A better understanding of the influenza epidemiology among primary care workers could guide future recommendations to prevent transmission in primary care practices. Therefore, we designed a pilot study to assess the feasibility of using a work-based online influenza surveillance system among primary care workers. Such an approach is of particular relevance in the context of the coronavirus disease (COVID-19) pandemic, as its findings could apply to other infectious diseases with similar mechanisms of transmission.This study aims to determine the feasibility of using a work-based online influenza surveillance system for primary care workers in Switzerland.Physicians and staff of one walk-in clinic and two selected primary care practices were enrolled in this observational prospective pilot study during the 2017-2018 influenza season. They were invited to record symptoms of influenza-like illness in a weekly online survey sent by email and to self-collect a nasopharyngeal swab in case any symptoms were recorded. Samples were tested by real-time polymerase chain reaction for influenza A, influenza B, and a panel of respiratory pathogens.Among 67 eligible staff members, 58% (n=39) consented to the study and 53% (n=36) provided data. From the time all participants were included, the weekly survey response rate stayed close to 100% until the end of the study. Of 79 symptomatic episodes (mean 2.2 episodes per participant), 10 episodes in 7 participants fitted the definition of an influenza-like illness case . One swab tested positive for influenza A H1N1 . Swabbing was considered relatively easy.A work-based online influenza surveillance system is feasible for use among primary care workers. This promising methodology could be broadly used in future studies to improve the understanding of influenza epidemiology and other diseases such as COVID-19. This could prove to be highly useful in primary care settings and guide future recommendations to prevent transmission. A larger study will also help to assess asymptomatic infections. Available estimates suggest that 5%-20% of the global population is affected by influenza annually . In EuroPrimary care physicians play a key role during seasonal influenza epidemics, even though most individuals presenting influenza-like symptoms do not seek a medical consultation . In SwitPrimary care physicians and staff working in primary care practices (collectively referred to as “primary care workers” hereafter) have a central role in patient care during the seasonal epidemics. For these reasons, they could potentially play a role in the influenza transmission chain. Indeed, primary care physicians were shown to have high levels of influenza antibody titers , and heaHowever, the role of primary care practices in the transmission chain is largely unknown. Patients visiting the emergency department during the influenza season were found to have a higher risk of influenza-like illnesses compared with community controls . SimilarThe wide availability of the internet and the growth of digital communication technologies has led to the increasing use of these resources in public health surveillance. Online systems to monitor the activity of influenza in the general population have been developed previously, based on data provided by volunteers who self-report their symptoms via the internet throughout the influenza season ,16. MoreAs part of a longer-term national project to clarify the role of primary care practices in the transmission of influenza, we conducted a pilot study to assess the feasibility of a prospective work-based online influenza surveillance system among primary care workers . The maiWe conducted a prospective observational study in three medical centers: one public walk-in clinic in Lausanne and two private family medicine practices purposively selected due to their regular collaboration with our department.Data collection took place from October 2017 to April 2018. The study population corresponded to the primary care workers active in the medical centers during the pilot study. Inclusion criteria for medical centers included any family medicine practices or walk-in clinics providing primary care in the canton of Vaud, that were willing to participate in the project. For individual participants, inclusion criteria were age≥18 years and the presence of an employment contract during the study period. Members of the Swiss influenza sentinel medical practice network (Sentinelled) were excluded as participant centers, and staff members without contact with patients were excluded as individual participants. Enrollment was open between the beginning of the influenza surveillance season in Switzerland (week 40) and the beginning of the influenza epidemic as declared by the national influenza surveillance system (week 51 in the 2017-2018 season).The staff was invited to participate in the survey by one of the medical center’s head physicians (center manager). After receiving a numbered information sheet, each staff member was asked to provide information about the inclusion criteria; respond about their intention to participate in the study; and, if applicable, sign an informed consent form. This action was reinforced by verbal reminders during a team meeting. For this pilot study, a convenience sample of 50 subjects was considered appropriate.The outline of the study is presented in The study participants were asked to complete a basic questionnaire about demographics, their function at the study site, type of contacts with patients, and compliance with vaccination protocols and other preventive measures. Subsequently, they had to answer a weekly questionnaire about influenza-like illnesses symptoms during the past week (or since the last completed questionnaire if the previous week’s data were missing), similar to the one used by the Vinylbenzene questionnaire ,20 Figu. In the Data were collected online using RedCap (Research Electronic Data Capture) software (Vanderbilt University), with a link sent to participants by email every Monday. The link was sent to the participant’s private or professional email address according to their preference. The questionnaire could be completed until the following Friday. One email reminder was sent if the questionnaire was not completed after 3 days. Participants with influenza-like illnesses symptoms who did not provide a nasopharyngeal swab within 3 weeks were asked about their reasons for not performing a nasopharyngeal swab. The evaluation of missing results and interrupted follow-ups was an integral part of the pilot study.Mycoplasma pneumoniae.Nasopharyngeal swabs were sent to the National Reference Centre of Influenza . They were tested weekly for influenza A and B by reverse transcriptase real-time polymerase chain reaction (rRT-PCR). Twice during the season, on weeks 3 and 16, samples were tested by rRT-PCR for a panel of respiratory pathogens including influenza A; influenza A (subtype H1N1); influenza B; rhinovirus; coronavirus species NL63, 229E, OC43, and HKU1; parainfluenza 1-4; human metapneumovirus A/B; bocavirus; respiratory syncytial virus A/B; adenovirus; enterovirus; parechovirus; and To preserve participants’ privacy, no participants’ study data were provided to center managers. This point was specified in the participants’ information sheet. The study was conducted in accordance with the principles of the Helsinki Declaration. Each study participant signed an informed consent form, and the human research ethics committee of the canton of Vaud approved the study (CER-VD2017-01519).P value<.05.Data were analyzed using Stata 13 statistical software (StataCorp). Results for primary and secondary outcomes were presented as proportion, incidence rates, and attack rates for the total study population. The chi-square and Wilcoxon rank-sum tests were used to compare proportions and medians, respectively, between categories . The significance level was set at 21=11.7; P=.001).A total of 77 primary care workers from the three centers were invited to participate in our study. Of the 67 eligible persons based on the inclusion and exclusion criteria, 39 (58%) participants, comprising 22 physicians and 17 medical assistants, consented to the study. The distribution of 39 participants was as follows: 19 of the available 47 (40%) primary care workers from the walk-in clinic and 20 of the available 20 (100%) from two private practices enrolled in the study. Of the 39 participants, 36 (92%) finally provided data . All 28 The proportion of workers responding to the weekly online survey per week increased during the first weeks of the study with progressive enrollment. From the time all participants were included, the response rate stayed close to 100% until the end of the study . Among tIn the context of survey responses, 23 (63%) participants answered the questionnaires mainly at work, and 12 (33.3%) mainly at home. In terms of access, 20 (55.6%) participants accessed the surveys using the workplace computer, 8 (22%) accessed them through their smartphone, and 7 (19%) accessed them through their private computer. The median time to complete the initial individual questionnaire was 3.0 (IQR 2.0-4.0) minutes and the median time to complete the final individual questionnaire was 2.5 (IQR 2.0-4.0) minutes. Completing the weekly survey took 10 seconds on average in the absence of symptoms and 2 minutes and 17 seconds in case of symptoms. All participants completed questionnaires until the end.P=.02), whereas no significant difference in discomfort was observed between heteroswabs and autoswabs .Of the 15 nasopharyngeal swabs , 6 (40.0%) were autoswabs, of which 5 were performed by physicians and 1 by a medical assistant. The remaining were heteroswabs. In terms of preference for methods, 9 of 10 medical assistants preferred a heteroswab instead of an autoswab. The median depth of the swab was 8.5 cm . Two participants (13.3%) mentioned nonsevere adverse effects of the swab . Median discomfort was estimated at 6 on a 10-point pain scale . The level of discomfort was significantly higher among medical assistants than among physicians , the diagnosis was not influenza (n=17), they already had taken a swab for that episode (n=5), a swab was unnecessary (n=3), a swab would be negative (n=1), or their symptoms did not fit the influenza-like illnesses case definition (n=1).23=2.2; P=.53).Of 79 symptomatic episodes (mean 2.2 per participant), 10 fitted the influenza-like illnesses case definition. Five participants said that they missed work for an average of 2 (range 1-5) days, and 9 participants reduced their daily activities for an average of 3.3 (range 1-10) days. For 31 of the 79 (39%) episodes, participants said they had worked without difference by practice while having symptoms of fever, sore throat, or cough  occurring in 16 participants, including 8 of the 10 influenza-like illnesses episodes. The swabs were performed a median of 3 days after the start of symptoms (IQR 1-5) and were received in the lab a median of 2 (IQR 1-3) days later. More than half of the initial symptomatic episodes were swabbed , compared to only 10% of the subsequent 40 episodes .A virus was identified in 10 of 19 (52%) symptomatic