The mitigation of diffuse sediment pollution requires reliable provenance information so that measures can be targeted. Sediment source fingerprinting represents one approach for supporting these needs, but recent methodological developments have resulted in an increasing complexity of data processing methods rendering the approach less accessible to non-specialists. A comprehensive new software programme  has therefore been developed which guides the user through critical data analysis decisions and automates all calculations. Multiple source group configurations and composite fingerprints are identified and tested using multiple methods of uncertainty analysis. This aims to explore the sediment provenance information provided by the tracers more comprehensively than a single model, and allows for model configurations with high uncertainties to be rejected. This paper provides an overview of its application to an agricultural catchment in the UK to determine if the approach used can provide a reduction in uncertainty and increase in precision. Five source group classifications were used; three formed using a k-means cluster analysis containing 2, 3 and 4 clusters, and two a-priori groups based upon catchment geology. Three different composite fingerprints were used for each classification and bi-plots, range tests, tracer variability ratios and virtual mixtures tested the reliability of each model configuration. Some model configurations performed poorly when apportioning the composition of virtual mixtures, and different model configurations could produce different sediment provenance results despite using composite fingerprints able to discriminate robustly between the source groups. Despite this uncertainty, dominant sediment sources were identified, and those in close proximity to each sediment sampling location were found to be of greatest importance. This new software, by integrating recent methodological developments in tracer data processing, guides users through key steps. Critically, by applying multiple model configurations and uncertainty assessment, it delivers more robust solutions for informing catchment management of the sediment problem than many previously used approaches.  •Sediment source fingerprinting methods have become complex and inaccessible.•SIFT is comprehensive, user-friendly and free sediment fingerprinting software.•Multiple source group classifications and composite fingerprints are used.•Different methods of uncertainty analysis are used to validate each model.•Localised sources were identified to contribute to channel bed sedimentation. It has,In response to the need to streamline sediment source fingerprinting data processing for accessible use by end users, a comprehensive new software programme  has been developed in R with a user-friendly GUI based around the Shiny package. SIFT guides the user through all critical data analysis decisions without the requirement for specialist knowledge. By way of example, this paper demonstrates the utility of SIFT for applying a combination of multiple different models and uncertainty assessment techniques to the same dataset to produce a more robust interpretation of sediment source fingerprinting results than the use of a single model.22 catchment was selected based on its heterogenous geology which is likely to exhibit large contrasts in topsoil properties allowing for evaluation of optimum source classification, discrimination and apportionment using SIFT. The lower catchment is composed of outcrops of Jurassic oordial ironstone and Lias mudstone. The middle of the catchment is underlain by Jurassic Blisworth formation and Cornbrash limestone, with Jurassic Kellaways member sandstone at the upper edge of this deposit. The upper catchment is underlain by Quaternary Oadby member diamicton and Jurassic Lias mudstone. The mudstone and diamicton geologies are classified as the same “clays” geology for this study as previous research within the Nene basin found them to be indistinguishable using magnetic, radionuclide and geochemical tracers , sandstone (20 samples), limestone (20 samples) and clay (mudstone and diamicton) topsoils (20 samples), and channel banks (20 samples) . Each toSamples of sediment deposited on the channel bed were retrieved from five locations  using th2O2) treatment  to gain an indication of the potential for the measured tracers to discriminate between these groups. Discrimination was evaluated using a bi-plot of the two largest discriminant functions and a confusion matrix. Where discrimination was judged to be unsuccessful, two or more source groups were combined into a single group. This stage of the methodology is aimed at limiting the potential for poor source group discrimination to undermine robust source apportionment. Two geology-based source group classifications were manually assigned at this stage in the SIFT methodology; Classification 1, where few source groups were strongly discriminated, and Classification 2, where more source groups were selected, and good discrimination was less certain although still likely.Three additional source group classifications were generated using a k-means cluster analysis based on the methods of 3.2.1.3A second LDA including all tracers was then used to identify any source samples which are likely to be misclassified in the two geology-based source classifications. Samples were evaluated using a scatter plot of the two largest discriminant functions, with samples identified as potentially misclassified in the analysis output highlighted in the colour of the source group they are a best fit to. In addition, a map of the catchment with misclassified samples highlighted is produced. Where it is clearly identified that the samples are misclassified for a genuine reason, samples are reclassified into their correct group. Where a sample has outlying tracer values which cannot be attributed to misclassification, it is removed to avoid introducing high within-source variability. Possible genuine reasons for sample misclassifications include: (1) outcrops are small or irregularly shaped causing the geology shown on the map to not reflect that actually present; (2) an underlying rock type covers too small an area to significantly impact the properties of its overlying soils; (3) soil erosion is causing material from upslope to form a blanket over native soils, meaning that the underlying geology is not reflected by the sample collected; (4) if channel banks are shallow and share their properties with surface material, and; (5) if channel bank collapse and slumping causes banks to be composed of displaced surface material. There is no test for outliers in the source groups as the un-mixing modelling approach does not assume a normal distribution, and therefore the potential for outliers to introduce uncertainty is minimised; however, outlying samples can be optionally removed at this point.3.2.2The ability of the tracers to discriminate robustly between the source groups/clusters comprising each of the five classification schemes was assessed by calculating tracer variability ratios . This reA ratio lower than 1 indicates that the noise of within-source group variability is larger than the between-group signal, which is likely to result in very high uncertainty associated with un-mixing model outputs . For thi3.2.2.12 higher than 0.8 are plotted against each other with the sediment samples overlaid onto the same plot. This determines if the relationships between pairs of tracers present in the source samples are maintained in the sediment samples. If a relationship is maintained, it suggests a high degree of tracer conservatism; alternatively, if the relationship is not maintained, tracers in question were removed from further analysis.The first test for tracer non-conservatism is based upon the use of bi-plots . Pairs o3.2.2.2To further minimise the likelihood of non-conservative tracers being used in the un-mixing model, it is determined if the concentrations of each tracer within the target sediment samples fall within the medians +/− one median absolute deviation (MAD) and the minimum – maximum range of the source groups . If each3.2.33.2.3.1The group/cluster membership of each source sample in each of the five source group classifications is plotted onto a map of the catchment. The three-different cluster analysis derived source groups were compared to catchment geology, land use and topography so that any correspondence of a cluster group with a specific landscape feature could be identified. This information is aimed at aiding the interpretation of the cluster results.3.2.3.2The percentage differences between the concentrations of the tracers in sources and sediments are calculated and mapped to give a preliminary indication of how likely each source sample is to contribute sediment to the river . These m3.2.43.2.4.1(i)The first fingerprint is a basic fingerprint selected using the LDA output, but with an option to include additional tracers via manual forcing. Forced inclusion is based upon an examination of the differences between sources and sediments maps, and by examining plots of the percentile distributions of each tracer in the source groups. Any tracer which is particularly effective at discriminating a specific source group can be forced into the composite fingerprint.(ii)A “conservative” fingerprint is formed by forcing in any tracers which passed the bi-plot conservatism test. This composite fingerprint aims to capture the tracers most likely to be unaffected by organic matter, particle size and diagenesis effects.