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Contemporary Approaches to Multidisciplinary Pain Management.
No full textIntegrated care models play a crucial role in improving outcomes for patients with chronic pain by addressing the complex biopsychosocial nature of pain. These models offer varying degrees of care integration and resource allocation, making them adaptable to the diverse needs of patients with chronic pain. Still, despite their proven benefits in the treatment of chronic pain, integrated care models face barriers to widespread implementation. This review highlights key characteristics of various integrated pain management models including multidisciplinary, interdisciplinary, and transdisciplinary care models
Multiomic Evidence for a Unified Model of Alzheimer\u27s Disease Etiology Linking Microglial Flux Capacity and Astrocyte-Neuron Metabolic Breakdown.
No full textAge and APOE genotype are the strongest known risk factors for late-onset Alzheimer\u27s disease (AD), but the mechanisms linking them to neuronal loss remain incompletely defined. Using multiomic data from the Alzheimer\u27s Disease Neuroimaging Initiative (ADNI), we propose a unified hypothesis in which two interdependent failure modes-saturation of microglial lipid flux capacity and disruption of the astrocyte-neuron lactate shuttle (ANLS) due to excess astrocytic membrane cholesterol-drive disease progression upstream of amyloid and tau pathology. Stratifying participants by cognitive score quartiles, we find consistent associations linking impaired lipid clearance, metabolic stress, and genetic variants regulating cholesterol handling. These processes appear to reinforce each other, resulting in accelerating neurodegeneration. Our hypothesis reframes AD as a systems-level collapse in metabolic coordination, rather than a purely linear pathological cascade. These insights emerged during the development of digital twin models for personalized interventions, highlighting the power of systems approaches to reveal hidden drivers of neurodegeneration
Longitudinal Genomic Analysis to Fine-Tune Targeted Therapy: Results of the Phase II LOGIC 2 Trial in Patients With BRAF V600-Mutant Metastatic Melanoma.
No full textPURPOSE: LOGIC 2 (NCT02159066), a multicenter, open-label, two-part, phase II study assessed encorafenib plus binimetinib combined with a third targeted agent after tumor progression on encorafenib plus binimetinib in patients with locally advanced unresectable or metastatic BRAF Patients and Methods: Adults with locally advanced unresectable or metastatic BRAF V600-mutant melanoma who were BRAF inhibitor/MEK inhibitor (BRAFi/MEKi)-treatment naive or pretreated received encorafenib plus binimetinib (Part I/Run-in). Based on the genomic testing at disease progression following encorafenib plus binimetinib, patients were assigned to one of four treatment arms to receive encorafenib plus binimetinib with an appropriate molecularly targeted agent (ribociclib, infigratinib, capmatinib, or buparlisib; Part II). The primary endpoint was best overall response; safety, biomarkers, pharmacokinetics, and other efficacy endpoints were also assessed.
RESULTS: In Part I/Run-in, 75 BRAFi/MEKi-naive patients and 83 BRAFi/MEKi-pretreated patients were treated; in Part II, 58 patients were treated (ribociclib, n=38; infigratinib, n=1; capmatinib, n=13; buparlisib, n=6). The overall confirmed response rate was 73.3% (95% CI, 61.9-82.9) in BRAFi/MEKi-naive patients, 25.3% (95% CI, 16.4-36.0) in pretreated patients, 2.6% (95% CI, 0.1-13.8) in the ribociclib arm, and 0% in the other three arms. Adverse events were manageable and consistent with the known safety profile of each drug.
CONCLUSIONS: LOGIC 2 supports the use of encorafenib plus binimetinib for treatment naive and previously treated locally advanced unresectable or metastatic BRAF V600-mutant melanoma. However, adding a third targeted agent following disease progression did not show meaningful efficacy; further research is needed to identify other therapeutic targets to circumvent resistance
International cooperation in cardiogenic shock is key to improving outcomes: Cardiogenic Shock Working Group impacts a single center in a developing country.
