Impact of narrowing perioperative antibiotic prophylaxis for left ventricular assist device implantation.

BACKGROUND: Although infections are a significant potential complication among patients undergoing left ventricular assist device (LVAD) implantation, standardized surgical infection prophylaxis (SIP) regimens are not well defined. At Montefiore Medical Center, a 4-drug SIP regimen containing fluconazole, ciprofloxacin, rifampin, and vancomycin was previously utilized. In January 2020, the antimicrobial stewardship program implemented a 2-drug SIP regimen of vancomycin and cefazolin to limit exposure to broad-spectrum antibiotics. This study evaluated LVAD-associated infection rates prior to and following the SIP revision. METHODS: A retrospective review of patients who underwent LVAD implantation from 1/2018 to 4/2021 was performed. Infections were classified using the International Society for Heart and Lung Transplantation definitions. Infection rates at 2 weeks, 30 days, and 90 days post-implantation in the 4-drug SIP regimen (1/2018-12/2019) and the 2-drug SIP regimen (1/2020 to 4/2021) were compared. RESULTS: A total of 71 patients were included. The number of patients with LVAD-associated infections (including surgical site infections) was not significantly different in either SIP group at 2 weeks (9% vs. 4%, p = .64), 30 days (9% vs. 11%, p = .99), or 90 days (19% vs. 14%, p = .75). There was no statistically significant difference in 30 or 90-day mortality. LVAD-associated gram-negative (7% vs. 7%; p > .99) and fungal (5% vs. 0%; p = .51) infections were uncommon. The most common organism isolated was Staphylococcus aureus, and the most common type of infection was pneumonia in both SIP groups. CONCLUSION: No significant difference in LVAD-associated infections or infection-related mortality was observed with de-escalation of perioperative antibiotics. Additional studies with larger sample sizes are needed to endorse the findings of this study.

MicroRNA mediators of early life stress vulnerability to depression and suicidal behavior.

Childhood environment can have a profound impact on brain structure and function. Epigenetic mechanisms have been shown to play a critical role in adaptive and maladaptive processes by regulating gene expression without changing the genome. Over the past few years, early life stress (ELS) has been established as a major risk factor for major depression and suicidal behavior along with other psychiatric illnesses in adulthood. In recent years, the emergence of small noncoding RNAs as a mega controller of gene expression has gained attention for their role in various disease processes. Among various noncoding RNAs, microRNAs (miRNAs) are the most studied and well characterized and have emerged as a major regulator of neural plasticity and higher brain functioning. More recently, although limited in number, studies are focusing on how miRNAs can play a role in the maladaptive processes associated with ELS both at adolescent and adult age and whether these processes are critical in developing depression and suicidal behavior. In this review, we critically evaluate how postnatal ELS relates to abnormalities in miRNA expression and functions from both animal and human literature and draw connections from these findings to depression and suicidal behavior later in life.

Streptococcus salivarius Isolates of Varying Acid Tolerance Exhibit F1F0-ATPase Conservation.

Genes encoding the subunits of the membrane-bound F1F0-ATPase (responsible for exporting protons from the cytoplasm and contributing to acid tolerance) were sequenced for 24 non-mutans streptococci isolated from carious lesions. Isolates, mostly Streptococcus salivarius, displayed a continuum of acid tolerance thresholds ranging from pH 4.55 to 3.39, but amino acid alignments of F1F0-ATPase subunits revealed few non-synonymous substitutions and these were unrelated to acid tolerance. Thus, the F1F0-ATPase is highly-conserved among S. salivarius isolates despite varying acid tolerance thresholds, supporting the contention that acid tolerance is determined by the level of gene/protein expression rather than variation in molecular structure.

Amygdala-Based Altered miRNome and Epigenetic Contribution of miR-128-3p in Conferring Susceptibility to Depression-Like Behavior via Wnt Signaling.

