Consensus recommendations for the assessment and management of idiopathic intracranial hypertension in children and young people.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a potentially disabling condition. There is a lack of evidence and national guidance on how to diagnose and treat paediatric IIH, leading to variation in clinical practice. We conducted a national Delphi consensus via the Children's Headache Network to propose a best-practice diagnostic and therapeutic pathway. METHODS: The Delphi process was selected as the most appropriate methodology for examining current opinion among experts in the UK. 104 questions were considered by 66 healthcare professionals, addressing important aspects of IIH care: assessment, diagnosis, treatment, follow-up and surveillance. General paediatricians, paediatric neurologists, ophthalmologists, opticians, neuroradiologists and neurosurgeons with a clinical interest or experience in IIH, were invited to take part. RESULTS: The Delphi process consisted of three rounds comprising 104 questions (round 1, 67; round 2, 24; round 3 (ophthalmological), 13) and was completed between March 2019 and August 2021. There were 54 and 65 responders in the first and second rounds, respectively. The Delphi was endorsed by the Royal College of Ophthalmologists, which engaged 59 ophthalmologists for round 3. CONCLUSIONS: This UK-based Delphi consensus process reached agreement for the management of paediatric IIH and has been endorsed by the Children's Headache Network and more broadly, the British Paediatric Neurology Association. It provides a basis for a pragmatic clinical approach. The recommendations will help to improve clinical care while minimising under and over diagnosis.

Super7 passaging method to improve Chinese hamster ovary cell fed-batch performance.

Chinese hamster ovary (CHO) cells are widely used to manufacture biopharmaceuticals, most of all monoclonal antibodies (mAbs). Some CHO cell lines exhibit production instability, where the productivity of the cells decreases as a function of time in culture. To counter this, we designed a passaging strategy that, rather than maximizing the time spent in log-growth phase, mimics the first 7 days of a fed-batch production process. Cultures passaged using this method had lower net growth rates and were more oxidative throughout 6 weeks of passaging. Fed-batch cultures inoculated by cells passaged using this method had increased net growth rates, oxidative metabolism, and volumetric productivity compared to cells passaged using a conventional strategy. Cells from unstable cell lines passaged by this new method produced 80%-160% more mAbs per unit volume than cells passaged by a conventional method. This new method, named Super7, provides the ability to mitigate the impact of production instability in CHO-K1 cell lines without a need for further cell line creation, genetic engineering, or medium development.

New quality outcome indicators for bone metastases: expert consensus analysis of patients, their families and specialist healthcare professionals.

OBJECTIVES: As workload increases, surgical care for patients with bone metastases is increasingly decentralised, with a shift in management away from primary bone tumour units to local centres. We must ensure that patients have similar outcomes regardless of where they receive their treatment. The aim was to develop and validate a set of quality outcome indicators (QOIs) to evaluate treatment success for patients undergoing surgery for bone metastases. METHODS: Outcome recommendations were adapted from the literature and field tested in a retrospective patient cohort to determine feasibility. The provisional outcome indicators were assessed during a modified RAND/Delphi consensus process by a group of patients, relatives and healthcare professionals with validated targets added. RESULTS: 1534 articles were reviewed. 38 quality objectives were extracted and assessed for feasibility using clinical records for 117 patients. 28 provisional outcome indicators proceeded to expert consensus and were reviewed by a group of 22 panellists including 10 patients and 4 relatives/carers. After two rounds, 15 QOIs were generated, with validated targets based on expert consensus. These included specific statements such as 'surgery improves pain and reduces the need for morphine, target: at follow-up, pain is documented in 80% of individuals and 50% of these have reduced need for morphine'. CONCLUSIONS: The published evidence and guidelines were adapted into a set of outcome indicators validated by patients, their family/carers and healthcare professionals. These can be used to compare care between centres and identify units of excellence in maximising good outcome after surgery for bone metastases.

Multifaceted roles of Meg3 in cellular senescence and atherosclerosis.

