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Permanent Trials for Spinal Cord Stimulation
No full textIntroduction: Prior to the permanent implant of a spinal cord stimulator, patients typically undergo a screening trial using a percutaneously placed lead to ensure adequate response. However, due to several factors, patients may not be candidates for this screening trial and therefore instead undergo a “permanent trial” where either a percutaneous lead or paddle lead is placed using a tunneled extension for the trial, with the intent of conversion to a permanent system. If these patients proceed with an implant, the epidural space is not re-accessed and only an impulse generator (IPG) is needed. Although this technique is commonly employed, there is a paucity of literature describing outcomes with the “permanent trial” methodology. We present here our clinical experience with this technique. Methods: Participants who underwent permanent trials at a single institution between 2014 and 2020 were identified. Charts were reviewed to collect demographic information, numerical rating score (NRS) data, length of follow-up, revisions, complications, and removals. Results: A total of 27 patients who underwent permanent trial placement were identified from a database of 762 patients who underwent SCS placement (3.54%). The permanent placement group included 7 paddle trials, 14 percutaneous trials, and 6 dorsal root ganglion (DRG) trials. The reasons for pursuing a permanent trial included previously aborted percutaneous trial (n = 8), inability to hold anticoagulation for a prolonged period (n = 4), previous thoracic spine surgery or presence of thoracic stenosis on MRI (n = 4), and significant medical comorbidities precluding typical percutaneous trial lead placement at a surgery center (n = 3). 24/27 (88.8%) proceeded to permanent implant, and 16/24 (66.7%) were considered responders (greater than 50% reduction in pain) after 3 months. Over an average follow-up of 28.7 months, complications included 1 peri-operative intracranial hemorrhage delaying IPG placement, 2 lead fractures, 1 lead migration, and 1 CSF leak. Three patients required revision surgery for lead migration, lead fracture, and CSF leak, respectively. One patient had his system explanted 25.9 months after initial placement due to increased pain from stimulation. Conclusion: This study aims to characterize our experience with permanent trials for SCS. Here we demonstrate a higher rate of trial-to-implant conversion than previously documented for traditional percutaneous trials. We show similar rates of revisions and complications, elucidating the important role of permanent SCS trials in high-risk patients
Bictegravir/Emtricitabine/Tenofovir Alafenamide in Adults With HIV-1 and End-Stage Kidney Disease on Chronic Haemodialysis
No full textIntroduction: Treatment for people with HIV-1 and end-stage kidney disease (ESKD) on haemodialysis (HD) has previously required complex dose-adjusted regimens, with limited data on the use of a single-tablet regimen in this population. Our aim was to assess the efficacy and safety of once-daily bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) and to evaluate the pharmacokinetics of bictegravir (BIC) in adults with HIV-1 and ESKD on HD. Methods: We performed an open-label extension (OLE) of an open-label, multicentre, single-group phase 3b study (NCT02600819) of adults with ESKD on HD and HIV-1 with virological suppression. Participants switched to elvitegravir/cobicistat/F/TAF (E/C/F/TAF) 150/150/200/10 mg for 96 weeks, following which a subgroup of US participants entered an OLE phase in which they switched to B/F/TAF 50/200/25 mg for 48 weeks, returning for study visits at weeks 4 and 12, and every 12 weeks thereafter. Study assessments included virological response, safety and pharmacokinetic analysis of BIC. Results: Ten participants entered the OLE (median age, 55 years). Virological suppression (HIV-1 RNA \u3c50 copies/mL) was maintained in all participants over 48 weeks of B/F/TAF treatment. B/F/TAF was well tolerated, with no treatment discontinuations. Mean BIC trough concentrations were lower than those previously reported for people with HIV-1 with normal kidney function, but remained four- to seven-fold higher than the established protein-adjusted 95% effective concentration against wild-type HIV-1. Conclusion: These findings support the use of the once-daily B/F/TAF single-tablet regimen for people with HIV-1 and ESKD on HD. This regimen offers a convenient treatment option for this population as it reduces the need for dose adjustment, eases pill burden and avoids potential drug–drug interactions associated with alternatives that may impact individuals on multiple medications or awaiting transplantation
