Theoretical Behavior Substitutions during the 24-Hour Day in Pregnancy and Infant Growth Outcomes.

PURPOSE: To assess associations of theoretically reallocating time from sleep, sedentary behavior, or light intensity physical activity (LPA) to moderate/vigorous intensity physical activity (MVPA) during pregnancy with infant growth outcomes. METHODS: We used data from a cohort of pregnant individuals with overweight or obesity (n = 116). At 9-15 and 30-36 weeks gestation, waking movement was measured using wrist-worn accelerometers and sleep duration was self-reported. Outcomes were obtained from delivery electronic health records (birth) and study visits (12 months). We used compositional isotemporal substitution models. RESULTS: In early pregnancy, reallocating 10 minutes of sleep, sedentary behavior, or LPA to MVPA was associated with 20% (RR = 0.80; 95%CI: 0.75,0.85), 21% (RR = 0.79; 95%CI: 0.75,0.84), and 25% (RR = 0.75; 95%CI: 0.70,0.81) lower risk of large-for-gestational age (LGA) birthweight, respectively, and 17% (RR = 0.83; 95%CI: 0.75,0.91), 18% (RR = 0.82; 95%CI: 0.75,0.91), and 22% (RR = 0.78; 95%CI: 0.70,0.88) lower risk of rapid infant growth (birth to 12 months), respectively. In late pregnancy, reallocating 10 minutes to MVPA was associated with 18% to 22% lower risk of LGA birthweight, but was not associated with rapid infant growth. Reallocating time to MVPA in early or late pregnancy was not associated with high newborn body fat percent. CONCLUSIONS: Our findings suggest beneficial associations of theoretically reallocating time from sleep, sedentary behavior, or LPA to MVPA, especially during early pregnancy, for reducing LGA birthweight and rapid infant growth.

2023 American Academy of Orthopaedic Surgeons Management of Osteoarthritis of the Hip Evidence-Based Clinical Practice Guideline: Case Studies.

The American Academy of Orthopaedic Surgeons, together with The Hip Society, American Association of Hip and Knee Surgeons, American College of Radiology, and American Physical Therapy Association, recently released the updated 2023 Management of Osteoarthritis of the Hip Evidence-Based Clinical Practice Guidelines. 8 recommendations and 9 options comprise these guidelines intended to optimize treatment outcomes in a patient population that is growing exponentially over time. In this article, we present case studies that illustrate utilization of the clinical practice guideline workgroup's evidence-based recommendations in clinical practice.

Increasing intracellular dNTP levels improves prime editing efficiency.

In primary cell types, intracellular deoxynucleotide triphosphate (dNTP) levels are tightly regulated in a cell cycle-dependent manner. We report that prime editing efficiency is increased by mutations that improve the enzymatic properties of Moloney murine leukemia virus reverse transcriptase and treatments that increase intracellular dNTP levels. In combination, these modifications produce substantial increases in precise editing rates.

Multimodal Analgesia and Small Opioid Prescriptions are the New Standard in Total Joint Arthroplasty: A Survey of the AAHKS Membership.

INTRODUCTION: The purpose of this survey study was to assess the current analgesia and anesthesia practices used by total joint arthroplasty (TJA) surgeon members of the American Association of Hip and Knee Surgeons (AAHKS) as well as identify changes in practice made by AAHKS members over time. METHODS: A survey of 37 questions was created and approved by the AAHKS Research Committee. The survey was distributed to all 3,243 practicing adult reconstruction surgeon members of AAHKS in May 2023. Results were compared to a nearly identical survey sent out to all board-certified adult reconstruction surgeon members of AAHKS five years previously in November 2018. RESULTS: There were 527 responses (16%) to the survey. Since 2018, the mean number of opioid pills prescribed after TJA has declined significantly from 49 to 32 pills after TKA and from 44 to 18 pills after THA. The use of multimodal analgesics in addition to opioids has also increased over the past five years from 74 to 93%. The most common medications utilized include nonsteroidal anti-inflammatories (98%), acetaminophen (80%), and gabapentinoids (32%). A majority of surgeons (78%) still use a spinal for total knee arthroplasty (TKA) and total hip arthroplasty (THA). However, there has been an increase in the number of surgeons using peripheral nerve blocks for TKA from 69% in 2018 to 84% in 2023. The routine use of periarticular injection or local infiltration anesthesia in THA and TKA has also increased over the past 5 years from 80 to 86%. CONCLUSION: Since 2018, there has been increased adoption of multimodal analgesia and anesthesia, and improved consensus regarding the optimal regimen among surveyed arthroplasty surgeon members of AAHKS. The number of opioid pills prescribed after THA and TKA has declined significantly over the past 5 years.