BACKGROUND AND AIMS: Long noncoding RNAs are involved in the pathogenesis of atherosclerosis. As long noncoding RNAs maternally expressed gene 3 (Meg3) prevents cellular senescence of hepatic vascular endothelium and obesity-induced insulin resistance, we decided to examine its role in cellular senescence and atherosclerosis. METHODS AND RESULTS: By analyzing our data and human and mouse data from the Gene Expression Omnibus database, we found that Meg3 expression was reduced in humans and mice with cardiovascular disease, indicating its potential role in atherosclerosis. In Ldlr-/- mice fed a Western diet for 12 weeks, Meg3 silencing by chemically modified antisense oligonucleotides attenuated the formation of atherosclerotic lesions by 34.9% and 20.1% in male and female mice, respectively, revealed by en-face Oil Red O staining, which did not correlate with changes in plasma lipid profiles. Real-time quantitative PCR analysis of cellular senescence markers p21 and p16 revealed that Meg3 deficiency aggravates hepatic cellular senescence but not cellular senescence at aortic roots. Human Meg3 transgenic mice were generated to examine the role of Meg3 gain-of-function in the development of atherosclerosis induced by PCSK9 overexpression. Meg3 overexpression promotes atherosclerotic lesion formation by 29.2% in Meg3 knock-in mice independent of its effects on lipid profiles. Meg3 overexpression inhibits hepatic cellular senescence, while it promotes aortic cellular senescence likely by impairing mitochondrial function and delaying cell cycle progression. CONCLUSIONS: Our data demonstrate that Meg3 promotes the formation of atherosclerotic lesions independent of its effects on plasma lipid profiles. In addition, Meg3 regulates cellular senescence in a tissue-specific manner during atherosclerosis. Thus, we demonstrated that Meg3 has multifaceted roles in cellular senescence and atherosclerosis.

Clostridium Bifermentans Infection of a Prosthetic Knee Joint in a Patient With Human Immunodeficiency Virus: A Case Report.

We reported a case of Clostridium bifermentans (C. bifermentans) infection in the prosthetic knee joint of a human immunodeficiency virus (HIV) patient, who presented with swelling, discomfort, pain, and redness in the right lower extremity. An uncommon yet potentially lethal human illness triggered by C. bifermentans. Foreign material is especially susceptible to local infection because of the local immunodeficiency close to the implant. Intravenous (IV) cefepime and IV ampicillin/sulbactam were administered to the patient. The idea of performing surgery to eradicate the infection was under consideration, but its necessity remained uncertain, and the decision to proceed with surgery had not been finalized.

Acute Total Knee Arthroplasty for Unicondylar Tibial Plateau Fracture Using Metaphyseal Cones.

Tibial plateau fractures (TPFs) in older adults are increasing in incidence and now account for 8% of all fractures in patients over 60 years of age. Although primary fixation remains standard, the risk of fixation failure, loss of reduction, and the development of posttraumatic osteoarthritis are all markedly increased in this age group with higher rates of conversion to total knee arthroplasty (TKA) of 12%. When joint depression is severe with significant subchondral bone loss, up to half ultimately require TKA. TPFs with unicondylar depression can be managed primarily using tibial cones in acute TKA. In this study, we report the surgical technique for performing acute TKA using tibial cones for the primary management of TPFs in older adults and illustrate this technique with case examples.

Surgical approaches to periprosthetic femoral fractures for plate fixation or revision arthroplasty.

Periprosthetic femoral fractures are increasing in incidence, and typically occur in frail elderly patients. They are similar to pathological fractures in many ways. The aims of treatment are the same, including 'getting it right first time' with a single operation, which allows immediate unrestricted weightbearing, with a low risk of complications, and one that avoids the creation of stress risers locally that may predispose to further peri-implant fracture. The surgical approach to these fractures, the associated soft-tissue handling, and exposure of the fracture are key elements in minimizing the high rate of complications. This annotation describes the approaches to the femur that can be used to facilitate the surgical management of peri- and interprosthetic fractures of the femur at all levels using either modern methods of fixation or revision arthroplasty.

Factors associated with failure of fixation of Vancouver B fractures around a cemented polished tapered stem: A 5 to 14 year follow up study.