Deletion of Murine Astrocytic Vesicular Nucleotide Transporter Increases Anxiety and Depressive-Like Behavior and Attenuates Motivation for Reward
No full textAstrocytes are multi-functional glial cells in the central nervous system that play critical roles in modulation of metabolism, extracellular ion and neurotransmitter levels, and synaptic plasticity. Astrocyte-derived signaling molecules mediate many of these modulatory functions of astrocytes, including vesicular release of ATP. In the present study, we used a unique genetic mouse model to investigate the functional significance of astrocytic exocytosis of ATP. Using primary cultured astrocytes, we show that loss of vesicular nucleotide transporter (Vnut), a primary transporter responsible for loading cytosolic ATP into the secretory vesicles, dramatically reduces ATP loading into secretory lysosomes and ATP release, without any change in the molecular machinery of exocytosis or total intracellular ATP content. Deletion of astrocytic Vnut in adult mice leads to increased anxiety, depressive-like behaviors, and decreased motivation for reward, especially in females, without significant impact on food intake, systemic glucose metabolism, cognition, or sociability. These behavioral alterations are associated with significant decreases in the basal extracellular dopamine levels in the nucleus accumbens. Likewise, ex vivo brain slices from these mice show a strong trend toward a reduction in evoked dopamine release in the nucleus accumbens. Mechanistically, the reduced dopamine signaling we observed is likely due to an increased expression of monoamine oxidases. Together, these data demonstrate a key modulatory role of astrocytic exocytosis of ATP in anxiety, depressive-like behavior, and motivation for reward, by regulating the mesolimbic dopamine circuitry
Aripiprazole Lauroxil: Development and Evidence-Based Review of a Long-Acting Injectable Atypical Antipsychotic for the Treatment of Schizophrenia
No full textThis review article describes why and how aripiprazole was formulated as aripiprazole lauroxil (AL), an extended-release antipsychotic agent that is delivered via a long-acting injectable formulation, and the clinical trials investigating its use. AL was formulated as an inactive prodrug of aripiprazole using LinkeRx® technology to provide a prolonged-release antipsychotic with predictable dissolution over time. The resulting AL pharmacokinetic profile is characterized by a long half-life and little peak-to-trough aripiprazole concentration variability across dosing intervals of every 1 month, every 6 weeks, and every 2 months. The prodrug technology was further refined to develop an AL initiation formulation with a somewhat faster release of aripiprazole, eliminating the need for a 21-day oral aripiprazole supplementation period. With this initiation formulation, AL treatment can be started in 1 day. Key AL characteristics, including pharmacokinetic profile and efficacy, safety, and tolerability data, are presented. In addition to the efficacy and safety established in clinical trials of oral aripiprazole, a placebo-controlled 12-week pivotal study investigated AL 441 mg and 882 mg monthly regimens in patients with acutely exacerbated schizophrenia and provided efficacy and safety information that led to US Food and Drug Administration approval in 2015. Thereafter, studies established the long-term safety profile and durability of the AL treatment effect. The 25-week, active-controlled ALPINE study evaluated the feasibility and effectiveness of AL 1064 mg every 2 months, initiated using the 1-day AL initiation regimen, without further oral supplementation beyond day 1, in patients hospitalized for acutely exacerbated schizophrenia with subsequent transition to outpatient care. In short-term and long-term studies, AL was generally well tolerated at initiation and during acute and maintenance treatment. Pharmacokinetic, efficacy, and safety characteristics support the use of AL across inpatient and outpatient treatment settings. with their first dose. The 1-day initiation regimen allows people with schizophrenia to start treatment during a doctor’s office visit or during a brief stay in the hospital. In short-term studies, aripiprazole lauroxil significantly reduced symptoms of acute schizophrenia. In longer-term studies, side effects were similar to those expected when using oral aripiprazole, and symptoms improved over extended durations of treatment lasting up to 3.5 years. Aripiprazole lauroxil’s safety and efficacy profile and multiple dosing and initiation options make it a treatment option for schizophrenia in inpatient and outpatient settings
