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Unlike the gender-based systems of noun categorization in many European languages, numerous semantic categories contribute to Bantu noun class systems. Kinyarwanda, the focus of our study, has a rich inventory of noun class prefixes, but it is unknown to what degree the semantic and morphological systems underlying these noun classes influence how speakers mentally categorize nominals in their language. To investigate this, speakers of Kinyarwanda (n = 46) were recruited to take part in an online triadic comparison experiment. Across 144 trials, participants were asked to identify the item most different from a written list of three nouns. These lists were constructed based on morphological similarity (from noun classes 3, 5, 7, or 9), semantic overlap (from the domains of ‘mammals’ and ‘tools’), or both. Results show an overall preference for semantic grouping in the triads, although the strength of these preferences differed across individuals. This variation turned out to be systematic and predictable: speakers of Kinyarwanda who spoke Kiswahili as an additional language generally preferred categorizing on the basis of noun class, while those who did not speak Kiswahili as an additional language were more likely to base their decisions on the shared semantic domains of the nouns. These data suggest that noun categorization choices in Kinyarwanda can be influenced by knowledge of other linguistic systems, highlighting the impact that learning additional languages may have on first-language lexical knowledge.

The pervasive presence of Staphylococcus epidermidis and other coagulase-negative staphylococci on the skin and mucous membranes has long underpinned a casual disregard for the infection risk that these organisms pose to vulnerable patients in healthcare settings. Prior to the recognition of biofilm as an important virulence determinant in S. epidermidis, isolation of this microorganism in diagnostic specimens was often overlooked as clinically insignificant with potential delays in diagnosis and onset of appropriate treatment, contributing to the establishment of chronic infection and increased morbidity or mortality. While impressive progress has been made in our understanding of biofilm mechanisms in this important opportunistic pathogen, research into other virulence determinants has lagged S. aureus. In this review, the broader virulence potential of S. epidermidis including biofilm, toxins, proteases, immune evasion strategies and antibiotic resistance mechanisms is surveyed, together with current and future approaches for improved therapeutic interventions.

Abstract Background The objective was to compare sevoflurane, a volatile sedation agent with potential bronchodilatory properties, with propofol on respiratory mechanics in critically ill patients with COPD exacerbation. Methods Prospective study in an ICU enrolling critically ill intubated patients with severe COPD exacerbation and comparing propofol and sevoflurane after 1:1 randomisation. Respiratory system mechanics (airway resistance, PEEPi, trapped volume, ventilatory ratio and respiratory system compliance), gas exchange, vitals, safety and outcome were measured at inclusion and then until H48. Total airway resistance change from baseline to H48 in both sevoflurane and propofol groups was the main endpoint. Results Sixteen patients were enrolled and were sedated for 126 h(61–228) in the propofol group and 207 h(171–216) in the sevoflurane group. At baseline, airway resistance was 21.6cmH2O/l/s(19.8–21.6) in the propofol group and 20.4cmH2O/l/s(18.6–26.4) in the sevoflurane group, (p = 0.73); trapped volume was 260 ml(176–290) in the propofol group and 73 ml(35–126) in the sevoflurane group, p = 0.02. Intrinsic PEEP was 1.5cmH2O(1–3) in both groups after external PEEP optimization. There was neither early (H4) or late (H48) significant difference in airway resistance and respiratory mechanics parameters between the two groups. Conclusions In critically ill patients intubated with COPD exacerbation, there was no significant difference in respiratory mechanics between sevoflurane and propofol from inclusion to H4 and H48.

Abstract Objective Although acute brain infarcts are common after surgical aortic valve replacement (SAVR), they are often unassociated with clinical stroke symptoms. The relationship between clinically “silent” infarcts and in‐hospital delirium remains uncertain; obscured, in part, by how infarcts have been traditionally summarized as global metrics, independent of location or structural consequence. We sought to determine if infarct location and related structural connectivity changes were associated with postoperative delirium after SAVR. Methods A secondary analysis of a randomized multicenter SAVR trial of embolic protection devices (NCT02389894) was conducted, excluding participants with clinical stroke or incomplete neuroimaging (N = 298; 39% female, 7% non‐White, 74 ± 7 years). Delirium during in‐hospital recovery was serially screened using the Confusion Assessment Method. Parcellation and tractography atlas‐based neuroimaging methods were used to determine infarct locations and cortical connectivity effects. Mixed‐effect, zero‐inflated gaussian modeling analyses, accounting for brain region‐specific infarct characteristics, were conducted to examine for differences within and between groups by delirium status and perioperative neuroprotection device strategy. Results 23.5% participants experienced postoperative delirium. Delirium was associated with significantly increased lesion volumes in the right cerebellum and temporal lobe white matter, while diffusion weighted imaging infarct‐related structural disconnection (DWI‐ISD) was observed in frontal and temporal lobe regions (p‐FDR

Summary: This paper argues that a range of current AI systems have learned how to deceive humans. We define deception as the systematic inducement of false beliefs in the pursuit of some outcome other than the truth. We first survey empirical examples of AI deception, discussing both special-use AI systems (including Meta’s CICERO) and general-purpose AI systems (including large language models). Next, we detail several risks from AI deception, such as fraud, election tampering, and losing control of AI. Finally, we outline several potential solutions: first, regulatory frameworks should subject AI systems that are capable of deception to robust risk-assessment requirements; second, policymakers should implement bot-or-not laws; and finally, policymakers should prioritize the funding of relevant research, including tools to detect AI deception and to make AI systems less deceptive. Policymakers, researchers, and the broader public should work proactively to prevent AI deception from destabilizing the shared foundations of our society. The bigger picture: AI systems are already capable of deceiving humans. Deception is the systematic inducement of false beliefs in others to accomplish some outcome other than the truth. Large language models and other AI systems have already learned, from their training, the ability to deceive via techniques such as manipulation, sycophancy, and cheating the safety test. AI’s increasing capabilities at deception pose serious risks, ranging from short-term risks, such as fraud and election tampering, to long-term risks, such as losing control of AI systems. Proactive solutions are needed, such as regulatory frameworks to assess AI deception risks, laws requiring transparency about AI interactions, and further research into detecting and preventing AI deception. Proactively addressing the problem of AI deception is crucial to ensure that AI acts as a beneficial technology that augments rather than destabilizes human knowledge, discourse, and institutions.

