Pediatric Burns: From Acute Care Through Reconstruction in 2024.

Children are disproportionately affected by burn injuries. Differences between adult and pediatric burns range from epidemiologic characteristics to pathophysiological considerations, which vary between different age subgroups. All these factors must be considered in each phase of burn care. This article reviews the most important aspects of the management of a pediatric burned patient starting from the acute through reconstructive phases.

Semi-automated protocol to quantify and characterize fluorescent three-dimensional vascular images.

The microvasculature facilitates gas exchange, provides nutrients to cells, and regulates blood flow in response to stimuli. Vascular abnormalities are an indicator of pathology for various conditions, such as compromised vessel integrity in small vessel disease and angiogenesis in tumors. Traditional immunohistochemistry enables the visualization of tissue cross-sections containing exogenously labeled vasculature. Although this approach can be utilized to quantify vascular changes within small fields of view, it is not a practical way to study the vasculature on the scale of whole organs. Three-dimensional (3D) imaging presents a more appropriate method to visualize the vascular architecture in tissue. Here we describe the complete protocol that we use to characterize the vasculature of different organs in mice encompassing the methods to fluorescently label vessels, optically clear tissue, collect 3D vascular images, and quantify these vascular images with a semi-automated approach. To validate the automated segmentation of vascular images, one user manually segmented one hundred random regions of interest across different vascular images. The automated segmentation results had an average sensitivity of 83±11% and an average specificity of 91±6% when compared to manual segmentation. Applying this procedure of image analysis presents a method to reliably quantify and characterize vascular networks in a timely fashion. This procedure is also applicable to other methods of tissue clearing and vascular labels that generate 3D images of microvasculature.

Sequence- and Structure-Dependent Cytotoxicity of Phosphorothioate and 2'-O-Methyl Modified Single-Stranded Oligonucleotides.

Single-stranded oligonucleotides (SSOs) are a rapidly expanding class of therapeutics that comprises antisense oligonucleotides, microRNAs, and aptamers, with ten clinically approved molecules. Chemical modifications such as the phosphorothioate backbone and the 2'-O-methyl ribose can improve the stability and pharmacokinetic properties of therapeutic SSOs, but they can also lead to toxicity in vitro and in vivo through nonspecific interactions with cellular proteins, gene expression changes, disturbed RNA processing, and changes in nuclear structures and protein distribution. In this study, we screened a mini library of 277 phosphorothioate and 2'-O-methyl-modified SSOs, with or without mRNA complementarity, for cytotoxic properties in two cancer cell lines. Using circular dichroism, nucleic magnetic resonance, and molecular dynamics simulations, we show that phosphorothioate- and 2'-O-methyl-modified SSOs that form stable hairpin structures through Watson-Crick base pairing are more likely to be cytotoxic than those that exist in an extended conformation. In addition, moderate and highly cytotoxic SSOs in our dataset have a higher mean purine composition than pyrimidine. Overall, our study demonstrates a structure-cytotoxicity relationship and indicates that the formation of stable hairpins should be a consideration when designing SSOs toward optimal therapeutic profiles.

Systematic review of non-invasive ventilation and craniofacial fractures: a multidisciplinary perspective and recommendations for management.

The anatomically complex craniofacial skeleton demands special consideration when caring for cases of polytrauma or medically compromised patients with craniofacial fractures. This paper utilises a systematic review and multidisciplinary opinions to create an algorithm for the hospital-based care of patients with craniofacial fractures (base of skull, orbit, paranasal sinus, and mandible) who require non-invasive ventilation (NIV). Each fracture location has a unique predisposition to a different type of emphysema and associated morbidity. The risk of developing emphysema, combined with its potential severity, is stratified against the harm of not providing NIV for the holistic care of the patient. The aim of this paper is to synthesise evidence from a systematic review of existing literature with multidisciplinary opinions to develop a concise algorithm that outlines the optimal treatment of patients with craniofacial fractures who require NIV.

Dynamics and recognition of homeodomain containing protein-DNA complex of IRX4.

