Therapeutic Levels Research Articles

Preparation irinotecan hydrochloride loaded PEGylated liposomes using novel method supercritical fluid and condition optimized by Box–Behnken design

A semi-synthetic camptothecin derivative known as irinotecan hydrochloride is frequently used to treat colorectal cancer, including colorectal adenocarcinoma and lung cancers involving small cells. Irinotecan has a very short half-life; therefore, continuous infusions are required to keep the drug’s blood levels at therapeutic levels, which could produce cumulative toxicities. Effective delivery techniques, including liposomes, have been developed to address these shortcomings. In this study, a continuous supercritical fluid approach dubbed Expansion Supercritical Fluid into an aqueous solution, in which the pressure decreases rapidly but remains over the critical pressure, is proposed to manufacture polyethylene glycolylated (PEGylated) liposomes carrying irinotecan hydrochloride. To accomplish this, PEGylated liposomes were created using a Box–Behnken design, and the operating parameters (flow rate, temperature, and pressure drop) were optimized. Encapsulation efficiency, mean size, and prepared liposome count were 94.6%, 55 nm, and 758 under ideal circumstances. Additionally, the stability of the PEGylated liposome was investigated during 8 weeks, and also PEGylated liposome-loaded irinotecan release profile was compared to conventional liposomes and free irinotecan, and a constant drug release was seen after the first burst release from liposomes.

Continuous Versus Intermittent Vancomycin Infusions for Coagulase-negative Staphylococcus Bacteremia in Neonates: A Propensity-matched Cohort Study.

Coagulase-negative staphylococci (CONS) are a major cause of late-onset neonatal sepsis, particularly in preterm infants, with high morbidity and mortality. While vancomycin is the first-line treatment for these infections, the optimal administration in neonates remains uncertain. We aim to compare the outcomes of neonates with CONS bacteremia treated with adjusted continuous infusion (CIV) versus standard intermittent infusion (IIV) of vancomycin. This retrospective study included 110 neonates, with 29 in the CIV group and 47 in the IIV group after propensity score matching. The primary outcome was treatment failure defined by the persistence of a positive blood culture for the same organism after at least 48 hours of vancomycin treatment. After matching, the CIV group exhibited significantly lower treatment failure rates [5/29 (17%) vs. 26/47 (44%); P = 0.014] and a higher rate of achieving therapeutic vancomycin levels after 24 hours [20/29 (69%) vs. 26/47 (44%); P = 0.002] compared to the IIV group. No significant differences were observed in terms of acute kidney failure between the 2 groups. Adjusted continuous vancomycin infusion in neonates with CONS bacteremia is associated with a lower treatment failure rate without an increase in renal toxicity compared to standard intermittent infusion. However, due to the observational design, larger prospective studies are needed to validate these results.

Ankle Fractures Treated with Locked Fibular Intramedullary Nailing: Description and Outcomes of a Minimally Invasive Open Technique

OBJECTIVES: To describe and report outcomes of a minimally invasive open intramedullary (IM) fibular nailing technique for fixation of ankle fractures. METHODS: Design: Case Series Setting: Urban Level 1 trauma center Patient Selection Criteria: Adult patients with ankle fractures (OTA 44A-C) treated with locked fibular IM nailing via a minimally invasive open technique for fracture and syndesmotic reduction between 2021 and 2024. Outcome Measures and Comparisons: Quality of reduction, complications, and patient-reported outcomes (PRO). RESULTS: A total of 150 consecutive patients operated by a single surgeon were included. Mean age was 53.3 (17-97) years, and mean BMI was 30.6 ± 7.4 kg/m2. 93(62%) patients were female, and 78 (52%) patients were Caucasian. 72 (48%) patients were obese, 40 (27.7%) patients were current/former smokers, 39 (26%) patients were diabetic, and 23 (15.3%) patients had open fractures. 37 (24.7%) patients had isolated lateral malleolus fractures, 48 (32%) had bimalleolar fractures, and 65(43.3%) had trimalleolar fractures. 123 (82%) patients had 2 syndesmotic screws placed, 26 (17.3%) had 1 screw, and 1 (0.7%) had none. Quality of reduction was good for 98%, fair for 2%, and poor for none per McLennan’s criteria. 113 patients (75.3%) were followed until clinical and radiographic union for a mean of 7.6 months (range 3-22) months). 110 patients (97.3%) went on to successful clinical and radiographic union following the index procedure. No patient had a superficial surgical-site infection, and 3 (2.6%) had deep surgical-site infections. 3 patients had a loss of reduction, and 6 patients had implant failure (5 broken syndesmotic screws, and 1 medial malleolus screw). 9 (8%) patients had unplanned reoperations (3 for debridement, 2 for loss of reduction, and 4 for removal of symptomatic implants). Mean ankle range of motion at final follow-up visit was 12.9° (0-40) of dorsiflexion, 39.6° (10-70) of plantarflexion, 23.5° (5-40) of inversion, and 18.2° (5-50) of eversion. Mean PROs at final follow-up visit were: Global Physical Health: 42.4 (23.5-67.6), Global Mental Health: 47.5 (21-67.6), Physical Function: 37.5 (14.7-57.8), Pain: 54.9 (22-72) and Mobility: 36.9 (16-65.3). CONCLUSIONS: Minimally invasive open fibular IM nailing allowed for excellent reduction and results in union with low rates of complications and good patient reported outcomes. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