BACKGROUND: Recent studies suggest that microRNAs (miRNAs) can participate in depression pathogenesis by altering a host of genes that are critical in corticolimbic functioning. The present study focuses on examining whether alterations in the miRNA network in the amygdala are associated with susceptibility or resiliency to develop depression-like behavior in rats. METHODS: Amygdala-specific altered miRNA transcriptomics were determined in a rat depression model following next-generation sequencing method. Target prediction analyses (cis- and trans) and qPCR-based assays were performed to decipher the functional role of altered miRNAs. miRNA-specific target interaction was determined using in vitro transfection assay in neuroblastoma cell line. miRNA-specific findings from the rat in vivo model were further replicated in postmortem amygdala of major depressive disorder (MDD) subjects. RESULTS: Changes in miRNome identified 17 significantly upregulated and 8 significantly downregulated miRNAs in amygdala of learned helpless (LH) compared with nonlearned helpless rats. Prediction analysis showed that the majority of the upregulated miRNAs had target genes enriched for the Wnt signaling pathway. Among altered miRNAs, upregulated miR-128-3p was identified as a top hit based on statistical significance and magnitude of change in LH rats. Target validation showed significant downregulation of Wnt signaling genes in amygdala of LH rats. A discernable increase in expression of amygdalar miR-128-3p along with significant downregulation of key target genes from Wnt signaling (WNT5B, DVL, and LEF1) was noted in MDD subjects. Overexpression of miR-128-3p in a cellular model lead to a marked decrease in the expression of Dvl1 and Lef1 genes, confirming them as validated targets of miR-128-3p. Additional evidence suggested that the amygdala-specific diminished expression of transcriptional repressor Snai1 could be potentially linked to induced miR-128-2 expression in LH rats. Furthermore, an amygdala-specific posttranscriptional switching mechanism could be active between miR-128-3p and RNA binding protein Arpp21 to gain control over their target genes such as Lef1. CONCLUSION: Our study suggests that in amygdala a specific set of miRNAs may play an important role in depression susceptibility, which could potentially be mediated through Wnt signaling.

Impact of the Sequence of Norepinephrine and Vasopressin Discontinuation in Patients Recovering From Septic Shock.

Background: Septic shock is a serious medical condition affecting millions of people each year and guidelines direct vasopressor use in these patients. However, there is little information as to which vasopressor should be discontinued first. Objective: The objective of this study was to assess the impact of the sequence of norepinephrine and vasopressin discontinuation on intensive care unit (ICU) length of stay. Methods: This was a single-center retrospective cohort study conducted at The University of Tennessee Medical Center in Knoxville, Tennessee. Patients included in this study were adults 18 years of age and older with a diagnosis of septic shock who received norepinephrine in combination with vasopressin. Patients were excluded if norepinephrine or vasopressin were not the last 2 vasoactive agents used or if the patient expired or care was withdrawn. Measurements and Main Results: A total of 86 patients were included in this study, with 34 patients in the norepinephrine discontinued first group (NDF) and 52 in the vasopressin discontinued first group (VDF). For the primary outcome of ICU length of stay, no statistically significant difference was found between the NDF and the VDF groups (9.38 days vs 11.07 days, P = .313). The secondary outcome of the dose of norepinephrine at which vasopressin was initiated was also found to not be significant between the NDF and VDF groups (22 µg/min vs 31.1 µg/min, P = .11). The rates of hypotension within 24 hours of discontinuation of the first agent were also not significant between the NDF and VDF groups (17% vs 31%, P = .38). Conclusions: Based on the results of this study, there was significant no difference in ICU length of stay based on the sequence of discontinuation between norepinephrine and vasopressin in patients recovering from septic shock.

Impact of Invasive Quantitative Respiratory Cultures on Antimicrobial Therapy for Suspected Pneumonia in Trauma.

