Fact vs. fiction: naloxone in the treatment of opioid-induced respiratory depression in the current era of synthetic opioids.

Opioid-induced respiratory depression (OIRD) deaths are ~80,000 a year in the US and are a major public health issue. Approximately 90% of fatal opioid-related deaths are due to synthetic opioids such as fentanyl, most of which is illicitly manufactured and distributed either on its own or as an adulterant to other drugs of abuse such as cocaine or methamphetamine. Other potent opioids such as nitazenes are also increasingly present in the illicit drug supply, and xylazine, a veterinary tranquilizer, is a prevalent additive to opioids and other drugs of abuse. Naloxone is the main treatment used to reverse OIRD and is available as nasal sprays, prefilled naloxone injection devices, and generic naloxone for injection. An overdose needs to be treated as soon as possible to avoid death, and synthetic opioids such as fentanyl are up to 50 times more potent than heroin, so the availability of new, higher-dose, 5-mg prefilled injection or 8-mg intranasal spray naloxone preparations are important additions for emergency treatment of OIRDs, especially by lay people in the community. Higher naloxone doses are expected to reverse a synthetic overdose more rapidly and the current formulations are ideal for use by untrained lay people in the community. There are potential concerns about severe withdrawal symptoms, or pulmonary edema from treatment with high-dose naloxone. However, from the perspective of first responders, the balance of risks would point to administration of naloxone at the dose required to combat the overdose where the risk of death is very high. The presence of xylazines as an adulterant complicates the treatment of OIRDs, as naloxone is probably ineffective, although it will reverse the respiratory depression due to the opioid. For these patients, hospitalization is particularly vital. Education about the benefits of naloxone remains important not only in informing people about how to treat emergency OIRDs but also how to obtain naloxone. A call to emergency services is also essential after administering naloxone because, although the patient may revive, they may overdose again later because of the short half-life of naloxone and the long-lasting potency of fentanyl and its analogs.

Patient-centric Comparability Assessment of Biopharmaceuticals.

The comparability assessment of a biological product after implementing a manufacturing process change should involve a risk-based approach. Process changes may occur at any stage of the product lifecycle: early development, clinical manufacture for pivotal trials, or post-approval. The risk of the change to impact product quality varies. The design of the comparability assessment should be adapted accordingly. A working group reviewed and consolidated industry approaches to assess comparability of traditional protein-based biological products during clinical development and post-approval. The insights compiled in this review article encompass topics such as a risk-evaluation strategy, the design of comparability studies, definition of assessment criteria for comparability, holistic evaluation of data, and the regulatory submission strategy. These practices can be leveraged across the industry to help companies in design and execution of comparability assessments, and to inform discussions with global regulators.

Outcomes of whole-body photobiomodulation on pain, quality of life, leisure physical activity, pain catastrophizing, kinesiophobia, and self-efficacy: a prospective randomized triple-blinded clinical trial with 6 months of follow-up.

Background: The management of fibromyalgia (FM) symptoms on a global scale remains a complex endeavor. This study endeavors to assess the impact of whole-body photobiomodulation (PBM) compared to placebo PBM on pain, functionality, and psychological symptoms in individuals afflicted with fibromyalgia. Objectives: The primary objectives of this research were to conduct a comparative analysis of the effects of whole-body photobiomodulation (PBM) and placebo PBM on pain, functionality, and psychological symptoms in patients suffering from fibromyalgia (FM). Methods: A total of 42 subjects were recruited from a private care practice for participation in this triple-blinded, placebo-controlled, randomized clinical trial. Participants underwent 12 treatment sessions, and assessments were conducted at various intervals, including baseline (T0), midway through the 12-session treatment (T1), at the completion of the 12 sessions (T2), and follow-ups at 2 weeks (T3), 3 months (T4), and 6 months (T5). Results: Statistical analysis revealed significant reductions in pain at T2, T3, and T5. Additionally, quality of life exhibited marked improvements after sessions at T1, T2, T3, T4, and T5. Leisure activity also demonstrated statistically significant improvements at T2, T3, T4, and T5. Furthermore, kinesiophobia showed significant differences between groups immediately after treatment at T2, T3, T4, and T5. Self-efficacy, when compared between groups, demonstrated significant differences at T3, T4, and T5 (two weeks after treatment). Lastly, pain catastrophizing exhibited significant differences only at T5. Conclusion: The findings of this study indicate that whole-body PBM treatment for 4 weeks resulted in significant pain reduction and improved quality of life in individuals suffering from FM. Furthermore, kinesiophobia and self-efficacy demonstrated improvements in both short-term and long-term assessments, while pain catastrophizing showed improvement at the 6-month follow-up. Consequently, whole-body PBM emerges as a promising multifactorial treatment option for FM patients, though further studies are required to validate and strengthen these results.Clinical Trial Registration:Clinicaltrials.gov, NCT0424897.