A Dynamic, D-dimer-based Thromboprophylaxis Strategy in Patients with COVID-19.

COVID-19 pandemics increases venous thromboembolism (VTE) risk during hospitalization, despite prophylactic anticoagulation. Limited radiological diagnosis in pandemic requires a guided protocol for anticoagulant adjustment. This retrospective cohort study was conducted at a single center as part of a quality improvement program evaluating the efficacy and safety of anticoagulation protocols. The study focused on implementing a guideline for anticoagulant dosing protocol based on dynamic changes in D-dimer levels in COVID-19 hospitalized patients. The dosing guideline allowed for dose escalation from standard prophylactic levels to escalated prophylactic or therapeutic levels, depending on the patient's risk profile for VTE. The primary endpoints included in-hospital survival comparing between fix and dynamic adjustment treatment groups. Secondary endpoints encompassed major and clinically relevant non-major bleeding (CRNMB) events, incidence of breakthrough thrombosis, length of hospitalization and ICU stay, days of mechanical ventilator use, and survival duration. Among the 260 COVID-19-infected patients hospitalized between March 15th and June 15th, 2020. The patients received fixed anticoagulant dosage in 188, 72.3%) patients, while 72 (27.7%) were up-titrated according to the protocol. In-hospital survival at 30 days demonstrated superiority among patients whose anticoagulation was up-titrated to either escalated prophylactic or therapeutic (80.2%) compared to receiving fixed anticoagulant dosage (51.3%) (p=0.01). Bleeding events were significantly higher in up-titrate group (12.5%) compared to fixed anticoagulant dosage group (2.13%). Most of them are CRNMB. A dynamic, D-dimer-based dose escalation of anticoagulation for hospitalized patients with COVID-19 holds promise in improving in-hospital mortality rates without a significant increase in fatal bleeding events.

Validating Orthopaedic Data Evaluation Panel (ODEP) Ratings Across 9 Orthopaedic Registries: Total Hip Implants with an ODEP Rating Perform Better Than Those without an ODEP Rating.