In this study, the microbiological quality of traditionally fermented milk from Northern Uganda and Western Kenya was analysed. Six samples of typical traditionally fermented milk were collected randomly from traditional cattle keepers in Karamojong (UG 1) and Acholi (UG 2) in Northern Uganda and Kalenjin in Western Kenya (KE). The microbial quality of the collected samples was assessed through the use of conventional methods for total aerobic mesophilic bacteria, total coliform, lactic acid bacteria, Staphylococcus aureus, Listeria monocytogenes, yeasts, and mould counts. The mean aerobic mesophilic bacterial counts were 5.14 × 109 coliform forming units (cfu)/mL. The mean counts for mesophilic lactobacilli ranged from 106 to 108 cfu/mL. The mean thermophilic lactobacilli count ranged from 107 to 109 cfu/mL, while the mean thermophilic lactococci counts ranged from 106 to 109 cfu/mL. On the other hand, the Streptococci counts were between 106 and 108 cfu/mL. The mean count for the non-sorbitol E. coli was 3.87 × 103 cfu/mL. These results suggest that although the pH of the traditional yoghurt in this study was low, the acidity was not sufficient to inhibit growth of microorganisms in the product. Although it is difficult to avoid the microbial contamination of milk during milking, it is of the utmost importance to maintain a very high level of hygiene in dairy farming practices, and the correct cleaning of teats during milking is very important for good udder health and optimum milk quality, and to ensure safety. The results regarding microbial contamination pose public health concerns, and therefore the appropriate government agencies must pay attention to ensure that the environment in which yoghurt is produced is in the best condition to reduce contamination.

Background: Enhanced Recovery After Surgery (ERAS) protocols for bariatric surgery improve clinical outcomes. However, the impact of ERAS protocols on patient satisfaction is unknown. Virtual reality has been implemented as an effective adjunct to standard analgesic regimens. This study seeks to find out if immersive virtual reality in the immediate postoperative period could improve the subjective quality of recovery and further reduce opioid requirements for bariatric surgery patients compared with ERAS care alone. Methods: This is a single-centre, randomised clinical trial of patients recovering from laparoscopic bariatric surgery. Once in the post-anaesthesia care unit (PACU), participants will receive either an immersive virtual reality plus ERAS protocol or ERAS protocol alone. The primary outcome will be the Quality of Recovery-15 (QoR-15) score at PACU discharge. Secondary outcomes include PACU opioid requirements, length of PACU stay, PACU pain scores, QoR-15 score on postoperative day 1, hospital length of stay, opioid requirements, and opioid-related adverse effects until hospital discharge. Conclusions: Positive findings from this study could introduce virtual reality as a non-pharmacological adjunct during PACU care that improves subjective recovery for patients undergoing bariatric surgery. Clinical trial registration: NCT04754165.

Abstract Machine learning-aided medical decision making presents three major challenges: achieving model parsimony, ensuring credible predictions, and providing real-time recommendations with high computational efficiency. In this paper, we formulate medical decision making as a classification problem and develop a moment kernel machine (MKM) to tackle these challenges. The main idea of our approach is to treat the clinical data of each patient as a probability distribution and leverage moment representations of these distributions to build the MKM, which transforms the high-dimensional clinical data to low-dimensional representations while retaining essential information. We then apply this machine to various pre-surgical clinical datasets to predict surgical outcomes and inform medical decision making, which requires significantly less computational power and time for classification while yielding favorable performance compared to existing methods. Moreover, we utilize synthetic datasets to demonstrate that the developed moment-based data mining framework is robust to noise and missing data, and achieves model parsimony giving an efficient way to generate satisfactory predictions to aid personalized medical decision making.

Abstract Background Cystic Fibrosis (CF) is a genetic condition characterized by neutrophilic inflammation and recurrent infection of the airways. How these processes are initiated and perpetuated in CF remains largely unknown. We have demonstrated a link between the intestinal microbiota-related metabolites bile acids (BA) and inflammation in the bronchoalveolar lavage fluid (BALF) from children with stable CF lung disease. To establish if BA indicate early pathological processes in CF lung disease, we combined targeted mass spectrometry and amplicon sequencing-based microbial characterization of 121 BALF specimens collected from 12-month old infants with CF enrolled in the COMBAT-CF study, a multicentre randomized placebo-controlled clinical trial comparing azithromycin versus placebo. We evaluated whether detection of BA in BALF is associated with the establishment of the inflammatory and microbial landscape of early CF lung disease, and whether azithromycin, a motilin agonist that has been demonstrated to reduce aspiration of gastric contents, alters the odds of detecting BA in BALF. We also explored how different prophylactic antibiotics regimens impact the early life BALF microbiota. Results Detection of BA in BALF was strongly associated with biomarkers of airway inflammation, more exacerbation episodes during the first year of life, increased use of oral antibiotics with prolonged treatment periods, a higher degree of structural lung damage, and distinct microbial profiles. Treatment with azithromycin, a motilin agonist, which has been reported to reduce aspiration of gastric contents, did not reduce the odds of detecting BA in BALF. Culture and molecular methods showed that azithromycin does not alter bacterial load or diversity in BALF. Conversely, penicillin-type prophylaxis reduced the odds of detecting BAs in BALF, which was associated with elevated levels of circulating biomarkers of cholestasis. We also observed that environmental factors such as penicillin-type prophylaxis or BAs detection were linked to distinct early microbial communities of the CF airways, which were associated with different inflammatory landscapes but not with structural lung damage. Conclusions Detection of BA in BALF portend early pathological events in CF lung disease. Benefits early in life associated with azithromycin are not linked to its antimicrobial properties. Video Abstract

