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Amyotrophic Lateral Sclerosis, the Endocannabinoid System, and Exogenous Cannabinoids: Current State and Clinical Implications.
No full textA unifying mechanistic cause for amyotrophic lateral sclerosis (ALS) remains uncertain. Multiple pathophysiological processes appear to occur simultaneously. Cannabinoids, including delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), and others found in cannabis, and cannabis extracts (CEs), appear to have activity in these pathogenic pathways, which have led to increasing interest in cannabinoids as therapeutic agents for ALS. The use of cannabinoids as a treatment strategy is substantiated by preclinical evidence suggesting a role for the endocannabinoid system (ECS) in ALS and other neurodegenerative disorders. Preclinical data indicate that cannabis and CEs have powerful antioxidative, anti-inflammatory, and neuroprotective effects in the SOD1G93A mouse model of ALS. The use of CEs in SOD1G93A murine models has been shown to prolong neuronal cell survival, which leads to delayed onset of the disease state, and slows progression of the disease. Although research in humans remains limited, a few studies suggest that cannabis and CBD, in humans, provide benefits for both motor symptoms, including rigidity, cramps, and fasciculations, and non-motor symptoms including sleep quality, pain, emotional state, quality of life, and depression. There remains a need for further, well-designed clinical trials to validate further the use of an individual cannabinoid, or a combination of cannabinoids, as a disease-modifying therapy for ALS
Pan scan for geriatric trauma patients: Overkill or necessary?
No full textBACKGROUND: Geriatric patients manifest pain and physical findings differently and are associated with higher mortality and complications. We hypothesized that physical exam (PE) is unreliable versus computed tomography (CT) for comprehensive injury identification in geriatric patients. Additionally, we quantified significant incidental radiologic findings.
STUDY DESIGN: Our institution adopted a policy of Pan Scan (PS) CT for trauma activations of patients ≥65 years. PS included CT of head/neck and chest/abdomen/pelvis. PE and imaging findings were extracted from physician reports.
RESULTS: 50 % of patients had clinically significant CT traumatic findings. Of these, 75 % had PE correlating to significant CT findings, while 25 % had significant PS findings not identifiable on PE (p \u3c 0.001). The NPV was 0.80 for the PE. 57.7 % had clinically significant incidental findings.
CONCLUSION: Physical exam alone is not sensitive enough to detect all traumatic injuries in elderly patients. As an added benefit to PS, important incidental findings are identified. These data support use of PS in geriatric trauma to optimize care
Endovascular Treatment of Stroke Due to Medium-Vessel Occlusion.
No full textBACKGROUND: Whether the large effect size of endovascular thrombectomy (EVT) for stroke due to large-vessel occlusion applies to stroke due to medium-vessel occlusion is unclear.
METHODS: In a multicenter, prospective, randomized, open-label trial with blinded outcome evaluation, we assigned patients with acute ischemic stroke due to medium-vessel occlusion who presented within 12 hours from the time that they were last known to be well and who had favorable baseline noninvasive brain imaging to receive EVT plus usual care or usual care alone. The primary outcome was the modified Rankin scale score (range, 0 [no symptoms] to 6 [death]) at 90 days, reported as the percentage of patients with a score of 0 or 1.
RESULTS: A total of 530 patients from five countries were enrolled between April 2022 and June 2024, with 255 patients assigned to the EVT group and 275 to the usual-care group. Most patients (84.7%) had primary occlusions in a middle-cerebral-artery branch. A modified Rankin scale score of 0 or 1 at 90 days occurred in 106 of 255 patients (41.6%) in the EVT group and in 118 of 274 (43.1%) in the usual-care group (adjusted rate ratio, 0.95; 95% confidence interval [CI], 0.79 to 1.15; P = 0.61). Mortality at 90 days was 13.3% in the EVT group and 8.4% in the usual-care group (adjusted hazard ratio, 1.82; 95% CI, 1.06 to 3.12). Symptomatic intracranial hemorrhage occurred in 14 of 257 patients (5.4%) in the EVT group and in 6 of 272 (2.2%) in the usual-care group.
CONCLUSIONS: Endovascular treatment for acute ischemic stroke due to medium-vessel occlusion within 12 hours did not lead to better outcomes at 90 days than usual care. (Funded by the Canadian Institutes for Health Research and Medtronic; ESCAPE-MeVO ClinicalTrials.gov number, NCT05151172.)
