Consideration of factors associated with inequalities in interventions that support health-care professionals' interaction with patients to reduce inappropriate antimicrobial use: a systematic review.

BACKGROUND: Tackling the public health challenge of antimicrobial resistance (AMR) requires promotion of appropriate antimicrobial use by health-care professionals. The objective of this review was to identify interventions that facilitate appropriate antimicrobial behaviours when health-care professionals interact with patients and any considerations for factors associated with health inequalities. METHODS: For this systematic review, we searched electronic databases (MEDLINE, EMBASE, Web of Science and Google Scholar) from Jan 31, 2023, to Feb 8, 2023. We included search terms such as antimicrobial use/prescribing, health-care professionals, and AMR programmes. We included any relevant primary study published from year 2010 and in English. We conducted forward and backward citation searching from included studies on March 27, 2023. We extracted information on the interventions following the Template for Intervention Description and Replication (TIDieR) guideline and examined reports on how the interventions might impact on inequalities. We performed quality assessment using the Mixed Methods Appraisal Tool (MMAT). We conducted descriptive synthesis. The protocol is registered with PROSPERO (CRD42023395642). FINDINGS: After screening 4979 records, we included 59 studies. Most studies were randomised trials (n=25) and qualitative/mixed methods studies (n=16). Included studies covered 16 countries, particularly the UK (n=16) and the USA (n=13). Most studies (n=34) fulfilled at least 80% of the relevant quality criteria, but 12 studies fulfilled less than 50%. Many interventions were established strategies (eg, TARGET: Treat Antibiotics Responsibly, Guidance, Education and Tools). Patient interaction elements of the interventions often involved using education materials (eg, digital/paper leaflets, and videos) and point-of-care testing. While many studies (n=49) included participants from disadvantaged groups, only three examined how outcomes differ between groups. In those studies, antimicrobial prescription was not associated with age, sex, and level of learning disability. Some other studies reported issues with language barriers and potential digital exclusion, especially for older people. INTERPRETATION: We might have missed some relevant studies due to publication year and language restrictions. Notwithstanding, this review showed that the potential impact of factors associated with health inequalities are not routinely considered during the implementation and evaluation of interventions to improve health-care professionals' interaction with patients. Future work should routinely consider this to help mitigate potential inequalities. FUNDING: UK Health Security Agency.

Habit training versus habit training with direct visual biofeedback in adults with chronic constipation: A randomized controlled trial.

AIM: The aim was to determine whether specialist-led habit training using Habit Training with Biofeedback (HTBF) is more effective than specialist-led habit training alone (HT) for chronic constipation and whether outcomes of interventions are improved by stratification to HTBF or HT based on diagnosis (functional defaecation disorder vs. no functional defaecation disorder) by radio-physiological investigations (INVEST). METHOD: This was a parallel three-arm randomized single-blinded controlled trial, permitting two randomized comparisons: HTBF versus HT alone; INVEST- versus no-INVEST-guided intervention. The inclusion criteria were age 18-70 years; attending specialist hospitals in England; self-reported constipation for >6 months; refractory to basic treatment. The main exclusions were secondary constipation and previous experience of the trial interventions. The primary outcome was the mean change in Patient Assessment of Constipation Quality of Life score at 6 months on intention to treat. The secondary outcomes were validated disease-specific and psychological questionnaires and cost-effectiveness (based on EQ-5D-5L). RESULTS: In all, 182 patients were randomized 3:3:2 (target 384): HT n = 68; HTBF n = 68; INVEST-guided treatment n = 46. All interventions had similar reductions (improvement) in the primary outcome at 6 months (approximately -0.8 points of a 4-point scale) with no statistically significant difference between HT and HTBF (-0.03 points; 95% CI -0.33 to 0.27; P = 0.85) or INVEST versus no-INVEST (0.22; -0.11 to 0.55; P = 0.19). Secondary outcomes showed a benefit for all interventions with no evidence of greater cost-effectiveness of HTBF or INVEST compared with HT. CONCLUSION: The results of the study at 6 months were inconclusive. However, with the caveat of under-recruitment and further attrition at 6 months, a simple, cheaper approach to intervention may be as clinically effective and more cost-effective than more complex and invasive approaches.

