Citations

Abstract Background Patient-reported outcome measures (PROMs) are frequently used to assess the impact of total knee arthroplasty (TKA) on patients. However, mere statistical comparison of PROMs is not sufficient to assess the value of TKA to the patient, especially given the risk profile of arthroplasty. Evaluation of treatment effect sizes is important to support the use of an intervention; this is often quantified with the minimum clinically important difference (MCID). MCIDs are unique to specific PROMs, as they vary by calculation methodology and study population. Therefore, a systematic review of calculated MCID values, their respective ranges, and assessment of their applications is important to guide and encourage their use as a critical measure of effect size in TKA outcomes research. Questions/purposes In this systematic review of MCID calculations and reporting in primary TKA, we asked: (1) What are the most frequently reported PROM MCIDs and their reported ranges in TKA? (2) What proportion of studies report distribution- versus anchor-based MCID values? (3) What are the most common methods by which these MCID values are derived for anchor-based values? (4) What are the most common derivation methods for distribution-based values? (5) How do the reported medians and corresponding interquartile ranges (IQR) compare between calculation methods for each PROM? Methods Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review was conducted using the PubMed, EMBASE, and MEDLINE databases from inception through March 2022 for TKA articles reporting an MCID value for any PROMs. Two independent reviewers screened articles for eligibility, including any article that calculated new MCID values for PROMs after primary TKA, and extracted these data for analysis. Overall, 576 articles were identified, 38 of which were included in the final analysis. These studies had a total of 710,128 patients with a median age of 67.7 years and median BMI of 30.9 kg/m 2 . Women made up more than 50% of patients in most studies, and the median follow-up period was 17 months (range 0.25 to 72 months). The overall risk of bias was assessed as moderate using the Jadad criteria for one randomized controlled trial (3 of 5 ideal global score) and the modified Methodological Index for Non-randomized Studies criteria for comparative studies (mean 17.2 ± 1.8) and noncomparative studies (mean 9.6 ± 1.3). There were 49 unique PROMs for which 233 MCIDs were reported. Calculated values were classified as anchor-based, distribution-based, or not reported. MCID values for each PROM, MCID calculation method, number of patients, and study demographics were extracted from each study. Anchor-based and distribution-based MCIDs were compared for each unique PROM using a Wilcoxon rank sum test given non-normal distribution of values. Results The WOMAC Function and Pain subscores were the most frequently reported MCID value, comprising 9% (22 of 233) and 9% (22 of 233), respectively. The composite Oxford Knee Score (OKS) was the next most frequently reported (9% [21 of 233]), followed by the WOMAC composite score (6% [13 of 233]). The median anchor-based values for WOMAC Function and Pain subscores were 23 (IQR 16 to 33) and 25 (IQR 14 to 31), while the median distribution-based values were 11 (IQR 10.8 to 11) and 22 (IQR 17 to 23), respectively. The median anchor-based MCID value for the OKS was 6 (IQR 4 to 7), while the distribution-based value was 7 (IQR 5 to 10). Thirty-nine percent (15 of 38) used an anchor-based method to calculate a new MCID, while 32% (12 of 38) used a distribution-based technique. Twenty-nine percent of studies (11 of 38) calculated MCID values using both methods. For studies reporting an anchor-based calculation method, a question assessing patient satisfaction, pain relief, or quality of life along a five-point Likert scale was the most commonly used anchor (40% [16 of 40]), followed by a receiver operating characteristic curve estimation (25% [10 of 40]). For studies using distribution-based calculations, all articles used a measure of study population variance in their derivation of the MCID, with the most common method reported as one-half the standard deviation of the difference between preoperative and postoperative PROM scores (45% [14 of 31]). Most reported median MCID values (15 of 19) did not differ by calculation method for each unique PROM (p > 0.05) apart from the WOMAC Function component score and the Knee Injury and Osteoarthritis Outcome Score Pain and Activities of Daily Living subscores. Conclusion Despite variability of MCIDs for each PROM, there is consistency in the methodology by which MCID values have been derived in published studies. Additionally, there is a consensus about MCID values regardless of calculation method across most of the PROMs we evaluated. Clinical Relevance Given their importance to treatment selection and patient safety, authors and journals should report MCID values with greater consistency. We recommend using a 7-point increase as the MCID for the OKS, consistent with the median reported anchor-based value derived from several high-quality studies with large patient groups that used anchor-based approaches for MCID calculation, which we believe are most appropriate for most applications in clinical research. Likewise, we recommend using a 10-point to 15-point increase for the MCID of composite WOMAC, as the median value was 12 (IQR 10 to 17) with no difference between calculation methods. We recommend use of median reported values for WOMAC function and pain subscores: 21 (IQR 15 to 33) and 23 (IQR 13 to 29), respectively.

