How far are we from predicting multi-drug interactions during treatment for COVID-19 infection?

Seriously ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and hospitalized in intensive care units (ICUs) are commonly given a combination of drugs, a process known as multi-drug treatment. After extracting data on drug-drug interactions with clinical relevance from available online platforms, we hypothesize that an overall interaction map can be generated for all drugs administered. Furthermore, by combining this approach with simulations of cellular biochemical pathways, we may be able to explain the general clinical outcome. Finally, we postulate that by applying this strategy retrospectively to a cohort of patients hospitalized in ICU, a prediction of the timing of developing acute kidney injury (AKI) could be made. Whether or not this approach can be extended to other diseases is uncertain. Still, we believe it represents a valuable pharmacological insight to help improve clinical outcomes for severely ill patients.

Polydisperse molecular architecture of connexin 26/30 heteromeric hemichannels revealed by atomic force microscopy imaging.

Connexin (Cx) protein forms hemichannels and gap junctional channels, which play diverse and profound roles in human physiology and diseases. Gap junctions are arrays of intercellular channels formed by the docking of two hemichannels from adjacent cells. Each hexameric hemichannel contains the same or different Cx isoform. Although homomeric Cxs forms have been largely described functionally and structurally, the stoichiometry and arrangement of heteromeric Cx channels remain unknown. The latter, however, are widely expressed in human tissues and variation might have important implications on channel function. Investigating properties of heteromeric Cx channels is challenging considering the high number of potential subunit arrangements and stoichiometries, even when only combining two Cx isoforms. To tackle this problem, we engineered an HA tag onto Cx26 or Cx30 subunits and imaged hemichannels that were liganded by Fab-epitope antibody fragments via atomic force microscopy. For Cx26-HA/Cx30 or Cx30-HA/Cx26 heteromeric channels, the Fab-HA binding distribution was binomial with a maximum of three Fab-HA bound. Furthermore, imaged Cx26/Cx30-HA triple liganded by Fab-HA showed multiple arrangements that can be derived from the law of total probabilities. Atomic force microscopy imaging of ringlike structures of Cx26/Cx30-HA hemichannels confirmed these findings and also detected a polydisperse distribution of stoichiometries. Our results indicate a dominant subunit stoichiometry of 3Cx26:3Cx30 with the most abundant subunit arrangement of Cx26-Cx26-Cx30-Cx26-Cx30-Cx30. To our knowledge, this is the first time that the molecular architecture of heteromeric Cx channels has been revealed, thus providing the basis to explore the functional effect of these channels in biology.

Function of P2X4 Receptors Is Directly Modulated by a 1:1 Stoichiometric Interaction With 5-HT3A Receptors.

Interacting receptors at the neuronal plasma membrane represent an additional regulatory mode for intracellular transduction pathways. P2X4 receptor triggers fast neurotransmission responses via a transient increase in intracellular Ca2+ levels. It has been proposed that the P2X4 receptor interacts with the 5-HT3A receptor in hippocampal neurons, but their binding stoichiometry and the role of P2X4 receptor activation by ATP on this crosstalking system remains unknown. Via pull-down assays, total internal reflection fluorescence (TIRF) microscopy measurements of the receptors colocalization and expression at the plasma membrane, and atomic force microscopy (AFM) imaging, we have demonstrated that P2X4/5-HT3A receptor complexes can interact with each other in a 1:1 stoichiometric manner that is preserved after ATP binding. Also, macromolecular docking followed by 100 ns molecular dynamics (MD) simulations suggested that the interaction energy of the P2X4 receptor with 5-HT3A receptor is similar at the holo and the apo state of the P2X4 receptor, and the interacting 5-HT3A receptor decreased the ATP binding energy of P2X4 receptor. Finally, the P2X4 receptor-dependent Ca2+ mobilization is inhibited by the 5-HT3A interacting receptor. Altogether, these findings provide novel molecular insights into the allosteric regulation of P2X4/5-HT3A receptor complex in lipid bilayers of living cells via stoichiometric association, rather than accumulation or unspecific clustering of complexes.