(iii)A “high variability” fingerprint is formed by forcing in the tracers with the highest variability ratios to attempt to achieve the lowest range of uncertainty in model outputs and limit the potential for uncertainties associated with sediment delivery from only a small area of the catchment which may have outlying tracer values. In this case study, one tracer was forced into the high variability fingerprint for each source group present, starting with the highest ratio tracer and working down a ranked list.Three composite fingerprints were produced for each of the five source classifications to assess variation in sediment provenance estimates dependent on the tracers used . Rather 3.2.4.2Bi-plots of the two largest discriminant functions generated by the LDAs were produced for each of the three composite fingerprints for each of the five source classifications. Samples belonging to each of the source groups were colour coded and the DF scores for the sediment samples were calculated and included in the plot. These plots provide an indication of sediment provenance which can be compared to the un-mixing model results as a form of model validation.3.2.52 > 0.8 the same correlation was maintained in the generated Monte Carlo random numbers  was calculated as the root mean square of relative errors between the modelled and the actual sediment tracer properties . Any mod3.2.63.2.6.1Virtual sample mixtures consisting of the tracer concentrations of hypothetical mixtures of different sources which have been mathematically calculated also represent a means to assess if the general modelling approach is likely to deliver an acceptably low range of uncertainty. Equifinality problems with source apportionment , the effThe tracer values of virtual mixtures were calculated to evaluate model accuracy and uncertainty . These c3.2.6.2The virtual mixtures can be used to trial a variety of weightings to determine if they improved source apportionment accuracy. The first weighting trialled was a variability ratio weighting, calculated by dividing the mean variability ratio for each tracer by the largest mean variability ratio for any tracer within the composite fingerprint. This ratio was aimed at representing a combination of the discriminatory efficiency and within-source group variability weightings developed by 3.2.6.3The sediment samples were run through the un-mixing model with each of the five source group classifications and three different composite fingerprints which produced an acceptable result for the virtual mixtures. Weightings were applied where they were shown to improve source apportionment. Any model where all of the Monte Carlo iterations fell below the 0.35 threshold was judged to have been unsuccessful and so was rejected.3.2.73.2.7.1The median, 25th and 75th percentile proportions are presented for each sediment sample for each source classification and composite fingerprint to summarise the un-mixing model results. These results were interpreted in the context of any sources of uncertainty identified in previous methodological steps and to determine if the results conform to what might be expected with the spatial distribution of the source groups and the observed catchment characteristics.3.2.7.2The average percentage contribution of each source sample to each sediment sample is calculated from every model producing an acceptable result when apportioning the composition of the virtual mixtures, and an acceptable GOF. These maps provide a simple yet detailed visualisation of the probable sources of each sediment sample.44.1Tracer concentrations in sediment samples Bed 1, 2, 4 and 6 fell within the full minimum to maximum range found in the source groups, and as such these samples were retained for further analysis. For sample Bed 5, R, G, HRGB and IRGB fell outside of the range of values found in the source samples, and for Bed 3 BackIRM fell outside of this range, indicating the non-conservatism of these tracers in these samples. However, as most of the measured tracers fell within the range of the source groups, these samples were retained for further analysis.Group 1: Ironstone and Group 2: Sandstone, Limestone, Clays and Channel Banks.The initial LDA identified that the two largest discriminant functions (DFs) were responsible for 86% of source discrimination . DF1 priGroup 1: Ironstone, Group 2: Sandstone, and Group 3: Limestone, Clays and Channel Banks.The second geology-based source classification with a greater number of individual groups comprised:In all three-cluster analysis derived source classifications, ironstone topsoils were mostly concentrated within the membership of one particular cluster  was identified as potentially misclassified and was a better fit to the ironstone source group in both of the geology-based source classifications . This sa4.3Mean variability ratios for all pairs of all tracers were 2.1 for the two-cluster classification, 3.8 for the three-cluster classification, 4.6 for the four-cluster classification, 3.1 for geology classification 1 and 2.5 for geology classification 2 . Both tw4.4p < 0.05; r2 > 0.8), and most of the colour traces were also significantly correlated  for most of the five source classifications and composite fingerprint types . The one4.8Only plots for the basic composite fingerprints are shown as all three fingerprints generally produced a similar plot for each source classification ; howeverThe two-cluster classification plot indicates that Cluster 2, which is primarily composed of non-ironstone sources, is likely to dominate contributions to the bed sediment samples. Reasonable discrimination between the two sources is present, with only one source sample overlapping the two clusters. The three-cluster solution also shows good discrimination. DF1 linearly discriminates between all three clusters and DF2 provides the separation of clusters 1 and 3, and cluster 2, which is necessary to avoid equifinality related uncertainties. However, DF2 represents only 8.79–9.13% of the total discriminatory power. A mixture of clusters 2 and 3 likely dominates contributions to three of the sediment samples, and cluster 3 appears to dominate contributions to two samples. For the four-cluster solution, clusters 1 and 2 appear to dominate contributions to three samples, and inputs from cluster 4 dominate contributions to two of the samples. DF1 is again able to discriminate linearly between the four clusters. DF2 representing 20% of total discrimination, discriminates clusters 1 and 4 from clusters 2 and 3. Discrimination between clusters 2 and 3 is limited to a small amount by DF1, suggesting that apportionment of contributions from these sources may have high associated uncertainties.Geology classification 1, with two source groups, shows good discrimination and sediment provenance dominated by non-ironstone sources. Geology classification 2 shows notably poorer discrimination between the source groups when compared to the other source classifications. Discrimination between the sandstone topsoil and limestone, clays and channel banks group is poor, and is only provided by DF2, which accounts for ~5% of total discriminatory power. A mixture between sandstone soils and limestone, clays and channel banks appears to dominate contributions to the sediment. Samples Bed 3 and Bed 5 fall outside of the range of the source samples in some plots, confirming the non-conservatism of magnetic and colour tracers in these samples.4.9Virtual mixture apportionment with the two-cluster classification produced the correct composition of the mixtures . UncertaWith the four-cluster classification, the un-mixing model correctly identified contributions from clusters 3 and 4. However, when apportioning contributions from clusters 1 and 2, uncertainties were high with significant overlap between the probability density functions (pdfs) for the two sources. It is therefore apparent that the three-cluster solution is the optimum for this specific dataset, as the four-cluster solution starts to exceed the discriminatory ability of the tracers. For the geology-based classifications, Classification 1 produced comparable results to the two-cluster groups but with a higher range of uncertainty. Source apportionment with all three fingerprints for geology-based Classification 2 was unsuccessful. A 100% contribution from clays, limestone and channel banks was not represented the un-mixing model results and equal proportions of the mixtures produced an output heavily biased towards high sandstone topsoil contributions.4.10The tracer variability ratio weighting had little effect on the virtual mixture model pdf outputs and therefore was not used for sediment source apportionment . The man4.11For the cluster analysis derived source classifications, >50% of model iterations exceeded the 0.35 GOF threshold . The exc4.12The apportionment results  producedWhen using the three-cluster classification, the uncertainties associated with conservative and high variability fingerprints were high for sample Bed 2 . This waCluster 1 represents primarily Ironstone samples in the lower catchment and all models suggest low contributions from this source. The highest contributions from ironstone samples are to sample Bed 3 suggesting that localised inputs from ironstone outcrops in channel banks or topsoil close to this sampling location many be of importance. This finding builds upon that identified for the two-cluster analysis, by suggesting that topsoil inputs in the lower catchment are primarily from soils which are not over the ironstone geology. There is a large discrepancy between the results for sample Bed 3 with the three composite fingerprints. The basic fingerprint estimated a higher contribution from cluster 1 than the other fingerprints. This is likely due to the probable non-conservatism of magnetic tracers (SIRM and BackIRM). Sample Bed 4 is entirely dominated by cluster 2 inputs. No result was produced for sample 5 other than using the high variability fingerprint resulted in very high uncertainty. For sample Bed 6, cluster 2 is predominantly made up of channel bank samples and cluster 3 is composed of topsoils; therefore, the results suggest comparable inputs from both sources.For the four-cluster source classifications , there wFor Geology classification 1 , the con4.13The maps of the combined median contribution to the sediment samples estimated by the reliable models  provide 5Numerous uncertainties were associated with this sediment fingerprinting study and these are common to applications of the approach. However, by incorporating within SIFT the use of conservatism tests, multiple source group classifications, virtual mixtures, bi-plots of source and sediment samples, multiple composite fingerprints and data visualisation, the modelling results can be interpreted in context of these uncertainties.When considering the use of multiple different source group classifications, the a-priori source groups proved of variable use as part of this study. Using Geology classification 1, it was determined that ironstone topsoils were minor sediment sources; however, one composite fingerprint suggested higher contributions than the others adding uncertainty to the overall result. Geology classification 1 also only had ironstone and non-ironstone sources as different groups, meaning that results do not provide relevant information about source provenance in the upper catchment where ironstone was not present. Geology classification 2 failed to produce models able to apportion accurately the composition of the virtual mixtures, despite the LDA producing theoretically viable fingerprints. Poor discrimination between all non-ironstone sources using the available tracers was the cause of this result. The cluster analysis derived source