Surfactant-Impregnated MOF-Coated Fabric for Antimicrobial Applications.

Since the onset of the SARS-CoV-2 pandemic, the world has witnessed over 617 million confirmed cases and more than 6.54 million confirmed deaths, but the actual totals are likely much higher. The virus has mutated at a significantly faster rate than initially projected, and positive cases continue to surge with the emergence of ever more transmissible variants. According to the CDC, and at the time of this manuscript submission, more than 77% of all current US cases are a result of the B.5 (omicron). The continued emergence of highly transmissible variants makes clear the need for more effective methods of mitigating disease spread. Herein, we have developed an antimicrobial fabric capable of destroying a myriad of microbes including betacoronaviruses. We have demonstrated the capability of this highly porous and nontoxic metal organic framework (MOF), γ-CD-MOF-1, to serve as a host for varied-length benzalkonium chlorides (BACs; active ingredient in Lysol). Molecular docking simulations predicted a binding affinity of up to -4.12 kcal·mol-1, which is comparable to that of other reported guest molecules for this MOF. Similar Raman spectra and powder X-ray diffraction patterns between the unloaded and loaded MOFs, accompanied by a decrease in the Brunauer-Emmett-Teller surface area from 616.20 and 155.55 m2 g-1 respectively, corroborate the suggested potential for pore occupation with BAC. The MOF was grown on polypropylene fabric, exposed to a BAC-loading bath, washed to remove excess BAC from the external surface, and evaluated for its microbicidal activity against various bacterial and viral classes. Significant antimicrobial character was observed against Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, bacteriophage, and betacoronavirus. This study shows that a common mask material (polypropylene) can be coated with BAC-loaded γ-CD-MOF-1 while maintaining the guest molecule's antimicrobial effects.

Pulmonary artery wave reflection and right ventricular function after lung resection.

BACKGROUND: Lung resection has been shown to impair right ventricular function. Although conventional measures of afterload do not change, surgical ligation of a pulmonary artery branch, as occurs during lobectomy, can create a unilateral proximal reflection site, increasing wave reflection (pulsatile component of afterload) and diverting blood flow through the contralateral pulmonary artery. We present a cardiovascular magnetic resonance imaging (MRI) observational cohort study of changes in wave reflection and right ventricular function after lung resection. METHODS: Twenty-seven patients scheduled for open lobectomy for suspected lung cancer underwent cardiovascular MRI preoperatively, on postoperative Day 2, and at 2 months. Wave reflection was assessed in the left and right pulmonary arteries (operative and non-operative, as appropriate) by wave intensity analysis and calculation of wave reflection index. Pulmonary artery blood flow distribution was calculated as percentage of total blood flow travelling in the non-operative pulmonary artery. Right ventricular function was assessed by ejection fraction and strain analysis. RESULTS: Operative pulmonary artery wave reflection increased from 4.3 (2.1-8.8) % preoperatively to 9.5 (4.9-14.9) % on postoperative Day 2 and 8.0 (2.3-11.7) % at 2 months (P<0.001) with an associated redistribution of blood flow towards the nonoperative pulmonary artery (r>0.523; P<0.010). On postoperative Day 2, impaired right ventricular ejection fraction was associated with increased operative pulmonary artery wave reflection (r=-0.480; P=0.028) and pulmonary artery blood flow redistribution (r=-0.545; P=0.011). At 2 months, impaired right ventricular ejection fraction and right ventricular strain were associated with pulmonary artery blood flow redistribution (r=-0.634, P=0.002; r=0.540, P=0.017). CONCLUSIONS: Pulsatile afterload increased after lung resection. The unilateral increase in operative pulmonary artery wave reflection resulted in redistribution of blood flow through the nonoperative pulmonary artery and was associated with right ventricular dysfunction. CLINICAL TRIAL REGISTRATION: NCT01892800.

Perioperative cardiovascular pathophysiology in patients undergoing lung resection surgery: a narrative review.

Although thoracic surgery is understood to confer a high risk of postoperative respiratory complications, the substantial haemodynamic challenges posed are less well appreciated. This review highlights the influence of cardiovascular comorbidity on outcome, reviews the complex pathophysiological changes inherent in one-lung ventilation and lung resection, and examines their influence on cardiovascular complications and postoperative functional limitation. There is now good evidence for the presence of right ventricular dysfunction postoperatively, a finding that persists to at least 3 months. This dysfunction results from increased right ventricular afterload occurring both intraoperatively and persisting postoperatively. Although many patients adapt well, those with reduced right ventricular contractile reserve and reduced pulmonary vascular flow reserve might struggle. Postoperative right ventricular dysfunction has been implicated in the aetiology of postoperative atrial fibrillation and perioperative myocardial injury, both common cardiovascular complications which are increasingly being appreciated to have impact long into the postoperative period. In response to the physiological demands of critical illness or exercise, contractile reserve, flow reserve, or both can be overwhelmed resulting in acute decompensation or impaired long-term functional capacity. Aiding adaptation to the unique perioperative physiology seen in patients undergoing thoracic surgery could provide a novel therapeutic avenue to prevent cardiovascular complications and improve long-term functional capacity after surgery.