Selective Enhancer Gain of Function Deregulates MYC Expression in Multiple Myeloma.

MYC deregulation occurs in the majority of multiple myeloma (MM) cases and is associated with progression and worse prognosis. Enhanced MYC expression occurs in about 70% of MM patients, but it is known to be driven by translocation or amplification events in only ~40% of myelomas. Here, we used CRISPR interference (CRISPRi) to uncover an epigenetic mechanism of MYC regulation whereby increased accessibility of a plasma cell-type specific enhancer leads to increased MYC expression. This native enhancer activity was not associated with enhancer hijacking events but led to specific binding of c-MAF, IRF4, and SPIB transcription factors that activated MYC expression in the absence of known genetic aberrations. In addition, focal amplification was another mechanism of activation of this enhancer in approximately 3.4% of MM patients. Together, these findings define an epigenetic mechanism of MYC deregulation in MM beyond known translocations or amplifications and point to the importance of non-coding regulatory elements and their associated transcription factor networks as drivers of MM progression.

Carboplatin and Paclitaxel Chemoradiation for Localized Anal Cancer in Patients Not Eligible for Mitomycin and 5-Fluorouracil.

BACKGROUND: Although squamous cell carcinoma of the anus (SCCA) is a relatively uncommon malignancy in the United States, it continues to increase in incidence. Treatment for locoregional disease includes mitomycin and 5-fluorouracil with radiation. This combination is associated with significant toxicity, limiting its use in patients who are older or have certain comorbidities. Carboplatin and paclitaxel (C/P) is an accepted treatment regimen for metastatic SCCA. We aim to evaluate the efficacy and toxicity of weekly C/P given with radiation for patients unable to receive standard chemoradiation for SCCA. METHODS: From our cancer registry, adult patients who received weekly intravenous C/P concurrent with standard-dose radiation for localized SCCA were included in this study. Clinical response was determined based on the evidence of disease on imaging and/or anoscopy. Toxicities were graded according to the CTCAE v5. RESULTS: Ten patients were included; eight were female, and the median age was 75.5 years (54-87). Six had T2 disease, and four had T3 tumors. Four had node-positive disease. The majority (70%) of patients were dosed at standard C (AUC 2) and P (50 mg/m2), with a limited subset requiring dose reduction for baseline performance status. Patients completed a mean of 78.3% (40-100%) of the intended treatments. A total of 89% of the patients achieved a complete clinical response. With a median follow-up of 25.8 months (3.4-50.4 months), 67% of the patients are alive and without recurrence. Two patients have had local recurrence, and one patient had metastatic progression. The most common toxicities of any grade included leukopenia (100%), anemia (100%), radiation dermatitis (100%), diarrhea (100%), and fatigue (100%). Grade 3 or higher toxicities included neutropenic fever (20%), neutropenia (30%), and anemia (30%). CONCLUSIONS: This study demonstrates promising tolerability and efficacy for weekly C/P chemoradiation for patients with anal cancer unable to receive mitomycin and 5-fluorouracil. This regimen merits further investigation in prospective clinical trials.

Alveolin proteins in the Toxoplasma inner membrane complex form a highly interconnected structure that maintains parasite shape and replication.