AIMS: There is increasing evidence for fixation as opposed to revision for Vancouver B fractures around polished taper slip stems, however it is remains unclear whether fixation is associated with stem loosening in the longer term. This study aims to assess survival of plate-fixation of Vancouver-B-fractures around a polished-taper- slip cemented stem and identify factors associated with failure. METHODS: Retrospective cohort study assessed 129 consecutive unilateral Vancouver-B-fractures around cemented Exeter stems at a minimum of 5 years following open-reduction-internal-fixation (ORIF) with unilateral non-locked unilateral plating+/-cerclage cables. The primary outcome measure was reoperation for any reason. Kaplan Meier survival analysis was performed. RESULTS: Fractures (B1 n = 31 (24%); B2 n = 91 (71%); and B3 n = 7 (5%)) occurred at median of 6 years (IQR 1.2-9.2) after primary surgery. Mean patient age was 78.2 (SD10.56, range 46-96) and 54 (42.9%) were female. Mean follow up was 8.7 years (SD 2.48, 5.7 to 14.4). Symptomatic femoral stem loosening requiring revision occurred in two B2 fractures of metaphyseal split and short spiral patterns. The most common mode of failure was non-union (n = 7, 5%). Both fixation failure (n = 6/31 Vs n = 3/91 vs n = 0/7, p = 0.008) and reoperation (n = 8/31 vs n = 6/91 vs n = 0/7, p = 0.008) were significantly higher following fixation of B1 fractures compared to B2 and B3 fractures. Overall 5year survival free from reoperation was 88.8% (82.0-94.7 95%CI). B1 fracture types were associated with an increase risk of failure (endpoints fixation failure p = 0.010; and reoperation p = 0.016). Transverse fractures (B1) were associated with a relative risk of reoperation of 4.22 (1.63-10.9 95% CI, p = 0.008). CONCLUSION: Fixation of Vancouver-B fractures around cemented Exeter stems, when the bone-cement interface is intact and the fracture is anatomically reducible, had an excellent 5-year survival. Only 2 (1.6%) cases of late femoral stem loosening occurred, however, B1 type transverse fractures were associated with a higher rate of reoperation.

The estimated lifetime risk of revision after primary knee arthroplasty is influenced by age, sex, and indication.

AIMS: The aim of this study was to assess factors associated with the estimated lifetime risk of revision surgery after primary knee arthroplasty (KA). METHODS: All patients from the Scottish Arthroplasty Project dataset undergoing primary KA during the period 1 January 1998 to 31 December 2019 were included. The cumulative incidence function for revision and death was calculated up to 20 years. Adjusted analyses used cause-specific Cox regression modelling to determine the influence of patient factors. The lifetime risk was calculated as a percentage for patients aged between 45 and 99 years using multiple-decrement life table methodology. RESULTS: The estimated lifetime risk of revision ranged between 32.7% (95% confidence interval (CI) 22.6 to 47.3) for patients aged 45 to 49 years and 0.6% (95% CI 0.1 to 4.5) for patients aged over 90 years. At 20 years, the overall cumulative incidence of revision (6.8% (95% CI 6.6 to 7.0)) was significantly less than that of death (66.3% (95% CI 65.4 to 67.1)). Adjusted analyses demonstrated converse effect of increasing age on risk of revision (hazard ratio (HR) 0.5 (95% CI 0.5 to 0.6)) and death (HR 3.6 (95% CI 3.4 to 3.7)). Male sex was associated with increased risks of revision (HR 1.1 (95% CI 1.1 to 1.2); p < 0.001) and death (HR 1.4 (95% CI 1.3 to 1.4); p < 0.001). Compared to patients undergoing primary KA for osteoarthritis, patients with inflammatory arthropathy had a higher risk of death (HR 1.7 (95% CI 1.7 to 1.8); p < 0.001), but were less likely to be revised (HR 0.9 (95% CI 0.7 to 1.0); p < 0.001). Patients with a greater number of comorbidities (HR 1.4 (95% CI 1.3 to 1.4)) and greater levels of socioeconomic deprivation (HR 1.4 (95% CI 1.4 to 1.5)) were at increased risk of death, but neither increased the risk of revision. CONCLUSION: The estimated lifetime risk of revision KA varied depending on patient sex, age, and underlying diagnosis. Patients aged between 45 and 49 years had a one in three risk of undergoing revision surgery within their lifetime, which decreased with age to one in 159 in those aged 90 years or more.Cite this article: Bone Joint J 2022;104-B(12):1313-1322.

