A Systematic Review and Meta-Analysis of MicroRNA as Predictive Biomarkers of Acute Kidney Injury.

Acute kidney injury (AKI) affects 10-15% of hospitalised patients and arises after severe infections, major surgeries, or exposure to nephrotoxic drugs. AKI diagnosis based on creatinine level changes lacks specificity and may be delayed. MicroRNAs are short non-coding RNA secreted by all cells. This review of studies measuring miRNAs in AKI aimed to verify miRNAs as diagnostic markers. The study included data from patients diagnosed with AKI due to sepsis, ischaemia, nephrotoxins, radiocontrast, shock, trauma, and cardiopulmonary bypass. Out of 71 studies, the majority focused on AKI in sepsis patients, followed by cardiac surgery patients, ICU patients, and individuals receiving nephrotoxic agents or experiencing ischaemia. Studies that used untargeted assays found 856 differentially regulated miRNAs, although none of these were confirmed by more than one study. Moreover, 68 studies measured miRNAs by qRT-PCR, and 2 studies reported downregulation of miR-495-3p and miR-370-3p in AKI patients with sepsis after the AKI diagnosis. In three studies, upregulation of miR-21 was reported at the time of the AKI diagnosis with a significant pooled effect of 0.56. MiR-21 was also measured 19-24 h after cardiac surgery in three studies. However, the pooled effect was not significant. Despite the considerable research into miRNA in AKI, there is a knowledge gap in their applicability as diagnostic markers of AKI in humans.

Maturation-dependent patterns of knee injuries among symptomatic pediatric soccer players on MRI.

OBJECTIVE: To systematically investigate the prevalence of knee MRI findings among symptomatic pediatric soccer players with respect to skeletal maturity and to identify predictors of surgery. METHODS: This IRB-approved, HIPAA-compliant retrospective study included soccer players (< 18 years of age) who underwent MRI examinations in the past 5 years (2018-2023). Two radiologists retrospectively and independently reviewed all examinations to categorize skeletal maturity and to identify osseous and soft tissue findings. Findings were compared between maturation groups, and logistic regression models were used to identify predictors of surgery. RESULTS: Ninety-seven players (45 boys, 52 girls) included 39 skeletally immature, 21 maturing, and 37 mature knees. Kappa coefficient for interobserver reliability ranged between 0.65 and 1.00. Osgood-Schlatter disease (OSD) was more common among immature than maturing and mature knees (25% vs 14% and 5%, p = 0.04); anterior cruciate ligament (ACL) injury was more common among maturing and mature than immature knees (59% and 48%, vs 15%, p < 0.01); and meniscal tears were more common among mature than immature and maturing knees (medial, 41% vs 18% and 14%, p = 0.03; lateral, 43% vs 21% and 19%, p = 0.04). Players in the mature group were more likely to undergo surgery (p = 0.01). The presence of an effusion (OR = 19.5, 95% CI 2.8-240.9, p = 0.01), ACL injury (OR = 170.0, 95% CI 1.3-6996.9, p < 0.01), and lateral meniscal tears (OR = 10.8, 95% CI 1.8-106.1, p = 0.02) were independent predictors of surgery. CONCLUSION: Differential patterns of injury were found among symptomatic pediatric soccer players; the presence of an effusion, ACL injury, and lateral meniscal tears were independent predictors of surgery, likely contributing to the higher rates of surgery among skeletally mature players.

Tarsal Navicular Bone Stress Injuries: A Multicenter Case Series Investigating Clinical Presentation, Diagnostic Approach, Treatment, and Return to Sport in Adolescent Athletes.

