Perioperative and safety outcomes following tissue-sparing posterior cervical fusion to revise a pseudarthrosis: A multicenter retrospective review of 150 cases.

Background: Posterior cervical fusion (PCF) with lateral mass screws is a favorable treatment option to revise a symptomatic pseudarthrosis due to reliable rates of arthrodesis; however, this technique introduces elevated risk for wound infection and hospital readmission. A tissue-sparing PCF approach involving facet fixation instrumentation reduces the rates of postoperative complications while stabilizing the symptomatic level to achieve arthrodesis; however, these outcomes have been limited to small study cohorts from individual surgeons commonly with mixed indications for treatment. Materials and Methods: One hundred and fifty cases were identified from a retrospective chart review performed by seven surgeons across six sites in the United States. All cases involved PCF revision for a pseudarthrosis at one or more levels from C3 to C7 following anterior cervical discectomy and fusion (ACDF). PCF was performed using a tissue-sparing technique with facet instrumentation. Cases involving additional supplemental fixation such as lateral mass screws, rods, wires, or other hardware were excluded. Demographics, operative notes, postoperative complications, hospital readmission, and subsequent surgical interventions were summarized as an entire cohort and according to the following risk factors: age, sex, number of levels revised, body mass index (BMI), and history of nicotine use. Results: The average age of patients at the time of PCF revision was 55 ± 11 years and 63% were female. The average BMI was 29 ± 6 kg/m2 and 19% reported a history of nicotine use. Postoperative follow-up visits were available with a median of 68 days (interquartile range = 41-209 days) from revision PCF. There were 91 1-level, 49 2-level, 8 3-level, and 2 4±-level PCF revision cases. The mean operative duration was 52 ± 3 min with an estimated blood loss of 14 ± 1.5cc. Participants were discharged an average of 1 ± 0.05 days following surgery. Multilevel treatment resulted in longer procedure times (single = 45 min, multi = 59 min, P = 0.01) but did not impact estimated blood loss (P = 0.94). Total nights in the hospital increased by 0.2 nights with multilevel treatment (P = 0.01). Sex, age, nicotine history, and BMI had no effect on recorded perioperative outcomes. There was one instance of rehospitalization due to deep-vein thrombosis, one instance of persistent pseudarthrosis at the revised level treated with ACDF, and four instances of adjacent segment disease. In patients initially treated with multilevel ACDF, revisions occurred most commonly on the caudal level (48% of revised levels), followed by the cranial (43%), and least often in the middle level (9%). Conclusions: This chart review of perioperative and safety outcomes provides evidence in support of tissue-sparing PCF with facet instrumentation as a treatment for symptomatic pseudarthrosis after ACDF. The most common locations requiring revision were the caudal and cranial levels. Operative duration and estimated blood loss were favorable when compared to open alternatives. There were no instances of postoperative wound infection, and the majority of patients were discharged the day following surgery.

Recovery duration and concussion severity in sport- and non-sport-related concussion among Pac-12 collegiate athletes: a retrospective cohort study.

OBJECTIVES: To examine non-sport- and sport-related concussion severity, clinical care frequency and delayed reporting in relation to recovery duration among collegiate athletes. DESIGN: Retrospective cohort study. SETTING: Pac-12 varsity collegiate athletes. PARTICIPANTS: 461 collegiate male and female athletes PRIMARY AND SECONDARY OUTCOME MEASURES: The incidence of sport-related concussion (SRC) and non-sport-related concussion (NRC) were collected as well as times to recovery and return-to-play (RTP), symptom score and symptom severity and reported a loss of consciousness (LOC), retrograde amnesia (RGA) and post-traumatic amnesia (PTA) following concussion incidence. RESULTS: Among 461 concussions, 388 (84%) occurred within sport and 73 (16%) occurred outside of sport. NRC, on average, required 3.5 more days to become asymptomatic (HR: 0.73, 95%confidence interval: 0.56 to 0.96, p=0.02) and 7 more days to RTP (HR: 0.64, 95% confidence interval: 0.49 to 0.85, p<0.01) compared with SRC. NRC were associated with an increase of 1.83 (p=0.07) symptoms reported at the time of diagnosis, an increase of 6.95 (p=0.06) in symptom severity and a higher prevalence of reported LOC (22% NRC vs. 3% SRC, p<0.001), PTA (15% NRC vs. 5% SRC, p<0.01) and RGA (10% NRC vs. 4% SRC, p=0.06), compared with SRC. There was no significant difference in clinical care (p=0.28) or immediate reporting (p=0.35) between NRC and SRC. CONCLUSION: NRC were associated with greater severity and longer recovery duration when compared with SRC in a cohort of collegiate athletes.