Laparoscopy is associated with decreased all-cause mortality in patients undergoing emergency general surgery procedures in a regional health system.

BACKGROUND: The aim of this study was to evaluate the use of laparoscopic surgery for common emergency general surgery (EGS) procedures within an integrated Acute Care Surgery (ACS) network. We hypothesized that laparoscopy would be associated with improved outcomes. METHODS: Our integrated health care system's EGS registry created from AAST EGS ICD-9 codes was queried from January 2013 to October 2015. Procedures were grouped as laparoscopic or open. Standard descriptive and univariate tests were performed, and a multivariable logistic regression controlling for open status, age, BMI, Charlson Comorbidity Index (CCI), trauma tier, and resuscitation diagnosis was performed. Laparoscopic procedures converted to open were identified and analyzed using concurrent procedure billing codes across episodes of care. RESULTS: Of 60,604 EGS patients identified over the 33-month period, 7280 (12.0%) had an operation and 6914 (11.4%) included AAST-defined EGS procedures. There were 4813 (69.6%) surgeries performed laparoscopically. Patients undergoing a laparoscopic procedure tended to be younger (45.7 ± 18.0 years vs. 57.2 ± 17.6, p < 0.001) with similar BMI (29.7 ± 9.0 kg/m2 vs. 28.8 ± 8.3, p < 0.001). Patients in the laparoscopic group had lower mean CCI score (1.6 ± 2.3 vs. 3.4 ± 3.2, p ≤ 0.0001). On multivariable analysis, open surgery had the highest association with inpatient mortality (OR 8.67, 4.23-17.75, p < 0.0001) and at all time points (30-, 90-day, 1-, 3-year). At all time points, conversion to open was found to be a statistically significant protective factor. CONCLUSION: Use of laparoscopy in EGS is common and associated with a decreased risk of all-cause mortality at all time points compared to open procedures. Conversion to open was protective at all time points compared to open procedures.

A Multicenter, Prospective Study Comparing Subxiphoid and Parasternal Views During Brief Echocardiography: Effect on Image Quality, Acquisition Time, and Visualized Anatomy.

BACKGROUND: Recent literature has suggested echocardiography (echo) may prolong pauses in chest compressions during cardiac arrest. OBJECTVES: We sought to determine the impact of the sonographic approach (subxiphoid [SX] vs. parasternal long [PSL]) on time to image completion, image quality, and visualization of cardiac anatomy during echo, as performed during Advanced Cardiac Life Support. METHODS: This was a multicenter, randomized controlled trial conducted at 29 emergency departments (EDs) assessing the time to image acquisition and image quality between SX and PSL views for echo. Patients were enrolled in the ED and imaged in a simulated cardiac arrest scenario. Clinicians experienced in echo performed both SX and PSL views, first view in random order. Image quality and time to image acquisition were recorded. Echos were evaluated for identification of cardiac landmarks. Data are presented as percentages or medians with interquartile ranges (IQRs). RESULTS: We obtained 6247 echo images, comprising 3124 SX views and 3123 PSL. Overall time to image acquisition was 9.0 s (IQR 6.7-14.1 s). Image acquisition was shorter using PSL (8.8 s, IQR 6.5-13.5 s) compared with SX (9.3 s, IQR 6.7-15.0 s). The image quality was better with the PSL view (3.86 vs. 3.54; p < 0.0001), twice as many SX images scoring in the worst quality category compared with PSL (8.6% vs. 3.7%). Imaging of the pericardium, cardiac chambers, and other anatomic landmarks was superior with PSL imaging. CONCLUSIONS: Echo was performed in < 10 s in > 50% of patients using either imaging technique. Imaging using PSL demonstrated improved image quality and improved identification of cardiac landmarks.

Microtubule and tubulin binding and regulation of microtubule dynamics by the antibody drug conjugate (ADC) payload, monomethyl auristatin E (MMAE): Mechanistic insights into MMAE ADC peripheral neuropathy.