BACKGROUND: Invasive quantitative respiratory cultures are generally not recommended because of a lack of demonstrated benefit. There is insufficient literature regarding specific populations such as trauma. The objective of this study was to evaluate the effect of invasive quantitative respiratory sampling on de-escalation to targeted antimicrobial therapy for the management of pneumonia in a trauma population. METHODS: This was a single-center retrospective cohort study conducted at an American College of Surgeons-verified Level II Trauma Center in Nashville, TN. Adult patients admitted to the trauma service and diagnosed with pneumonia from July 2013 to August 2018 were divided into 2 groups: invasive quantitative respiratory sampling versus noninvasive respiratory sampling. The primary endpoint was rate of targeted antimicrobial therapy. Secondary endpoints included in-hospital mortality, antibiotic days of therapy, and frequency of discontinuation of antibiotics when quantitative cultures were below the diagnostic threshold. RESULTS: A total of 88 patients were sampled, with 27 in the invasive quantitative group and 66 in the noninvasive group. There was no difference in rates of targeted therapy in patients with invasive quantitative sampling (17 [63%] vs. 35 [57%]; relative risk = 1.10; 95% confidence interval [0.76, 1.57]). No statistically significant differences were observed for in-hospital mortality (8 patients vs. 6 patients, p = .35) or antimicrobial days of therapy (10.3 ± 8.8 vs. 7.8 ± 3.6, p = .161). Only 2 patients (17%) had antibiotics withheld when below the diagnostic threshold. CONCLUSIONS: Invasive quantitative respiratory sampling did not result in significant changes in targeted antibiotic therapy in a trauma population.

How many sites should an orthopedic trauma prospective multicenter trial have? A marginal analysis of the Major Extremity Trauma Research Consortium completed trials.

BACKGROUND: Multicenter trials in orthopedic trauma are costly, yet crucial to advance the science behind clinical care. The number of sites is a key cost determinant. Each site has a fixed overhead cost, so more sites cost more to the study. However, more sites can reduce total costs by shortening the study duration. We propose to determine the optimal number of sites based on known costs and predictable site enrollment. METHODS: This retrospective marginal analysis utilized administrative and financial data from 12 trials completed by the Major Extremity Trauma Research Consortium. The studies varied in size, design, and clinical focus. Enrollment across the studies ranged from 1054 to 33 patients. Design ranged from an observational study with light data collection to a placebo-controlled, double-blinded, randomized controlled trial. Initial modeling identified the optimal number of sites for each study and sensitivity analyses determined the sensitivity of the model to variation in fixed overhead costs. RESULTS: No study was optimized in terms of the number of participating sites. Excess sites ranged from 2 to 39. Excess costs associated with extra sites ranged from $17K to $330K with a median excess cost of $96K. Excess costs were, on average, 7% of the total study budget. Sensitivity analyses demonstrated that studies with higher overhead costs require more sites to complete the study as quickly as possible. CONCLUSIONS: Our data support that this model may be used by clinical researchers to achieve future study goals in a more cost-effective manner. TRIAL REGISTRATION: Please see Table 1 for individual trial registration numbers and dates of registration.

Minimal Clinically Important Difference (MCID) for the Short Musculoskeletal Function Assessment (SMFA) in Severe Lower Extremity Trauma: Pooled Data from 7 Multicenter, Prospective Clinical Trials.