Orthopaedic Data Evaluation Panel (ODEP) ratings of total hip (TH) and total knee (TK) implants are informative for assessing implant performance. However, the validity of ODEP ratings across multiple registries is unknown. Therefore, we aimed to assess, across multiple registries, whether TH and TK implants with a higher ODEP rating (i.e., an A* rating) have lower cumulative revision risks (CRRs) than those with a lower ODEP rating (i.e., an A rating) and the extent to which A* and A-rated implants would be A*-rated on the basis of the pooled registries' CRR. Implant-specific CRRs at 3, 5, and 10 years that were reported by registries were matched to ODEP ratings on the basis of the implant name. A meta-analysis with random-effects models was utilized for pooling the CRRs. ODEP benchmark criteria were utilized to classify these pooled CRRs. A total of 313 TH cups (54%), 356 TH stems (58%), 218 TH cup-stem combinations (34%), and 68 TK implants (13%) with unique brand names reported by registries were matched to an ODEP rating. Given the low percentage that matched, TK implants were not further analyzed. ODEP-matched TH implants had lower CRRs than TH implants without an ODEP rating at all follow-up time points, although the difference for TH stems was not significant at 5 years. No overall differences in CRRs were found between A* and A-rated TH implants, with the exception of TH cup-stem combinations, which demonstrated a significantly lower CRR for A*A*-rated cup-stem combinations at the 3-year time point. Thirty-nine percent of A*-rated cups and 42% of A*-rated stems would receive an A* rating on the basis of the pooled registries' CRR at 3 years; however, 24% of A-rated cups and 31% of A-rated stems would also receive an A* rating, with similar findings demonstrated at longer follow-up. At all follow-up time points, ODEP-matched TH implants had lower CRRs than TH implants without an ODEP rating. Given that the performance of TH implants varied across countries, registries should first validate ODEP ratings with use of country-specific revision data to better guide implant selection in their country. Data source transparency and the use of revision data from multiple registries would strengthen the ODEP benchmarks. Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Ocular pharmacokinetics of acetazolamide from intravitreal implants by high-performance liquid chromatography coupled to tandem mass spectrometry

Glaucoma, a leading cause of irreversible blindness, affects about 70 million people globally. Its treatment focuses on reducing intraocular pressure. Acetazolamide, a potent anti-glaucoma drug, is currently used only systemically due to low solubility and permeation, which cause severe side effects. Developing topical medications with acetazolamide requires robust analytical methods for its detection in biological samples. In this context, this study aimed to develop a method to quantify acetazolamide in rabbit vitreous humor samples. The method involved a simple, fast, inexpensive, and environmentally friendly protein precipitation step for sample preparation, needing just 50 μL of sample and 200 μL of organic solvent, with adequate recovery. This was combined with high-performance liquid chromatography coupled to tandem mass spectrometry, enabling highly sensitive (LOQ of 5 ng/mL) quantification within only 5 min. The method proved to be selective, precise, and accurate, with well-fitted analytical curves, with no carryover, and no matrix effect impacting reliability. The method was successfully applied to analyze vitreous humor samples from rabbits in pharmacokinetic studies, monitoring drug release from intravitreal implants. Results showed a controlled release profile, with a maximum drug concentration (Cmax) of 426.01 ± 64.57 ng/mL, time to reach Cmax (Tmax) of 28 days, and area under the curve (AUC0–42 and AUC0-∞) of 7722.66 ± 1125.96 ng days/mL and 8998.11 ± 1311.92 ng days/mL, respectively. The device demonstrated significantly slower elimination, ensuring therapeutic levels for an extended period when compared to intravitreal injection.

Pharmacokinetics of Extended-release Buprenorphine and Clinical Efficacy for Postoperative Pain Management in the Domestic Ferret (Mustela putorius furo).

Buprenorphine hydrochloride (Bup-HCl) is a common injectable opioid analgesic. In ferrets, Bup-HCl must be administered every 8 to 12 h to maintain clinical efficacy. Extended-release analgesics offer multiple advantages, including reduced handling and injection frequency, improved compliance, and increased protection from end-of-dose failure. Although efficacy of extended-release buprenorphine formulations has been demonstrated in other species, their use in the domestic ferret has not been investigated. In this study, we evaluated the pharmacokinetics of a compounded polymeric formulation of buprenorphine (Bup-ER) and a pharmaceutical-grade, FDA-indexed liposomal suspension (Bup-XR). Two doses each of Bup-ER (0.12 and 0.2 mg/kg) and Bup-XR (0.2 and 0.6 mg/kg SC) were administered to young adult female ferrets and plasma concentrations were measured between 0 and 96 h (n = 4 animals per timepoint). All doses of both drugs achieved therapeutic plasma levels by 30 min. Furthermore, high-dose Bup-XR maintained therapeutic levels for 72 h, followed by high-dose Bup-ER (less than 48 h), low-dose Bup-XR (24 h), and low-dose Bup-ER (less than 24 h). In this study, we also developed a pain scoring system and utilized this to compare analgesic efficacy between single high-dose Bup-XR (0.6 mg/kg SC) and a standard postoperative course of Bup-HCl (0.02 mg/kg SC every 10 to 12 h for 8 doses) after ovariohysterectomy. Ferrets receiving Bup-XR had significantly lower respiratory rate and posture scores in the first 24 h postoperatively than did those that received Bup-HCl and were less likely to react to palpation of the surgical incision. Of note, ferrets that received high-dose Bup-ER had a significantly higher incidence of injection site reactions than ferrets that received Bup-HCl (P = 0.0137). This study demonstrates that a single dose of Bup-XR (0.6 mg/kg SC) is a safe and effective analgesic in female ferrets, with a duration of action up to 72 h and minimal side effects, offering a refinement to analgesia in this species.

