Associations of measured and genetically predicted leukocyte telomere length with vascular phenotypes: a population-based study.

Shorter leukocyte telomere length (LTL) is associated with cardiovascular dysfunction. Whether this association differs between measured and genetically predicted LTL is still unclear. Moreover, the molecular processes underlying the association remain largely unknown. We used baseline data of the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany [56.2% women, age: 55.5 ± 14.0 years (range 30 - 95 years)]. We calculated genetically predicted LTL in 4180 participants and measured LTL in a subset of 1828 participants with qPCR. Using multivariable regression, we examined the association of measured and genetically predicted LTL, and the difference between measured and genetically predicted LTL (ΔLTL), with four vascular functional domains and the overall vascular health. Moreover, we performed epigenome-wide association studies of three LTL measures. Longer measured LTL was associated with better microvascular and cardiac function. Longer predicted LTL was associated with better cardiac function. Larger ΔLTL was associated with better microvascular and cardiac function and overall vascular health, independent of genetically predicted LTL. Several CpGs were associated (p < 1e-05) with measured LTL (n = 5), genetically predicted LTL (n = 8), and ΔLTL (n = 27). Genes whose methylation status was associated with ΔLTL were enriched in vascular endothelial signaling pathways and have been linked to environmental exposures, cardiovascular diseases, and mortality. Our findings suggest that non-genetic causes of LTL contribute to microvascular and cardiac function and overall vascular health, through an effect on the vascular endothelial signaling pathway. Interventions that counteract LTL may thus improve vascular function.

Serum Cystatin C Levels as a Predictor of Severity and Mortality Among Patients With COVID-19 Infection.

INTRODUCTION: The pandemic caused by SARS Corona Virus-2 (COVID-19) has caused widespread mortality globally. The hallmark of the disease is the "cytokine storm," which is caused due to dysregulated immune system activation. Numerous inflammatory markers are used to predict the severity and mortality of the infection. Serum Cystatin C levels are associated with immune responses to exogenous and endogenous antigens. Our study was done to assess serum cystatin C as a marker of severity and mortality among patients admitted with COVID-19 infection. METHODOLOGY: This cross-sectional study was conducted in a tertiary care center in South India. Sixty-nine patients with mild and severe COVID-19 infection admitted to the hospital were included in the study. Serum Cystatin C levels were estimated at admission. The levels were correlated with disease severity and mortality. Receiver operating characteristic curves (ROCs) was constructed for Cystatin C to predict severity and mortality. The computation of sensitivity, specificity, and positive and negative predictive values was done using optimal cut-off points. SPSS 18 was used for the statistical analysis. Version 18.0 of PASW Statistics for Windows. SPSS Inc., Chicago. RESULTS: Out of 69 patients, 28 (40.5%) had a mild illness, and 41 patients (59.4%) had severe COVID-19 illness. Mean serum Cystatin C levels measured at the time of admission among patients with mild illness was 1.83 (SD-1.53), and among patients with severe illness was 3.84 (SD- 2.59) (p<0.001). The area under receiver operating characteristic curves (ROC) for serum cystatin C for predicting COVID-19 severity and mortality was 0.904 and 0.768, respectively (p<0.001). CONCLUSION: Patients with severe COVID-19 disease had considerably higher serum levels of Cystatin C than those with mild COVID-19 illness. Cystatin C levels can be useful for predicting mortality and severity among patients admitted with COVID-19 infection.

Neuromyelitis optica spectrum disorder with AQP4-IgG presenting as area postrema syndrome and progressing to myelitis: A rare case report.

Key Clinical Message: Neuromyelitis optica spectrum disorders can less commonly present with area postrema syndrome progressing to myelitis. Management involves intravenous glucocorticoids, plasma exchange, and preventive immunotherapy. Abstract: Neuromyelitis optica spectrum disorders can less commonly present with area postrema syndrome progressing to myelitis. The majority of patients have positive AQP4-Ab. Diagnosis is based on clinical and imaging findings. These patients can be treated with intravenous glucocorticoids, plasma exchange, and preventive immunotherapy.