Background: Postoperative depression is not well characterised. We investigated the incidence of postoperative depression with the hypothesis that after controlling for confounders, new onset depression would vary significantly by surgical type. Methods: We conducted a retrospective cohort study using the Optum Clinformatics Datamart. The primary outcome was new onset postoperative depression, defined by a new diagnosis of depression or new prescription for an antidepressant in the year after surgery using International Classification of Diseases (ICD) 9/10 codes and drug names. Adjustment for preoperative comorbidities and predictors of depression was with multivariable Cox regression and propensity score matching. Sensitivity analyses defining new onset depression as both a new diagnosis of depression and a new prescription for an antidepressant, or either outcome separately, were conducted. Results: Data from 132 390 cardiac surgery, 12 538 thoracotomy, 32 630 video-assisted thoracoscopic surgery (VATS), 96 750 hip fracture surgery, 157 484 hip replacement, and 347 878 laparoscopic cholecystectomy patients from January 2004 to June 2021 were analysed. The incidence of new onset postoperative depression was 18.8% for hip fracture surgery, 16.1% for thoracotomy, 12.6% for cardiac surgery, 12.4% for VATS, 8.6% for laparoscopic cholecystectomy, and 6.8% for hip replacement. After multivariable adjustment, hip fracture surgery patients were most likely to develop new onset postoperative depression (hazard ratio [95% confidence interval]) 1.56 [1.45–1.68]), followed by thoracotomy (1.12 [1.03–1.22]), cardiac surgery (1.09 [1.04–1.12]), VATS (0.95 [0.90–1.00]), and hip replacement (0.55 [0.52–0.57]) compared with patients undergoing laparoscopic cholecystectomy (hazard ratio=1). Results from propensity score matched analyses and sensitivity analyses were similar. Conclusions: The risk of postoperative depression differs by surgical type after controlling for preoperative characteristics.

Background. Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of global mortality, often associated with high blood levels of LDL cholesterol (LDL-c). Medications like statins and PCSK9 inhibitors, are used to manage LDL-c levels and reduce ASCVD risk. Recent findings connect the gut microbiota and its metabolites to ASCVD development. We showed that statins modulate the gut microbiota including the production of microbial metabolites involved in the regulation of cholesterol metabolism such as short chain fatty acids (SCFAs) and bile acids (BAs). Whether this pleiotropic effect of statins is associated with their antimicrobial properties or it is secondary to the modulation of cholesterol metabolism in the host is unknown. In this observational study, we evaluated whether alirocumab, a PCSK9 inhibitor administered subcutaneously, alters the stool-associated microbiota and the profiles of SCFAs and BAs. Methods. We used stool and plasma collected from patients enrolled in a single-sequence study using alirocumab. Microbial DNA was extracted from stool, and the bacterial component of the gut microbiota profiled following an amplicon sequencing strategy targeting the V3-V4 region of the 16S rRNA gene. Bile acids and SCFAs were profiled and quantified in stool and plasma using mass spectrometry. Results. Treatment with alirocumab did not alter bacterial alpha (Shannon index, p = 0.74) or beta diversity (PERMANOVA, p = 0.89) in feces. Similarly, circulating levels of SCFAs (mean difference (95% confidence interval (CI)), 8.12 [−7.15–23.36] µM, p = 0.25) and BAs (mean difference (95% CI), 0.04 [−0.11–0.19] log10(nmol mg−1 feces), p = 0.56) were equivalent regardless of PCSK9 inhibition. Alirocumab therapy was associated with increased concentration of BAs in feces (mean difference (95% CI), 0.20 [0.05–0.34] log10(nmol mg−1 feces), p = 0.01). Conclusion. In statin-treated patients, the use of alirocumab to inhibit PCSK9 leads to elevated levels of fecal BAs without altering the bacterial population of the gut microbiota. The association of alirocumab with increased fecal BA concentration suggests an additional mechanism for the cholesterol-lowering effect of PCSK9 inhibition.

Abstract Background Minimally invasive thoracic surgery (MITS) has been shown to reduce postoperative pain and contribute to better postoperative quality of life as compared to open thoracic surgery (Bendixen et al., Lancet Oncol 17:836–44, 2016). However, it still causes significant post-operative pain. Regional anaesthesia techniques including fascial plane blocks such as the erector spinae plane block (ESP) have been shown to contribute to post-operative pain control after MITS (Finnerty et al., Br J Anaesth 125:802–10, 2020). Case reports relating to ESP catheters have described improved quality of pain relief using programmed intermittent boluses (PIB) instead of continuous infusion (Bendixen et al., Lancet Oncol 17:836–44, 2016). It is suggested that larger, repeated bolus dose may provide superior pain relief, possibly because of improved spread of the local anaesthetic medications (Ilfeld and Gabriel, Reg Anesth Pain Med 44:285–86, 2019). Evidence for improved spread of local anaesthetic may be found in one study which demonstrated that PIB increased the spread of local anaesthetic medication compared to continuous infusions for continuous paravertebral blocks, which are another type of regional anaesthesia technique for the chest wall (Hida et al., Reg Anesth Pain Med 44:326–32, 2019). Similarly, regarding labour epidural analgesia, the weight of evidence is in favour of PIB providing better pain relief compared with continuous infusion (Onuoha, Anesthesiol Clin 35:1–14, 2017). Since fascial plane blocks, such as ESP, rely on the spread of local anaesthetic medication between muscle layers of the chest wall, intermittent boluses may be particularly useful for this group of blocks. However, until recently, pumps capable of providing automated boluses in addition to patient-controlled boluses were not widely available. To best of our knowledge, there are no randomised controlled trials comparing continuous infusion versus intermittent bolus strategies for erector spinae plane block for MITS in terms of patient centred outcomes such as quality of recovery. Methods This trial will be a prospective, double-blinded, randomised controlled superiority trial. A total of 60 eligible patients will be randomly assigned to receive an intermittent bolus regime of local anaesthetic vs a continuous infusion of local anaesthetic. The medication will be delivered via an ultrasound-guided erector spinae plane block catheter which will be inserted by an anaesthesiologist while the patient is under general anaesthetic before their MITS surgery begins. The primary outcome being measured is the Quality of Recovery (QoR-15) score between the two groups 24 h after surgery. Secondary outcomes include respiratory testing of maximal inspiratory volume measured with a calibrated incentive spirometer, area under the curve for Verbal Rating Score for pain at rest and on deep inspiration versus time over 48 h, total opioid consumption over 48 h, QoR-15 score at 48 h and time to first mobilisation. Discussion Despite surgical advancements in thoracic surgery, severe acute post-operative pain following MITS is still prevalent. This study will provide new knowledge and possible recommendations about the efficacy of programmed intermittent bolus regimen of local anaesthetic vs a continuous infusion of local anaesthetic via an ultrasound-guided erector spinae plane catheter for patients undergoing MITS. Trial registration This trial was pre-registered on ClinicalTrials.gov Identifier: NCT05181371 . Registered on 6 January 2022. All item from the World Health Organization Trial Registration Data set have been included.