Monomethyl auristatin E (MMAE) is a potent anti-cancer microtubule-targeting agent (MTA) used as a payload in three approved MMAE-containing antibody drug conjugates (ADCs) and multiple ADCs in clinical development to treat different types of cancers. Unfortunately, MMAE-ADCs can induce peripheral neuropathy, a frequent adverse event leading to treatment dose reduction or discontinuation and subsequent clinical termination of many MMAE-ADCs. MMAE-ADC-induced peripheral neuropathy is attributed to non-specific uptake of the ADC in peripheral nerves and release of MMAE, disrupting microtubules (MTs) and causing neurodegeneration. However, molecular mechanisms underlying MMAE and MMAE-ADC effects on MTs remain unclear. Here, we characterized MMAE-tubulin/MT interactions in reconstituted in vitro soluble tubulin or MT systems and evaluated MMAE and vcMMAE-ADCs in cultured human MCF7 cells. MMAE bound to soluble tubulin heterodimers with a maximum stoichiometry of ~1:1, bound abundantly along the length of pre-assembled MTs and with high affinity at MT ends, introduced structural defects, suppressed MT dynamics, and reduced the kinetics and extent of MT assembly while promoting tubulin ring formation. In cells, MMAE and MMAE-ADC (via nonspecific uptake) suppressed proliferation, mitosis and MT dynamics, and disrupted the MT network. Comparing MMAE action to other MTAs supports the hypothesis that peripheral neuropathy severity is determined by the precise mechanism(s) of each individual drug-MT interaction (location of binding, affinity, effects on morphology and dynamics). This work demonstrates that MMAE binds extensively to tubulin and MTs and causes severe MT dysregulation, providing convincing evidence that MMAE-mediated inhibition of MT-dependent axonal transport leads to severe peripheral neuropathy.

Testing for lynch syndrome in people with endometrial cancer using immunohistochemistry and microsatellite instability-based testing strategies - A systematic review of test accuracy.

BACKGROUND: Lynch syndrome is an inherited genetic condition that is associated with an increased risk of cancer, including endometrial and colorectal cancer. We assessed the test accuracy of immunohistochemistry and microsatellite instability-based testing (with or without MLH1 promoter methylation testing) for Lynch syndrome in women with endometrial cancer. METHODS: We conducted a systematic review of literature published up to August 2019. We searched bibliographic databases, contacted experts and checked reference lists of relevant studies. Two reviewers conducted each stage of the review. RESULTS: Thirteen studies were identified that included approximately 3500 participants. None of the studies was at low risk of bias in all domains. Data could not be pooled due to the small number of heterogeneous studies. Sensitivity ranged from 60.7-100% for immunohistochemistry, 41.7-100% for microsatellite instability-based testing, and 90.5-100% for studies combining immunohistochemistry, microsatellite instability-based testing, and MLH1 promoter methylation testing. Specificity ranged from 60.9-83.3% (excluding 1 study with highly selective inclusion criteria) for immunohistochemistry, 69.2-89.9% for microsatellite instability-based testing, and 72.4-92.3% (excluding 1 study with highly selective inclusion criteria) for testing strategies that included immunohistochemistry, microsatellite instability-based testing, and MLH1 promoter methylation. We found no statistically significant differences in test accuracy estimates (sensitivity, specificity) in head-to-head studies of immunohistochemistry versus microsatellite instability-based testing. Reported test failures were rare. CONCLUSIONS: Sensitivity of the index tests were generally high, though most studies had much lower specificity. We found no evidence that test accuracy differed between IHC and MSI based strategies. The evidence base is currently small and at high risk of bias.

A systematic review of economic evaluations for donor human milk versus standard feeding in infants.