Geriatric Pharmacotherapy Case Series: Clotting and Gender-Affirming Care.

Background A transfeminine patient is a 79-year-old with past medical history significant for type 2 diabetes mellitus, hypertension, gender dysphoria, chronic kidney disease, dyslipidemia, total left hip replacement, and recent provoked deep venous thromboembolism (DVT). She was seen by a pharmacist in a primary care clinic after her discharge from a skilled nursing facility. The patient was experiencing symptoms of gender dysphoria after discontinuation of her estradiol in setting of her DVT. Assessment Her renal function was calculated to ensure she was on appropriate dosing of her medications. Because her DVT was provoked, providers determined she would require only 3 months of anticoagulation. Her laboratory test results showed a subtherapeutic estradiol level and her estradiol was restarted. Additionally, aspirin was being prescribed for primary prevention of atherosclerotic cardiovascular disease and was discontinued. Outcome She has significant improvement in her gender dysphoria symptoms with resuming her estradiol and now has a therapeutic estradiol level. She is tolerating her direct oral coagulant well and reports good quality of life. Conclusion When reviewing medications for patients it is important to take several factors into account, including dose, appropriate indication, and patient preference. Pharmacists play a key role, through collaboration with providers, in assessing these medication-specific factors. Estradiol was stopped in this patient because of her DVT, but given her DVT was provoked after a recent surgery, it was unlikely that estradiol was the cause of her clot. Weighing the risks and benefits for any patient is important when determining what medications are appropriate to continue. Additionally, calculating renal function appropriately in a gender-non-conforming patients ensures appropriate and safe dosing.

Pharmacokinetics of Injectable Meloxicam and Buprenorphine in the Naked Mole-Rat (Heterocephalus glaber).

Unique characteristics of the naked mole-rat (NMR) have made it increasingly popular as a laboratory animal model. These rodents are used to study many fields of research including longevity and aging, cancer, circadian rhythm, pain, and metabolism. Currently, the analgesic dosing regimens used in the NMR mirror those used in other rodent species. However, there is no pharmacokinetic (PK) data supporting the use of injectable analgesics in the NMR. Therefore, we conducted 2 independent PK studies to evaluate 2 commonly used analgesics in the NMR: meloxicam (2 mg/kg SC) and buprenorphine (0.1 mg/kg SC). In each study, blood was collected at 8 time points after subcutaneous injection of meloxicam or buprenorphine (0 [predose], 0.25, 0.5, 1, 2, 4, 8, and 24 h). Three NMRs were used per time point for a total of 24 animals per PK study. Plasma concentrations of meloxicam were highest between 0.5 and 1 h postinjection. Levels remained above the extrapolated dog and cat therapeutic threshold levels (390 to 911 ng/mL) for at least 24 h. Plasma concentrations of buprenorphine were highest between 0.25 and 0.5 h postinjection. Levels remained above the human therapeutic threshold (1 ng/mL) for up to 21 h. No skin reactions were seen in association with injection of either drug. In summary, these data support dosing meloxicam (2 mg/kg SC) once every 24 h and buprenorphine (0.1 mg/kg SC) once every 8 to 12 h in the NMR. Further studies should be performed to evaluate the clinical efficacy of these drugs by correlating plasma concentrations with postoperative pain assessments.

Facile, eco-friendly and sensitive fluorimetric approach for detection of chlorpromazine: Application in biological fluids and tablet formulations as well as greenness evaluation of the analytical method.

