Therapeutic Levels Research Articles

Low-Dose Baclofen-Induced Encephalopathy in a Patient with End-Stage Renal Disease: A Case Report

Baclofen, a gamma-aminobutyric acid-B receptor agonist, is commonly used for central-origin muscle spasticity and spasm and neuropathic pain. Baclofen toxicity has been reported to cause a range of symptoms including drowsiness, confusion, respiratory depression, seizures, and even coma, particularly with dosage significantly exceeding therapeutic levels. Given that the baclofen is predominantly eliminated through the kidneys, patients with renal failure are at substantial risk for neurotoxic effects. We report a case of baclofen-induced encephalopathy in a patient with end-stage renal disease, characterized by an altered mental state with myoclonus following the consumption of a low dose of baclofen.

Prevalence of Rhesus D negativity and barriers to immuno- prophylaxis among obstetric patients in Kitengela Sub- county Hospital: A cross-sectional study

Background: Rhesus (Rh) alloimmunization is a serious but preventable disease that develops in women who are Rh(D)-negative. This disease contributes significantly to perinatal morbidity and mortality. Prevalence data of Rh(D)-negative blood type among pregnant women in Kenya are scarce. This study aimed to determine the prevalence of Rh(D)-negative blood type, barriers to immunoprophylaxis, and ABO blood type patterns among the obstetric population in Kitengela Subcounty Hospital, Kajiado, Kenya. Methods: A cross-sectional study design was employed in which medical records of Rh-negative women as documented at the first antenatal visit were retrieved. Data were collected, extracted into a data collection tool, and analyzed using the Statistical Package for Social Scientists Software (SPSS version 23). Results: Of the 7141 women screened, 1.2 % (85) were Rh-negative. Among these, blood group O was the most common (48.2%), followed by blood groups B (24.7%), A (23.5%), and AB (3.5%). Most Rh-negative women (45.9%) were aged 15-23 years. Following delivery, only half of the women received anti-D immunoglobulin. Among those who did not receive anti-D postnatally, 80.8% lacked a documented reason, whereas 12.2% and 4.9% of the patients lacked access and did not know their Rh status, respectively. None of these patients had fetal blood grouping conducted before anti-D administration. Conclusion: Rh(D) negativity remains prevalent in the Kenyan population. However, access restrictions at both diagnostic and therapeutic levels remain. In addition, there is an overt hiatus in neonatal blood grouping.

A sub-pharmacological test dose does not predict individual docetaxel exposure in prostate cancer patients.

Docetaxel is a cytotoxic drug used for first-line treatment of various malignancies. It has a narrow therapeutic index and shows wide interpatient variability in clearance and toxicity. Tools for individual dose optimization are needed to maximize efficacy and avoid toxicity. We performed a proof-of-concept study (EudraCT 2016-003785-77) to evaluate whether pharmacokinetics after a sub-pharmacological test dose of 1000µg docetaxel (millidose) could be used to predict therapeutic dose exposure. Thirty prostate cancer patients eligible for treatment with docetaxel as part of routine clinical care were included. An intravenous docetaxel millidose was administered 1-7 days prior to therapeutic docetaxel. After both doses plasma docetaxel concentrations were measured by ultra- high performance liquid chromatography-tandem mass spectrometry. The docetaxel clearance was estimated with non-linear mixed effects modeling. Geometric mean docetaxel clearance was 57.9L/h (GCV 78.6%) after admission of a millidose and 40.3L/h (GCV 60.7%) after admission of a therapeutic dose. The millidose and therapeutic dose in a single patient were not significantly correlated (Spearman's rho R = 0.02, P = 0.92). Docetaxel pharmacokinetics at milli- and therapeutic dose level showed insufficient correlation for individual dose optimization. However, the clearance of a docetaxel millidose and full dose are within the same order of magnitude. Therefore, docetaxel millidose pharmacokinetics could potentially facilitate prediction of docetaxel pharmacokinetics at a population level in situations where therapeutic dose levels are impractical, such as pharmacokinetic drug-drug interaction studies or pediatric studies.

