Use of the DMAIC Lean Six Sigma quality improvement framework to improve beta-lactam antibiotic adequacy in the critically ill.

BACKGROUND: Beta-lactam antibiotics are widely used in the intensive care unit due to their favorable effectiveness and safety profiles. Beta-lactams given to patients with sepsis must be delivered as soon as possible after infection recognition (early), treat the suspected organism (appropriate), and at a dose that eradicates the infection (adequate). Early and appropriate antibiotic delivery occurs in >90% of patients, but less than half of patients with sepsis achieve adequate antibiotic exposure. This project aimed to address this quality gap and improve beta-lactam adequacy using the DMAIC Lean Six Sigma quality improvement framework. METHODS: A multidisciplinary steering committee was formed and completed a stakeholder analysis to define the gap in practice. An Ishikawa cause and effect (Fishbone) diagram was used to identify the root causes and an impact/effort grid facilitated prioritization of interventions. An intervention which included bundled education with the use of therapeutic drug monitoring (TDM; i.e., drug level testing) was projected to have the highest impact relative to the amount of effort and selected to address beta-lactam inadequacy in the critically ill. RESULTS: The education and TDM intervention were deployed through a Plan, Do, Study, Act (PDSA) cycle. In the three months after 'go-live,' 54 episodes of beta-lactam TDM occurred in 41 unique ICU patients. The primary quality metric of beta-lactam adequacy was achieved in 94% of individuals after the intervention. 94% of clinicians gauged the education provided as sufficient. The primary counterbalance of antimicrobial days of therapy, a core antimicrobial stewardship metric, was unchanged over time (favorable result; p=0.73). CONCLUSIONS: Application of the DMAIC Lean Six Sigma quality improvement framework effectively improved beta-lactam adequacy in critically ill patients. The approach taken in this quality improvement project is widely generalizable to other drugs, drug classes, or settings to increase the adequacy of drug exposure.

Melanoma Management: Exploring Staging, Prognosis, and Treatment Innovations.

Melanoma, a malignant neoplasm originating from melanocytes, stands as one of the most prevalent cancers globally, ranking fifth in terms of estimated new cases in recent years. Its aggressive nature and propensity for metastasis pose significant challenges in oncology. Recent advancements have led to a notable shift towards targeted therapies, driven by a deeper understanding of cutaneous tumor pathogenesis. Immunotherapy and tyrosine kinase inhibitors have emerged as promising strategies, demonstrating the potential to improve clinical outcomes across all disease stages, including neoadjuvant, adjuvant, and metastatic settings. Notably, there has been a groundbreaking development in the treatment of brain metastasis, historically associated with poor prognosis in oncology but showcasing impressive results in melanoma patients. This review article provides a comprehensive synthesis of the most recent knowledge on staging and prognostic factors while highlighting emerging therapeutic modalities, with a particular focus on neoadjuvant and adjuvant strategies, notably immunotherapy and targeted therapies, including the ongoing trials.

Nucleation dynamics of a model biomolecular liquid.

Liquid-liquid phase separation in biology has recently been shown to play a major role in the spatial control of biomolecular components within the cell. However, as they are phase transitions, these processes also display nontrivial dynamics. A model phase-separating system of DNA nanostars provides unique access to nucleation physics in a biomolecular context, as phase separation is driven near room temperature by highly thermo-responsive DNA hybridization and at modest DNA concentrations. By measuring the delay time for phase-separated droplets to appear, we demonstrate that the dynamics of DNA nanostar phase separation reflect that of a metastable binary mixture of patchy particles. For sufficiently deep temperature quenches, droplets undergo spinodal decomposition and grow spontaneously, driven by Brownian motion and coalescence of phase-separated droplets, as confirmed by comparing experimental measurements to particle-based simulations. Near the coexistence boundary, droplet growth slows substantially, indicative of a nucleation process. The temperature dependence of droplet appearance times can be predicted by a classical nucleation picture with mean field exponents and demonstrates that a theory previously used to predict equilibrium phase diagrams can also distinguish spinodal and nucleation dynamical regimes. These dynamical principles are relevant to behaviors associated with liquid-liquid phase separating systems, such as their spatial patterning, reaction coupling, and biological function.

