted CI 0.84 – 1.05), or reduction in need for mechanical ventilation (15.7% vs. 15.4%; OR 1.01 [0.92 – 1.11]; p = 0.82; I2 = 0%; TSA adjusted CI 0.91 – 1.13), or ICU admission (22.4% vs. 16.7%; OR 0.80 (0.21 – 3.09); p = 0.75; I2 = 63%; TSA adjusted CI 0.0 – 196.05). Meta-regression did not reveal any association with titre of convalescent plasma, timing of administration, nor risk of death and treatment effect (p>0.05). Risk of bias was high in most studies. / Conclusions: In patients with COVID-19, there was no clear mortality benefit associated with convalescent plasma. In patients with mild disease, convalescent plasma did not prevent either the need for mechanical ventilation or ICU admission. PROSPERO registration CRD42021234201

DNA Nanodevices with Selective Immune Cell Interaction and Function

DNA nanotechnology produces precision nanostructures of defined chemistry. Expanding their use in biomedicine requires designed biomolecular interaction and function. Of topical interest are DNA nanostructures that function as vaccines with potential advantages over nonstructured nucleic acids in terms of serum stability and selective interaction with human immune cells. Here, we describe how compact DNA nanobarrels bind with a 400-fold selectivity via membrane anchors to white blood immune cells over erythrocytes, without affecting cell viability. The selectivity is based on the preference of the cholesterol lipid anchor for the more fluid immune cell membranes compared to the lower membrane fluidity of erythrocytes. Compacting DNA into the nanostructures gives rise to increased serum stability. The DNA barrels furthermore functionally modulate white blood cells by suppressing the immune response to pro-inflammatory endotoxin lipopolysaccharide. This is likely due to electrostatic or steric blocking of toll-like receptors on white blood cells. Our findings on immune cell-specific DNA nanostructures may be applied for vaccine development, immunomodulatory therapy to suppress septic shock, or the targeting of bioactive substances to immune cells

Biological sex is associated with heterogeneous responses to IL-6 receptor inhibitor treatment in COVID-19—A retrospective cohort study

COVID-19 is associated with higher inflammatory markers, illness severity and mortality in males compared to females. Differences in immune responses to COVID-19 may underpin sex- specific outcome differences. We hypothesised that anti-IL-6 receptor monoclonal antibodies are associated with heterogenous treatment effects between male and female patients. We conducted a retrospective cohort study assessing the interaction between biological sex and anti-IL-6 receptor antibody treatment with respect to hospital mortality or progression of respiratory failure. We used a Cox proportional hazards regression model to adjust for age, ethnicity, steroid use, baseline C-reactive protein, and COVID-19 variant. We included 1274 patients, of which 58% were male and 15% received anti-IL-6 receptor antibodies. There was a significant interaction between sex and anti-IL-6 receptor antibody use on progression to respiratory failure or death (p = 0.05). For patients who did not receive anti-IL-6 receptor antibodies, the risk of death was slightly higher in males (HR = 1.13 (0.72–1.79)), whereas in patients who did receive anti-IL-6 receptor antibodies, the risk was lower in males (HR = 0.65 (0.32–1.33)). There was a heterogenous treatment effect with anti-IL-6 receptor antibodies between males and females; with anti-IL-6 receptor antibody use having a greater benefit in preventing progression to respiratory failure or death in males (p = 0.05)