Monitoring antipsychotic drugs in biological fluids, such as human serum and urine, is important for ensuring the safety and efficacy of psychiatric treatments. This process helps maintain therapeutic drug levels, minimize side effects, and optimize patient well-being. Chlorpromazine (CZ) is a widely prescribed antipsychotic drug used for conditions like schizophrenia, bipolar disorder, and acute psychosis. Almost all existing sensing techniques for CZ are either insensitive spectrophotometric methods or involve long and complex chromatographic procedures, limiting their routine use. In this work, we introduce a facile, green, and sensitive fluorimetric strategy with high reproducibility for detecting CZ in its pure form, tablet formulation, and spiked human plasma and urine without the need for derivatization reactions. The proposed method relies on the inhibition of the intramolecular photoinduced electron transfer (PET) effect by using 2.0 M acetic acid. This approach enables the linear detection of CZ from 3.0 to 600 ng/mL with remarkably low quantitation and detection limits of 1.51 and 0.49 ng/mL, respectively. Moreover, the developed method's greenness was evaluated.

Schatzker IV tibial plateau fractures: are they always unicondylar?

The objectives of this study were to describe the incidence and morphology of medial tibial plateau fractures that extend into the lateral articular surface and to describe trends in their management. Retrospective. Level I Urban Trauma Center. Seventy consecutive patients sustaining OTA/AO 41 B1 and B3 fractures. Open reduction internal fixation of medial tibial plateau fractures. Incidence of medial tibial plateau fractures that extend into the lateral articular surface. Secondary outcomes include localization of lateral articular surface depression, neurovascular injury, and trends in surgical management. Seventy patients were included with 9 fractures (12.9%) isolated to the medial condyle (MC) and 61 fractures (87.1%) extending to the lateral condyle (LC). Compartment syndrome was present in 2 patients (2.9%), peroneal nerve palsy in 2 (2.9%), and arterial injury in 1 (1.4%). Initial external fixation was used more frequently in the LC group compared with the MC group (P = 0.028). Of the 61 fractures in the LC group, 49 (80.3%) included lateral articular surface depression which localized to the posteromedial quadrant of the lateral articular surface in 36 of 49 fractures (73.5%). Lateral articular surface depression depth ≥10.6 mm was associated with the use of dual incisions (P < 0.001). Schatzker IV fractures frequently extend to the lateral condyle and often present with depression of the posteromedial lateral articular surface. Fractures with lateral articular surface depression depth ≥10.6 mm were more likely to undergo fixation with dual incisions. Therapeutic level IV.

Cervical Collar Use Following Cervical Spine Surgery: A Systematic Review.

The utility and risks associated with the use of cervical collars in the postoperative period after cervical spine surgery have been of debate. The purpose of this study was to systematically review the currently available evidence on the use of cervical collars after cervical spine surgery to assess their impact on outcomes. A literature search of the PubMed database was performed using keywords "cervical collar," "anterior cervical discectomy and fusion (ACDF)," "posterior cervical decompression and fusion," "laminoplasty," "post-operative orthotic bracing," "cervical decompression," and "cervical orthosis" in all possible combinations. All English studies with the level of evidence of I to IV that were published from May 1, 1986, to December 3, 2023, were considered for inclusion. A total of 25 articles meeting the inclusion criteria were identified and reviewed. Regarding anterior and posterior fusion procedures, cervical collar use demonstrated improved short-term patient-reported outcomes and pain control. While surgeon motivation for collar use was to increase fusion rates, this is not well drawn out in the literature with the majority of studies demonstrated no significant difference in fusion rates between patients who wore a cervical collar and those who did not. Regarding motion-preserving procedures such as cervical laminoplasty, patients with prolonged postoperative cervical collar use demonstrated increased rates of axial neck pain and decreased final range of motion (ROM). Surgeon motivation for postoperative cervical collar immobilization after completion of fusion procedures is to increase fusion rates and improve postoperative pain and disability despite this not being fully drawn out in the literature. After completion of motion-sparing procedures, the benefits of collar immobilization diminish with their prolonged use which could lead to increased rates of axial neck pain and decreased ROM. Cervical collar immobilization in the postoperative period should be considered its own intervention, with its own associated risk-benefit profile. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

An Opioid-Sparing Pain Protocol of Intravenous and Oral Ketorolac Reduces Opioid Consumption and Pain Levels After Arthroscopic Meniscus Surgery: A Prospective, Randomized Controlled Trial