Effect of the 2018 NCAA Kickoff Rule Change on Concussion Rates in Collegiate Football: Results From a Division 1 Conference.

Background: Kickoff plays in American football are associated with an increased risk of concussion compared with other play types. In 2018, the National Collegiate Athletic Association (NCAA) Football Rules Committee altered the kickoff rules so a fair catch inside the 25-yard line results in a touchback, with the ensuing drive starting on the 25-yard line. The intention was to decrease the number of kickoff returns with a corresponding decrease in the rate of concussions on kickoff plays. Purpose: To determine whether the 2018 rule changes had the intended effects in an NCAA Division 1 Conference. Study Design: Cohort study; Level of evidence, 3. Methods: The study population included football athletes in the NCAA Pacific-12 (Pac-12) Conference. Data on the total number of plays, punts, kickoffs, touchbacks, and fair catches were obtained for all in-conference games from the 2016 to 2021 seasons. The number of game concussions and the play type were provided by each conference institution. Incidence of concussions occurring during kickoff plays before (2016-2017) and after (2018-2021) the rule change were compared with a difference-in-difference analysis using Poisson general linear models. Results: There were 242 concussions in 108,774 total plays in the study period, with an overall concussion rate of 2.2 per 1000 plays. The percentage of touchbacks increased significantly from 45% to 51% (P < .001) and the percentage of fair catches increased from 1% to 7% (P < .001) from before to after the rule change. Kickoffs accounted for 6% of plays both before and after the rule change and 11% of concussions before and 14% after the change. The mean annual concussion rate (per 1000 plays) on kickoffs was 3.42 before and 5.31 after the rule change (rate difference: 1.89; 95% confidence interval, -1.22 to 5.01). Conclusion: Touchbacks and fair catches increased after the kickoff rule change, but there was not a corresponding decrease in concussions during kickoff plays as anticipated. Concussions occurring during other football plays remained stable.

Multicentre evaluation of anxiety and mood among collegiate student athletes with concussion.

Objectives: Mental health problems are a premorbid and postinjury concern among college student athletes. Clinical phenotypes of anxiety and mood disruption are prevalent following mild traumatic brain injury, including concussion, a common sports injury. This work examined whether concussed student athletes with a history of mental health problems and higher symptoms of anxiety and mood disruption at baseline were more likely to have higher postinjury reports of mood and anxiety as well as prolonged resolution of postconcussive symptoms to near-baseline measures. Methods: This was a retrospective cohort study of a multi-institutional database of standardised baseline and postinjury assessments among college student athletes. Anxiety/mood evaluation data among varsity college athletes from four institutions over 1 year were measured and compared at baseline and postconcussion recovery using descriptive statistics and multilevel/mixed-effects analysis. Results: Data from 2248 student athletes were analysed, with 40.6% reporting at least one symptom of anxiety and/or mood disruption at baseline. Of the 150 distinct concussions, 94.7% reported symptoms of anxiety/mood disruption during recovery (recovery time=0-96 days). Higher anxiety/mood scores at baseline were significantly associated with higher scores following concussion (p<0.001). Recovery trajectories of anxiety/mood scores showed different patterns by sex and prolonged recovery. Conclusion: Symptoms of anxiety and mood disruption are common at baseline among college student athletes. These students are at higher risk for symptomatology following injury, representing a screening cohort that may benefit from early counselling. Almost all student athletes will experience symptoms of anxiety and/or mood disruption following concussion.

Pac-12 Health Analytics Program: An Innovative Approach to Health Care Operations, Data Analytics, and Clinical Research in Intercollegiate Athletics.