Extracorporeal carbon dioxide removal in acute hypoxaemic respiratory failure: a systematic review, Bayesian meta-analysis and trial sequential analysis.

PURPOSE: To assess the safety and efficacy of extracorporeal carbon dioxide removal (ECCO2R) versus standard care in patients with acute hypoxaemic respiratory failure (AHRF). METHODS: MEDLINE, Embase and clinical trial registries were searched from 1994 to 31 December 2021. We included randomised controlled trials (RCTs) and observational studies. Pairs of reviewers independently extracted data and assessed the risk of bias. The primary outcome was mortality. Secondary outcomes included ventilator-free days, length of stay, safety and adverse events and physiological changes. As a primary analysis, we performed a meta-analysis of mortality until day 30 using a Bayesian random effects model. We then performed a trial sequential analysis of RCTs. RESULTS: 21 studies met inclusion criteria: three RCTs, enrolling 531 patients, and 18 observational studies. In a pooled analysis of RCTs, the posterior probability of increased mortality with the use of ECCO2R was 73% (relative risk 1.19, 95% credible interval 0.70-2.29). There was substantial heterogeneity in the reporting of safety and adverse events. However, the incidence of extra and intracranial haemorrhage was higher (relative risk 3.00, 95% credible interval 0.41-20.51) among those randomised to ECCO2R. Current trials have accumulated 80.8% of the diversity-adjusted required information size and the lack of effect reaches futility for a 10% absolute risk reduction in mortality. CONCLUSIONS: The use of ECCO2R in patients with AHRF is not associated with improvements in clinical outcomes. Furthermore, it is likely that further trials of ECCO2R aiming to achieve an absolute risk reduction in mortality of ≥10% are futile.

Outcome following unplanned critical care admission after lung resection.

Objectives: Patients undergoing lung resection are at risk of perioperative complications, many of which necessitate unplanned critical care unit admission in the postoperative period. We sought to characterize this population, providing an up-to-date estimate of the incidence of unplanned critical care admission, and to assess critical care and hospital stay, resource use, mortality, and outcomes. Methods: A multicenter retrospective cohort study of patients undergoing lung resection in participating UK hospitals over 2 years. A comprehensive dataset was recorded for each critical care admission (defined as the need for intubation and mechanical ventilation and/or renal replacement therapy), in addition to a simplified dataset in all patients undergoing lung resection during the study period. Multivariable regression analysis was used to identify factors independently associated with critical care outcome. Results: A total of 11,208 patients underwent lung resection in 16 collaborating centers during the study period, and 253 patients (2.3%) required unplanned critical care admission with a median duration of stay of 13 (4-28) days. The predominant indication for admission was respiratory failure (68.1%), with 77.8% of patients admitted during the first 7 days following surgery. Eighty-seven (34.4%) died in critical care. On multivariable regression, only the diagnosis of right ventricular dysfunction and the need for both mechanical ventilation and renal-replacement therapy were independently associated with critical care survival; this model, however, had poor predictive value. Conclusions: Although resource-intensive and subject to prolonged stay, following unplanned admission to critical care after lung resection outcomes are good for many patients; 65.6% of patients survived to hospital discharge, and 62.7% were discharged to their own home.

Phage K gp102 Drives Temperature-Sensitive Antibacterial Activity on USA300 MRSA.

There is widespread interest in using obligately lytic bacteriophages ("phages") to treat human bacterial infections. Among Staphylococcus aureus infections, the USA300 lineage is a frequent cause of invasive disease. We observed that phage K, a model S. aureus myophage, exhibits temperature-sensitive growth on USA300 strains, with the wild-type phage providing poorer growth suppression in broth and forming smaller and fainter plaques at 37 °C vs. 30 °C. We isolated 65 mutants of phage K that had improved plaquing characteristics at 37 °C when compared to the parental phage. In all 65 mutants, this phenotype was attributable to loss-of-function (LoF) mutations in gp102, which encodes a protein of unknown function that has homologs only among the Herelleviridae (SPO1-like myophages infecting gram-positive bacteria). Additional experiments with representative mutants consistently showed that the temperature-sensitive plaque phenotype was specific to USA300 MRSA strains and that Gp102 disruption was correlated with improved suppression of bacterial growth in broth and improved antibacterial activity in a mouse model of upper respiratory tract infection. The same genotype and in vitro phenotypes could be replicated in close relatives of phage K. Gp102 disruption did not have a detectable effect on adsorption but did delay cell culture lysis relative to wild-type under permissive infection conditions, suggesting that gp102 conservation might be maintained by selective pressure for more rapid replication. Expression of gp102 on a plasmid was toxic to both an MSSA and a USA300 MRSA strain. Molecular modeling predicts a protein with two helix-turn-helix domains that displays some similarity to DNA-binding proteins such as transcription factors. While its function remains unclear, gp102 is a conserved gene that is important to the infection process of Kayvirus phages, and it appears that the manner in which USA300 strains defend against them at 37 °C can be overcome by gp102 LoF mutations.