The primary purpose was to compare ketorolac to oxycodone-acetaminophen with respect to pain and opioid consumption after arthroscopic meniscus surgery. The secondary purpose was to compare short-term functional outcomes between the 2 protocols. A power analysis demonstrated that 43 patients were required. In this randomized control trial, patients with meniscal pathology undergoing arthroscopic meniscus surgery were included. Group 1 received oxycodone-acetaminophen alone. Group 2 received 1 dose of intravenous ketorolac intraoperatively, oral ketorolac upon discharge, and "rescue" oxycodone-acetaminophen. Patients recorded the number of opioid tablets consumed and visual analog pain scale (VAS) scores 3 times per day for 5 days postoperatively. Opioids were converted to morphine milligram equivalents (MMEs). VAS, Lysholm Knee Scoring Scale, and Knee injury and Osteoarthritis Outcome Score were obtained. Forty-eight patients were randomized. There were 25 patients in the control group and 23 patients in the ketorolac group. The mean (SD) age was 47.9 (14.3) years. Fifty-two percent (n= 25) of the population were female. Three patients (6.3%) underwent meniscal repair. During the first 5 days postoperatively, the mean VAS score (β= -13.2, SE= 5.97, P= .029) and the MMEs consumed were significantly lower (β= -4.7, SE= 1.93, P= .015) per time point in the ketorolac group relative to the control group. The control group had better Lysholm Knee Scoring Scale (mean [SD] 80.6 [18.5] vs 65 [21.5], P= .016) and Knee injury and Osteoarthritis Outcome Score (mean [SD], 74.1 [16.7] vs 61.9 [18.6], P= .029) scores at 6 weeks. There were no significant differences in the rates of side effects. An opioid-sparing pain protocol of intravenous and oral ketorolac is associated with significant reductions in VAS scores and MME consumption in the first 5 days after arthroscopic meniscus surgery. There were significant differences in patient-reported outcomes at final follow-up, favoring the control group. There were no significant differences in adverse reactions and side effects. Therapeutic Level II, prospective randomized controlled trial.

Therapeutic Gene Editing for Hemoglobinopathies.

In the last ten years, a consistent number of clinical studies have evaluated different gene approaches for the treatment of patients with sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT). Initial studies of gene therapy for hemoglobinopathies involved the use of lentiviral vectors to add functional copies of the gene encoding β-globin in defective CD34 cells; more recently, gene editing techniques have been used involving either CRISPR-Cas9, transcription activation-like effector protein nuclease, zinc finger nuclease, and base editing to either induce fetal hemoglobin production at therapeutic levels or to genetically repair the underlying molecular defect causing the disease. Here, we review recent gene editing studies that have started the development of a new era in the treatment of hemoglobinopathies and, in general, monoallelic hereditary diseases.

Pharmacokinetics of ganciclovir eye drops: a comparative study of solutions prepared from ganciclovir for intravenous infusion and ganciclovir gel.

To evaluate the pharmacokinetics of ganciclovir eye drops by comparing solutions prepared from ganciclovir for intravenous infusion and ganciclovir gel and to assess the impact of systemic administration on drug levels in ocular tissues and serum. Experimental study design. Ganciclovir solutions (0.5% and 1.0%) prepared by diluting DENOSINE ® IV Infusion in saline and 0.15% ganciclovir gel (Virgan®) were topically administered in rabbit eyes, with and without concomitant systemic administration of ganciclovir. The concentrations of ganciclovir in the corneal epithelium, stroma, and endothelium, aqueous humor; and blood plasma were analyzed by high-performance liquid chromatography (HPLC). The ganciclovir solutions (0.5% and 1.0%) maintained therapeutic ganciclovir levels in the corneal endothelium above the effective dose required for 50% inhibition (ED50) up to 6h, albeit with a swift decline thereafter. The 0.15% ganciclovir gel maintained higher therapeutic concentrations in the corneal endothelium for up to 12h, exceeding the ED50. Serum concentrations of ganciclovir were significantly elevated in the groups receiving combined systemic administration. Topical application of 0.15% ganciclovir gel maintained high endothelial concentrations, well above the therapeutic threshold, with or without systemic administration. Furthermore, the observed increase in ganciclovir levels within the plasma and aqueous humor following systemic administration posits it as a viable strategy for severe cases of cytomegalovirus corneal endotheliitis or those inadequately managed by local treatments alone.