Reviews on the cost/outcome of donor human milk (DHM) for infants requiring care in the neonatal intensive care unit (NICU) setting have been undertaken. However, the cost-effectiveness evidence is unclear. Therefore, we conducted a systematic review of published full economic evaluations of DHM versus standard feeding in infants in neonatal care with the aim of undertaking a narrative synthesis of the cost-effectiveness evidence and critical appraisal of the methods used. MEDLINE, EMBASE, Web of Science, Cochrane Library, Centre for Reviews and Dissemination (CRD) and PROSPERO databases were searched. Studies were included if they were full economic evaluations (model-based or trial-based), the participants were infants in neonatal units requiring nutritional support, the intervention was DHM and the comparator was any standard feeding option. There were no restrictions on outcome measures. Two authors independently assessed eligibility, extracted data, assessed quality and cross-checked results, with disagreements resolved by consensus. Information extracted focused on study context, and economic evaluation methods and results. Of 2861 studies, seven were included. Six (86%) studies originated from high-income countries. Four (57%) of the studies were model-based. Although we could not directly compare the different studies, due to the heterogenous nature of health and economic parameters used in the studies, all DHM interventions indicated cost-effective or cost saving results. This review suggests that economic evaluation of DHM interventions is an expanding area of research. Although these interventions show promise, future economic evaluations of DHM interventions need to explicitly provide more details on long-term costs and consequences.

Nitrogen-Containing, Light-Absorbing Oligomers Produced in Aerosol Particles Exposed to Methylglyoxal, Photolysis, and Cloud Cycling.

Aqueous methylglyoxal chemistry has often been implicated as an important source of oligomers in atmospheric aerosol. Here we report on chemical analysis of brown carbon aerosol particles collected from cloud cycling/photolysis chamber experiments, where gaseous methylglyoxal and methylamine interacted with glycine, ammonium, or methylammonium sulfate seed particles. Eighteen N-containing oligomers were identified in the particulate phase by liquid chromatography/diode array detection/electrospray ionization high-resolution quadrupole time-of-flight mass spectrometry. Chemical formulas were determined and, for 6 major oligomer products, MS2 fragmentation spectra were used to propose tentative structures and mechanisms. Electronic absorption spectra were calculated for six tentative product structures by an ab initio second order algebraic-diagrammatic-construction/density functional theory approach. For five structures, matching calculated and measured absorption spectra suggest that they are dominant light-absorbing species at their chromatographic retention times. Detected oligomers incorporated methylglyoxal and amines, as expected, but also pyruvic acid, hydroxyacetone, and significant quantities of acetaldehyde. The finding that ∼80% (by mass) of detected oligomers contained acetaldehyde, a methylglyoxal photolysis product, suggests that daytime methylglyoxal oligomer formation is dominated by radical addition mechanisms involving CH3CO*. These mechanisms are evidently responsible for enhanced browning observed during photolytic cloud events.

Successful Salvage of Central Venous Catheters in Patients with Catheter-Related or Central Line-Associated Bloodstream Infections by Using a Catheter Lock Solution Consisting of Minocycline, EDTA, and 25% Ethanol.

In cancer patients with long-term central venous catheters (CVC), removal and reinsertion of a new CVC at a different site might be difficult because of the unavailability of accessible vascular sites. In vitro and animal studies showed that a minocycline-EDTA-ethanol (M-EDTA-EtOH) lock solution may eradicate microbial organisms in biofilms, hence enabling the treatment of central line-associated bloodstream infections (CLABSI) while retaining the catheter in situ Between April 2013 and July 2014, we enrolled 30 patients with CLABSI in a prospective study and compared them to a historical group of 60 patients with CLABSI who had their CVC removed and a new CVC inserted. Each catheter lumen was locked with an M-EDTA-EtOH solution for 2 h administered once daily, for a total of 7 doses. Patients who received locks had clinical characteristics that were comparable to those of the control group. The times to fever resolution and microbiological eradication were similar in the two groups. Patients with the lock intervention received a shorter duration of systemic antibiotic therapy than that of the control patients (median, 11 days versus 16 days, respectively; P < 0.0001), and they were able to retain their CVCs for a median of 74 days after the onset of bacteremia. The M-EDTA-EtOH lock was associated with a significantly decreased rate of mechanical and infectious complications compared to that of the CVC removal/reinsertion group, who received a longer duration of systemic antimicrobial therapy. (This study has been registered at ClinicalTrials.gov under registration no. NCT01539343.).

Case-Control Study of Telavancin as an Alternative Treatment for Gram-Positive Bloodstream Infections in Patients with Cancer.

