The complexity of multiple sclerosis (MS) treatment means that doctors and decision-makers need the best available evidence to make the best decisions for patient care. Randomized controlled trials ...(RCTs) are accepted as the gold standard for assessing the efficacy and safety of any new drug, but conclusions of these trials do not always aid in daily decision-making processes. Indeed, RCTs are usually conducted in ideal conditions, so can measure efficacy only in restricted and unrepresentative populations. In the past decade, a growing number of MS databases and registries have started to produce long-term outcome data from large cohorts of patients with MS treated with disease-modifying therapies in real-world settings. Such observational studies are addressing issues that are otherwise difficult or impossible to study. In this Review, we focus on the most recently published observational studies designed to identify predictors of poor outcome and treatment response or failure, and to evaluate the relative and long-term effectiveness of currently used MS treatments. We also outline the statistical approaches that are most commonly used to reduce bias and limitations in these studies, and the challenges associated with the use of 'big MS data' to facilitate the implementation of personalized medicine in MS.
IMPORTANCE: Emerging evidence suggests that risk of bacterial sexually transmitted infections (STIs) increases among gay and bisexual men following initiation of HIV preexposure prophylaxis (PrEP). ...OBJECTIVE: To describe STI incidence and behavioral risk factors among a cohort of predominantly gay and bisexual men who use PrEP, and to explore changes in STI incidence following PrEP commencement. DESIGN, SETTING, AND PARTICIPANTS: The Pre-exposure Prophylaxis Expanded (PrEPX) Study, a multisite, open-label intervention study, was nested within the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance (ACCESS) clinic network. A total of 4275 participants were enrolled (July 26, 2016–April 1, 2018) in Victoria, Australia. Of these, 2981 enrolled at 5 ACCESS clinics (3 primary care, 1 sexual health, and 1 community-based HIV rapid testing service), had at least 1 follow-up visit, and were monitored until April 30, 2018. EXPOSURES: Upon enrollment, participants received daily oral tenofovir disoproxil fumurate and emtricitabine for HIV PrEP, quarterly HIV and STI testing, and clinical monitoring. MAIN OUTCOMES AND MEASURES: The primary outcome was incidence of chlamydia, gonorrhea, or syphilis. Incidence rates and hazard ratios describing behavioral risk factors of STI diagnosis were calculated. Incidence rate ratios (IRRs), adjusted for change in testing frequency, described changes in STI incidence from 1-year preenrollment to study follow-up among participants with preenrollment testing data (n = 1378). RESULTS: Among the 2981 individuals (median age, 34 years interquartile range, 28-42), 98.5% identified as gay or bisexual males, 29% used PrEP prior to enrollment, 89 (3%) withdrew and were censored at date of withdrawal, leaving 2892 (97.0%) enrolled at final follow-up. During a mean follow-up of 1.1 years (3185.0 person-years), 2928 STIs were diagnosed among 1427 (48%) participants (1434 chlamydia, 1242 gonorrhea, 252 syphilis). STI incidence was 91.9 per 100 person-years, with 736 participants (25%) accounting for 2237 (76%) of all STIs. Among 2058 participants with complete data for multivariable analysis, younger age, greater partner number, and group sex were associated with greater STI risk, but condom use was not. Among 1378 participants with preenrollment testing data, STI incidence increased from 69.5 per 100 person-years prior to enrollment to 98.4 per 100 person-years during follow-up (IRR, 1.41 95% CI, 1.29-1.56). After adjusting for testing frequency, the increase in incidence from 1 year preenrollment to follow-up was significant for any STI (adjusted IRR, 1.12 95% CI, 1.02-1.23) and for chlamydia (adjusted IRR, 1.17 95% CI, 1.04-1.33). CONCLUSIONS AND RELEVANCE: Among gay and bisexual men using PrEP, STIs were highly concentrated among a subset, and receipt of PrEP after study enrollment was associated with an increased incidence of STIs compared with preenrollment. These findings highlight the importance of frequent STI testing among gay and bisexual men using PrEP.
