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Self-replicating RNA (srRNA) technology, in comparison to mRNA vaccines, has shown dose-sparing by approximately 10-fold and more durable immune responses. However, no improvements are observed in the adverse events profile. Here, we develop an srRNA vaccine platform with optimized non-coding regions and demonstrate immunogenicity and safety in preclinical and clinical development. Optimized srRNA vaccines generate protective immunity (according to the WHO defined thresholds) at doses up to 1,000,000-fold lower than mRNA in female mouse models of influenza and rabies. Clinically, safety and immunogenicity of RBI-4000, an srRNA vector encoding the rabies glycoprotein, was evaluated in a Phase I study (NCT06048770). RBI-4000 was able to elicit de novo protective immunity in the majority of healthy participants when administered at a dose of 0.1, 1, or 10 microgram (71%, 94%, 100%, respectively) in a prime-boost schedule. Similarly, we observe immunity above the WHO benchmark of protection following a single administration in most participants at both 1 and 10 microgram doses. There are no serious adverse events reported across all cohorts. These data establish the high therapeutic index of optimized srRNA vectors, demonstrating feasibility of both low dose and single dose approaches for vaccine applications. Here the authors report an optimized self-replicating RNA (srRNA) vaccine approach that generates protective immunity at much lower doses than mRNA vaccines in mice. In a Phase 1 study using rabies glycoprotein as antigen, they show robust immune responses at doses as low as 0.1 µg, with a favorable safety profile. [ABSTRACT FROM AUTHOR]

As anterior cruciate ligament (ACL) reconstruction has evolved to less invasive, more anatomical approaches, rehabilitation of the injured athlete has likewise become more progressive and innovative, with a sound understanding of graft and fixation strength and biologic healing-remodeling constraints. This review discusses these innovations including specific considerations before surgery, when planning rehabilitation timetables, and the importance of reestablishing nonimpaired active and passive knee range of motion and biarticular musculotendinous extensibility in positions of function. Concepts of self-efficacy or confidence and reestablishing the "athlete role" are also addressed. Since ACL injury and reinjury are largely related to the influence of structure-form-function on dynamic knee joint stability, the interrelationships between sensorimotor, neuromuscular, and conventional resistance training are also discussed. Although pivot shift "giving way" relates to function loss following ACL injury, anterior translational laxity often does not. Although there is growing evidence that progressive eccentric training may benefit the patient following ACL reconstruction, there is less evidence supporting the use of functional ACL knee braces. Of considerable importance is selecting and achieving a criteria-based progression to sports-specific training, reestablishing osseous homeostasis and improved bone density, blending open and closed kinetic chain exercises at the appropriate time period, and appreciating the influence of the trunk, upper extremities, and sports equipment use on knee loads. We believe that knee dysfunction and functional recovery should be considered from a local, regional, and global perspective. These concepts are consolidated into our approach to prepare patients for return to play including field testing and maintenance training [ABSTRACT FROM AUTHOR]

An 8-week-old, male, mixed breed puppy was presented because of progressive respiratory distress. Thoracic radiographs revealed innumerable coalescing pulmonary bullae throughout the lungs with increased soft tissue opacity of the remaining pulmonary parenchyma and tension pneumothorax. Necropsy and histopathological findings were compatible with bullous emphysema and marked neutrophilic to histiocytic bronchointerstitial pneumonia with necrosis, bronchiectasis, fibrosis, dystrophic mineralization, and vasculitis with thrombosis. Tests for agents of infectious disease did not reveal an underlying etiological agent. This case highlights the radiographic, gross necropsy, and histopathologic features of a puppy with bullous emphysema and severe bronchointerstitial pneumonia with necrosis., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)