episodes and 4 of 8 (50%) influenza-like illnesses episodes, respectively. One swab was positive for influenza A H1N1 .Participation was much better in smaller private practices than in the public walk-in patient clinic. Moreover, participation was better among regular staff than among rotating staff  and administrative staff (secretaries), suggesting that permanent staff are more readily involved in a research project that extends over several months than rotating staff. These findings can also be related to the size of the facility, which allows for more personalized contacts with participants when presenting the study and answering their questions. From the perspective of a future larger-scale study in Switzerland, this observation represents an advantage, as the size of the two practices included in the study closely matches the size of the majority of Swiss primary care practices.The time spent in providing data and the impact on the privacy of participants can influence the feasibility as well as the participation in a surveillance system. In our study, the median time needed to complete the questionnaires was noticeably short. In addition, most of the participants answered the questionnaires on their workplace and accessed the surveys using the workplace computer.During an influenza episode, the affected person can be expected to stay at home. For this reason, we decided to distribute swab material to all participants and gave them the freedom to either self-administer the swab or ask a colleague to administer it to them when they fitted the influenza-like illnesses case definition, thereby maximizing the chances of a swab to be performed when indicated. Providing a choice to perform an autoswab or a heteroswab was an effective strategy, as nearly half of the smears taken were autoswabs that did not seem to have caused any problems for physicians, while a little more than half were heteroswabs, mainly among medical assistants. To maximize the number of swabs performed by participants and to study their feasibility under the best possible conditions, we used a less restrictive influenza-like illness case definition than official definitions . In someIn such a study, addressing the issue of privacy is important, as it could lead to underreported episodes by participants because of the risk of being absent from work or being penalized for not staying home in case of symptoms. For this reason, it was made clear to participants that employers were not receiving any information about their employees’ study data. During terminal team meetings at the end of the study conducted to present and discuss the results, participants did not identify any privacy issues.In our study, the attack rate of influenza during the 2017-2018 season was low, but considering the large confidence interval, it was within the range of that estimated by other studies conducted either in the general population or among health care workers ,23. ThisThe inclusion of only three practices is not sufficiently representative. However, they are typical of the most frequent type of medical practices in Switzerland, due to their location in a suburban region and their organization as a team of doctors and medical assistants . The walA work-based online influenza surveillance system among primary care workers, combined by self-administrated nasopharyngeal swabs performed by participants, is a promising methodology for conducting a large-scale study that combines data on staff and patients. Precise estimation of the influenza attack rate among primary care workers, of both symptomatic and asymptomatic infections, will make it possible to recommend preventive measures for primary care practices. This could be immensely useful in guiding future recommendations for preventing nosocomial transmission.In infectious diseases, including the recent COVID-19 outbreak that displays a high risk of spread with a similar nosocomial transmission, applying such a surveillance system among primary care workers could limit virus spread. Symptomatic primary care workers could be isolated quickly, limiting the risk of contamination. In the context of infectious disease where transmission by asymptomatic carriers is important, surveillance could include systematic testing to identify healthy carriers among primary care workers.


Dupuytren’s disease is a common fibrotic condition that causes the fingers to flex irreversibly into the palm. Treatments for late-stage disease all have limitations, and there is no approved treatment for early-stage disease. We identified tumour necrosis factor as a therapeutic target in Dupuytren’s disease, and in a dose ranging trial found 40 mg adalimumab in 0·4 mL to be most efficacious. Here we aimed to assess the effects of intranodular injection of adalimumab in early-stage disease.In this phase 2b, randomised, double-blind, placebo-controlled trial adults with early-stage Dupuytren’s disease and an established clinically distinct nodule with a clear history of progression in the preceding 6 months were recruited from two clinical centres in the UK and were randomly assigned 1:1 to receive four injections of adalimumab or saline every 3 months. Participants and assessors were masked. The primary outcome was nodule hardness measured with a durometer at 12 months. Data were analysed by linear mixed effects regression models in the intention-to-treat population with multiple imputation for missing primary outcome data. The trial is registered at the ISRCTN registry, ISRCTN 27786905 and is complete.Between Feb 17, 2017, and Jan 11, 2019, 284 participants were screened in the UK and 140 were enrolled. 47 (34%) participants were female and 93 (66%) were male. Mean age of participants was 59·7 years (SD 10·0). Primary outcome data were available from 113 participants. Nodule hardness was lower  in the adalimumab compared with the saline group at 12 months. There were no related serious adverse events; the most common adverse events were minor injection site reactions.Intranodular injections of adalimumab in participants with early-stage Dupuytren’s disease resulted in softening and reduction in size of the nodules. Longer follow-up would be required to assess the effect of tumour necrosis factor inhibition on disease progression, extension deficit and hand function. Factors associated with diathesis include early age of onset (<50 years), positive family history, and ectopic disease.5 The cords cause flexion deformities of the fingers, which can significantly affect activities of daily living. Existing guidance is for treatment to be deferred until the finger joints are flexed to 30° with impairment of hand function,6 when the diseased tissue can be surgically excised, or the cords can be disrupted by means of a needle or collagenase. However, the disease recurs in 21% of patients following surgical excision (fasciectomy) and in 85% following needle fasciotomy at 5 years.7 Treatments for late-stage disease are also associated with potential complications, ranging from transient swelling and bruising to nerve and tendon injury.9Dupuytren’s disease is a common fibrotic condition involving the palm of the hand and affects around 4−7% of the general population in the UK and USA. It is more prevalent in older people, with 12% of those aged 55 years and 29% of those aged 75 years being affected in western countries.10 Our systematic review11 identified various non-surgical treatments used for patients with early-stage disease. Intranodular steroid injections and radiotherapy have been reported to lead to subjective softening of the nodules and retard disease progression. However, all the studies identified in that systematic review were poorly designed, with no controls, and neither the observers nor patients were masked.11 A randomised, double-blind, placebo controlled trial of collagenase injection reported reduction in nodule size and hardness over an 8-week period.12 More recently, a randomised trial of 52 patients reported that extracorporeal shock wave therapy reduced pain.13The ideal treatment would be effective during the early nodular stages of the disease to prevent the development of cords and progression to finger contractures. Surgical excision of early-stage disease is associated with high risk of recurrence.14 together with a minority (11%) of immune cells.15 Dupuytren’s disease is a localised inflammatory disorder, with differentiation and activation of myofibroblasts promoted by TNF expressed by local M2 macrophages and mast cells acting via TNF receptor 2 and the canonical Wnt signalling pathway.16 Genome-wide association studies have also highlighted the role of Wnt signalling in Dupuytren’s disease.17 In a dose ranging phase 2a study, we found that intranodular injection of 40 mg adalimumab in 0·4 mL resulted in down-regulation of the myofibroblast phenotype as characterised by reduced expression of alpha-smooth muscle actin (α-SMA) and procollagen type I proteins 2 weeks after injection.18 Here, we report the outcome of a randomised, phase 2b trial comparing four injections of adulimumab or placebo given once every 3 months in participants with early-stage Dupuytren’s disease.We have shown that the nodules of patients with early-stage Dupuytren’s disease are a complex ecosystem of myofibroblasts and fibroblasts, each comprising several subpopulations, including highly contractile myofibroblasts, a separate cycling myofibroblast population, and immune regulatory fibroblasts,19 Protocol amendments were mostlyminor (Repurposing anti-TNF for Dupuytren’s disease (RIDD) is a phase 2, randomised, participant and assessor masked (double-blinded) placebo-controlled study to assess the efficacy of local injection of adalimumab in participants with early-stage Dupuytren’s disease. The protocol was approved by the South Central Oxford B Research Ethics Committee (reference number 15/SC/0259) and the Medicine and Healthcare products Regulatory Authority (EudraCT no 2015-001780-40), and has been published.tlyminor . Our oritlyminor . Our inttlyminor  and the tlyminor . The oriThis study was done as part of the portfolio of trials in the registered UKCRC Oxford Clinical Trials Research Unit at the University of Oxford. It has followed their Standard Operating Procedures ensuring compliance with the principles of Good Clinical Practice and the Declaration of Helsinki and any applicable regulatory requirements. Two UK centres  recruited adult participants older than 18 years through posters displayed in general practitioner surgeries and information on the British Dupuytren’s Society website, the trial website, and Facebook and Twitter accounts. Eligibility criteria included adults with early-stage Dupuytren’s disease  and an established clinically distinct nodule with a clear history of progression in the preceding 6 months. Criteria for progression included patient-reported increase in nodule size, pain or tenderness, and itching. We recruited participants with no previous treatment for Dupuytren’s disease to the affected digit or radiotherapy to the hand and screened them for tuberculosis, HIV, and hepatitis B and C using serological testing and chest x-ray in accordance with local standard