No full textThe Cardiogenic Shock Working Group (CSWG) is an international research consortium formed in 2016. The National Institute of Cardiology Ignacio Chavez joined in 2021 and launched a cardiogenic shock (CS) program in 2022. This study evaluates the impact of CSWG core standards on outcomes in a middle-income country reference center of 9,430 patients with CS (Society for Cardiovascular Angiography and Interventions [SCAI] stages B→E) from a registry of 28,054 admissions (2005-2023). Using multivariate Cox regression and propensity score matching, outcomes were compared between historic pre-CSWG (2005-2021) and contemporary pre-CSWG (2017-2021) eras vs the CSWG era (2022-2023). Adoption of CS-team standards increased the use of pulmonary artery catheters (4.2%, 4% vs 7.9%, p \u3c 0.001) and mechanical circulatory support devices (8.1% to 10.3%, p = 0.014) only in the legacy era. Reducing mortality from 22.3% and 20.5% vs 15.3% (p \u3c 0.001). The adjusted hazard ratio for mortality in the pre-CSWG era was 1.22 (p = 0.015) for the historical cohort and 1.20 (p = 0.047) for the contemporary cohort. CS-international collaboration enhanced outcomes through standardized protocols, advanced interventions, and dedicated CS teams, underscoring the importance of international cooperation in CS care
Impact of BRCA mutations, age, surgical indication, and hormone status on the molecular phenotype of the human Fallopian tube.
No full textThe human Fallopian tube (FT) is an important organ in the female reproductive system and has been implicated as a site of origin for pelvic serous cancers, including high-grade serous tubo-ovarian carcinoma (HGSC). We have generated comprehensive whole-genome bisulfite sequencing, RNA-seq, and proteomic data of over 100 human FTs, with detailed clinical covariate annotations. Our results challenge existing paradigms that extensive epigenetic, transcriptomic and proteomic alterations exist in the FTs from women carrying heterozygous germline BRCA1/2 pathogenic variants. We find minimal differences between BRCA1/2 carriers and non-carriers prior to loss of heterozygosity. Covariates such as age and surgical indication can confound BRCA1/2-related differences reported in the literature, mainly through their impact on cell composition. We systematically document and highlight the degree of variations across normal human FT, defining five groups capturing major cellular and molecular changes across various reproductive stages, pregnancy, and aging. We are able to associate gene, protein, and epigenetic changes with these and other clinical covariates, but not heterozygous BRCA1/2 mutation status. This sheds new light into prevention and early detection of tumorigenesis in populations at high-risk for ovarian cancer
Avoidance of Major Vascular Injury in Transcranial Brain Tumor Surgery Using Real-Time Doppler Navigation: Technical Note and Case Series.
No full textBACKGROUND AND OBJECTIVES: In endoscopic endonasal surgery, the Doppler probe has proven useful for localizing the paraclival and cavernous internal carotid arteries (ICA) and avoiding ICA injury. Similarly, during transcranial brain tumor removal, the Doppler probe may help avoid major vascular injury, particularly for tumors encasing or adherent to Circle of Willis branches. In this study, we describe the technique, outcomes, and potential neurovascular benefits of real-time navigation using the Doppler probe during craniotomy for brain tumor removal.
METHODS: Patients from 2015 to 2022 who underwent craniotomy for brain tumor resection and the Doppler probe was used were retrospectively analyzed. Data collection included demographics, tumor pathology, incidence of major/minor vascular injury, MRI-confirmed stroke/infarction, and extent of tumor resection.
RESULTS: In total, 695 patients underwent 840 craniotomies for brain tumor resection; in 501 craniotomies (59.6%), the Doppler was used. One major vascular injury (0.2%) of a supraclinoid ICA was directly attributed to non-Doppler probe use immediately before vessel injury, leading to stroke and severe neurological decline. There were 7 strokes (1.4%) leading to permanent neurological deficit attributable to vasospasm or small vessel injury and 26 asymptomatic infarctions/strokes (5.2%) attributable to unrecognized vascular injury or spasm at the time of surgery.
CONCLUSION: In this series of 501 craniotomies for brain tumor removal where the Doppler probe was used, the rate of direct large vessel injury was under 1%. Although our data show that smaller vessel injuries can still occur and may lead to permanent neurological deficits, routine Doppler probe use may help guide tumor dissection and aggressiveness of removal, avoiding inadvertent major arterial injury. Our experience suggests that it is most useful as tumor dissection progresses as the resulting brain shift makes stereotactic neuronavigation less reliable. We recommend routine Doppler probe use during transcranial brain tumor removal, particularly for tumors encasing or adherent to major arteries
Pridopidine in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial.
No full textIMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.
OBJECTIVE: To determine the effects of pridopidine, a σ1-receptor agonist, in ALS.
DESIGN, SETTINGS, AND PARTICIPANTS: Pridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.
INTERVENTIONS: Eligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.
MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.
RESULTS: Among 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR \u3c 1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).
CONCLUSIONS AND RELEVANCE: In this 24-week study, pridopidine did not impact the progression of ALS.
TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04297683, NCT04615923
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