Recent advances in prime editing technologies and their promises for therapeutic applications.

Prime editing (PE) is a groundbreaking genome editing technology offering unparalleled precision in targeted genome modifications and has great potential for therapeutic applications. This review delves into the core principles of PE and emphasizes its advancements, applications, and prospects. We begin with a brief introduction to PE principles, followed by a detailed examination of recent improvements in efficiency, precision, and the scale of feasible edits. These improvements have been made to the PE systems through guide RNA engineering, protein engineering, DNA repair pathway screening, chromosomal or epigenomic modification, and in silico design and optimization tools. Furthermore, we highlight in vivo studies showcasing the therapeutic potential of PE to model and treat genetic diseases. Moreover, we discuss PE's versatile applications in saturation genome editing and its applicability to nonhuman organisms. In conclusion, we address the challenges and opportunities linked with PE, emphasizing its profound impact on biological research and therapeutics.

Nuclear Pyruvate Dehydrogenase Complex Regulates Histone Acetylation and Transcriptional Regulation in the Ethylene Response.

Ethylene plays its essential roles in plant development, growth, and defense responses by controlling the transcriptional reprograming, in which EIN2-C-directed regulation of histone acetylation is the first key-step for chromatin to perceive ethylene signaling. But how the nuclear acetyl coenzyme A (acetyl CoA) is produced to ensure the ethylene-mediated histone acetylation is unknown. Here we report that ethylene triggers the accumulation of the pyruvate dehydrogenase complex (PDC) in the nucleus to synthesize nuclear acetyl CoA to regulate ethylene response. PDC is identified as an EIN2-C nuclear partner, and ethylene triggers its nuclear accumulation. Mutations in PDC lead to an ethylene-hyposensitivity that results from the reduction of histone acetylation and transcription activation. Enzymatically active nuclear PDC synthesize nuclear acetyl CoA for EIN2-C-directed histone acetylation and transcription regulation. These findings uncover a mechanism by which PDC-EIN2 converges the mitochondrial enzyme mediated nuclear acetyl CoA synthesis with epigenetic and transcriptional regulation for plant hormone response.

Full and Partial Mid-substance ACL Rupture Using Mechanical Tibial Displacement in Male and Female Mice.

The anterior cruciate ligament (ACL) is the most commonly injured knee ligament. Surgical reconstruction is the gold standard treatment for ACL ruptures, but 20-50% of patients develop post-traumatic osteoarthritis (PTOA). ACL rupture is thus a well-recognized etiology of PTOA; however, little is known about the initial relationship between ligamentous injury and subsequent PTOA. The goals of this project were to: (1) develop both partial and full models of mid-substance ACL rupture in male and female mice using non-invasive mechanical methods by means of tibial displacement; and (2) to characterize early PTOA changes in the full ACL rupture model. A custom material testing system was utilized to induce either partial or full ACL rupture by means of tibial displacement at 1.6 or 2.0 mm, respectively. Mice were euthanized either (i) immediately post-injury to determine rupture success rates or (ii) 14 days post-injury to evaluate early PTOA progression following full ACL rupture. Our models demonstrated high efficacy in inciting either full or partial ACL rupture in male and female mice within the mid-substance of the ACL. These tools can be utilized for preclinical testing of potential therapeutics and to further our understanding of PTOA following ACL rupture.

Fifteen-week window for recurrent muscle strains in football: a prospective cohort of 3600 muscle strains over 23 years in professional Australian rules football.

OBJECTIVES: To determine the rates of muscle strain injury recurrence over time after return to play in Australian football and to quantify risk factors. METHODS: We analysed Australian Football League player data from 1992 to 2014 for rates of the four major muscle strain injury types (hamstring, quadriceps, calf and groin) diagnosed by team health professionals. Covariates for analysis were: recent history (≤8 weeks) of each of the four muscle strains; non-recent history (>8 weeks) of each; history of hip, knee anterior cruciate ligament, knee cartilage, ankle sprain, concussion or lumbar injury; age; indigenous race; match level and whether a substitute rule was in place. RESULTS: 3647 (1932 hamstring, 418 quadriceps, 458 calf and 839 groin) muscle strain injuries occurred in 272 759 player matches. For all muscle strains combined, the risk of injury recurrence gradually reduced, with recurrence risks of 9% (hamstring), 5% (quadriceps), 2% (calf) and 6% (groin) in the first match back and remaining elevated for 15 weeks after return to play. The strongest risk factor for each muscle injury type was a recent history of the same injury (hamstring: adjusted OR 13.1, 95% CI 11.5 to 14.9; calf OR 13.3, 95% CI 9.6 to 18.4; quadriceps: OR 25.2, 95% CI 18.8 to 33.8; groin OR 20.6, 95% CI 17.0 to 25.0), followed by non-recent history of the same injury (hamstring: adjusted OR 3.5, 95% CI 3.2 to 3.9; calf OR 4.4, 95% CI 3.6 to 5.4; quadriceps OR 5.2, 95% CI 4.2 to 6.4; groin OR 3.5, 95% CI 3.0 to 4.0). Age was an independent risk factor for calf muscle strains (adjusted OR 1.6, 95% CI 1.3 to 2.0). Recent hamstring injury increased the risk of subsequent quadriceps (adjusted OR 1.8, 95% CI 1.2 to 2.7) and calf strains (OR 1.8, 95% CI 1.2 to 2.6). During the 'substitute rule' era (2011-2014), hamstring (adjusted OR 0.76, 95% CI 0.67 to 0.86), groin (OR 0.78, 95% CI 0.65 to 0.93) and quadriceps (OR 0.70, 95% CI 0.53 to 0.92) strains were less likely than outside of that era but calf (OR 1.6, 95% CI 1.3 to 1.9) strains were more likely than before the substitute rule era. CONCLUSION: Recent injury is the greatest risk factor for the four major muscle strains, with increased risk persisting for 15 weeks after return to play.

