Responses to a "Typical" Morning Dose of Kratom in People Who Use Kratom Regularly: A Direct-Observation Study.

INTRODUCTION: Use of kratom has outpaced systematic study of its effects, with most studies reliant on retrospective self-report. METHODS: We aimed to assess acute effects following kratom use in adults who use regularly, and quantify alkaloids in the products, urine, and plasma. Between July and November 2022, 10 adults came to our clinic and orally self-administered their typical kratom dose; blinding procedures were not used. Physiological measures included blood pressure, respiratory rate, heart rate, pulse oximetry, temperature, and pupil diameter. Subjective outcomes included Subjective Opioid Withdrawal Scale, Addiction Research Center Inventory, and Drug Effects Questionnaire. Psychomotor performance was also assessed. RESULTS: Participants were 6 men and 4 women, mean age 41.2 years. Nine were non-Hispanic White; 1 was biracial. They had used kratom for 6.6 years (SD, 3.8 years) on average (2.0-14.1). Sessions were 190.89 minutes on average (SD, 15.10 minutes). Mean session dose was 5.16 g (median, 4.38 g; range, 1.1-10.9 g) leaf powder. Relative to baseline, physiological changes were minor. However, pupil diameter decreased (right, b = -0.70, P < 0.01; left, b = -0.73, P < 0.01) 40-80 minutes postdose and remained below baseline >160 minutes. Subjective Opioid Withdrawal Scale pre-dosing was mild (5.5 ± 3.3) and decreased postdose (b = [-4.0, -2.9], P < 0.01). Drug Effects Questionnaire "feeling effects" increased to 40/100 (SD, 30.5) within 40 minutes and remained above baseline 80 to 120 minutes (b = 19.0, P = 0.04), peaking at 72.7/100; 6 participants rated euphoria as mild on the Addiction Research Center Inventory Morphine-Benzedrine-scale. Psychomotor performance did not reliably improve or deteriorate postdosing. CONCLUSIONS: Among regular consumers, we found few clinically significant differences pre- and post-kratom dosing. Alkaloidal contents in products were within expected ranges.

An update on the clinical pharmacology of kratom: uses, abuse potential, and future considerations.

INTRODUCTION: Kratom (Mitragyna speciosa) has generated substantial clinical and scientific interest as a complex natural product. Its predominant alkaloid mitragynine and several stereoisomers have been studied for activity in opioid, adrenergic, and serotonin receptors. While awaiting clinical trial results, the pre-clinical evidence suggests a range of potential therapeutic applications for kratom with careful consideration of potential adverse effects. AREAS COVERED: The focus of this review is on the pharmacology, pharmacokinetics, and potential drug-drug interactions of kratom and its individual alkaloids. A discussion on the clinical pharmacology and toxicology of kratom is followed by a summary of user surveys and the evolving concepts of tolerance, dependence, and withdrawal associated with kratom use disorder. EXPERT OPINION: With the increasing use of kratom in clinical practice, clinicians should be aware of the potential benefits and adverse effects associated with kratom. While many patients may benefit from kratom use with few or no reported adverse effects, escalating dose and increased use frequency raise the risk for toxic events in the setting of polysubstance use or development of a use disorder.

Neonatal Achilles Tendon Microstructure is Negatively Impacted by Decorin and Biglycan Knockdown After Injury and During Development.

Interest in studying neonatal development and the improved healing response observed in neonates is increasing, with the goal of using this work to create better therapeutics for tendon injury. Decorin and biglycan are two small leucine-rich proteoglycans that play important roles in collagen fibrillogenesis to develop, maintain, and repair tendon structure. However, little is known about the roles of decorin and biglycan in early neonatal development and healing. The goal of this study was to determine the effects of decorin and biglycan knockdown on Achilles tendon structure and mechanics during neonatal development and recovery of these properties after injury of the neonatal tendon. We hypothesized that knockdown of decorin and biglycan would disrupt the neonatal tendon developmental process and produce tendons with impaired mechanical and structural properties. We found that knockdown of decorin and biglycan in an inducible, compound decorin/biglycan knockdown model, both during development and after injury, in neonatal mice produced tendons with reduced mechanical properties. Additionally, the collagen fibril microstructure resembled an immature tendon with a large population of small diameter fibrils and an absence of larger diameter fibrils. Overall, this study demonstrates the importance of decorin and biglycan in facilitating tendon growth and maturation during neonatal development.