The right ventricular response to lung resection.

OBJECTIVES: Lung cancer is a leading cause of cancer death and in suitable cases the best chance of cure is offered by surgery. Lung resection is associated with significant postoperative cardiorespiratory morbidity, with dyspnea and reduced functional capacity as dominant features. These changes are poorly associated with deterioration in pulmonary function and a potential role of right ventricular (RV) dysfunction has been hypothesized. Cardiovascular magnetic resonance imaging is a reference method for noninvasive assessment of RV function and has not previously been applied to this population. METHODS: We used cardiovascular magnetic resonance imaging to assess the RV response to lung resection. Cardiovascular magnetic resonance imaging with volume and flow analysis was performed on 27 patients preoperatively, on postoperative day 2 and at 2 months. Left ventricular ejection fraction and RV ejection fraction, the ratio of stroke volume to end systolic volume, pulmonary artery acceleration time, and distensibility of main and branch pulmonary arteries were studied. RESULTS: Mean ± standard deviation RV ejection fraction deteriorated from 50.5% ± 6.9% preoperatively to 45.6% ± 4.5% on postoperative day 2 and remained depressed at 44.9% ± 7.7% by 2 months (P = .003). The ratio of stroke volume to end systolic volume deteriorated from median 1.0 (quartile 1, quartile 3: 0.9, 1.2) preoperatively to median 0.8 (quartile 1, quartile 3: 0.7, 1.0) on postoperative day 2 (P = .011). On postoperative day 2 there was a decrease in pulmonary artery acceleration time and operative pulmonary artery distensibility (P < .030 for both). There were no changes in left ventricular ejection fraction during the study period (P = .621). CONCLUSIONS: These findings suggest RV dysfunction occurs following lung resection and persists 2 months after surgery. The deterioration in the ratio of stroke volume to end systolic volume suggests a mismatch between afterload and contractility. There is an increase in indices of pulsatile afterload resulting from the operative pulmonary artery.

Structural characterization and computer-aided optimization of a small-molecule inhibitor of the Arp2/3 complex, a key regulator of the actin cytoskeleton.

CK-666 (1) is a recently discovered small-molecule inhibitor of the actin-related protein 2/3 (Arp2/3) complex, a key actin cytoskeleton regulator with roles in bacterial pathogenesis and cancer cell motility. Although 1 is commercially available, the crystal structure of Arp2/3 complex with 1 bound has not been reported, making its mechanism of action uncertain. Furthermore, its relatively low potency increases its potential for off-target effects in vivo, complicating interpretation of its influence in cell biological studies and precluding its clinical use. Herein we report the crystal structure of 1 bound to Arp2/3 complex, which reveals that 1 binds between the Arp2 and Arp3 subunits to stabilize the inactive conformation of the complex. Based on the crystal structure, we used computational docking and free-energy perturbation calculations of monosubstituted derivatives of 1 to guide optimization efforts. Biochemical assays of ten newly synthesized compounds led to the identification of compound 2, which exhibits a threefold increase in inhibitory activity in vitro relative to 1. In addition, our computational analyses unveiled a surface groove at the interface of the Arp2 and Arp3 subunits that can be exploited for additional structure-based optimization.

Pushing the limits of steric demand around a biaryl axis: synthesis of tetra-ortho-substituted biaryl naphthalenes.

The synthesis of tetra-ortho-substituted biaryl naphthalenes, including examples bearing multiple ortho-isopropyl groups, has been developed via a catalytic rearrangement process.

Synthesis of substituted naphthalenes via a catalytic ring-expansion rearrangement.

A new methodology for the preparation of substituted naphthalenes starting from readily available indenones, organometal reagents, and trimethylsilyldiazomethane via a catalytic rearrangement process is described. Hindered biaryl naphthalenes, including triortho-substituted biaryls, can be accessed through our method. Our results are consistent with a mechanism involving a benzobenzvalene intermediate.