Patella Denervation With Circumferential Electrocautery in Primary Knee Arthroplasty: A Randomized Controlled Trial.

BACKGROUND: The aim of this study was to investigate the clinical effectiveness of patella rim electrocautery "denervation" versus no denervation in patients undergoing total knee arthroplasty (TKA). METHODS: We conducted a single-center, double-blind randomized controlled trial. Patients aged 40 years or older, due to undergo a TKA who did not have patella resurfacing (usual care) were randomized with or without circumferential patella electrocautery. This was undertaken according to a randomly generated sequence of treatment allocation that was placed into numbered, sealed opaque envelopes. Participants were blinded to treatment allocation. There was no crossover. The primary outcome was Oxford Knee Score at 1 year postoperatively. Secondary outcomes were Bartlett Patella Score, Western Ontario and McMaster Universities Arthritis Index (WOMAC), and 12-Item Short Form Survey. Linear regression analyses were performed with adjustments by age, sex, and baseline (preoperative) scores. There were 142 participants recruited, of which 49 (35%) were allocated to the denervation intervention. Recruitment was stopped early when interim statistical analyses confirmed adequate numbers in both groups despite an imbalance in early treatment allocation rates due to the randomization method. The mean patient age was 71 years (range, 50 to 85) and 51% (n = 74) were women. RESULTS: No difference in Oxford Knee Score was detected at 1 year (mean difference [MD] 1.87; 95% confidence interval [CI] -1.28 to 5.03). No difference was detected in Bartlett Patella Score (MD 0.490; 95% CI -1.61 to 2.59) or 12-Item Short Form Survey (MD 0.196; 95% CI -2.54 to 2.93). A statistically significant difference in WOMAC was detected, but at a level less than the minimal clinically important difference for WOMAC (MD 4.79; 95% CI 1.05 to 8.52). CONCLUSION: No clinically relevant benefit was detected from patella rim electrocautery in patients undergoing TKA who did not have patella resurfacing (including no benefit in terms of anterior knee pain). This treatment is therefore not recommended for clinical practice. LEVEL OF EVIDENCE: Level 1.

A Randomized Trial of Autologous Chondrocyte Implantation Versus Alternative Forms of Surgical Cartilage Management in Patients With a Failed Primary Treatment for Chondral or Osteochondral Defects in the Knee.

BACKGROUND: There are limited randomized controlled trials with long-term outcomes comparing autologous chondrocyte implantation (ACI) versus alternative forms of surgical cartilage management within the knee. PURPOSE: To determine at 5 years after surgery whether ACI was superior to alternative forms of cartilage management in patients after a failed previous treatment for chondral or osteochondral defects in the knee. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: In total, 390 participants were randomly assigned to receive either ACI or alternative management. Patients aged 18 to 55 years with one or two symptomatic cartilage defects who had failed 1 previous therapeutic surgical procedure in excess of 6 months prior were included. Dual primary outcome measures were used: (1) patient-completed Lysholm knee score and (2) time from surgery to cessation of treatment benefit. Secondary outcome measures included International Knee Documentation Committee and Cincinnati Knee Rating System scores, as well as number of serious adverse events. Analysis was performed on an intention-to-treat basis. RESULTS: Lysholm scores were improved by 1 year in both groups (15.4 points [95% CI, 11.9 to 18.8] and 15.2 points [95% CI, 11.6 to 18.9]) for ACI and alternative, with this improvement sustained over the duration of the trial. However, no evidence of a difference was found between the groups at 5 years (2.9 points; 95% CI, -1.8 to 7.5; P = .46). Approximately half of the participants (55%; 95% CI, 47% to 64% with ACI) were still experiencing benefit at 5 years, with time to cessation of treatment benefit similar in both groups (hazard ratio, 0.97; 95% CI, 0.72 to 1.32; P > .99). There was a differential effect on Lysholm scores in patients without previous marrow stimulation compared with those with marrow stimulation (P = .03; 6.4 points in favor of ACI; 95% CI, -0.4 to 13.1). More participants experienced a serious adverse event with ACI (P = .02). CONCLUSION: Over 5 years, there was no evidence of a difference in Lysholm scores between ACI and alternative management in patients who had previously failed treatment. Previous marrow stimulation had a detrimental effect on the outcome of ACI. REGISTRATION: International Standard Randomised Controlled Trial Number: 48911177.