Background: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes. Objective: Investigate the contributions of vascular factors and cancer to dementia and neuropathology. Methods: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology. Results: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95–106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19–0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39–163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17–0.78]; p < 0.01) and lower Braak stage (p = 0.01). Conclusion: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-β plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old.

A man in his 60s presented to the emergency room with fever and fatigue after a 2.5-month course of corticosteroids. His medical history was significant for bioprosthetic aortic valve replacement and moderately severe ulcerative colitis treated with balsalazide and daily lactobacillus-containing probiotics. Initial investigations revealed Lactobacillus rhamnosus bacteraemia without complication. Four days after hospital discharge, the patient experienced acute-onset right-sided paraesthesia and lower-limb paresis. On return to the emergency room, MRI of the brain demonstrated innumerable ring-enhancing lesions with haemorrhagic transformation. Transoesophageal echocardiogram revealed a small mobile density on the bioprosthetic aortic valve, raising the suspicion for L. rhamnosus infective endocarditis with secondary septic emboli to the brain. The patient was subsequently treated with intravenous gentamycin and ampicillin, with transition to indefinite oral amoxicillin suppressive therapy. The current case highlights the potential risk of lactobacilli translocation in an immunosuppressed patient with ulcerative colitis taking probiotics.

Abstract Aims In catecholaminergic polymorphic ventricular tachycardia (CPVT), the exercise-stress test (EST) is the cornerstone for the diagnosis, risk stratification, and assessment of therapeutic efficacy, but its repeatability is unknown. We aimed to test the repeatability of ventricular arrhythmia characteristics on the EST in patients with CPVT. Methods and results EST-pairs (ESTs performed within 18 months between 2005 and 2021, on the same protocol, and without or on the exact same treatment) of patients with RYR2-mediated CPVT from two specialized centres were included. The primary endpoint was the repeatability of the maximum ventricular arrhythmia score [VAS: 0 for the absence of premature ventricular contractions (PVCs); 1 for isolated PVCs; 2 for bigeminal PVCs; 3 for couplets; and 4 for non-sustained ventricular tachycardia]. Secondary outcomes were the repeatability of the heart rate at the first PVC and the ΔVAS (the absolute difference in VAS between the EST-pairs). A total of 104 patients with 349 EST-pairs were included. The median duration between ESTs was 343 (interquartile range, 189–378) days. Sixty (17.2%) EST-pairs were off therapy. The repeatability of the VAS was moderate {Krippendorf α, 0.56 [95% confidence interval (CI), 0.48–0.64]}, and the repeatability of the heart rate at the first PVC was substantial [intra-class correlation coefficient, 0.78 (95% CI, 0.71–0.84)]. The use of medication was associated with a higher odds for a ΔVAS &gt; 1 (odds ratio = 3.52; 95% CI, 2.46–4.57; P = 0.020). Conclusion The repeatability of ventricular arrhythmia characteristics was moderate to substantial. This underlines the need for multiple ESTs in CPVT patients and CPVT suspicious patients and it provides the framework for assessing the therapeutic efficacy of novel CPVT therapies.

AbstractBackgroundPatients with prostate cancer suffer significant sexual dysfunction after treatment which negatively affects them and their partners psychologically, and strain their relationships.AimWe convened an international panel with the aim of developing guidelines that will inform clinicians, patients and partners about the impact of prostate cancer therapies (PCT) on patients’ and partners’ sexual health, their relationships, and about biopsychosocial rehabilitation in prostate cancer (PC) survivorship.MethodsThe guidelines panel included international expert researchers and clinicians, and a guideline methodologist. A systematic review of the literature, using the Ovid MEDLINE, Scopus, CINAHL, PsychINFO, LGBT Life, and Embase databases was conducted (1995–2022) according to the Cochrane Handbook for Systematic Reviews of Interventions. Study selection was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Each statement was assigned an evidence strength (A-C) and a recommendation level (strong, moderate, conditional) based on benefit/risk assessment, according to the nomenclature of the American Urological Association (AUA). Data synthesis included meta-analyses of studies deemed of sufficient quality (3), using A Measurement Tool to Assess Systematic Reviews (AMSTAR).OutcomesGuidelines for sexual health care for patients with prostate cancer were developed, based on available evidence and the expertise of the international panel.ResultsThe guidelines account for patients’ cultural, ethnic, and racial diversity. They attend to the unique needs of individuals with diverse sexual orientations and gender identities. The guidelines are based on literature review, a theoretical model of sexual recovery after PCT, and 6 principles that promote clinician-initiated discussion of realistic expectations of sexual outcomes and mitigation of sexual side-effects through biopsychosocial rehabilitation. Forty-seven statements address the psychosexual, relationship, and functional domains in addition to statements on lifestyle modification, assessment, provider education, and systemic challenges to providing sexual health care in PC survivorship.Clinical ImplicationsThe guidelines provide clinicians with a comprehensive approach to sexual health care for patients with prostate cancer.Strengths & LimitationsThe strength of the study is the comprehensive evaluation of existing evidence on sexual dysfunction and rehabilitation in prostate cancer that can, along with available expert knowledge, best undergird clinical practice. Limitation is the variation in the evidence supporting interventions and the lack of research on issues facing patients with prostate cancer in low and middle-income countries.ConclusionThe guidelines document the distressing sexual sequelae of PCT, provide evidence-based recommendations for sexual rehabilitation and outline areas for future research.