Biodiversity of Parasitic Hymenoptera Across Sky Islands of Arkansas, United States.

Sky islands are often areas of endemism and high species diversity around the world. In central North America, the Ozark and Ouachita Highlands contain numerous modestly high elevational islands that are slightly cooler and wetter than surrounding lowlands and these areas are known to contain many unique species. We studied parasitic Hymenoptera biodiversity on three sky islands in Arkansas, both in canopy and understory strata of mature post oak forests. We found that morphospecies diversity was high, and community structure varied both within (canopy versus understory) and between sky islands. Each mountaintop showed a high level of distinctiveness with few morphospecies found in multiple locations. The high intersky island variation indicates that individual sky islands in the region harbor unique Hymenoptera assemblages, a pattern that likely extends to the broader insect community. Our study suggests that these highland areas are important regions of North American biodiversity and that they should be evaluated individually for conservation efforts in order to preserve their distinctive community structure.

Opposing global change drivers counterbalance trends in breeding North American monarch butterflies.

Many insects are in clear decline, with monarch butterflies (Danaus plexippus) drawing particular attention as a flagship species. It is well documented that, among migratory populations, numbers of overwintering monarchs have been falling across several decades, but trends among breeding monarchs are less clear. Here, we compile >135,000 monarch observations between 1993 and 2018 from the North American Butterfly Association's annual butterfly count to examine spatiotemporal patterns and potential drivers of adult monarch relative abundance trends across the entire breeding range in eastern and western North America. While the data revealed declines at some sites, particularly the US Northeast and parts of the Midwest, numbers in other areas, notably the US Southeast and Northwest, were unchanged or increasing, yielding a slightly positive overall trend across the species range. Negative impacts of agricultural glyphosate use appeared to be counterbalanced by positive effects of annual temperature, particularly in the US Midwest. Overall, our results suggest that population growth in summer is compensating for losses during the winter and that changing environmental variables have offsetting effects on mortality and/or reproduction. We suggest that density-dependent reproductive compensation when lower numbers arrive each spring is currently able to maintain relatively stable breeding monarch numbers. However, we caution against complacency since accelerating climate change may bring growing threats. In addition, increases of summer monarchs in some regions, especially in California and in the south, may reflect replacement of migratory with resident populations. Nonetheless, it is perhaps reassuring that ubiquitous downward trends in summer monarch abundance are not evident.

Long-term mortality rates and associated risk factors following primary and revision knee arthroplasty : 107,121 patients from the Scottish Arthroplasty Project.

AIMS: The aim of this study was to determine the long-term mortality rate, and to identify factors associated with this, following primary and revision knee arthroplasty (KA). METHODS: Data from the Scottish Arthroplasty Project (1998 to 2019) were retrospectively analyzed. Patient mortality data were linked from the National Records of Scotland. Analyses were performed separately for the primary and revised KA cohorts. The standardized mortality ratio (SMR) with 95% confidence intervals (CIs) was calculated for the population at risk. Multivariable Cox proportional hazards were used to identify predictors and estimate relative mortality risks. RESULTS: At a median 7.4 years (interquartile range (IQR) 4.0 to 11.6) follow-up, 27.8% of primary (n = 27,474/98,778) and 31.3% of revision (n = 2,611/8,343) KA patients had died. Both primary and revision cohorts had lower mortality rates than the general population (SMR 0.74 (95% CI 0.73 to 0.74); p < 0.001; SMR 0.83 (95% CI 0.80 to 0.86); p < 0.001, respectively), which persisted for 12 and eighteight years after surgery, respectively. Factors associated with increased risk of mortality after primary KA included male sex (hazard ratio (HR) 1.40 (95% CI 1.36 to 1.45)), increasing socioeconomic deprivation (HR 1.43 (95% CI 1.36 to 1.50)), inflammatory polyarthropathy (HR 1.79 (95% CI 1.68 to 1.90)), greater number of comorbidities (HR 1.59 (95% CI 1.51 to 1.68)), and periprosthetic joint infection (PJI) requiring revision (HR 1.92 (95% CI 1.57 to 2.36)) when adjusting for age. Similarly, male sex (HR 1.36 (95% CI 1.24 to 1.49)), increasing socioeconomic deprivation (HR 1.31 (95% CI 1.12 to 1.52)), inflammatory polyarthropathy (HR 1.24 (95% CI 1.12 to 1.37)), greater number of comorbidities (HR 1.64 (95% CI 1.33 to 2.01)), and revision for PJI (HR 1.35 (95% 1.18 to 1.55)) were independently associated with an increased risk of mortality following revision KA when adjusting for age. CONCLUSION: The SMR of patients undergoing primary and revision KA was lower than that of the general population and remained so for several years post-surgery. However, approximately one in four patients undergoing primary and one in three patients undergoing revision KA died within tenten years of surgery. Several patient and surgical factors, including PJI, were associated with the risk of mortality within ten years of primary and revision surgery. Cite this article: Bone Joint J 2022;104-B(1):45-52.

