The functional and psychological impact of delayed hip and knee arthroplasty: a systematic review and meta-analysis of 89,996 patients.

This systematic review and meta-analysis aimed to determine the impact of presurgical waiting times on pre-/post-operative joint specific pain and function, health-related quality of life (HRQOL) and perspectives of patients awaiting primary elective total hip (THR) and knee (TKR) replacements. MEDLINE, EMBASE, PUBMED, and CENTRAL databases were searched from inception until 30th January 2023 (CRD42022288128). Secondary literature and unpublished datasets containing paediatric, non-elective, partial, or revision replacement populations were excluded. PRISMA 2020 reporting and GRADE certainty of evidence guidelines were followed. Residual maximum likelihood meta-analysis and linear meta-regression was performed to elucidate the influence of presurgical waiting time. Twenty-six studies were eligible for systematic review and sixteen for meta-analysis, capturing 89,996 patients (60.6% female, mean age 67.4 years) between 2001 and 2022. A significant deterioration in joint function (mean difference (MD):0.0575%; 95% CI 0.0064, 0.1086; p = 0.028(4d.p.); I2 = 73.1%) and HRQOL (MD: 0.05%; 95% CI - 0.0001.0009; p = 0.011(4 d.p.); I2 = 80.6%) was identified per additional day of waiting. Despite qualitative evidence, meta-analysis could not observe a relationship with postoperative outcome data. Patient responses to delayed THR and TKR surgery were unanimously negative. Immediate action should seek to reduce the increased patient anxiety and significant reductions in pre-operative joint functionality and HRQOL associated with prolonged pre-surgical waiting time, whilst mitigating any potential deleterious post-operative effects.

Systematic reanalysis of genomic data improves quality of variant interpretation.

As genomic sequencing expands, so does our knowledge of the link between genetic variation and disease. Deeper catalogs of variant frequencies improve identification of benign variants, while sequencing affected individuals reveals disease-associated variation. Accumulation of human genetic data thus makes reanalysis a means to maximize the benefits of clinical sequencing. We implemented pipelines to systematically reassess sequencing data from 494 individuals with developmental disability. Reanalysis yielded pathogenic or likely pathogenic (P/LP) variants that were not initially reported in 23 individuals, 6 described here, comprising a 16% increase in P/LP yield. We also downgraded 3 LP and 6 variants of uncertain significance (VUS) due to updated population frequency data. The likelihood of identifying a new P/LP variant increased over time, as ~22% of individuals who did not receive a P/LP variant at their original analysis subsequently did after 3 years. We show here that reanalysis and data sharing increase the diagnostic yield and accuracy of clinical sequencing.

Transforming Growth Factor-ß3 Therapy Delays Postoperative Reossification and Improves Craniofacial Growth in Craniosynostotic Rabbits.

Postoperative reossification is a common clinical correlate following surgery. It has been suggested that an underexpression of transforming growth factor-ß3 (TGF-ß3) may be related to craniosynostosis and postoperative reossification. Adding TGF-ß3 may delay reossification and improve postoperative growth. The present study was designed to test this hypothesis. Thirty 10-day-old New Zealand white rabbits with hereditary coronal suture synostosis were divided into three groups: (1) suturectomy controls (n = 14), (2) suturectomy treated with bovine serum albumin (n = 8), and (3) suturectomy treated with TGF-ß3 protein (n = 8). At 10 days of age, a 3-mm × 15-mm coronal suturectomy was performed, and serial three-dimensional (3D) computed tomography (CT) scans and cephalographs were taken at 10, 25, 42, and 84 days of age. Calvaria were harvested at 84 days of age for histomorphometric analysis. Mean differences were analyzed using a group by age analysis of variance. Analysis of the 3D CT scan data revealed that sites treated with TGF-ß3 had significantly (P < .05) greater defect areas and significantly (P < .05) greater intracranial volumes through 84 days of age compared with controls. Histomorphometry showed that sites treated with TGF-ß3 had patent suturectomy sites and significantly (P < .001) less new bone in the suturectomy site compared with controls. Serial radiograph data revealed significant (P < .05) differences in craniofacial growth from 25 to 84 days in TGF-ß3-treated rabbits compared with controls. Data show that TGF-ß3 administration delayed reossification and improved craniofacial growth in this rabbit model. These findings also suggest that this molecular-based therapy may have potential clinical use.

Guidelines for investigating causality of sequence variants in human disease.

The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.

p53 is a major component of the transcriptional and apoptotic program regulated by PI 3-kinase/Akt/GSK3 signaling.