groups also produced variable results. As with geology-based Classification 1, the two-cluster classification separated ironstone (cluster 1) from non-ironstone sources (cluster 2), but with some added and subtracted samples from each group. The results of the un-mixing models were more constant as within-source group variability was lower. The consistency may, however, have been due to all magnetic tracers failing to achieve a maximum variability ratio >2, resulting in only colour tracers being used.2O2 and the tracing of a narrow particle size range were aimed at reducing the potential for organic matter and particle size related uncertainties but may have been insufficient to achieve this aim. It was also observed that vegetation within the channel trapped large quantities of sediment in anoxic conditions which may have caused the dissolution of minerals within the sediment, producing a source of uncertainty the sample preparation methodology was unable to account for. The use of the bi-plot and range tests were therefore important so that the tracing results could be interpreted in the context of these uncertainties.The bi-plot and range tests indicated that both colour and magnetic tracers were non-conservative in some sediment samples. The use of HThe three-cluster Classification appears to be the optimal combination of highest variability ratios, accurate apportionment of the virtual mixtures, high model GOF, and consistency between the results of different composite fingerprints, whilst dividing the catchment into source groups sufficiently spatially-explicit for catchment management purposes which were predominantly ironstone toposils (cluster 1) and spatially distinct patches of topsoils and channel banks (clusters 2 and 3). The four-cluster source groups resulted in lower variability ratios than the three-cluster solution and, as a result, a larger range of uncertainty in virtual mixture and sediment source apportionment and poorer consistency between the results derived using different composite fingerprints was encountered. As the magnetic and colour tracers used were mostly correlated with other tracers of the same type, only two major discriminant functions were present using the available tracers and, as a result, it is not surprising that effective source discrimination was limited to three source groups. This was likely a result of equifinality where multiple model solutions are mathematically correct using the limited DFs . The fouA limitation with the cluster analysis derived source groups was that the sampling campaign did not effectively cover the entire catchment at a high resolution. Therefore, there is some difficulty in interpreting which areas of the catchment should be classified into each cluster group so that catchment management interventions can be targeted. A stratified sampling campaign which ensures all areas of the catchment are sampled would be required to overcome this limitation. Whilst this is achievable in small catchments, in larger basins, such a sampling scheme would require significantly more source samples to be collected than when representing sources by land use or geology.The identification of misclassified source samples as an initial stage of the methodology appears a useful addition when a-priori source groups are used, allowing for an increase in discrimination and decrease in within-source variability. However, the need for personal judgement as to which samples are misclassified potentially introduces uncertainty if poorly discriminated samples are mistakenly misclassified. Therefore, it is recommended that reclassification only be used where robust justification exists for each specific sample. Scale dependency can be a large source of uncertainty in predicted source apportionment and is likely to depend on the specific nature of sediment delivery and the variability in source properties in a catchment . Sample The current SIFT software is only useful with discrete tracers. Some researchers have used alternative spectra-based fingerprints. Overall, the sources of bed sediment appear localised to each bed sediment sampling location. Therefore, the results of this work would best be combined with an analysis of the quantities of bed sediment along reaches to identify where bed sedimentation is most substantial so that management can be targeted accordingly. It remains important to include multiple channel sampling locations in a source fingerprinting study as a means of addressing the scale dependency problem. This result suggests that sediment is likely deposited onto channel beds during periods of low flow from well-connected sources, rather than being deposited during the falling limb of a high flow event following mobilisation and delivery from distal sources.6www.rothamsted.ac.uk/facilities-and-resources#DATAREPOSITORIESMODELSANDSOFTWARE-3. An image of each page of SIFT (v1.0) is provided in the online supplementary material.This trial of the multiple unmixing model and uncertainty assessment approach used in the SIFT software identified that some un-mixing model configurations produced highly uncertain results, and therefore, its use of multiple different model configurations and assessments may be essential to produce robust results for some datasets. The current version of SIFT can be accessed from the Rothamnsted Research website at: The colour (A) and magnetic (B) signatures used, their method of calculation and the property they represent. Colour signatures are based upon their use by Supplementary Table 1Supplementary figuresImage 1The following are the supplementary data related to this article.


Differentiated thyroid cancer (DTC) is a malignancy that is occurring with greater frequency. Between the years 2006 and 2010, the incidence increased at an annual rate of 5.4% in men and 6.5% in women . AlthougRadioactive iodine is generally considered in patients with a high risk of locoregional recurrence or metastatic disease . This has been the mainstay of treatment for extrathyroidal disease, but it has been determined that two-thirds of these patients do not respond to RAI -approved treatment option for these patients was doxorubicin, but the treatment landscape is changing with the development of targeted therapies. The first targeted agent to be approved for the treatment of RAI-refractory DTC was sorafenib . Renal cell carcinoma (RCC) accounts for nearly 2.6% of all cancers in men and women . PrimaryNovel targeted therapies allow for an opportunity to significantly improve the treatment options of difficult-to-treat cancers such as DTC and RCC. Lenvatinib (Lenvima) is an oral multiple receptor tyrosine kinase inhibitor initially approved in February 2015 for the treatment of DTC that is recurrent, progressive, or refractory to RAI . As of MLenvatinib is a multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4); fibroblast growth factor receptors FGFR 1, 2, 3, and 4; as well as platelet-derived growth factor receptor alpha, KIT, and RET. Each of these receptor tyrosine kinases plays a key role in angiogenesis, which is one of the main processes that allows tumor growth and progress. Inhibition of these receptors allows for the minimization of an essential factor that the tumor needs to grow, allowing for a decrease in the tumor size and slowing of the progression of the cancer . When lenvatinib is used in combination with everolimus, which is a mechanistic target of rapamycin (mTOR) inhibitor, the antiangiogenic and antitumor activity of the drug is enhanced. This further minimizes the endothelial cell proliferation, tubule formation, and VEGF signaling that is an essential inhibitory mechanism necessary to combat RCC .Lenvatinib is primarily metabolized by the hepatic enzyme CYP3A4 and aldehyde oxidase. Its half-life nears 28 hours, and it is mostly excreted through feces. The drug’s peak effect initiates 1 to 4 hours after consumption .Differentiated Thyroid CancerThe SELECT trial was a multicenter, 2:1 randomized, double-blind, placebo-controlled phase III study that evaluated lenvatinib for the treatment of recurrent, progressive and/or refractory DTC. In this study, 392 patients with locally recurrent or metastatic RAI-refractory DTC who presented with radiographic evidence of disease progression within the 12 months prior to the initiation of the trial were randomized in a 2:1 ratio to treatment and placebo groups. The treatment group received 24 mg of lenvatinib once daily . p < .001) in comparison to the placebo arm (3.6 months). The lenvatinib arm also produced a statistically significant ORR  in comparison to the placebo arm (2%). Median OS had not been achieved in either treatment arm at the time of data collection  using the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints included objective response rate (ORR) and overall survival (OS). The study revealed the lenvatinib arm provided a statistically significant improvement in PFS , lenvatinib yielded significantly improved PFS  but not against lenvatinib alone . The study also found that single-agent lenvatinib significantly prolonged PFS in comparison to everolimus alone . The lenvatinib plus everolimus arm also produced a statistically significant ORR  in comparison to the single-agent everolimus arm (4%) but only a numerically improved ORR in comparison to the lenvatinib-alone group , lenvatinib plus everolimus (n = 51), and everolimus (n = 50) groups. The study found that lenvatinib plus everolimus significantly improved PFS (14.6 months) when compared against everolimus alone , diarrhea (59.4%), fatigue or asthenia (59.0%), decreased appetite (50.2%), decreased weight (46.4%), and nausea  Guidelines for thyroid carcinoma support the use of lenvatinib in the treatment of metastatic thyroid cancer that is structurally persistent, refractory to RAI, and/or recurrent. The guidelines also state that other agents such as sorafenib can be used as alternative agents. Of the two agents, lenvatinib is the preferred drug, but the agent ultimately used is dependent on patient-specific factors such as comorbidities. These therapies are listed as an option, meaning they are based upon a lower level of evidence, but there is uniform consensus that the therapy is appropriate among the panelists who developed the guidelines. Other small-molecule kinase inhibitors not currently FDA approved for this indication can be considered if no clinical trials are available . The monThe NCCN Guidelines for RCC state that the combination of lenvatinib plus everolimus is an option for the second-line treatment of metastatic RCC. This recommendation is based upon high-level evidence and a uniform consensus from the panelists who developed