BACKGROUND: The Short Musculoskeletal Function Assessment (SMFA) is a well validated, widely used patient-reported outcome (PRO) measure for orthopaedic patients. Despite its widespread use and acceptance, this measure does not have an agreed upon minimal clinically important difference (MCID). The purpose of the present study was to create distributional MCIDs with use of a large cohort of research participants with severe lower extremity fractures. METHODS: Three distributional approaches were used to calculate MCIDs for the Dysfunction and Bother Indices of the SMFA as well as all its domains: (1) half of the standard deviation (one-half SD), (2) twice the standard error of measurement (2SEM), and (3) minimal detectable change (MDC). In addition to evaluating by patient characteristics and the timing of assessment, we reviewed these calculations across several injury groups likely to affect functional outcomes. RESULTS: A total of 4,298 SMFA assessments were collected from 3,185 patients who had undergone surgical treatment of traumatic injuries of the lower extremity at 60 Level-I trauma centers across 7 multicenter, prospective clinical studies. Depending on the statistical approach used, the MCID associated with the overall sample ranged from 7.7 to 10.7 for the SMFA Dysfunction Index and from 11.0 to 16.8 for the SMFA Bother Index. For the Dysfunction Index, the variability across the scores was small (<5%) within the sex and age subgroups but was modest (12% to 18%) across subgroups related to assessment timing. CONCLUSIONS: A defensible MCID can be found between 7 and 11 points for the Dysfunction Index and between 11 and 17 points for the Bother Index. The precise choice of MCID may depend on the preferred statistical approach and the population under study. While differences exist between MCID values based on the calculation method, values were consistent across the categories of the various subgroups presented. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The VANCO Trial Findings Are Generalizable to a North American Trauma Registry.

OBJECTIVES: To estimate the generalizability of treatment effects observed in the VANCO trial to a broader population of patients with tibial plateau or pilon fractures. METHODS: Design and Setting: Clinical trial data from 36 United States trauma centers and Trauma Quality Programs registry data from more than 875 Level I-III trauma centers in the United States and Canada.Patient Selection Criteria: Patients enrolled in the VANCO trial treated with intrawound vancomycin powder from January 2015 to June 2017 and 31,924 VANCO-eligible TQP patients admitted in 2019 with tibial plateau and pilon fractures.Outcome Measure and Comparisons: Deep surgical site infection and gram-positive deep surgical site infection estimated in the TQP sample weighed by the inverse probability of trial participation. RESULTS: The 980 patients in the VANCO trial were highly representative of 31,924 TQP VANCO-eligible patients (Tipton generalizability index 0.96). It was estimated that intrawound vancomycin powder reduced the odds of deep surgical infection by odds ratio (OR) = 0.46 (95% confidence interval [CI] 0.25-0.86) and gram-positive deep surgical infection by OR = 0.39 (95% CI, 0.18-0.84) within the TQP sample of VANCO-eligible patients. For reference, the trial average treatment effects for deep surgical infection and gram-positive deep surgical infection were OR = 0.60 (95% CI, 0.37-0.98) and OR = 0.44 (95% CI, 0.23-0.80), respectively. CONCLUSIONS: This generalizability analysis found that the inferences of the VANCO trial generalize and might even underestimate the effects of intrawound vancomycin powder when observed in a wider population of patients with tibial plateau and pilon fractures. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

The Rates of Postmastectomy Immediate Breast Reconstruction during the Initial Months of the COVID-19 Pandemic.

Background: Coronavirus disease 2019 (COVID-19) pandemic-related changes may have led to changes in immediate breast reconstruction (IBR) rates. We aimed to evaluate these changes before, during, and after the initial wave of COVID-19. Methods: We retrospectively reviewed women who underwent mastectomy with or without IBR from January 1 to September 30, 2019 and from January 1 to September 30, 2020, and compared demographic, clinical, and surgical variables between defined time periods. Results: A total of 202 mastectomies were included. Fewer patients underwent IBR during the initial surge of COVID-19 (surge period) compared with the months before (presurge period; 38.46% versus 70.97%, P = 0.0433). When comparing the postsurge period with a year before (postsurge control), fewer patients underwent reconstruction even after the initial surge had passed (53.13% versus 81.25%, P = 0.0007). Those who underwent IBR were older than the year before (59.34 versus 53.06, P = 0.0181). The median number of postoperative visits in the postsurge period was 8.50 (interquartile range: 6-12) compared with 14 (interquartile range: 8-20.50) in the year before (P = 0.0017). The overall incidences of complications and unanticipated resource utilization were also significantly lower in the postsurge period compared with the year before [5.88% versus 30.77% (P = 0.0055), and 14.71% versus 28.85% (P = 0.0103), respectively]. Conclusions: IBR rates were lower even after the initial surge than at the year before. Furthermore, during the pandemic, IBR patients were older, had fewer follow-up visits, and fewer reported complications.