Apicomplexan parasites possess several specialized structures to invade their host cells and replicate successfully. One of these is the inner membrane complex (IMC), a peripheral membrane-cytoskeletal system underneath the plasma membrane. It is composed of a series of flattened, membrane-bound vesicles and a cytoskeletal subpellicular network (SPN) comprised of intermediate filament-like proteins called alveolins. While the alveolin proteins are conserved throughout the Apicomplexa and the broader Alveolata, their precise functions and interactions remain poorly understood. Here, we describe the function of one of these alveolin proteins in Toxoplasma, IMC6. Disruption of IMC6 resulted in striking morphological defects that led to aberrant invasion and replication but surprisingly minor effects on motility. Deletion analyses revealed that the alveolin domain alone is largely sufficient to restore localization and partially sufficient for function. As this highlights the importance of the IMC6 alveolin domain, we implemented unnatural amino acid photoreactive crosslinking to the alveolin domain and identified multiple binding interfaces between IMC6 and 2 other cytoskeletal IMC proteins-IMC3 and ILP1. This provides direct evidence of protein-protein interactions in the alveolin domain and supports the long-held hypothesis that the alveolin domain is responsible for filament formation. Collectively, our study features the conserved alveolin proteins as critical components that maintain the parasite's structural integrity and highlights the alveolin domain as a key mediator of SPN architecture.

Equity in the Early Pain Management of Long Bone Fractures in Black vs White Patients: We Have Closed the Gap.

Introduction: Patients with long bone fractures often present to the emergency department (ED) with severe pain and are typically treated with opioid and non-opioid analgesics. Historical data reveals racial disparities in analgesic administration, with White patients more likely to receive analgesics. With the diversifying US population, health equity is increasingly crucial. In this study we aimed to evaluate the early administration of opioid and non-opioid analgesia among Black and White patients with long bone and femur fractures in EDs over different time frames using a substantial database. Methods: We retrospectively extracted Information from 57 US healthcare organizations within the TriNetX database, encompassing 95 million patients. The ED records from 2003-2023 were subjected to propensity score matching for age and gender. We focused on four cohorts: two comprising Black and White patients diagnosed with long bone fractures, and another two with Black and White patients diagnosed solely with femur fractures. We examined analgesic administration rates over 20 years (2003-2023) at five-year intervals (2003-2008; 2008-2013; 2013-2018; 2018-2023), and further analyzed the rates for the most recent two-year period (2021-2023). Results: Disparities in analgesic administration significantly diminished over the study period. For patients with long bone fractures (1,095,052), the opioid administration gap narrowed from 6.3% to 1.1%, while non-opioid administration disparities reduced from 4.4% to 0.3%. Similar trends were noted for femur fractures (265,181). By 2021-2023, no significant differences in analgesic administration were observed between racial groups. Conclusion: Over the past 20 years, the gap in early administration of opioid and non-opioid analgesics for Black and White patients presenting with long bone fractures or femur fractures has been disappearing.

Antibiotic Treatment Practices and Microbial Profile in Diabetic Foot Ulcers: A Retrospective Cohort Study.

Aim and objective Diabetic foot ulcers (DFUs) are a frequent complication of diabetes mellitus, impacting more than one in 10 diabetic patients, with roughly half of these ulcers progressing to infection. Existing literature indicates that these infections are predominantly polymicrobial, with gram-positive isolates being the most common. This microbial profile informs the empiric antibiotic strategies employed in first-world countries, often including highly potent nephrotoxic antibiotics. This retrospective cohort study aims to assess the microbial profile and antibiotic treatment practices in patients with infected DFUs at Ochsner LSU Health Shreveport Academic Medical Center in Shreveport, Louisiana, United States. Materials and methods A total of 115 patients diagnosed with infected DFUs were included in the study. Patient records were reviewed to identify bacterial pathogens cultured from foot wounds, antibiotic treatment regimens administered, and the prevalence of acute kidney injury (AKI). Results The study found a predominance of gram-negative isolates (199; 59.4%), facultative anaerobes (246; 73.4%), and polymicrobial infections (67; 78.8%) in infected DFUs. Vancomycin was administered to 95 patients (82.6%), with only a small number subsequently testing positive for methicillin-resistant Staphylococcus aureus (MRSA). Combination therapy with vancomycin and Zosyn was given to 71 patients (61.7%), which increased the potential risk of antibiotic-induced nephrotoxicity. AKI was prevalent, affecting 58 patients (50.4%). Conclusions This study highlights a discrepancy between the microbial profile of infected DFUs and empiric antibiotic treatment practices at Ochsner LSU Health Shreveport Academic Medical Center. The predominance of gram-negative bacteria underscores the need for a polymicrobial, gram-negative-focused empiric treatment approach. Alternative antibiotics with broad-spectrum coverage and minimal nephrotoxicity, such as ceftriaxone, clindamycin, metronidazole, amoxicillin-clavulanate, and linezolid, should be considered. Tailored antibiotic strategies, guided by local microbial profiles and patient-specific factors, are essential to optimize treatment outcomes in this high-risk population.