Is injury associated with team performance in elite Australian football? 20 years of player injury and team performance data that include measures of individual player value.

OBJECTIVES: To determine whether specific injury measures were associated with team performance in the Australian Football League (AFL). METHODS: 15 289 injuries caused players from 18 teams to miss 51 331 matches between 1997 and 2016. Data were aggregated to the team level. We analysed the associations among injury measures and team performance (reaching finals/playoffs and specific ladder/table position). Injury measures per team included: injury incidence, injury severity, injury burden, player match availability and percentage of the full player roster injured. We also weighted injury measures by five measures of player value. RESULTS: AFL teams' injury burden and player match availability were associated with final table position (r2=0.03, p<0.05). Player value weighted injury burden was different between finalists and non-finalists (mean difference=-8, p<0.001) and explained 12% of the variation in the table position of teams (p<0.001). For a team, nine missed matches due to injury (burden weighted by a best and fairest player rating system) was associated with one lower table position. Player match availability weighted by player value was higher for finalists than non-finalists (mean difference=1.7, p<0.01) and explained 7% of the variation in the table position of teams (p<0.001). DISCUSSION AND POTENTIAL IMPLICATIONS: The impact of injury (burden weighted by best and fairest) explained up to 12% of the variation in final table position-this is particularly relevant to making/not making playoffs as well as home ground/travel advantages for those teams that make the one-game format of AFL playoffs (not home-away or best of seven format).

Prescription Medication Obtainment Methods and Misuse.

BACKGROUND: Abuse of prescription medications is an ever-expanding epidemic in the United States. OBJECTIVE: This study intends to help provide physicians with more knowledge about the behaviors that patients with a substance use disorder may exhibit in an effort to obtain medications. DESIGN: Patients who were willing to participate in the survey were interviewed by a physician. SETTING: Patients were screened, selected, and interviewed while participating in an inpatient rehabilitation program. RESULTS: Thirty-six patients completed the survey. There was a mean of 50.2 prescriptions per person. An average of 1.2 states was utilized by the surveyed patient population. There was an average of 2.11 providers seen per patient. Data show that 78% of patients surveyed utilized more than one pharmacy. The type of medications obtained by respondents were as follows: opioids, 35 (97.2%); sedative-hypnotics, 17 (47.4%); and amphetamines, 2 (5.5%). Seventy-five percent of patients (27 of the 36) stated that they feigned symptoms in attempts to obtain prescriptions. Two patients used a falsified (via mislabeling) magnetic resonance image of injury. Two patients paid a physician outright for the prescription. Three patients (8.3%) stated they would physically harm themselves in an attempt to obtain prescription medications. CONCLUSIONS: It may be noted that patients seeking prescription medications tend to utilize more than one physician and more than one pharmacy. On the basis of survey results, it seems that primary care and pain management physicians are considered the easiest venues to obtain prescription medications. It suggests that patients will go to great lengths to obtain prescription medications.

Cerebral sinovenous thrombosis in children: diagnosis and treatment.

Cerebral sinovenous thrombosis (CSVT) is a pediatric stroke syndrome that occurs uncommonly in association with a number of common pediatric problems, most notably dehydration and infection-otitis media in older children, in particular. Cerebral sinovenous thrombosis involves considerable risk of morbidity and mortality. In the pediatric population, neonates are most commonly affected, but no age group is spared. The clinical manifestations of CSVT vary across age groups and include headache, nausea/vomiting, diplopia, seizures, altered mental status, cranial nerve palsies, and papilledema. Neuroimaging is critical to establishing the diagnosis, and although a variety of modalities are available, the diagnosis is most convincingly made via magnetic resonance imaging with venographic sequencing. Management of CSVT combines medical and surgical approaches and should occur in a multidisciplinary pediatric hospital setting. Anticoagulation is a controversial but generally recommended element of CSVT treatment. Prognosis is related to the extent of vessel and brain parenchymal involvement as well to timeliness of diagnosis and institution of therapy. Long-term follow-up should involve pediatric neurology and ophthalmology and, whenever indicated, rehabilitational therapy as well.