Whilst evidence of use of face masks in reducing COVID-19 cases is increasing, the impact of mandatory use across a large population has been difficult to assess. Introduction of mandatory mask use ...on July 22, 2020 during a resurgence of COVID-19 in Melbourne, Australia created a situation that facilitated an assessment of the impact of the policy on the epidemic growth rate as its introduction occurred in the absence of other changes to restrictions.
Exponential epidemic growth or decay rates in daily COVID-19 diagnoses were estimated using a non-weighted linear regression of the natural logarithm of the daily cases against time, using a linear spline model with one knot (lspline package in R v 3.6.3). The model's two linear segments pivot around the hinge day, on which the mask policy began to take effect, 8 days following the introduction of the policy. We used two forms of data to assess change in mask usage: images of people wearing masks in public places obtained from a major media outlet and population-based survey data. Potential confounding factors (including daily COVID-19 tests, number of COVID-19 cases among population subsets affected differentially by the mask policy-e.g., healthcare workers) were examined for their impact on the results. Daily cases fitted an exponential growth in the first log-linear segment (k = +0.042, s.e. = 0.007), and fitted an exponential decay in the second (k = -0.023, s.e. = 0.017) log-linear segment. Over a range of reported serial intervals for SARS-CoV-2 infection, these growth rates correspond to a 22-33% reduction in an effective reproduction ratio before and after mandatory mask use. Analysis of images of people in public spaces showed mask usage rose from approximately 43% to 97%. Analysis of survey data found that on the third day before policy introduction, 44% of participants reported "often" or "always" wearing a mask; on the fourth day after, 100% reported "always" doing so. No potentially confounding factors were associated with the observed change in growth rates.
The mandatory mask use policy substantially increased public use of masks and was associated with a significant decline in new COVID-19 cases after introduction of the policy. This study strongly supports the use of masks for controlling epidemics in the broader community.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To assess the comparative effectiveness and temporal changes in quality of life (QoL) outcomes after revascularisation, major lower extremity amputation (MLEA), and conservative management (CM) in ...chronic limb threatening ischaemia (CLTI).
MEDLINE, Embase, PsycINFO, CINAHL, and Web of Science.
A systematic review and meta-analysis were performed on QoL measured by any QoL instrument in adult patients with CLTI after open surgery (OS), endovascular intervention (EVI), MLEA, or CM. Randomised controlled trials and prospective observational studies published in any language between 1 January 1990 and 21 May 2021 were included. There was a pre-specified measurement time point of six months. Random effects meta-analysis was conducted on total scores for each QoL instrument. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations approach (PROSPERO registration: CRD42021253953).
Fifty-five studies with 8 909 patients were included. There was significant heterogeneity in the methods used to measure QoL, and the study characteristics. In particular, 14 different QoL instruments were used with various combinations of disease specific and generic instruments within each study. A narrative summary is therefore presented. Comparative effectiveness data showed there was reasonable certainty that QoL was similar between OS and EVI at six months. Temporal outcomes suggested small to moderate improvements in QOL six months after OS and EVI compared with baseline. Limited data indicated that QoL can be maintained or slightly improved after MLEA or CM. Treatment effects were overestimated owing to small study effects, selective non-reporting, attrition, and survivorship bias.
QoL after OS and EVI appears to be similar. Revascularisation may provide modest QoL benefits, while MLEA or CM can maintain QoL. However, certainty of evidence is generally low or very low, and interpretation is hampered by significant heterogeneity. There is a need for a CLTI specific QoL instrument and methodological standardisation in QoL studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Undifferentiated pleomorphic sarcoma (UPS) is a rare malignant tumour of mesenchymal origin, which was conceived following re‐classification of malignant fibrous histiocytoma (MFH). The ...objective of this study is to determine prognostic factors for the outcome of UPS, following multi‐modal treatment.
Methods
Data of UPS tumours from 1996 to 2016 were collected, totalling 266 unique UPS patients. Median follow‐up was 7.8 years. All tumours were retrospectively analysed for prognostic factors of the disease, including local recurrence (LR) and metastatic disease (MD) at diagnosis, tumour size, grade, location and depth, patient age, adjuvant therapy and surgical margin. Overall survival (OS), post‐treatment LR and metastatic‐free survival were assessed as outcomes.