A Dose-Finding, Biomarker Validation, and Effectiveness Study of Transcranial Magnetic Stimulation for Adolescents With Depression.

OBJECTIVE: Research and clinical application of transcranial magnetic stimulation (TMS) for adolescents with major depressive disorder (MDD) has advanced slowly. Significant gaps persist in our understanding of optimized, age-specific protocols and dosing strategies. This study aimed to compare the clinical effects of 1 Hz versus 10 Hz TMS regimens and examine a biomarker-informed treatment approach with glutamatergic intracortical facilitation (ICF). METHOD: Participants with moderate-to-severe symptoms of MDD were randomized to 30 sessions of left prefrontal 1 Hz or 10 Hz TMS, stratified by baseline ICF measures. The primary clinical outcome measure was the Children's Depression Rating Scale, Revised (CDRS-R). The CDRS-R and ICF biomarker were collected weekly. RESULTS: Forty-one participants received either 1 Hz (n = 22) or 10 Hz (n = 19) TMS treatments. CDRS-R scores improved compared to baseline in both 1 Hz and 10 Hz groups. For participants with low ICF at baseline, the overall least squares means of CDRS-R scores over the 6-week trial showed that depressive symptom severity was lower for the group treated with 1 Hz TMS than for those who received 10 Hz TMS. There were no significant changes in weekly ICF measurements across the 6 weeks of TMS treatment. CONCLUSION: Low ICF may reflect optimal glutamatergic N-methyl-d-aspartate (NMDA) receptor activity that facilitates the therapeutic effect of 1 Hz TMS through long-term depression-like mechanisms on synaptic plasticity. The stability of ICF suggests that it is a tonic, trait-like measure of NMDA receptor-mediated neurotransmission, with potential utility to inform parameter selection for therapeutic TMS in adolescents with MDD.

Efficacy and Safety of Alpha-2 Agonists in Autism Spectrum Disorder: A Systematic Review.

BACKGROUND: This analysis is a systematic literature review assessing efficacy and adverse effects of three alpha-2 agonists for the symptomatic management of autism spectrum disorder (ASD). METHODS: The present investigation involved an extensive systematic search for eligible studies in PubMed, Embase, Cochrane Library, and Google Scholar. Nine studies, collectively incorporating 226 patients, were assessed. RESULTS: The results demonstrated promising indications for use of alpha-2 agonists in the symptomatic management of autism spectrum disorders, including improvement of hyperactivity, impulsivity, attention deficit symptoms, irritability, and stereotypies in many of the participants studied. CONCLUSION: The present investigation encourages physicians to consider treatment outcomes of clonidine, guanfacine, and lofexidine to determine the most effective management of ASD-related symptoms and to minimize adverse effects. However, our review cannot provide definitive treatment protocols related to various study limitations.

Perioperative Systemic Corticosteroids in Modern Total Hip and Knee Arthroplasty: A Primer for Clinical Practice.