The objective of this study was to describe the purpose, methods, and effects of the Pac-12 Health Analytics Program (HAP) approach on sports medicine informatics, research, analytics, and health care operations. Sports injury-surveillance initiatives have been supporting the clinical research community in sports medicine for nearly 4 decades. Whereas the initial systems tracked only a few sports, current surveillance programs have expanded to include entire professional and elite athlete organizations, providing important statistics on sports injury risk management. The HAP is a conference-wide data-sharing and-analytics program. It collects authorized, deidentified clinical data, encompassing multiple domains of sports medicine injury management, including sports injuries and illnesses, concussions, risk exposure, and COVID-19 testing elements. The HAP provides clinicians with access to curated data to inform evidence-based practice and support local health care operations with respect to emerging sports injury trends. The HAP supplies approved research groups with access to a data repository that describes a homogeneous, elite intercollegiate athlete sample, thereby supporting nonresearch clinical initiatives as well as contributions to peer-reviewed research that can improve the health and well-being of Pac-12 student-athletes. The HAP is a novel approach to sports injury epidemiology and surveillance that has allowed the Pac-12 Conference to meet larger objectives regarding improving the student-athlete experience and clinical research among its member schools. Data quality control has improved the accuracy of the data and value to clinical athletic trainers within the conference. Curated dashboards displaying aggregated project data offer clinicians data-driven decision-making tools that help inform sports injury risk management. As of 2021, the HAP had supported more than 3 dozen data requests. These investigations have resulted in numerous peer-reviewed research contributions to the sports medicine community with findings that have great potential to improve the health and well-being of Pac-12 student-athletes.

Effects of Mycobacterium vaccae NCTC 11659 and Lipopolysaccharide Challenge on Polarization of Murine BV-2 Microglial Cells.

Previous studies have shown that the in vivo administration of soil-derived bacteria with anti-inflammatory and immunoregulatory properties, such as Mycobacterium vaccae NCTC 11659, can prevent a stress-induced shift toward an inflammatory M1 microglial immunophenotype and microglial priming in the central nervous system (CNS). It remains unclear whether M. vaccae NCTC 11659 can act directly on microglia to mediate these effects. This study was designed to determine the effects of M. vaccae NCTC 11659 on the polarization of naïve BV-2 cells, a murine microglial cell line, and BV-2 cells subsequently challenged with lipopolysaccharide (LPS). Briefly, murine BV-2 cells were exposed to 100 µg/mL whole-cell, heat-killed M. vaccae NCTC 11659 or sterile borate-buffered saline (BBS) vehicle, followed, 24 h later, by exposure to 0.250 µg/mL LPS (Escherichia coli 0111: B4; n = 3) in cell culture media vehicle (CMV) or a CMV control condition. Twenty-four hours after the LPS or CMV challenge, cells were harvested to isolate total RNA. An analysis using the NanoString platform revealed that, by itself, M. vaccae NCTC 11659 had an "adjuvant-like" effect, while exposure to LPS increased the expression of mRNAs encoding proinflammatory cytokines, chemokine ligands, the C3 component of complement, and components of inflammasome signaling such as Nlrp3. Among LPS-challenged cells, M. vaccae NCTC 11659 had limited effects on differential gene expression using a threshold of 1.5-fold change. A subset of genes was assessed using real-time reverse transcription polymerase chain reaction (real-time RT-PCR), including Arg1, Ccl2, Il1b, Il6, Nlrp3, and Tnf. Based on the analysis using real-time RT-PCR, M. vaccae NCTC 11659 by itself again induced "adjuvant-like" effects, increasing the expression of Il1b, Il6, and Tnf while decreasing the expression of Arg1. LPS by itself increased the expression of Ccl2, Il1b, Il6, Nlrp3, and Tnf while decreasing the expression of Arg1. Among LPS-challenged cells, M. vaccae NCTC 11659 enhanced LPS-induced increases in the expression of Nlrp3 and Tnf, consistent with microglial priming. In contrast, among LPS-challenged cells, although M. vaccae NCTC 11659 did not fully prevent the effects of LPS relative to vehicle-treated control conditions, it increased Arg1 mRNA expression, suggesting that M. vaccae NCTC 11659 induces an atypical microglial phenotype. Thus, M. vaccae NCTC 11659 acutely (within 48 h) induced immune-activating and microglial-priming effects when applied directly to murine BV-2 microglial cells, in contrast to its long-term anti-inflammatory and immunoregulatory effects observed on the CNS when whole-cell, heat-killed preparations of M. vaccae NCTC 11659 were given peripherally in vivo.

Association of Cardiac Arrest With Opioid Overdose in Transport.