Results
The 5‐ and 10‐year OS rates for all ages were 60% and 48%, respectively, with a median survival time of 10.1 years. Multivariate analysis revealed that the adverse prognostic factors associated with decreased OS were older age (P < 0.001; hazard ratio 1.03) and MD at diagnosis (P = 0.001; 2.89), with upper extremity tumours being favourable (P = 0.043; 2.30). Poor prognosis for post‐operative LR was associated with older age (P = 0.046; 1.03) and positive surgical margins (P = 0.028; 2.68). Increased post‐treatment MD was seen in patients with large tumours (5–9 cm (P < 0.001; 4.42), ≥10 cm (P < 0.001; 6.80)) and MD at diagnosis (P < 0.001; 3.99), adjuvant therapy was favourable, shown to reduce MD (P < 0.001; 0.34).
Conclusions
UPS is a high‐grade soft tissue sarcoma, for which surgery striving for negative margins, with radiotherapy, is the treatment of choice. Older age, lower extremity location, MD at presentation, large size and positive surgical margins, were unfavourable.
Undifferentiated pleomorphic sarcoma is a high‐grade soft tissue sarcomas, for which the combination of surgery and radiation therapy is the treatment of choice. Our institution, a tertiary sarcoma referral centre, collated 20 years of undifferentiated pleomorphic sarcoma patient data to determine prognostic factors for the disease. Older age, lower extremity location, metastatic disease at presentation, large size and positive surgical margins, were unfavourable; with adjuvant radiotherapy being shown to reduce both mortality and metastatic spread of disease.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Background Indications for total knee arthroplasty (TKA) currently depend on clinical judgment. Up to one fifth of those who undergo primary TKA do not report a clinically meaningful ...improvement in pain and function after surgery. Our aim was to develop and internally validate a prognostic tool for predicting the probability of nonresponse to surgery at 12 months. Methods Patients from 1 center who underwent primary TKA (N = 615) between 2012 and 2013. The Western Ontario and McMaster Universities Arthritis Index was collected pre- and 12 months after TKA from which nonresponse to surgery was determined using the Outcome Measures in Rheumatology-Osteoarthritis Research Society International responder criteria. Using independent prognostic correlates of postoperative nonresponse observed in adjusted modeling, we derived a prognostic nomogram to estimate the probability of nonresponse to TKA based on this suite of explanatory variables. Results A total of 90/615 (15%) cases were nonresponders to TKA. The degree of contribution (odds ratio, 95% confidence interval) of each explanatory factor to nonresponse nomogram points was body mass index ≥40 kg/m2 (3.48; 1.97-6.12), Kellgren and Lawrence <4 (2.59; 1.58-4.24), mental disability on Short Form Health Survey (SF-12) mental component score (3.30; 1.44-7.58), and every 10-point increase in preoperative Western Ontario and McMaster Universities Arthritis Index score (0.81; 0.68-0.97). The concordance index for this model was 0.74. Conclusion We have created a prognostic nomogram that displays the predictive probabilities of nonresponse to TKA as a source of decision support for clinicians and patients, about their likely functional outcome from TKA. Although our own internal validation suggested good nomogram performance, external validation in a comparable surgical population is required to confirm generalizability of the nomogram.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Discontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course ...are lacking.
(1) To compare time to first relapse and disability progression among 'DMT stoppers' and propensity-score matched 'DMT stayers' in the MSBase Registry; (2) To identify predictors of time to first relapse and disability progression in DMT stoppers.
Inclusion criteria for DMT stoppers were: age ≥18 years; no relapses for ≥5 years at DMT discontinuation; follow-up for ≥3 years after stopping DMT; not restarting DMT for ≥3 months after discontinuation. DMT stayers were required to have no relapses for ≥5 years at baseline, and were propensity-score matched to stoppers for age, sex, disability (Expanded Disability Status Score), disease duration and time on treatment. Relapse and disability progression events in matched stoppers and stayers were compared using a marginal Cox model. Predictors of first relapse and disability progression among DMT stoppers were investigated using a Cox proportional hazards model.