ABSTRACT The purine-derived signaling molecules c-di-AMP and (p)ppGpp control mecA/PBP2a-mediated β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) raise the possibility that purine availability can control antibiotic susceptibility. Consistent with this, exogenous guanosine and xanthosine, which are fluxed through the GTP branch of purine biosynthesis, were shown to significantly reduce MRSA β-lactam resistance. In contrast, adenosine (fluxed to ATP) significantly increased oxacillin resistance, whereas inosine (which can be fluxed to ATP and GTP via hypoxanthine) only marginally increased oxacillin susceptibility. Furthermore, mutations that interfere with de novo purine synthesis (pur operon), transport (NupG, PbuG, PbuX) and the salvage pathway (DeoD2, Hpt) increased β-lactam resistance in MRSA strain JE2. Increased resistance of a nupG mutant was not significantly reversed by guanosine, indicating that NupG is required for guanosine transport, which is required to reduce β-lactam resistance. Suppressor mutants resistant to oxacillin/guanosine combinations contained several purine salvage pathway mutations, including nupG and hpt. Guanosine significantly increased cell size and reduced levels of c-di-AMP, while inactivation of GdpP, the c-di-AMP phosphodiesterase negated the impact of guanosine on β-lactam susceptibility. PBP2a expression was unaffected in nupG or deoD2 mutants, suggesting that guanosine-induced β-lactam susceptibility may result from dysfunctional c-di-AMP-dependent osmoregulation. These data reveal the therapeutic potential of purine nucleosides, as β-lactam adjuvants that interfere with the normal activation of c-di-AMP are required for high-level β-lactam resistance in MRSA. IMPORTANCE The clinical burden of infections caused by antimicrobial resistant (AMR) pathogens is a leading threat to public health. Maintaining the effectiveness of existing antimicrobial drugs or finding ways to reintroduce drugs to which resistance is widespread is an important part of efforts to address the AMR crisis. Predominantly, the safest and most effective class of antibiotics are the β-lactams, which are no longer effective against methicillin-resistant Staphylococcus aureus (MRSA). Here, we report that the purine nucleosides guanosine and xanthosine have potent activity as adjuvants that can resensitize MRSA to oxacillin and other β-lactam antibiotics. Mechanistically, exposure of MRSA to these nucleosides significantly reduced the levels of the cyclic dinucleotide c-di-AMP, which is required for β-lactam resistance. Drugs derived from nucleotides are widely used in the treatment of cancer and viral infections highlighting the clinical potential of using purine nucleosides to restore or enhance the therapeutic effectiveness of β-lactams against MRSA and potentially other AMR pathogens.

The gut microbiome plays a significant role in regulating the host’s ability to store fat, which impacts the development of obesity. This observational cohort study recruited obese adult men and women scheduled to undergo sleeve gastrectomy and followed up with them 6 months post-surgery to analyse their microbial taxonomic profiles and associated metabolites in comparison to a healthy control group. There were no significant differences in the gut bacterial diversity between the bariatric patients at baseline and at follow-up or between the bariatric patients and the cohort of healthy controls. However, there were differential abundances in specific bacterial groups between the two cohorts. The bariatric patients were observed to have significant enrichment in Granulicatella at baseline and Streptococcus and Actinomyces at follow-up compared to the healthy controls. Several operational taxonomic units assigned to commensal Clostridia were significantly reduced in the stool of bariatric patients both at baseline and follow-up. When compared to a healthy cohort, the plasma levels of the short chain fatty acid acetate were significantly higher in the bariatric surgery group at baseline. This remained significant when adjusted for age and sex (p = 0.013). The levels of soluble CD14 and CD163 were significantly higher (p = 0.0432 and p = 0.0067, respectively) in the bariatric surgery patients compared to the healthy controls at baseline. The present study demonstrated that there are alterations in the abundance of certain bacterial groups in the gut microbiome of obese patients prior to bariatric surgery compared to healthy individuals, which persist post-sleeve gastrectomy.