procedures for anti-TNF screening. Participants with significant renal, hepatic, or systemic inflammatory disease, moderate or severe heart failure, demyelinating disorder, history of repeated infections, treatment with coumarin anticoagulants, concomitant disease modifying anti-rheumatic drugs treatment, or history of cancer were excluded. All participants provided written, informed consent before enrolment.vs ≥50 years). The randomisation was computer generated once each participant was registered onto the trial by means of a telephone-web-based system administered independently by the Oxford Clinical Trials Research Unit.19 The adalimumab or saline were drawn up in a separate room and the syringe and needle used for injection were identical, maintaining masking of the participant. The medically qualified health professional doing the injection did not assess any of the outcomes, which were done by a masked individual who was not present during the preparation and delivery of the injection.Participants were randomly assigned 1:1 by means of variable permuted blocks and stratification for trial centre and age . Nodule size was assessed by means of ultrasound scan . The nodule was marked and photographed with a scale marker, active and passive extension deficit of the joints of the affected digit was measured by means of a goniometer , and grip strength was assessed by means of a Jamar hand meter Sammons Preston, Bolingbrook, IL USA). The study nodule was injected after completion of all the measurements, and pain scores were recorded during and immediately after the injection, as well as any adverse effects at the injection site.We recorded all systemic adverse events graded 3 or above in accordance with the protocol. In view of the well documented safety profile of adalimumab, the frequency of injection  and the limited number of injections , we and the regulators did not feel that collection of adverse events below grade 3 was necessary. We recorded all local adverse events, irrespective of severity.11 or collagenase.12 We used a standard probe durometer to quantitatively assess nodule hardness at 12 months as our primary outcome, with data for this and most secondary outcomes also being collected at 3, 6, 9, 12, and 18 months. The measurement site was marked on the skin at the baseline visit and photographed with a scale marker. This was used as a reference for measurement on each subsequent occasion to ensure consistency. Secondary outcomes included ultrasound-based measurement of the nodule cross-sectional area in the sagittal plane, nodule height, and maximum feret , by a single masked observer (CB). The underlying tissue landmarks, including the skeleton, were used to ensure that the same cross-sectional site was imaged on each occasion. Other secondary outcomes comprised extension deficit of the joints of the affected digit, grip strength, patient reported outcome measures20 (Michigan Hand Questionnaire [MHQ] and most restricted activity), progression to surgery, injection experience (pain during and immediately after injection), and adverse events. EuroQol five-dimensional five level instrument and resource use were measured and are reported separately in a parallel health economic analysis, which will be detailed in a follow-up report.We assessed nodule hardness as the primary outcome measure as it has been used in previous studies examining the effect of intralesional steroid injection, radiotherapy,To assess whether the development of antibodies to adalimumab correlated with outcomes, tertiary outcomes at 3 months and 12 months included concentrations of antibodies to adalimumab. These were initially established by means of a semiquantitative screening assay  followed by a quantitative assay  for those that exceeded the screening assay threshold. We also measured concentrations of circulating adalimumab  at 3 months and 12 months.19 and statistical analysis plan, which was approved by the trial management team and finalised before the data were received for the final analysis  were required to achieve 90% power with a two-sided 5% significance level to detect a moderate standardised effect size of 0·625, and allowing for 20% loss of follow-up. Assuming a common SD of 8, the effect size of 0·625 corresponds to a five-point change in nodule hardness measured by the standard durometer.Statistical analyses were done according to the protocol22 The imputation model included durometer data, nodule area and feret, flexion deformity, randomisation site, randomisation date, and participant age. Missing baseline data were mean imputed before the imputation, which was run separately by treatment group. 50 imputations were generated. The primary outcome was analysed by means of linear mixed effects regression models adjusting for baseline values of the outcome variable and stratification factors . Secondary outcomes were analysed by means of similar statistical models, including all available data without imputation of missing follow-up data; missing baseline data were mean imputed. Treatment effects with corresponding 95% CI were estimated for each follow-up timepoint, and the 12-month estimates were considered the follow-up of principal interest. Sensitivity analyses accounted for the effect of missing data by considering missing not at random scenarios , the effect of delayed assessments due to COVID-19, and the per-protocol population, excluding participants with fewer than three injections, or those who received a non-randomised treatment or surgery during the follow-up. Unmasked data were analysed by the trial statisticians  and subsequently made available to the remainder of the trial team. The trial was monitored by independent data monitoring and safety, and trial steering committees. The trial was registered on ISRCTN (27786905) and ClinicalTrials.gov (NCT03180957).Durometer readings were not available on some occasions (117 [14%] of 840), especially at later timepoints when in some participants progression of the disease precluded reliable assessment owing to the relatively wide base plate of the standard durometer. However, ultrasound scan measurements were available for these participants, and missing data for the primary endpoint were handled by multiple imputation by chained equations using predictive mean matching (which used the ten closest observations).The study was funded by the Health Innovation Challenge Fund . Funding for purchase of the adalimumab was provided by 180 Life Sciences Corp. The funders had no involvement in study design or data analyses. The study was sponsored by the University of Oxford.Between Feb 17, 2017, and Jan 11, 2019, 284 participants were screened in the UK and 140 were randomly assigned . 47 34%.The primary outcome of nodule hardness at 12 months was significantly lower in the adalimumab group  and decreased further by 18 months  to draw any meaningful comparisons  participants received at least three of the four injections offered to them and 117 (84%) of 140 received all four injections. Circulating concentrations of adalimumab at 3 months and 12 months were negligible in the saline group and low in the adalimumab group  and were recorded on 25 occasions  would need to be treated, and we anticipate that each of these nodules would need to be injected separately. We would envisage that following completion of a course of four injections, nodule development could be followed expectantly, and the treatment repeated in the event of reactivation of the disease. We have previously shown that plasma concentrations of adalimumab 2 weeks following injection into Dupuytren’s nodules are similar to when it is administered systemically in patients with rheumatoid or psoriatic arthritis.18 It is possible that effects might be more pronounced and extend over a more prolonged time with a depot preparation of adalimumab, which currently does not exist.Adalimumab is usually administered every 2 weeks for systemic inflammatory disorders. Our decision to administer four doses at 3 month intervals was based on the results of an end user survey of 40 participants, 20 with early-stage and 20 with late-stage Dupuytren’s disease, regarding the number of injections they would find acceptable per annum. Adalimumab has a mean half-life of 2 weeks. Our findings that the nodules continued to soften and regress on ultrasound at the 18-month timepoint, 9 months after administration of the final injection, suggests that local administration has a profound local biological effect. We have previously shown that Dupuytren’s disease is a low-grade localised inflammatory disorder and the myofibroblast phenotype characterised by expression of α-SMA and collagen type I, and contractility is critically dependent on the production of low concentrations of TNF locally.24 The relatively high concentrations of circulating anti-adalimumab antibodies seen in some of our participants might be related to lack of administration of concomitant disease modifying agents such as methotrexate, which are usually administered in patients with rheumatoid arthritis.25 However, we did not find a correlation between the concentration of anti-adalimumab antibodies and response . This might be owing to the high dose delivered locally not being influenced by subsequent clearance from the circulation.When adalimumab is administered systemically, development of antidrug antibodies is associated with poorer disease control.18 there was no difference in pain scores between the citrate-free concentrated formulation of adalimumab  and saline.Palmar injections are painful owing to the high density of innervation of the skin and large cortical representation, resulting in median visual analogue pain scores of around 7−8/10 during the injection. However, the pain rapidly subsided to a median of 2/10 immediately after the injection. As reported previously,20 and even more so for patients with early-stage disease. Previous studies assessing the effect of intranodular steroid injections or radiotherapy have relied on subjective assessment of nodule hardness and size.20 The Rex Gauge Type OO standard durometer was previously been found to be reliable and sensitive for assessing skin hardness in patients with scleroderma.26 Before the report of the use of a durometer in early-stage Dupuytren’s disease,12 we trialled the standard durometer in a small pilot study21 before using it to quantitatively assess nodule hardness. The slim durometer, which has a smaller baseplate that is less likely to impinge on the surrounding skin, was used in participants from the Netherlands as the anticipated accelerated disease progression would have made it more challenging to use the standard probe at later timepoints. We had expected that the readings for the standard and slim durometers would be similar as they are identical (Rex Gauge RX-1600-OO) except for the diameter of the foot plate. However, our data show that the slim durometer is less accurate, and we were unable to use crosswalk methodology to map the results from the standard durometer to those from the slim durometer. We achieved the sample size in the UK that was consistent with our original protocol specification. Therefore, our main analysis used outcomes