Iroquois Homeobox 4 (IRX4) belongs to a family of homeobox TFs having roles in embryogenesis, cell specification, and organ development. Recently, large scale genome-wide association studies and epigenetic studies have highlighted the role of IRX4 and its associated variants in prostate cancer. No studies have investigated and characterized the structural aspect of the IRX4 homeodomain and its potential to bind to DNA. The current study uses sequence analysis, homology modeling, and molecular dynamics simulations to explore IRX4 homeodomain-DNA recognition mechanisms and the role of somatic mutations affecting these interactions. Using publicly available databases, gene expression of IRX4 was found in different tissues, including prostate, heart, skin, vagina, and the protein expression was found in cancer cell lines (HCT166, HEK293), B cells, ascitic fluid, and brain. Sequence conservation of the homeodomain shed light on the importance of N- and C-terminal residues involved in DNA binding. The specificity of IRX4 homodimer bound to consensus human DNA sequence was confirmed by molecular dynamics simulations, representing the role of conserved amino acids including R145, A194, N195, S190, R198, and R199 in binding to DNA. Additional N-terminal residues like T144 and G143 were also found to have specific interactions highlighting the importance of N-terminus of the homeodomain in DNA recognition. Additionally, the effects of somatic mutations, including the conserved Arginine (R145, R198, and R199) residues on DNA binding elucidated the importance of these residues in stabilizing the protein-DNA complex. Secondary structure and hydrogen bonding analysis showed the roles of specific residues (R145, T191, A194, N195, R198, and R199) in maintaining the homogeneity of the structure and its interaction with DNA. The differences in relative binding free energies of all the mutants shed light on the structural modularity of this protein and the dynamics behind protein-DNA interaction. We also have predicted that the C-terminal sequence of the IRX4 homeodomain could act as a potential cell-penetrating peptide, emphasizing the role these small peptides could play in targeting homeobox TFs.

Targeting the COMMD4-H2B protein complex in lung cancer.

BACKGROUND: Lung cancer is the biggest cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85-90% of all lung cancers. Identification of novel therapeutic targets are required as drug resistance impairs chemotherapy effectiveness. COMMD4 is a potential NSCLC therapeutic target. The aims of this study were to investigate the COMMD4-H2B binding pose and develop a short H2B peptide that disrupts the COMMD4-H2B interaction and mimics COMMD4 siRNA depletion. METHODS: Molecular modelling, in vitro binding and site-directed mutagenesis were used to identify the COMMD4-H2B binding pose and develop a H2B peptide to inhibit the COMMD4-H2B interaction. Cell viability, DNA repair and mitotic catastrophe assays were performed to determine whether this peptide can specially kill NSCLC cells. RESULTS: Based on the COMMD4-H2B binding pose, we have identified a H2B peptide that inhibits COMMD4-H2B by directly binding to COMMD4 on its H2B binding binding site, both in vitro and in vivo. Treatment of NSCLC cell lines with this peptide resulted in increased sensitivity to ionising radiation, increased DNA double-strand breaks and induction of mitotic catastrophe in NSCLC cell lines. CONCLUSIONS: Our data shows that COMMD4-H2B represents a novel potential NSCLC therapeutic target.

Determinants of lipid clinic referral and attendance in a multi-ethnic adult population in south London: a cross-sectional study.