¼ Perioperative corticosteroids are strongly recommended for reducing the incidence and severity of postoperative nausea and vomiting following elective total hip or total knee arthroplasty.¼ Corticosteroids may reduce postoperative pain and opioid requirements. Similarly, corticosteroids appear to have a neutral-to-positive effect on length of stay, venous thromboembolism, mobility, delirium, acute kidney injury, and bone cement implantation syndrome (i.e., decreased length of stay).¼ Perioperative corticosteroids may induce hyperglycemia among both diabetic and nondiabetic patients; however, there is no strong evidence indicating that these transient corticosteroid-induced glycemic derangements may increase the risk of postoperative infectious complications.¼ The dosage and frequency of perioperative corticosteroid administration play a critical role in optimizing postoperative outcomes, with higher doses showing promise in reducing opioid consumption, postoperative pain, and length of stay.¼ The optimal dosage and frequency of corticosteroids remain unclear; however, the perioperative administration of 8 to 16 mg dexamethasone, or equivalent steroid, appears reasonable and safe in most cases.

Function, cognition, and quality of life among older adults with lung cancer who live alone: A prospective cohort study.

INTRODUCTION: Among older adults without cancer, living alone is associated with poor health outcomes. However, among older adults with non-small cell lung cancer (NSCLC) who live alone, data on function, cognition, and quality of life (QOL) during systemic treatment remain limited. MATERIALS AND METHODS: We enrolled adults aged ≥65 with advanced NSCLC starting a new chemotherapy, immunotherapy, and/or targeted therapy regimen with non-curative intent. Patients completed geriatric assessments including instrumental activities of daily living (IADL), Montreal Cognitive Assessment, and QOL pretreatment and at 1, 2, 4, and 6 months, or until treatment discontinuation, whichever occurred earlier. We categorized change in IADL, cognition, and QOL as stable/improved, declined with recovery, or declined without recovery using clinically meaningful definitions of change. We used multinomial logistic regression to compare change between patients who lived alone versus with others. RESULTS: Among 149 patients, median age was 73; 21% lived alone. Pretreatment IADL, cognition, and QOL scores were similar between older adults who lived alone versus with others. During NSCLC treatment, older adults who lived alone had similar trajectories of function (52% functional decline vs 38%), cognition (43% cognitive decline vs 50%), and QOL (45% QOL decline vs 44%) compared with those who lived with others. In unadjusted analyses, patients who lived alone were more likely to develop functional decline with recovery (reference category: stable/improved function) than those who lived with others (relative risk ratio 4.07, 95% CI 1.14-14.6, p = 0.03). However, this association was not observed after adjusting for age, race, prior NSCLC treatment, current treatment group, and pretreatment geriatric assessment differences. There were no differences in cognitive or QOL trajectories in unadjusted or adjusted analyses. DISCUSSION: Approximately half of older adults with advanced NSCLC who lived alone were able to maintain their function, cognition, and QOL during NSCLC treatment, which was similar to older adults who lived with others. Many older adults with advanced NSCLC who live alone can receive systemic treatment with individualized supportive care.

Gender differences in the association between education and late-life cognitive function in the LifeAfter90 Study: A multiethnic cohort of the oldest-old.

INTRODUCTION: Few studies have examined the relationship between education and cognition among the oldest-old. METHODS: Cognitive assessments were conducted biannually for 803 participants (62.6% women) of LifeAfter90, a longitudinal study of individuals ≥ 90 years old. Gender differences in associations between education (< high school, high school, some college, and ≥ college) and cognition (verbal episodic memory, semantic memory, and executive function) were examined at baseline and longitudinally using linear mixed models. RESULTS: Higher education levels were associated with better cognitive performance at baseline for both men and women. College completion was more strongly associated with better baseline executive function among women. Education-cognition associations for baseline verbal episodic memory and baseline semantic memory did not differ by gender. Education was not associated with a decline in any domain-specific cognitive scores, regardless of gender. DISCUSSION: Education is associated with cognitive function among the oldest-old and varies by gender and cognitive domain at baseline but not over time. HIGHLIGHTS: In the oldest-old, higher education was associated with better cognitive function. College completion was more strongly associated with executive function in women. Education was not associated with cognitive decline after age 90 regardless of gender. Improving education could decrease gaps in cognitive level among older individuals.