Consumers Accessing Their Mobile Phone in an Acute Inpatient Mental Health Unit: Experiences of Consumers and Staff

Mobile phones are an essential means for remaining connected, yet many acute inpatient mental health units restrict consumer access to their mobile phones due to safety concerns. The ubiquitous nature of mobile phones makes this approach seemingly incongruent with contemporary mental health practice. One Local Health District in Australia evaluated the implementation of a process that provided mental health consumers access to their mobile phones while in hospital. This study used a mixed methods design to explore the views of consumers and nurses, both before and after implementation. Participants were asked about their perceptions of the importance of mobile phone access to people in acute units, and their views about any perceived (pre) and actual (post) issues, challenges or benefits associated with the change in practice. Survey responses showed significant differences across group on all measures, with consumers more likely to rate the importance and frequency of mobile phone use higher, while also significantly more likely to rate potential issues lower. Issues associated with consumer phone access were rated lower in the post surveys. Descriptive content analysis of qualitative data identified differences in the level of concern between staff and consumers about consumers having access to their phone before implementation. Views about the therapeutic benefits and level of concern also changed post implementation. The need to have a clear process for implementation and governance was identified by both groups. The findings support consumers having access to their phone during admissions to acute mental health units.

Physicochemical and Biological Properties of Vancomycin-Containing Antibacterial Polysaccharide Gels for Biocomposite Bone Implant Impregnation.

Polymeric drugs containing up to 60% by weight of the antibiotic vancomycin were synthesized based on dextran carriers activated with epichlorohydrin. Vancomycin was covalently bound, involving the primary amino group of the molecule through the hydroxypropyl radical to the C6 position of the anhydroglucose units of the dextran main chain. Covalent binding is necessary to prevent spontaneous release of the antibiotic from the gel, thereby reducing the risk of bacterial multiresistance. Antibacterial depot gels were obtained from those polymers, containing up to 17.5% by weight of polysaccharide with a cross-linking density of q = 3-5 nodes per macromolecule for the deposition of another type of drugs not covalently bound to the polymer gel. They were used to coat the surface of the internal pores of biocomposite bone implants based on bovine cancellous bone used in orthopedics. The chemical structure of the polymer was studied using 13C NMR spectroscopy and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry. The stiffness of the gels was evaluated by the values of the accumulation modulus G' = 170-270 kPa and the loss modulus G″ = 3.7-4.2 kPa determined on a rheometer. Their values are close to those typical for materials used to replace soft tissue in plastic surgery. The minimum inhibitory concentration of the gels against Staphylococcus aureus P209 depends on the antibiotic content in the polymer. It equals 2.5 mg/L for vancomycin we used and 100 mg/L for a polymer containing 50% by weight of covalently bound antibiotic. The cytotoxic concentration measured with cell culture HEK 293T exceeds 1200 mg/L in 24 h exposure. The release dynamics of drugs not covalently bound to dextran from the depot gel were studied using fluorescein as a model. The release time is independent of the gel density and lasts up to 6 days for a 2 mm thick layer. Both the gel and the bone implants impregnated with it maintained consistently high antibacterial activity throughout the experiment, up to its completion after 168 h, with the local concentration of the released antibiotic at the site of bacterial attack exceeding the therapeutic level by 200 times.

Nanosuspensions in Breast Cancer Therapy: A Comprehensive Overview

Nanosuspensions offer a promising avenue for enhancing breast cancer treatment through improved drug delivery, solubility, and targeting. These colloidal dispersions contain submicron drug particles, significantly increasing surface area and enhancing drug solubility and dissolution rates. This improvement can lead to increased drug bioavailability, enabling lower doses and reduced side effects. It is also possible to engineer nanosuspensions so that they are controlled-release drugs, providing sustained therapeutic levels at the tumor site. Nanosuspensions facilitate targeted drug delivery, which is one of their key advantages. In order to minimize systemic toxicity, nanosuspensions contain targeting ligands or antibodies that adhere to the surface of nanoparticles in order to deliver drugs specifically to breast cancer cells. The nanosuspension platform also allows a combination therapy approach to be used, allowing multiple drugs to be delivered simultaneously in order to achieve synergistic effects and combat drug resistance. Nanosuspension treatments can be beneficial both therapeutically and for imaging and diagnostic purposes. Using nanoparticles labeled with imaging agents, it is possible to visualize tumors and monitor treatment responses. Nanosuspensions may reduce side effects associated with traditional chemotherapy by improving drug targeting and reducing systemic exposure. A nanosuspension represents a promising treatment option for breast cancer. Nanosuspensions must be fully exploited for their full potential to improve outcomes and quality of life for patients.