Closed suction drainage has no benefits in revision total hip arthroplasty: a randomized controlled trial.

PURPOSE: Several studies have failed to show significant benefits of closed suction drainage (CSD) in routine primary total hip arthroplasty (THA). However, blood loss, haematoma formation and wound complications are generally much greater in revision THA as compared to primary THA. The purpose of this study was to determine if CSD is beneficial for revision THA patients. METHODS: We conducted a prospective, randomized, controlled trial at our institution between July 2013 and July 2014. Eighty-eight patients undergoing revision THA were enrolled and randomly assigned to receive a CSD (n = 44) or to not receive a CSD (n = 44). All first-stage revision surgeries for infection were excluded. Primary outcomes were haemoglobin loss and number of patients transfused. Secondary outcomes included functional outcome evaluated with Harris hip score (HHS), pain evaluated with visual analogue scale (VAS), and length of hospital stay. RESULTS: There were significantly more patients in the CSD group that required blood transfusions (20/44 as compared to 11/44, p = 0.04). Patients in the no CSD group were discharged earlier than patients in the CSD group (4.3 days as compared to 5.4 days, p = 0.002). No statistical significant difference was found in the HHS or pain VAS between the groups. CONCLUSIONS: This study did not demonstrate any benefit with the use of CSD for revision THA with regard to wound related complications, infection or early functional outcome. Post-operative blood loss, transfusion rate, and length of hospital stay may be higher with CSD.

Arthroplasty for unstable pertrochanteric hip fractures may offer a lower re-operation rate as compared to cephalomedullary nailing.

PURPOSE: Cephalomedullary (CM) nailing is widely used for the treatment of pertrochanteric hip fractures. Fixation failures with CM nailing tend to occur in unstable fracture patterns often necessitating revision surgery. The purpose of this study was to compare the complications and clinical outcomes of primary arthroplasty to CM nailing for the treatment of unstable pertrochanteric hip fractures. METHODS: We conducted an age-, sex-, and fracture type-matched case-controlled study and identified 29 patients who underwent hip arthroplasty for an unstable pertrochanteric fracture (AO/OTA classification type 31A2.2/3 and 31.A3) at our institution. Their outcome was compared to a matched control group of 29 patients treated with a CM nail. RESULTS: There was one major complication in the arthroplasty group (3.4 %), whereas there were six major complications in the nailing group (20.7 %) (P = 0.04). We found no significant difference between the groups with regards to blood loss, operative time, hospitalization time and the number of patients discharged to rehabilitation. Clinical outcome measured with Oxford hip score and SF-12 at the time of final follow-up was not significantly different between the groups. CONCLUSIONS: Arthroplasty is a viable option for treatment of unstable pertrochanteric fractures in an elderly population. Arthroplasty may offer a lower re-operation rate in the treatment of unstable pertrochanteric hip fractures as compared to CM nailing.

Complications following conversion of a hip hemiarthroplasty to a total hip arthroplasty.

PURPOSE: Conversion of hip hemiarthroplasty to total hip arthroplasty (CTHA) is a complication-prone procedure with high dislocation rates and early component loosening. The purpose of this study was to evaluate the complications of CTHA performed using contemporary implants. METHODS: Forty-six patients who had CTHA were retrospectively matched to a control group of 46 patients who had a first-time THA revision. The mean follow-up was 47 (range 6-149) and 23 (range 6-139) months for CTHA and control groups, respectively. Radiographs taken at the last follow-up visit were evaluated for signs of loosening or other modes of failure. Clinical outcome was evaluated with the Harris Hip Score (HHS). RESULTS: Complications occurred in five patients (10.9 %) in the CTHA group, and all required repeat revision. Two patients (4.3 %) were revised due to recurrent dislocation. The other re-revisions were done for acetabular or femoral component loosening and deep infection. In the control group, complications occurred in six patients (13.0 %), and three (6.5 %) were revised with a constrained liner due to recurrent dislocations. CONCLUSIONS: Dislocation rates and re-revision for CTHA were not significantly different than those of first-time THA revision when using contemporary revision implants.