Acute Coxiella burnetii Infection: A 10-Year Clinical Experience at a Tertiary Care Center in the United States.

Background: Identifying and treating patients with acute Q fever who are at an increased risk of progressing to persistent disease is crucial for preventing future complications. In this study, we share our decade-long clinical experience with acute Q fever, highlighting the challenges that clinicians encounter from making an initial diagnosis and performing risk stratification to determining the appropriate prophylaxis regimen and duration. Methods: We retrieved records of adult Mayo Clinic patients (≥18 years) with positive Coxiella burnetii serology results between 1 January 2012 and 31 March 2022. Patients with Q fever anti-phase II immunoglobulin G ≥1:256 by indirect immunofluorescence were further analyzed. Results: Thirty-one patients were included. Their median age was 58 years (IQR, 50-64), and the majority were men (84%). Acute hepatitis (29%), flu-like illness (25.8%), and pneumonia (16%) were the most common presentations. Thirteen patients (42%) received antibiotic prophylaxis to prevent disease progression, with significant variation in the indications and duration across physicians. The combination of doxycycline and hydroxychloroquine was the preferred regimen. Prophylaxis was administered for a median 333 days (IQR, 168-414). Four patients (13%) progressed to Q fever native valve infective endocarditis, with elevated anticardiolipin immunoglobulin G levels being the sole risk factor in 2 cases. The small sample size precluded drawing conclusions on the impact of prophylaxis in preventing disease progression. Conclusions: Management of acute Q fever is complicated by the lack of comprehensive clinical guidelines leading to varied clinical practices. There is a critical need for randomized trials to establish robust evidence-based protocols for management.

Nucleic acid liquids.

The confluence of recent discoveries of the roles of biomolecular liquids in living systems and modern abilities to precisely synthesize and modify nucleic acids (NAs) has led to a surge of interest in liquid phases of NAs. These phases can be formed primarily from NAs, as driven by base-pairing interactions, or from the electrostatic combination (coacervation) of negatively charged NAs and positively charged molecules. Generally, the use of sequence-engineered NAs provides the means to tune microsopic particle properties, and thus imbue specific, customizable behaviors into the resulting liquids. In this way, researchers have used NA liquids to tackle fundamental problems in the physics of finite valence soft materials, and to create liquids with novel structured and/or multi-functional properties. Here, we review this growing field, discussing the theoretical background of NA liquid phase separation, quantitative understanding of liquid material properties, and the broad and growing array of functional demonstrations in these materials. We close with a few comments discussing remaining open questions and challenges in the field.

Sequential Time to Positivity as a Prognostic Indicator in Staphylococcus aureus Bacteremia.

Background: We aimed to determine the factors associated with sequential blood culture time to positivity (STTP) and validate the previously defined time to positivity (TTP) ratio threshold of 1.5 in predicting adverse disease outcomes and mortality of Staphylococcus aureus bacteremia (SAB). Methods: We conducted an observational study of adult patients with SAB. The TTP ratio was calculated by dividing the TTP of the second blood culture by that of the first. Results: Of 186 patients, 69 (37%) were female, with a mean age of 63.6 years. Median TTP was 12 hours (interquartile range [IQR], 10-15 hours) from the initial and 21 hours (17-29) from sequential blood cultures. Methicillin-resistant S aureus (MRSA)-infected patients had significantly shorter STTPs (P < .001) and lower TTP ratios (P < .001) compared to patients with methicillin-susceptible S aureus (MSSA). A significant correlation between initial and STTP was observed in patients with MRSA (r = 0.42, P = .002) but not in those with MSSA. A higher rate of native valve endocarditis (NVE) significantly correlated with a TTP ratio of ≤1.5 (odds ratio, 2.65 [95% confidence interval, 1.3-5.6]; P = .01). The subgroup having an initial TTP <12 hours combined with a TTP ratio ≤1.5 showed the highest prevalence of NVE. Conclusions: The STTP varies based on methicillin susceptibility of S aureus isolate. This study suggests a potential clinical utility of the STTP to identify patients at a higher risk of NVE. However, prospective studies are required to validate these findings.

