A Retrospective Study Evaluating Neonatal Vancomycin Loading Doses to Achieve a Therapeutic Target.

BACKGROUND: Vancomycin is a glycopeptide antibiotic that has been used to treat hospital-acquired gram-positive infections for more than 5 decades. However, the literature is divided regarding the therapeutic advantages of vancomycin loading doses in neonates. OBJECTIVES: This study aimed to investigate the effect of vancomycin loading doses on therapeutic target attainment in neonates with sepsis. METHODS: A retrospective cohort study was conducted to compare the vancomycin target attainment (area under the curve 0-24 hours/minimum inhibitory concentration ≥400) in neonates before and after the 2019 change in vancomycin prescription guidelines at a neonatal unit in Cape Town, South Africa. As the standard of care, Bayesian modelling software was used to compute the area under the curve from the trough concentrations. RESULTS: Two hundred ten neonates were included. Multivariate regression analysis showed a 2-fold increase in the odds of target attainment among neonates receiving a loading dose of vancomycin. Early target attainment (within 8-12 hours of treatment initiation) was significantly higher in the loading dose group compared with the no loading dose group [97/105 (92.4%) versus 64/105 (61.0%); P < 0.001]. However, the overall proportion of neonates achieving target attainment at 24 hours was similar between groups [73/105 (69.5%) in the loading dose group versus 62/105 (59.0%) in the no loading dose group; P = 0.110]. The nephrotoxicity rates were low [2/105 (1.9%) in the loading dose group and 2/105 (1.9%) in the no loading dose group]. CONCLUSIONS: The addition of a vancomycin loading dose to neonates may facilitate early therapeutic target attainment.

Oil and gas produced waters fail to meet beneficial reuse recommendations for use as dust suppressants.

Produced water from conventional oil and gas wells (O&G PW) is beneficially reused as an inexpensive alternative to commercial dust suppressants which minimize inhalable particulate matter (PM10) from unpaved roads. The efficacy and environmental impacts of using O&G PW instead of commercial products have not been extensively investigated, although O&G PW has been used for dust suppression for decades and often has elevated concentrations of environmental pollutants. In this study, the effectiveness of O&G PW is compared to commercial products under variable humidity conditions by measuring total generated PM10 emissions from treated road aggregate discs. To measure environmental impacts, model roadbeds were treated with six O&G PW and commercial products then subjected to a simulated two-year, 24-h storm event. Generated runoff water was collected and characterized. In efficacy studies, O&G PW offered variable dust reduction (10-85 %) compared to rainwater controls under high humidity (50 %) conditions but performed similarly or worse than controls when humidity was low (20 %). Conversely, all but two commercial products reduced dust emissions by over 90 % regardless of humidity. In rainfall-runoff experiments, roads treated with O&G PWs and CaCl2 Brine generated runoff that was hypersaline, indicating that mobilization of soluble salts could contribute to freshwater salinization. Though most runoff concentrations were highest from roadbeds treated with CaCl2 Brine, runoff from roadbeds treated with O&G PW had the highest concentrations of combined radium (83.6 pCi/L), sodium (3560 mg/L), and suspended solids (5330 mg/L). High sodium concentrations likely dispersed clay particles, which increased road mass loss by 47.2 kg solids/km/storm event compared to rainwater controls. Roadbeds treated with CaCl2 Brine, which had low sodium concentrations, reduced solid road mass loss by 98.1 kg solids/km/storm event. Based on this study, O&G PW do not perform as well as commercial products and pose unique risks to environmental health.

A Geometrical Explanation for Change in Pelvic Tilt (or Lack of Change) Following Long Spinal Fusions.

STUDY DESIGN: Retrospective Cohort. OBJECTIVE: Examine the relationship between compensatory pelvic retroversion, positive sagittal imbalance (measured by C2 tilt), and the C2 pelvic angle (C2PA) in patients prior to long spinal fusions; and to determine the association between changes in C2PA and pelvic tilt (PT) following long spinal fusions. BACKGROUND: Adult spinal deformity surgical goals often include a PT target, yet patients frequently demonstrate persistent compensatory pelvic retroversion following surgery. MATERIALS AND METHODS: Adults>18y undergoing long spinal fusions (>4 levels) with standing preoperative and postoperative radiographs were included. To examine drivers of preoperative sagittal balance, regression models were fit to estimate the association between preoperative C2PA and pelvic incidence, with preoperative PT and C2 tilt. To predict postoperative change in PT, multivariable regression was used to estimate change in PT, adjusting for change in C2PA and preoperative C2 tilt. RESULTS: Among 80 patients identified, median age was 61 (IQR, 45 to 72) and 46 (58%) were female. Median number of levels fused was 10 (IQR, 8 to 13) and 55 (69%) were instrumented to the sacrum/pelvis. Preoperative C2PA had a significant nonlinear association with preoperative PT (r2=0.81, P<0.001), and preoperative C2 tilt (r2=0.41, P=0.002). Postoperative change in PT was strongly associated with change in C2PA (ß=0.81; P<0.001) and preoperative C2 tilt (ß=0.55; P<0.001). CONCLUSIONS: Following long spinal fusions, change in PT (or lack thereof) can be reliably predicted based on change in C2PA and preoperative C2 tilt. In patients with normal preoperative C2 tilt, the change in C2PA is nearly equivalent to the change in PT, but in patients with more positive C2 tilt (sagittal imbalance), a greater change in C2PA will be required to achieve equivalent change in PT. LEVEL OF EVIDENCE: III.

Increasing hub disruption parallels dementia severity in autosomal dominant Alzheimer disease.