the guidelines. Although this is a strong recommendation, phase III studies (METEOR and CheckMate 025) state that eligible patients should receive cabozantinib (Cabometyx) and nivolumab (Opdivo) over everolimus. In these trials, cabozantinib and nivolumab were only studied against everolimus as monotherapy, so their preference over the combination of lenvatinib and everolimus cannot be accurately extrapolated . The monLenvatinib is a once-daily oral capsule used for DTC that is progressive, metastatic, or refractory to RAI and for RCC that has previously been treated with an antiangiogenic agent. This is an agent likely to be actively utilized by prescribers due to the lack of substantial treatment options for the previously mentioned indications as well as the development of resistance to alternative treatments within the same class .The recommended dosing of lenvatinib is indication-based: 24 mg (two 10-mg capsules and one 4-mg capsule) for patients with DTC and 18 mg (one 10-mg capsule and two 4-mg capsules) for patients with RCC. Lenvatinib is dispensed in 30-day therapy packs. The 24-mg therapy pack comes with 90 capsules: sixty 10-mg capsules and thirty 4-mg capsules. The 18-mg therapy pack also comes with 90 capsules: thirty 10-mg capsules and sixty 4-mg capsules.Regardless of indication, the medication is to be taken at the same time once a day without regard to food. The capsules should be swallowed whole, but if the patient is unable to do so, the capsules can be dissolved in a small amount of liquid. A missed dose should not be taken within 12 hours of the next dose, and the patient should never take two doses at one time. It is important to hydrate well throughout therapy .Dosing adjustments for lenvatinib are needed for preexisting renal and hepatic impairment. If the patient presents with a creatinine clearance of less than 30 mL/min, the dose must be adjusted to 14 mg once daily for DTC and 10 mg once daily for RCC. If the patient suffers severe hepatic impairment (presents with Child-Pugh class C disease), the dose must be adjusted to 14 mg once daily for DTC and 10 mg once daily for RCC .Major interactions associated with lenvatinib include the worsening of QTc prolongation when administered with other moderate- or high-risk QTc-prolonging agents. The risk associated with QTc-prolonging agents is stratified by the following categories: X (avoid combination), D (consider therapy modification), and C (monitor therapy). If combinations of lenvatinib and these drugs are used, electrocardiograms should be obtained to monitor for the prolongation of QTc. A complete list of agents and their risk stratification is provided in As lenvatinib is a UGT1A1 inhibitor, it can increase serum concentrations of irinotecan products, which are active metabolites of UGT1A1. The combination of lenvatinib and irinotecan products should be avoided. Although lenvatinib is primarily metabolized through CYP3A4, it is a minor substrate of the enzyme, so no dose adjustments or drug interactions need to be monitored .In the DTC study, 68% of patients taking lenvatinib suffered adverse drug reactions (ADRs) that led to dose reduction (average 17.2 mg), and 18% had ADRs that led to treatment discontinuation. The primary reactions that led to dose reduction included hypertension and proteinuria . Dose inIn the RCC study, 49% of patients taking lenvatinib and everolimus suffered ADRs that led to dose reduction, and 24% had ADRs that led to treatment discontinuation. The most common grade 3 and 4 toxicities associated with the combination regimen included diarrhea and hypertension . Dose inFor patients who have or develop hypertension, it is imperative to monitor blood pressure prior to and throughout the treatment course. Antihypertensive medications should be adjusted and maximized to achieve blood pressure control. If the patient’s hypertension is not controlled with a maximal antihypertensive regimen, lenvatinib therapy should be held until hypertension is ≤ grade 2.For patients who develop ≥ 2 g proteinuria in 24 hours, lenvatinib therapy should be held. Proteinuria can be associated with an increase in blood pressure and an early sign of kidney damage. A dipstick test should be used to monitor these patients before initiation and periodically throughout treatment. If the urine dipstick proteinuria is ≥ 2+, then the patient needs a 24-hour urine protein level. Once the condition has resolved to < 2 g proteinuria in 24 hours, lenvatinib can be resumed at a reduced dose.The suggested dose reductions are specific to the disease state being treated. For patients who develop diarrhea, prompt medical management is suggested prior to interrupting lenvatinib therapy. Once the diarrhea has resolved, lenvatinib may be reinitiated at the current or reduced dose. If diarrhea persists regardless of optimal medication management, lenvatinib therapy should be discontinued and not resumed. Disease-specific dose reductions can be found in As seen in the SELECT study, lenvatinib alone can serve as primary and secondary options for the treatment of DTC refractory to RAI. The agent provides a positive PFS and durable response rate to a disease state with a previously poor prognosis. The currently ongoing trial evaluating lenvatinib use in advanced RCC shows that lenvatinib, alone or in combination with everolimus, provides greater PFS, but the length of the ORR indicates the combination regimen may be more beneficial. In either case, this agent offers a safer and more efficacious treatment alternative to patients who may not have had that opportunity previously. Clinical data discussed in this review have proved lenvatinib serves as an effective medication option in DTC and RCC, but there are other factors to consider prior to administering it. One such factor is the adverse-effect profile of lenvatinib. The SELECT and RCC studies reported the three primary adverse effects of lenvatinib that led to dose modifications were hypertension, proteinuria, and diarrhea. Two of these adverse effects (hypertension and diarrhea) can be medically managed prior to any dose reduction or discontinuation of therapy. Proteinuria, on the other hand, requires a hold in therapy followed by a dose reduction upon continuation. These side effects are comparable, and in some cases minimal, to the other agents that would be used for DTC and RCC.Another factor to consider is the cost. Targeted therapies such as VEGF inhibitors have the potential to serve as first- and second- line treatment options for difficult-to-treat malignancies such as DTC and RCC. Their unique mechanism of action hinders a key process in tumor growth and survival, thus limiting disease progression and allowing for tumor shrinking. The response of these agents in patients whose malignancies have poor prognoses has garnered much excitement.


It is well-recognized that there is a need for medicine to migrate to a platform of delivering preventative care based on an individual's genetic make-up. The US National Research Council, the National Institute of Health and the American Heart Association all support the concept of utilizing genomic information to enhance the clinical management of patients. It is believed this type of precision healthcare will revolutionize health management. This current attitude of some of the most respected institutes in healthcare sets the stage for the utilization of the haptoglobin (Hp) genotype to guide precision management in type 2 diabetics (DM). There are three main Hp genotypes: 1-1, 2-1, 2-2. The Hp genotype has been studied extensively in (DM) and from the accumulated data it is clear that Hp should be considered in all DM patients as an additional independent cardiovascular disease (CVD) risk factor. In DM patients Hp2-2 generates five times increased risk of CVD compared to Hp1-1 and three times increased risk compared to Hp2-1. Data has also shown that carrying the Hp2-2 gene in DM compared to carrying an Hp1-1 genotype can increase the risk the microvascular complications of nephropathy and retinopathy. In addition, the Hp2-2 gene enhances post percutaneous coronary intervention (PCI) complications such as, in stent restenosis and need for additional revascularization during the first-year post PCI. Studies have demonstrated significant mitigation of CVD risk in Hp2-2 DM patients with administration of vitamin E and maintaining tight glycemic control. CVD is the leading cause of death and disability in DM as well-representing a huge financial burden. As such, evaluating the Hp genotype in DM patients can enhance the predictability and management of CVD risk. The current number of Americans diagnosed with DM is approximately 21 million . CVD repnd 0.010 . A more nd 0.010 . Data hand 0.010 . EvaluatDespite the above evidence, the associated increased CV risk of being an Hp2-2 diabetic is not without controversy. The large genome wide association study (GWAS) CARDIoGRAMplusC4D consortium called into question this association as none of the Hp single-nucleotide polymorphisms (SNPs) showed any increased risk of CAD in DM . HoweverThe biochemical and physiologic properties of Hp were described more than 75 years ago –13. The 2-glycoprotein produced in the liver with a major function in the physiological recycling of free hemoglobin (Hb). Biologically, Hp has high affinity to Hb in order to promote iron conservation following hemolysis  from the vasculature and intravascular spaces. Free Hb is routinely released into tissues as result of intravascular hemolysis following the destruction and recycling of senescent red blood cells (RBC), this process occurs at a rate of 2 × 10r second , 28. Sevr second , 30. Hapr second –34. Concr second . The binr second , 36, 37.r second –41. The r second . The abir second . The losr second .Including Hp testing into the clinical arena allows for precision based healthcare decisions on the CVD vulnerability of the DM patient. These patients have complex CV health issues that require individualized attention. High-density lipoprotein (HDL) particle is a modifiable CV risk in the management of patients with DM. The levels of HDL are generally low in DM and functionality diminished . PatientManaging CVD in DM patients drives around $200 billion of annual healthcare costs in USA. Vitamin E appears to provide significant benefit for the high CV risk in Hp2-2 DM patients . This thThe latest guidelines for glycemic control issued in March of 2018 call for a softening of glucose control . The newMechanistically, the relationship between Hp2-2 status and glycemic control is believed to involve heightened oxidative stress. Glycosylation of Hb is an additional factor that reduces