BACKGROUND: Primary dyslipidaemias, including familial hypercholesterolaemia, are underdiagnosed genetic disorders that substantially increase risk for premature coronary artery disease in adults. Early identification of primary dyslipidaemias via lipid clinic referral optimises patient management and enables cascade screening of relatives. Improving the identification of primary dyslipidaemias, and understanding disparities in ascertainment and management, is an NHS priority. We aimed to assess determinants of lipid clinic referral or attendance (LCR) in ethnically diverse adults. METHODS: We did a retrospective cross-sectional study using the Lambeth DataNet containing anonymised data from 41 general practitioner (GP) practices in south London. We looked at referral data for adult patients aged 18 years and older from Jan 1, 1995, until May 14, 2018. LCR was the main outcome. We used sequential multilevel logistic regression models adjusted for practice effects to estimate the odds of LCR assessed across six ethnic groups (reference group White) and patient-level factors (demographic, socioeconomic, lifestyle, comorbidities, total cholesterol [TC] >7·5mmol/L, statin prescription, and practice factors). The study was approved by NHS South East London Clinical Commissioning Group (CCG) and NHS Lambeth CCG. FINDINGS: 780 (0·23%) of 332 357 adult patients were coded as referred (n=538) or seen (n=252) in a lipid clinic. 164 487 (46·49%) were women (appendix). The fully adjusted model for odds of LCR showed the following significant associations for age (odds ratio [OR] 0·96, 95% CI 0·96-0·97, p<0·001); Black, African, Caribbean, or Black-British ethnicity (0·67, 0·53-0·84, p=0·001); ex-smoker status (1·29, 1·05-1·57, p=0·014); TC higher than 7·5 mmol/L (12·18, 9·60-15·45, p<0·001); statin prescription (14·01, 10·85-18·10, p<0·001); diabetes (0·72, 0·58-0·91, p=0·005); high-frequency GP attendance at seven or more GP consultations in the past year (1·49, 1·21-1·84, p<0·001); high GP-density (0·5-0·99 full-time equivalent GPs per 1000 patients; 2·70, 1·23-5·92, p=0·013). Sensitivity analyses for LCR restricted to familial hypercholesterolaemia-coded patients (n=581) found associations with TC higher than 7·5 mmol/L (4·26, 1·89-9·62, p<0·001), statin prescription (16·96, 2·19-131·36, p=0·007), and high GP-density (5·73, 1·27-25·93, p=0·023), with no significant associations with ethnicity. The relative contribution of GP practices to LCR was 6·32% of the total variance. There were no significant interactions between ethnicity and deprivation, age, or obesity. INTERPRETATION: While interpretation is limited by the accuracy and completeness of coded records, the study showed factors associated with a higher likelihood of LCR included individuals recorded as having TC higher than 7·5 mmol/L, statin prescription, ex-smoker status, high-frequency GP attendance, and registration at a GP practice with 0·5-0·99 GP density. Patients with increasing age; Black, African, Caribbean, or Black-British ethnicity patients; and patients with diabetes had lower odds of LCR. Finally, the difference in odds of LCR between Black and White patients highlights potential health inequalities. FUNDING: NHS Race & Health Observatory.

Elevated Intraocular Pressure in Periorbital Sweet's Syndrome.

A 66-year-old immunocompromised man presented with cellulitis around the left eye that was initially concerning for necrotizing fasciitis. Exam findings were remarkable for exquisite periocular tenderness with rigid, immobile eyelids resulting from severe erythema, edema, and induration. Given the concern for orbital compartment syndrome and a necrotizing infection, the patient was taken urgently to the operating room for debridement of the eyelid skin as well as an urgent lateral canthotomy and cantholysis. His eye exam revealed 360° of hemorrhagic chemosis, no relative afferent pupillary defect, and an ipsilateral elevated intraocular pressure of 35 mm Hg. No visual acuity measurement could be obtained secondary to the patient's altered mental status. His intraocular pressure normalized after treatment with antihypertensive drops and further extension of the canthotomy. Histopathological analysis showed extensive neutrophilic infiltrate of the dermis which was compatible with a diagnosis of Sweet's syndrome.

Chronic kidney disease promotes cerebral microhemorrhage formation.

BACKGROUND: Chronic kidney disease (CKD) is increasingly recognized as a stroke risk factor, but its exact relationship with cerebrovascular disease is not well-understood. We investigated the development of cerebral small vessel disease using in vivo and in vitro models of CKD. METHODS: CKD was produced in aged C57BL/6J mice using an adenine-induced tubulointerstitial nephritis model. We analyzed brain histology using Prussian blue staining to examine formation of cerebral microhemorrhage (CMH), the hemorrhagic component of small vessel disease and the neuropathological substrate of MRI-demonstrable cerebral microbleeds. In cell culture studies, we examined effects of serum from healthy or CKD patients and gut-derived uremic toxins on brain microvascular endothelial barrier. RESULTS: CKD was induced in aged C57BL/6J mice with significant increases in both serum creatinine and cystatin C levels (p < 0.0001) without elevation of systolic or diastolic blood pressure. CMH was significantly increased and positively correlated with serum creatinine level (Spearman r = 0.37, p < 0.01). Moreover, CKD significantly increased Iba-1-positive immunoreactivity by 51% (p < 0.001), induced a phenotypic switch from resting to activated microglia, and enhanced fibrinogen extravasation across the blood-brain barrier (BBB) by 34% (p < 0.05). On analysis stratified by sex, the increase in CMH number was more pronounced in male mice and this correlated with greater creatinine elevation in male compared with female mice. Microglial depletion with PLX3397 diet significantly decreased CMH formation in CKD mice without affecting serum creatinine levels. Incubation of CKD serum significantly reduced transendothelial electrical resistance (TEER) (p < 0.01) and increased sodium fluorescein permeability (p < 0.05) across the endothelial monolayer. Uremic toxins (i.e., indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide) in combination with urea and lipopolysaccharide induced a marked drop in TEER compared with the control group (p < 0.0001). CONCLUSIONS: CKD promotes the development of CMH in aged mice independent of blood pressure but directly proportional to the degree of renal impairment. These effects of CKD are likely mediated in part by microglia and are associated with BBB impairment. The latter is likely related to gut-derived bacteria-dependent toxins classically associated with CKD. Overall, these findings demonstrate an important role of CKD in the development of cerebral small vessel disease.