Gram-positive bacterial infections are an important cause of morbidity and death among cancer patients, despite current therapy. In this case-control study, we evaluated the clinical outcomes and safety of telavancin in cancer patients with uncomplicated Gram-positive bloodstream infections (BSIs). Between March 2011 and May 2013, we enrolled cancer patients with uncomplicated Gram-positive BSIs to receive intravenous telavancin therapy for at least 14 days for Staphylococcus aureus and 7 days for other Gram-positive cocci. Patients with baseline creatinine clearance (CLCR) values of >50 ml/min received 10 mg/kg/day of telavancin, and those with CLCR values between 30 and 49 ml/min received 7.5 mg/kg/day. Patients were compared with a retrospective cohort of 39 historical patients with Gram-positive BSIs, matched for underlying malignancy, infecting organism, and neutropenia status, who had been treated with vancomycin. A total of 78 patients were analyzed, with 39 in each group. The most common pathogen causing BSIs was S. aureus (51%), followed by alpha-hemolytic streptococci (23%), Enterococcus spp. (15%), coagulase-negative staphylococci (8%), and beta-hemolytic streptococci (3%). Sixty-two percent of patients had hematological malignancies, and 38% had solid tumors; 51% of the patients were neutropenic. The overall response rate determined by clinical outcome and microbiological eradication at 72 h following the initiation of therapy, in the absence of relapse, deep-seated infections, and/or infection-related death, was better with telavancin than with vancomycin (86% versus 61%; P = 0.013). Rates of drug-related adverse events were similar in the two groups (telavancin, 31%; vancomycin, 23%; P = 0.79), with similar rates of renal adverse events. Telavancin may provide a useful alternative to standard vancomycin therapy for Gram-positive BSIs in cancer patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01321879.).

Effects of eribulin on microtubule binding and dynamic instability are strengthened in the absence of the ßIII tubulin isotype.

Eribulin mesylate (Halaven) is a microtubule-targeted anticancer drug used to treat patients with metastatic breast cancer who have previously received a taxane and an anthracycline. It binds at the plus ends of microtubules and has been shown to suppress plus end growth selectively. Because the class III ß tubulin isotype is associated with resistance to microtubule targeting drugs, we sought to determine how ßIII tubulin might mechanistically influence the effects of eribulin on microtubules. We found that while [(3)H]eribulin bound to bovine brain soluble tubulin depleted of ßIII tubulin in a manner similar to that of unfractionated tubulin, it bound to plus ends of microtubules that were depleted of ßIII-depleted tubulin with a maximal stoichiometry (20 ± 3 molecules per microtubule) higher than that of unfractionated microtubules (9 ± 2 molecules per microtubule). In addition, eribulin suppressed the dynamic instability behavior of ßIII-depleted microtubules more strongly than and in a manner different from that of microtubules containing ßIII tubulin. Specifically, with ßIII tubulin present in the microtubules, 100 nM eribulin suppressed the growth rate by 32% and marginally reduced the catastrophe frequency (by 17%) but did not modulate the rescue frequency. However, in the absence of ßIII tubulin, eribulin not only reduced the growth rate but also strongly reduced the shortening rate (by 43%) and the catastrophe and the rescue frequencies (by 49 and 32%, respectively). Thus, when present in microtubules, ßIII tubulin substantially weakens the effects of eribulin.

Percutaneous cannulation for extracorporeal membrane oxygenation by intensivists: a retrospective single-institution case series.