Perforated peptic ulcer disease in transferred patients is associated with significant increase in length of stay.

BACKGROUND: Perforated peptic ulcer disease (PPUD) has a prevalence of 0.004-0.014% with mortality of 23.5% (Tarasconi et al. in World J Emerg Surg 15(PG-3):3, 2020). In this single center study, we examined the impact associated with patient transfer from outside facilities to our center for definitive surgical intervention (exploratory laparotomy). METHODS: Using EPIC report workbench, we identified 27 patients between 2018 and 2021 undergoing exploratory laparotomy with a concurrent diagnosis of peptic ulcer disease, nine of which were transferred to our institution for care. We queried this population for markers of disease severity including mortality, length of stay, intensive care unit (ICU) length of stay, and readmission rates. Manual chart reviews were performed to examine these outcomes in more detail and identify patients who had been transferred to our facility for surgery from an outside hospital. RESULTS: A total of 27 patients were identified undergoing exploratory laparotomy for definitive treatment of PPUD. The majority of patients queried underwent level A operations, the most urgent level of activation. In our institution, a Level A operation needs to go to the operating room within one hour of arrival to the hospital. Average mortality for this patient population was 14.8%. The readmission rate was 40.1%, and average length of ICU stay post-operatively was 16 days, with 83% of non-transfer patients requiring ICU admission and 100% of transfer patients requiring ICU admission, although this was not found to be statistically significant. Average length of hospital stay was 27 days overall. For non-transfer patients and transfer patients, LOS was 20 days and 41 days, respectively, which was statistically significant by one-sided t-test (p = 0.05). CONCLUSION: Patients transferred for definitive care of PPUD in a population otherwise notable for high mortality and high readmission rates: their average length of stay compared to non-transfer patients was over twice the length, which was statistically significant. Transferred patients also had higher rates of ICU care requirement although this was not statistically significant. Further inquiry to identify modifiable variables to facilitate the care of transferred patients is warranted, especially in the context of improving quality metrics known to enhance patient outcomes, satisfaction, and value.

CD11c is not required by microglia to convey neuroprotection after prion infection.

Prion diseases are caused by the misfolding of a normal host protein that leads to gliosis, neuroinflammation, neurodegeneration, and death. Microglia have been shown to be critical for neuroprotection during prion infection of the central nervous system (CNS), and their presence extends survival in mice. How microglia impart these benefits to the infected host are unknown. Previous transcriptomics and bioinformatics studies suggested that signaling through the heterodimeric integrin receptor CD11c/CD18, expressed by microglia in the brain, might be important to microglial function during prion disease. Herein, we intracerebrally challenged CD11c-/- mice with prion strain RML and compared them to similarly infected C57BL/6 mice as controls. We initially assessed changes in the brain that are associated with disease such as astrogliosis, microgliosis, prion accumulation, and survival. Targeted qRT-PCR arrays were used to determine alterations in transcription in mice in response to prion infection. We demonstrate that expression of Itgax (CD11c) and Itgb2 (CD18) increases in the CNS in correlation with advancing prion infection. Gliosis, neuropathology, prion deposition, and disease progression in prion infected CD11c deficient mice were comparable to infected C57BL/6 mice. Additionally, both CD11c deficient and C57BL/6 prion-infected mouse cohorts had a similar consortium of inflammatory- and phagocytosis-associated genes that increased as disease progressed to clinical stages. Ingenuity Pathway Analysis of upregulated genes in infected C57BL/6 mice suggested numerous cell-surface transmembrane receptors signal through Spleen Tyrosine Kinase, a potential key regulator of phagocytosis and innate immune activation in the prion infected brain. Ultimately, the deletion of CD11c did not influence prion pathogenesis in mice and CD11c signaling is not involved in the neuroprotection provided by microglia, but our analysis identified a conspicuous phagocytosis pathway in the CNS of infected mice that appeared to be activated during prion pathogenesis.

Monte Carlo based dosimetry of extraoral photobiomodulation for prevention of oral mucositis.