Long-COVID incidence proportion in adults and children between 2020 and 2024.
No full textBACKGROUND: Incidence estimates of post-acute sequelae of SARS-CoV-2 infection, also known as long-COVID, have varied across studies and changed over time. We estimated long-COVID incidence among adult and pediatric populations in three nationwide research networks of electronic health records (EHR) participating in the RECOVER Initiative using different classification algorithms (computable phenotypes).
METHODS: This EHR-based retrospective cohort study included adult and pediatric patients with documented acute SARS-CoV-2 infection and two control groups-- contemporary COVID-19 negative and historical patients (2019). We examined the proportion of individuals identified as having symptoms or conditions consistent with probable long-COVID within 30-180 days after COVID-19 infection (incidence proportion). Each network (the National COVID Cohort Collaborative (N3C), National Patient-Centered Clinical Research Network (PCORnet), and PEDSnet) implemented its own long-COVID definition. We introduced a harmonized definition for adults in a supplementary analysis.
RESULTS: Overall, 4% of children and 10-26% of adults developed long-COVID, depending on computable phenotype used. Excess incidence among SARS-CoV-2 patients was 1.5% in children and ranged from 5-6% among adults, representing a lower-bound incidence estimation based on our control groups. Temporal patterns were consistent across networks, with peaks associated with introduction of new viral variants.
CONCLUSION: Our findings indicate that preventing and mitigating long-COVID remains a public health priority. Examining temporal patterns and risk factors of long-COVID incidence informs our understanding of etiology and can improve prevention and management
Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.
No full textIMPORTANCE: The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression.
OBJECTIVE: To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS.
DESIGN, SETTING, AND PARTICIPANTS: Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens.
INTERVENTIONS: Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing.
MAIN OUTCOMES AND MEASURES: The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR;benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164).
RESULTS: Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified.
CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04297683
Recurrent Nipple Duct Obstruction in Two Breastfeeding Patients: A Case Report and Discussion of the Underlying Pathophysiology.
No full textNipple pain is a common reason for premature breastfeeding cessation. There exists anecdotal evidence that one cause of lactational nipple pain is a ductal obstruction, but there is no published literature describing this phenomenon. Herein we present two case reports for two patients who experienced breast and nipple pain concurrent with milk flow reduction. Both patients removed a small stone-like obstructing object from their nipple; this action was painful for one of the patients, resulting in immediate release of milk and relief from breast pain. Both patients experienced recurrence of stone formation in their nipple ducts. We analyzed the mineral composition of the obstructing objects and breast milk using inductively coupled mass spectroscopy. We use literature on teat obstructions in dairy cows and dacryolith and sialolith formation to propose hypotheses as to how the formation of obstructing objects in milk ducts might occur. Future research directions for determining the pathophysiology, clinical presentation, and management of human nipple duct obstructions are discussed
A Rare Case of Autoimmune Hepatitis-Primary Biliary Cholangitis Overlap Syndrome in a Male Patient.
No full textAutoimmune liver diseases, such as autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), present significant diagnostic and therapeutic challenges due to overlapping features and potential for severe complications. AIH-PBC overlap syndrome, a rare condition, combines characteristics of both diseases but lacks standardized treatment protocols. We present the case of a 42-year-old male with elevated liver function tests, pruritus, flatulence, and epigastric pain. Laboratory findings revealed a cholestatic liver function pattern, a highly positive antinuclear antibody titer, weakly positive anti-smooth muscle antibody, elevated immunoglobulin G, and negative viral and anti-mitochondrial antibody markers. Diagnostic imaging, including abdominal ultrasound and magnetic resonance cholangiopancreatography, demonstrated mild fatty liver, slight irregularity in the left biliary duct wall, and a normal common bile duct without significant abnormalities. Liver biopsy confirmed chronic hepatitis with dense portal lymphoplasmacytic infiltrate, scattered eosinophils, moderate interface hepatitis, and mild lobular necroinflammation, consistent with AIH-PBC overlap syndrome. The Paris criteria were used to establish the diagnosis. Treatment with ursodeoxycholic acid, prednisolone, and azathioprine resulted in significant clinical and biochemical improvement
American Society for Gastrointestinal Endoscopy guideline on gastrostomy feeding tubes: methodology and review of evidence.