Complex life histories predispose aphids to recent abundance declines.

Many animals change feeding habits as they progress through life stages, exploiting resources that vary in space and time. However, complex life histories may bring new risks if rapid environmental change disrupts the timing of these switches. Here, we use abundance times series for a diverse group of herbivorous insects, aphids, to search for trait and environmental characteristics associated with declines. Our meta dataset spanned three world regions and >300 aphid species, tracked at 75 individual sites for 10-50 years. Abundances were generally falling, with median changes of -8.3%, -5.6%, and -0.1% per year in the central USA, northwestern USA, and United Kingdom, respectively. Aphids that obligately alternated between host plants annually and those that were agricultural pests exhibited the steepest declines, relative to species able to persist on the same host plant year-round or those in natural areas. This suggests that host alternation might expose aphids to climate-induced phenology mismatches with one or more of their host plant species, with additional risks from exposure to insecticides and other management efforts. Warming temperatures through time were associated with milder aphid declines or even abundance increases, particularly at higher latitudes. Altogether, while a warming world appeared to benefit some aphid species in some places, most aphid species that had time-sensitive movements among multiple host plants seemed to face greater risk of decline. More generally, this suggests that recent human-induced rapid environmental change is rebalancing the risks and rewards associated with complex life histories.

Metastatic bone disease: new quality performance indicator development.

OBJECTIVES: Patients with metastatic bone disease (MBD) should receive the same standard of care regardless of which centre they are treated in. The aim was to develop and test a set of quality performance indicators (QPIs) to evaluate care for patients with MBD referred to orthopaedics. METHODS: QPIs were adapted from the literature and ranked on feasibility and necessity during a modified RAND/Delphi consensus process. They were then validated and field tested in a retrospective cohort of 108 patients using indicator-specific targets set during consensus. RESULTS: 2568 articles including six guidelines were reviewed. 43 quality objectives were extracted and 40 proceeded to expert consensus. After two rounds, 18 QPIs for MBD care were generated, with the following generating the highest consensus: 'Patients with high fracture risk should receive urgent assessment' (combined mean 6.7/7, 95% CI 6.5 to 6.8) and 'preoperative workup should include full blood tests including group and save' (combined mean 6.7/7, 95% CI 6.5 to 6.9). In the pilot test, targets were met for 5/18 QPIs (mean 52%, standard deviation 22%). The median deviation from projected target was -14% (interquartile range -11% to -31%, range -74% to 11%). The highest scoring QPI was 'adults with fractures should have surgery within 7 days' (target 80%:actual 92%). CONCLUSIONS: The published evidence and guidelines were adapted into a set of validated QPIs for MBD care which can be used to evaluate variation in care between centres. These QPIs should be correlated with outcome scores to determine whether they can act as predictors of outcome after surgery.

Immediate weight-bearing is safe following lateral locked plate fixation of periprosthetic distal femoral fractures.