for the standard durometer in the UK population and we would recommend it be used in future studies.There is a lack of consensus on the optimal outcome measures for patients with late-stage Dupuytren’s disease20 Measurement of nodule surface area has been reported to be subject to relatively low intraobserver and interobserver agreement for some digits.27 We used ultrasound imaging to assess nodule size more reliably. A systematic review28 concluded that ultrasound scans would be useful for following the course of early-stage disease, a finding subsequently validated in a cohort of 50 patients.29 An operator masked to the treatment allocation did all the ultrasound scans in the UK and also did all of the measurements. Reliability of sequential imaging was improved by ensuring that the images were recorded with the same deep landmarks, including the bones and joints, on each occasion. The settings on the ultrasound scan equipment and probe were optimised to accurately delineate all the anatomical structures. Although there are no published data on the relationship of cross-sectional area on ultrasound scan and disease progression, the surface area of Dupuytren’s disease has been reported to correlate with extension deficit. Over a period of 20 months, each cm2 increase in area was predicted to increase the risk of being in Tubiana grading stage 4  by an odds ratio of 3· 2.30Previous studies also relied on subjective assessment of nodule size.4 and a limitation of our study is that we only followed patients for 18 months from baseline. Consequently, we did not observe a significant change in the extensor deficit of the joint affected by the treated nodule over the course of the study. Approximately 20% of patients with Dupuytren’s disease progressed to the development of finger contractures over 7 years in one study;3 in another study, progression was reported in about 35% patients over the course of 18 years.4 Therefore, follow-up for 10 years or more would be required to ascertain whether intranodular injection of adalimumab and the observed significant reduction in nodule hardness and nodule size on ultrasound scan would affect the development of finger deformities and hand function as assessed by patient-reported outcome measures such as MHQ. Predictably, there was no change in grip strength over time in either treatment group. Only a small number of participants, three in the adalimumab and ten in the placebo group, progressed to surgery during the trial or were planning to undergo surgery related to the study nodule at the 18 month timepoint. Follow-up over a much longer period would be required to ascertain whether this trend would be reflected as significant differences although as noted previously, we would suggest that participants might consider another course of four injections of adalimumab if the nodule were to re-activate.The data from the most restricted activity indicates that most participants had some difficulty with grip and associated tasks. However, the difficulty with such tasks did not appear to have a significant effect on overall hand function, with the MHQ scoring about 80 in both groups throughout the course of the trial. It is probable that MHQ is not sufficiently sensitive to detect small differences in participants with early-stage Dupuytren’s disease, which has relatively little impairment of hand function, and is subject to a ceiling effect. There was also no change in the most restricted activity selected by each participant. Dupuytren’s disease typically progresses over several yearsAnti-TNF drugs have been administered to over 10 million people worldwide and adalimumab to approximately 5 million. Adalimumab has an excellent safety record, with the major adverse effects relating to infection or reactivation of latent tuberculosis. We screened all participants for tuberculosis and also applied all the other exclusion criteria used in routine clinical care for patients with systemic inflammatory disorders. There were no related serious adverse events. Minor local injection related reactions occurred on 25 occasions and were unrelated to substance injected.Another limitation of our study is that we did not collect data on the race and ethnicity of the trial participants (which was not standard practice in 2017).16 and our earlier phase 2a data showing that 40 mg of adalimumab in 0· 4 mL reduces the expression of α-SMA and procollagen type 1 proteins,18 the data from this phase 2b trial suggest that intranodular injections of adalimumab might reduce progression of early-stage Dupuytren’s disease. Follow-up over a period of approximately 10 years would be required to assess the effect on flexion deformity and hand function.In conclusion, this phase 2b, randomised trial shows that four injections of 40 mg adalimumab in 0·4 mL at 3 month intervals resulted in reduction in nodule hardness and size, both of which continued to decrease for the duration of the follow-up period, which was 9 months after the last injection. Adalimumab was found to be safe, and the development of anti-adalimumab antibodies did not affect the outcomes. Taken together with our findings that anti-TNF down-regulates the myofibroblast phenotype (α-SMA and collagen type 1 expression and contractility) in vitro,appendix


A randomized trial demonstrated that among people living with late-stage human immunodeficiency virus (HIV) infection initiating antiretroviral therapy, screening serum for cryptococcal antigen (CrAg) combined with adherence support reduced all-cause mortality by 28%, compared with standard clinic-based care. Here, we present the cost-effectiveness.HIV-infected adults with CD4 count <200 cells/μL were randomized to either CrAg screening plus 4 weekly home visits to provide adherence support or to standard clinic-based care in Dar es Salaam and Lusaka. The primary economic outcome was health service care cost per life-year saved as the incremental cost-effectiveness ratio (ICER), based on 2017 US dollars. We used nonparametric bootstrapping to assess uncertainties and univariate deterministic sensitivity analysis to examine the impact of individual parameters on the ICER.Among the intervention and standard arms, 1001 and 998 participants, respectively, were enrolled. The annual mean cost per participant in the intervention arm was US$339 , resulting in an incremental cost of the intervention of US$77 . The incremental cost was similar when analysis was restricted to persons with CD4 count <100 cells/μL. The ICER for the intervention vs standard care, per life-year saved, was US$70  for all participants with CD4 count up to 200 cells/μL and US$91  among those with CD4 counts <100 cells /μL. Cost-effectveness was most sensitive to mortality estimates.Screening for cryptococcal antigen combined with a short period of adherence support, is cost-effective in resource-limited settings. In a large phase 3 randomized controlled trial among persons presenting with late-stage HIV infection, we showed that cryptococcal meningitis screening and community-based early adherence support was a highly cost-effective strategy in reducing all-cause mortality. Antiretroviral therapy (ART) is available widely in Africa, but human immunodeficiency virus (HIV)–associated mortality remains high, particularly during the first few months that patients come into care . Most ofWe recently conducted a large randomized controlled trial among HIV-infected patients starting ART with CD4 count <200 cells/μL in Dar es Salaam, Tanzania and in Lusaka, Zambia, known as the Reduction of Early Mortality Among HIV-infected Subjects Starting Antiretroviral Therapy (REMSTART) trial . The intFindings from the trial informed the World Health Organization (WHO) guidelines on the management of late-stage HIV infection in Africa . HoweverThe REMSTART trial results have been published , 11. In In the intervention arm, the participants were screened for serum CrAg using lateral flow tests  and promptly started on fluconazole (800 mg per day for 2 weeks followed by 400 mg per day for 8 weeks) if they were CrAg positive. In addition, they received up to 4 weekly home visits by trained lay workers during the first 4 weeks of starting ART. The primary endpoint was all-cause mortality at 12 months of follow-up.The economic evaluation was nested within the trial and done from a healthcare provider’s perspective , 12. TheHealth cost data were collected in 2012 and capital costs were discounted using a discount rate of 7.8% equal to the 2-year Tanzanian government bond at the time of calculation, June 2014 . All cosLife-years gained was used as the primary outcome measure. As the morbidity effects of the intervention relative to the mortality effect are likely to be minimal in this context, these can be used to approximate Disability Adjusted Life Years saved. To estimate life-years gained, we computed the difference in the annual probability of death between the intervention and control arms (rather than the incidence rates of death per person-years of observation used in the main paper ) and mulDifferences between the intervention and standard care in costs and mortality were estimated using seemingly unrelated regression equations to account for the correlation between costs and mortality . The modUnivariate deterministic sensitivity analyses were done to assess the impact of parameter uncertainty on the ICER and were presented as a standard tornado sensitivity graph. The parameter ranges used for sensitivity analysis were based on 95% CIs calculated from the REMSTART data and the observed life expectancy CIs . We condThe study was approved by the ethics committee of the London School of Hygiene and Tropical Medicine, the Ethics and Research Science Committee in Zambia, and the National Health Research Ethics Subcommittee in Tanzania.The total mean costs per patient did not differ by CD4 count category for either arm . The intThe absolute reductions in death rates between the intervention and standard care did not differ significantly by CD4 cell count category . The morThe intervention was more costly but more effective than the standard care . AverageThe probability that the intervention is cost-effective when compared with the standard care if the decision makers are willing to pay between US$100 and US$150 for an additional life-year saved varies between 84% and 95% in persons with CD4 count <200 cells/μL and between 62% and 82% in persons with CD4 count <100 cells/μL .In sensitivity analyses, the most influential parameter of the ICER was the mortality rate . If the Our analysis demonstrates that screening of patients presenting with advanced HIV disease for cryptococcal meningitis combined with a short intensive period of adherence support is likely to be cost-effective for most settings in Africa . The aveThe home-based adherence support component involved the use of trained lay workers visiting the homes of patients by public transport. The cost of home visits—up to about $80 for most participants—was the major driver of total costs. Trial participants were scattered and lay workers traveled between patient houses. In a small subsample, we estimated that the lay workers took about 50–60 minutes to