Hypertelorbitism Corrected by Facial Bipartition Improves Exotropia.

BACKGROUND: The purpose of this study was to detail perioperative ophthalmologic evaluations to characterize functional ocular outcomes after facial bipartition surgery. METHODS: Patients with hypertelorbitism who underwent facial bipartition surgery were studied specifically for eye motility disorders by separating patients into rare craniofacial clefts (midline and paramedian) (n = 34) and craniofacial dysostosis (Apert, Crouzon, and Pfeiffer) (n = 74). Preoperative and postoperative (12 months) ophthalmologic examinations (with depth perception tests), computed tomography scans, and magnetic resonance imaging scans were analyzed. RESULTS: Among craniofacial cleft patients, mean interdacryon distance was reduced from 39 ± 4 mm to 17 ± 2 mm, with strabismus improved from 88 percent (exotropia 82 percent) preoperatively to only 29 percent postoperatively. Depth perception improved to a lesser degree, with abnormal tests at a rate of 79 percent preoperatively to 56 percent postoperatively. Wider hypertelorbitism had a higher degree of strabismus. Among craniofacial dysostotic patients, mean interdacryon distance was reduced from 37 ± 3 mm to 17 ± 2 mm, and strabismus improved from 55 percent to only 14 percent. Depth perception improved to a lesser degree, with 68 percent abnormal tests preoperatively and 46 percent postoperatively. Apert patients had more V-pattern strabismus and exotropia (79 percent) than did other craniofacial dysostosis patients (42 percent). CONCLUSIONS: The authors' data indicate that facial bipartition for hypertelorbitism-known to improve periorbital aesthetics-also improves eye motility disturbances. Thus, vision problems related to exotropia should be considered a functional indication for facial bipartition surgery in patients with hypertelorbitism. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Current Practices in Dorsal Augmentation Rhinoplasty.

BACKGROUND: Dorsal augmentation rhinoplasty addresses the aesthetic and functional impairments caused by a deficient nasal dorsum. Augmentation rhinoplasty can be performed using a variety of different surgical techniques and grafting materials that all have distinct advantages and disadvantages. METHODS: Grafting materials have unique characteristics, uses, and safety profiles. A detailed overview of various grafting materials and their uses, risks, and benefits is provided. RESULTS: Autologous grafting materials include septal cartilage, auricular cartilage, and costal cartilage. These donor sites can provide various amounts of en bloc or diced cartilage. Alternatively, bone may be used when strong structural stability is required, and soft tissue may be used to fill mild to moderate defects. Homologous grafts (e.g., irradiated and nonirradiated rib) and acellular dermal matrices are alternatives to autologous graft with many similar advantages and no need for an additional surgical site. Lastly, alloplastic implants may be successfully used for dorsal augmentation if both patient and surgeon understand their associated risks. CONCLUSION: To perform successful dorsal augmentation, surgeons should be familiar with the wide variety of operative approaches and augmentation materials that are currently available and understand their risks, benefits, and uses.

Kidney Function Is Not Related to Brain Amyloid Burden on PET Imaging in The 90+ Study Cohort.