Collagen V haploinsufficiency in female murine patellar tendons results in altered matrix engagement and cellular density, demonstrating decreased healing.

Collagen V (Col5) is a quantitatively minor component of collagen fibrils comprising tendon, however, plays a crucial role in regulation of development and dynamic healing processes. Clinically, patients with COL5a1 haploinsufficiency, known as classic Ehlers-Danlos Syndrome (cEDS), present with hyperextensible skin, joint instability and laxity, with females more likely to be affected. Previous studies in Col5-deficient mice indicated that reduced Col5a1 expression leads to a reduction in stiffness, fibril deposition, and altered fibril structure. Additionally, Col5-deficient male tendons demonstrated altered healing compared to wild-type tendons, however female mice have not yet been studied utilizing this model. Along with clinical differences between sexes in cEDS patient populations, differences in hormone physiology may be a factor influencing tendon health. Therefore, the objective of this study was to utilize a Col5a1+/ - female mouse model, to determine the effect of Col5 on tendon cell morphology, cell density, tissue composition, and mechanical properties throughout healing. We hypothesized that reduction in Col5 expression would result in an abnormal wound matrix post-injury, resulting in reduced mechanical properties compared to normal tendons. Following patellar tendon surgery, mice were euthanized at 1, 3, and 6-week post-injury. Col5-deficient tendons demonstrated altered and decreased healing compared to WT tendons. The lack of resolution in cellularity by 6-week post-injury in Col5-deficient tendons influenced the decreased mechanical properties. Stiffness did not increase post-injury in Col5-deficient mice, and collagen fiber realignment was delayed during mechanical loading. Therefore, increased Col5a1 expression post-injury is necessary to re-establish matrix engagement and cellularity throughout tendon healing.

Novel application of in vivo microdialysis in a rat Achilles tendon acute injury model.

Tendon injury and healing involve intricate changes to tissue metabolism, biology, and inflammation. Current techniques often require animal euthanasia or tissue destruction, limiting assessment of dynamic changes in tendon, including treatment response, disease development, rupture risk, and healing progression. Microdialysis, a minimally invasive technique, offers potential for longitudinal assessment, yet it has not been applied to rat tendon models. Therefore, the objective of this study is to adapt a novel application of an in vivo assay, microdialysis, using acute injury as a model for extreme disruption of the tendon homeostasis. We hypothesize that microdialysis will be able to detect measurable differences in the healing responses of acute injury with high specificity and sensitivity. Overall results suggest that microdialysis is a promising in vivo technique for longitudinal assessment for this system with strong correlations between extracellular fluid (ECF) and dialysate concentrations and reasonable recovery rates considering the limitations of this model. Strong positive correlations were found between dialysate and extracellular fluid (ECF) concentration for each target molecule of interest including metabolites, inflammatory mediators, and collagen synthesis and degradation byproducts. These results suggest that microdialysis is capable of detecting changes in tendon healing following acute tendon injury with high specificity and sensitivity. In summary, this is the first study to apply microdialysis to a rat tendon model and assess its efficacy as a direct measurement of tendon metabolism, biology, and inflammation.NEW & NOTEWORTHY This study adapts a novel application of microdialysis to rat tendon models, offering a minimally invasive avenue for longitudinal tendon assessment. Successfully detecting changes in tendon healing after acute injury, it showcases strong correlations between extracellular fluid and dialysate concentrations. The results highlight the potential of microdialysis as a direct measure of tendon metabolism, biology, and inflammation, bypassing the need for animal euthanasia and tissue destruction.

Presumed Melanocytoma-Associated Choroidal Neovascular Membrane with Hemorrhage Successfully Treated with Intravitreal Aflibercept Injections.