The phosphatidylinositol (PI) 3-kinase/Akt signaling pathway has a prominent role in cell survival and proliferation, in part, by regulating gene expression at the transcriptional level. Previous work using global expression profiling identified FOXOs and the E-box-binding transcription factors MITF and USF1 as key targets of PI 3-kinase signaling that lead to the induction of proapoptotic and cell cycle arrest genes in response to inhibition of PI 3-kinase. In this study, we investigated the role of p53 downstream of PI 3-kinase signaling by analyzing the effects of inhibition of PI 3-kinase in Rat-1 cells, which have wild-type p53, compared with Rat-1 cells expressing a dominant-negative p53 mutant. Expression of dominant-negative p53 conferred partial resistance to apoptosis induced by inhibition of PI 3-kinase. Global gene expression profiling combined with computational and experimental analysis of transcription factor binding sites demonstrated that p53, along with FOXO, MITF and USF1, contributed to gene induction in response to PI 3-kinase inhibition. Activation of p53 was mediated by phosphorylation of the histone acetyltransferase Tip60 by glycogen synthase kinase (GSK) 3, leading to activation of p53 by acetylation. Many of the genes targeted by p53 were also targeted by FOXO and E-box-binding transcription factors, indicating that p53 functions coordinately with these factors to regulate gene expression downstream of PI 3-kinase/Akt/GSK3 signaling.

The effects of testosterone on craniosynostotic calvarial cells: a test of the gene/environmental model of craniofacial anomalies.

INTRODUCTION: The gene-environmental interaction model for craniofacial development proposes that if a genetic predisposition for an anomaly is coupled with an environmental factor that can exacerbate this predisposition, more severe phenotypes will result. Here, we utilize cells derived from our non-syndromic rabbit model of craniosynostosis to test the hypothesis that an insult, testosterone (TP) administration (exogenous source) will alter the osteogenic activity of these cells. DESIGN: Calvarial cells from wild-type (WT) (N=13) or craniosynostotic (CS) rabbits (N=11) were stimulated with TP, an androgen receptor blocker, flutamide, and combined treatments. Proliferation and differentiation assays were conducted after 7 days. anova and t-tests were used to determine differences in stimulation and cell type. RESULTS: The CS cells had significantly greater proliferation after TP administration compared to WT. There were no appreciable changes in differentiation after TP stimulation. Flutamide administration or combined TP and flutamide administration decreased both proliferation and differentiation for both cell types similarly. CONCLUSIONS: Testosterone exposure caused an increase in cell proliferation for CS osteoblast cells. However, a therapy targeted to mitigate this response (flutamide therapy) similarly affected CS and WT cells, suggesting that the administration of flutamide or TP in the presence of flutamide decreases osteogenesis of these cells. Thus, although our data support a mechanism of gene-environmental interaction, these results would not support a therapeutic intervention based on this interaction.

Saving mothers' lives: reviewing maternal deaths to make motherhood safer: 2006-8: a review.

This review of the eighth report of the United Kingdom Enquiries into Maternal Deaths, Saving Mothers' Lives, is written primarily for anaesthetists and critical care specialists involved in both maternity and gynaecology services. Direct maternal deaths from systemic sepsis secondary to infection of the genital tract have increased. Systemic sepsis requires early recognition, immediate treatment and multidisciplinary management involving anaesthetists and critical care specialists. The incidence of deaths related to anaesthesia remains unchanged at seven in the three year period. Airway related problems unfortunately still cause maternal death. The role of early communication between obstetricians and anaesthesia and intensive care specialists is highlighted. The review summarizes the recommendations relating to anaesthesia and intensive care.

Composite tissue vasculopathy and degeneration following multiple episodes of acute rejection in reconstructive transplantation.

Transplant vasculopathy has not been systematically investigated in composite tissue allotransplantation (CTA). The impact of multiple acute rejections (ARs) on long-term graft outcomes in reconstructive transplantation remains unknown. This study in a rat hind-limb allotransplantation model systematically analyzes vasculopathy and tissue-specific pathological changes secondary to multiple AR episodes. LEW rats were transplanted with BN rat hind limbs and treated as follows: Group 1 (Iso): isografts. Group 2 (CsA): Cyclosporine (CsA) qd; Group 3 (mult AR): CsA and dexamethasone only when AR was observed. No AR was observed in Groups 1 and 2. Multiple AR were observed in Group 3, and each episode was completely reversed (clinically) with pulsed CsA + dexamethasone treatment. Group 3 animals demonstrated significant vascular lesions along with skin and muscle atrophy, upregulation of profibrotic gene expression and fibrosis when compared to Groups 1 and 2. In addition, allograft bone was sclerotic, weak and prone to malunion and nonunion. Interestingly, vasculopathy was a late finding, whereas muscle atrophy with macrophage infiltration was seen early, after only a few AR episodes. Taken together, multiple AR episodes lead to vasculopathy and tissue-specific pathology in CTA. This is the first evidence of 'composite tissue vasculopathy and degeneration (CTVD)' in CTA.