Introduction: Drug overdose is the leading cause of injury-related death in the United States. It has been linked to respiratory depression and cardiac toxicity, both of which can lead to cardiac arrest. Despite this potential association, few studies have examined this relationship, particularly in transport to the hospital. The purpose of this research was to determine if there was a relationship between opioid overdose and cardiac arrest in transport. Methods: A sample (n = 1 000 000) was utilized from the National EMS Information System (NEMSIS) from the year 2019. A logistic regression model was used to predict cardiac arrest from dispatch reason with gender, race, and age included as controls. Results: Overdose-related dispatch reason was associated with an increased likelihood of cardiac arrest in transport (Odds Ratio = 1.65, 95% Confidence Interval: [1.22, 2.22]). Conclusions: Opioid overdose is associated with an increased incidence of cardiac arrest in transport in the United States.

Risk of Concussion After a Targeting Foul in Collegiate American Football.

BACKGROUND: The targeting rule was adopted by the National Collegiate Athletic Association (NCAA) in 2008 to discourage dangerous contact during collegiate American football competition. Although targeting rules have been emphasized as a means to reduce concussion rates, there is currently no evidence that targeting plays are higher risk for concussion than other plays in American football. PURPOSE: To compare the rate of concussion occurring during targeting versus nontargeting plays in American collegiate football. STUDY DESIGN: Cross-sectional study. METHODS: Concussions occurring in games in the 2016-2019 Pac-12 Conference were classified as having occurred during either (1) a play where a targeting penalty was called or (2) all other plays. Targeting plays were further categorized to either those in which the call was upheld or those overturned by the on-field official after replay review. The number of targeting plays and the total number of plays during games were also recorded. Concussion incidence (per 1000 plays) and risk ratios were calculated. RESULTS: Overall, 538 games with 68,670 plays were reviewed, during which 213 concussions occurred (15 during plays where targeting was called and 198 on other plays) and 141 targeting penalties were called. The incidence of concussion was 106.4/1000 plays for targeting plays (including 141.2/1000 upheld targeting fouls and 53.6/1000 overturned targeting fouls) and 2.9/1000 plays for nontargeting plays. The risk of concussion during targeting plays was 36.9 (95% CI, 22.4-60.7) times greater than that for all other plays. The risk of concussion during targeting plays upheld was 49.0 (95% CI, 28.5-84.2) times greater than that for all other plays. CONCLUSION: Concussion risk was significantly higher during plays in which targeting was called, especially those in which targeting fouls were upheld. CLINICAL RELEVANCE: This study supports eliminating or reducing targeting from American football. The results of this study suggest that players should be screened for concussion after targeting plays are called.

Diagnostic accuracy and reliability of sideline concussion evaluation: a prospective, case-controlled study in college athletes comparing newer tools and established tests.

OBJECTIVE: To assess diagnostic accuracy and reliability of sideline concussion tests in college athletes. METHODS: Athletes completed baseline concussion tests including Post-Concussion Symptom Scale, Standardised Assessment of Concussion (SAC), modified Balance Error Scoring System (m-BESS), King-Devick test and EYE-SYNC Smooth Pursuits. Testing was repeated in athletes diagnosed acutely with concussion and compared to a matched teammate without concussion. RESULTS: Data were collected on 41 concussed athletes and 41 matched controls. Test-retest reliability for symptom score and symptom severity assessed using control athletes was 0.09 (-0.70 to 0.88) and 0.08 (-1.00 to 1.00) (unweighted kappa). Intraclass correlations were SAC 0.33 (-0.02 to 0.61), m-BESS 0.33 (-0.2 to 0.60), EYE-SYNC Smooth Pursuit tangential variability 0.70 (0.50 to 0.83), radial variability 0.47 (0.19 to 0.69) and King-Devick test 0.71 (0.49 to 0.84). The maximum identified sensitivity/specificity of each test for predicting clinical concussion diagnosis was: symptom score 81%/94% (3-point increase), symptom severity score 91%/81% (3-point increase), SAC 44%/72% (2-point decline), m-BESS 40%/92% (5-point increase), King-Devick 85%/76% (any increase in time) and EYE-SYNC Smooth Pursuit tangential variability 48%/58% and radial variability 52%/61% (any increase). Adjusted area under the curve was: symptom score 0.95 (0.89, 0.99), symptom severity 0.95 (95% CI 0.88 to 0.99), SAC 0.66 (95% CI 0.54 to 0.79), m-BESS 0.71 (0.60, 0.83), King-Devick 0.78 (0.69, 0.87), radial variability 0.47 (0.34, 0.59), tangential variability 0.41 (0.30, 0.54) CONCLUSION: Test-retest reliability of most sideline concussion tests was poor in uninjured athletes, raising concern about the accuracy of these tests to detect new concussion. Symptom score/severity had the greatest sensitivity and specificity, and of the objective tests, the King-Devick test performed best.