Socioeconomic Disparities and Trends in the Utilization of Regional and Neuraxial Anesthesia for Pediatric Femur Fracture Repair
No full textPediatric femur fractures often necessitate surgical intervention, with pain management being critical for both immediate and long-term outcomes. Peripheral nerve blocks (PNBs) and neuraxial techniques are effective in providing targeted pain relief while minimizing systemic opioid exposure. Despite their benefits, the utilization of these anesthesia techniques in pediatric orthopedic surgeries is limited, particularly among socioeconomically disadvantaged patients. This study aims to evaluate the association between socioeconomic status (SES) and the use of regional and neuraxial anesthesia in pediatric femur fracture repairs, focusing on healthcare resource utilization (HRU) outcomes such as hospital length of stay (LOS), total hospital charges, and discharge disposition. Using the 2016–2020 NIS database, we identified 43,605 pediatric patients who underwent femur fracture repair. Only 1 % received PNB, and 0.1 % received spinal block (SB). Our analysis revealed that PNB was less likely to be administered to patients from lower SES backgrounds, those with subtrochanteric fractures, or those requiring delayed repair. Conversely, PNB was associated with reduced HRU, while SB was linked to increased HRU. The findings underscore significant disparities in the application of regional anesthesia, influenced by socioeconomic factors. Our study highlights the need for standardized guidelines and interventions to address these disparities, ensuring equitable access to effective pain management techniques in pediatric orthopedic care. Further research is warranted to understand the barriers to the utilization of PNB and to develop strategies to enhance its adoption, particularly among underserved populations
Cardiorenal Outcomes Associated With Sodium-Glucose Co-Transporter-2 Inhibitors in Chronic Kidney Disease Stage 5 (CKD V): A Propensity Score-Matched Analysis
No full textBackground: There remains a paucity of data regarding the cardio-renal benefits of sodium-glucose co-transporter-2 inhibitors (SGLT2i) in patients with chronic kidney disease stage 5 (CKD V) based on major clinical trials. Objective: This retrospective study aimed to identify potential cardiovascular and renal outcomes associated with SGLT2i use in CKD V patients. Methods: We queried the TriNetX Global collaborative network from Jan 2014 – Aug 2023 for patients ≥18 years diagnosed with CKD V but not on dialysis. Patients were stratified based on SGLT2i use. Propensity score matching for sociodemographics, comorbidities, and medication use resulted in 3465 patients in each cohort. The primary outcome was a composite of all-cause mortality, progression to end-stage renal disease (ESRD), or heart failure (HF). Secondary outcomes were ESRD, heart failure, all-cause mortality, acute myocardial infarction (AMI), ischemic stroke, cardiac arrest, hypertensive urgency, and hypertensive crisis. Cox proportional HRs were used to compare outcomes over a 5-year follow-up period. Results: The SGLT2i cohort was associated with a significantly lower risk of the primary composite outcome (HR 0.644; 95 % CI: 0.601–0.733, p \u3c 0.0001). SGLT2i use was also associated with lower risks of some secondary outcomes including all-cause mortality (HR 0.649; 0.587–0.717, p \u3c 0.0001), ESRD (HR 0.597; 0.547–0.652, p \u3c 0.0001), heart failure (HR 0.726; 0.625–0.844, p \u3c 0.0001), development of AMI (0.649; 0.542–0.776, p \u3c 0.0001), cardiac arrest (HR 0.595; 0.462–0.766, p \u3c 0.0001), hypertensive urgency (HR 0.578; 0.3451–0.740, p \u3c 0.0001), and hypertensive crisis (HR 0.603; 0.481–0.755, p \u3c 0.0001). Conclusion: Among CKD V patients, SGLT2i was associated with a significantly slowed progression of CKD to ESRD and reduced cardiac morbidity and mortality
Length of Post-Treatment Immobilization Following Medial Humeral Epicondyle Avulsion Fracture Predicts Return of Full Range of Motion