Hub regions in the brain, recognized for their roles in ensuring efficient information transfer, are vulnerable to pathological alterations in neurodegenerative conditions, including Alzheimer Disease (AD). Given their essential role in neural communication, disruptions to these hubs have profound implications for overall brain network integrity and functionality. Hub disruption, or targeted impairment of functional connectivity at the hubs, is recognized in AD patients. Computational models paired with evidence from animal experiments hint at a mechanistic explanation, suggesting that these hubs may be preferentially targeted in neurodegeneration, due to their high neuronal activity levels-a phenomenon termed "activity-dependent degeneration". Yet, two critical issues were unresolved. First, past research hasn't definitively shown whether hub regions face a higher likelihood of impairment (targeted attack) compared to other regions or if impairment likelihood is uniformly distributed (random attack). Second, human studies offering support for activity-dependent explanations remain scarce. We applied a refined hub disruption index to determine the presence of targeted attacks in AD. Furthermore, we explored potential evidence for activity-dependent degeneration by evaluating if hub vulnerability is better explained by global connectivity or connectivity variations across functional systems, as well as comparing its timing relative to amyloid beta deposition in the brain. Our unique cohort of participants with autosomal dominant Alzheimer Disease (ADAD) allowed us to probe into the preclinical stages of AD to determine the hub disruption timeline in relation to expected symptom emergence. Our findings reveal a hub disruption pattern in ADAD aligned with targeted attacks, detectable even in pre-clinical stages. Notably, the disruption's severity amplified alongside symptomatic progression. Moreover, since excessive local neuronal activity has been shown to increase amyloid deposition and high connectivity regions show high level of neuronal activity, our observation that hub disruption was primarily tied to regional differences in global connectivity and sequentially followed changes observed in Aß PET cortical markers is consistent with the activity-dependent degeneration model. Intriguingly, these disruptions were discernible 8 years before the expected age of symptom onset. Taken together, our findings not only align with the targeted attack on hubs model but also suggest that activity-dependent degeneration might be the cause of hub vulnerability. This deepened understanding could be instrumental in refining diagnostic techniques and developing targeted therapeutic strategies for AD in the future.

The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Zmpste24 -/- Progeria Mouse Model.

Aging leads to several geriatric conditions including osteoporosis (OP) and associated frailty syndrome. Treatments for these conditions are limited and none target fundamental drivers of pathology, and thus identifying strategies to delay progressive loss of tissue homeostasis and functional reserve will significantly improve quality of life in elderly individuals. A fundamental property of aging is the accumulation of senescent cells. Senescence is a cell state defined by loss of proliferative capacity, resistance to apoptosis, and the release of a proinflammatory and anti-regenerative senescence-associated secretory phenotype (SASP). The accumulation of senescent cells and SASP factors is thought to significantly contribute to systemic aging. Senolytics-compounds which selectively target and kill senescent cells-have been characterized to target and inhibit anti-apoptotic pathways that are upregulated during senescence, which can elicit apoptosis in senescent cells and relieve SASP production. Senescent cells have been linked to several age-related pathologies including bone density loss and osteoarthritis in mice. Previous studies in murine models of OP have demonstrated that targeting senescent cells pharmacologically with senolytic drugs can reduce symptomology of the disease. Here, we demonstrate the efficacy of senolytic drugs (dasatinib, quercetin, and fisetin) to improve age-associated degeneration in bone using the Zmpste24-/- (Z24-/-) progeria murine system for Hutchinson-Gilford progeria syndrome (HGPS). We found that the combination of dasatinib plus quercetin could not significantly mitigate trabecular bone loss although fisetin administration could reduce bone density loss in the accelerated aging Z24-/- model. Furthermore, the overt bone density loss observed in the Z24-/- model reported herein highlights the Z24 model as a translational model to recapitulate alterations in bone density associated with advanced age. Consistent with the "geroscience hypothesis," these data demonstrate the utility of targeting a fundamental driver of systemic aging (senescent cell accumulation) to alleviate a common condition with age, bone deterioration.

Median Time to Return to Sports After Concussion Is Within 21 Days in 80% of Published Studies.

PURPOSE: To perform a systematic review of the literature and evaluate the return to play (RTP) time frame after a concussion diagnosis. Our secondary purpose was to analyze and compare different prognostic variables affecting concussions, time to return to school, time to symptom resolution of concussive symptoms, and time each patient spent in the RTP protocol. METHODS: A PubMed, Scopus, Medline, Embase, and Cochrane Library database literature review was performed in August 2022. The studies needed to report, in days, the length of time a patient/athlete was removed from play due to concussion management. The Risk of Bias in Non-Randomized Studies of Interventions tool was used for risk of bias for each study, and Methodological Index for Non-Randomized Studies criteria were used for quality assessment. RESULTS: There were 65 studies included in the systematic review and a total of 21,966 patients evaluated. The RTP time intervals ranged from 1 to 1,820 days, with 80.7% of the median RTP time frames for each study within 21 days. Preconcussion risk factors for prolonged RTP included female sex, younger age, presence of psychiatric disorders, and history of previous concussion. Postconcussion risk factors included severe symptom scores at initial clinic visit, loss of consciousness, nonelite athletes, and delayed removal from competition. The most common sports resulting in concussion were contact sports, most commonly football and soccer. Median time to return to school was 3 to 23 days. Median time to symptom resolution ranged from 2 to 11 days. Median time in RTP protocol was 1 to 6 days. CONCLUSIONS: Median time to return to sports after concussion is within 21 days in 80% of published studies. LEVEL OF EVIDENCE: IV, systematic review of Level I to IV studies.