Dried blood spot sampling coupled with liquid chromatography-tandem mass for simultaneous quantitative analysis of multiple cardiovascular drugs

Dried Blood Spots (DBS) revolutionize therapeutic drug monitoring using LC-MS for the precise quantification of cardiovascular drugs (CDs), enabling personalized treatment adapted to patient-specific pharmacokinetics with minimal invasiveness. This study aims to achieve simultaneous quantification of eight CDs in DBS, overcoming physicochemical challenges. A two-step protein precipitation method was used for simple and precise sample preparation. The drugs were analyzed using LC-MS/MS in ESI positive-ion mode, showing high sensitivity and linearity, with a correlation coefficient (r2) exceeding 0.999, after being separated on a reversed-phase chromatography by gradient elution of DW-acetonitrile containing 0.1 % formic acid + 2 mM ammonium formate. The validation results indicate good selectivity, with no observed matrix effect and carry-over. The intra- and inter-day accuracy and precision were within 6 % for most drugs, except for digoxin and deslanoside at low therapeutic levels where the variation was within 20 %. Stability tests confirmed suitable DBS handling and storage conditions, indicating drug stability for at least 30 days at room temperature. The analysis of whole spot has demonstrated remarkable precision and reliability in all target drugs. The analysis of 3 mm internal diameter discs, punched in and out of DBS, presumed to contain 3 µL of blood, showed acceptable accuracy for most drugs, with less polar drugs like digoxin and deslanoside showing lower accuracy, indicating a need for further correction due to non-uniform drug distribution. Consequently, the developed LC-MS/MS method enables the quantification of multiple CDs in a single DBS analysis, while suggesting the potential for accuracy-based analysis.

Ten years of maintenance treatment of severe melancholic depression in an adult woman including discontinuation experiences.

There are only few publications on long-term treatments for major depressive disorder (MDD) lasting 5 years or longer. Most clinical controlled trials lasted no longer than 2 years and some recent studies suggested an advantage of cognitive behavioral therapy (CBT) over antidepressants in relapse prevention of MDD. Exclusively outpatient "real world" treatment of severe melancholia, prospectively documented over 10 years with different serial treatment strategies, discontinuation phenomena and complications. Compared to CBT, agomelatine, mirtazapine, bupropion and high-dose milnacipran, high-dose venlafaxine (extended-release form, XR) was effective, even sustainably. Asymptomatic premature ventricular contractions (PVCs) were found at the beginning of the treatment of the MDD, which initially led to the discontinuation of high-dose venlafaxine (300 mg daily). Even the various treatment strategies mentioned above were unable to compensate for or prevent the subsequent severe deterioration in MDD (2 rebounds, 1 recurrence). Only the renewed use of high-dose venlafaxine was successful. PVC no longer occurred and the treatment was also well tolerated over the years, with venlafaxine serum levels at times exceeding 5 times the recommended upper therapeutic reference level (known bupropion-venlafaxine interaction, otherwise 2.5 to 3-fold increase with high-dose venlafaxine alone). During dose reduction or after gradual discontinuation of high-dose venlafaxine, rather mild withdrawal symptoms occurred, but as described above, also two severe rebounds and one severe recurrence happened. This long-term observation supports critical reflections on the discontinuation of successful long-term treatment with antidepressants in severe MDD, even if it should be under "the protection" of CBT. The PVC seemed to be more related to the duration of the severe major depressive episode than to the venlafaxine treatment itself. A particular prospective observation of this longitudinal case study is that relapses (in the sense of rebounds) during or after previous venlafaxine tapering seemed to herald the recurrence after complete recovery. Remarkably, neither relapses nor recurrence could be prevented by CBT. In this case, high-dose venlafaxine has a particular relapse-preventive (and "recurrence-preventive") effect with good long-term tolerability.

Knee braces and foot orthoses multimodal 3-month treatment of medial knee osteoarthritis in a randomised crossover trial.