No full textThis article from the American Society for Gastrointestinal Endoscopy (ASGE) provides a full description of the methodology used to inform the final guidance outlined in the accompanying summary and recommendations article for strategies to manage endoscopically placed gastrostomy tubes. This article was developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework and specifically addresses the utility of PEG versus interventional radiology-guided gastrostomy (IR-G), the need for withholding antiplatelet and anticoagulant medications, appropriate timing to initiate tube feedings, and appropriate selection of the gastrostomy technique in patients with malignant dysphagia. In patients needing enteral access, the ASGE suggests PEG as the preferred technique for initial gastrostomy over IR-G. The ASGE recommends that tube feeding can be safely started within 4 hours of the gastrostomy without the need for an intentional delay. The ASGE suggests that a PEG can be performed without the need to withhold antiplatelet medications. In patients on anticoagulants who need to undergo PEG placement, the ASGE suggests that the periprocedural management of anticoagulants should be based on a multidisciplinary discussion with the patient regarding the risk of bleeding versus cardiovascular adverse events. In patients with malignant dysphagia, either transoral Pull PEG or transcutaneous Direct PEG can be performed for initial enteral access
Discontinuation and Reinitiation of Dual-Labeled GLP-1 Receptor Agonists Among US Adults With Overweight or Obesity.
No full textIMPORTANCE: Adherence to glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is important for their effectiveness. Discontinuation and reinitiation patterns are not well understood.
OBJECTIVE: To describe rates of and factors associated with discontinuation and subsequent reinitiation of GLP-1 RAs among adults with overweight or obesity.
DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, 125 474 adults with overweight or obesity newly initiated treatment with a dual-labeled GLP-1 RA (liraglutide, semaglutide, or tirzepatide) between January 1, 2018, and December 31, 2023, with a baseline body mass index of 27 or more, an available weight measurement within 60 days before initiation, and regular care in the year before initiation were identified using electronic health record data from a collective of US health care systems. Patients were followed up for up to 2 years to assess discontinuation and for 2 additional years to assess reinitiation.
EXPOSURE: Patients were stratified by presence of type 2 diabetes at baseline.
MAIN OUTCOMES AND MEASURES: Proportions of patients discontinuing and reinitiating GLP-1 RA were estimated from Kaplan-Meier models. Associations of sociodemographic characteristics, health factors, weight changes, and gastrointestinal adverse events with discontinuation and reinitiation outcomes were modeled using time-varying Cox proportional hazards regression models. All analyses were conducted separately for patients with and patients without type 2 diabetes.
RESULTS: In this cohort study of 125 474 adults (mean [SD] age, 54.4 [13.1] years; 82 063 women [65.4%]), 76 524 (61.0%) had type 2 diabetes. One-year discontinuation was significantly higher for patients without type 2 diabetes (64.8% [95% CI, 64.4%-65.2%]) compared with those with type 2 diabetes (46.5% [95% CI, 46.2%-46.9%]). Higher weight loss (1% reduction in weight from baseline was associated with a 3.1% [95% CI, 2.9%-3.2%] lower hazard of discontinuation for patients with type 2 diabetes and a 3.3% [95% CI, 3.2%-3.5%] lower hazard of discontinuation for patients without type 2 diabetes) and higher income (type 2 diabetes only; \u3e$80 000: hazard ratio [HR], 0.72 [95% CI, 0.69-0.76]) were significantly associated with lower rates of discontinuation, while moderate or severe incident gastrointestinal adverse events were associated with a higher hazard of discontinuation (with type 2 diabetes: HR, 1.38 [95% CI, 1.31-1.45]; without type 2 diabetes: HR, 1.19 [95% CI, 1.12-1.27]). Of 41 792 patients who discontinued and had a discontinuation weight measurement available, 1-year reinitiation was lower for those without type 2 diabetes (36.3% [95% CI, 35.6%-37.0%]) compared with those with type 2 diabetes (47.3% [95% CI, 46.6%-48.0%]). Weight regain of 1% from discontinuation was significantly associated with increased hazards of reinitiation of 2.3% (95% CI, 1.9%-2.8%) for patients with type 2 diabetes and 2.8% (95% CI, 2.4%-3.2%) for patients without type 2 diabetes.
CONCLUSIONS AND RELEVANCE: In this cohort study, most patients with overweight or obesity discontinued GLP-1 RA therapy within 1 year, but those without type 2 diabetes had higher discontinuation rates and lower reinitiation rates. Inequities in access and adherence to effective treatments have the potential to exacerbate disparities in obesity
