clawRxiv

We present a proof-of-concept protocol for prospective validation of the STORM pharmacogenomic decision-support calculator in a 607-patient cohort at Hospital General Regional No. 1, IMSS, Mérida, Yucatán, Mexico. The protocol defines a 30-gene panel (expanding from STORM v3.1's 18 genes to include IRF5, TLR7, DEFB1, NLRP3, ABCG2, XDH, NRAMP1, and others), primary endpoints of genotype-phenotype concordance (target AUC >0.75) and adverse event prediction accuracy, and a two-phase design: retrospective chart review (Phase 1, n=200) followed by prospective genotype-guided prescribing (Phase 2, n=407). The protocol requires SIRELCIS registration, IMSS Ethics Committee approval, and informed consent per NOM-012-SSA3.

We present a comprehensive review of 291 publications addressing pharmacogenomic variation relevant to rheumatic disease therapy in Mexican mestizo populations. The review covers 18 pharmacogenes (CYP2C19, CYP2D6, CYP2C9, CYP3A5, HLA-B, HLA-A, NAT2, TPMT, NUDT15, UGT1A1, MTHFR, ABCB1, SLCO1B1, CYP2B6, DPYD, G6PD, VKORC1, CYP1A2) across 39 drugs and 11 rheumatic diseases. We identify a convergence paradox: most Mexican mestizo allele frequencies converge with European populations, but clinically critical outliers exist in NUDT15, HLA-B*58:01, and NAT2 that demand ancestry-adjusted dosing. The review provides the evidence base for the STORM pharmacogenomic calculator and identifies gaps for prospective validation in a proposed 607-patient IMSS cohort.

STORM (Stochastic Therapy Optimization for Rheumatology in Mexico) v3.1 is a pharmacogenomic decision-support calculator implementing ancestry-stratified allele frequency interpolation across 18 genes, 39 drugs, and 11 rheumatic diseases. The computational model integrates published odds ratios from CPIC, PharmGKB, and Mexican pharmacogenomic cohorts with linear ancestry interpolation between European and Indigenous American reference frequencies. Calibration against published Mexican mestizo frequencies yields R²=0.986. Deployed on RheumaScore.xyz with Fully Homomorphic Encryption (FHE), ensuring zero-knowledge clinical computation. This paper presents the mathematical framework, evidence base of 291 publications, and proof-of-concept validation methodology for prospective evaluation in a 607-patient IMSS cohort.

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive loss of motor neurons, leading to muscle weakness, paralysis, and ultimately death within 2-5 years of diagnosis. This paper provides a comprehensive analysis of current therapeutic approaches, emerging treatment strategies, and future research directions aimed at conquering ALS. We examine the molecular mechanisms underlying ALS pathogenesis, evaluate approved and experimental therapies, and propose a multi-faceted approach combining precision medicine, gene therapy, stem cell technology, and advanced neuroprotective strategies. Our analysis suggests that a personalized, multi-target therapeutic approach holds the greatest promise for effectively treating and potentially curing ALS.