the effectiveness of Hp2-2 to perform as an antioxidant. Therefore, when the Hp-Hb complex attaches to HDL particles it generates oxidation of HDL-particles and its components, such as glutathione and apolipoprotein A. This modification creates an HDL particle, which is proatherogenic and prothrombotic. Obtaining the Hp genotype of the DM patient would allow for precision glycemic management. This is a clear example of entering an age where we can render care to an individual patient based on their biological uniqueness. Guidelines treat patients as averages of the study populations. Personalized and precision care through genotyping should promote better outcomes. Hp genotyping would assist in establishing glycemic control goals in DM patients .Hp2-2 is structurally too large to enter the intimal space of the artery wall. This can be particularly detrimental in a patient with DM who presents with active arterial disease. Progression of atherosclerosis in DM has been demonstrated to involve neovascularization and intra-plaque hemorrhage, leading to the further release of Hb . BecauseIt is becoming clearer that Hp2-2 genotype is a risk factor for the development of atherosclerosis, aneurysm, and carotid stenosis that is independent of other classical risk factors such as smoking, hypertension, high cholesterol, diabetes, and hyperhomocystenemia , 62, 63.The hypothesis that patients with Hp2-2 genotype are far more vulnerable to oxidative damage in arteries with existing atherosclerotic plaques is supported by the literature and testing patients for Hp2-2 genotype will be of clinical merit and it's utility is likewise supported by the literature. Data and literature accumulated over the past two decades clearly illustrates that Hp genotyping should be considered as a predictor of cardiovascular complication and a measure of future patient prognosis and outcome.As noted by Cheng et al. personalized medicine involves the “coupling of established clinical and pathological indexes with state-of-the-art molecular profiling to create diagnostic, prognostic, and therapeutic strategies precisely tailored to each patient's requirements—hence the term precision medicine” . TreatinIn terms of assessing for CV risk, it now appreciated that identifying subclinical coronary, carotid or femoral atherosclerosis has bearing on risk for heart attack, stroke and CV death. Discovering such disease can enhance patient management and increase compliance , 70 SuchInflammation is the cause of arterial disease and the trigger for CV events , 73. TheIn terms of therapy, the current guidelines for DM do an excellent job addressing blood pressure goals and lipid goals however, the event rates and recidivistic rates of CVD in DM continue to create substantial financial and personal loss . It was In addition to the above strategies to mitigate CVD risk, clinicians should strive to optimally manage other known CV risk factors in the high risk Hp2-2 DM population. These factors include: sleep, psychosocial issues, periodontal disease, endodontic disease, and other inflammatory diseases –84. ApplA randomized prospective study should be done in Hp2-2 DM patients to assess the CV risk reduction achieved with the above proposed comprehensive assessment and management vs. the current standard of care for DM patients. Another study should be done to determine if there is any potential benefit for vitamin E therapy in Hp2-2 individuals along the continuum of insulin resistance prior to the diagnosis of DM. In the interim, since Hp testing is arguably inexpensive with a cost of >$300 up front and obviously inexpensive long term as it is a one-time test, it seems reasonable with the current scientific knowledge to measure Hp genotype in all DM patients. Hp testing augments the current standards in this vulnerable population yielding the opportunity to dramatically improve patient outcomes. Approximately, one third (~ 7 million) will be Hp2-2. Those individuals can be targeted for additional assessment and management beyond current guidelines. Such care may help stimulate our current system to a more value based prevention model. Hp testing for DM patients is in direct support of the American Heart Association's mission to practice precision healthcare, especially in the most vulnerable CV patient populations, such as the DM patient. Hp testing in DM has the opportunity to enhance personalized and precision healthcare.The authors contributed equally to the writing and development of the manuscript.ALD and BFB are Medical Consultants for Mygenetx Clinical Laboratory. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The presence of significant pain and swelling during the acute stage following total knee arthroplasty (TKA) may limit the patients’ ability to cooperate in intensive physiotherapy interventions. Low-intensity pulsed ultrasound is one of the modalities that can be used for acute pain and swelling management. However, only one study investigated the effect of this modality in patients with TKA. There is limited documentation of the effects of combining low-intensity pulsed ultrasound in TKA rehabilitation in the recovery of physical impairments and how these influence the recovery of function after TKA. Therefore, this study is proposed with the aim to evaluate the effects of low-intensity pulsed ultrasound as an adjunct to conventional physiotherapy on the recovery of physical impairments, functional performance and quality of life after TKA surgery.This is an assessor-blinded quasi-experimental study comparing two approaches of physiotherapy, namely pulsed ultrasound-added physiotherapy and conventional physiotherapy. Total number of participants with TKA required for this study will be calculated based on the result of a pilot study. Participants will be alternately allocated into either pulsed ultrasound-added physiotherapy group  or control group . Pulsed ultrasound-added physiotherapy group will receive low-intensity pulsed ultrasound starting at post-operative day 2 (4–5 times for the first-week after surgery and 2–3 times a week for a further 2 weeks). Both groups will receive conventional physiotherapy 4 to 5 times for the first-week after surgery and 2 to 3 times a week for a further 11 weeks. This procedure and process will be tested and established in a pilot study. Primary outcomes of interest are pain level, swelling, active range of knee motion, and quadriceps strength. The secondary outcomes are functional performance and quality of life.This study will fill the gaps in knowledge relating the benefits of including low-intensity pulsed ultrasound into conventional physiotherapy for patients with TKA.Australian New Zealand Clinical Trials Registry, ACTRN12618001226291 However, total knee arthroplasty (TKA) is recommended as an intervention for managing severe knee OA or when the conservative treatments have failed. The TKA followed by post-operative rehabilitation interventions namely exercises, education, dietary advice, use of insoles, and pain medication has been shown as beneficial to reduce pain and improve function of patients with moderate-to-severe knee OA. The patients after TKA demonstrated excellent and good early functional outcomes.Patients with knee OA may receive electrotherapy,–17 knee swelling,,19 limitation of knee range of motion,,19,20 and quadriceps weakness,19,20 varies. Pain and swelling,21 after TKA were shown to lead to the development of quadriceps weakness and limitation of knee range of motion. These problems can result in reduced functional performance.,21,22 The pain experience and decreased knee mobility after TKA may further weaken the muscles and prevent the patients from being independent in functional activities. A study stated that pain control at early stage of acute recovery is important to improve physical function after TKA. Thus, it is essential to address acute post-operative pain and swelling in order to optimize effectiveness of other interventions and improve functional recovery after TKA.Previous studies have shown that the recovery of physical impairments after TKA which consist of pain,,25 transcutaneous electrical nerve stimulation (TENS) and music therapy,28 on recovery from pain following TKA. Cryotherapy is a common method used for patients with TKA in reducing acute post-operative pain and swelling. However, the evidence on the effects of cryotherapy remains inconclusive. Markert reported in general evidence shown that cryotherapy did not significantly help to reduce knee swelling, decrease in blood loss and improve range of motion of the operative knee. However, the researcher believed that cryotherapy is still useful for patients with TKA; there is evidence that the cold and compression effect provide positive outcomes. Besides, a review study reported that although some benefits have been shown from the use of cryotherapy following TKA, it is still inconclusive due to the limited number of Level 1 studies to support the use of cryotherapy. Another review study reported that most of previous studies showed positive findings on the use of cryotherapy after knee arthroplasty such as reduced pain and the use of analgesic, and improved knee range of motion and patients’ satisfaction. The study also recommended an application of cryotherapy for knee arthroplasty patients. Despite this, the researchers still highlighted that several studies did not show a significant positive effect of the application of cryotherapy.Past studies had explored the effects of adjunct modalities such as cryotherapy However to date, this finding was reported only in one study. The researchers investigated the effect of combining low-intensity pulsed ultrasound with cryotherapy on recovery of joint function and the inflammatory index C-reactive protein in female patients with TKA. No adverse effects were reported, indicating that the modality is safe to be used on patients with TKA. The researchers found that patients who received low-intensity pulsed ultrasound in combination with cryotherapy shown greater improvement in the recovery of joint function, knee range of motion and reduction of inflammation compared to patients who received cryotherapy or low-intensity pulsed ultrasound alone. However, the study did not look into the effect of the adjunct modality on the recovery of all physical impairments which also include pain, swelling and quadriceps weakness during early stage post-TKA and how these influence the recovery of function in the post-acute phases. Further resources for acute management after TKA are needed to improve acute pain control and future research on the effect of impairment-targeted interventions in acute hospital and inpatient