Polygenic risk scores for schizophrenia are associated with oculomotor endophenotypes.

BACKGROUND: Schizophrenia is a heterogeneous disorder with substantial heritability. The use of endophenotypes may help clarify its aetiology. Measures from the smooth pursuit and antisaccade eye movement tasks have been identified as endophenotypes for schizophrenia in twin and family studies. However, the genetic basis of the overlap between schizophrenia and these oculomotor markers is largely unknown. Here, we tested whether schizophrenia polygenic risk scores (PRS) were associated with oculomotor performance in the general population. METHODS: Analyses were based on the data of 2956 participants (aged 30-95) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Genotyping was performed on Omni-2.5 exome arrays. Using summary statistics from a recent meta-analysis based on the two largest schizophrenia genome-wide association studies to date, we quantified genetic risk for schizophrenia by creating PRS at different p value thresholds for genetic markers. We examined associations between PRS and oculomotor performance using multivariable regression models. RESULTS: Higher PRS were associated with higher antisaccade error rate and latency, and lower antisaccade amplitude gain. PRS showed inconsistent patterns of association with smooth pursuit velocity gain and were not associated with saccade rate during smooth pursuit or performance on a prosaccade control task. CONCLUSIONS: There is an overlap between genetic determinants of schizophrenia and oculomotor endophenotypes. Our findings suggest that the mechanisms that underlie schizophrenia also affect oculomotor function in the general population.

Associations of genetic liability for Alzheimer's disease with cognition and eye movements in a large, population-based cohort study.

To identify cognitive measures that may be particularly sensitive to early cognitive decline in preclinical Alzheimer's disease (AD), we investigated the relation between genetic risk for AD and cognitive task performance in a large population-based cohort study. We measured performance on memory, processing speed, executive function, crystallized intelligence and eye movement tasks in 5182 participants of the Rhineland Study, aged 30 to 95 years. We quantified genetic risk for AD by creating three weighted polygenic risk scores (PRS) based on the genome-wide significant single-nucleotide polymorphisms coming from three different genetic association studies. We assessed the relation of AD PRS with cognitive performance using generalized linear models. Three PRS were associated with lower performance on the Corsi forward task, and two PRS were associated with a lower probability of correcting antisaccade errors, but none of these associations remained significant after correction for multiple testing. Associations between age and trail-making test A (TMT-A) performance were modified by AD genetic risk, with individuals at high genetic risk showing the strongest association. We conclude that no single measure of our cognitive test battery robustly captures genetic liability for AD as quantified by current PRS. However, Corsi forward performance and the probability of correcting antisaccade errors may represent promising candidates whose ability to capture genetic liability for AD should be investigated further. Additionally, our finding on TMT-A performance suggests that processing speed represents a sensitive marker of AD genetic risk in old age and supports the processing speed theory of age-related cognitive decline.

Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities.

Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-ß, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.

Anatomical pelvic loading of a monoblock polyethylene acetabular component.