BACKGROUND: Tarsal navicular bone stress injuries (BSIs) are considered "high risk" because of prolonged healing times and higher rates of nonunion in adult populations but, to our knowledge, have not been comprehensively examined in adolescent athletes. PURPOSE: To describe the characteristics of tarsal navicular BSIs in adolescents. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A retrospective analysis of patients aged 10 to 19 years with a radiographically diagnosed tarsal navicular BSI was performed at 8 academic centers over a 9-year study period. Age, sex, body mass index (BMI), primary sport, physical examination findings, imaging, treatment, surgical technique, return-to-sport time, and complications were analyzed. RESULTS: Among 110 patients (mean age, 14.7 ± 2.7 years; 65% female), common primary sports were cross-country/track and field (29/92 [32%]) and gymnastics/dance (25/92 [27%]). Grade 4 BSIs were identified in 44% (48/110) of patients, with fracture lines present on radiography or magnetic resonance imaging. Nonoperative treatment (mean age, 14.4 ± 2.6 years), consisting of protected weightbearing and either a protective boot (69/88 [78%]) or a cast (19/88 [22%]), was trialed in all patients and was successful in 94 patients (85%). Operative treatment (mean age, 17.1 ± 1.4 years) was ultimately pursued for 16 patients (15%). Patients who required surgery had a higher BMI and a higher percentage of fracture lines present on imaging (nonoperative: 36/94 [38%]; operative: 14/16 [88%]). The median time to return to weightbearing, running, and full sport was significantly longer in duration for the operative group than the nonoperative group (P <.05). Complications associated with surgery included 1 case each of delayed union, nonunion, and painful implants, the latter of which required secondary surgery. CONCLUSION: Adolescent tarsal navicular BSIs were identified most commonly in female patients in leanness sports. Adolescents who required surgery were more likely to be older, have higher BMIs, and have grade 4 BSIs, and they returned to sport within a median of 5 months after single- or double-screw fixation with a low risk of postoperative complications. A better understanding of the presenting signs and symptoms and appropriate diagnostic imaging of navicular BSIs may lead to an earlier diagnosis and improved outcomes.

Linking Patients' Goals and Priorities to Recommendations for Medication Changes in a Polypharmacy-Focused Structured Clinical Pathway.

Polypharmacy is associated with poorer health outcomes in older adults. It is challenging to minimize the harmful effects of medications while maximizing benefits of single-disease-focused recommendations. Integrating patient input can balance these factors. The objectives are to describe the goals, priorities, and preferences of participants asked about these in a structured process to polypharmacy, and to describe the extent that decision-making within the process mapped onto these, signaling a patient-centered approach. This is a single-group quasi-experimental study, nested within a feasibility randomized controlled trial. Patient goals and priorities were mapped to medication recommendations made during the intervention. Overall, there were 33 participants who reported 55 functional goals and 66 symptom priorities, and 16 participants reported unwanted medications. Overall, 154 recommendations for medication alterations occurred. Of those, 68 (44%) recommendations mapped to the individual's goals and priorities, whereas the rest were based on clinical judgment where no priorities were expressed. Our results signal this process supports a patient-centered approach: allowing conversations around goals and priorities in a structured process to polypharmacy should be integrated into subsequent medication decisions.

Team approach to polypharmacy evaluation and reduction: feasibility randomized trial of a structured clinical pathway to reduce polypharmacy.

BACKGROUND: Polypharmacy is associated with poorer health outcomes in older adults. Other than the associated multimorbidity, factors contributing to this association could include medication adverse effects and interactions, difficulties in managing complicated medication regimes, and reduced medication adherence. It is unknown how reversible these negative associations may be if polypharmacy is reduced. The purpose of this study was to determine the feasibility of implementing an operationalized clinical pathway aimed to reduce polypharmacy in primary care and to pilot measurement tools suitable for assessing change in health outcomes in a larger randomized controlled trial (RCT). METHODS: We randomized consenting patients ≥ 70 years old on ≥ 5 long-term medications into intervention or control groups. We collected baseline demographic information and research outcome measures at baseline and 6 months. We assessed four categories of feasibility outcomes: process, resource, management, and scientific. The intervention group received TAPER (team approach to polypharmacy evaluation and reduction), a clinical pathway for reducing polypharmacy using "pause and monitor" drug holiday approach. TAPER integrates patients' goals, priorities, and preferences with an evidence-based "machine screen" to identify potentially problematic medications and support a tapering and monitoring process, all supported by a web-based system, TaperMD. Patients met with a clinical pharmacist and then with their family physician to finalize a plan for optimization of medications using TaperMD. The control group received usual care and were offered TAPER after follow-up at 6 months. RESULTS: All 9 criteria for feasibility were met across the 4 feasibility outcome domains. Of 85 patients screened for eligibility, 39 eligible patients were recruited and randomized; two were excluded post hoc for not meeting the age requirement. Withdrawals (2) and losses to follow-up (3) were small and evenly distributed between arms. Areas for intervention and research process improvement were identified. In general, outcome measures performed well and appeared suitable for assessing change in a larger RCT. CONCLUSIONS: Results from this feasibility study indicate that TAPER as a clinical pathway is feasible to implement in a primary care team setting and in an RCT research framework. Outcome trends suggest effectiveness. A large-scale RCT will be conducted to investigate the effectiveness of TAPER on reducing polypharmacy and improving health outcomes. TRIAL REGISTRATION: clinicaltrials.gov NCT02562352 , Registered September 29, 2015.

Team approach to polypharmacy evaluation and reduction: study protocol for a randomized controlled trial.