rehabilitation setting is recommended.Recently, another modality, namely pulsed ultrasound with low-intensity has been found useful in the acute management of patients with TKA. The therapy was also not stated as a contraindication for the patient with metal implants.The objective of this quasi-experimental assessor-blinded study is to evaluate the effects of low-intensity pulsed ultrasound as an adjunct to conventional physiotherapy on the recovery of physical impairments, functional performance and quality of life in patients with TKA. This study also intends to assess the influence of the recovery of physical impairments following Pulsed ultrasound-added physiotherapy on functional performance and quality of life of patients with TKA.22.1This is a quasi-experimental assessor-blinded study comparing two approaches of physiotherapy, namely Pulsed ultrasound-added physiotherapy group or control group with the participant's allocation ratio is 1:1. This study will be conducted at orthopedic wards and physiotherapy department in the Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia. The flow of the study is shown in Figure 2.2Inclusion criteria are as follows:1.Aged 50 to 80 years.2.Patients who are listed for TKA surgery due to knee OA.3.The TKA with posterior stabilized cemented total knee replacement.4.Patients who reported able to walk and climb up and down stairs with or without walking aids.Exclusion criteria are as follows:1.Any contraindications to pulsed ultrasound .2.Coexistence or history of diseases which might limit the physical function and functional performance such as old fractures in the lower limb, neurology conditions , and other musculoskeletal problems.3.Has TKA complication(s) such as myocardial infarction, deep vein thrombosis, septic arthritis and neurological deficit due to regional anesthesia complications.2.3A systematic allocation method is used to allocate participants alternately into either pulsed ultrasound-added physiotherapy group or control group. The first participant is allocated to one of the groups at random  by a research assistant who is blinded from the intervention groups. Then, the next participant will be allocated to the other, and the process continues.2.4The interventions in this study will be conducted for 12 weeks. The Pulsed ultrasound-added physiotherapy group will receive low-intensity pulsed ultrasound and conventional physiotherapy, while the control group will receive conventional physiotherapy alone. Pulsed ultrasound-added physiotherapy and control groups will receive conventional physiotherapy interventions 4 to 5 times for the first-week post-TKA and 2 to 3 times a week for a further 11 weeks. Besides, the application of low-intensity pulsed ultrasound (4–5 times for the first-week after surgery and 2–3 times a week for a further 2 weeks) in the pulsed ultrasound-added physiotherapy group will be started at post-operative day 2. and functional exercises provide better outcome in recovery following TKA.–37 The rehabilitation program for TKA is shown in Table The conventional physiotherapy that will be used in this study is based on the therapy program for TKA implemented in the Universiti Kebangsaan Malaysia Medical Centre and also based on evidences which showed that exercise interventions which include stretching, strengthening,Low-intensity pulsed ultrasound  will be administrated for 5 minutes with the pulse ratio of 1:4 (20% duty cycle); 3 MHz frequency; and the intensity will be determined based on the thickness of the individual patient's tissues. The designated surgeon will measure the thickness of tissues using patella caliper during the surgical procedure. The area to be treated is the medial aspect of the knee which is about 1 cm away from the medial border of the patella. Transducer head and any equipment related to the pulsed ultrasound treatment will be cleaned with alcohol-based swab before and after the application.All participants will be instructed to do home exercise program 2 times per day. The home exercise program is adopted from an exercises program for knee surgery used by physiotherapy in the university medical center  are as follows:1.Pain will be measured using a 10 cm visual analogue scale (VAS) which 0 cm for “no pain” and 10 cm for “unbearable pain.” The VAS has been shown as a valid and reliable measure for assessing pain after TKA.2.Knee swelling will be determined by measuring the knee circumference  using a measuring tape. The value nearest 0.1 cm will be recorded. This outcome measure has excellent reliability on patients with TKA, with the smallest detectable difference of 1 cm.3.A standard long-arm goniometer  will be used to identify any limitation of active knee range of motion with the participant positioned in supine. The participant will be asked to actively slide his/her heels on the bed to do knee flexion and extension, and the maximal active knee flexion and extension will be measured. The reliability of active knee range of motion measurement using goniometer was established in patients with TKA.4.,21 The measurement will be taken with the participant in supine position and the knee in 30° flexion (a roll of the towel will be placed under the knee). The hand-held dynamometer force pad will be placed proximal to the ankle joint. The participant will be asked to push against the dynamometer force pad as maximum as possible. The participants will perform two trials for 5 s hold per each trial and 30 s of rest between the trials. The knee extensor strength will be recorded in kilograms force which the higher peak force achieved between 2 trials will be used.Quadriceps strength will be measured isometrically using a hand-held dynamometer . The hand-held dynamometer had been used to assess change in quadriceps strength of patients with TKA in the previous studies.The secondary outcomes are as follows:1.Functional performance measuresTimed up and go (TUG) measures the time taken by a participant to complete rising from a chair, walking 3 m, and turning, walking back to the chair and sitting. The armed chair (seat height of 47 cm) will be used. The participant will be instructed to walk safely as quickly as possible. This test measures patients’ mobility with excellent reliability on patients following TKA.11-step stair test will also be used to assess functional performance of the participant. This test will use a staircase with eleven steps (17 cm height steps with a depth of 30 cm and 110 cm width) with handrails on both sides, and a platform at the top and one at the bottom (110 cm by 140 cm). The participant will start the test with climbing up the stairs, turn around on the top platform, and climbing down the stairs, as fast as possible. The participants will be allowed to use 1 handrail if required. The time to complete the test will be recorded. This test has good reliability on the patient with TKA in measuring the physical performance of the patient.Six-minute walk test will be used to measure how far the participants could walk in 6 min. The participants will be instructed to walk as far as possible on a level surface in 6 min and allowed to use an assistive device if necessary. The assessor will use a measuring wheel to record total distance covered. The participants could also rest for a while during the test as needed. This test has an excellent reliability in assessing functional performance of patients with TKA.2.,44 Besides, the Malays version of EQ-5D was shown can be used in Malaysia with the acceptable psychometric properties.Quality of life will be assessed using the 5-level EQ-5D. This outcome measure has two parts which are the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D descriptive system consists of 5 dimensions which are mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels of health state . Besides, the EQ VAS has a vertical VAS which will be used by the participants to rate their health. The scale is numbered from 0  to 100 . The EQ-5D was used as the generic health measure for patients with TKA in previous studies.2.6Two days prior to TKA surgery, a researcher will verbally invite potential participants and briefly explain the purpose and procedure of the study before distributing the information sheets to them. At post-operative day 2, the participants will be further screened for eligibility and an informed consent will be obtained from patients who are eligible and agreed to participate. Once recruited, the socio-demography, information of height, weight and body mass index (BMI) of the participants will be recorded. The dose of analgesic medication used will be obtained from patients’ medical record (in-patient) and based on the patients’ report (out-patient).All participants will undergo baseline assessments before allocated alternately into the two groups at post-operative day 2 for physical impairments, and quality of life following removal of drainage tubes and discontinuation of patient-control analgesia. Baseline assessment for functional performance will be performed at week 1 after the surgery.Assessment of outcomes following intervention will be conducted at 4 assessment time points which are at week 1, 4, and 12 following TKA surgery and at 3-month follow-up (6 months after the surgery). Outcomes on physical impairments will be assessed at the end of week 1, 4, and 12 following the surgery and at 3-month follow-up. Whereas, outcome on the functional performance will be assessed at week 4 and 12 after the surgery and at 3-month follow-up. Finally, the interventions’ outcome on quality of life of the participants will be assessed at 3-month follow-up or 6-month post-surgery.A trained physiotherapist who is blinded to the participants’ group allocation is responsible to conduct and record all assessments. To avoid recall bias, the recorded measurements of patient's pre-intervention status will not be accessible to others during the patient's post-intervention assessment.2.7 The approximates of parameters, mainly effect size, obtained from the pilot study will then be inputted in G∗Power 3.1. ANOVA repeated measures, within-between interaction statistical test, with the number of groups and measurements 2 and 5 respectively will be used in the calculation. Level of significance is set at an alpha level of 0.05 and a statistical power of 80% will be chosen.The sample size required for this study will be calculated based on the results of an ongoing pilot study. The pilot study involves 10 subjects per group; a sample size which is considered adequate to assess the effect size in a pilot study of clinical trial.2.8All data will be analyzed by the researcher using the statistical package for the social