A patient presented with melanocytoma and associated choroidal neovascular membrane with hemorrhage involving the macula. The patient was treated with monthly aflibercept (Eylea) injections with significant improvement of best corrected visual acuity. In this report, we explore the development of a choroidal neovascular membrane (CNVM) formation in a patient with melanocytoma and the effect of intravitreal aflibercept (Eylea) on disease course. Case report study used patient data obtained from examination and imaging. The patient was treated with monthly intravitreal aflibercept injections leading to complete resolution of CNVM and hemorrhage, with significant improvement of best corrected visual acuity. Awareness and proper monitoring for the sequelae of melanocytoma are important for early detection and prevention of visually threatening outcomes. In cases of melanocytoma-associated CNVM formation with large subretinal hemorrhage, intravitreal aflibercept can be an effective tool for inducing CNVM regression and allowing improvement of visual acuity.

The Subject Is a Patient.

Although it is common in academic and government research settings to speak of study participants as "subjects," this perspective piece argues against doing so. In particular, the relationship of the study physician with study participants is unique and still retains many elements of the usual patient-physician relationship that exists in general clinical practice.

The Opioid Overdose Resuscitation Education for Addiction Counselors and Trainees (Opioid Overdose REACT) naloxone response education pilot project improved confidence and knowledge among addiction counselors and trainees.

INTRODUCTION: Community programs to teach nonmedical laypeople how to recognize an opioid overdose and effectively resuscitate the victim using naloxone have proliferated recently as a significant component of harm-reduction efforts. Although many such programs target laypeople like first responders or friends and family members of people who use drugs, there are currently no programs that specifically target addiction counselors, despite their work with a client population at high risk of an opioid overdose. METHODS: The four-hour curriculum designed by the authors covered opioid agonist and antagonist pharmacology; opioid toxidrome signs; legal implications and indications for using the naloxone kits; and hands-on training. Participants were two cohorts of addiction counselors and addiction counseling trainees at our institution and an affiliated Opioid Treatment Program methadone clinic. Surveys testing participant knowledge and confidence were conducted at baseline, immediately post-training, six months post-training, and 12 months post-training. RESULTS: Overall, opioid and naloxone pharmacology knowledge, as well as the confidence to intervene in an overdose emergency, improved among participants in both cohorts. Knowledge scores at baseline (n = 36, median 5/10) improved significantly immediately post-training (n = 31, median 7/10, P < 0.0001, Wilcoxon signed-rank test) and were sustained six (n = 19) and 12 months (n = 11) later. Two participants reported using their naloxone kits to successfully reverse a client overdose in the 12 months after taking the course. DISCUSSION: These results from our knowledge translation pilot project suggest that our educational program to train addiction counselors in opioid pharmacology and toxicology, allowing them to recognize and respond to an opioid overdose, is feasible and could be effective. Specific barriers to implementing such educational programs include cost, stigma, and unclear best practice for designing and conducting these programs. CONCLUSIONS: Further study of providing opioid pharmacology education and overdose and naloxone training to addiction counselors and counseling trainees appears to be warranted.

Investigating the temporal roles of decorin and biglycan in tendon healing.

The small leucine-rich proteoglycans, decorin and biglycan, are minor components of the tendon extracellular matrix that regulate fibrillogenesis and matrix assembly. Our study objective was to define the temporal roles of decorin and biglycan during tendon healing using inducible knockout mice to include genetic knockdown at specific phases of healing: time of injury, the proliferative phase, and the remodeling phase. We hypothesized that knockdown of decorin or biglycan would adversely affect tendon healing, and that by prescribing the timing of knockdown, we could elucidate the temporal roles of these proteins during healing. Contrary to our hypothesis, decorin knockdown did not affect tendon healing. However, when biglycan was knocked down, either alone or coupled with decorin, tendon modulus was increased relative to wild-type mice, and this finding was consistent among all induction timepoints. At 6 weeks postinjury, we observed increased expression of genes associated with the extracellular matrix and growth factor signaling in the biglycan knockdown and compound decorin-biglycan knockdown tendons. Interestingly, these groups demonstrated opposing trends in gene expression as a function of knockdown-induction timepoint, highlighting distinct temporal roles for decorin and biglycan. In summary, this study finds that biglycan plays multiple functions throughout tendon healing, with the most impactful, detrimental role likely occurring during late-stage healing. Statement of clinical importance: This study helps to define the molecular factors that regulate tendon healing, which may aid in the development of new clinical therapies.