Oral delivery of systemic monoclonal antibodies, peptides and small molecules using gastric auto-injectors.

Oral administration provides a simple and non-invasive approach for drug delivery. However, due to poor absorption and swift enzymatic degradation in the gastrointestinal tract, a wide range of molecules must be parenterally injected to attain required doses and pharmacokinetics. Here we present an orally dosed liquid auto-injector capable of delivering up to 4-mg doses of a bioavailable drug with the rapid pharmacokinetics of an injection, reaching an absolute bioavailability of up to 80% and a maximum plasma drug concentration within 30 min after dosing. This approach improves dosing efficiencies and pharmacokinetics an order of magnitude over our previously designed injector capsules and up to two orders of magnitude over clinically available and preclinical chemical permeation enhancement technologies. We administered the capsules to swine for delivery of clinically relevant doses of four commonly injected medications, including adalimumab, a GLP-1 analog, recombinant human insulin and epinephrine. These multi-day dosing experiments and oral administration in awake animal models support the translational potential of the system.

Transformation of nanoparticles into compacts: A study on PLGA and celecoxib nanoparticles.

Oral delivery of nanoparticles possesses many advantages for delivery of active pharmaceutical ingredients (APIs) to the gastrointestinal tract. However, the poor physical stability of nanoparticles in liquid state is often a challenge. Removing water from the nanosuspensions and transforming the nanoparticles into solid particulate matter in the form of, e.g., tablets could be a potential approach to increase the stability of nanoparticles. The aim of this study was to transform nanoparticles into compacts and to investigate the redispersion of nanoparticles from compacts as well as the dissolution behavior of these compacts. DL-lactide-co-glycolide copolymer (PLGA) nanoparticles and celecoxib (CLX) nanoparticles were used as two model nanoparticle systems and fabricated into nano-embedded microparticles (NEMs) and subsequently compressed into compacts. The compacts were evaluated with respect to the redispersibility of the nanoparticles, as well as the dissolution characteristics of CLX. The results showed that the NEMs could be readily compressed into compacts with sufficient mechanical strength. The size of the redispersed PLGA nanoparticles from the compacts using 2-hydroxypropyl-ß-cyclodextrin (HPßCD) as stabilizer was comparable to the original nanoparticles. In contrast, the redispersibility of CLX nanoparticles from the compacts was not as effective as for the PLGA nanoparticles evidenced by a significant increase in the size and polydispersity index (PDI) of the redispersed nanoparticles. Nonetheless, an obvious enhancement in dissolution rate of CLX was observed from the compacts with CLX nanoparticles. It is concluded that transforming polymeric nanoparticles into compacts via NEMs provides stabilization and allows redispersion into original nanoparticles. Despite the reduced redispersibility, compacts loaded with nanoparticles exhibited improved dissolution rate compared with the crystalline drug. Loading of nanoparticles into compacts is a promising approach to overcome the poor stability of nanoparticle within oral drug delivery of nanoparticles.

Pac-12 CARE-Affiliated Program: structure, methods and initial results.

Sport-related concussion has garnered increasing scientific attention and research over the last decade. Collegiate student-athletes represent an important cohort in this field. As such, the Pac-12 CARE-Affiliated Program (CAP) was formed in 2017 as a regional hub of the Concussion Assessment, Research and Education (CARE) consortium. CAP is multisite, prospective, longitudinal study that aims to improve student-athlete health by identifying factors associated with concussion incidence and recovery and using this knowledge to inform best clinical practices and policy decisions. CAP employed a staggered rollout across the Pac-12, with the first four institutions enrolling in fall 2018. After receiving institutional review board (IRB) approval, these institutions began consenting student-athletes to share clinical concussion and baseline data for research purposes. Athletes completed baseline testing that included a medical questionnaire, concussion history and a battery for clinical concussion assessments. Concussed student-athletes were given the same battery of assessments in addition to full injury and return to play reports. Clinicians at each university worked with a data coordinator to ensure appropriate reporting, and the Pac-12 Concussion Coordinating Unit at the University of Colorado Boulder provided oversight for quality control of the data study wide. During year 1, CAP consented 2181 student-athletes and tracked 140 concussions. All research was conducted with the appropriate IRB approval across the participating Pac-12 institutions. Data security and dissemination are managed by the Presagia Sports Athlete Electronic Health Record software (Montreal, Quebec, Canada) and QuesGen Systems (San Francisco, California, USA).