Clinical outcomes of non-surgical root canal obturations using NeoMTA: A retrospective series of case reports.

NeoMTA is a commercially available tricalcium silicate-based cement intended for contact with pulp and periradicular tissues. The purpose of this study was to retrospectively evaluate the outcomes of non-surgical root canal treatments with NeoMTA obturations. Patients were treated in a private endodontic practice between 2015 and 2018. All cases, including initial treatments and retreatments, were either fully obturated with NeoMTA, or using gutta-percha with NeoMTA as an endodontic sealer. Outcomes were assessed using follow-up examination data with digital periapical radiographs with a minimum of a 1-year recall. Teeth were classified based on the clinical examination as: healed/healing (success), or non-healed (failure). 265 teeth were included with an average follow-up time of 1.3 years. The overall success rate was 91.7%. Only the presence of a pre-operative periapical radiolucency was found to significantly affect success. Comparison of obturation techniques demonstrated no effect on outcomes. NeoMTA is suitable for endodontic obturation.

Predictors of participation in online self-management programs: A longitudinal observational study.

PURPOSE/OBJECTIVE: Lack of patient participation and engagement remains a barrier to implementing effective online self-management and behavioral health interventions. Identifying patient characteristics associated with engagement rates may lead to interventions that improve engagement in traditional and online self-management programs. In this study, two online self-management and recovery programs were evaluated to identify factors that predict patient engagement. RESEARCH METHOD/DESIGN: Predictors were collected in a questionnaire at baseline before 435 participants started either of the two interventions. One or two online lessons were completed per week with seven or eight total lessons to complete in each program, and each lesson took about 20-30 min to finish. Full patient engagement was defined as completing all lessons and assessments in the program and partial engagement as attempting at least one lesson or assessment. RESULTS: Predictors of full patient engagement were self-rated confidence in completing the program or being over 60 years of age. Predictors of at least partial patient engagement were experienced ordering online or being over 50 years of age. CONCLUSIONS/IMPLICATIONS: Identifying profiles of individuals who predict poor engagement may improve implementation and the health outcomes of intervention programs. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Delivery of Lung-protective Ventilation for Acute Respiratory Distress Syndrome: A Hybrid Implementation-Effectiveness Trial.

Rationale: Lung-protective ventilation (LPV) improves outcomes for patients with acute respiratory distress syndrome (ARDS), but adherence remains inadequate. Objectives: To measure the process and clinical impacts of implementation of a science-based intervention to improve LPV adherence for patients with ARDS, in part by increased use of clinical decision support (CDS). Methods: We conducted a type III hybrid implementation/effectiveness pilot trial enrolling adult patients with ARDS admitted to three hospitals before and after the launch of a multimodal implementation intervention to increase the use of mechanical ventilation CDS and improve LPV adherence. The primary outcome was patients' percentage of time adherent to low tidal volume (⩽6.5 ml/kg predicted body weight) ventilation (LTVV). Secondary outcomes included adherence to prescribed oxygenation settings, the use of the CDS tool's independent oxygenation and ventilation components, ventilator-free days, and mortality. Analyses employed multivariable regression to compare adjusted pre- versus postintervention outcomes after the exclusion of a postintervention wash-in period. A sensitivity analysis measured process outcomes' level and trend change postintervention using segmented regression. Results: The 446 included patients had a mean age of 60 years, and 43% were female. Demographic and clinical characteristics were similar pre- versus postintervention. The adjusted proportion of adherent time increased postintervention for LTVV (9.2%; 95% confidence interval [CI], 3.8-14.5%) and prescribed oxygenation settings (11.9%; 95% CI, 7.2-16.5%), as did the probability patients spent ⩾90% of ventilated time on LTVV (adjusted odds ratio [aOR] 2.58; 95% CI, 1.64-4.10) and use of ventilation CDS (aOR, 41.3%; 95% CI, 35.9-46.7%) and oxygenation CDS (aOR, 54.3%; 95% CI, 50.9-57.7%). Ventilator-free days (aOR, 1.15; 95% CI, 0.81-1.62) and 28-day mortality (aOR, 0.78; 95% CI, 0.50-1.20) did not change significantly after intervention. Segmented regression analysis supported a causal relationship between the intervention and improved CDS usage but suggested trends before intervention rather than the studied intervention could explain increased LPV adherence after the intervention. Conclusions: In this pilot trial, a multimodal implementation intervention was associated with increased use of ventilator management CDS for patients with ARDS but was not associated with differences in clinical outcomes and may not have independently caused the observed postintervention improvements in LPV adherence. Clinical trial registered with www.clinicaltrials.gov (NCT03984175).