Immediate biomechanical and functional benefits of knee braces and lateral wedge foot orthoses (FO) are often reported on patients with medial knee osteoarthritis. However, the effectiveness of their combined use in a longer-term orthotic treatment remains unclear. The aim was to evaluate pain, function, comfort and knee adduction moment (KAM) during the stance phase of gait with three modalities of orthotic treatment. Twenty-two patients with knee osteoarthritis were analysed in a randomised crossover trial including a knee brace with valgus and external rotation functions (VER), FO and their combined use (VER + FO). Western Ontario and McMaster Universities scale (WOMAC) and Knee injury and Osteoarthritis Outcome Scores and KAM during gait were obtained before and after each orthotic treatment of 3 months. Repeated measures analyses of variance contrasted the factors orthosis (VER, FO, VER + FO), treatment (pre and post) and wear (without and with) on pain, function, comfort and KAM. An interaction between orthosis and treatment on the WOMAC pain (effect size [ES] = 0.17) and a main effect on the pain visual analogue score (ES = 0.24) indicated that VER and VER + FO were more alleviating than FO. The three modalities of orthotic treatment significantly improved functional scores (ES > 0.2) and reduced discomfort (ES = 0.25). A significant multivariate interaction between orthosis and wear (ES = 0.73) showed that the KAM reduction while wearing the orthoses was more pronounced with the VER and VER + FO than the FO. The VER-brace obtained more effectiveness than FO on pain and KAM after 3 months for medial knee osteoarthritis and the combined treatment did not substantially improve biomechanical and functional outcomes. Therapeutic study level I randomised crossover trial.

Formulation and dermal delivery of a new active pharmaceutical ingredient in an in vitro wound model for the treatment of chronic ulcers

The aim of this study was to investigate dermal delivery of the new active pharmaceutical ingredient (API) TOP-N53 into diabetic foot ulcer using an in vitro wound model consisting of pig ear dermis and elucidate the impact of drug formulation and wound dressing taking into consideration clinical relevance in the home care setting and possible bacterial infection. Different formulation approaches for the poorly water-soluble API including colloidal solubilization, drug micro-suspension and cosolvent addition were investigated; moreover, the effect of (micro-)viscosity of hydrogels used as primary wound dressing on delivery was assessed. Addition of Transcutol® P as cosolvent to water improved solubility and was significantly superior to all other approaches providing a sustained three-day delivery that reached therapeutic drug levels in the tissue. Solubilization in micelles or liposomes, on the contrary, did not boost delivery while micro-suspensions exhibited sedimentation on the tissue surface. Microbial contamination was responsible for considerable metabolism of the drug leading to tissue penetration of metabolites which may be relevant for therapeutic effect. Use of hydrogels under semi-occlusive conditions significantly reduced drug delivery in a viscosity-dependent fashion. Micro-rheologic analysis of the gels using diffusive wave spectroscopy confirmed the restricted diffusion of drug particles in the gel lattice which correlated with the obtained tissue delivery results. Hence, the advantages of hydrogel dressings from the applicatory characteristic point of view must be weighed against their adverse effect on drug delivery. The employed in vitro wound model was useful for the assessment of drug delivery and the development of a drug therapy concept for chronic diabetic foot ulcer. Mechanistic insights about formulation and dressing performance may be applied to drug delivery in other skin conditions such as digital ulcer.

In vitro to in vivo extrapolation from 3D hiPSC-derived cardiac microtissues and physiologically based pharmacokinetic modeling to inform next-generation arrhythmia risk assessment.

Proarrhythmic cardiotoxicity remains a substantial barrier to drug development as well as a major global health challenge. In vitro human pluripotent stem cell-based new approach methodologies have been increasingly proposed and employed as alternatives to existing in vitro and in vivo models that do not accurately recapitulate human cardiac electrophysiology or cardiotoxicity risk. In this study, we expanded the capacity of our previously established 3D human cardiac microtissue model to perform quantitative risk assessment by combining it with a physiologically based pharmacokinetic model, allowing a direct comparison of potentially harmful concentrations predicted in vitro to in vivo therapeutic levels. This approach enabled the measurement of concentration responses and margins of exposure for 2 physiologically relevant metrics of proarrhythmic risk (i.e. action potential duration and triangulation assessed by optical mapping) across concentrations spanning 3 orders of magnitude. The combination of both metrics enabled accurate proarrhythmic risk assessment of 4 compounds with a range of known proarrhythmic risk profiles (i.e. quinidine, cisapride, ranolazine, and verapamil) and demonstrated close agreement with their known clinical effects. Action potential triangulation was found to be a more sensitive metric for predicting proarrhythmic risk associated with the primary mechanism of concern for pharmaceutical-induced fatal ventricular arrhythmias, delayed cardiac repolarization due to inhibition of the rapid delayed rectifier potassium channel, or hERG channel. This study advances human-induced pluripotent stem cell-based 3D cardiac tissue models as new approach methodologies that enable in vitro proarrhythmic risk assessment with high precision of quantitative metrics for understanding clinically relevant cardiotoxicity.