Practical Acoustic Energy-Based Estimation of Inhalation Flow Rate for Asthma Monitoring.

The estimation of inhalation flow rate (IFR) using acoustic devices has recently received attention. While existing work often assumes that the microphone is placed at a fixed distance from the acoustic device, this assumption does not hold in real settings. This leads to poor estimation of the IFR since the received acoustic energy varies significantly with the distance. Despite the fact that the acoustic source is passive and only one microphone is used, we show in this paper that the distance can be estimated by exploiting the inhaler actuation sound, generated when releasing the medication. Indeed, this sound is used as a reference acoustic signal which is leveraged to estimate the distance in real settings. The resulting IFR estimation is shown to be highly accurate (R2 = 80.3%).

Treatment of acute lung inflammation by pulmonary delivery of anti-TNF-α siRNA with PAMAM dendrimers in a murine model.

To improve the efficacy of nucleic acid-based therapeutics, e.g., small interfering RNA (siRNA), transfection agents are needed for efficient delivery into cells. Several classes of dendrimers have been found useful as transfection agents for the delivery of siRNA because their surface can readily be functionalized, and the size of the dendriplexes they form with siRNA is within the range of conventional nanomedicine. In this study, commercially available generation 3 poly(amidoamine) (PAMAM) dendrimer was investigated for pulmonary delivery of siRNA directed against tumor necrosis factor (TNF) α for the treatment of acute lung inflammation. Delivery efficiency was assessed in vitro in the RAW264.7 macrophage cell line activated with lipopolysaccharide (LPS), and efficacy was evaluated in vivo in a murine model of LPS-induced lung inflammation upon pre-treatment with TNF-α siRNA. The PAMAM dendrimer-siRNA complexes (dendriplexes) displayed strong siRNA condensation and high cellular uptake in macrophages compared with non-complexed siRNA. Q-PCR analyses showed that the dendriplexes mediated efficient and specific TNF-α silencing in vitro, as compared to non-complexed siRNA and dendriplexes with negative control siRNA. Also in vivo, the PAMAM dendriplexes induced efficacious TNF-α siRNA inhibition, as compared to non-complexed siRNA, upon pulmonary administration to mice with LPS-induced lung inflammation. Hence, these data suggest that PAMAM dendrimers are promising for the local delivery of TNF-α siRNA in the treatment of lung inflammation via pulmonary administration.

Antioxidant-mediated control of degradation and drug release from surface-eroding poly(ethylene carbonate).

Surface-eroding polymers are of significant interest for various applications in the field of controlled drug delivery. Poly(ethylene carbonate), as an example, offers little control over the rate of degradation and, thus, drug release, which usually conflicts with the requirements for long-acting medications. Here, we challenged an option to decelerate the degradation of poly(ethylene carbonate) in vitro and in vivo. When polymer films loaded with distinct antioxidants (vitamins) along with the model drugs leuprorelin and risperidone were incubated in superoxide radical solution and phagocyte culture, the mass loss and drug release from the delivery vehicle was a function of the type and dose of the utilized antioxidant. Once the polymer surface was "attacked" by reactive oxygen species, the antioxidants were released on demand quenching the polymer-degrading radicals. Accordingly, specific combinations of polymer and radical scavengers resulted in controlled release medications with an extended "life-time" of one month or longer, which is difficult to achieve for poly(ethylene carbonate) in the absence of antioxidants. A comparable degradation and drug release behavior was observed when antioxidant-loaded poly(ethylene carbonate) films were implanted in rats. Furthermore, linear correlations were obtained between the mass loss of the polymer films and the released fraction of drug (with slopes close to 1), a clear indication for the surface erosion of poly(ethylene carbonate) in vitro and in vivo. Overall, an addition of antioxidants to poly(ethylene carbonate)-based controlled drug delivery vehicles represents a reasonable approach to modify the performance of long-acting medications, especially when a "life time" of weeks to months needs to be achieved. STATEMENT OF SIGNIFICANCE: Surface-eroding poly(ethylene carbonate) (PEC) is of significant interest for long-acting injectable formulations. However, PEC offers only little control over the rate of degradation and, thus, drug release kinetics. We describe an option to decelerate the degradation rate of PEC in vitro and in vivo. When polymer films loaded with distinct antioxidants along with model drugs were incubated in superoxide radical solution, phagocyte culture and implanted in rats, their mass loss and drug release was a function of the type and dose of the utilized antioxidant. Accordingly, specific combinations of polymer and radical scavengers resulted in controlled release medications with an extended "life-time" of one month or longer, which is difficult to achieve for PEC in the absence of antioxidants.