Photobiomodulation therapy (PBMT) is recommended for prevention and treatment of oral mucositis, a painful condition that occurs in cancer patients. Intraoral PBMT is limited to treating distal oral mucosa and oropharynx. Extraoral PBMT may provide a more efficient intervention. The goal of this study was to develop a clinically viable protocol for extraoral PBMT. Monte Carlo modeling was used to predict the distribution of 850 nm light for four treatment sites, using anatomical data obtained from MRI and optical properties from the literature. Simulated incident light power density was limited to 399 mW/cm2 to ensure treatment safety and to prevent tissue temperature increase. The results reveal that total tissue thickness determines fluence rate at the oral mucosa, whereas the thickness of individual tissue layers and melanin content are of minor importance. Due to anatomical differences, the fluence rate varied greatly among patients. Despite these variations, a universal protocol was established using a median treatment time methodology. The determined median treatment times required to deliver efficacious dose between 1 and 6 J/cm2 were within 15 min. The developed PBMT protocol can be further refined using the combination of pretreatment imaging and the Monte Carlo simulation approach implemented in this study.

Strategies for the Management of Patients with Pancreatic Cancer with PARP Inhibitors.

A subset of patients with pancreatic adenocarcinomas (PDAC) harbor mutations that are exploitable in the context of DNA-damage response and repair (DDR) inhibitory strategies. Between 8-18% of PDACs harbor specific mutations in the DDR pathway such as BRCA1/2 mutations, and a higher prevalence exists in high-risk populations (e.g., Ashkenazi Jews). Herein, we will review the current trials and data on the treatment of PDAC patients who harbor such mutations and who appear sensitive to platinum and/or poly ADP ribose polymerase inhibitor (PARPi) based therapies due to a concept known as synthetic lethality. Although this current best-in-class precision treatment shows clinical promise, the specter of resistance limits the extent of therapeutic responses. We therefore also evaluate promising pre-clinical and clinical approaches in the pipeline that may either work with existing therapies to break resistance or work separately with combination therapies against this subset of PDACs.

A PrP EGFR signaling axis controls neural stem cell senescence through modulating cellular energy pathways.

Mis-folding of the prion protein (PrP) is known to cause neurodegenerative disease; however, the native function of this protein remains poorly defined. PrP has been linked with many cellular functions, including cellular proliferation and senescence. It is also known to influence epidermal growth factor receptor (EGFR) signaling, a pathway that is itself linked with both cell growth and senescence. Adult neural stem cells (NSCs) persist at low levels in the brain throughout life and retain the ability to proliferate and differentiate into new neural lineage cells. KO of PrP has previously been shown to reduce NSC proliferative capacity. We used PrP KO and WT NSCs from adult mouse brain to examine the influence of PrP on cellular senescence, EGFR signaling, and the downstream cellular processes. PrP KO NSCs showed decreased cell proliferation and increased senescence in in vitro cultures. Expression of EGFR was decreased in PrP KO NSCs compared with WT NSCs and additional supplementation of EGF was sufficient to reduce senescence. RNA-seq analysis confirmed that significant changes were occurring at the mRNA level within the EGFR signaling pathway and these were associated with reduced expression of mitochondrial components and correspondingly reduced mitochondrial function. Metabolomic analysis of cellular energy pathways showed that blockages were occurring at critical sites for production of energy and biomass, including catabolism of pyruvate. We conclude that, in the absence of PrP, NSC growth pathways are downregulated as a consequence of insufficient energy and growth intermediates.

Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling.

Junctions between the endoplasmic reticulum (ER) and the plasma membrane (PM) are specialized membrane contacts ubiquitous in eukaryotic cells. Concentration of intracellular signaling machinery near ER-PM junctions allows these domains to serve critical roles in lipid and Ca2+ signaling and homeostasis. Subcellular compartmentalization of protein kinase A (PKA) signaling also regulates essential cellular functions, however, no specific association between PKA and ER-PM junctional domains is known. Here, we show that in brain neurons type I PKA is directed to Kv2.1 channel-dependent ER-PM junctional domains via SPHKAP, a type I PKA-specific anchoring protein. SPHKAP association with type I PKA regulatory subunit RI and ER-resident VAP proteins results in the concentration of type I PKA between stacked ER cisternae associated with ER-PM junctions. This ER-associated PKA signalosome enables reciprocal regulation between PKA and Ca2+ signaling machinery to support Ca2+ influx and excitation-transcription coupling. These data reveal that neuronal ER-PM junctions support a receptor-independent form of PKA signaling driven by membrane depolarization and intracellular Ca2+, allowing conversion of information encoded in electrical signals into biochemical changes universally recognized throughout the cell.