Clinical Outcomes Following Operative and Nonoperative Management of Odontoid Fractures Among Elderly Individuals with Dementia.

The incidence of odontoid fractures among the elderly population has been increasing in recent years. Elderly individuals with dementia may be at increased risk for inferior outcomes following such fractures. Although surgical intervention has been maintained to optimize survival and recovery, it is unclear if this benefit extends to patients with dementia. We hypothesized that patients with dementia who were treated operatively for odontoid fractures would experience improved survival and lower rates of hospice admission but higher rates of delirium and of intensive interventions. We used Medicare claims data (2017 to 2018) to identify community-dwelling individuals with dementia who sustained type-II odontoid fractures. We considered treatment strategy (operative or nonoperative) as the primary predictor and survival as the primary outcome. The secondary outcomes consisted of post-treatment delirium, hospice admission, post-treatment intensive intervention, and post-discharge admission to a nursing home or a skilled nursing facility. In all models, we controlled for age, biological sex, race, Elixhauser Comorbidity Index, Frailty Index, admission source, treating hospital, and dual eligibility. Adjusted analyses for survival were conducted using Cox proportional hazards regression. Adjusted analyses for secondary outcomes were performed using generalized estimating equations. To address confounding by indication, we performed confirmatory analyses using inverse probability of treatment weighting. In this study, we included 1,030 patients. The median age of the cohort was 86.5 years (interquartile range, 80.9 to 90.8 years), 60.7% of the patients were female, and 90% of the patients were White. A surgical procedure was performed in 19.8% of the cohort. Following an adjusted analysis, patients treated surgically had a 28% lower hazard of mortality (hazard ratio, 0.72 [95% confidence interval (CI), 0.53 to 0.98]), but higher odds of delirium (odds ratio, 1.64 [95% CI, 1.10 to 2.44]). These findings were preserved in the inverse probability weighted analysis. We found that, among individuals with dementia who sustain a type-II odontoid fracture, surgical intervention may confer a survival benefit. A surgical procedure may be an appropriate treatment strategy for individuals with dementia whose life-care goals include life prolongation and maximizing quality of life in the short term following an injury. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Safe and effective liver-directed AAV-mediated homology-independent targeted integration in mouse models of inherited diseases

Liver-directed adeno-associated viral (AAV) vector-mediated homology-independent targeted integration (AAV-HITI) by CRISPR-Cas9 at the highly transcribed albumin locus is under investigation to provide sustained transgene expression following neonatal treatment. We show that targeting the 3' end of the albumin locus results in productive integration in about 15% of mouse hepatocytes achieving therapeutic levels of systemic proteins in two mouse models of inherited diseases. We demonstrate that full-length HITI donor DNA is preferentially integrated upon nuclease cleavage and that, despite partial AAV genome integrations in the target locus, no gross chromosomal rearrangements or insertions/deletions at off-target sites are found. In line with this, no evidence of hepatocellular carcinoma is observed within the 1-year follow-up. Finally, AAV-HITI is effective at vector doses considered safe if directly translated to humans providing therapeutic efficacy in the adult liver in addition to newborn. Overall, our data support the development of this liver-directed AAV-based knockin strategy.

Solvent bar microextraction based on using deep eutectic solvent and multivariate optimization for simultaneous determination of antidepressant and antiepileptic drugs in biological fluids