Reduction of bioburden on large area surfaces through use of a supplemental residual antimicrobial paint.

Paint is a versatile material that can be used to coat surfaces for which routine disinfection practices may be lacking. EPA-registered copper-containing supplemental residual antimicrobial paints could be used to reduce the bioburden on often-neglected surfaces. An interventional study was conducted by painting the walls of a preschool restroom and metal locker surfaces in two hospital locker rooms with a copper-containing antimicrobial paint to evaluate the potential for bioburden reduction compared to a non-copper-containing control paint. The antimicrobial paint reduced the bioburden on the preschool restroom walls by 57% and on lockers in one locker room by 63% compared to the control paint; no significant difference was observed between the two paint types in the second locker room. The upper quartile bacterial counts, which drive the overall risk by increasing exposure to pathogens, also exhibited 63% and 47% reductions for the antimicrobial paint compared to the control paint in the preschool restroom and the first locker room, respectively. Because detectible levels of bioburden are found on large-area surfaces such as walls and lockers, surfaces painted with copper-containing paints may make large-area surfaces that are prone to contamination safer in a way that is practical and economical.

Why Are Contemporary Primary Ceramic-on-Highly Crosslinked Polyethylene Total Hip Arthroplasties Failing? An Analysis of Over 5,500 Cases.

INTRODUCTION: Ceramic-on-highly crosslinked polyethylene (HXLPE) has become the most common bearing surface utilized in primary total hip arthroplasty (THA). The purpose of this study was to determine the implant survivorship and clinical outcomes of THAs with ceramic-on-HXLPE in a large, single institutional, series. METHODS: We identified 5,536 primary THAs performed from 2007 to 2017 using a ceramic-on-HXLPE bearing through our total joint registry. The mean age was 60 years, 51% were women, and the mean body mass index (BMI) was 30. A cementless femoral component was used in 98% of cases, and a head size of ≥ 36 was used in 75%. Kaplan-Meier survivorship analyses were completed to assess survivorship free of any revision or reoperation. Clinical outcomes were assessed via Harris Hip Scores (HHS). The mean follow-up was 4 years. RESULTS: The 5-year survivorship free of any revision was 97%. The most common indications for revision were dislocation (41 hips), periprosthetic joint infection (PJI) (39 hips), and periprosthetic femur fracture (18 hips). The 5-year survivorship free of any reoperation was 96%. There were an additional 70 reoperations, with the most common indications being wound dehiscence (32 hips), iliopsoas impingement (11 hips), and periprosthetic femur fracture (11 hips). There were only two bearing surface failures: one HXLPE liner fractured and one dissociated. There were no ceramic head fractures or failures. The mean HHS increased from 57 to 92 (P < 0.0001). CONCLUSION: In over 5,500 THAs completed with modern ceramic-on-HXLPE bearings, failures of the bearing surface were nearly eliminated at midterm follow-up, and overall 5-year survivorship free of revision was excellent. Dislocation, PJI, and periprosthetic femur fracture were the most common causes of failure. As bearing surfaces have evolved, traditional failure mechanisms such as polyethylene wear, corrosion and metal reactions, and ceramic fractures have become nearly extinct.

Safety and factors associated with early discharge in revisional laparoscopic Roux-en-Y gastric bypass: analysis of the MBSAQIP database.

