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CNS disorders are on the rise despite advancements in our understanding of their pathophysiological mechanisms. A major hurdle to the treatment of these disorders is the blood–brain barrier (BBB), which serves as an arduous janitor to protect the brain. Many drugs are being discovered for CNS disorders, which, however fail to enter the market because of their inability to cross the BBB. This is a pronounced challenge for the pharmaceutical fraternity. Hence, in addition to the discovery of novel entities and drug candidates, scientists are also developing new formulations of existing drugs for brain targeting. Several approaches have been investigated to allow therapeutics to cross the BBB. As the molecular structure of the BBB is better elucidated, several key approaches for brain targeting include physiological transport mechanisms such as adsorptive-mediated transcytosis, inhibition of active efflux pumps, receptor-mediated transport, cell-mediated endocytosis, and the use of peptide vectors. Drug-delivery approaches comprise delivery from microspheres, biodegradable wafers, and colloidal drug-carrier systems (e.g., liposomes, nanoparticles, nanogels, dendrimers, micelles, nanoemulsions, polymersomes, exosomes, and quantum dots). The current review discusses the latest advancements in these approaches, with a major focus on articles published in 2015 and 2016. In addition, we also cover the alternative delivery routes, such as intranasal and convection-enhanced diffusion methods, and disruption of the BBB for brain targeting.

The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (B CSF ) are two of the most complex and sophisticated concierges that defend the central nervous system (CNS) by numerous mechanisms. While they maintain the neuro-ecological homeostasis through the regulated entry of essential biomolecules, their conservative nature challenges the entry of most of the drugs intended for CNS delivery. Targeted delivery challenges for a diverse spectrum of therapeutic agents/drugs (non-small molecules, small molecules, gene-based therapeutics, protein and peptides, antibodies) are diverse and demand specialized delivery and disease-targeting strategies. This review aims to capture the trends that have shaped the current brain targeting research scenario. This review discusses the physiological, neuropharmacological, and etiological factors that participate in the transportation of various drug delivery cargoes across the BBB/B CSF and influence their therapeutic intracranial concentrations. Recent research works spanning various invasive, minimally invasive, and non-invasive brain- targeting approaches are discussed. While the pre-clinical outcomes from many of these approaches seem promising, further research is warranted to overcome the translational glitches that prevent their clinical use. Non-invasive approaches like intranasal administration, P-glycoprotein (P-gp) inhibition, pro-drugs, and carrier/targeted nanocarrier-aided delivery systems (alone or often in combination) hold positive clinical prospects for brain targeting if explored further in the right direction.

HighlightsDue to their multifaceted oncological applications and immense translational potential, the bio-nanocarriers and nano-biodevices are being conceived as a futuristic panacea for cancer.Aspects impeding promising prognosis of lung cancer, various nano-biotools, and their plausible benefits over the conventional nanocarriers for lung cancer management have been briefed upon in this review.Research findings from relevant investigations, perspectives, and stipulations for the overall management of lung cancer have also been deliberated.Lung cancer is a complex thoracic malignancy developing consequential to aberrations in a myriad of molecular and biomolecular signaling pathways. It is one of the most lethal forms of cancers accounting to almost 1.8 million new annual incidences, bearing overall mortality to incidence ratio of 0.87. The dismal prognostic scenario at advanced stages of the disease and metastatic/resistant tumor cell populations stresses the requisite of advanced translational interdisciplinary interventions such as bionanotechnology. This review article deliberates insights and apprehensions on the recent prologue of nanobioengineering and bionanotechnology as an approach for the clinical management of lung cancer. The role of nanobioengineered (bio-nano) tools like bio-nanocarriers and nanobiodevices in secondary prophylaxis, diagnosis, therapeutics, and theranostics for lung cancer management has been discussed. Bioengineered, bioinspired, and biomimetic bio-nanotools of considerate translational value have been reviewed. Perspectives on existent oncostrategies, their critical comparison with bio-nanocarriers, and issues hampering their clinical bench side to bed transformation have also been summarized.