AIMS: Uncemented metal acetabular components show good osseointegration, but material stiffness causes stress shielding and retroacetabular bone loss. Cemented monoblock polyethylene components load more physiologically; however, the cement bone interface can suffer fibrous encapsulation and loosening. It was hypothesized that an uncemented titanium-sintered monoblock polyethylene component may offer the optimum combination of osseointegration and anatomical loading. METHODS: A total of 38 patients were prospectively enrolled and received an uncemented monoblock polyethylene acetabular (pressfit) component. This single cohort was then retrospectively compared with previously reported randomized cohorts of cemented monoblock (cemented) and trabecular metal (trabecular) acetabular implants. The primary outcome measure was periprosthetic bone density using dual-energy x-ray absorptiometry over two years. Secondary outcomes included radiological and clinical analysis. RESULTS: Although there were differences in the number of males and females in each group, no significant sex bias was noted (p = 0.080). Furthermore, there was no significant difference in age (p = 0.910) or baseline lumbar bone mineral density (BMD) (p = 0.998) found between any of the groups (pressfit, cemented, or trabecular). The pressfit implant initially behaved like the trabecular component with an immediate fall in BMD in the inferior and medial regions, with preserved BMD laterally, suggesting lateral rim loading. However, the pressfit component subsequently showed a reversal in BMD medially with recovery back towards baseline, and a continued rise in lateral BMD. This would suggest that the pressfit component begins to reload the medial bone over time, more akin to the cemented component. Analysis of postoperative radiographs revealed no pressfit component subsidence or movement up to two years postoperatively (100% interobserver reliability). Medial defects seen immediately postoperatively in five cases had completely resolved by two years in four patients. CONCLUSION: Initially, the uncemented monoblock component behaved similarly to the rigid trabecular metal component with lateral rim loading; however, over two years this changed to more closely resemble the loading pattern of a cemented polyethylene component with increasing medial pelvic loading. This indicates that the uncemented monoblock acetabular component may result in optimized fixation and preservation of retroacetabular bone stock. Cite this article: Bone Joint J 2021;103-B(5):872-880.

Staff testing for COVID-19 via an online pre-registration form

Structured AbstractO_ST_ABSBackgroundC_ST_ABSHealthcare workers are at increased risk of contracting SARS-CoV-2 and potentially causing institutional outbreaks. Staff testing is critical in identifying and isolating infected individuals while also reducing unnecessary workforce depletion. Tygerberg Hospital implemented an online pre-registration system to expedite staff and cluster testing. ObjectivesWe aimed to identify (1) specific presentations associated with a positive or negative result for SARS-CoV-2 and (2) staff sectors where enhanced strategies for testing might be required. MethodsRetrospective descriptive study involving all clients making use of the hospitals pre-registration system during May 2020. ResultsOf 799 clients, most were young and female with few comorbidities. The most common occupation was nurses followed by administrative staff, doctors and general assistants. Doctors tested earlier compared to other staff (median: 1.5 vs 4 days). The most frequent presenting symptoms were headache, sore throat, cough and myalgia. Amongst those testing positive (n=105), fever, altered smell, altered taste sensation, chills and history of fever were the most common symptoms. Three or more symptoms was more predictive of a positive test, but 12/145 asymptomatic clients also tested positive. ConclusionStaff coronavirus testing using an online pre-registration form is a viable and acceptable strategy. While some presentations are less likely to be associated with SARS-CoV-2 infection, no symptom can completely exclude it. Staff testing should form part of a bundle of strategies to protect staff including wearing masks, regular hand washing, buddy screening, physical distancing, availability of PPE and special dispensation for COVID-19-related leave. Unstructured AbstractHospital staff testing is critical to identify and isolate SARS-CoV-2 infected individuals while reducing unnecessary workforce depletion. Tygerberg Hospital implemented an online pre-registration system to expedite staff testing. In a retrospective descriptive study of all clients registering during May 2020 (N=799), we found rapid and sustained uptake of the system. The most frequent presenting symptoms were headache, sore throat, cough and myalgia. Amongst those testing positive (n=105), fever, altered smell, altered taste sensation and chills were the most likely symptoms, but 12/145 asymptomatic clients also tested positive. Staff testing should form part of a bundle of strategies to protect staff.

Hypokalaemic Periodic Paralysis in a Patient with Subclinical Hyperthyroidism: A Rare Case.