PURPOSE: This study aimed to determine whether unrestricted weight-bearing as tolerated (WBAT) following lateral locking plate (LLP) fixation of periprosthetic distal femoral fractures (PDFFs) is associated with increased failure and reoperation, compared with restricted weight-bearing (RWB). MATERIALS AND METHODS: In a retrospective cohort study of consecutive patients with unilateral PDFFs undergoing LLP fixation, patients prescribed WBAT were compared with those prescribed 6 weeks of RWB. The primary outcome measure was reoperation. Kaplan-Meier and Cox multivariable analyses were performed. RESULTS: There were 43 patients (mean age 80.9 ± 11.7 years, body mass index 26.8 ± 5.7 kg/m2 and 86.0% female): 28 WBAT and 15 RWB. There were more interprosthetic fractures in the RWB group (p = 0.040). Mean follow-up was 3.8 years (range 1.0-10.4). Eight patients (18.6%) underwent reoperation. Kaplan-Meier analysis demonstrated no difference in 2-year survival between WBAT (80.6%, 95% CI 65.3-95.9) and RWB (83.3%, 95% CI 62.1-100.0; p = 0.54). Cox analysis showed increased reoperation risk with medial comminution (hazard ratio 10.7, 95% CI 1.5-80; p = 0.020) and decreased risk with anatomic reduction (hazard ratio 0.11, 95% CI 0.01-1.0; p = 0.046). Immediate weight-bearing did not significantly affect the risk of reoperation compared with RWB (relative risk 1.03, 95% CI 0.61-1.74; p = 0.91). CONCLUSIONS: LLP fixation failure was associated with medial comminution and non-anatomic reductions, not with postoperative weight-bearing. Medial comminution should be managed with additional fixation. Weight-bearing restrictions additional to this appear unnecessary and should be avoided.

Patient-reported assessment of outcome after surgery for bone metastases.

Regardless of prognosis, surgery is often considered in metastatic bone disease (MBD) as a palliative procedure to improve function and quality of life. Traditional focus on objective outcomes such as mortality is inappropriate in this group, and there is a drive to assess outcomes via patient-reported outcome measures (PROMs). This is an overview of current understanding of MBD outcomes and how this should influence future decision-making and research. The objectives of this review were to identify difficulties in measuring PROMs in the MBD patient population and explore alternatives to patientreported outcomes. We also provide an overview of current understanding of outcomes in MBD and how this should influence decision-making and direct research.

The effect of hospital case volume on re-revision following revision total knee arthroplasty.

AIMS: The aim of this study was to measure the effect of hospital case volume on the survival of revision total knee arthroplasty (RTKA). METHODS: This is a retrospective analysis of Scottish Arthroplasty Project data, a nationwide audit which prospectively collects data on all arthroplasty procedures performed in Scotland. The primary outcome was RTKA survival at ten years. The primary explanatory variable was the effect of hospital case volume per year on RTKA survival. Kaplan-Meier survival curves were plotted with 95% confidence intervals (CIs) to determine the lifespan of RTKA. Multivariate Cox proportional hazards were used to estimate relative revision risks over time. Hazard ratios (HRs) were reported with 95% CI, and p-value < 0.05 was considered statistically significant. RESULTS: From 1998 to 2019, 8,301 patients (8,894 knees) underwent RTKA surgery in Scotland (median age at RTKA 70 years (interquartile range (IQR) 63 to 76); median follow-up 6.2 years (IQR 3.0 to 10.2). In all, 4,764 (53.6%) were female, and 781 (8.8%) were treated for infection. Of these 8,894 knees, 957 (10.8%) underwent a second revision procedure. Male sex, younger age at index revision, and positive infection status were associated with need for re-revision. The ten-year survival estimate for RTKA was 87.3% (95% CI 86.5 to 88.1). Adjusting for sex, age, surgeon volume, and indication for revision, high hospital case volume was significantly associated with lower risk of re-revision (HR 0.78 (95% CI 0.64 to 0.94, p < 0.001)). The risk of re-revision steadily declined in centres performing > 20 cases per year; risk reduction was 16% with > 20 cases; 22% with > 30 cases; and 28% with > 40 cases. The lowest level of risk was associated with the highest volume centres. CONCLUSION: The majority of RTKA in Scotland survive up to ten years. Increasing yearly hospital case volume above 20 cases is independently associated with a significant risk reduction of re-revision. Development of high-volume tertiary centres may lead to an improvement in the overall survival of RTKA. Cite this article: Bone Joint J 2021;103-B(4):602-609.