RATIONALE:Intensive care unit (ICU) delirium is highly prevalent and a potentially avoidable hospital complication. The current cost of ICU delirium is unknown. OBJECTIVES:To specify the association between the daily occurrence of delirium in the ICU with costs of ICU care accounting for time-varying illness severity and death. RESEARCH DESIGN:We performed a prospective cohort study within medical and surgical ICUs in a large academic medical center. SUBJECTS:We analyzed critically ill patients (N=479) with respiratory failure and/or shock. MEASURES:Covariates included baseline factors (age, insurance, cognitive impairment, comorbidities, Acute Physiology and Chronic Health Evaluation II Score) and time-varying factors (sequential organ failure assessment score, mechanical ventilation, and severe sepsis). The primary analysis used a novel 3-stage regression methodfirst, estimation of the cumulative cost of delirium over 30 ICU days and then costs separated into those attributable to increased resource utilization among survivors and those that were avoided on the account of delirium’s association with early mortality in the ICU. RESULTS:The patient-level 30-day cumulative cost of ICU delirium attributable to increased resource utilization was $17,838 (95% confidence interval, $11,132–$23,497). A combination of professional, dialysis, and bed costs accounted for the largest percentage of the incremental costs associated with ICU delirium. The 30-day cumulative incremental costs of ICU delirium that were avoided due to delirium-associated early mortality was $4654 (95% confidence interval, $2056–7869). CONCLUSIONS:Delirium is associated with substantial costs after accounting for time-varying illness severity and could be 20% higher (∼$22,500) if not for its association with early ICU mortality.

To determine the association between postoperative delirium (POD) and cognitive outcomes at least 1 month after surgery in elderly patients, and synthesize the dynamic risk trajectory of cognition impairment after POD. Meta-analysis searching PubMed, Cochrane and EMBASE from inception to November 1, 2020. The terms postoperative delirium, delirium after surgery, postsurgical delirium, postoperative cogniti*, postoperative cognitive dysfunction, postoperative cognition decline, cognitive decline, cognitive impair* and dement* were searched alone or in combination. Inclusion criteria were prospective cohort studies investigating the association between POD and cognitive outcomes in patients aged ≥60 years underwent surgery. The primary outcome was the association between POD and cognitive outcomes at 1 or more months after surgery. We considered cognitive outcomes measured up to 12 months after surgery as short-term and beyond 12 months as long-term. Two authors performed the study screening, data extraction and quality assessments. Effect sizes were calculated as Hedges g or Odds ratio (OR) based on random- and fixed-effects models. Meta-regression was conducted to analyze the role of potential contributors to heterogeneity. Eighteen studies were included. Our result showed a significant and medium association between POD and cognitive outcomes after at least 1 month postoperatively (g = 0.61 95% CI 0.43–0.79; I2 = 65.1%), indicating that patients with POD were associated with worse cognitive outcomes. The association of POD with short- and long-term cognitive impairment were also both significant (short-term: g = 0.46 95% CI 0.24–0.68; I2 = 53.1%; and long-term: g = 0.82 95% CI 0.57–1.06; I2 = 57.1%). A multivariate meta-regression suggested that age and measure of delirium were significant sources of heterogeneity. POD was also associated with the significant risk for dementia (OR = 6.08 95% CI 3.80–9.72; I2 = 0) as well as attention (OR = 1.74 95% CI 1.13–2.68; I2 = 0), executive (OR = 1.33 95% CI 1.00–1.80; I2 = 0) and memory impairment (OR = 1.59 95% CI 1.20–2.10; I2 = 43.0%). Additionally, our results showed that the risk trajectory for cognitive decline associated with POD within five years after surgery revealed exponential growth. This is the first meta-analysis quantifying the association between POD and cognitive outcomes. Our results showed that POD was significantly associated with worse cognitive outcomes, including short- and long-term cognitive outcomes following surgery. •POD was significantly associated with worse short- and long-term cognitive outcomes.•POD was associated with dementia as well as attention, execution and memory damage.•The relation between POD and cognitive impairment was time- and dose-dependent.

The agent that should be used for light sedation of patients requiring mechanical ventilation is unclear. This randomized trial compared dexmedetomidine with propofol for the light sedation of critically ill patients with sepsis who required mechanical ventilation. No clinically important differences were found.

