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Microgravity-induced bone loss results in a 1% bone mineral density loss monthly and can be a mission critical factor in long-duration spaceflight. Biomolecular therapies with dual osteogenic and anti-resorptive functions are promising for treating extreme osteoporosis. We previously confirmed that NELL-like molecule-1 (NELL-1) is crucial for bone density maintenance. We further PEGylated NELL-1 (NELL-polyethylene glycol, or NELL-PEG) to increase systemic delivery half-life from 5.5 to 15.5 h. In this study, we used a bio-inert bisphosphonate (BP) moiety to chemically engineer NELL-PEG into BP-NELL-PEG and specifically target bone tissues. We found conjugation with BP improved hydroxyapatite (HA) binding and protein stability of NELL-PEG while preserving NELL-1's osteogenicity in vitro. Furthermore, BP-NELL-PEG showed superior in vivo bone specificity without observable pathology in liver, spleen, lungs, brain, heart, muscles, or ovaries of mice. Finally, we tested BP-NELL-PEG through spaceflight exposure onboard the International Space Station (ISS) at maximal animal capacity (n = 40) in a long-term (9 week) osteoporosis therapeutic study and found that BP-NELL-PEG significantly increased bone formation in flight and ground control mice without obvious adverse health effects. Our results highlight BP-NELL-PEG as a promising therapeutic to mitigate extreme bone loss from long-duration microgravity exposure and musculoskeletal degeneration on Earth, especially when resistance training is not possible due to incapacity (e.g., bone fracture, stroke).

Introduction: Acetaminophen poisoning is commonly treated by emergency physicians. First-line therapy is N-acetylcysteine (NAC), traditionally administered intravenously via a US Food and Drug Administration (FDA)-approved three-bag protocol in which each bag has a unique concentration and infusion duration. Recently, simplified, off-label two-bag NAC infusion protocols have become more common. The purpose of this review is to summarize the effectiveness and safety of two-bag NAC.Methods: We undertook a comprehensive search of PubMed, EMBASE, and MEDLINE from inception to December 13, 2022, for articles describing human acetaminophen poisonings treated with two-bag NAC, defined as any regimen involving two discrete infusions in two separate bags. Outcomes included effectiveness (measured by incidence of liver injury); incidence of non-allergic anaphylactoid reactions (NAAR); gastrointestinal, cutaneous, and systemic reactions; treatments for NAARs; incidence of NAC-related medication errors; and delays or interruptions in NAC administration.Results: Twelve articles met final inclusion, 10 of which compared two-bag NAC to the three-bag regimen. Nine articles evaluated the two-bag/20-hour regimen, a simplified version of the FDA-approved three-bag regimen in which the traditional first and second bags are combined into a single four-hour infusion. Nine articles assessed comparative effectiveness of two-bag NAC in terms of liver injury, most commonly assessed for by incidence of hepatotoxicity (aspartate aminotransferase or alanine aminotransferase >1,000 international units per liter). No difference in liver injury was observed between two-bag and three-bag regimens. Of nine articles comparing incidence of NAARs, eight demonstrated statistically fewer NAARs with two-bag regimens, and one showed no difference. In seven articles evaluating treatment for NAARs (antihistamines, corticosteroids, epinephrine), all showed that patients received fewer medications for NAARs with two-bag NAC. Three articles evaluated NAC-related medication errors; two demonstrated no difference, while one study evaluating only children showed fewer errors with two-bag NAC. Two studies evaluated delays and/or interruptions in NAC infusions; both favored two-bag NAC.Conclusion: For patients with acetaminophen poisoning, two-bag NAC regimens appear to have similar outcomes to the traditional three-bag regimen in terms of liver injury. Two-bag NAC regimens are associated with fewer adverse events and fewer treatments for those events than the three-bag regimen and fewer interruptions in antidotal therapy.

ObjectiveDescribe emergency department (ED) management and patient outcomes for febrile infants 29-60 days of age who received a lumbar puncture (LP), with focus on timing of antibiotics and type of physician performing LP.MethodsRetrospective observational study of 35 California EDs from January 1, 2010 through December 31, 2019. Primary analysis was among patients with successful LP and primary outcome was hospital length of stay (LOS). Logistic regression analysis included variables associated with LOS of at least 2 days. Secondary outcomes were bacterial meningitis, hospital admission, length of antibiotics, and readmission.ResultsAmong 2569 febrile infants (median age 39 days), 667 underwent successful LP and 633 received intravenous antibiotics. Most infants (n = 559, 88.3%) had their LP before intravenous antibiotic administration. Pediatricians performed 54% of LPs and emergency physicians 34%. Sixteen infants (0.6% of 2569) were diagnosed with bacterial meningitis, and none died. Five hundred and fifty-eight (88%) infants receiving an LP were hospitalized. Among patients receiving an LP and antibiotics (n = 633), 6.5% were readmitted within 30 days. Patients receiving antibiotics before LP had a longer length of antibiotics (+ 7.9 hours, 95% confidence interval [CI] 3.8-13.4). Primary analysis found no association between timing of antibiotics and LOS (odds ratio [OR] 0.67, 95% CI 0.34-1.30), but shorter LOS when emergency physicians performed the LP (OR 0.66, 95% CI 0.45-0.97).ConclusionsFebrile infants in the ED had no deaths and few cases of bacterial meningitis. In community EDs, where a pediatrician is often not available, successful LP by emergency physician was associated with reduced inpatient LOS.

Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer's disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P

Anaerobic fungi and methanogenic archaea are two classes of microorganisms found in the rumen microbiome that metabolically interact during lignocellulose breakdown. Here, stable synthetic co-cultures of the anaerobic fungus Caecomyces churrovis and the methanogen Methanobacterium bryantii (not native to the rumen) were formed, demonstrating that microbes from different environments can be paired based on metabolic ties. Transcriptional and metabolic changes induced by methanogen co-culture were evaluated in C. churrovis across a variety of substrates to identify mechanisms that impact biomass breakdown and sugar uptake. A high-quality genome of C. churrovis was obtained and annotated, which is the first sequenced genome of a non-rhizoid-forming anaerobic fungus. C. churrovis possess an abundance of CAZymes and carbohydrate binding modules and, in agreement with previous studies of early-diverging fungal lineages, N6-methyldeoxyadenine (6mA) was associated with transcriptionally active genes. Co-culture with the methanogen increased overall transcription of CAZymes, carbohydrate binding modules, and dockerin domains in co-cultures grown on both lignocellulose and cellulose and caused upregulation of genes coding associated enzymatic machinery including carbohydrate binding modules in family 18 and dockerin domains across multiple growth substrates relative to C. churrovis monoculture. Two other fungal strains grown on a reed canary grass substrate in co-culture with the same methanogen also exhibited high log2-fold change values for upregulation of genes encoding carbohydrate binding modules in families 1 and 18. Transcriptional upregulation indicated that co-culture of the C. churrovis strain with a methanogen may enhance pyruvate formate lyase (PFL) function for growth on xylan and fructose and production of bottleneck enzymes in sugar utilization pathways, further supporting the hypothesis that co-culture with a methanogen may enhance certain fungal metabolic functions. Upregulation of CBM18 may play a role in fungal-methanogen physical associations and fungal cell wall development and remodeling.

Introduction: Droperidol carries a boxed warning from the United States Food and Drug Administration for QT prolongation and torsades des pointes (TdP). After a six-year hiatus, droperidol again became widely available in the US in early 2019. With its return, clinicians must again make decisions regarding the boxed warning. Thus, the objective of this study was to report the incidence of QT prolongation or TdP in patients receiving droperidol in the ED.Methods: Patients receiving droperidol at an urban Level I trauma center from 1997–2001 were identified via electronic health record query. All patients were reviewed for cardiac arrest. We reviewed electrocardiogram (ECG) data for both critically-ill and noncritical patients and recorded Bazett’s corrected QT intervals (QTc). ECGs from critically-ill patients undergoing resuscitation were further risk-stratified using the QT nomogram.Results: Of noncritical patients, 15,374 received 18,020 doses of droperidol; 2,431 had an ECG. In patients with ECGs before and after droperidol, the mean QTc was 424.3 milliseconds (ms) (95% confidence interval [CI], 419.7-428.9) before and 427.6 ms (95% CI, 424.3-430.9), after droperidol(n = 170). Regarding critically-ill patients, 1,172 received droperidol and 396 had an ECG. In the critically-ill group with ECGs before and after droperidol mean QTc was 435.7 ms (95% CI, 426.7–444.7) before and 435.8 ms (95% CI, 427.5–444.1) after droperidol (n = 114). Of 337 ECGs suitable for plotting on the QT nomogram, 13 (3.8%) were above the “at-risk” line; 3/136 (2.2%; 95% CI, 0.05-6.3%) in the before group, and 10/202 (4.9%; 95% CI, 2.4%-8.9%) in the after group. A single case of TdP occurred in a patient with multiple risk factors that did not reoccur after a droperidol rechallenge. Thus, the incidence of TdP was 1/16,546 (0.006%; 95% CI, 0.00015 - 0.03367%).Conclusion: We found the incidence of QTc prolongation and TdP in ED patients receiving droperidol to be extremely rare. Our data suggest the FDA “black box warning” is overstated, and that close ECG monitoring is useful only in high-risk patients.