Characteristics and management of periprosthetic joint infections caused by rapidly growing mycobacteria: a retrospective study and a review of the literature.

Background: Periprosthetic joint infection (PJI) following total joint arthroplasty is a serious complication associated with significant morbidity. While Gram-positive cocci are the predominant causative organisms, PJIs caused by rapidly growing mycobacteria (RGM) have been reported, albeit at a lower frequency. This study aimed to investigate the characteristics and management of PJI caused by RGM. Methods: A retrospective review was conducted using an institutional PJI database to identify patients diagnosed with PJI due to RGM from January 2010 to December 2021. Clinical data, including demographics, symptoms, comorbidity information, laboratory parameters, surgical procedures, medical treatment and outcomes, were collected and analyzed. Results: A total of eight patients were identified with PJI caused by RGM during the study period. The median age was 66 years old, and most cases occurred in patients with total knee arthroplasty (n=6). The isolated RGM species included Mycobacterium abscessus (three cases), M. fortuitum (three cases), and one case each of M. immunogenum and M. mageritense. Surgical debridement was performed in all cases, with six patients undergoing two-stage revision and two patients requiring amputation. Combination antimicrobial therapy was administered based on antimicrobial susceptibility testing, and the median duration of treatment was 7.5 months. Adverse events related to therapy occurred in 75 % of cases. No relapses were observed during the median follow-up period of 39.6 months. Conclusions: PJI caused by RGM is a rare complication of total joint arthroplasty. Surgical debridement and combination antimicrobial therapy are the mainstays of treatment. Although clinical cure rates are high, amputation may be required in severe cases.

Effect of Preoperative Antibiotic Therapy on Operative Culture Yield for Diagnosis of Native Joint Septic Arthritis.

BACKGROUND: Native joint septic arthritis (NJSA) is definitively diagnosed by a positive Gram stain or culture, along with supportive clinical findings. Preoperative antibiotics are known to alter synovial fluid cell count, Gram stain and culture results and are typically postponed until after arthrocentesis to optimize diagnostic accuracy. However, data on the impact of preoperative antibiotics on operative culture yield for NJSA diagnosis are limited. METHODS: We retrospectively reviewed adult cases of NJSA who underwent surgery at Mayo Clinic facilities from 2012-2021 to analyze the effect of preoperative antibiotics on operative culture yield through a paired analysis of preoperative culture (POC) and operative culture (OC) results using logistic regression and generalized estimating equations. RESULTS: Two hundred ninety-nine patients with NJSA affecting 321 joints were included. Among those receiving preoperative antibiotics, yield significantly decreased from 68.0% at POC to 57.1% at OC (p < .001). In contrast, for patients without preoperative antibiotics there was a non-significant increase in yield from 60.9% at POC to 67.4% at OC (p = 0.244). In a logistic regression model for paired data, preoperative antibiotic exposure was more likely to decrease OC yield compared to non-exposure (OR = 2.12; 95% CI = 1.24-3.64; p = .006). Within the preoperative antibiotic group, additional antibiotic doses and earlier antibiotic initiation were associated with lower OC yield. CONCLUSION: In patients with NJSA, preoperative antibiotic exposure resulted in a significant decrease in microbiologic yield of operative cultures as compared to patients in whom antibiotic therapy was held prior to obtaining operative cultures.