AbstractMonitoring medications in biological fluids is an essential aspect of patient care, particularly in cases of altered mental status where accurate diagnosis, effective treatment, and even forensic examinations are crucial. In this study, a new approach combining hydrophobic-deep-eutectic and solvent-bar-microextraction (HDE-SBME) followed by a high-performance liquid chromatography-diode array detector (HPLC-DAD) was developed for the simultaneous determination of desipramine, clomipramine, as antidepressant and carbamazepine as antiepileptic agents in untreated human urine and plasma samples. The HDE solvents, synthesized using various ratios of menthol and fatty acids, were utilized in the SBME setups. Computational methods were employed to predict the structure and modes of interaction between HDE and the chosen analytes. Central composite design methodology (CCD) was used for multivariate optimization of the effects of different parameters influencing the extraction efficiency of the proposed method. Under optimized experimental conditions, the calibration graph of the spiked selected drugs in urine and plasma samples demonstrated excellent linearity (R2 ≥ 0.994), with limits of detection/quantification below 0.60/2.02 μg L−1. The extraction recoveries achieved were 88–97%, and the repeatability/reproducibility (RSD%, n = 5) was less than 6.12/7.57. The proposed method was successfully applied to determine selected drugs in patients' urine and plasma samples. The proposed method detects three drugs in patients' urine and plasma samples without using toxic volatile organic solvents. The proposed microextraction technique exhibited a confident sensitivity, feasible operation, and simplicity compared with other published methods. Thus, it can be considered a promising method for monitoring the therapeutic levels of specific antidepressant and antiepileptic drugs in urine and plasma samples.

Differences in Positive Airway Pressure Requirements in Obstructive Sleep Apnea Between Black and White Patients.

There are disparities between Black and White patients in the utilization of positive airway pressure (PAP) alternatives for obstructive sleep apnea (OSA). Given low utilization rates among Black patients, there is limited knowledge of PAP alternative outcomes in this group. Therapeutic PAP levels are clinically accessible measures that have been shown to predict PAP alternative outcomes. Herein, we examined differences in PAP requirements between Black and White patients in a large clinical sample. Cross-sectional. Academic sleep center. We included OSA patients prescribed autoadjusting PAP between January 2018 and 2020 with baseline apnea-hypopnea index (AHI) ≥ 10. Mean and 90th percentile PAP levels were compared between White and Black patients who used PAP for ≥1 hour daily using linear regression controlling for age, sex, body mass index (BMI), AHI, oxygen saturation nadir, and mask type. There were 157 Black and 234 White patients who were generally obese (BMI, 37.3 ± 8.7) with severe OSA (AHI, 36.9 ± 25.6). Black patients had a 0.68 cm higher (95% confidence interval [CI]: 0.36, 1.35) mean PAP level and 0.85 cm H2O higher (95% CI: 0.36, 1.35) 90th percentile PAP level than white patients. Although statistically significant, differences were small and not clinically meaningful. Black and White OSA patients had clinically insignificant differences in PAP requirements, suggesting comparable upper airway collapsibility. Considering the predictive value of therapeutic PAP levels, our findings suggest Black and White patients may have comparable PAP alternative responses from a collapsibility standpoint. Future studies should explore reasons for low utilization of PAP alternatives among Black patients.

Incidence of and Risk Factors for Reoperation and Revision Following Total Elbow Arthroplasty with an Anatomic Convertible Prosthesis.

Total elbow arthroplasty (TEA) remains a valuable tool for treating inflammatory, degenerative, and traumatic elbow conditions. This study aimed to understand the incidence of and risk factors for reoperation following TEA at a high-volume center utilizing an implant with a convertible linkage and the potential for anatomic lateral column reconstruction. All patients undergoing primary TEA with the Latitude prosthesis (Stryker) from July 2001 to May 2020 were identified. Patient characteristics, the surgical indication, and implant characteristics were obtained. Additionally, the indications and timing were identified for reoperations. Postoperative radiographs were analyzed to assess cement quality, implant position, lateral column reconstruction, and distal humeral bone loss. Two hundred and nineteen TEAs were performed in 206 patients; 162 (74.0%) were in female patients, the mean patient age was 61 years (range, 23 to 95 years), and the mean follow-up was 11.8 years (range, 2 to 21 years). The most common indication for surgery was sequelae of trauma (36%). Ninety elbows (41.1%) required 200 reoperations at a mean of 19.6 months. Forty TEAs (18.3%) required revision of nonmodular implants, with 14 (6.4%) undergoing definitive explantation. The 5 and 10-year survivorship was 86.1% and 79.7%, respectively. The most common of the reasons for revision was aseptic loosening (53.8%), and the most common cause for non-revision reoperation was infection (23%). Younger age and greater follow-up duration were associated with greater revision and reoperation risks. Aseptic ulnar loosening was associated with a short ulnar stem length and component linkage (30% of short linked ulnar stems loosened; p < 0.001). Aseptic humeral loosening was associated with less-than-adequate cement-mantle quality (p = 0.04). Extended follow-up of the Latitude prosthesis at a high-volume center demonstrates that TEA continues to be hampered by a high reoperation rate, primarily due to infection and aseptic loosening. Technical factors such as good cement-mantle quality, longer stem length, and unlinked implants may play a role in preventing aseptic loosening. Further work is required to optimize long-term outcomes following TEA through improved understanding of appropriate surgical indications, techniques, and implant utilization. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