Cognitive decline is common in chronic kidney disease (CKD). While the evidence of vascular cognitive impairment in this population is robust, the role of Alzheimer's pathology is unknown. We evaluated serum cystatin C-estimated glomerular filtration rate (eGFR), brain amyloid-ß positron emission tomography (PET) imaging, and cognitive function in 166 participants from The 90+ Study. Mean age was 93 years (range 90-107) and 101 (61%) were women; 107 participants had normal cognitive status while 59 participants had cognitive impairment no dementia (CIND) or dementia. Mean ± standard deviation cystatin C was 1.59 ± 0.54 mg/L with eGFR 40.7 ± 18.7 ml/min/1.73m2. Higher amyloid-ß burden was associated with dementia, but not with age, diabetes, hypertension, or cardiovascular disease. We found no association between brain amyloid-ß burden and cystatin C eGFR. We previously reported that kidney function was associated with cognition and cerebral microbleeds in the same cohort of oldest-old adults (90+ years old). Collectively, these findings suggest that microvascular rather than Alzheimer's pathology drives CKD-associated cognitive dysfunction in this population.

Osseous Genioplasty: Prevention of Witch's Chin Deformity with No-Degloving Technique.

BACKGROUND: Osseous genioplasty is a powerful procedure that can correct chin dysmorphology; however, traditional techniques may result in chin ptosis or a "witch's chin" deformity. Iatrogenic chin ptosis is thought to be caused by excessive degloving of soft tissue with a failure to reattach the mentalis muscle. In the authors' study, they compared the "no-degloving" technique (using a 90-degree plate with lag-screw fixation) to the "traditional" technique, for minimization of chin ptosis. METHODS: The authors compared genioplasty techniques for consecutive patients: group 1 (traditional) underwent degloving for fixation of a stair-step plate, whereas group 2 (no-degloving) underwent lag-screw fixation (n = 50; 25 patients per group). The authors compared operating room time, advancement, complications, preoperative-to-postoperative vertical height change of the pogonion and menton (obtained through cone beam computed tomographic scans), surgeons' assessment of witch's chin, and FACE-Q surveys. RESULTS: No-degloving versus traditional groups had similar age and sex distributions, horizontal/vertical change (5 mm/2 mm versus 6 mm/2 mm), length of surgery, and complication rate (5 percent). The traditional group had more deviation from expected position for both the pogonion (3.4 mm versus 1.2 mm; p ≤ 0.05) and menton (2.9 mm versus 0.8 mm; p ≤ 0.05), and more occurrences of witch's chin (six versus zero). No-degloving was superior for several FACE-Q scales, including Chin Appearance, Quality of Life, Satisfaction with Decision to Undergo Procedure, and Satisfaction with Outcome. CONCLUSION: No-degloving osseous genioplasty is a safe, reproducible technique that results in decreased soft-tissue ptosis and increased patient satisfaction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Pathology Examination of Breast Reduction Specimens: Dispelling the Myth.

More than 100,000 reduction mammaplasties are performed in the United States each year. There is large variance in reported incidence of cancerous/high-risk lesions, ranging from 0.06% to 4.6%. There has been debate whether histological review of breast reduction specimen is necessary. This study aimed to determine the incidence of cancerous/high-risk lesions and to evaluate risk factors for their occurrence. METHODS: A retrospective review was conducted for all patients who underwent reduction mammaplasty in 2018 by the senior author. Variables collected included demographics, comorbidities, history of breast surgery, family/personal history of breast cancer, weight of specimen, and pathologic findings. All specimens underwent pathologic evaluation and categorized as benign, proliferative, or malignant. RESULTS: A total of 155 patients underwent 310 reduction mammaplasties. Pathologic evaluations found that 11 patients (7.1%) had positive findings, 9 (5.8%) had proliferative lesions, and 2 (1.29%) had cancerous lesions. Patients with pathology were older (P = 0.038), had a family history of breast cancer (P = 0.026), and had a greater weight of resected tissue (P = 0.005). Multivariable analysis showed family history of breast cancer (P = 0.001), prior breast surgery (P = 0.026), and greater weight of resected breast tissue (P = 0.008) had a higher likelihood of positive pathology. CONCLUSIONS: These findings demonstrate an incidence of positive pathology higher than that reported and illustrate the importance of histologic review of breast reduction specimens. Family history of breast cancer, prior breast surgery, and a greater weight of resected tissue increase risk for proliferative/cancerous lesions.