Examining the paradoxical effects of kratom: a narrative inquiry.

Introduction: Surveys and case reports have documented kratom use in the United States (US) for over a decade. However, those reports have generally not examined in depth the role kratom plays in the lives of those who use it regularly for sustained periods. Until there are controlled studies of the pharmacology and subjective effects of kratom alkaloids in humans, one of the best sources of insight on kratom-product use remains qualitative data with nuanced descriptions of kratom effects from those who use it regularly. Method: We conducted semistructured qualitative interviews with adults who regularly use kratom products, as part of a laboratory study of kratom-product self-administration. This qualitative component of the study was conducted as a narrative case-report series (n = 10). Results: Despite some differences among participants, all experienced acute combination effects that were largely, even simultaneously, analgesic and stimulatory. Most participants had decreased their dosages over time, and one planned to quit. Five of the 10 participants met DSM-5-based criteria for kratom-use disorder (3 mild, 1 moderate, 1 severe, by symptoms counts). When kratom was inadvertently taken in larger than intended doses, participants described a constellation of symptoms that they called "the wobbles" (a jittery feeling accompanied by what seemed to be nystagmus); this was rare, but could be of scientific and clinical interest as a possible manifestation of serotonin syndrome. Most participants described tolerance but considered kratom generally safe at low-moderate doses, providing perceived benefits with less potential risk for adverse effects compared to pharmaceuticals or illicit drugs. Discussion: In-depth interview data like these help confirm and clarify findings from larger survey studies and clinician-driven case reports. They are needed to inform the policy practice regarding kratom and may also help inform future experimental designs.

Knockdown of biglycan reveals an important role in maintenance of structural and mechanical properties during tendon aging.

Biglycan, a small leucine-rich proteoglycan (SLRP), is involved in collagen fibrillogenesis and also acts as a signaling molecule. Although decorin has been considered as the primary SLRP in developing and maintaining tendon structure and mechanics, more recent work using inducible knockdown models suggests that biglycan is involved in tendon homeostasis. The purpose of the study was to determine the role of biglycan in tendon homeostasis to maintain mechanical and structural integrity in aged mice. Aged (485 days old) female Bgn+/+ control (wild type [WT], n = 16) and 16 bitransgenic conditional Bgnflox/flox mice (I-Bgn-/- , n = 16) with a tamoxifen-inducible Cre (driven by ROSA) were utilized. After biglycan knockdown, the transgenic model demonstrated effective knockdown of the target gene without any compensation from other SLRPs or type I collagen. Patellar tendon cellularity was not modified after biglycan knockdown. However, biglycan knockdown had an impact on collagen fibrillogenesis with a higher percentage of small diameter fibrils (25-45 nm) and a lower percentage of medium size fibrils (150-165 nm) in I-Bgn-/- tendons. Biglycan knockdown also induced a reduction in the midsubstance modulus and maximum stress compared to WT. Stress relaxation was reduced at 4% strain in I-Bgn-/- tendons but no changes were observed in dynamic modulus and tan delta. As in mature tendons (120 days old), this study showed significant effects of biglycan knockdown on mechanical and structural properties of aged tendons only 30 days after knockdown. These data suggest that biglycan has a major role in maintaining homeostasis in aged tendon.

NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.

Multicenter analysis of stereotactic radiosurgery for multiple brain metastases from EGFR and ALK driven non-small cell lung cancer.