Development of A Standardized Opsonophagocytosis Killing Assay for Group B Streptococcus and Assessment in an Interlaboratory Study.

The placental transfer of antibodies that mediate bacterial clearance via phagocytes is likely important for protection against invasive group B Streptococcus (GBS) disease. A robust functional assay is essential to determine the immune correlates of protection and assist vaccine development. Using standard reagents, we developed and optimized an opsonophagocytic killing assay (OPKA) where dilutions of test sera were incubated with bacteria, baby rabbit complement (BRC) and differentiated HL60 cells (dHL60) for 30 min. Following overnight incubation, the surviving bacteria were enumerated and the % bacterial survival was calculated relative to serum-negative controls. A reciprocal 50% killing titer was then assigned. The minimal concentrations of anti-capsular polysaccharide (CPS) IgG required for 50% killing were 1.65-3.70 ng/mL (depending on serotype). Inhibition of killing was observed using sera absorbed with homologous CPS but not heterologous CPS, indicating specificity for anti-CPS IgG. The assay performance was examined in an interlaboratory study using residual sera from CPS-conjugate vaccine trials with international partners in the Group B Streptococcus Assay STandardisatiON (GASTON) Consortium. Strong correlations of reported titers between laboratories were observed: ST-Ia r = 0.88, ST-Ib r = 0.91, ST-II r = 0.91, ST-III r = 0.90 and ST-V r = 0.94. The OPKA is an easily transferable assay with accessible standard reagents and will be a valuable tool to assess GBS-specific antibodies in natural immunity and vaccine studies.

Application of Bayesian Methods to Help Interpret the VANCO Trial Results.

OBJECTIVE: To determine whether a Bayesian analysis changes the results of the VANCO trial. DESIGN: A secondary analysis of a randomized clinical trial using Bayesian methods. SETTING: Thirty-six US trauma centers. PATIENTS: Patients ages 18-80 years with a tibial plateau or pilon fracture deemed high risk of infection and definitively treated with plate and screw fixation. INTERVENTION: Patients were randomly allocated to receive 1000 mg of intrawound vancomycin powder at their definitive fixation or to a control group that received no topical antibiotics. MAIN OUTCOME MEASUREMENTS: A deep surgical site infection requiring operative treatment within 6 months of definitive fixation. Secondary outcomes included gram-positive and gram-negative-only deep surgical site infections. RESULTS: Of the 980 patients randomized, 874 (89%) had at least 140 days of follow-up and were included in this Bayesian analysis. The estimated probability that intrawound vancomycin powder reduces the risk of a deep surgical site infection is >98% [relative risk (RR), 0.66; 95% credible interval (CrI), 0.46-0.98]. There is a >99% chance intrawound vancomycin powder reduces gram-positive infections and an 80% chance the magnitude of this risk reduction exceeds 35% (RR, 0.52; 95% CrI, 0.33-0.84) exists. It is unlikely (44%) that intrawound vancomycin powder prevents gram-negative surgical site infections (RR, 1.06; 95% CrI, 0.48-2.45). CONCLUSIONS: There is a high probability (>98%) that intrawound vancomycin powder reduces deep surgical site infections in patients with tibial plateau or pilon fractures at high risk of infection and even more likely it reduces deep infections with gram-positive pathogens (>99%). LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Enhanced immunogenicity of Mycobacterium bovis BCG through CRISPRi mediated depletion of AftC.