Epidural analgesia and breastfeeding: a randomised controlled trial of epidural techniques with and without fentanyl and a non-epidural comparison group.

We compared breastfeeding initiation and duration in 1054 nulliaparae randomised to bupivacaine Control epidural, Combined Spinal Epidural or Low Dose Infusion and 351 matched non-epidural comparisons. Women were interviewed after delivery and completed a postal questionnaire at 12 months. Regression analysis determined factors which independently predicted breastfeeding initiation. Breastfeeding duration was subjected to Kaplan-Meier analysis. A similar proportion of women in each epidural group initiated breastfeeding. Women with no epidural did not report a higher initiation rate relative to epidural groups and those who received pethidine reported a lower initiation rate than control epidural (p = 0.002). Older age groups (p < 0.001) and non-white ethnicity (p < 0.026) were predictive of breastfeeding. Epidural fentanyl dose, delivery mode and trial group were not predictive. Mean duration for breastfeeding was similar across epidural groups (Control 13.3, Combined Spinal Epidural 15.5, Low Dose Infusion 15.0 weeks). Our data do not support an effect of epidural fentanyl on breastfeeding initiation.

Satisfaction, control and pain relief: short- and long-term assessments in a randomised controlled trial of low-dose and traditional epidurals and a non-epidural comparison group.

BACKGROUND: Childbirth is an important life event for which a positive experience is important to many women. METHODS: As secondary outcomes from the randomised controlled Comparative Obstetric Mobile Epidural Trial, various aspects of satisfaction were assessed in women who had one of three types of regional analgesia (two of which were low-dose techniques and a high-dose control using 0.25% epidural bupivacaine) and a comparison group who did not have epidural analgesia, shortly after delivery and 12 months later. RESULTS: The predominant finding was satisfaction with spontaneous vaginal delivery whatever the mode of analgesia. The overall immediate and long-term satisfaction was similar for all three neuraxial techniques. Satisfaction with the speed of pain relief and the amount of mobility were significantly greater for the combined spinal-epidural technique compared with the low-dose infusion (P<0.001). The degree of control felt by women who had combined spinal-epidural analgesia was greater than with the high-dose (P<0.05). Women in the non-epidural comparison group did not report a greater feeling of control. Among those who delivered spontaneously, more women in the combined spinal-epidural group (30%) felt in full control compared with the high-dose group (17%) (P<0.05). By comparison 22% in the low-dose infusion group and only 15% who had no epidural felt in full control. CONCLUSIONS: Whilst satisfaction with the experience of childbirth appears intimately related to the attainment of a spontaneous delivery, mobile epidurals enhance women's feeling of control in labour and are popular for future choice of regional analgesia.

Ambulation in labour and delivery mode: a randomised controlled trial of high-dose vs mobile epidural analgesia.

Compared to high-dose epidurals where mobility is impossible, mobile epidurals have been shown to reduce instrumental vaginal delivery rates. The mechanism for this benefit may depend on women walking or adopting upright postures during labour. We investigated maternal motor power and ambulation of 1052 primparous women randomised to high-dose epidural (Control), Combined Spinal Epidural (CSE) or Low-Dose Infusion (LDI) as a pre-specified, secondary outcome of the Comparative Obstetric Mobile Epidural Trial. Modified Bromage power scores and the level of mobility a woman actually achieved were recorded each hour after epidural placement during first and second stage, until delivery. Relative to control, significantly more women maintained normal leg power throughout labour in both mobile groups and significantly more women with CSE maintained superior leg power for longer than with LDI. Observational analysis did not demonstrate an association between the level of ambulation a woman actually achieved after epidural placement and delivery mode.

Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant.