Henry Devlin,1,* Stephanie Fulaz,1,* Dishon Wayne Hiebner,1 James P O’Gara,2 Eoin Casey1 1UCD School of Chemical and Bioprocess Engineering, University College Dublin, Dublin, Ireland; 2Department of Microbiology, School of Natural Sciences, National University of Ireland, Galway, Ireland*These authors contributed equally to this workCorrespondence: Eoin CaseyUCD School of Chemical and Bioprocess Engineering, University College Dublin, Belfield, Dublin, IrelandEmail eoin.casey@ucd.ieBackground: Staphylococcus aureus biofilms pose a unique challenge in healthcare due to their tolerance to a wide range of antimicrobial agents. The high cost and lengthy timeline to develop novel therapeutic agents have pushed researchers to investigate the use of nanomaterials to deliver antibiofilm agents and target biofilm infections more efficiently. Previous studies have concentrated on improving the efficacy of antibiotics by deploying nanoparticles as nanocarriers. However, the dispersal of the extracellular polymeric substance (EPS) matrix in biofilm-associated infections is also critical to the development of novel nanoparticle-based therapies.Methods: This study evaluated the efficacy of enzyme-functionalized mesoporous silica nanoparticles (MSNs) against methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) biofilms. MSNs were functionalized with the enzyme lysostaphin, which causes cell lysis of S. aureus bacteria. This was combined with two other enzyme functionalized MSNs, serrapeptase and DNase I which will degrade protein and eDNA in the EPS matrix, to enhance eradication of the biofilm. Cell viability after treatment with enzyme-functionalized MSNs was assessed using a MTT assay and CLSM, while crystal violet staining was used to assess EPS removal.Results: The efficacy of all three enzymes against S. aureus cells and biofilms was significantly improved when they were immobilized onto MSNs. Treatment efficacy was further enhanced when the three enzymes were used in combination against both MRSA and MSSA. Regardless of biofilm maturity (24 or 48 h), near-complete dispersal and killing of MRSA biofilms were observed after treatment with the enzyme-functionalized MSNs. Disruption of mature MSSA biofilms with a polysaccharide EPS was less efficient, but cell viability was significantly reduced.Conclusion: The combination of these three enzymes and their functionalization onto nanoparticles might extend the therapeutic options for the treatment of S. aureus infections, particularly those with a biofilm component.Keywords: MRSA, lysostaphin, antimicrobial, antibiofilm, EPS matrix

While early empiric antibiotic therapy is beneficial for patients presenting with sepsis, the presentation of sepsis from Clostridioides difficile (formerly Clostridium difficile) infection (CDI) has not been well studied in large cohorts. We sought to determine whether the combination of extreme leukocytosis and diarrhea was strongly predictive of CDI in a cohort of 8659 patients admitted to the intensive care unit. We found that CDI was present in 15.0% (95% CI, 12.1–18.3%) of patients with extreme leukocytosis and diarrhea and that mortality for those with CDI, diarrhea, and extreme leukocytosis was 33.8% (95% CI, 23.2–44.3%). These data support consideration of empiric treatment for CDI in unstable critically ill patients with extreme leukocytosis and diarrhea, along with treatment of other possible sources of sepsis as appropriate. Empiric treatment for CDI can usually be discontinued promptly, along with narrowing of other broad-spectrum antimicrobial coverage, if a sensitive C. difficile test is negative.

Background: The “July effect”, the perception of worse outcomes in the first month of training, has been previously demonstrated in critical care medicine and general surgery. However, the July effect in the context of structural heart interventions (i.e., transcatheter aortic valve replacement [TAVR] and MitraClip) remains unknown. Methods: All adult patients undergoing TAVR or MitraClip in the 2012-2016 National Inpatient Sample were included. Outcomes were compared by procedure month and academic year quartiles (i.e., between the first academic year quartile [Q1] vs. the fourth quartile [Q4]). Outcomes between teaching and nonteaching hospitals were compared using risk-adjusted logistic difference-in-difference regression. Results: During the study period, 94,170 TAVR (Q1: 25,250; Q4: 23,170) and 8750 MitraClip (Q1: 2220; Q4: 2150) procedures were performed. In-hospital mortality did not vary as per academic year quartiles for either procedure, even after risk adjustment. These findings persisted in sensitivity analysis by procedure month and newer device era (2015-2016; all p > 0.05). In the subgroup analysis, the unadjusted and adjusted Q1 vs. Q4 in-hospital mortality between teaching and nonteaching hospitals were similar for either procedure. In-hospital mortality also did not vary by procedure month when stratified by hospital teaching status for both procedures. However, postprocedural complication rates appeared to be improving among the TAVR teaching hospitals for stroke, major bleeding, and vascular complications (all p < 0.05). Conclusions: In this large, nationwide study, the July effect was not evident for structural heart interventions. With increasing interest and growth in transcatheter procedures, early resident and fellow teaching can be achieved with appropriate supervision.

Nickel hypersensitivity is a rarely reported complication of percutaneous patent foramen ovale/atrial septal defect closure. Herein, we report a case of systemic allergic contact dermatitis to nickel present in a GORE CARDIOFORM (W.L. Gore, Flagstaff, Arizona) septal occluder that resolved following explanation. To our knowledge this is the first published case of nickel hypersensitivity associated with this device. (Level of Difficulty: Beginner.)