travel from one patient’s house to the next, and that this was about twice the amount of time that they actually spent at a patient’s home. Furthermore, on some days, particularly near the start of the trial, some lay workers made only 1 or 2 home visits a day because we had not recruited sufficient numbers of patients. In real life, if this approach was rolled out universally, many patients would be on therapy and the increased patient density would reduce travel distances. Health services would also identify long-term, lower-cost ways of traveling between houses, such as field workers traveling on bicycles or motorbikes, which were not practical during the normal course of trial. The costs could be reduced further by use of alternative methods of providing support, such as through mobile phones. If the cost per home visit decreased from $19.51 to $5, this will result in an average incremental cost of $33 for the intervention, subsequently reducing the average ICER to $30 per life-year saved, using a conservative life expectancy of 24 years. If we assume a life expectancy of 35 years for participants on ART, the ICER becomes $20 per life-year saved.In the CrAg screening component, we have overestimated the cost of CrAg testing. The cost of a single test was $5 and a single test was done to identify a single CrAg-positive person. The CrAg test is simple and its cost will fall with expanded use. Also, the prevalence of CrAg positivity was lower in our study than the average reported in Africa , 28.Finally, we calculated cost-effectiveness based on a healthcare perspective and did not assess societal benefits, for example, the benefits of increased productivity arising from improved health status. We also used a conservative estimate of life expectancy, calculated taking CD4 cell count into account. Had we used WHO estimates of life expectancy for Tanzania , the ICEThus, all in all, the intervention tested will be highly cost-effective, with a likely ICER of somewhere between $10 and $20 per life-year saved.With complex interventions, as that employed here, it is impossible to disentangle the effects of the CrAg individual component from the enhanced adherence component, but it is very clear that, as combined, this is an important new intervention for African HIV services to consider for persons with advanced HIV disease. The effects of CrAg screening beyond CD4 count of ≥100 cells/μL are unknown as there are no other data, besides ours, that have tested for CrAg at higher than this CD4 count. Our study found fewer CrAg-positive cases in the group that had CD4 counts between 100 and 200 cells/μL, and as expected, the death rate in this group was lower than in those with lower CD4 counts. This lowers the ICER. In our study, the combined intervention was as cost-effective at CD4 count <200 cells/μL as at CD4 count <100 cells/μL, presumably because survival is better achieved when we initiate interventions at an earlier disease stage. More data are needed of CrAg prevalence among CD4 counts >100 cells/μL.Because of the limited evidence around cost-effectiveness, coverage of CrAg screening combined with preemptive fluconazole has remained low , despiteFor patients who are CrAg positive, mortality is 2–3 times higher even with prompt preemptive treatment with fluconazole and combined with enhanced adherence support than that in CrAg negatives . A more The number of persons presenting with advanced disease is likely to remain high for the foreseeable future, as alongside the large number of people who still delay accessing ART services, there are many dropping out of care or failing on ART. With the findings of this analysis and the recent trial of the management of cryptococcal meningitis , we can


There is a lack of research on the effectiveness of online peer support groups for reducing social isolation and depressive symptoms among caregivers, and previous research has mixed results.This study aimed to test whether military caregivers who joined a new online peer support community or engaged with an existing online community experienced decreased perceived social isolation and improved depressive symptoms over 6 months.We conducted a longitudinal study of 212 military caregivers who had newly joined an online community and those who were members of other military caregiver groups. Multiple indicators of perceived social isolation and depressive symptoms were assessed at baseline and at 3 and 6 months.b=0.49, SE 0.19, 95% CI 0.87 to 0.02), but this effect did not persist at 6 months. Those who engaged more with new or existing groups experienced less perceived social isolation over time , and this relationship was mediated by increased interactions with other military caregivers (95% CI 0.0046 to 0.0961). Engagement with an online group was not associated with improvements in depressive symptoms.Compared with caregivers in the comparison group, caregivers who joined the new group experienced less perceived social isolation at 3 months (eg, number of caregivers in social network [unstandardized regression coefficients] Online communities might help reduce social isolation when members engage with the group, but more intensive treatment is needed to improve depressive symptoms. Serving as a caregiver to a relative or friend who is ill or wounded can be an isolating experience. Time spent caregiving can be significant  and may Support groups have sprung up online to provide military caregivers with an opportunity to interact with their peers and receive support and guidance . However, it is unclear how well these online groups function in terms of reducing social isolation and improving mental health among military caregivers. This study explored this question by focusing on members of a new online community for military caregivers compared with caregivers who were members of existing online support groups.Extensive research and theory suggest that people have a need to form meaningful social connections with others—that they have a need to belong —so much Research that examines tangible deficits in social connections considers someone to be socially isolated if they live alone, have few people in their social network, or have infrequent contact with others . A recenPeople can also be socially isolated if they perceive that they have a deficit in social connections with others when they feel lonely ,15. Feelgroup of people who share similar experiences or identities  could represent a decrease in social isolation and may potentially foster psychological well-being.Finally, social connections cannot only be fulfilled through tangible or perceived connections with individuals but also through perceived connections with a group . Factor Online forums have become popular in recent years as a way to allow peers in similar circumstances or dealing with common hardships to interact with one another, form personal bonds, and provide support to one another. One advantage of these online communities is the ability of members to elicit support from others who are dealing with similar issues but who are geographically dispersed ,25. AnotHowever, there is a lack of research on the effectiveness of online peer support groups, and previous research has shown mixed results for improving depressive symptoms -30. One lurking) is associated with similar improvements in social outcomes compared with those who post to a community website , how often have you visited the [group] website? Where group was either MVCN network or the online group with which comparison group participants engaged the most. Response options and numeric codes were every day (6), almost every day (5), two or three times a week (4),once a week (3), two or three times a month (2), once a month or less (1), or I have not visited the website for [group] since joining this group (0). The length of time spent on the site was measured by asking, “When you visit, how much time do you usually spend on the [group] website?” Where group was either MVCN network or the online group with which comparison group participants engaged the most. Response options and numeric codes were less than 10 min (1), between 10 and 20 min (2), 20 to 30 min (3), 30 min to an hour (4), or an hour or more (5).Passive engagement with the online community was assessed by measuring the frequency of visits to the website and the time spent on the website. The frequency of visits to the community website was measured via 1 item: group]? Where group was either MVCN network or the online group with which comparison group participants engaged the most. Their responses were coded 1 if yes and 0 if no.Active engagement with the online community via posts to the online forum was assessed by asking, “Have you posted any comments, questions, or links to the [t tests, chi-square tests, and regression analyses were used to test for differences, as appropriate. A conservative criterion of P<.10 was used in these analyses. We found that MVCN and comparison group participants differed in veteran care recipient age . No other differences emerged between the MVCN and comparison group participants. Being a member of another online or in-person support group was associated with more visits to the MVCN or comparison group community website. In addition, males spent more time on the respective community website, as did those caregivers who helped their care recipients with more tasks and those who lived outside of metropolitan areas. Those caring for older veterans, living outside of metropolitan areas, and who were members of another support group were more likely to discontinue participation in the study over time. Thus, we controlled for these 3 variables plus caregiver gender, membership in other online support groups, and number of caregiver tasks in all analyses. Note that all analyses reported below replicate when these covariates were not included in the models. Finally, to distinguish the effects of visits to the website from time spent on the site and posts to the forum, we controlled for any visits to the website (yes/no) in the analysis of these variables.We examined several potential covariates for inclusion in the analysis, including caregiver age, gender, race, level of education, household income, hours spent providing care in a typical week, caregiver’s relationship with the care recipient, whether the care recipient served during the pre- or post-9/11 period, the number of activities of daily living and instrumental activities of daily living that the care recipient needed help performing, membership in other structured support groups, veteran’s age, years spent caring for the care recipient, and whether the caregiver lived in a metropolitan area. For each of these, we examined whether the variable was significantly related to MVCN membership, any of the engagement variables, or attrition from the study at 3 and 6 months. P values for the tests, we provided 95% CIs for each result and interpreted our findings based on these CIs and the pattern of results across findings, rather than based on the statistical significance of any one test.Our analytic approach focused on assessing changes in outcomes from the baseline assessment to the 3- and 6-month assessments. We