Defining the Familial Fold of the Vicilin-Buried Peptide Family.

Plants and their seeds have been shown to be a rich source of cystine-stabilized peptides. Recently a new family of plant seed peptides whose sequences are buried within precursors for seed storage vicilins was identified. Members of this Vicilin-Buried Peptide (VBP) family are found in distantly related plant species including the monocot date palm, as well as dicotyledonous species like pumpkin and sesame. Genetic evidence for their widespread occurrence indicates that they are of ancient origin. Limited structural studies have been conducted on VBP family members, but two members have been shown to adopt a helical hairpin fold. We present an extensive characterization of VBPs using solution NMR spectroscopy, to better understand their structural features. Four peptides were produced by solid phase peptide synthesis and shown to favor a helix-loop-helix hairpin fold, as a result of the I-IV/II-III ladderlike connectivity of their disulfide bonds. Interhelical interactions, including hydrophobic contacts and salt bridges, are critical for the fold stability and control the angle at which the antiparallel α-helices interface. Activities reported for VBPs include trypsin inhibitory activity and inhibition of ribosomal function; however, their diverse structural features despite a common fold suggest that additional bioactivities yet to be revealed are likely.

The State of Plastic Surgery Education Outside of the Operating Room.

BACKGROUND: Plastic surgery education consists of technical skills, surgical decision-making, and the knowledge necessary to provide safe patient care. Competency in these modalities is ensured by requiring case minimums and oral and written examinations. However, there is a paucity of information detailing what teaching modalities residency programs use outside of the operating room. METHODS: A 16-question survey was sent to all integrated and independent program directors. Information regarding nonsurgical resident education was collected and analyzed. RESULTS: There were 44 responses (46 percent). Most programs had six to 10 faculty (43 percent), and a majority (85 percent) required faculty to participate in resident education outside of the operating room. Residents most commonly had 3 to 4 hours (43 percent) of protected educational time 1 day per week (53 percent). Nonsurgical education consisted of weekly lectures by attending physicians (44 percent) and residents (54 percent), in addition to weekly CoreQuest (48 percent), teaching rounds (38 percent), and Plastic Surgery Education Network lectures (55 percent). Monthly activities included morbidity and mortality conference (81 percent) and journal club (86 percent). Indications conference was either monthly (41 percent) or weekly (39 percent). Cadaver laboratories, visiting professors, board preparation, in-service review, and meetings with the program director occurred yearly or several times per year. Forty-nine percent of programs sponsor one educational course per resident. In addition, most programs (65 percent) do not receive outside funding for education. CONCLUSIONS: These findings improve understanding of the current state of nonsurgical resident education in plastic surgery. They illustrate that residents participate in a diverse number of nonsurgical educational activities without any significant standardization.

The Therapeutic Potential of DNA Damage Repair Pathways and Genomic Stability in Lung Cancer.

Despite advances in our understanding of the molecular biology of the disease and improved therapeutics, lung cancer remains the most common cause of cancer-related deaths worldwide. Therefore, an unmet need remains for improved treatments, especially in advanced stage disease. Genomic instability is a universal hallmark of all cancers. Many of the most commonly prescribed chemotherapeutics, including platinum-based compounds such as cisplatin, target the characteristic genomic instability of tumors by directly damaging the DNA. Chemotherapies are designed to selectively target rapidly dividing cells, where they cause critical DNA damage and subsequent cell death (1, 2). Despite the initial efficacy of these drugs, the development of chemotherapy resistant tumors remains the primary concern for treatment of all lung cancer patients. The correct functioning of the DNA damage repair machinery is essential to ensure the maintenance of normal cycling cells. Dysregulation of these pathways promotes the accumulation of mutations which increase the potential of malignancy. Following the development of the initial malignancy, the continued disruption of the DNA repair machinery may result in the further progression of metastatic disease. Lung cancer is recognized as one of the most genomically unstable cancers (3). In this review, we present an overview of the DNA damage repair pathways and their contributions to lung cancer disease occurrence and progression. We conclude with an overview of current targeted lung cancer treatments and their evolution toward combination therapies, including chemotherapy with immunotherapies and antibody-drug conjugates and the mechanisms by which they target DNA damage repair pathways.