Magnetic tweezers characterization of the entropic elasticity of intrinsically disordered proteins and peptoids.

Understanding the conformational behavior of biopolymers is essential to unlocking knowledge of their biophysical mechanisms and functional roles. Single-molecule force spectroscopy can provide a unique perspective on this by exploiting entropic elasticity to uncover key biopolymer structural parameters. A particularly powerful approach involves the use of magnetic tweezers, which can easily generate lower stretching forces (0.1-20 pN). For forces at the low end of this range, the elastic response of biopolymers is sensitive to excluded volume effects, and they can be described by Pincus blob elasticity model that allow robust extraction of the Flory polymer scaling exponent. Here, we detail protocols for the use of magnetic tweezers for force-extension measurements of intrinsically disordered proteins and peptoids. We also discuss procedures for fitting low-force elastic curves to the predictions of polymer physics models to extract key conformational parameters.

Impact of hypoalbuminemia on clinical outcomes among patients with obesity treated with ceftriaxone.

The use of ceftriaxone, a highly protein-bound drug, in the setting of hypoalbuminemia may result in suboptimal drug exposure. Patients with obesity also exhibit higher absolute drug clearance. We aimed to evaluate the impact of hypoalbuminemia on clinical success among hospitalized adults with obesity who were treated with ceftriaxone. This retrospective review included adult inpatients with weight >100 kg or body mass index >40 kg/m2 who received ceftriaxone 2 g intravenously every 12 hours for at least 72 hours. The primary outcome was clinical success, a composite of clinical cure and microbiologic cure. Secondary outcomes included clinical cure, microbiologic cure, length of stay, ICU length of stay, mortality, 30-day readmission, and adverse events. In all, 137 patients were included, 34 of whom had a serum albumin of ≤2.5 g/dL. In a propensity-score-weighted analysis, clinical success was significantly more common among those without hypoalbuminemia (91.2%) as compared to those with hypoalbuminemia (77.8%) (P = 0.038). Death within 30 days (13.7% vs 0%, P < 0.001) and 30-day readmission (31.6% vs 12.0%, P = 0.008) were more common in the hypoalbuminemia group. In a univariate analysis, serum albumin and indication for ceftriaxone use were found to be predictors of clinical success. Hypoalbuminemia was associated with a lower rate of clinical success among patients with obesity who were treated with ceftriaxone 2 g every 12 hours.

Perimyocarditis Associated with Immune Checkpoint Inhibitors: A Case Report and Review of the Literature.

Patient prognoses have been significantly enhanced by immune checkpoint inhibitors (ICIs), altering the standard of care in cancer treatment. These novel antibodies have become a mainstay of care for metastatic non-small-cell lung cancer (mNSCLC) patients. Several types of adverse events related to ICIs have been identified and documented as a result of the launch of these innovative medicines. We present here a 74-year-old female patient with a stage IV lung adenocarcinoma, treated with nivolumab plus ipilimumab, who developed perimyocarditis two weeks after receiving the third cycle of immune checkpoint inhibitor therapy. The patient was diagnosed using troponin levels, computed tomography (CT) angiography, and echocardiography. After hospitalization, her cardiac condition was successfully resolved with corticosteroids, colchicine, and symptomatic treatment. To the best of our knowledge, this is one of the rarest cases to be reported of perimyocarditis as a toxicity of immunotherapy in a patient treated for adenocarcinoma of the lung.

From isolated polyelectrolytes to star-like assemblies: the role of sequence heterogeneity on the statistical structure of the intrinsically disordered neurofilament-low tail domain.