Abstract Aims and Objectives To determine the frequency, timing, and duration of post‐acute sequelae of SARS‐CoV‐2 infection (PASC) and their impact on health and function. Background Post‐acute sequelae of SARS‐CoV‐2 infection is an emerging major public health problem that is poorly understood and has no current treatment or cure. PASC is a new syndrome that has yet to be fully clinically characterised. Design Descriptive cross‐sectional survey ( n = 5163) was conducted from online COVID‐19 survivor support groups who reported symptoms for more than 21 days following SARS‐CoV‐2 infection. Methods Participants reported background demographics and the date and method of their covid diagnosis, as well as all symptoms experienced since onset of covid in terms of the symptom start date, duration, and Likert scales measuring three symptom‐specific health impacts: pain and discomfort, work impairment, and social impairment. Descriptive statistics and measures of central tendencies were computed for participant demographics and symptom data. Results Participants reported experiencing a mean of 21 symptoms (range 1–93); fatigue (79.0%), headache (55.3%), shortness of breath (55.3%) and difficulty concentrating (53.6%) were the most common. Symptoms often remitted and relapsed for extended periods of time (duration M = 112 days), longest lasting symptoms included the inability to exercise ( M = 106.5 days), fatigue ( M = 101.7 days) and difficulty concentrating, associated with memory impairment ( M = 101.1 days). Participants reported extreme pressure at the base of the head, syncope, sharp or sudden chest pain, and “brain pressure” among the most distressing and impacting daily life. Conclusions Post‐acute sequelae of SARS‐CoV‐2 infection can be characterised by a wide range of symptoms, many of which cause moderate‐to‐severe distress and can hinder survivors' overall well‐being. Relevance to Clinical Practice This study advances our understanding of the symptoms of PASC and their health impacts.

Abstract Objective The objective of this study is to report results from the open-label extension (OLE) of the OPTIMAL trial of oral octreotide capsules (OOC) in adults with acromegaly, evaluating the long-term durability of therapeutic response. Design The study design is an OLE of a double-blind placebo-controlled (DPC) trial. Methods Patients completing the 36-week DPC period on the study drug (OOC or placebo) or meeting predefined withdrawal criteria were eligible for OLE enrollment at 60 mg/day OOC dose, with the option to titrate to 40 or 80 mg/day. The OLE is ongoing; week 48 results are reported. Results Forty patients were enrolled in the OLE, 20 each having received OOC or placebo, with 14 and 5 patients completing the DPC period as responders, respectively. Ninety percent of patients completing the DPC period on OOC and 70% of those completing on placebo completed 48 weeks of the OLE. Maintenance of response in the OLE (i.e. insulin-like growth factor I (IGF1) ≤ 1.0 × upper limit of normal (ULN)) was achieved by 92.6% of patients who responded to OOC during the DPC period. Mean IGF1 levels were maintained between the end of the DPC period (0.91 × ULN; 95% CI: 0.784, 1.045) and week 48 of the OLE (0.90 × ULN; 95% CI: 0.750, 1.044) for those completing the DPC period on OOC. OOC safety was consistent with previous findings, with no increased adverse events (AEs) associated with the higher dose and improved gastrointestinal tolerability observed over time. Conclusions Patients with acromegaly maintained long-term biochemical response while receiving OOC, with no new AEs observed with prolonged OOC exposure.