BACKGROUND: Improvements in bariatric surgery outcomes have prompted policy initiatives that explore shifting bariatric surgery toward outpatient procedures. While the safety of early discharge after primary laparoscopic Roux-en-Y gastric bypass (LRYGB) has been reported, its safety for revisional LRYGB remains uncertain. Our study aimed to investigate the safety and patient factors associated with early discharge in patients undergoing revisional LRYGB compared with primary LRYGB. METHODS: We identified adult patients who underwent primary and revisional LRYGB from 2020 to 2022 in the MBSAQIP database. Patients discharged early, i.e., same-day discharge (SDD) and next-day discharge (NDD) were compared to inpatients. Outcomes included 30-day complications (minor = Clavien-Dindo 1-2; major = Clavien-Dindo 3-4), mortality, readmissions, and reoperations. Multivariable logistic regression models adjusting for patient demographics, comorbidities, and operative time were fitted to assess the study outcomes. RESULTS: SDD rate was similar after primary (3,422/137,406; 2.5%) and revisional LRYGB (781/32,721; 2.4%), while NDD rate was higher in primary LRYGB (59.8% vs 54.7%, respectively; p < 0.001). SDD patients had lower odds of major complications compared to inpatients following primary (2% vs 7%, aOR: 0.30, 95%CI 0.24-0.38) and revisional LRYGB (3.7% vs 9.3%, aOR: 0.43, 95%CI 0.29-0.62, respectively). NDD patients had similarly lower odds of morbidity outcomes. ASA Classification IV/V was associated with lower odds of SDD compared to Class I/II (Primary: 0.9% vs. 3%, aOR: 0.61, 95% CI 0.48-0.78; Revisions: 0.9% vs. 3%, aOR: 0.24, 95%CI 0.10-0.55). CONCLUSION: Early discharge after revisional LRYGB, particularly after an overnight stay, can be accomplished safely in carefully selected patients. However, SDD rates remain low limiting its safety assessment. Further, almost half of the patients stay more than 48 h in the hospital suggesting that policy initiatives toward outpatient management after bariatric surgery may be inappropriate for this patient population.

Gabapentinoids increase the potency of fentanyl and heroin and decrease the potency of naloxone to antagonize fentanyl and heroin in rats discriminating fentanyl.

Despite a significant decrease in the number of prescriptions for opioids, the opioid crisis continues, fueled in large part by the availability of the phenylpiperadine mu opioid receptor (MOR) agonist fentanyl. In contrast, the number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically with gabapentinoids commonly detected in opioid overdose victims. Although gabapentinoids can decrease the potency of the opioid receptor antagonist naloxone to reverse heroin-induced hypoventilation in male rats, the specificity and nature of interaction between gabapentinoids and MOR agonists and any potential sex difference in those interactions are not well characterized. Gabapentinoids were studied in female and male rats discriminating fentanyl (0.0032 mg/kg, i.p.) or cocaine (3.2 mg/kg, i.p.). Alone, neither gabapentin nor pregabalin significantly increased fentanyl- or cocaine-appropriate responding. In rats discriminating fentanyl, each gabapentinoid dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the left whereas naloxone dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the right. Each gabapentinoid (100 mg/kg) significantly decreased the potency of naloxone to antagonize the discriminative stimulus effect of fentanyl or heroin. In contrast, each gabapentinoid dose-dependently shifted the cocaine discrimination dose-effect function to the right. There were no significant sex differences in this study. These results suggest that gabapentinoids impact the misuse of opioids, the co-use of opioids and stimulant drugs, and the increasing number of overdose deaths in individuals using opioids, stimulant drugs, and gabapentinoids in mixtures. Significance Statement The number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically with gabapentinoids commonly detected in opioid overdose victims. This study reports that in rats gabapentinoids increase the potency of fentanyl and heroin to produce discriminative stimulus effects while decreasing the potency of naloxone to antagonize those effects of fentanyl and heroin. These results can help guide policies for regulating gabapentinoids and treating opioid misuse and overdose.

Melatonin: Evolving Physiological Understanding and Potential Therapeutic Role in Pain Medicine Including Intervertebral Disc Degeneration.