sciences (SPSS) 20.0 software, IBM Corporation. If missing data are identified, intention-to-treat will be used to ensure unbiased estimates of treatment effects between the two groups, and all participants who are recruited at baseline will be included in the outcome analysis.P < .05.The characteristics of the participants will be presented in descriptive statistics. Mixed model ANOVA will be used to evaluate time, group and interaction effects of the interventions on participants’ pain, knee swelling, knee range of motion and quadriceps strength, as well as on the patients’ functional performance and quality of life. Further, multiple regression will be used to determine how much do recovery in physical impairments following low-intensity pulsed ultrasound as an adjunct to conventional physiotherapy influence the functional performance and quality of life of the patients. The level of significance is set as 2.9The study received ethical approval from Research Ethics Committee of the Universiti Kebangsaan Malaysia Medical Centre (study code NN-2018-111). Each participant can withdraw anytime during the study without giving any explanation. All personal information and data provided by participants will be kept confidential. Investigators in this study will have access to the final trial dataset. The findings of this study will be published in a peer-reviewed journal.3 did not specifically look at the effect of the interventions on the recovery of other important physical impairments such as pain, swelling and quadriceps weakness after TKA. Therefore, this study will provide knowledge regarding the effects of adding low-intensity pulsed ultrasound in post-operative rehabilitation into conventional physiotherapy on recovery of more physical impairments which are pain, swelling, knee range of motion, and quadriceps strength of patients with TKA.This study will compare the changes in physical impairments between patients with TKA who received low-intensity pulsed ultrasound as an adjunct to conventional physiotherapy and patients who received conventional physiotherapy only. Previous study Results of this study will be further analyzed to assess the influence of the recovery of physical impairments following pulsed ultrasound-added conventional physiotherapy on functional performance and quality of life of patients with TKA.Further, results of the secondary outcomes will provide information on the recovery of the functional performance and quality of life between patients with TKA who received low-intensity pulsed ultrasound and patients who did not receive the treatment. Well-targeted post-operative rehabilitation intervention can further improve the patients’ recovery, and eventually enhance the patients’ functional performance and quality of life. A study stated that pain and lower limbs function are important predictors for the improvement in quality of life of patients after TKA.It is our hope to be able to determine the benefits of adding low-intensity pulsed ultrasound into conventional physiotherapy in enhancing the recovery of physical functions in patients with TKA. Findings from this study can therefore be used as a reference for designing future studies and in establishing evidence regarding the use of low-intensity pulsed ultrasound on population after TKA surgery.We thank Efri Noor Muhammad Hendri, physiotherapist in the university medical center who shared the information on rehabilitation program and home exercise program for TKA patients at the center.Study conceptualization and design: Munayati Munajat, Nor Azlin Mohd Nordin, Nor Hamdan Mohamad Yahya, Ahmad Hafiz ZulkiflyConceptualization: Nor Azlin Mohd Nordin, Munayati Munajat, Nor Hamdan Mohamad Yahya, Ahmad Hafiz Zulkifly.Methodology: Nor Azlin Mohd Nordin, Munayati Munajat, Nor Hamdan Mohamad Yahya, Ahmad Hafiz Zulkifly.Writing – original draft: Munayati Munajat.Writing – review & editing: Nor Azlin Mohd Nordin, Munayati Munajat.


More than half of artemisinin combination therapies (ACTs) consumed globally are dispensed in the retail sector, where diagnostic testing is uncommon, leading to overconsumption and poor targeting. In many malaria-endemic countries, ACTs sold over the counter are available at heavily subsidized prices, further contributing to their misuse. Inappropriate use of ACTs can have serious implications for the spread of drug resistance and leads to poor outcomes for nonmalaria patients treated with incorrect drugs. We evaluated the public health impact of an innovative strategy that targets ACT subsidies to confirmed malaria cases by coupling free diagnostic testing with a diagnosis-dependent ACT subsidy.n = 4,653). The gender of enrolled participants was balanced in children , but more adult women were enrolled than men . At baseline, 67.6%  of participants took an ACT for their illness, and 40.3% (n = 810) of all participants took an ACT purchased from a retail outlet. At 12 months, 50.5% (n = 454) in the intervention arm and 43.4% (n = 389) in the control arm had a malaria diagnostic test for their recent fever . By 18 months, the ARR had increased to 1.25 . Rational use of ACTs in the intervention area increased from 41.7% (n = 279) at baseline to 59.6% (n = 403) and was 40% higher in the intervention arm at 18 months . While intervention effects increased between 12 and 18 months, we were not able to estimate longer-term impact of the intervention and could not independently evaluate the effects of the free testing and the voucher on uptake of testing.We conducted a cluster-randomized controlled trial in 32 community clusters in western Kenya . Eligible clusters had retail outlets selling ACTs and existing community health worker (CHW) programs and were randomly assigned 1:1 to control and intervention arms. In intervention areas, CHWs were available in their villages to perform malaria rapid diagnostic tests (RDTs) on demand for any individual >1 year of age experiencing a malaria-like illness. Malaria RDT-positive individuals received a voucher for a discount on a quality-assured ACT, redeemable at a participating retail medicine outlet. In control areas, CHWs offered a standard package of health education, prevention, and referral services. We conducted 4 population-based surveys—at baseline, 6 months, 12 months, and 18 months—of a random sample of households with fever in the last 4 weeks to evaluate predefined, individual-level outcomes. The primary outcome was uptake of malaria diagnostic testing at 12 months. The main secondary outcome was rational ACT use, defined as the proportion of ACTs used by test-positive individuals. Analyses followed the intention-to-treat principle using generalized estimating equations (GEEs) to account for clustering with prespecified adjustment for gender, age, education, and wealth. All descriptive statistics and regressions were weighted to account for sampling design. Between July 2015 and May 2017, 32,404 participants were tested for malaria, and 10,870 vouchers were issued. A total of 7,416 randomly selected participants with recent fever from all 32 clusters were surveyed. The majority of recent fevers were in children under 18 years  and retail medicine outlets. Our intervention was specifically designed to reach individuals purchasing drugs over the counter and to incorporate the retail sector, which delivers the majority of ACTs in Kenya.The CHWs provided free malaria testing in the community using simple point-of-care malaria rapid diagnostic tests (RDTs) and issued a voucher to anyone with a positive test, which could be redeemed at a retail medicine outlet in exchange for a discounted ACT.The voucher allowed the ACT subsidy to be targeted only to patients with a confirmed malaria infection and created an incentive for patients to be tested by a CHW before buying a drug. Individuals with a negative test or without a test had to pay a higher price for retail ACTs.We tested the effect of this intervention on testing before treatment and correct use of ACTs in a cluster-randomized controlled trial. After 18 months, the intervention improved the proportion of fevers tested before treatment by 25% and improved the proportion of ACT dispensed to true malaria cases by 40% compared to the control arm.Making ACT subsidies conditional on the diagnostic test result could help ensure that the information from the test informs treatment.Community-based interventions that include the private sector can have an important impact on diagnostic testing and population-wide rational use of ACTs, as well as potentially improve care for the millions of suspected malaria cases seeking treatment in retail outlets. Each year, half of the 215 million cases of malaria—and hundreds of millions of cases of nonmalaria febrile illnesses—seek care in the informal health sector , 4. By 2There has been enormous global investment in publicly subsidized ACTs delivered through the private retail sector, but targeting of ACTs to those with a malaria diagnosis remains poor in this context. Malaria diagnostic testing is largely absent from the retail sector , and as There are compelling individual and public health benefits to improving targeting of ACTs. Malaria can quickly become life-threatening if inappropriately treated. The precipitous decline in malaria mortality has been attributed largely to expanding access to ACTs . On the Seventy percent of the population of Kenya is at risk for malaria . Since 2We estimate the public health impact of free malaria testing and conditional antimalarial subsidies implemented through a partnership between CHWs and the private retail sector. We conducted a cluster-randomized trial in 32 community units  across a population of more than 160,000 people . CHWs ofThe full study protocol has been published . EthicalWe conducted the study in 3 subcounties in western Kenya , which all experience moderate to high perennial transmission with seasonal peaks. More than 40% of the population of the 3 subcounties live below the poverty line .Each subcounty is divided into CUs. A CU is a geographically defined administrative unit consisting of approximately 1,000 households served by 10 to 22 CHWs who are supervised by a government-employed community health extension worker. Each CHW is assigned to specific households within their CU. All CUs with active, preexisting CHWs in each subcounty were eligible to participate in the study —were enrolled in the study, and study participants could redeem their vouchers for a discounted quality-assured AL . The price to the participant was fixed according to the age-specific dose . The CHWIn control areas, households had access to normal avenues for treatment, including government health