Estimating optimal therapeutic drug levels of anti-tuberculosis medications based on treatment safety and effectiveness.

Therapeutic drug ranges (TDR) for standard anti-tuberculosis (TB) treatment have been determined based on expected drug levels at least 2 hours after taking the dose. In this study we constructed TDR for TB drug levels based on minimizing drug toxicity and maximizing treatment effectiveness. Participants were followed prospectively in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil observational cohort study. We focused on participants with culture-confirmed drug-susceptible pulmonary TB who underwent standard TB therapy. TDR were estimated for each TB drug separately: isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA). TDR were defined as drug concentrations that were both safe and effective: safety was defined as the probability of having an ADR of at most 5%, while effectiveness was defined as a probability of at least 95% of not having either TB treatment failure or recurrence. There were 765 plasma samples from 448 patients; 110 (24.6%) were people with HIV, 9 (2.0%) had a grade 3 or higher ADR, and 15 (3.3%) had treatment failure/recurrence. Higher drug concentrations of INH, RIF and EMB were associated with increased odds of having ADR. High concentrations of INH suggested protection against treatment failure/recurrence. Estimated therapeutic drug range for INH (2.3-8.2 µg/ml) and for RIF (0.5-7.5 µg/ml) differed from the currently recommended drug ranges (3-5 µg/ml and 8-24 µg/ml, respectively). Estimates for PZA and EMB were similar to the currently recommended values. Our estimated upper end TDR were higher for INH and lower for RIF compared to currently recommended ranges.

Using an Intraoperative Stress Exam to Direct Treatment in Posterior Femoral Head Fracture-Dislocations.

To examine the results of a treatment algorithm incorporating an EUA performed intraoperatively after fixation of the femoral head through a Smith Petersen approach to determine need for posterior wall or capsule repair. Design: Retrospective review. Two Level 1 trauma centers. All acute, traumatic femoral head fractures from posterior hip dislocations treated at participating centers over a 5-year period from 2017-2022. Injuries were classified according to the Pipkin system. The primary outcome was the result of intraoperative EUA performed after femoral head fixation to determine the need for Kocher-Langenbeck exposure for posterior wall and/or capsule fixation. The secondary outcomes included rates of avascular necrosis, heterotopic bone formation, late instability, and conversion to total hip arthroplasty. Studied were 63 males and 22 females with mean age 32.5 (range 18-71). 79 of 85 (92.9%) patients had a stable EUA after fixation of the femoral head through a Smith-Petersen approach. Six (6/85, 7.1%) underwent an additional Kocher-Langenbeck approach for posterior wall or capsule fixation. This included 1 Pipkin I, 1 Pipkin II, and 4 Pipkin IV injuries. Of the Pipkin IV injuries, 51/55 (92.7%) had stable EUA and did not require fixation of their posterior wall. This included 7 patients with wall involvement >20%. Five patients were excluded because of planned fixation of their posterior wall based on preoperative imaging. Of patients with at least 6 months follow up, 16 of 65 (26.4%) developed radiographic evidence of AVN and 21 of 65 (32.3%) evidence of heterotopic bone formation. Seven out of 65 (10.8%) were converted to total hip arthroplasty over the study period. When comparing patients with a single exposure with those with additional KL exposure, they did not vary in their rate of AVN (27.1% vs. 0.0%, P=0.3228), HO formation (30.5% vs. 50.0%, P=0.3788), or conversion to total hip arthroplasty (10.2% vs. 16.7%, P=0.510). This study found residual posterior hip instability after femoral head fixation in patients with and without posterior wall fractures after posterior dislocations. The results of this study support use of an EUA after femoral head fixation to identify residual posterior hip instability in all femoral head fractures from posterior hip dislocations, regardless of Pipkin type. Use of the Smith-Petersen exposure remains a viable surgical option and may be improved with incorporation of an EUA after femoral head fixation. For Pipkin IV injuries with posterior wall fractures with indeterminate stability, an EUA accurately identifies residual instability. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Harnessing Nanoparticles to Overcome Antimicrobial Resistance: Promises and Challenges.