BACKGROUND: Melatonin, one of the most versatile hormones in the body, is well appreciated in managing circadian rhythm and for antioxidant properties. Produced in the pineal gland and within mitochondria, melatonin influences many physiologic processes through receptor mediated and direct effects. OBJECTIVE: The present investigation explores the evolving pharmacologic properties of melatonin, as well as current therapeutic uses in areas where mitigating oxidative stress, inflammation, and cellular senescence. This review also delves into novel therapeutic potential of melatonin and how current research is revealing a wide array of therapeutic promise in pain medicine. STUDY DESIGN: A systematic review of randomized controlled trials (RCTs) and observational studies was performed using various search engines focused on melatonin and its role in pain medicine. METHODS: The available literature on melatonin and pain medicine was reviewed. A comprehensive literature search of multiple databases from 1966 to July 2024, including manual searches of the bibliography of known review articles was performed. Quality assessment of the included studies and best evidence synthesis were incorporated into qualitative and quantitative evidence synthesis. OUTCOME MEASURES: The primary outcome measure was the proportion of patients receiving melatonin with significant relief and functional improvement of greater than 50% of at least 3 months. Duration of relief was categorized as short-term (less than 6 months) and long-term (greater than 6 months). RESULTS: Melatonin can affect intervertebral disc (IVD) health through the enhancement of survival and function of nucleus pulposus cells, primarily through activation of the ERK1/2 signaling pathway. Melatonin also influences the biochemical environment of the IVD by modulating inflammation and oxidative stress, crucial factors in the pathogenesis of disc degeneration. Melatonin has been shown to reduce senescence and promote autophagy within disc cells, vital for clearing out damaged cellular components, preserving cellular function and preventing deterioration associated with aging and degenerative diseases. LIMITATIONS: Despite the availability of multiple studies, the paucity of clinical pain related literature is considered as the major drawback. CONCLUSION: Based on the present systematic review, melatonin plays a critical role in sleep, but evolving studies have demonstrated substantive roles in mitigating degenerative conditions in various tissues, including IVD degeneration. Ongoing studies will better clarify the role of melatonin as a potential therapeutic agent, including the targeted delivery to various body regions.

Posterior Sacroiliac Fusion Surgery: A Retrospective Single Center Study.

BACKGROUND: Chronic sacroiliitis has variable etiologies with numerous treatments of varying efficacy. In recent years, a novel posterior approach utilizing bone matrix has been developed although to date, there is limited data in the literature regarding efficacy and safety through this approach. Benefits described include reduced adverse outcomes and quicker recovery when compared to the lateral approach. OBJECTIVE: The present investigation focused on sacroiliac joint fusion through the posterior approach and outcomes including disability, pain, and use of analgesics post-surgery. STUDY DESIGN: This retrospective, single-center study was conducted evaluating safety and efficacy of sacroiliac fusion allograft implants (LinQ Implant System from PainTEQ; PsiF System from Omnia Medical). METHODS: A total of 72 posterior approach sacroiliac joint fusions were performed. Fifty-three individuals were enrolled and followed at LSU Health Shreveport as the sole investigational site between August 2020 and June 2024. Selected participant age ranged between 28 and 79 years, with a mean age of 53.4 years. The LinQ Implant System was the primary surgical hardware selected for implantation (83.0%), with the PsiF System chosen in the remaining cases. OUTCOME MEASURES: VAS Scores, disability changes, adverse outcomes, and analgesic use were compared after sacroiliac joint fusion via the posterior approach. RESULTS: Mean VAS Scores for SIJ Pain Intensity significantly decreased by 3.6 cm from a baseline score of 9.5 cm by the Specified End (June 1st, 2024). In this regard, 65.4% of patients experienced a 20% or greater improvement in pain, 38.5% of patients experienced a 50% or greater improvement in pain, and 26.9% of patients experienced a 70% or greater improvement in pain.  Zero (0) procedure-related adverse events nor intra- or post-operative complications occurred throughout the duration of the investigation. LIMITATIONS: Retrospective nature of the study without a control group. Fifty-four percent (39 of 72) completed minimum one year follow up. Further, the withdrawal rate was 26%. CONCLUSION: The results of the present investigation demonstrated effective outcomes with minimal adverse effects and improvements in disability over a three-year period in the largest single center study to date involving posterior approach sacroiliac joint fusion.