OBJECTIVE: Extracorporeal membrane oxygenation provides support for patients with severe acute cardiopulmonary failure, allowing the application of lung or myocardial rest in anticipation of organ recovery, or as a bridge to long-term support. Advances in technology have improved the safety and ease of application of extracorporeal membrane oxygenation. Percutaneous cannulation is one of these advances and is now preferred over surgical cannulation in most cases. Percutaneous cannulation is increasingly performed by intensivists, cardiologists, interventional radiologists, and related specialties. The objective of this study is to review the experience of percutaneous cannulation by intensivists at a single institution. DESIGN: A retrospective review of 100 subjects undergoing percutaneous cannulation for extracorporeal membrane oxygenation. SETTING: Adult ICUs and PICUs at a tertiary academic medical institution. PATIENTS: Critically ill neonatal, pediatric, and adult subjects with severe respiratory and/or cardiac failure undergoing percutaneous cannulation for extracorporeal membrane oxygenation. Modes of support included venoarterial, venovenous, venovenoarterial, and arteriovenous. INTERVENTIONS: Percutaneous extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS: Case reports submitted to the Extracorporeal Life Support Organization and hospital records of the subjects were retrospectively reviewed. Subject demographics, type of support, cannulation configuration, types of cannulas, use of imaging modalities, and complications were recorded and summarized. One hundred ninety cannulations with cannula sizes from size 12 to 31F were performed by four intensivists in 100 subjects. Twenty-three were arterial (12-16F) and 167 were venous (12-31F). Preinsertion ultrasound was performed in 93 subjects (93%), fluoroscopic guidance in 79 subjects (85% of nonarteriovenous subjects), and ultrasound-guided insertion was performed in 65 subjects (65%). Two major complications occurred, each associated with mortality. Cannulation was successful in all other subjects (98% of subjects and 99% of cannulations). There were no cases of cannula-related bloodstream infection. CONCLUSIONS: Percutaneous cannulation for extracorporeal membrane oxygenation by intensivists can be performed with a high rate of success and a low rate of complications when accompanied by imaging support.

The taccalonolides and paclitaxel cause distinct effects on microtubule dynamics and aster formation.

BACKGROUND: Microtubule stabilizers suppress microtubule dynamics and, at the lowest antiproliferative concentrations, disrupt the function of mitotic spindles, leading to mitotic arrest and apoptosis. At slightly higher concentrations, these agents cause the formation of multiple mitotic asters with distinct morphologies elicited by different microtubule stabilizers. RESULTS: We tested the hypothesis that two classes of microtubule stabilizing drugs, the taxanes and the taccalonolides, cause the formation of distinct aster structures due, in part, to differential effects on microtubule dynamics. Paclitaxel and the taccalonolides suppressed the dynamics of microtubules formed from purified tubulin as well as in live cells. Both agents suppressed microtubule dynamic instability, with the taccalonolides having a more pronounced inhibition of microtubule catastrophe, suggesting that they stabilize the plus ends of microtubules more effectively than paclitaxel. Live cell microscopy was also used to evaluate the formation and resolution of asters after drug treatment. While each drug had similar effects on initial formation, substantial differences were observed in aster resolution. Paclitaxel-induced asters often coalesced over time resulting in fewer, larger asters whereas numerous compact asters persisted once they were formed in the presence of the taccalonolides. CONCLUSIONS: We conclude that the increased resistance of microtubule plus ends to catastrophe may play a role in the observed inability of taccalonolide-induced asters to coalesce during mitosis, giving rise to the distinct morphologies observed after exposure to these agents.

Recurrent Peritonsillar Abscess Caused by Vaginal Flora: A Common Problem From a Unique Source.

Peritonsillar abscesses (PTAs) are typically caused by group A Streptococcus or mixed oral flora. Gardnerella vaginalis is a part of the normal vaginal microbiome, and overgrowth can cause bacterial vaginosis. We present a case of recurrent PTA with G. vaginalis superinfection, which occurred after the patient performed oral sex on a female after incision and drainage of her initial PTA. The patient continued to have recurrent PTAs until G. vaginalis was identified, and antibiotic coverage was broadened to cover both group A Streptococcus and G. vaginalis. This case highlights the importance of culturing PTA aspirate for directed antibiosis in persistent or recurrent infections. The rare superinfection also raises the question of advising abstinence from oral-genital contact after oral procedures to minimize risk of superinfection.

Improving healthcare professionals' interactions with patients to tackle antimicrobial resistance: a systematic review of interventions, barriers, and facilitators.