conducted two separate sets of models using multiple regression: one set of models regressed 3-month outcomes on baseline predictors controlling for baseline levels of outcomes and covariates, and the other set regressed 6-month outcomes on baseline predictors controlling for baseline levels of outcomes and covariates. For each set of models, to answer research question 1, we first analyzed changes from baseline for new members of an online community (MVCN) in comparison with those who were already members of one or more online communities other than MVCN (comparison group). To answer research question 2, we used cross-lagged models to examine changes in outcomes from baseline to 6 months as a function of engagement with the online community at 3 months . We also assessed whether this relationship differed for MVCN and comparison participants, based on an interaction between MVCN membership (vs comparison group) and 3-month engagement. Cross-lagged models allow for explanatory predictions of present outcomes based on past behaviors and are thus more likely to reflect causal effects than are regressions using cross-sectional measures. Although we conducted statistical tests for each model and included the associated Finally, for research question 3, we conducted mediational analyses for models where engagement significantly predicted both interactions with other military caregivers and one or more outcomes. Engagement at 3 months was entered as the predictor variable, with changes in the frequency of interactions with other military caregivers from baseline to 6 months serving as the mediator. A difference score was calculated for changes in interactions from baseline to 6 months, and we included the baseline measure of interactions as a covariate to control for the possibility that the extent of changes in interactions was driven by baseline levels of interactions. Outcomes were measured at month 6, and changes in outcomes were assessed by including baseline levels of each outcome in the models. Mediational analyses were conducted in SAS 9.3 (SAS Institute Inc) using the INDIRECT macro, which uses asymptotic bootstrapping calculations to test for the significance of indirect effects . The INDOf the 212 participants who completed all 3 waves of the study, 199 (93.9%) were female, 166 78.3%) were non-Hispanic white, 23 (10.8%) were Hispanic, and 23 (10.8%) were in other racial/ethnic groups. The majority of caregivers were spouses or partners of the veteran for whom they provided care , and the remaining caregivers were mostly other family members (1 participant was a friend or neighbor of the veteran). Most caregivers were under the age of 40 years , with an additional 74 (34.9%) aged between 40 and 59 years. The care recipients were mostly male , with 125 (59.0%) serving during the post-9/11 period. Almost all veterans had been diagnosed with one or more physical health conditions , with 182 (85.8%) diagnosed with more than one physical health problem. In addition, 87.7% (186/211) of veterans had been diagnosed with one or more psychological health conditions, with 174 (82.1%) veterans diagnosed with PTSD. We compared those who completed all 3 waves of the survey with those who did not complete all surveys on baseline-level demographic characteristics and all variables included in this study and found no significant differences between groups. In comparison with the overall population of military caregivers studied by Ramchand et al [8.3% were210=2.08; P=.04).Means and SDs for outcome variables (at baseline) and engagement variables (at 3 months) are shown in 21=0.1; P=.74), and the comparison group participants visited the website more often than MVCN participants . Among those who visited their community’s website, the average time spent on the website was around 10 and 20 min (coded as 2). MVCN group participants were also less likely to have posted to the site than were comparison participants .Among engagement variables measured at 3 months, 25.8% (42/163) of MVCN and 23.3% (10/43) of comparison group participants indicated that they had not visited the community website since baseline , and the relationship between the number of visits and the changes in social network connections was reduced to marginal significance . Analyses confirmed that the mediation model was significant (95% CI 0.0046 to 0.0961).The number of visits to the online community at 3 months was significantly associated with changes in the frequency of interactions with other military caregivers (the hypothesized mediator) and with the total number of military caregivers included in one’s social network and collective connectedness with other military caregivers. First, examining the number of military caregivers in one’s social network, analysis using the INDIRECT macro in SAS  replicatb=0.19; SE 0.04; P<.001), but the relationship between the number of visits and changes in collective connectedness remained significant . Analyses confirmed that the mediation model was significant (95% CI 0.0022 to 0.0719).Next, examining changes in collective connectedness with other military caregivers, analysis using the INDIRECT macro replicated our earlier findings: number of visits at 3 months was significantly associated with an increase in collective connectedness from baseline to 6 months and with changes in interactions with other military caregivers. When included in the full model, an increase in interactions with other military caregivers was also significantly associated with changes in collective connectedness  having a PHQ-8 score of 10 or above at baseline, suggesting probable major depressive disorder. A review of web-based interventions for caregivers revealed that these interventions show some promise for reducing depressive symptoms , and recEngagement in online communities across the MVCN and comparison groups was associated with a decrease in social isolation at 6 months. Cross-lagged models predicting 6-month outcomes from engagement at 3 months revealed that more visits to the community at 3 months were associated with greater gains in the number of military caregivers in one’s social network and increased collective connectedness with other military caregivers at 6 months. Furthermore, both these relationships were mediated by an increase in participant interactions with other military caregivers, suggesting that simply visiting an online community of peers more often can increase interactions with peers, which is then associated with reduced social isolation. In addition, spending more time on the community website was associated with increased collective connectedness and decreased feelings of loneliness at 6 months. Posting to online community forums was only associated with gains in social network connections with military caregivers at 6 months. Thus, across the three indicators of engagement with an online community of peers, we found that increased engagement was associated with decreased social isolation over time, and more active engagement in the forums through posting was not associated with additional improvements in loneliness or social network size. Although engagement was not associated with a decrease in depression, our results support the theory that engaging with online social networks might help reduce social isolation, particularly when they enable users to make meaningful connections with others , which sOne aspect of the MVCN community forum that might have affected engagement with the group was the active role that online forum moderators play in that group. Users prefer online support groups that are facilitated by trained peer moderators that provide trustworthy information . The MVCb=0.49; SE 0.23; 2-tailed t181=2.15; P=.03; ΔR2=0.017). This finding suggests that the decision to keep new MVCN members at 6 months in the comparison group made our results comparing the two groups more conservative, rather than biasing the results toward significant differences. However, in combination with the lack of random assignment, the results distinguishing the MVCN participants from the comparison group participants need to be interpreted with caution. In addition, we did not control engagement in online communities, so individual differences in propensity to engage with online communities could have driven the effects reported here. Finally, engagement was self-reported, so individual biases in reporting engagement could have affected the results. Using a within-person design and examining cross-lagged effects helps correct for these biases but does not completely rule them out. Future research should randomly assign participants to groups and manipulate engagement with online communities to better assess causality.Although this study has several strengths, including 3 waves of data, several measures of social isolation, and the ability to conduct causal analyses using cross-lagged models, it also has several limitations. First, participants were not randomly assigned to groups, so MVCN participants could have systematically differed from comparison group participants in ways that affected our results, including their motivation or ability to engage with their online community and their proclivity for change over time. Furthermore, we did not control group membership, so comparison group participants were able to join MVCN during the study, and 10 comparison group participants included in this study had joined MVCN at the 3-month survey. We made an a priori decision to include these participants in the MVCN group because their data at 3 and 6 months would reflect similar experiences with MVCN as those who had joined MVCN at baseline. Most (8/10) of these new members had joined MVCN between 2 and 3 months before the 3-month survey. However, an additional 9 comparison group participants indicated that they had joined MVCN at the 6-month survey and were counted as comparison group participants for the purposes of this study. A post hoc analysis excluding these participants from the study did not substantially change the results, although a significant effect of the MVCN group on the number of military caregivers in one’s social network emerged at the 6-month assessment, with MVCN members reporting increased numbers of military caregivers in their social network from baseline to 6 months relative to comparison group members (Although helping military caregivers to overcome feelings of social isolation is an important contribution of online support groups such as MVCN, our study indicates that more intensive efforts may be needed to improve depressive symptoms. This will likely include opportunities that promote treatment seeking and offer more structured peer or professional support through online  or in-pe