Objective To evaluate the safety, feasibility, and efficacy of combined adrenergic blockade with propranolol and clonidine in patients with severe traumatic brain injury (TBI). Background Administration of adrenergic blockade after severe TBI is common. To date, no prospective trial has rigorously evaluated this common therapy for benefit. Methods This phase II, single-center, double-blinded, pilot randomized placebo-controlled trial included patients aged 16–64 years with severe TBI (intracranial hemorrhage and Glasgow Coma Scale score ≤ 8) within 24 h of ICU admission. Patients received propranolol and clonidine or double placebo for 7 days. The primary outcome was ventilator-free days (VFDs) at 28 days. Secondary outcomes included catecholamine levels, hospital length of stay, mortality, and long-term functional status. A planned futility assessment was performed mid-study. Results Dose compliance was 99%, blinding was intact, and no open-label agents were used. No treatment patient experienced dysrhythmia, myocardial infarction, or cardiac arrest. The study was stopped for futility after enrolling 47 patients (26 placebo, 21 treatment), per a priori stopping rules. There was no significant difference in VFDs between treatment and control groups [0.3 days, 95% CI (− 5.4, 5.8), p  = 1.0]. Other than improvement of features related to sympathetic hyperactivity (mean difference in Clinical Features Scale (CFS) 1.7 points, CI (0.4, 2.9), p  = 0.012), there were no between-group differences in the secondary outcomes. Conclusion Despite the safety and feasibility of adrenergic blockade with propranolol and clonidine after severe TBI, the intervention did not alter the VFD outcome. Given the widespread use of these agents in TBI care, a multi-center investigation is warranted to determine whether adrenergic blockade is of therapeutic benefit in patients with severe TBI. Trial Registration Number NCT01322048.

In a multicenter trial in 566 patients with critical illness who had delirium, the use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the duration of delirium or coma. Side effects and extrapyramidal disorders occurred at similar rates in all groups.

Background Delirium is a frequent manifestation of acute brain dysfunction and is associated with cognitive impairment. The hypothesized mechanism of brain dysfunction during critical illness is centered on neuroinflammation, regulated in part by the cholinergic system. Point-of-care serum cholinesterase enzyme activity measurements serve as a real-time index of cholinergic activity. We hypothesized that cholinesterase activity during critical illness would be associated with delirium in the intensive care unit (ICU) and cognitive impairment after discharge. Methods We enrolled adults with respiratory failure and/or shock and measured plasma acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity on days 1, 3, 5, and 7 after enrollment. AChE values were also normalized per gram of hemoglobin (AChE/Hgb). We assessed for coma and delirium twice daily using the Richmond Agitation Sedation Scale and the Confusion Assessment Method for the ICU to evaluate daily mental status (delirium, coma, normal) and days alive without delirium or coma. Cognitive impairment, disability, and health-related quality of life were assessed at up to 6 months post-discharge. We used multivariable regression to determine whether AChE, AChE/Hgb, and BChE activity were associated with outcomes after adjusting for relevant covariates. Results We included 272 critically ill patients who were a median (IQR) age 56 (39–67) years and had a median Sequential Organ Failure Assessment score at enrollment of 8 (5–11). Higher daily AChE levels were associated with increased odds of being delirious versus normal mental status on the same day (Odds Ratio [95% Confidence Interval] 1.64 [1.11, 2.43]; P  = 0.045). AChE/Hgb and BChE activity levels were not associated with delirious mental status. Lower enrollment BChE was associated with fewer days alive without delirium or coma ( P  = 0.048). AChE, AChE/Hgb, and BChE levels were not significantly associated with cognitive impairment, disability, or quality of life after discharge. Conclusion Cholinesterase activity during critical illness is associated with delirium but not with outcomes after discharge, findings that may reflect mechanisms of acute brain organ dysfunction. Trial Registration: NCT03098472. Registered 31 March 2017.

Timely management of trauma patients is crucial. Better team performance means faster care, but roles of specific communication practices remain unclear. We hypothesized that overlapping communication is associated with less efficient resuscitations. This single-center prospective observational study included hypotensive trauma patients from June–September 2023. Data were collected using Trauma Video Review. The association between overlapping communication and resuscitation length was assessed using multivariable linear regression adjusting for demographics, injury mechanism, Injury Severity Score (ISS), vitals, and number of procedures performed. We included 87 patients with median ISS 26.0 [interquartile range IQR: 14.0–34.0] and median systolic blood pressure 84.0 [70.0–90.5]. Median resuscitation length was 19.1 [15.4–23.1] minutes. Overlapping communication occurred for median 1.22 [0.7–2.1] minutes. Overlapping communication was associated with longer resuscitations (p ​< ​0.0001). Overlapping communication was associated with less efficient resuscitations in hypotensive trauma patients. Training for trauma teams should target “one voice at a time”. •Trauma video review was used to assess communication in 87 resuscitations.•Overlapping communication was associated with increased resuscitation duration.•Silence during blood pressure auscultation was not associated with timely transfusion.