Intrinsically disordered proteins (IDPs) are a subset of proteins that lack stable secondary structure. Given their polymeric nature, previous mean-field approximations have been used to describe the statistical structure of IDPs. However, the amino-acid sequence heterogeneity and complex intermolecular interaction network have significantly impeded the ability to get proper approximations. One such case is the intrinsically disordered tail domain of neurofilament low (NFLt), which comprises a 50 residue-long uncharged domain followed by a 96 residue-long negatively charged domain. Here, we measure two NFLt variants to identify the impact of the NFLt two main subdomains on its complex interactions and statistical structure. Using synchrotron small-angle x-ray scattering, we find that the uncharged domain of the NFLt induces attractive interactions that cause it to self-assemble into star-like polymer brushes. On the other hand, when the uncharged domain is truncated, the remaining charged N-terminal domains remain isolated in solution with typical polyelectrolyte characteristics. We further discuss how competing long- and short-ranged interactions within the polymer brushes dominate their ensemble structure and, in turn, their implications on previously observed phenomena in NFL native and diseased states.

Controlling the size and adhesion of DNA droplets using surface- enriched DNA molecules.

Liquid droplets of biomolecules serve as organizers of the cellular interior and are of interest in biosensing and biomaterials applications. Here, we investigate means to tune the interfacial properties of a model biomolecular liquid consisting of multi-armed DNA 'nanostar' particles. We find that long DNA molecules that have binding affinity for the nanostars are preferentially enriched on the interface of nanostar droplets, thus acting as surfactants. Fluorescent measurements indicate that, in certain conditions, the interfacial density of the surfactant is around 20 per square micron, indicative of a sparse brush-like structure of the long, polymeric DNA. Increasing surfactant concentration leads to decreased droplet size, down to the sub-micron scale, consistent with droplet coalesence being impeded by the disjoining pressure created by the brush-like surfactant layer. Added DNA surfactant also keeps droplets from adhering to both hydrophobic and hydrophilic solid surfaces, apparently due to this same disjoining effect of the surfactant layer. We thus demonstrate control of the size and adhesive properties of droplets of a biomolecular liquid, with implications for basic biophysical understanding of such droplets, as well as for their applied use.

Temporal trends in antifungal susceptibility of Cryptococcus neoformans isolates from a reference laboratory in the United States, 2011-2021.

BACKGROUND: There are no established clinical breakpoints for antifungal agents against Cryptococcus species; however, epidemiological cut-off values can help distinguish wild-type (WT) isolates without any acquired resistance from non-WT strains, which may harbour resistance mechanisms. PATIENTS/METHODS: We describe the trends of antifungal MICs and percentages of WT C. neoformans species complex (CNSC) isolates processed in our reference laboratory from November 2011 to June 2021. There were only nine isolates in 2011, thus, we included them in the year 2012 for data analysis. Clinical data is also described when available. RESULTS: We identified 632 CNSC, the majority collected from blood (n = 301), cerebrospinal fluid (n = 230), and respiratory (n = 71) sources. The overall percentage of WT isolates for amphotericin B (AMB), 5-flucytosine, and fluconazole was 77%, 98%, and 91%, respectively. We noticed a statistically significant change in the percentage of AMB WT isolates over the years, with 98% of isolates being WT in 2012 compared to 79% in 2021 (p < .01). A similar change was not observed for other antifungal agents. Clinical data was available for 36 patients, primarily non-HIV immunocompromised patients with disseminated cryptococcosis. There were no statistically significant differences in the clinical characteristics and outcomes between patients with WT (58.3%) versus non-WT (41.7%) isolates, but we noticed higher mortality in patients infected with an AMB non-WT CNSC isolate. CONCLUSIONS: We observed an increase in the percentage of AMB non-WT CNSC isolates in the past decade. The clinical implications of this finding warrant further evaluation in larger studies.

Powassan Virus Encephalitis: A Tertiary Center Experience.