Introduction: Expanding naloxone availability is important to reduce opioid-related deaths. Recent data suggest low, variable urban naloxone availability. No reports describe naloxone availability at the point of sale (POSN). We characterize POSN without prescription across a Midwestern metropolitan area, via a unique poison center-based study.Methods: Pharmacies were randomly sampled within a seven-county metropolitan area, geospatially mapped, and distributed among seven investigators, who visited pharmacies and asked, “May I purchase naloxone here without a prescription from my doctor?” Following “No,” investigators asked, “Are you aware of the state statute that allows you to dispense naloxone to the public under a standing order?” Materials describing statutory support for POSN were provided. Responses were uploaded to REDCap in real time. We excluded specialty (veterinary, mail order, or infusion) pharmacies a priori. POSN availability is presented as descriptive statistics; characteristics of individual sites associated with POSN availability are reported.Results: In total, 150 pharmacies were prospectively randomized, with 52 subsequently excluded or unavailable for survey. Thus, 98 were included in the final analysis. POSN was available at 71 (72.5%) of 98 pharmacies. POSN availability was more likely at chain than independent pharmacies (84.7% vs 38.5%, p

BackgroundThe Janus kinase (JAK) and signal transduction and activation of transcription (STAT) signaling pathway is an attractive target in multiple cancers. Activation of the JAK-STAT pathway is important in both tumorigenesis and activation of immune responses. In diffuse large B-cell lymphoma (DLBCL), the transcription factor STAT3 has been associated with aggressive disease phenotype and worse overall survival. While multiple therapies inhibit upstream signaling, there has been limited success in selectively targeting STAT3 in patients. Antisense oligonucleotides (ASOs) represent a compelling therapeutic approach to target difficult to drug proteins such as STAT3 through of mRNA targeting. We report the evaluation of a next generation STAT3 ASO (AZD9150) in a non-Hodgkin's lymphoma population, primarily consisting of patients with DLBCL.MethodsPatients with relapsed or treatment refractory lymphoma were enrolled in this expansion cohort. AZD9150 was administered at 2 mg/kg and the 3 mg/kg (MTD determined by escalation cohort) dose levels with initial loading doses in the first week on days 1, 3, and 5 followed by weekly dosing. Patients were eligible to remain on therapy until unacceptable toxicity or progression. Blood was collected pre- and post-treatment for analysis of peripheral immune cells.ResultsThirty patients were enrolled, 10 at 2 mg/kg and 20 at 3 mg/kg dose levels. Twenty-seven patients had DLBCL. AZD9150 was safe and well tolerated at both doses. Common drug-related adverse events included transaminitis, fatigue, and thrombocytopenia. The 3 mg/kg dose level is the recommended phase 2 dose. All responses were seen among DLBCL patients, including 2 complete responses with median duration of response 10.7 months and 2 partial responses. Peripheral blood cell analysis of three patients without a clinical response to therapy revealed a relative increase in proportion of macrophages, CD4+, and CD8+ T cells; this trend did not reach statistical significance.ConclusionsAZD9150 was well tolerated and demonstrated efficacy in a subset of heavily pretreated patients with DLBCL. Studies in combination with checkpoint immunotherapies are ongoing.Trial registrationRegistered at ClinicalTrials.gov: NCT01563302 . First submitted 2/13/2012.

Objective: This study aims to explore the perspectives and experiences of Australian caregivers and community pharmacists about pediatric melatonin use. Methods: A convenience sample of caregivers with children (aged 11–16 years) using melatonin as a sleep aid and community pharmacists (including pharmacist interns) were recruited. Participants first completed an online survey followed by an online semi-structured interview. Interviews were guided by a schedule of questions for the respective participant groups, broadly exploring their beliefs about melatonin, experiences in using/supplying melatonin, and perceived facilitators/barriers for melatonin use. Interviews were digitally recorded, transcribed verbatim, and analyzed using the Framework Approach. Results: Fourteen caregivers of predominantly neurodiverse adolescents and 24 community pharmacists were interviewed. While melatonin was perceived by caregivers of both typically developing and neurodiverse dependants as safer than pharmacological sleep aids, treatment was only initiated after trialling non-pharmacological strategies first. Pharmacists expressed concerns around the ambiguities in practice and the limited scope of existing resources for guiding pediatric melatonin use. Caregivers frequently deferred to the information available online to procure products or self-adjust doses and dosing schedules. Both pharmacists and caregivers emphasized the need for more affordable and age-appropriate proprietary formulations that are readily accessible. Conclusion: Melatonin is administered predominantly by caregivers of neurodiverse adolescents to address their sleep disturbances. The findings underscore the need for reliable, evidence-based information to guide safe and appropriate use of melatonin in pediatric populations. Patient education is also warranted to address maladaptive medication-administration practices. Lastly, there is a need for stronger regulatory oversight of melatonin products to ensure their quality and safety of use. [ABSTRACT FROM AUTHOR]