In silico design and 3D printing of microfluidic chips for the preparation of size-controllable siRNA nanocomplexes.

Small interfering RNA (siRNA) is regarded as one of the most powerful tools for the treatment of various diseases by downregulating the expression of aberrant proteins. Delivery vehicle is often necessary for getting siRNA into the cells. Nanocomplex using polyamidoamine (PAMAM) is regarded a promising approach for the delivery of siRNA. The size of siRNA nanocomplexes is a critical attribute in order to achieve high gene silencing efficiency in vivo. Microfluidics provides advantages in the preparation of siRNA nanocomplexes due to better reproducibility and a potential for more robust process control. The mixing efficiency of siRNA and PAMAM is different in microfluidics systems with different geometries, therefore, resulting in nanocomplexes with varying size attributes. In this study, hydrodynamic flow focusing microfluidic chips with different channel designs, i.e. diameters/widths, channel shapes (cylindrical/rectangular) and inter-channel spacings were optimized in silico and rapidly prototyped using 3D printing and finally, used for production of siRNA nanocomplexes. The fluid mixing inside the microfluidic chips was simulated using the finite element method (FEM) with the single-phase laminar flow interface in connection with the transport of diluted species interface. The digital design and optimization of microfluidic chips showed consistency with experimental results. It was concluded that the size of siRNA nanocomplexes can be controlled by adjusting the channel geometry of the microfluidic chips and the simulation with FEM could be used to facilitate the design and optimization of microfluidic chips in order to produce nanocomplexes with desirable attributes.

Medication Tracking: Design and Fabrication of a Dry Powder Inhaler with Integrated Acoustic Element by 3D Printing.

PURPOSE: Asthma is a prevalent lung disorder that cause heavy burdens globally. Inhalation medicaments can relieve symptoms, improve lung function and, thus, the quality of life. However, it is well-documented that patients often do not get the prescribed dose out of an inhaler and the deposition of drug is suboptimal, due to incorrect handling of the device and wrong inhalation technique. This study aims to design and fabricate an acoustic dry powder inhaler (ADPI) for monitoring inhalation flow and related drug administration in order to evaluate whether the patient receives the complete dose out of the inhaler. METHODS: The devices were fabricated using 3D printing and the impact of the acoustic element geometry and printing resolution on the acoustic signal was investigated. Commercial Foradil (formoterol fumarate) capsules were used to validate the availability of the ADPI for medication dose tracking. The acoustic signal was analysed with Partial-Least-Squares (PLS) regression. RESULTS: Indicate that specific acoustic signals could be generated at different air flow rates using a passive acoustic element with specific design features. This acoustic signal could be correlated with the PLS model to the air flow rate. A more distinct sound spectra could be acquired at higher printing resolution. The sound spectra from the ADPI with no capsule, a full capsule and an empty capsule are different which could be used for medication tracking. CONCLUSIONS: This study shows that it is possible to evaluate the medication quality of inhaled medicaments by monitoring the acoustic signal generated during the inhalation process.

Characteristics and Incidence of Concussion Among a US Collegiate Undergraduate Population.

Importance: Concussion on university campuses is a significant health problem. Characterizing the incidence of concussion on college campuses may inform education and resource allocation policy at student health care centers. Objectives: To establish a measure of concussion incidence among collegiate undergraduate students and to describe characteristics associated with concussion incidence, including sex, cause, and month. Design, Setting, and Participants: This prospective cohort study included data from 3 academic years from August 2015 to April 2018 at a large, public university in the United States. Participants included any undergraduate student or varsity athlete who was diagnosed with at least 1 concussion during the academic year. Exposures: Sport- and non-sport-related activities of undergraduate students. Main Outcomes and Measures: Concussion diagnosis. Results: Among 954 undergraduate students from the general undergraduate population with at least 1 concussion, including 502 men and 452 women, 1020 concussions were diagnosed in 3 academic years. During 2 academic years, a total of 80 concussions occurred among the varsity athlete population, including 26 men and 54 women. Overall, concussion incidence among both the general undergraduate population and varsity athletes was 132.4 (95% CI, 123.2-142.0) concussions per 10 000 students. Men sustained concussions at a rate of 126.1 (95% CI, 114.1-139.0) concussions per 10 000 students and women sustained concussions at a rate of 140.0 (95% CI, 126.2-155.3) concussions per 10 000 students for the 2016 to 2017 and 2017 to 2018 academic years. Concussion incidence peaked in August at the start of the academic year and the rate of non-sport-related concussions (81.0 [95% CI, 73.9-88.7] concussions per 10 000 students for academic years 2016-2017 and 2017-2018) was higher than the rate of sport-related concussions (51.5 [95% CI, 49.5-57.7] concussions per 10 000 students for academic years 2016-2017 and 2017-2018). Conclusions and Relevance: This cohort study found concussions to be common among this US collegiate population. While concussion is often associated with sport, the incidence of non-sport-related concussion was higher than that of sport-related concussion throughout the academic year. Additional research is warranted to determine if this incidence measure among undergraduate students is generalizable to other university populations.