BACKGROUND: Polypharmacy in older adults can be associated with negative outcomes including falls, impaired cognition, reduced quality of life, and general and functional decline. It is not clear to what extent these are reversible if the number of medications is reduced. Primary care does not have a systematic approach for reducing inappropriate polypharmacy, and there are few, if any, approaches that account for the patient's priorities and preferences. The primary objective of this study is to test the effect of TAPER (Team Approach to Polypharmacy Evaluation and Reduction), a structured operationalized clinical pathway focused on reducing inappropriate polypharmacy. TAPER integrates evidence tools for identifying potentially inappropriate medications, tapering, and monitoring guidance and explicit elicitation of patient priorities and preferences. We aim to determine the effect of TAPER on the number of medications (primary outcome) and health-related outcomes associated with polypharmacy in older adults. METHODS: We designed a multi-center randomized controlled trial, with the lead implementation site in Hamilton, Ontario. Older adults aged 70 years or older who are on five or more medications will be eligible to participate. A total of 360 participants will be recruited. Participants will be assigned to either the control or intervention arm. The intervention involves a comprehensive multidisciplinary medication review by pharmacists and physicians in partnership with patients. This review will be focused on reducing medication burden, with the assumption that this will reduce the risks and harms of polypharmacy. The control group is a wait list, and control patients will be given appointments for the TAPER intervention at a date after the final outcome assessment. All patients will be followed up and outcomes measured in both groups at baseline and 6 months. DISCUSSION: Our trial is unique in its design in that it aims to introduce an operationalized structured clinical pathway aimed to reduce polypharmacy in a primary care setting while at the same time recording patient's goals and priorities for treatment. TRIAL REGISTRATION: Clinical Trials.gov NCT02942927. First registered on October 24, 2016.

C acid decarboxylases required for C photosynthesis are active in the mid-vein of the C species Arabidopsis thaliana, and are important in sugar and amino acid metabolism.

Cells associated with veins of petioles of C(3) tobacco possess high activities of the decarboxylase enzymes required in C(4) photosynthesis. It is not clear whether this is the case in other C(3) species, nor whether these enzymes provide precursors for specific biosynthetic pathways. Here, we investigate the activity of C(4) acid decarboxylases in the mid-vein of Arabidopsis, identify regulatory regions sufficient for this activity, and determine the impact of removing individual isoforms of each protein on mid-vein metabolite profiles. This showed that radiolabelled malate and bicarbonate fed to the xylem stream were incorporated into soluble and insoluble material in the mid-vein of Arabidopsis leaves. Compared with the leaf lamina, mid-veins possessed high activities of NADP-dependent malic enzyme (NADP-ME), NAD-dependent malic enzyme (NAD-ME) and phosphoenolpyruvate carboxykinase (PEPCK). Transcripts derived from both NAD-ME, one PCK and two of the four NADP-ME genes were detectable in these veinal cells. The promoters of each decarboxylase gene were sufficient for expression in mid-veins. Analysis of insertional mutants revealed that cytosolic NADP-ME2 is responsible for 80% of NADP-ME activity in mid-veins. Removing individual decarboxylases affected the abundance of amino acids derived from pyruvate and phosphoenolpyruvate. Reducing cytosolic NADP-ME activity preferentially affected the sugar content, whereas abolishing NAD-ME affected both the amino acid and the glucosamine content of mid-veins.

Light and plastid signals regulate the expression of the pea plastocyanin gene through a common region at the 5' end of the coding region.

Expression of the pea plastocyanin gene (PetE) is regulated by light and plastid signals. Previous work indicated that light and plastid regulation of pea PetE operates post-transcriptionally in transgenic tobacco, and requires the correct 5' terminus of the PetE transcript and the PetE-coding region. The post-transcriptional light and plastid regulation of pea PetE has now been demonstrated to operate in transgenic Arabidopsis, where in contrast the endogenous PETE gene is regulated transcriptionally. Transgenic tobacco seedlings containing constructs with progressive 3' deletions of the PetE-coding region fused to the luciferase (Luc) reporter gene demonstrate that the first 60 nucleotides of the coding region are sufficient for regulated accumulation of Luc transcripts by light and plastid signalling pathways affected by treatment with norflurazon and lincomycin. PetE constructs containing premature stop codons were generated to investigate whether translation has a role in light or plastid regulation. Insertion of a stop codon in place of the second codon of the PetE-coding region diminished both light and plastid regulation of PetE transcripts, whereas stop codons inserted later in the transcript had no effect on light or plastid regulation. These experiments indicate that the 5' end of the plastocyanin-coding region contains sequences important for regulation by light and plastid signals.