Mycobacterium tuberculosis causes the disease tuberculosis and affects a third of the world's population. The recent COVID-19 pandemic exacerbated the situation with a projected 27% increase in tuberculosis related deaths. M. tuberculosis has an elaborate cell wall consisting of peptidoglycan, arabinogalactan and mycolic acids which shield the bacilli from the toxic bactericidal milieu within phagocytes. Amongst, the numerous glycosyltransferase enzymes involved in mycobacterial cell wall biosynthesis, arabinofuranosyltransferase C (aftC) is responsible for the branching of the arabinan domain in both arabinogalactan and lipoarabinomannan. Using Clustered Regularly Interspaced Short Palindromic Repeats interference (CRISPRi) we have generated aftC knockdowns in Mycobacterium bovis BCG and demonstrated the generation of a truncated, immunogenic lipoarabinomannan within its cell envelope. The aftC depleted BCG mutants were unable to form characteristic mycobacterial pellicular biofilms and elicit a potent immunostimulatory phenotype compared to wild type M. bovis BCG in a THP1 cell line. This study paves the way to further explore novel BCG mutants as promising vaccine boosters in preventing pulmonary tuberculosis.

Generation of a Universal Human Complement Source by Large-Scale Depletion of IgG and IgM from Pooled Human Plasma.

Complement is a key component of functional immunological assays used to evaluate vaccine-mediated immunity to a range of bacterial and viral pathogens. However, standardization of these assays is complicated due to the availability of a human complement source that lacks existing antibodies acquired either through vaccination or natural circulation of the pathogen of interest. We have developed a method for depleting both IgG and IgM in 200 mL batches from pooled hirudin-derived human plasma by sequential affinity chromatography using a Protein G Sepharose column followed by POROS™ CaptureSelect™ IgM Affinity resin. The production of large IgG- and IgM-depleted batches of human plasma that retains total hemolytic and alternative pathway activities allows for improved assay standardization and comparison of immune responses in large clinical trials.

An alert tool to promote lung protective ventilation for possible acute respiratory distress syndrome.

Objective: Computer-aided decision tools may speed recognition of acute respiratory distress syndrome (ARDS) and promote consistent, timely treatment using lung-protective ventilation (LPV). This study evaluated implementation and service (process) outcomes with deployment and use of a clinical decision support (CDS) synchronous alert tool associated with existing computerized ventilator protocols and targeted patients with possible ARDS not receiving LPV. Materials and Methods: We performed an explanatory mixed methods study from December 2019 to November 2020 to evaluate CDS alert implementation outcomes across 13 intensive care units (ICU) in an integrated healthcare system with >4000 mechanically ventilated patients annually. We utilized quantitative methods to measure service outcomes including CDS alert tool utilization, accuracy, and implementation effectiveness. Attitudes regarding the appropriateness and acceptability of the CDS tool were assessed via an electronic field survey of physicians and advanced practice providers. Results: Thirty-eight percent of study encounters had at least one episode of LPV nonadherence. Addition of LPV treatment detection logic prevented an estimated 1812 alert messages (41%) over use of disease detection logic alone. Forty-eight percent of alert recommendations were implemented within 2 h. Alert accuracy was estimated at 63% when compared to gold standard ARDS adjudication, with sensitivity of 85% and positive predictive value of 62%. Fifty-seven percent of survey respondents observed one or more benefits associated with the alert. Conclusion: Introduction of a CDS alert tool based upon ARDS risk factors and integrated with computerized ventilator protocol instructions increased visibility to gaps in LPV use and promoted increased adherence to LPV.