Stephanie Fulaz,1,* Henry Devlin,1,* Stefania Vitale,1 Laura Quinn,1 James P O’Gara,2 Eoin Casey1 1UCD School of Chemical and Bioprocess Engineering, University College Dublin, Dublin, Ireland; 2Department of Microbiology, School of Natural Sciences, National University of Ireland, Galway, Ireland*These authors contributed equally to this workCorrespondence: Eoin CaseyUCD School of Chemical and Bioprocess Engineering, University College Dublin, Belfield, Dublin 4, Dublin, IrelandEmail eoin.casey@ucd.ieBackground: Considering the timeline required for the development of novel antimicrobial drugs, increased attention should be given to repurposing old drugs and improving antimicrobial efficacy, particularly for chronic infections associated with biofilms. Methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) are common causes of biofilm-associated infections but produce different biofilm matrices. MSSA biofilm cells are typically embedded in an extracellular polysaccharide matrix, whereas MRSA biofilms comprise predominantly of surface proteins and extracellular DNA (eDNA). Nanoparticles (NPs) have the potential to enhance the delivery of antimicrobial agents into biofilms. However, the mechanisms which influence the interactions between NPs and the biofilm matrix are not yet fully understood.Methods: To investigate the influence of NPs surface chemistry on vancomycin (VAN) encapsulation and NP entrapment in MRSA and MSSA biofilms, mesoporous silica nanoparticles (MSNs) with different surface functionalization (bare-B, amine-D, carboxyl-C, aromatic-A) were synthesised using an adapted Stöber method. The antibacterial efficacy of VAN-loaded MSNs was assessed against MRSA and MSSA biofilms.Results: The two negatively charged MSNs (MSN-B and MSN-C) showed a higher VAN loading in comparison to the positively charged MSNs (MSN-D and MSN-A). Cellular binding with MSN suspensions (0.25 mg mL− 1) correlated with the reduced viability of both MSSA and MRSA biofilm cells. This allowed the administration of low MSNs concentrations while maintaining a high local concentration of the antibiotic surrounding the bacterial cells.Conclusion: Our data suggest that by tailoring the surface functionalization of MSNs, enhanced bacterial cell targeting can be achieved, leading to a novel treatment strategy for biofilm infections.Keywords: Staphylococcus aureus, mesoporous silica nanoparticles, EPS matrix, antimicrobial, vancomycin, nanoparticle-biofilm interactions

Background: The association between impaired fasting glucose level (IFG) and coronary heart disease (CAD) remain controversial. In the present study, we sought to ascertain a relationship of IFG with the number of diseased coronary artery and occurrence of myocardial infarction, among CAD cases.Methods: We studied 1,451 consecutive no-diabetic patients who underwent coronary angiography at the First Affiliated Hospital of Shantou University Medical College in Southern China. Demographic, biochemical, clinical and angiographic data were collected.Results: The prevalence of IFG was higher in patients with angiographically confirmed CAD than in subjects without angiographic evidence of CAD (33.4 versus 28.2%, p = 0.034). Compared with CAD cases without IFG, CAD cases with IFG had a higher odds ratio (OR) of having triple-vessel disease as opposed to having single- or double-vessel disease [OR = 1.53, 95% confidence interval (CI) = 1.13–2.07]. Furthermore, the occurrence of MI was higher in CAD cases with IFG than in CAD cases without IFG (OR = 1.73, 95% CI = 1.27–2.36).Conclusions: There is an association between IFG and a predisposition to severe CAD indicated by triple vessel disease or myocardial infarction.

Introduction Common anesthesia practice for hand surgery combines a preoperative regional anesthetic and intraoperative monitored anesthesia care (MAC). Despite adequate regional anesthesia, patients may receive doses of intraoperative sedatives which can result in oversedation and potentially avoidable complications. VR could prove to be a valuable tool for patients and providers by distracting the mind from processing noxious stimuli resulting in minimized sedative use and reduced risk of oversedation without negatively impacting patient satisfaction. Our hypothesis was that intraoperative VR use reduces sedative dosing during elective hand surgery without detracting from patient satisfaction as compared to a usual care control. Methods Forty adults undergoing hand surgery were randomized to receive either intraoperative VR in addition to MAC, or usual MAC. Patients in both groups received preoperative regional anesthesia at provider discretion. Intraoperatively, the VR group viewed programming of their choice via a head-mounted display. The primary outcome was intraoperative propofol dose per hour (mg · hr-1). Secondary outcomes included patient reported pain and anxiety, overall satisfaction, functional outcome, and post anesthesia care unit (PACU) length of stay (LOS). Results Of the 40 enrolled patients, 34 completed the perioperative portion of the trial. VR group patients received significantly less propofol per hour than the control group (Mean (±SD): 125.3 (±296.0) vs 750.6 (±334.6) mg · hr-1, pConclusion VR immersion during hand surgery led to significant reductions in intraoperative propofol dose and PACU LOS without negatively impacting key patient reported outcomes.

Ocean Sampling Day was initiated by the EU-funded Micro B3 (Marine Microbial Biodiversity, Bioinformatics, Biotechnology) project to obtain a snapshot of the marine microbial biodiversity and function of the world's oceans. It is a simultaneous global mega-sequencing campaign aiming to generate the largest standardized microbial data set in a single day. This will be achievable only through the coordinated efforts of an Ocean Sampling Day Consortium, supportive partnerships and networks between sites. This commentary outlines the establishment, function and aims of the Consortium and describes our vision for a sustainable study of marine microbial communities and their embedded functional traits.

Introduction: Wound healing is characterised by haemostatic, inflammatory, proliferative and remodelling phases. In the presence of comorbidities such as diabetes, healing can stall and chronic wounds may result. Infection is detrimental to these wounds and associated with poor outcomes. Wounds are contaminated with microbes and debris, and factors such as host resistance, bacterial virulence, species synergy and bioburden determine whether a wound will deteriorate to critically colonised/infected states. Biofilms are sessile microbial communities, exhibiting high-level antibiotic tolerance and resistance to host defences. Biofilm in critically colonised wounds can contribute to delayed healing. Little is known about clinical presentation and diagnosis of wound biofilms. Objective: To identify from the literature clinical signs, symptoms and biomarkers that may indicate biofilm presence in chronic wounds. Methods: This review will be guided by the Preferred Reporting Items for Systematic Reviews extension for Scoping Reviews (PRISMA-ScR), and the Joanna Briggs Institute Manual for Evidence Synthesis. Studies of any design in any language recruiting adult patients with venous, diabetic, pressure or mixed arterial-venous ulcers and reporting data on clinical signs/symptoms of biofilm are eligible. Searches of Medline, Embase, CINAHL, Cochrane Central and BASE will be conducted from inception to present. Reference scanning and contact with content experts will be employed. Title/abstract screening and full text selection will be executed by two reviewers independently. Discrepancies will be resolved by discussion between reviewers or through third party intervention. Data will be extracted by a single reviewer and verified by a second. Clinical signs and symptoms data will be presented in terms of study design, setting and participant demographic data. Discussion: Understanding biofilm impact on chronic wounds is inconsistent and based largely on in vitro research. This work will consolidate clinical signs, symptoms and biomarkers of biofilm in chronic wounds reported in the literature.