Introduction: Antimicrobial resistance (AMR) is a major public health threat. With the growing emphasis on patient-centred care/ shared decision making, it is important for healthcare professionals' (HCPs) who prescribe, dispense, administer and/or monitor antimicrobials to be adequately equipped to facilitate appropriate antimicrobial use. We systematically identified existing interventions which aim to improve HCPs interaction with patients and examined barriers and facilitators of appropriate the use of such interventions and appropriate antimicrobial use among both HCPs and patientsantimicrobial use while using these interventions. Methods: We searched MEDLINE, EMBASE, Web of Science, Google Scholar, and internet (via Google search engine). We included primary studies, published in English from 2010 to 2023 [PROSPERO (CRD42023395642)]. The protocol was preregistered with PROSPERO (CRD42023395642). We performed quality assessment using mixed methods appraisal tool. We applied narrative synthesis and used the COM-B (Capability, Opportunity, Motivation -Behaviour) as a theoretical framework for barriers and facilitators at HCP and patient levels. Results: Of 9,172 citations retrieved from database searches, From 4,979 citations remained after removal of duplicates. We included 59 studies spanning over 13 countries. Interventions often involved multiple components beyond HCPs' interaction with patients. From 24 studies reporting barriers and facilitators, we identified issues relating to capability (such as, knowledge/understanding about AMR, diagnostic uncertainties, awareness of interventions and forgetfulness); opportunity (such as, time constraint and intervention accessibility) and motivation (such as, patient's desire for antibiotics and fear of litigation). Conclusion: The findings of this review should be considered by intervention designers/adopters and policy makers to improve utilisation and effectiveness.

Bacteriophage Therapy of Multidrug-resistant Achromobacter in an 11-Year-old Boy With Cystic Fibrosis Assessed by Metagenome Analysis.

BACKGROUND: Cystic fibrosis (CF) is a genetic disease associated with lung disease characterized by chronic pulmonary infection, increasingly caused by multiple drug-resistant pathogens after repeated antibiotic exposure, limiting antibiotic treatment options. Bacteriophages can provide a pathogen-specific bactericidal treatment used with antibiotics to improve microbiologic and clinical outcomes in CF. METHODS: Achromobacter species isolates from sputum of a chronically infected person with CF, were assessed for susceptibility to bacteriophages: 2 highly active, purified bacteriophages were administered intravenously every 8 hours, in conjunction with a 14-day piperacillin/tazobactam course for CF exacerbation. Sputum and blood were collected for metagenome analysis during treatment, with sputum analysis at 1-month follow-up. Assessments of clinical status, pulmonary status and laboratory evaluation for safety were conducted. RESULTS: Bacteriophage administration was well-tolerated, with no associated clinical or laboratory adverse events. Metagenome analysis documented an 86% decrease in the relative proportion of Achromobacter DNA sequence reads in sputum and a 92% decrease in blood, compared with other bacterial DNA reads, comparing pretreatment and posttreatment samples. Bacteriophage DNA reads were detected in sputum after intravenous administration during treatment, and at 1-month follow-up. Reversal of antibiotic resistance to multiple antibiotics occurred in some isolates during treatment. Stabilization of lung function was documented at 1-month follow-up. CONCLUSIONS: Bacteriophage/antibiotic treatment decreased the host pulmonary bacterial burden for Achromobacter assessed by metagenome analysis of sputum and blood, with ongoing bacteriophage replication documented in sputum at 1-month follow-up. Prospective controlled studies are needed to define the dose, route of administration and duration of bacteriophage therapy for both acute and chronic infection in CF.

Intercostal nerve cryoablation during surgical stabilization of rib fractures decreases post-operative opioid use, ventilation days, and intensive care days.

BACKGROUND: Intercostal nerve cryoablation is an adjunctive measure that has demonstrated pain control, decrease in opioid consumption, and decrease in hospital length of stay (LOS) in patients who undergo surgical stabilization of rib fractures (SSRF). METHODS: SSRF patients from January 2015 to September 2021 were retrospectively compared. All patients received multimodal pain regimens post-operatively and the independent variable was intraoperative cryoablation. RESULTS: 241 patients met inclusion criteria. 51 (21%) underwent intra-operative cryoablation during SSRF and 191 (79%) did not. Patients with standard treatment consumed 9.4 more daily MME (p = 0.035), consumed 73 percent more post-operative total MME (p = 0.001), spent 1.55 times as many days in the intensive care unit (p = 0.013), and spent 3.8 times as many days on the ventilator than patients treated with cryoablation, respectively. Overall hospital LOS, operative case time, pulmonary complications, MME at discharge, and numeric pain scores at discharge were no different (all p>0.05). CONCLUSION: Intercostal nerve cryoablation during SSRF is associated with fewer ventilator days, ICU LOS, total post-operative, and daily opioid use without increasing time in the operating room or perioperative pulmonary complications.