Time to first relapse among 485 DMT stoppers and 854 stayers was similar (adjusted HR, aHR=1.07, 95% CI 0.84 to 1.37; p=0.584), while time to confirmed disability progression was significantly shorter among DMT stoppers than stayers (aHR=1.47, 95% CI 1.18 to 1.84, p=0.001). The difference in hazards of progression was due mainly to patients who had not experienced disability progression in the prebaseline treatment period.
Patients with MS who discontinued injectable DMT after a long period of relapse freedom had a similar relapse rate as propensity score-matched patients who continued on DMT, but higher hazard for disability progression.
The city of Melbourne, Australia experienced two waves of the COVID-19 epidemic peaking, the first in March and a more substantial wave in July 2020. During the second wave, a series of control ...measure were progressively introduced that initially slowed the growth of the epidemic then resulted in decreasing cases until there was no detectable local transmission.
To determine the relative efficacy of the progressively introduced intervention measures, we modelled the second wave as a series of exponential growth and decay curves. We used a linear regression of the log of daily cases vs time, using a four-segment linear spline model corresponding to implementation of the three successive major public health measures. The primary model used all reported cases between 14 June and 15 September 2020 then compared the projection of the model with observed cases predicting future case trajectory up until the 31 October 2020 to assess the use of exponential models in projecting the future course and planning future interventions. The main outcome measures were the exponential daily growth constants, analysis of residuals and estimates of the 95% confidence intervals for the expected case distributions, comparison of predicted daily cases.
The exponential growth/decay constants in the primary analysis were: 0.122 (s.e. 0.004), 0.035 (s.e. 0.005), - 0.037 (s.e. 0.011), and - 0.069 (s.e. 0.003) for the initial growth rate, Stage 3, Stage 3 + compulsory masks and Stage 4, respectively. Extrapolation of the regression model from the 14 September to the 31 October matched the decline in observed cases over this period.
The four-segment exponential model provided an excellent fit of the observed reported case data and predicted the day-to-day range of expected cases. The extrapolated regression accurately predicted the decline leading to epidemic control in Melbourne.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
It is difficult to counsel patients with bilateral osteoarthritis who are unsatisfied with their first knee replacement as to whether they are likely to have a better outcome after the ...contralateral knee is replaced. The purpose of this study was to determine whether predictive factors can be found to prognosticate outcome of the second-side knee replacement when a patient has an unsatisfactory response to the first, with the hypothesis that predictors, such as prosthetic factors and radiographic level of osteoarthritis, may be able to predict a satisfactory response to the contralateral knee replacement.
Materials and methods
An analysis of staged bilateral knee replacements performed at a tertiary arthroplasty centre from 2012 to 2018 was undertaken. A total of 550 knee replacements in 275 patients were included in this study. The primary variable measured was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score. Satisfactory response to surgery was defined as a WOMAC score improved by 17 points or more, and 56 or greater. Patients who did not achieve a satisfactory response with their first knee replacement were further analysed for predictive factors (age, sex, pre-operative score, mental score, socioeconomic status, type of prosthesis, use of navigation, patella resurfacing and radiographic osteoarthritis) of an unsatisfactory response for their contralateral knee replacement.
Results
Overall, 44 (16%) patients failed to achieve a satisfactory response from both their first and contralateral knee replacements. The factor most predictive of an unsatisfactory response to their first knee replacement was pre-operative mental health score. However, in patients who did not achieve a satisfactory response with their first knee replacement, radiographic osteoarthritis, as measured by the Kellgren-Lawrence (KL) score was the main predictor of satisfactory response for their contralateral knee replacement. Only patients with KL grade 4 osteoarthritis were likely to have a satisfactory response with their contralateral knee replacements (KL4 versus KL3, Odds ratio 3.57 (CI 1.26—10.03)
p
= 0.016*). Patients with KL grade 3 osteoarthritis were unlikely to have a satisfactory response, and in this series, no patient with KL grade 2 osteoarthritis had a satisfactory response.
Conclusion
In a patient who has an unsatisfactory response to their first knee replacement, the best predictor of achieving a satisfactory response to his/her contralateral knee replacement is the level of radiographic osteoarthritis in that knee.
Level of evidence
IV: Retrospective Cohort study.
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EMUNI, FSPLJ, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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