A systematic review of patient-reported outcome measures used in maternal postpartum anxiety.

OBJECTIVE: This study aimed to conduct a systematic review and to evaluate the psychometric measurement properties of instruments for postpartum anxiety using the Consensus-Based Standards for the Selection of Health Measurement Instruments guidelines to identify the best available patient-reported outcome measure. DATA SOURCES: We searched 4 databases (CINAHL, Embase, PubMed, and Web of Science in July 2022) and included studies that evaluated at least 1 psychometric measurement property of a patient-reported outcome measurement instrument. The protocol was registered with the International Prospective Register for Systematic Reviews under identifier CRD42021260004 and followed the Consensus-Based Standards for the Selection of Health Measurement Instruments guidelines for systematic reviews. STUDY ELIGIBILITY: Studies eligible for inclusion were those that assessed the performance of a patient-reported outcome measure for screening for postpartum anxiety. We included studies in which the instruments were subjected to some form of psychometric property assessment in the postpartum maternal population, consisted of at least 2 questions, and were not subscales. METHODS: This systematic review used the Consensus-Based Standards for the Selection of Health Measurement Instruments and the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to identify the best patient-reported outcome measurement instrument for examining postpartum anxiety. A risk of bias assessment was performed, and a modified GRADE approach was used to assess the level of evidence with recommendations being made for the overall quality of each instrument. RESULTS: A total of 28 studies evaluating 13 instruments in 10,570 patients were included. Content validity was sufficient in 9 with 5 instruments receiving a class A recommendation (recommended for use). The Postpartum Specific Anxiety Scale, Postpartum Specific Anxiety Scale Research Short Form, Postpartum Specific Anxiety Scale Research Short Form Covid, Postpartum Specific Anxiety Scale-Persian, and the State-Trait Anxiety Inventory demonstrated adequate content validity and sufficient internal consistency. Nine instruments received a recommendation of class B (further research required). No instrument received a class C recommendation (not recommended for use). CONCLUSION: Five instruments received a class A recommendation, all with limitations, such as not being specific to the postpartum population, not assessing all domains, lacking generalizability, or evaluation of cross-cultural validity. There is currently no freely available instrument that assess all domains of postpartum anxiety. Future studies are needed to determine the optimum current instrument or to develop and validate a more specific measure for maternal postpartum anxiety.

Pharmacological agents for prevention of pruritus in women undergoing Caesarean delivery with neuraxial morphine: a systematic review and Bayesian network meta-analysis.

BACKGROUND: Neuraxial opioids provide effective analgesia for Caesarean delivery, however, pruritus can be a troubling side-effect. Effective agents to prevent pruritus are needed. Our objective was to perform an updated systematic review and network meta-analysis to provide clinicians with a comparison of relative efficacy of available interventions to reduce the incidence of pruritus, induced by either intrathecal or epidural single-shot morphine, in women undergoing Caesarean delivery. METHODS: Databases systematically searched (up to January 2022) included PubMed MEDLINE, Web of Science, EBSCO CINAHL, Embase, LILACS, and two Cochrane databases. We included randomised, controlled trials involving adult female patients undergoing Caesarean delivery. We pooled trials comparing interventions used for preventing pruritus after Caesarean delivery and performed a Bayesian model network meta-analysis. RESULTS: The final primary network included data from comparisons of 14 distinct interventions (including placebo) used to reduce the incidence of pruritus in 6185 participants. We judged five interventions to be 'definitely superior' to placebo: propofol, opioid agonist-antagonists (neuraxial), opioid antagonists, opioid agonist-antagonists (systemic), and serotonin antagonists. For the network evaluating the incidence of severe pruritus (warranting additional therapeutic treatment of pruritus), data were available for 14 interventions (including placebo) in 4489 patients. For this outcome, we judged three interventions to be 'definitely superior' to placebo: dopamine antagonists (neuraxial) and systemic and neuraxial opioid agonist-antagonists. CONCLUSION: Our analysis found several interventions to be effective in reducing the incidence of pruritus. Although sub-hypnotic doses of propofol appear to have an antipruritic effect, replication of this finding and further investigation of optimal dosing are warranted. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42022367058).

Acute Colonic Pseudo-obstruction Following Spinal Fixation for Trauma.