No full textBackground: Medial epicondyle fractures of the distal humerus are common pediatric fractures, which are increasing in frequency among pediatric and adolescent athletes. Residual elbow stiffness is a feared complication of both surgical and nonoperative treatment. The purpose of this study is to investigate the association of the relevant variables with the ability of patients to regain full elbow range of motion (ROM). Methods: Patients 8-18 years old enrolled in the Medial Epicondyle Multicenter Outcomes prospective cohort with ≥3 mm of displacement, and \u3e1 year of follow-up data were included. Bilateral elbow range of motion (ROM), complications, length of immobilization following definitive treatment (surgical vs. nonoperative), participation in formal physical or occupational therapy (PT/OT), and weeks from injury to treatment were recorded. Results: The study cohort consisted of 202 patients (aged 12.7 ± 2.3 years; 59% male). A greater proportion of surgically managed patients regained full ROM compared to nonoperatively managed patients (71% vs 56%, P = .05). Immobilization time was significantly shorter in surgical than in nonoperative patients (2.0 ± 1.1 weeks vs. 3.0 ± 1.2 weeks, P \u3c .001). In multivariable logistic regression analysis, only immobilization time was an independent predictor of regaining full ROM (β = −0.353, P = .02), which remained statistically significant while controlling for PT/OT (β = 0.079, P = .829) and treatment strategy (β = −0.375, P = .35). While controlling for treatment strategy and whether a patient received PT/OT, each week of prolonged immobilization decreased the chance of regaining full ROM by 35%. Conclusions: This large multicenter cohort study found that of the variables studied, increased immobilization time was the only independent predictor of residual elbow stiffness following medial epicondyle fractures in children, independent of treatment strategy and receiving PT/OT. With surgical treatment often warranting shorter post-treatment immobilization times, surgery may provide an avenue for consistently regaining full ROM when treating these fractures, especially in the setting of concomitant dislocation. In cases of minimally displaced fractures, implementing protected early ROM in nonoperative cases could be considered. However, when nonoperatively-treated patients in this study were analyzed separately, earlier mobilization was not associated with a protective effect against residual stiffness. Further prospective study into the nuances of surgical indications as well as nonoperative and postoperative immobilization and early motion strategies is therefore warranted
Serotonin Syndrome Associated With High-Dose Diphenhydramine Use Complicating Abdominoplasty and Mastopexy
No full textSerotonin syndrome is a condition associated with increased serotonergic transmission in the central nervous system. Although shortfalls with diagnostic criteria have led to misleading associations with multiple medications, a possible precipitant is diphenhydramine. Documentation of such an association would prove important for physician practice, as diphenhydramine remains one of the most popular antihistamines available. We present a case of a 43-year-old woman who developed serotonin syndrome after bilateral mastopexy, miniabdominoplasty, and liposuction. The patient was on multiple serotonergic medications, including duloxetine, asenapine, and trazodone, in addition to high-dose diphenhydramine. Postoperatively, she developed tachycardia, leukocytosis, respiratory distress, and elevated lactate, initially leading to concerns of sepsis; however, further evaluation revealed the likely diagnosis of serotonin syndrome, triggered by the combination of serotonergic agents and intraoperative fentanyl. Management included an intensive care unit admission with discontinuation of serotonergic medications, administration of benzodiazepines, intravenous fluids, and norepinephrine for shock. The patient\u27s condition improved for 36 hours, and she was discharged with adjustments to her psychiatric medications. This case contributes to the growing body of literature highlighting the risks of serotonin syndrome in patients on serotonergic polytherapy, particularly in the postoperative period. The interaction between our patient\u27s chronic diphenhydramine abuse and multiple other serotonergic medications likely precipitated this condition. Preoperative medication reconciliation, early recognition of triggers and signs, and prompt intervention are key to preventing adverse outcomes in serotonin syndrome