3D-Printed Metaphyseal Cones in Revision Total Knee Arthroplasties: Excellent Survivorship of 740 Cones at 5 Years.

Porous metaphyseal cones are frequently utilized during revision total knee arthroplasty (TKA) procedures. The purpose of the present study was to evaluate 3D-printed metaphyseal cones used for revision TKA, with specific emphasis on implant survivorship, radiographic appearance, and clinical outcomes after short-term follow-up. We identified 740 cones (498 tibial, 242 femoral) that had been inserted during 533 revision TKA procedures that had been performed at a single tertiary care academic institution. Aseptic loosening (n = 199), periprosthetic joint infection (PJI) (n = 183), and instability (n = 84) were the most common reasons for the index revision. Type-2B or 3 bone loss was present in 67% of the knees. The mean age was 66 years, the mean body mass index was 34 kg/m2, and 55% of the patients were female. Serial radiographs were reviewed. The mean duration of follow-up was 4 years. The 5-year cumulative incidence of cone revision for aseptic loosening was 1% (95% confidence interval [CI], 0% to 3%). The 5-year cumulative incidence of any cone revision or removal was 6% (95% CI, 4% to 9%). In total, 37 cones (19 femoral, 18 tibial) were revised, with PJI (n = 23; 14 recurrent), periprosthetic femoral fracture (n = 3), arthrofibrosis (n = 3), and aseptic loosening of the femoral component and femoral cone (n = 3) as the most common reasons for cone revision. The 5-year cumulative incidence of any TKA re-revision was 14% (95% CI, 11% to 18%). There were a total of 67 re-revisions, with PJI (n = 38), persistent drainage (n = 6), and extensor mechanism disruption (n = 3) being the most common reasons. Radiographically, 2 unrevised femoral cones and 1 unrevised tibial cone appeared to be possibly loose; all 3 cones were in knees with distal femoral replacements or hinged constructs. This large series showed that 3D-printed titanium metaphyseal cones were very durable at short-term follow-up, with a 5-year cumulative incidence of cone revision for aseptic loosening of 1%. PJI was the most common reason for cone revision and any revision. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

10-Year Heterogeneity of Minimal Important Change and Patient Acceptable Symptom State After Lumbar Fusions.

Cohort study. To evaluate heterogeneity (fluctuation) in minimal important change (MIC) and patient acceptable symptom state (PASS) for patient-reported outcomes (PROMs) through 10 years after lumbar fusion. PROMs have become key determinants in spine surgery outcomes studies. MIC and PASS were established to aid PROM interpretations. However, their long-term stability has not yet been reported. A consecutive series of elective lumbar fusions were followed-up using the Oswestry Disability Index (ODI) and Visual Analogue Scale (VAS) for pain. Improvement was rated by a 4-point Likert scale into "improved" or "non-improved". Satisfaction-to-treatment was rated by the patients' willingness to undergo surgery again. Receiver operating characteristics (ROC) curve analysis estimated MIC (95% confidence interval, CI) as the PROM change that best predicted improvement at distinct time-points. PASS (CI) was estimated as the lowest PROM score at which the patients were still satisfied. Heterogeneity across thresholds was evaluated using the DeLong algorithm. MIC for ODI represented heterogeneity across 10-years, ranging from -21 (-24 to -16) at 2-years to -8 (-7 to -4) at 5-years, P <0.001. The areas under the ROC curves (AUCs) (0.79-0.85) indicated acceptable to excellent discrimination. Heterogeneity was not significant in the MICs for the pain scores. At 1-year, MIC for back pain was -24 (-38 to -15), AUC 0.77, and for leg pain it was -26 (-44 to -8), AUC 0.78. No significant heterogeneity was observed in 10-year PASS scores. At 1-year, PASS for ODI was 22 (15 to 29), AUC 0.85. Similarly, 1-year PASS for back pain was 38 (20 to 56), AUC 0.81, and for leg pain it was 49 (26 to 72), AUC 0.81. MIC for ODI fluctuated over 10-years after lumbar fusions. PASS values for all PROMs seemed most stable over time. Caution is needed when generic MIC values are used in long-term studies. Therapeutic Level III.