BACKGROUND: Genomic disorders are often caused by non-allelic homologous recombination between segmental duplications. Chromosome 16 is especially rich in a chromosome-specific low copy repeat, termed LCR16. METHODS AND RESULTS: A bacterial artificial chromosome (BAC) array comparative genome hybridisation (CGH) screen of 1027 patients with mental retardation and/or multiple congenital anomalies (MR/MCA) was performed. The BAC array CGH screen identified five patients with deletions and five with apparently reciprocal duplications of 16p13 covering 1.65 Mb, including 15 RefSeq genes. In addition, three atypical rearrangements overlapping or flanking this region were found. Fine mapping by high-resolution oligonucleotide arrays suggests that these deletions and duplications result from non-allelic homologous recombination (NAHR) between distinct LCR16 subunits with >99% sequence identity. Deletions and duplications were either de novo or inherited from unaffected parents. To determine whether these imbalances are associated with the MR/MCA phenotype or whether they might be benign variants, a population of 2014 normal controls was screened. The absence of deletions in the control population showed that 16p13.11 deletions are significantly associated with MR/MCA (p = 0.0048). Despite phenotypic variability, common features were identified: three patients with deletions presented with MR, microcephaly and epilepsy (two of these had also short stature), and two other deletion carriers ascertained prenatally presented with cleft lip and midline defects. In contrast to its previous association with autism, the duplication seems to be a common variant in the population (5/1682, 0.29%). CONCLUSION: These findings indicate that deletions inherited from clinically normal parents are likely to be causal for the patients' phenotype whereas the role of duplications (de novo or inherited) in the phenotype remains uncertain. This difference in knowledge regarding the clinical relevance of the deletion and the duplication causes a paradigm shift in (cyto)genetic counselling.

High dependency care in an obstetric setting in the UK.

Our objective was to establish the utilisation and pattern of high dependency care in a tertiary referral obstetric unit. Data of pregnant or recently pregnant women admitted to the obstetric high dependency unit from 1984 to 2007 were included to evaluate the admission rate. Four years' information of an ongoing prospective audit was collated to identify the indications for admission, maternal monitoring, transfers to intensive care unit, and location of the baby. The overall high dependency unit admission rate is 2.67%, but increased to 5.01% in the most recent 4 years. Massive obstetric haemorrhage is now the most common reason for admission. Invasive monitoring was undertaken in 30% of women. Two-thirds of neonates (66.3%) stayed with their critically ill mothers in the high dependency unit. Transfer to the intensive care unit was needed in 1.4 per 1000 deliveries conducted. We conclude that obstetric high dependency care provides holistic care from midwives, obstetricians and anaesthetists while retaining the opportunity of early bonding with babies for critically ill mothers.

Chondrogenesis, bone morphogenetic protein-4 and mesenchymal stem cells.

OBJECTIVE: As adult cartilage has very limited potential to regenerate, cartilage repair is challenging. Available treatments have several disadvantages, including formation of fibrocartilage instead of hyaline-like cartilage, as well as eventual ossification of the newly formed tissue. The focus of this review is the application of bone morphogenetic protein-4 (BMP-4) and mesenchymal stem cells (MSCs) in cartilage repair, a combination that could potentially lead to the formation of permanent hyaline-like cartilage in the defect. METHODS: This review is based on recent literature in the orthopaedic and tissue engineering fields, and is focused on MCSs and bone morphogenetic proteins (BMPs). RESULTS: BMP-4, a stimulator of chondrogenesis, both in vitro and in vivo, is a potential therapeutic agent for cartilage regeneration. BMP-4 delivery can improve the healing process of an articular cartilage defect by stimulating the synthesis of the cartilage matrix constituents: type II collagen and aggrecan. BMP-4 has also been shown to suppress chondrogenic hypertrophy and maintain regenerated cartilage. Use of an appropriate carrier for BMP-4 is crucial for successful reconstruction of cartilage defects. Due to the relatively short half-life in vivo of BMP-4, there is a need to localize and maintain the delivery of BMP-4 to the injury site. Additionally, the delivery of MSCs to the wound site could improve cartilage regeneration; therefore, the carrier should function both as a cell and a protein delivery vehicle. CONCLUSION: The role of BMP-4 in chondrogenesis is significant, and successful methods to deliver BMP-4, with or without MSCs, to the cartilage defect site are a promising therapy to treat cartilage defects.

Relationship of premaxillary bone and its sutures to deciduous dentition in nonhuman primates.