Study objective: The Coronary Vasomotor Disorders International Study Group (COVADIS) invited leading experts to address strategies to enhance our clinical understanding of INOCA with an emphasis on the management of coronary vasomotor disorders. Design: Under-recognition of coronary vasomotor disorders, distinguishing different presentations of angina due to vasospasm and/or abnormal microvascular vasodilatation, developing invasive/non-invasive testing and treatment protocols, integrating diagnostic protocols into cardiologists' workflow and trials to inform guideline development were identified as key knowledge gaps and will be briefly addressed in this Viewpoint article. Setting: Virtual international meeting. Participants: Leading international experts in ischemic heart disease with no obstructive coronary artery disease. Interventions: None. Main outcome measures: None. Results: Topics discussed include: 1. Obstructive epicardial disease, functional vasospasm and microvascular disorders; 2. Under-recognition of coronary vasomotor disorders in clinical practice; 3. Complexity of coronary vasomotor disorders; 4. Understanding different presentations - vasospastic disease and microvascular angina; 5. Invasive/noninvasive testing and treatment protocols for vasospasm and microvascular angina assessment; 6. Treatment challenges; 7. Integrating diagnostic protocols into cardiologists' workflow; 8. The path forward to advance our approach to managing myocardial ischemia. Conclusions: Obstructive epicardial disease, functional vasospasm and microvascular disorders often co-exist and contribute to myocardial ischemia. Under-recognition, the complexity of coronary vasomotor disorders, understanding different presentations, testing and treatment protocols, treatment challenges, and integrating diagnostic protocols into cardiologists' workflow all contribute to the path forward to advance our management of myocardial ischemia for improved patient outcomes.

Background: Previous studies have reported that biomarkers of liver injury and renal dysfunction were associated with hypertensive disorders of pregnancy (HDP). However, the associations of these biomarkers in early pregnancy with the risk of HDP and longitudinal blood pressure pattern during pregnancy were rarely investigated in prospective cohort studies.Methods: A total of 1,041 pregnant women were enrolled in this prospective cohort study. BP was assessed in four stages throughout pregnancy. The following biomarkers were measured at early pregnancy before 18 weeks gestation: lactate dehydrogenase (LDH), aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), uric acid (UA), and estimated glomerular filtration rate (eGFR). Linear mixed-effects and logistic regression models were used to examine the associations of these biomarkers with longitudinal BP pattern during pregnancy and HDP incidence, respectively.Results: In unadjusted models, higher serum UA, GGT, ALP, and LDH levels, as well as lower eGFR and AST/ALT, were associated with higher BP levels during pregnancy and an increased risk of HDP. After adjustment for maternal age, pre-pregnancy BMI and other potential confounders, UA, GGT, ALP, and LDH remained positively associated with both BP and HDP. However, eGFR and AST/ALT were not associated with HDP after adjusting for potential confounders. When including all 6 biomarkers simultaneously in multivariable analyses, increased UA, GGT, and ALP significantly associated with gestational hypertension and preeclampsia.Conclusion: This study suggests that increased UA, GGT, and ALP in early-pregnancy are independent risk factors of gestational hypertension and preeclampsia.

An unprecedented number of young children in Sub-Saharan Africa are being adversely affected by the HIV/AIDS pandemic, yet programs specifically designed to meet the developmental needs of orphaned and vulnerable children (OVC) from birth to age 8 are rare. This article summarizes the daunting array of challenges facing young OVC in Sub-Saharan Africa, and profiles research and action projects undertaken by four members of the inaugural graduate-level cohort of the ECDVU to promote high-quality developmentally appropriate ECD care for young OVC in their respective countries. The projects underscore the pressing need for community-based, national and international stakeholders to reach beyond the escalating immediate demands for survival-level support for these children--culturally appropriate ECD training and resources for both overburdened extended family and institution-based caregivers of young OVC must also be promoted as essential priorities. Higher levels of physical, cognitive, and emotional well-being and increased lifetime learning and earning are associated with good early childhood care; timely provision of integrated quality ECD training and care is urgently needed if today's young OVC are to mature into productive and contributing members to Sub-Saharan African society in their adult years. (Contains 3 notes.)

Abstract Background Advancements in virtual reality (VR) technology have resulted in its expansion into health care. Preliminary studies have found VR to be effective as an adjunct to anesthesia to reduce pain and anxiety for patients during upper gastrointestinal endoscopies, dental procedures and joint arthroplasties. Current standard care practice for upper extremity surgery includes a combination of regional anesthesia and intraoperative propofol sedation. Commonly, patients receive deep propofol sedation during these cases, leading to potentially avoidable risks of over-sedation, hypotension, upper airway obstruction, and apnea. The objective of this study is to evaluate the effectiveness of VR technology to promote relaxation for patients undergoing upper extremity surgery, thereby reducing intraoperative anesthetic requirements and improving the perioperative patient experience. Methods In this single-center, randomized controlled trial, 40 adult patients undergoing upper extremity orthopedic surgery will be randomly allocated to either intraoperative VR immersion or usual care. VR immersion is designed to provide patients with a relaxing virtual environment to alleviate intraoperative anxiety. All patients receive a peripheral nerve block prior to surgery. Patients in the intervention group will select videos or immersive environments which will be played in the VR headset during surgery. An anesthesia provider will perform their usual clinical responsibilities intraoperatively and can administer anesthetic medications if and when clinically necessary. Patients in the control arm will undergo perioperative anesthesia according to standard care practice. The primary outcome is the difference in intraoperative propofol dose between the groups. Secondary outcomes include postoperative analgesia requirements and pain scores, length of stay in the postanesthesia care unit, overall patient satisfaction and postoperative functional outcomes. Discussion It is unknown whether the use of VR during upper extremity surgery can reduce intraoperative anesthetic requirements, reduce perioperative complications, or improve the postoperative patient experience. A positive result from this clinical trial would add to the growing body of evidence that demonstrates the effectiveness of VR as an adjunct to anesthesia in reducing intraoperative pain and anxiety for multiple types of procedure. This could lead to a change in practice, with the introduction of a nonpharmacologic intervention potentially reducing the burden of over-sedation while still providing a satisfactory perioperative experience. Trial registration ClinicalTrials.gov, NCT03614325. Registered on 9 July 2018.