Background Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes. Objectives We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease. Design This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab. Setting Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated. Participants Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of < 50 ml/minute/1.73 m2 or diffuse alveolar haemorrhage attributable to active anti-neutrophil cytoplasm antibody-associated vasculitis. Interventions Participants received seven sessions of plasma exchange within 14 days or no plasma exchange. Oral glucocorticoids commenced with prednisolone 1 mg/kg/day and were reduced over different lengths of time to 5 mg/kg/day, such that cumulative oral glucocorticoid exposure in the first 6 months was 50% lower in patients allocated to the reduced-dose regimen than in those allocated to the standard-dose regimen. All patients received the same glucocorticoid dosing from 6 to 12 months. Subsequent dosing was at the discretion of the treating physician. Primary outcome The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial. Results The study recruited 704 patients from June 2010 to September 2016. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86, 95% confidence interval 0.65 to 1.13; p = 0.3). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023, 95% confidence interval 0.034 to 0.08; p = 0.5), thus meeting our non-inferiority hypothesis. Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% confidence interval 0.52 to 0.93; p = 0.016). Conclusions Plasma exchange did not prolong the time to death and/or end-stage renal disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis with severe renal or pulmonary involvement. A reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen and was associated with fewer serious infections. Future work A meta-analysis examining the effects of plasma exchange on kidney outcomes in anti-neutrophil cytoplasm antibody-associated vasculitis is planned. A health-economic analysis of data collected in this study to examine the impact of both plasma exchange and reduced glucocorticoid dosing is planned to address the utility of plasma exchange for reducing early end-stage renal disease rates. Blood and tissue samples collected in the study will be examined to identify predictors of response to plasma exchange in anti-neutrophil cytoplasm in antibody-associated vasculitis. The benefits associated with reduced glucocorticoid dosing will inform future studies of newer therapies to permit further reduction in glucocorticoid exposure. Data from this study will contribute to updated management recommendations for anti-neutrophil cytoplasm antibody-associated vasculitis. Limitations This study had an open-label design which may have permitted observer bias; however, the nature of the end points, end-stage renal disease and death, would have minimised this risk. Despite being, to our knowledge, the largest ever trial in anti-neutrophil cytoplasm antibody-associated vasculitis, there was an insufficient sample size to assess clinically useful benefits on the separate components of the primary end-point: end-stage renal disease and death. Use of a fixed-dose plasma exchange regimen determined by consensus rather than data-driven dose ranging meant that some patients may have been underdosed, thus reducing the therapeutic impact. In particular, no biomarkers have been identified to help determine dosing in a particular patient, although this is one of the goals of the biomarker plan of this study. Trial registration This trial is registered as ISRCTN07757494, EudraCT 2009-013220-24 and Clinicaltrials.gov NCT00987389. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 38. See the NIHR Journals Library website for further project information.

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons, causing progressive muscle weakness and respiratory failure. The presence of an expanded hexanucleotide repeat in chromosome 9 open reading frame 72 (C9ORF72) accounts for most cases of familial ALS and frontotemporal dementia (FTD). To determine if suppressing expression of C9ORF72 gene products can reduce toxicity, we designed a set of artificial microRNAs (amiRNA) targeting the human C9ORF72 gene. Here we report that an AAV9-mediated amiRNA significantly suppresses expression of the C9ORF72 mRNA, protein, and toxic poly-dipeptides generated by the expanded repeat in the brain and spinal cord.

Takotsubo cardiomyopathy or Takotsubo Syndrome (TTS) is a reversible left ventricular dysfunction syndrome that is increasingly being recognized. Recent advances in nuclear imaging have allowed us to study TTS in greater detail. We searched the PubMed and Medline databases and identified 53 publications with 221 patients reporting nuclear imaging findings in TTS. The age of the patients ranged from 17 to 87 years and were predominantly women (88.2%). The TTS variant was apical (typical) in 170 (76.9%), mid-ventricular in 23 (10.4%), and basal (reverse TTS) in 2 (0.9%). Cardiac perfusion was assessed using 99mTc sestamibi (MIBI) SPECT, 99mTc tetrofosmin SPECT, 201Tl SPECT, 82Rb PET, 201Tl SPECT, and 13N ammonia PET. Additional studies used were 123I MIBG SPECT, 123I BMIPP SPECT, 18F FDG PET, 67Ga citrate, and 11C hydroxy-ephedrine. A perfusion defect was seen in 69 (31.2%), and an inverse perfusion–metabolism mismatch (normal or near-normal perfusion with absent myocardial metabolic activity) was seen in 183 (82.8%) patients. Nuclear imaging has a significant role in evaluating, diagnosing, and prognosticating patients with TTS. As nuclear imaging technology evolves, we will surely gain more insights into this fascinating disorder.