Redisplacement following fracture reduction is a known sequela during the casting period in children treated for distal radius fracture. Kirschner wire pinning can be alternatively used to maintain the reduction during fracture healing. This study was conducted to compare the outcomes at skeletal maturity of distal radius fractures in children treated with a cast alone or together with a Kirschner wire transfixation.This was a retrospective study involving 57 children with metaphyseal and physeal fractures of the distal radius. There were 30 patients with metaphyseal fractures, 19 were casted, and 11 were wire transfixed. There were 27 patients with physeal fractures, 19 were treated with a cast alone, and the remaining eight underwent pinning with Kirschner wires. All were evaluated clinically, and radiologically, and their overall outcome assessed according to the scoring system, at or after skeletal maturity, at the mean follow-up of 6.5 years (3.0 to 9.0 years).In the metaphysis group, patients treated with wire fixation had a restriction in wrist palmar flexion (p=0.04) compared with patients treated with a cast. There was no radiological difference between cast and wire fixation in the metaphysis group. In the physis group, restriction of motion was found in both dorsiflexion (p=0.04) and palmar flexion (p=0.01) in patients treated with wire fixation. There was a statistically significant difference in radial inclination (p=0.01) and dorsal tilt (p=0.03) between cast and wire fixation in physis group with a more increased radial inclination in wire fixation and a more dorsal tilt in patients treated with a cast. All patients were pain-free except one (5.3%) in the physis group who had only mild pain. Overall outcomes at skeletal maturity were excellent and good in all patients. Grip strength showed no statistical difference in all groups. Complications of wire fixation included radial physeal arrests, pin site infection and numbness.Cast and wire fixation showed excellent and good outcomes at skeletal maturity in children with previous distal radius fracture involving both metaphysis and physis. We would recommend that children who are still having at least two years of growth remaining be treated with a cast alone following a reduction unless there is a persistent unacceptable reduction warranting a wire fixation. The site of the fracture and the type of treatment have no influence on the grip strength at skeletal maturity. Of these, metaphyseal and physeal fractures comprised of 20.2% and 15%, respectively5. The associated distal ulnar fracture was approximately 56%6. Most of the injury occurred from falls from low-energy trauma9, followed by injury at the playground or contact activities9. Motor vehicle accident only accounted for 7.9%7. An undisplaced or minimally displaced fracture could be treated nonoperatively with cast immobilisation for a short period of four to six weeks11. Displaced fracture, however, required reduction with or without wire stabilisation and immobilisation with an above-elbow cast for at least four weeks13. Redisplacement indeed was a common complication of casting alone following a satisfactory initial reduction, ranging from 7% to 39%18. Some authors recommended a primary wire fixation to maintain reduction during fracture healing, especially in cases with a high risk for redisplacement21.The incidence of distal radius fractures in children was 20%-35% of all paediatric fractures24. Therefore, we conducted this study to evaluate the clinical, radiological and overall outcomes of these fractures, comparing the outcomes between cast and wire fixation at or after skeletal maturity.Little is known on the outcomes of the distal radius fractures in children specifically at or after skeletal maturityThis retrospective study was conducted in a single institution at our centre from 1st November 2017 to 31st January 2019 looking into children with displaced distal radius fracture who had an initial injury at a skeletally immature age. They were treated either by cast alone or by a cast with additional K-wire fixation. The decision to treat whether with cast alone or with wire fixation and between closed and open reduction was solely dependent on the surgeon’s preference, mainly based on the degree of fracture displacement, the timing of presentation, the age of the patient, the type of fracture, closed or open fracture and the difficulty in achieving an acceptable reduction. They were immobilised for an average of 37 days after reduction. The age of assessment was at or after the skeletal maturity, which was 14 years old and above for girls and 16 years old and above for boys. Ethics approval was obtained from the Research Ethics Board of Medical Sciences at our centre.The inclusion criteria were children having at least two years of growth remaining since the initial injury, distal radius fractures involving the physis, complete metaphyseal fractures of the distal radius, fracture treated with a cast alone, fracture treated with a cast with additional K-wire fixation, fracture treated with a closed or an open reduction and fracture associated with or without an ipsilateral ulna fracture.The exclusion criteria were fractures treated with plate, screws, external fixation, fracture with ipsilateral neurovascular compromise, diaphyseal or proximal third radius fractures, incomplete distal radius fracture, fractures associated with ipsilateral distal radioulnar joint disruption and pathological fractures.13. Physis fracture was defined as a fracture involving the growth plate and classified according to the Salter-Harris classification system4. Fracture displacement in this study was defined when the angulation of fracture was greater than 15° or when the fracture had less than 50% of bony contact or when there was a complete displacement of the fracture at the initial injury.The metaphyseal fracture was defined as a fracture proximal and within four cm from the growth plate of the distal radiusThe data of all distal radius fractures were traced using medical and radiology records. All radiographs of the distal radius were carefully evaluated using the Picture Archiving and Communication System (PACS), which was a computerised radio-imaging system in our centre. The patients who fulfilled the above inclusion and exclusion criteria were selected. The demographic data were also recorded from the medical notes. The long-term functional and radiological outcomes were documented from the selected patients. They were asked to come to the clinic for the assessment at or after their skeletal maturity; boys, at or after the age of 16, and girls at or after the age of 14. The informed consent was obtained from patients or parents, and the patients were assessed for pain perception and the active range of motion. A radiological assessment was made of both the injured and the uninjured wrists. The grip strength was assessed for both hands.et al22: pain-free and mild pain if it occurred at the extremes of movement and did not interfere with daily activity; moderate pain if it was sufficient to cause alteration in work of leisure activities; and severe pain if it occurred during activities of daily living or at rest22.The patients were asked regarding pain perception over the injured wrist. The pain grading system was based on Zimmermann The active ranges of motion of both injured and uninjured wrists were measured and compared. The measurement included dorsiflexion, palmar flexion, radial and ulnar deviation, and supination and pronation. The measurements were taken using a hand-held Goniometer and were recorded in degrees. Restriction in the range of motion on the injured side was compared to the normal ipsilateral side and was documented. Excessive terminal motion on the injured site beyond the maximum limit of the uninjured site was not taken into account.et al22 . The ratio from the study by Kamarul The measurements of the active range of motion were conducted with two independent examiners during the clinic visit to verify the reliability using the inter-class correlation coefficients (ICC). A single examiner conducted the grip strength and the radiological measurement throughout the study period.et al22. The parameters used in the scoring system included pain, restriction of active range of motion and radiological angulation. The scores were graded into excellent 3-4 points, good 5-6 points, moderate 7-8 points and poor 9-12 points22, as shown in The long-term assessments were recorded as overall results in accordance with the scoring system proposed by Zimmermann All statistical analyses were conducted using SPSS  version 24.0. Non-parametric analyses were used because the sample size was relatively small and was not normally distributed. The comparisons between each group for restriction of range of motion, radiological parameters and grip strength were performed using Mann Whitney-U test. The categorical data for pain perception was compared using the Fisher Exact test. The p-value < 0.05 was considered as statistically significant. The inter-observer variability was analysed using the intra-class coefficient correlation.Between the years 2009 and 2014, there were a total of 57 patients with displaced distal radius fracture of a skeletally immature age. They fulfilled the criteria for this study and returned to the clinic for a long-term assessment. Informed consents were obtained from patients and parents at the clinic visit. In terms of pain perception at the final assessment, there was no statistically significant difference between the interventions and the type of fractures . All patThe inter-class coefficient correlation for the measurement of active range of motion showed good reliability (0.76 - 0.97). In terms of restriction of the active range of motion of the wrist and forearm over the injured side compared to the non-injured side , there wThe evaluation of radiological parameters showed no statistically significant difference in the metaphysis group for both cast and wire . HoweverAssessment of grip strength revealed that there was no statistically significant difference between the cast and the wire fixation in both metaphysis and physis groups after taking into consideration hand dominance and gender .In terms of overall results, both the metaphysis and the physis group showed excellent and good overall results . In the Almost all patients treated with the cast alone underwent manual reduction except in three cases in which the fractures were displaced as defined, but the surgeon preferred not to do any manual reduction. However, these three cases still showed good outcome at skeletal maturity.In this study, the complications of distal radius fractures were pin site infection (5%), nonspecific mild numbness over the hand (5%), radial physeal arrest (21%) and ulnar physeal arrest (5%). There were no cases of vascular complication and osteomyelitis.The fracture configurations pre-reduction, post-reduction and the final bone union at skeletal maturity are illustrated in 11. However, the loss of initial reduction is the most common complication during the casting period18. Thus, several authors recommend wire fixation at initial injury in fractures with a high risk of redisplacement to ensure that the reduction is well maintained during fracture healing21. On the other hand, some authors accept more angulation up to 20°-30° in patients aged less than 9-10 years without the need for a secondary manipulation with wire stabilisation, with acceptable functional outcomes27. Remodelling continues to occur as long as the physis is still open. Any injury near or at growth plate requires a final assessment at or after