The rise of antimicrobial resistance (AMR) has become a serious global health issue that kills millions of people each year globally. AMR developed in bacteria is difficult to treat and poses a challenge to clinicians. Bacteria develop resistance through a variety of processes, including biofilm growth, targeted area alterations, and therapeutic drug alteration, prolonging the period they remain within cells, where antibiotics are useless at therapeutic levels. This rise in resistance is linked to increased illness and death, highlighting the urgent need for effective solutions to combat this growing challenge. Nanoparticles (NPs) offer unique solutions for fighting AMR bacteria. Being smaller in size with a high surface area, enhancing interaction with bacteria makes the NPs strong antibacterial agents against various infections. In this review, we have discussed the epidemiology and mechanism of AMR development. Furthermore, the role of nanoparticles as antibacterial agents, and their role in drug delivery has been addressed. Additionally, the potential, challenges, toxicity, and future prospects of nanoparticles as antibacterial agents against AMR pathogens have been discussed. The research work discussed in this review links with Sustainable Development Goal 3 (SDG-3), which aims to ensure disease-free lives and promote well-being for all ages.

Patellar bone defect grafting does not reduce anterior knee pain after bone-patellar tendon-bone anterior cruciate ligament reconstruction.

Donor site morbidity is the main drawback to using bone-patellar tendon-bone (BPTB) as a graft in anterior cruciate ligament (ACL) reconstruction. The objective of the study was to determine whether refilling the patellar bone defect after BPTB harvesting with autograft bone decreased kneeling pain to a greater degree when compared with a group in which bone defect is left unaddressed. This is a randomised single-blinded controlled study. Forty patients were randomised into two groups; group 1: Patellar bone defect filled with autologous bone; group 2: Bone defect left undressed. Pain was measured by means of pressure algometry (PA). Functional outcomes were measured with the Kujala and Victorian Institute of Sport Assessment-Patella (VISA-P) score. Magnetic resonance imaging (MRI) was done to measure bone buildup between groups at the 1-year follow-up. No differences were observed in the different algometry measurements and the scores were assessed at 3, 6 and 12 months postoperatively. The ratio of void filled remained consistently higher (p = 0.003) in group 1 when compared to group 2. Although refilling the lower pole of the patella with autologous bone from the harvested BPTB autograft loads the bone defect, it does not reduce pain at the donor site 1 year after surgery. Therapeutic study level 1.

Finding individualised treatment in obese needing enoxaparin (FIT ONE): a multicentre study of therapeutic enoxaparin and the role of anti-factor Xa monitoring.

Enoxaparin is dosed according to actual body weight in treatment of arterial and venous thrombosis. Due to its hydrophilic nature, it distributes according to lean body mass which may be problematic when dosing obese patients as this may increase the risk of bleeding events in this population. The aimwasto evaluate current therapeutic enoxaparin dosing strategies, including Antifactor Xa (AFXa) level monitoring, in obese patients and to identify factors that contribute to treatment failure and excess anticoagulation. A retrospective cohort study was conducted reviewing patients administered therapeutic enoxaparin between May 2020 and April 2021. Data were collected on patient characteristics, enoxaparin therapy, AFXa monitoring, and outcomes. Regression models were constructed to assess variables of interest to estimate any association with AFXa levels. In total 762 patients were included in the analysis. The mean initial weight-based dose was 0.95mg/kg twice daily (SD: ± 0.12, IQR 0.92-1.01) and 1.04mg/kg once daily (SD: ± 0.26, IQR 0.93-1.12) and 14.4% of patients had AFXa monitoring. Treatment failure was experienced by 2.2%, 5% experienced bleeding. There was no association between the mean actual milligram per kilogram weight-based twice daily doses and subtherapeutic, therapeutic and supratherapeutic AFXa levels(P = 0.135). Obesity was not includedin the final regression models due to lack of significance. At a mean therapeutic enoxaparin dose of 0.95mg/kg twice daily and 1.04mg/kg once daily no excess in treatment failure or bleeding events were observed in obese patients compared to the product information. Obesity was not an independent variable that affected the achievement of target AFXa levels.