BACKGROUND: Powassan virus (POWV) is an emerging arthropod-borne flavivirus, transmitted by Ixodes spp. ticks, which has been associated with neuroinvasive disease and poor outcomes. METHODS: A retrospective study was conducted at Mayo Clinic from 2013 to 2022. We included clinical and epidemiologic data of probable and confirmed neuroinvasive POWV cases. RESULTS: Sixteen patients with neuroinvasive POWV were identified; their median age was 63.2 years, and 62.5% were male. Six patients presented with rhombencephalitis, 4 with isolated meningitis, 3 with meningoencephalitis, 2 with meningoencephalomyelitis, and 1 with opsoclonus myoclonus syndrome. A median time of 18 days was observed between symptom onset and diagnosis. Cerebrospinal fluid analysis showed lymphocytic pleocytosis with elevated protein and normal glucose in the majority of patients. Death occurred within 90 days in 3 patients (18.8%), and residual neurologic deficits were seen in 8 survivors (72.7%). CONCLUSIONS: To our knowledge, this is the largest case series of patients with neuroinvasive POWV infection. We highlight the importance of a high clinical suspicion among patients who live in or travel to high-risk areas during the spring to fall months. Our data show high morbidity and mortality rates among patients with neuroinvasive disease.

Risk factors for positive follow-up blood cultures in Gram-negative bacteremia among immunocompromised patients with neutropenia.

INTRODUCTION: Gram-negative bacillary bloodstream infection (GN-BSI) is a frequent clinical challenge among immunocompromised hosts and is associated with a high mortality. The utility of follow-up blood cultures (FUBCs) for GN-BSI in this population, particularly in the setting of neutropenia, is poorly defined. METHODS: We conducted a single-center, retrospective cohort study between the period of July 2018 and April 2022 to investigate the utility of FUBCs and delineate risk factors for positive cultures among neutropenic patients with monomicrobial GN-BSI. Univariate logistic regression was performed to assess risk factors associated with positive FUBCs. RESULTS: Of 206 patients, 98% had FUBCs performed, and 9% were positive. Risk factors for positive FUBCs included multidrug-resistant GN infection (OR 3.26; 95% confidence interval [CI] 1.22-8.72) and vascular catheter source (OR 4.82; CI 1.76-13.17). Among patients lacking these risk factors, the prevalence of positive FUBCs was low (2.8%) and the negative predictive value was 92%. Those with positive and negative FUBCs had similar rates of all-cause mortality (16.7% vs. 16.6%; p = .942) and microbiologic relapse (11.1% vs. 6.0%; p = .401) within 90-days of treatment completion. However, positive FUBCs were associated with prolonged hospitalization and longer duration of antimicrobial therapy. CONCLUSION: Positive FUBCs were infrequent in neutropenic patients with GN-BSI, and their occurrence did not significantly impact mortality or microbiologic relapse. Risk factors for positive FUBCs included multidrug resistant Gram-negative infection and vascular catheter source. Prospective studies will be necessary to elucidate the benefits and risks of FUBCs when managing GN-BSI in patients with underlying immune compromise.

Cemiplimab as First Line Therapy in Advanced Penile Squamous Cell Carcinoma: A Real-World Experience.

In the treatment of cancer, immune checkpoint inhibitors (ICIs) have demonstrated significantly greater effectiveness compared to conventional cytotoxic or platinum-based chemotherapies. To assess the efficacy of ICI's in penile squamous cell carcinoma (pSCC) we performed a retrospective observational study. We reviewed electronic medical records of patients with penile squamous cell carcinoma (SCC), diagnosed between January 2020 and February 2023. Nine patients were screened, of whom three were ineligible for chemotherapy and received immunotherapy, cemiplimab, in a first-line setting. Each of the three immunotherapy-treated patients achieved almost a complete response (CR) after only a few cycles of therapy. The first patient had cerebral arteritis during treatment and received a high-dose steroid treatment with resolution of the symptoms of arteritis. After tapering down the steroids dose, the patient continued cemiplimab without further toxicity. The other two patients did not have any toxic side effects of the treatment. To the best of our knowledge, this is the first real world report of near CR with cemiplimab as a first-line treatment in penile SCC.