INTRODUCTION: Patients with brain metastases (BrMs) arising from EGFR and ALK driven non-small cell lung cancer (NSCLC) have favorable prognoses and evolving treatment options. We evaluated multicenter outcomes for stereotactic radiosurgery (SRS) to multiple (≥4) BrMs, where randomized data remain limited. METHODS: Data were collected retrospectively from 5 academic centers on EGFR and ALK NSCLC who received SRS to ≥4 BrMs with their first SRS treatment between 2008 and 2018. Analyzed endpoints included overall survival (OS), freedom from CNS progression (FFCNSP), and freedom from whole-brain radiotherapy (FFWBRT). RESULTS: Eighty-nine patients (50 EGFR, 39 ALK) received a total of 159 SRS treatments to 1,080 BrMs, with a median follow up of 51.3 months. The median number of BrMs treated with SRS treatment-1 was 6 (range 4-26) and median for all treatments was 9 (range 4-47). Sixteen patients (18 %) had received WBRT prior to SRS treatment-1. The median OS was 24.2, 21.2, and 33.2 months for all patients, EGFR, and ALK subsets, respectively. After multivariable adjustment, only receipt of a next-generation tyrosine kinase inhibitor was associated with OS (HR 0.40, p = 0.005). No differences in OS were observed based on number of BrMs treated. The median FFCNSP was 9.4, 11.6, and 7.5 months, for all patients, EGFR, and ALK subsets, respectively. After multivariable adjustment, the number of BrMs (continuous) treated during treatment-1 was the only negative prognostic factor associated with FFCNSP (HR 1.071, p = 0.045). The 5-year FFWBRT was 73.6 %. CONCLUSIONS: This multicenter analysis over a >10-year period demonstrated favorable OS, FFCNSP, and FFWBRT, in patients with EGFR and ALK driven NSCLC receiving SRS to ≥4 BrMs. These data support SRS as an option in the upfront and salvage setting for higher burden CNS disease in this population.

Factors Associated with Reconstruction Failure and Major Complications After Postmastectomy Radiation to a Reconstructed Breast.

PURPOSE: Postmastectomy radiation therapy is known to increase risk of complications in the reconstruction setting. We aim to identify the variables associated with reconstruction failure and other major complications. METHODS AND MATERIALS: A prospectively collected institutional database was queried for patients with up to stage IIIC breast cancer treated from 2000 to 2017, undergoing mastectomy, immediate implant or autologous tissue reconstruction, and radiation to the reconstructed breast within 1 year of surgery. Reconstruction failure was defined as complication requiring surgical revision or implant removal. Additional major complications were defined as any infection, contracture, necrosis, or fibrosis. Covariates of interest included age, body mass index, smoking status, stage, hormone receptor and HER2 status, systemic therapy timing, radiation technique, nodal irradiation, and interval between surgery and start of postmastectomy radiation therapy. Differences in complication rates were assessed with χ² or Fisher exact tests. Competing risk regression was used to estimate hazard ratios; covariates were included one at a time to avoid over adjustment. RESULTS: A total of 206 reconstructed breasts in 202 patients resulted from our initial query, with 139 treated with intensity-modulated radiation therapy (IMRT) and 67 treated with conventional radiation therapy (CRT). Median follow-up was 45 months (range, 4-210 months); patient cohorts were generally similar. Eight patients were excluded from toxicity analysis for insufficient follow-up (<2 years). Overall, reconstruction failure and major complication rates were significantly lower in the IMRT group. Reconstruction failure rates were 3.0% for IMRT versus 16.4% for CRT (P = .002), and major complication rates were 6.8% for IMRT versus 24.6% for CRT (P < .001). On univariate analysis, CRT was significantly predictive of implant failure (hazard ratio, 5.54; P = .003) and increased complication rates (hazard ratio, 3.83; P = .001). Significance persisted on multivariable analysis. Survival outcomes were similar, with no difference in 2 year overall survival (P = .12) and local recurrence (P = .41). CONCLUSIONS: Using IMRT may improve reconstruction outcomes over CRT, with significantly lower reconstruction failure and complication rates without compromising local control or survival.

Post-injury tendon mechanics are not affected by tamoxifen treatment.