Thyrotoxic Periodic Paralysis (TPP) is an uncommon disorder. Though many cases of hypokalaemic periodic paralysis are reported in overt hyperthyroidism, hypokalaemic paralysis in subclinical hyperthyroidism is very rare. Subclinical hyperthyroidism is characterised by circulating TSH levels below reference range and normal thyroid hormone levels. We describe a case of 32-year-old Asian male who presented to the emergency department with acute onset weakness and hypokalaemia with no previous history of thyroid disorder or any signs and symptoms suggestive of hyperthyroidism. He was subsequently diagnosed with Graves' disease with subclinical hyperthyroidism.

Actinobacillus hominis osteomyelitis: First reported case in the English language medical literature.

INTRODUCTION: Actinobacillus hominis is currently a rarely reported pathogen. It has previously been associated with respiratory tract infections and bacteraemia in debilitated patients. However, under-reporting may occur due to misidentification by commonly used laboratory bacterial identification systems. This case is, to the best of our knowledge, the first reported case of A. hominis osteomyelitis in the English language medical literature. CASE PRESENTATION: A 37-year-old male presented with a painful foot. He had no previous foot problems, history of injury or animal contact. Osteomyelitis was confirmed by magnetic resonance imaging (MRI), and blood cultures were positive for Gram-variable bacilli. The organism was identified initially as Pasteurella pneumotropica by the local routine diagnostic laboratory and as a Pasteurella species by the UK National Reference Laboratory (Colindale, London, UK), using standard operating procedures at the time. It was finally identified as an A. hominis using 16S rRNA gene sequence analysis. Difficulties in the accurate identification of this organism remain current, as other biochemical identification systems have also resulted in misidentifications. The patient refused admission and intravenous antibiotics. He was successfully treated using an 8-week course of oral ciprofloxacin and amoxicillin based on antibiotic disc susceptibility testing resulting in clinical, serological and radiological resolution. CONCLUSION: Laboratories should maintain a high index of suspicion for A. hominis as several commonly used bacterial identification systems may not accurately identify the organism. Colonial morphology and absence of animal contact should prompt consideration of this organism in appropriate clinical situations. Oral ciprofloxacin and amoxicillin treatment was successful in this case.

The effect of tibial component sizing on patient reported outcome measures following uncemented total knee replacement.

UNLABELLED: When performing total knee replacement (TKR), surgeons are required to decide on the most appropriate size of tibial component. As implants are predominantly selected from incremental sizes of a preferred design, it may be necessary for a surgeon to slightly under or oversize the component. There are concerns that overhang could lead to pain from irritation of soft tissues, and an undersized component could lead to subsidence and failure. Patient reported outcome measures were recorded in 154 TKRs at one year postoperatively (in 100 TKRs) and five years post-operatively (in 54 TKRs) in 138 patients. The Oxford Knee Score (OKS), WOMAC and SF-12 were recorded, and a composite pain score was derived from the OKS and WOMAC pain questions. Tibial component size and position were assessed on scaled radiographs and implants were grouped into anatomic sized tibial component (78 TKRs), undersized component (48 TKRs), minor overhang one to three mm (10 TKRs) or major overhang ≥ 3 mm (18 TKRs). There was no statistically significant difference between the mean post-operative OKS, WOMAC, SF-12 or composite pain score of each group. Furthermore, localisation of the site of pain did not correlate with medial or lateral overhang of the tibial component. Our results suggest that tibial component overhang or undersizing is not detrimental to outcome measures or pain. LEVEL OF EVIDENCE: II.

Does orthopaedic surgical training induce hypertension? A pilot study.