Association of Adolescent Sport Participation With Cognition and Depressive Symptoms in Early Adulthood.

BACKGROUND: Recent studies have associated sport-related concussion with depression and impaired cognitive ability later in life in former professional football players. However, population studies with two 1950s-era cohorts did not find an association between high school football participation and impaired cognition or depressive symptoms in late adulthood. PURPOSE/HYPOTHESIS: This study assessed whether actual/intended participation in contact sports during adolescence had an adverse effect on participants' cognition or depressive symptoms in early adulthood. We hypothesized that there would not be an association. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: This study used a subsample (n = 10,951) from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a nationally (United States) representative prospective cohort study following participants through 4 waves of data collection from 1994 through 2008. Participants were categorized as actual/intended participation in no sports, noncontact sports only, and contact sports. We constructed 6 multivariate and logistic regression models predicting word recall, number recall, modified Center for Epidemiologic Studies Depression Scale, depression diagnosis, suicide ideation, and suicide attempts at wave IV as a function of sport participation during wave I. Sport participation was treated as a factor with the referent category noncontact sports. This analysis was repeated on a males-only sample (n = 5008). In the males-only analysis, participants were classified as actual/intended participation in no sports, noncontact sports, contact sports other than American football, and American football. The referent category remained noncontact sports. RESULTS: Intention to participate in contact sports was not significantly associated with any of the outcomes in the full-sample analysis. Intention to participate in football was significantly associated with a reduced odds of depression diagnosis in adulthood (odds ratio, 0.70; P = .02) when compared with noncontact sports participation in the males-only sample. Football was not significantly associated with impaired cognitive ability, increased depressive symptoms, or increased suicide ideation. CONCLUSION: Actual/intended participation in contact sports during adolescence did not adversely affect Add Health participants' cognition or depressive symptoms in young adulthood.

Impact of drug loading in mesoporous silica-amorphous formulations on the physical stability of drugs with high recrystallization tendency.

In this study, a method is described to determine the monolayer loading capacity (MLC) of the drugs naproxen and ibuprofen, both having high recrystallization tendencies, in mesoporous silica (MS), a well known carrier that is able to stabilize the amorphous form of a drug. The stabilization has been suggested to be due to direct absorption of the drug molecules onto the MS surface, i.e. the drug monolayer. In addition, drug that is not in direct contact with MS surface can fill the pores up to its pore filling capacity (PFC) and is potentially stabilized by confinement due to the pore size being smaller than a crystal nuclei. For drugs with high recrystallization tendencies, any drug outside the pores crystallizes due to its poor physical stability. The drug monolayer does not contribute to the glass transition temperature (Tg ) in the DSC, however, the confined amorphous drug above MLC has a Tg and the heat capacity (ΔC p) over the Tg increases with an increasing fraction of confined amorphous drug. Hence, several drug loading values above the MLC were investigated towards the presence of a Tg and ΔC p using differential scanning calorimetry (DSC). A linear correlation between the amount of confined amorphous drug and its ΔC p was identified for the mixtures between the MLC and PFC. By subsequent extrapolation to zero ΔC p the experimental MLC could be determined. Using theoretical density functional theory (DFT) and ab initio Molecular Dynamics (AIMD), the binding energies for the monolayer suggested that the monolayer in fact is thermodynamically more favorable than the crystalline form, whereas the confined amorphous form is thermodynamically less favorable. Consequently, a physical stability study showed that the confined amorphous drugs above the MLC were thermodynamically unstable and consequently flowing out of the pores in order to crystallize, whereas the monolayer remained physically stable.