OBJECTIVE: The relationship of the human premaxillary bone (Pmx) to neighboring craniofacial structures is clouded by its embryonic union with the maxillary bone proper. Only humans among all primates have such early fusion of the premaxillomaxillary suture (PS). This study surveyed the relationship of the PS to the upper deciduous dentition in nonhuman primates, and describes the distribution of bone cells along the osseous margins of the Pmx. METHOD: Twenty-eight subadult primates were studied using gross, CT, and histologic observations. Location of the anterior deciduous dentition relative to the PS was assessed. In sections of selected specimens, observations of bone cells on the osseous boundaries of the Pmx were made. Osteopontin (OPN) immunohistochemistry was used to isolate osteoclastic binding sites along the Pmx boundaries. RESULTS: The PS was consistently found between deciduous incisor and canine in strepsirrhines of all ages, whereas the suture passed variably closer to the incisor or canine in haplorhines. In all species, the anterior part of the Pmx was nonarticulating and mostly osteoblastic, except for osteoclastic margins adjacent to dentition and the nasal fossa. Superolaterally, the osteogenic fronts of the PS were osteoblastic, while more inferiorly, at the level of the deciduous canine, the PS was often osteoclastic. Results from OPN immunohistochemistry support the findings on bone cell distribution. CONCLUSION: Bone cell distribution patterns in perinatal nonhuman primates resemble those described for the prenatal human Pmx, suggesting that differences among species relate to magnitude rather than the pattern of osteogenesis.

Anaesthesia chapter from Saving mothers' lives; reviewing maternal deaths to make pregnancy safer.

This chapter concerning maternal mortality due to anaesthesia, reprinted with permission from Saving Mothers' Lives, is the 18th in a series of reports within the Confidential Enquiries into Maternal and Child Health (CEMACH) in the UK. In the years 2003-05 there were six women who died from problems directly related to anaesthesia, which is the same as the 2000-02 triennium. Obesity was a factor in four of these women who died. Two of these deaths were in women in early pregnancy, who received general anaesthesia for gynaecological surgery by inexperienced anaesthetists who failed to manage the airway and ventilation adequately. When trainee anaesthetists are relatively inexperienced their consultants must know the limits of their competence and when close supervision and help may be needed. One death was due to bupivacaine toxicity due to a drug administration error when a bag of dilute local anaesthetic was thought to be intravenous fluid. In a further 31 cases poor perioperative management may have contributed to death. Obesity was again a relevant factor. Other cases could be categorized into poor recognition of women being sick and poor clinical management of haemorrhage, sepsis and of pre-eclampsia. Early warning scores of vital signs may help identify the mother who is seriously ill. Learning points are highlighted in relation to the clinical management of these obstetric complications.

Craniofacial morphology in myostatin-deficient mice.

GDF-8 (myostatin) is a negative growth regulator of skeletal muscle, and myostatin-deficient mice are hypermuscular. Muscle size and force production are thought to influence growth of the craniofacial skeleton. To test this relationship, we compared masticatory muscle size and craniofacial dimensions in myostatin-deficient and wild-type CD-1 control mice. Myostatin-deficient mice had significantly (p < 0.01) greater body (by 18%) and masseter muscle weight (by 83%), compared with wild-type controls. Significant differences (p < 0.05) were noted for cranial vault length, maxillary length, mandibular body length, and mandibular shape index. Significant correlations were noted between masseter muscle weight and mandibular body length (r = 0.68; p < 0.01), cranial vault length (r = -0.57; p < 0.05), and the mandibular shape index (r = -0.56; p < 0.05). Masticatory hypermuscularity resulted in significantly altered craniofacial morphology, probably through altered biomechanical stress. These findings emphasize the important role that masticatory muscle function plays in the ontogeny of the cranial vault, the maxilla, and, most notably, the mandible.

Haemodynamic effects of oxytocin given as i.v. bolus or infusion on women undergoing Caesarean section.

BACKGROUND: The cardiovascular effects of oxytocin in animal models and women undergoing Caesarean section include tachycardia, hypotension and decrease in cardiac output. These can be sufficient to cause significant compromise in high-risk patients. We aimed to find a simple way to decrease these risks whilst retaining the benefits of oxytocin in decreasing bleeding after delivery. Method. We recruited 30 women undergoing elective Caesarean section. They were randomly allocated to receive 5 u of oxytocin either as a bolus injection (bolus group) or an infusion over 5 min (infusion group). These women had their heart rate and intra-arterial blood pressure recorded every 5 s throughout the procedure. The haemodynamic data, along with the estimated blood loss, were compared between the groups. RESULTS: Marked cardiovascular changes occurred in the bolus group; the heart rate increased by 17 (10.7) beats min(-1) [mean (sd)] compared with 10 (9.7) beats min(-1) in the infusion group. The mean arterial pressure decreased by 27 (7.6) mm Hg in the bolus group compared with 8 (8.7) mm Hg in the infusion group. There were no differences in the estimated blood loss between the two groups. CONCLUSION: We recommend that bolus doses should be used with caution, and further studies should ascertain if oxytocin is equally effective in reducing blood loss when given at a slower rate.