BACKGROUND: Elevated blood pressure (BP) is associated with increased cardiovascular risks manifested by ischemic heart disease and stroke. Studies of cardiothoracic surgeons and neurosurgeons suggest surgery induces a hemodynamic stress malresponse. However, it is unclear whether these occur in orthopaedic surgeons. QUESTIONS/PURPOSES: We measured the BP of surgeons during hallux valgus surgery, TKA, and THA with the: (1) trainee assisting the trainer, (2) the trainer assisting the trainee, (3) the trainee operating independently, and (4) compared the intraoperative changes in BP and heart rate of orthopaedic surgeons with those of a clinic day and during an exercise tolerance test. METHODS: We used an ambulatory BP monitor to measure the BP and heart rate of three consultants and their respective trainees during hallux valgus surgery, TKA, or THA. We noted if there were any differences in the stress response of the lead surgeon in comparison to when the same individual was assisting a trainee, and vice versa. Additionally, we recorded the trainee's BP and heart rate when they were operating independently. The intraoperative changes in BP and heart rate of orthopaedic surgeons were compared with those measured during a clinic day and during an exercise tolerance test. RESULTS: When the trainer was leading the operation, their mean arterial pressure gradually increased to 105 (range, 102-109) until implant placement. However, when the trainee was operating and the trainer assisting, the trainer's BP peaked (mean, 101; range, 95-111) at the beginning of the procedure and slowly declined as it progressed. The trainee's BP remained elevated throughout. The highest peaks for trainees were noted during independent operating. All of the surgeons had higher average BP readings (mean, 100; range, 95-108) and heart rate (mean, 86; range, 57-117) on days when they did surgery compared with baseline. CONCLUSIONS: The elective operations studied induced a hypertensive response. The response was more marked in trainees than in trainers, particularly if the trainee was operating independently.

A novel technique for femoral canal occlusion during cement pressurization in proximal femoral arthroplasty.

We describe a novel technique for occluding the femoral canal distal to the isthmus during proximal femoral arthroplasty. Synthetic bone models were reamed and sectioned to simulate loss of the proximal femur. Two experimental conditions were used. The first used no restrictor to act as a control. The second used calcium sulphate pellets impacted in distal femoral canal. A 100 × 12 mm Limb Preservation System stem (DePuy, Leeds, UK) was used in all experiments. We recorded cement pressure, leakage of cement, and penetration of cement into the femoral condyles. The calcium sulphate pellets prevented cement leakage, enabled higher cementing pressures, and prevented penetration of the cement into the femoral condyles. We would recommend this technique in cases where loss of proximal femoral bone loss requires the use of a cemented proximal femoral replacement.

Improving the accuracy of acetabular cup implantation using a bulls-eye spirit level.

Acetabular introducers have a built-in inclination of 45 degrees to the handle shaft. With patients in the lateral position, surgeons aim to align the introducer shaft vertical to the floor to implant the acetabulum at 45 degrees. We aimed to determine if a bulls-eye spirit level attached to an introducer improved the accuracy of implantation. A small circular bulls-eye spirit level was attached to the handle of an acetabular introducer. A saw bone hemipelvis was fixed to a horizontal, flat surface. A cement substitute was placed in the acetabulum and subjects were asked to implant a polyethylene cup, aiming to obtain an angle of inclination of 45 degrees. Two attempts were made with the spirit level masked and two with it unmasked. The distance of the air bubble from the spirit level's center was recorded by a single assessor. The angle of inclination of the acetabular component was then calculated. Subjects included both orthopedic consultants and trainees. Twenty-five subjects completed the study. Accuracy of acetabular implantation when using the unmasked spirit level improved significantly in all grades of surgeon. With the spirit level masked, 12 out of 50 attempts were accurate at 45 degrees inclination; 11 out of 50 attempts were "open," with greater than 45 degrees of inclination, and 27 were "closed," with less than 45 degrees. With the spirit level visible, all subjects achieved an inclination angle of exactly 45 degrees. A simple device attached to the handle of an acetabular introducer can significantly improve the accuracy of implantation of a cemented cup into a saw bone pelvis in the lateral position.

Patellar button dissociation in a mobile-bearing LCS patellofemoral joint arthroplasty.

Patellofemoral arthroplasty is an effective treatment for isolated patellofemoral arthritis. Midterm results reveal a success rate of approximately 80% to 90% with modern designs. The reported failure mechanisms associated with patellofemoral arthroplasty include progressive tibiofemoral arthritis, patellar pain, catching or subluxation caused by soft-tissue imbalance, component malposition, and problematic designs. We present a previously unreported new complication of patellar button dissociation in a mobile-bearing LCS Patellofemoral Joint Replacement Prosthesis.