PURPOSE: A growing interest in the mechanisms that govern tendon healing has resulted in the develop-ment of tools, such as the tamoxifen-inducible mouse knockdown model, to address these questions. However, tamoxifen is a selective estrogen receptor modulator and may interfere with the tendon healing process. The objective of this study was to evaluate the effects of tamoxifen on post-injury tendon mechanics in wild-type mice. METHODS: The mice underwent treatment at the time of injury using an established mouse injury model and the injured tendons were evaluated 3 weeks post-injury. The treatment contained tamoxifen suspended in corn oil and was compared to a treatment with only corn oil, as well as mice with no treatment. Tendons were evaluated by measuring the quasi-static and viscoelastic mechanics, collagen fiber realignment, cellularity, and nuclear morphology. RESULTS: Mechanical testing of the tendons post-injury revealed no changes to viscoelastic mechanics, quasi-static mechanics, or collagen realignment during loading after tamoxifen treatment with the dosage regimen utilized (three daily injections of 4.5 mg/40 g body weight). Additionally, histological analysis revealed no changes to cellularity or cell nuclear shape. CONCLUSION: Overall, this study revealed that tamoxifen treatment at the time of tendon injury did not result in changes to tendon mechanics or the histological parameters at 3 weeks post-injury.

Primary and secondary focal choroidal excavation morphologic phenotypes, associated ocular disorders and prognostic implications.

AIMS: To characterise and classify the morphological, clinical and tomographic characteristics of focal choroidal excavation (FCE) lesions to determine their prognostic implications. METHODS: 36 eyes with FCE (32 patients) underwent multimodal imaging, including spectral domain optical coherence tomography and fundus autofluorescence. FCE lesions were classified into three subtypes: (1) type 1: myopic (central choroidal thickness: <100 µm), (2) type 2: suspected congenital (central choroidal thickness: 100-200 µm, without associated chorioretinal pathology) and (3) type 3: secondary or acquired (central choroidal thickness: >200 µm, with associated chorioretinal pathology). RESULTS: 80.6% of eyes were followed longitudinally (26.8±18.8 months). There were 9 type 1 FCEs (myopic), 8 type 2 FCEs (U-shaped, congenital) and 19 type 3 FCEs (V-shaped, secondary). Type 2 FCEs trended towards larger maximum widths (p=0.0563). Type 3 FCEs were associated with central serous chorioretinopathy or pachyvessels (47.4%), but were also seen in pattern dystrophy, geographic atrophy, inactive choroiditis, torpedo maculopathy and adult-onset vitelliform dystrophy. Choroidal neovascular membranes (CNVMs) were more prevalent in type 3 FCE (41.2% compared with 11.1% for type 1 FCE, p=0.251, and 0% for type 2 FCE, p=0.043). CONCLUSIONS: The FCE types, stratified by central choroidal thickness, demonstrated distinct morphological characteristics and associated findings. The classification scheme held prognostic implications as type 3 FCE with V shapes were associated with other chorioretinal conditions and were more likely to develop CNVM.

Protecting Infants from Sudden Unexpected Infant Death: Guidelines for Interventions during the Perinatal Period from the French National College of Midwives.

With 300-400 annual deaths in France, sudden unexpected infant death (SUID) is the leading cause of mortality in France among infants from the end of their first through their 12th month of life. These clinical practice guidelines aim to identify strategies for (future) parents to prevent avoidable SUIDs. They are based on a narrative literature review and an analysis of the existing reports and guidelines available on the topic in 2019-2020. In summary, it is recommended that parents ensure that their infants sleep on their back on a firm, empty surface in a sufficiently ventilated environment, share the parental bedroom, and be breastfed and vaccinated. All of these actions create protective factors against SUID. Conversely, parents should know that several factors increase the risk of SUID: unsafe sleep, maternal smoking, passive smoking after birth, exposure to alcohol or other psychoactive substances, and excessive heat. Precis: Sudden Unexpected Infant Death prevention includes infants being breastfed and vaccinated, sleeping on their back, on a firm, empty surface, near parents, and that they are not overheated.