skeletal maturity age, particularly in those who have a fracture near to skeletal maturity age in which the remodelling capacity becomes less predictable28. To our knowledge, there are only a few reports in the medical literature on the long-term functional and radiological outcomes of fractures at, or after, skeletal maturity, particularly comparing between the usage of the cast alone and the cast with a wire fixation in these fractures24.Displaced distal radius fracture in children, usually requires initial reduction and a short period of cast immobilisation29. With at least two years of growth remaining, the residual angulation up to 20°, was still expected to remodel adequately, based on remodelling speeds in the published studies31. Friberg et al30, showed that the exponential pattern of radial correction was 0.9° per month in dorsal-palmar direction and 0.8° per month in radio-ulnar direction. Nietosvaara et al21, also demonstrated a remodelling speed of 1° to 2.7° per month in his series. This finding was also supported by Jeroense et al31, who showed an overall average rate of correction of 2.5° per month.In our study, we included only patients who had an initial injury at least two years before reaching skeletal maturity age. Girls and boys are expected to reach skeletal maturity at the age of 14 and 16 years old, respectively21. Choi et al20, performed an immediate wire fixation in an age less than 16 years with a high risk for redisplacement, where there was a loss of contact of more than 50% between fragments, and found that only 9 (6.4%) of 140 children had lost their reduction20. Similarly, Van Leemput et al12 and Hang et al32, recommended primary wire fixation in unstable distal radius fracture, with a complete initial redisplacement and an associated distal ulnar fracture. However, Luscombe et al33, evaluated their institutional protocol for selective wiring for unstable displaced distal radius fracture and found that wire fixation did not alter the rate of redisplacement and secondary manipulation. Mani et al17, also demonstrated that radial translation carried significant risk factor for redisplacement and advocated immediate wire fixation in cases of radial translation of more than 50%. In our study, failure after reduction with complete fracture displacement was among the indications for a wire fixation.Now the question is, when should we consider using a Kirschner wire in distal radius fracture in children? Previously published literature suggested a wire fixation for the fractures with a high risk of redisplacementWe believe that fracture with complete displacement initially and fracture with loss of more than 50% contact in between the fragments are those with a high risk of displacement and these fractures warrant wire fixation if closed reduction with the cast fails. Repeated attempts of reduction in these high-risk fractures may damage the growth plate partially or even completely. The wire fixation itself, of course, will not guarantee to prevent redisplacement in all high-risk cases, but we strongly believe that the wire fixation will minimise the rate of redisplacement and help to maintain the reduction while the fracture is uniting. Knowing that the remodelling potential is good especially in children, the proper initial reduction must still be carried out rather than leaving totally for the remodelling process to realign and to recontour the fracture without any attempt at reduction. Good initial reduction is still important as it will ensure that the fracture will heal in proper alignment and angulation without any visible deformity or functional limitation that the patient and the parents have to face over months or years. We can take full advantage of the remodelling process that the children have, to gradually correct the deformity after a fracture. However, depending solely on the remodelling process without any attempt at a reduction is unwise since the fracture may not have complete remodelling in some instances, leaving the deformity persistent until adulthood.et al34, accepted angulation less than 15° in any direction and shortening less 1cm as it subsequently achieved complete remodelling without functional limitations. Mani et al17, also agreed that angulation exceeding 15° regardless of direction or bayonetting fragments was not acceptable. In a long-term study by Zimmermann et al22, they found that angulation more than 20° or apposition less than 50% between fragments had the worst functional outcomes. However, in those studies, they did not mention age factors in term of the remodelling potential. Angulation of less than 30° was accepted by Roth et al27, in an age less than nine years and by Planka et al26, in an age less than twelve years. In our study, four cases in the cast group had reangulation of more than 20° during the casting period, but they did not undergo second remanipulation and wire stabilisation. At skeletal maturity, these four patients had no or minimal restriction of motion as compared to the wire fixation group. In our study, the majority of patients had wire fixation when the angulation was more than 20°. There were only two cases with angulation less than 20° that had wire fixation.The acceptable degree of angulation after fracture reduction still varied in previous literature. Do et al22, that angulation of 20° is the maximum limit for acceptability in distal radius fracture. However, we limit this angulation for those who are still having two years of growth remaining which is evident in our series that all four children with angulation around 20° post-reduction did well after skeletal maturity. For children younger than ten years old with more years of growth remaining and remodelling, we accept the angulation up to 30°, which is in accordance with the study published by Roth et al27, previously.We agree with Zimmerman 23. In our series, the rate of radial physeal arrest was higher in comparison to the reported incidence. Four of our distal radius physeal arrests initially had Salter-Harris type II fracture at the time of injury. The distal ulna physeal arrest was documented to have a metaphyseal fracture, but it was later treated with wire fixation. We think that the higher incidence of growth arrest in our study was attributed to two cases of open physeal fractures. Both cases were complicated by physeal arrest. Other reported complications in previous literature included wire migrations into bone (5%) and out of bone (1%), hypergranulation of the wound (5%), infected wound (3%), ulnar nerve neuropraxia (1%) pin site infection (5.7%), superficial radial nerve injury in one case and extensor tendon problem in one case20.Complications of distal radius fractures in our study include radial physeal arrest , associated ulnar physeal arrest , pin site infection  and numbness . In previous literature, radial physeal arrest was a rare complication, ranging from 1% to 7%et al23, in which they found that none of the patients reviewed at follow-up, complained of any symptom related to their previous injury, not even those engaged in heavy manual labour. Another study by Ramoutar et al9, in his short-term retrospective review of 248 metaphyseal distal radius fracture, revealed that 87% had no functional deficit, but 10% had mild, 2% had moderate, and 1% had a severe functional limitation. They also noted that the functional limitation was attributed to the residual angulation exceeding 15°, as compared to a group with less than 15° of residual angulation9. However, their mean follow-up was only 6.6 weeks in which the residual angulation exceeding 15° might have not completely remodelled, thus producing functional limitation still at that particular time.For overall results, the majority of the patients in our study had excellent and good outcomes in both metaphysis and physis groups regardless of whether they were treated with a cast alone or with additional wire fixation. Although the findings showed discrete limitation in dorsiflexion, palmar flexion, altered radial inclination and dorsal tilt, the activities of daily living were not significantly affected in our study. A similar finding was also noted in a retrospective study on Salter-Harris type II fracture distal radius with a mean follow-up of 35.5 years by Cannata 33. Nietosvaara et al21, performed percutaneous pin fixation only in 5 out of 109 children who had physeal fracture of the distal radius. Luscombe et al33, also, achieved a perfect fracture reduction in all children who sustained Salter-Harris II injury, and these patients required neither remanipulation nor percutaneous wire fixation. We also found that patients were reluctant to return to the clinic a few years after the initial injury since they did not complain of limitation during daily activities.In our study, the small numbers of patients with fractures involving the physis, and treated with the wire resulted in difficulties in the analysis. However, reports in the literature have small sample numbers as well, when reporting fractures involving the physis treated with wire, reflecting on the difficulty in recruiting the casesSurgical training for proper fracture reduction and insertion of wire should be emphasised to prevent the incidence of physeal arrest. The long-term outcomes at skeletal maturity are essential in aiding decision making for surgical intervention. It also helps in counselling anxious parents who are concerned with apparent deformity of the wrist because of the residual angulation.et al24, measured the grip strength of both hands in Salter-Harris type II epiphyseal plate injury of the distal radius using Martin’s Vigrometer (Germany) with a median follow-up of 8.5 years and reported that the grip strength was normal in all 85 patients. Similarly, Roth et al27, studied 66 distal metaphyseal forearm fractures in children and found that after a mean of four years, all had a full grip strength and all had returned to normal activities without restrictions. These findings were consistent with our study, which showed no difference in the grip strength between both hands after a mean follow-up of 6.4 years. Cannata et al23, found four of 139 (2.9%) Salter-Harris type II distal radius fractures, who were followed for an average of 25.5 years where there was an associated decreased grip strength. This study had the longest follow-up on the long-term outcome of the grip strength following the distal radius fractures in children.Studies specifically looking into the grip strength following the distal radius fracture in children are still few. Houshian Cast and wire fixation show excellent and good outcomes at skeletal maturity in children with previous distal radius fracture involving both metaphysis and physis. We would recommend that children who are still having at least two years of growth remaining can still be treated with a cast alone following a reduction unless unacceptable reduction persists warranting wire fixation. The site of the fracture and the type of treatment have no influence on the grip strength at skeletal maturity. Despite discrete functional and radiological differences, no limitation was seen in the activities of daily living at the final follow-up in our study.