The impact of storm events on a riverbed system and its hydraulic conductivity at a site of induced infiltration.

The spatial and temporal variability of riverbed vertical hydraulic conductivity (K(v)) was investigated at a site of induced infiltration, associated with a municipal well field, to assess the impact of high-stage events on scour and subsequently the riverbed K(v). Such impacts are important when considering the potential loss of riverbank filtration capacity due to storm events. The study site, in and along the Great Miami River in southwest Ohio, overlaid a highly productive glacial-outwash aquifer. A three-layer model for this system was conceptualized: a top layer of transient sediment, a second layer comprising large sediment resistant to scour, but clogged with finer sediment (the armor/colmation layer), and a third layer that was transitional to the underlying higher-K(v) aquifer. One location was studied in detail to confirm and quantify the conceptual model. Methods included seepage meters, heat-flow modeling, grain-size analyses, laboratory permeameter tests, slug tests and the use of scour chains and pressure-load cells to directly measure the amount of sediment scour and re-deposition. Seepage meter measured riverbed K(v) ranged from 0.017 to 1.7 m/d with a geometric mean of 0.19 m/d. Heat-transport model-calibrated estimates were even lower, ranging from 0.0061 to 0.046 m/d with a mean of 0.017 m/d. The relatively low K(v) was indicative of the clogged armor layer. In contrast, slug tests in the underlying riverbed sediment yielded K(v) values an order of magnitude greater. There was a linear relationship between scour chain measured scour and event intensity with a maximum scour of only 0.098 m. Load-cell pressure sensor data over a 7-month period indicated a total sediment-height fluctuation of 0.42 m and a maximum storm-event scour of 0.28 m. Scour data indicated that the assumed armor/colmation layer almost always remained intact. Based on measured layer conductivities and thicknesses, the overall K(v) of this conceptualized system was 1.6 m/d. Sensitivity analyses indicated that even complete scour of the armor/colmation layer would likely increase the overall K(v) only by a factor of 1.5. Most scour events observed removed only the transient sediment, having very little effect on the entire system indicating low risk of losing filtration capacity during storms. The research, however, focused on the point bar, depositional side of the river. More research of the entire river profile is necessary.

Small molecule modulation of the p75 neurotrophin receptor suppresses age- and genotype-associated neurodegeneration in HIV gp120 transgenic mice.

The persistence of HIV in the central nervous system leads to cognitive deficits in up to 50% of people living with HIV even with systemic suppression by antiretroviral treatment. The interaction of chronic inflammation with age-associated degeneration places these individuals at increased risk of accelerated aging and other neurodegenerative diseases and no treatments are available that effectively halt these processes. The adverse effects of aging and inflammation may be mediated, in part, by an increase in the expression of the p75 neurotrophin receptor (p75NTR) which shifts the balance of neurotrophin signaling toward less protective pathways. To determine if modulation of p75NTR could modify the disease process, we treated HIV gp120 transgenic mice with a small molecule ligand designed to engage p75NTR and downregulate degenerative signaling. Daily treatment with 50 mg/kg LM11A-31 for 4 months suppressed age- and genotype-dependent activation of microglia, increased microtubule associated protein-2 (MAP-2), reduced dendritic varicosities and slowed the loss of parvalbumin immunoreactive neurons in the hippocampus. An age related accumulation of microtubule associated protein Tau was identified in the hippocampus in extracellular clusters that co-expressed p75NTR suggesting a link between Tau and p75NTR. Although the significance of the relationship between p75NTR and Tau is unclear, a decrease in Tau-1 immunoreactivity as gp120 mice entered old age (>16 months) suggests that the Tau may transition to more pathological modifications; a process blocked by LM11A-31. Overall, the effects of LM11A-31 are consistent with strong neuroprotective and anti-inflammatory actions that have significant therapeutic potential.