Comparison of Operative and Nonoperative Management of Elderly Fragility Pelvic Ring Fractures.

To compare outcomes of nonoperative and percutaneous fixation of geriatric fragility lateral compression 1 (LC1) pelvic ring fractures. Retrospective. Two level 1 trauma centers. Included were patients who were 60 years or older with an isolated LC1 pelvic ring fracture managed nonoperatively or those who failed mobilization and were managed operatively with percutaneous sacral fixation. Patients with high-energy mechanisms of injury or polytrauma were excluded. The primary outcome was pain as measured by using the visual analog scale (VAS) after treatment. Secondary outcomes included length of stay, discharge disposition, mortality, readmission rates, and complications. In total, 231 patients were included with a mean age of 79.5 years (range 60-100). One hundred eighty-five (80.0%) patients were female. Sixty-two (26.8%) patients received percutaneous sacral fixation after failed mobilization, and 169 (73.2%) were managed nonoperatively. In the operative group, the median time to surgery was hospital day 4. Nonoperative patients were older (81.5 ± 10.0 years vs. 74.2 ± 9.4 years, P < 0.01) and had a shorter hospital length of stay (4.8 ± 6.2 days) than the operative group (10.6 ± 9.5 days, P < 0.01). Patients in the operative group had more pain (VAS 7.9 ± 3.0) than those in the nonoperative group (VAS 6.6 ± 3.0) ( P = 0.01) on admission but had similar pain control postoperatively (VAS 4.4 ± 3.0) compared with the nonoperative group (VAS 4.5 ± 3.6) on the equivalent hospital day ( P = 0.91). Thus, patients in the operative group experienced more improvement in pain (VAS 3.3 ± 2.7) compared with the nonoperative group (VAS 1.9 ± 3.9) after treatment ( P = 0.02). Ninety-day mortality ( P = 0.21) and readmission rates ( P = 0.27) were similar for both groups. Two patients in the operative cohort sustained nerve injuries, whereas 1 patient in the nonoperative group had a nonunion and underwent surgery. Patients who undergo percutaneous surgical fixation for low-energy LC1 injuries have similar discharge disposition, mortality, complication rates, and readmission rates compared with patients treated nonoperatively. Percutaneous surgical fixation may provide significant pain relief for patients who failed conservative management. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Development of a population pharmacokinetic model for the novel long-acting injectable antipsychotic risperidone ISM®.

The aims of this study were to develop a population pharmacokinetic (PK) model for risperidone ISM® and to investigate the relationships between active moiety exposure, as described by apparent clearance (CL40), and several covariates using all data from five clinical studies. A population PK model was developed using active moiety concentrations from a study in healthy volunteers and two studies in patients with schizophrenia. Data from a comparative bioavailability study in medically stable patients and a Phase III study in patients with acute exacerbation of schizophrenia were then incorporated, using empirical Bayesian feedback and model refinement in NONMEM. Finally, covariate analysis was performed on CL40. The final model adequately described the pharmacokinetics of 6288 active moiety concentrations in 17 healthy volunteers and 430 patients with schizophrenia. This one-compartment disposition model had a complex absorption process, combining a small amount immediately entering the central active moiety compartment, two first-order absorption processes and a combined zero-order and first order process, with first-order elimination from the central compartment. Significant covariates on CL40 were BMI and sex. Goodness-of-fit (GOF) plots and visual predictive checks (VPC) confirmed acceptable description of the data. The population PK model adequately described active moiety concentrations from five clinical studies after risperidone ISM® administration. Relationships between active moiety exposure and covariates were defined in order to facilitate simulations for future studies. The model showed that risperidone ISM® rapidly achieves therapeutic plasma levels within the first hours after the first injection that are maintained sustainedly throughout the whole dosing interval following once-monthly gluteal injections of 100 mg and 75 mg.