Objectives Data supporting routine infectious diseases (ID) consultation in gram-negative bloodstream infection (GN-BSI) are limited. We evaluated the association between ID consultation and mortality in patients with GN-BSI in a retrospective population-wide cohort study in Ontario using linked health administrative databases. Methods Hospitalized adult patients with GN-BSI between April 2017 and December 2021 were included. The primary outcome was time to all-cause mortality censored at 30 days, analyzed using a mixed effects Cox proportional hazards model with hospital as a random effect. ID consultation 1–10 days after the first positive blood culture was treated as a time-varying exposure. Results Of 30 159 patients with GN-BSI across 53 hospitals, 11 013 (36.5%) received ID consultation. Median prevalence of ID consultation for patients with GN-BSI across hospitals was 35.0% with wide variability (range 2.7%–76.1%, interquartile range 19.6%–41.1%). In total, 1041 (9.5%) patients who received ID consultation died within 30 days, compared to 1797 (9.4%) patients without ID consultation. In the fully adjusted multivariable model, ID consultation was associated with mortality benefit (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI].77–.88, P <.0001; translating to absolute risk reduction of −3.8% or number needed to treat [NNT] of 27). Exploratory subgroup analyses of the primary outcome showed that ID consultation could have greater benefit in patients with high-risk features (nosocomial infection, polymicrobial or non-Enterobacterales infection, antimicrobial resistance, or non-urinary tract source). Conclusions Early ID consultation was associated with reduced mortality in patients with GN-BSI. If resources permit, routine ID consultation for this patient population should be considered to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Canadian health systems fare poorly in providing timely access to elective surgical care, which is crucial for quality, trust, and satisfaction. Methods: We conducted a cross-sectional analysis of surgical wait times for adults receiving non-urgent cataract surgery, knee arthroplasty, hip arthroplasty, gallbladder surgery, and non-cancer uterine surgery in Ontario, Canada, between 2013 and 2019. We obtained data from the Wait Times Information System (WTIS) database. Inter- and intra-hospital and surgeon variations in wait time were described graphically with caterpillar plots. We used non-nested 3-level hierarchical random effects models to estimate variation partition coefficients, quantifying the proportion of wait time variance attributable to surgeons and hospitals. Results: A total of 942,605 procedures at 107 healthcare facilities, conducted by 1,834 surgeons, were included in the analysis. We observed significant intra- and inter-provider variations in wait times across all five surgical procedures. Inter-facility median wait time varied between six-fold for gallbladder surgery and 15-fold for knee arthroplasty. Inter-surgeon variation was more pronounced, ranging from a 17-fold median wait time difference for cataract surgery to a 216-fold difference for non-cancer uterine surgery. The proportion of variation in wait times attributable to facilities ranged from 6.2% for gallbladder surgery to 23.0% for cataract surgery. In comparison, surgeon-related variation ranged from 16.0% for non-cancer uterine surgery to 28.0% for cataract surgery. Implications: There is extreme variability in surgical wait times for five common, high-volume, non-urgent surgical procedures. Strategies to address surgical wait times must address the variation between service providers through better coordination of supply and demand. Approaches such as single-entry models could improve surgical system performance. [ABSTRACT FROM AUTHOR]

Objectives The risk factors and outcomes associated with persistent bacteraemia in Gram-negative bloodstream infection (GN-BSI) are not well described. We conducted a follow-on analysis of a retrospective population-wide cohort to characterize persistent bacteraemia in patients with GN-BSI. Methods We included all hospitalized patients >18 years old with GN-BSI between April 2017 and December 2021 in Ontario who received follow-up blood culture (FUBC) 2–5 days after the index positive blood culture. Persistent bacteraemia was defined as having a positive FUBC with the same Gram-negative organism as the index blood culture. We identified variables independently associated with persistent bacteraemia in a multivariable logistic regression model. We evaluated whether persistent bacteraemia was associated with increased odds of 30- and 90-day all-cause mortality using multivariable logistic regression models adjusted for potential confounders. Results In this study, 8807 patients were included; 600 (6.8%) had persistent bacteraemia. Having a permanent catheter, antimicrobial resistance, nosocomial infection, ICU admission, respiratory or skin and soft tissue source of infection, and infection by a non-fermenter or non-Enterobacterales/anaerobic organism were associated with increased odds of having persistent bacteraemia. The 30-day mortality was 17.2% versus 9.6% in those with and without persistent bacteraemia (aOR 1.65, 95% CI 1.29–2.11), while 90-day mortality was 25.5% versus 16.9%, respectively (aOR 1.53, 95% CI 1.24–1.89). Prevalence and odds of developing persistent bacteraemia varied widely depending on causative organism. Conclusions Persistent bacteraemia is uncommon in GN-BSI but is associated with poorer outcomes. A validated risk stratification tool may be useful to identify patients with persistent bacteraemia. [ABSTRACT FROM AUTHOR]