Combinatorial Tau pseudophosphorylation: markedly different regulatory effects on microtubule assembly and dynamic instability than the sum of the individual parts.

Tau is a multiply phosphorylated protein that is essential for the development and maintenance of the nervous system. Errors in Tau action are associated with Alzheimer disease and related dementias. A huge literature has led to the widely held notion that aberrant Tau hyperphosphorylation is central to these disorders. Unfortunately, our mechanistic understanding of the functional effects of combinatorial Tau phosphorylation remains minimal. Here, we generated four singly pseudophosphorylated Tau proteins (at Thr(231), Ser(262), Ser(396), and Ser(404)) and four doubly pseudophosphorylated Tau proteins using the same sites. Each Tau preparation was assayed for its abilities to promote microtubule assembly and to regulate microtubule dynamic instability in vitro. All four singly pseudophosphorylated Tau proteins exhibited loss-of-function effects. In marked contrast to the expectation that doubly pseudophosphorylated Tau would be less functional than either of its corresponding singly pseudophosphorylated forms, all of the doubly pseudophosphorylated Tau proteins possessed enhanced microtubule assembly activity and were more potent at regulating dynamic instability than their compromised singly pseudophosphorylated counterparts. Thus, the effects of multiple pseudophosphorylations were not simply the sum of the effects of the constituent single pseudophosphorylations; rather, they were generally opposite to the effects of singly pseudophosphorylated Tau. Further, despite being pseudophosphorylated at different sites, the four singly pseduophosphorylated Tau proteins often functioned similarly, as did the four doubly pseudophosphorylated proteins. These data lead us to reassess the conventional view of combinatorial phosphorylation in normal and pathological Tau action. They may also be relevant to the issue of combinatorial phosphorylation as a general regulatory mechanism.

Platelet Aggregation, Mitochondrial Function and Morphology in Cold Storage: Impact of Resveratrol and Cytochrome c Supplementation.

Donated platelets are critical components of hemostasis management. Extending platelet storage beyond the recommended guidelines (5 days, 22 °C) is of clinical significance. Platelet coagulation function can be prolonged with resveratrol (Res) or cytochrome c (Cyt c) at 4 °C. We hypothesized that storage under these conditions is associated with maintained aggregation function, decreased reactive oxygen species (ROS) production, increased mitochondrial respiratory function, and preserved morphology. Donated platelets were stored at 22 °C or 4 °C supplemented with 50 µM Res or 100 µM Cyt c and assayed on days 0 (baseline), 5, 7 and 10 for platelet aggregation, morphology, intracellular ROS, and mitochondrial function. Declining platelet function and increased intracellular ROS were maintained by Res and Cyt c. Platelet respiratory control ratio declined during storage using complex I + II (CI + CII) or CIV substrates. No temperature-dependent differences (4 °C versus 22 °C) in respiratory function were observed. Altered platelet morphology was observed after 7 days at 22 °C, effects that were blunted at 4 °C independent of exposure to Res or Cyt c. Storage of platelets at 4 °C with Res and Cyt c modulates ROS generation and platelet structural integrity.

Modeling the effects of drug binding on the dynamic instability of microtubules.

We propose a stochastic model that accounts for the growth, catastrophe and rescue processes of steady-state microtubules assembled from MAP-free tubulin in the possible presence of a microtubule-associated drug. As an example of the latter, we both experimentally and theoretically study the perturbation of microtubule dynamic instability by S-methyl-D-DM1, a synthetic derivative of the microtubule-targeted agent maytansine and a potential anticancer agent. Our model predicts that among the drugs that act locally at the microtubule tip, primary inhibition of the loss of GDP tubulin results in stronger damping of microtubule dynamics than inhibition of GTP tubulin addition. On the other hand, drugs whose action occurs in the interior of the microtubule need to be present in much higher concentrations to have visible effects.