Summary In recent years, the marine environment has been the subject of increasing attention from biotechnological and pharmaceutical industries. A combination of unique physicochemical properties and spatial niche‐specific substrates, in wide‐ranging and extreme habitats, underscores the potential of the marine environment to deliver on functionally novel bioactivities. One such area of ongoing research is the discovery of compounds that interfere with the cell–cell signalling process called quorum sensing (QS). Described as the next generation of antimicrobials, these compounds can target virulence and persistence of clinically relevant pathogens, independent of any growth‐limiting effects. Marine sponges are a rich source of microbial diversity, with dynamic populations in a symbiotic relationship. In this study, we have harnessed the QS inhibition (QSI) potential of marine sponge microbiota and through culture‐based discovery have uncovered small molecule signal mimics that neutralize virulence phenotypes in clinical pathogens. This study describes for the first time a marine sponge Psychrobacter sp. isolate B98C22 that blocks QS signalling, while also reporting dual QS/QSI activity in the Pseudoalteromonas sp. J10 and ParacoccusJM45. Isolation of novel QSI activities has significant potential for future therapeutic development, of particular relevance in the light of the pending perfect storm of antibiotic resistance meeting antibiotic drug discovery decline.

Abstract Background Patients undergoing cardiac surgery with cardiopulmonary bypass are at an increased risk of developing postoperative pulmonary complications, potentially leading to excess morbidity and mortality. It is likely that pulmonary ischemia-reperfusion (IR) injury during cardiopulmonary bypass is a major contributor to perioperative lung injury. Therefore, interventions that can minimize IR injury would be valuable in reducing the excess burden of this potentially preventable disease process. Volatile anesthetics including sevoflurane have been shown in both preclinical and human trials to effectively limit pulmonary inflammation in a number of settings including ischemia-reperfusion injury. However, this finding has not yet been demonstrated in the cardiac surgery population. The Anesthetics to Prevent Lung Injury in Cardiac Surgery (APLICS) trial is a randomized controlled trial (RCT) investigating whether sevoflurane anesthetic maintenance can modulate pulmonary inflammation occurring during cardiac surgery with cardiopulmonary bypass and whether this potential effect can translate to a reduction in postoperative pulmonary complications. Methods APLICS is a prospective RCT of adult cardiac surgical patients. Participants will be randomized to receive intraoperative anesthetic maintenance with either sevoflurane or propofol. Patients in both groups will be ventilated according to protocols intended to minimize the influences of ventilator-induced lung injury and hyperoxia. Bronchoalveolar lavage (BAL) and blood sampling will take place after anesthetic induction and 2–4 h after pulmonary reperfusion. The primary outcome is a difference between groups in the degree of post-bypass lung inflammation, defined by BAL concentrations of TNFα. Secondary outcomes will include differences in additional relevant BAL and systemic inflammatory markers and the incidence of postoperative pulmonary complications. Discussion APLICS investigates whether anesthetic choice can influence lung inflammation and pulmonary outcomes following cardiac surgery with cardiopulmonary bypass. A positive result from this trial would add to the growing body of evidence describing the lung protective properties of the volatile anesthetics and potentially reduce unnecessary morbidity for cardiac surgery patients. Trial registration ClinicalTrials.gov, NCT02918877. Registered on 29 September 2016.

Abstract Background Cardiac surgical procedures are associated with postoperative neurological complications such as cognitive decline and delirium, which can complicate recovery and impair quality of life. Perioperative depression and anxiety may be associated with increased mortality after cardiac surgeries. Surgical prehabilitation is an emerging concept that includes preoperative interventions to potentially reduce postoperative complications. While most current prehabilitation interventions focus on optimizing physical health, mind–body interventions are an area of growing interest. Preoperative mind–body interventions such as Isha Kriya meditation, may hold significant potential to improve postsurgical outcomes. Methods This is a prospective, randomized controlled feasibility trial. A total of 40 adult patients undergoing cardiac surgery will be randomized to one of three study groups. Participants randomized to either of the two intervention groups will receive meditative intervention: (1) commencing two weeks before surgery; or (2) commencing only from the day after surgery. Meditative intervention will last for four weeks after the surgery in these groups. Participants in the third control group will receive the current standard of care with no meditative intervention. All participants will undergo assessments using neurocognitive, sleep, depression, anxiety, and pain questionnaires at various time points in the perioperative period. Blood samples will be collected at baseline, preoperatively, and postoperatively to assess for inflammatory biomarkers. The primary aim of this trial is to assess the feasibility of implementing a perioperative meditative intervention program. Other objectives include studying the effect of meditation on postoperative pain, sleep, psychological wellbeing, cognitive function, and delirium. These will be used to calculate effect size to design future studies. Discussion This study serves as the first step towards understanding the feasibility of implementing a mind–body intervention as a prehabilitative intervention to improve postoperative surgical outcomes after cardiac surgery. Trial registration Clinicaltrials.gov, NCT03198039. Registered on 23 June 2017.