BACKGROUND: Acute colonic pseudo-obstruction (ACPO) is a potentially highly morbid surgical complication. The incidence of ACPO following spinal trauma is unknown, but is likely higher than after elective spinal fusion. The purpose of this study was to establish the incidence of ACPO in patients with major trauma undergoing spinal fusion for unstable thoracic and lumbar fracture, and secondly, to characterize the nature of ACPO in this group, including treatment and complications. METHODS: A metropolitan hospital prospective trauma database was utilized to identify all patients from November 2015 to December 2021 meeting major trauma criteria and undergoing thoracic or lumbar spinal fusion for fracture. Individual records were then evaluated for occurrence of ACPO. ACPO was defined as radiologic evidence of colonic dilation without mechanical obstruction in symptomatic patients undergoing dedicated abdominal imaging. RESULTS: After exclusions, 456 patients with major trauma undergoing thoracic or lumbar spinal fusion were identified. ACPO occurred in 34-an incidence rate of 7.5%. There was no evidence of difference in terms of the spinal fracture type, level, surgical approach, or number of segments fused. There were no perforations; only 2 patients required colonoscopic decompression and none required surgical resection. CONCLUSIONS: ACPO occurred at a high frequency in this group of patients, although it required relatively simple treatment. High vigilance for ACPO should be maintained in trauma patients requiring thoracic or lumbar fixation, with a view to early intervention. The etiology driving the high rates of ACPO in this cohort is not understood and would benefit from further investigation.

Photobiomodulation in dental extraction therapy: Postsurgical pain reduction and wound healing.

BACKGROUND: This scoping review and analysis were designed to assess the amount of time spent delivering photobiomodulation (PBM) light therapy after dental extraction to improve postoperative pain and wound healing. TYPES OF STUDIES REVIEWED: The scoping review was performed according to the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Publications were specific for human randomized controlled clinical trials, PBM after dental extraction therapy, and related clinical outcomes. Online databases searched included PubMed, Embase, Scopus, and Web of Science. Analyses were conducted to analyze the prescribed intervals of time (seconds) per application of PBM. RESULTS: Of the 632 studies initially identified, 22 studies fulfilled the inclusion criteria. Postoperative pain and PBM were reported in 20 articles for 24 treatment groups, with treatment times ranging from 17 through 900 seconds and wavelengths from 550 through 1,064 nm. Clinical wound healing outcomes were reported in 6 articles for 7 groups with treatment times ranging from 30 through 120 seconds and wavelengths from 660 through 808 nm. PBM therapy was not associated with adverse events. CONCLUSIONS AND PRACTICAL IMPLICATIONS: There is future potential to integrate PBM after dental extraction therapy to improve postoperative pain and clinical wound healing. The amount of time spent delivering PBM will vary by wavelength and the type of device. Further investigation is needed to translate PBM therapy into human clinical care.

Comparison of different nonsteroidal anti-inflammatory drugs for cesarean section: a systematic review and network meta-analysis.

BACKGROUND: Cesarean section is associated with moderate to severe pain and nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly employed. The optimal NSAID, however, has not been elucidated. In this network meta-analysis and systematic review, we compared the influence of control and individual NSAIDs on the indices of analgesia, side effects, and quality of recovery. METHODS: CDSR, CINAHL, CRCT, Embase, LILACS, PubMed, and Web of Science were searched for randomized controlled trials comparing a specific NSAID to either control or another NSAID in elective or emergency cesarean section under general or neuraxial anesthesia. Network plots and league tables were constructed, and the quality of evidence was evaluated with Grading of Recommendations Assessment, Development and Evaluation (GRADE) analysis. RESULTS: We included 47 trials. Cumulative intravenous morphine equivalent consumption at 24 h, the primary outcome, was examined in 1,228 patients and 18 trials, and control was found to be inferior to diclofenac, indomethacin, ketorolac, and tenoxicam (very low quality evidence owing to serious limitations, imprecision, and publication bias). Indomethacin was superior to celecoxib for pain score at rest at 8-12 h and celecoxib + parecoxib, diclofenac, and ketorolac for pain score on movement at 48 h. In regard to the need for and time to rescue analgesia COX-2 inhibitors such as celecoxib were inferior to other NSAIDs. CONCLUSIONS: Our review suggests the presence of minimal differences among the NSAIDs studied. Nonselective NSAIDs may be more effective than selective NSAIDs, and some NSAIDs such as indomethacin might be preferable to other NSAIDs.