facilities, private health facilities, and pharmacies or retail medicine outlets. CHWs continued to provide health promotion and referral services according to government guidelines as they had before the study.nth household, such that n is the sampling interval that gives the desired number of households in that cluster. Each survey represents an independent random sample, and only 1 random fever per household was included. The sampling interval and starting point were different in each wave of data collection in order to minimize the occurrence of the same household being surveyed in multiple waves. The parent or guardian of a child less than 18 years responded on their behalf. We recorded information about treatment seeking, testing, and drug consumption. Trained field researchers interviewed respondents, and information was collected via electronic forms on android tablets. Verbal informed consent was obtained from respondents who participated in the surveys.We collected individual-level study outcomes based on a population-based survey sampling strategy in order to assess the community-level impact of the testing and voucher program. We conducted repeated cross-sectional household surveys at 4 time points: baseline, 6 months, 12 months, and 20 months post baseline. The final survey was planned for 18 months post baseline, but a nationwide doctor’s strike forced a 2-month delay. Each cross-sectional survey targeted households in which at least one member >1 year of age had a fever or malaria-like illness in the last 1 month. A systematic random sampling approach was used in which the first household in each cluster was selected by starting at a random household and visiting every The primary outcome that we compare across the intervention and control arms is uptake of testing, defined as the percent of fevers in the previous 4 weeks that receive a malaria diagnostic test from any source. The main secondary outcomes are the percent of all ACTs used that were taken by people with a positive malaria test  that received a malaria diagnostic test of any type .We chose 3 secondary outcomes that are each a composite of other outcomes. Each has a different denominator and provides a different understanding of ACT use.Test adherence: Positives taking ACT or negatives not taking ACT evaluated among all individuals tested. Individuals not tested are not included. This is a measure of how people use information from a test.Targeted ACT use: Positives taking ACT or negatives not taking ACT evaluated among all fevers. Individuals not tested are included in the denominator. This is a measure of the population-level targeting of ACTs among recent fevers.Rational ACT use: The percent of all ACTs used that were taken by people with a positive malaria test. WHO defines rational drug use as when “patients receive medications appropriate to their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and their community.” [http://www.who.int/medicines/areas/rational_use/en/]. We tailor this definition to focus on the proportion of all ACTs consumed in the last month that were used “rationally” according to the results of the diagnostic test.We also report the following simple outcomes:Took an ACT after a positive test: Positives who took an ACT evaluated among all those who tested positive.Took an ACT after a negative test: Negatives who took an ACT evaluated among all those who tested negative.Took an ACT without a test: Untested individuals who took an ACT evaluated among all untested participants.Received an age-appropriate dose of ACT: Individuals who received the correct number of AL tablets based on their age evaluated among all those who took ACT. Information for this outcome was not available at baseline; therefore, we have restricted our treatment of this outcome to a descriptive analysis.Less than 2% of participants used an ACT other than AL, and none of those were quality-assured (WHO-preapproved). Therefore, we restrict our analysis to AL use.t test for the comparison of 2 proportions at a single time point under a matched design ) and absolute effects (risk differences [RDs]) to compare individual-level binary outcomes between intervention and control arms at each time point. We used the modified Poisson  approachn effect . Adjusten effect . All secn effect . Given tOwing to the repeated cross-sectional c-RCT design, we did not need to account for missing data due to attrition of study participants in order to estimate the intention-to-treat effect for the intervention. Instead, survey nonresponse may lead to nonrepresentativeness of the cross-sectional samples. The nonresponse rates did not appear to differ between arms and were overall very low (<3 per arm per survey), therefore we did not perform additional analyses to account for nonresponse . In linehttps://doi.org/10.5061/dryad.59p4111)  versus 51.9% [n = 364]; ARR 0.70; 95% CI 0.60–0.83, n = 309] versus 59.6% [n = 403]; ARR 1.40; 95% CI 1.19–1.64, n = 487) compared to 60.9% (n = 405) in the control arm  of individuals with a positive test reported taking an ACT, and 34.3% (n = 42) of individuals who tested negative also took an ACT. After the intervention, adherence to malaria test results was higher among both positive and negative cases in the intervention arm at both the 12- and 18-month follow-up survey time point, resulting in a significantly higher proportion of test adherence among those tested at 18 months  of all recent fevers used an antibiotic  of recent fevers reported taking an antibiotic , and targeted ACT use across all fevers in children was 60% higher in the intervention arm .We looked at the influence of participant age on the intervention effect for children 5 years and below, all children less than 18 years, and adults (18 years and above). There were no significant differences in treatment effects when children less than 5 years were compared to older participants. There were significant age effects when children less than 18 years were compared to adults . Age-strWe also investigated whether estimates of intervention effects differed when we restricted our analyses to those who provided documentation of their malaria test result . We saw In 2016, there were an estimated 216 million cases of malaria globally, but more than 400 million courses of ACT distributed , 41 and We designed our intervention to leverage the simple demand response—in which consumers purchase less of a good when the price is higher—rather than complex regulatory strategies to target delivery of drugs. During the study period, retail-sector ACTs in Kenya were partially subsidized by the government. In the absence of these subsidies, the price difference for those with a positive test would be even larger and potentially present a greater incentive for testing, thereby enhancing uptake of testing and rational ACT use. In our study, improved targeting of ACTs was due to a combination of modest improvements in appropriate ACT consumption by those with a malaria test and a reduction in ACT consumption by those without a test. The latter may be at least partly explained by self-selection into the tested group by participants who strongly believe they have malaria or may be more likely to use information from a diagnostic test.It is worth noting that the impact of the intervention on testing grew incrementally over time. The effect, which was small at 6 months, was large by 12 months and showed an additional improvement by 18 months. Impact on ACT consumption took even longer to emerge and was not apparent until 18 months. It is likely that targeting may have continued to improve beyond 18 months. This points to the importance of allowing sufficient time for penetration of the intervention, adoption, and positive learning experiences before evaluating the population-wide impact of community-based interventions. This is especially pertinent for interventions that seek to influence individual behavior at the community level, where individuals’ prior beliefs about the effectiveness of a new technology might take time to evolve.Our intervention approach—community-based testing coupled with a diagnosis-dependent voucher to be redeemed at a retail outlet—is a hybrid approach between that of offering RDTs in retail outlets and community case management (CCM) of malaria, in which CHWs perform RDTs and dispense free ACTs to RDT-positive individuals. In our hybrid model, we rely on the robust supply chain of the retail sector to maintain a supply of ACTs. CHWs are still responsible for the RDTs, but in case RDTs are out of stock, this does not disrupt access to ACTs. There were 3 specific goals of our intervention design: (1) create a mechanism and an incentive (in the form of the voucher) for individuals who routinely seek care in the retail sector to receive a diagnostic test, (2) target the subsidy to individuals with parasitologically confirmed malaria by means of the voucher, and (3) place the information from the test in the hands of the individual, allowing them to decide how to act on it. This third aspect is distinct from most other approaches in which the patient plays a passive role, and it is the health care worker, CHW, or shop attendant who acts on the results. Shop-based  or commuPrior to retail-sector subsidies or widespread availability of RDTs, Cohen and colleagues  offered This work has several limitations. First, we are not able to separate the effects of free testing from the voucher on uptake of testing. A similar study that deploys free testing in the absence of a conditional voucher in the control arm would be required to resolve this. Second, we were not able to continue the intervention in order to measure the long-term effects and therefore do not know the maximum possible impact that might have been achieved. Third, our outcomes are based on self-reporting by the participant or respondent. However, we stratified our analysis to include only those individuals with documentation of a test  targeting ACTs to individuals who objectively need them, (2) leveraging the effective supply chain of the private retail sector, and (3) allowing consumers without a confirmed infection to contribute more to the cost of the drug. Our results have significant policy implications. We demonstrate a high demand for malaria diagnostic testing and show that individuals use the information from a test. Moreover, these effects appear to increase over time. Scale-up of such a program would require thoughtful attention to monitoring ; however, a similar voucher program for insecticide-treated nets in Tanzania showed little evidence of abuse . In our In summary, we demonstrate that it is possible to target ACT subsidies to diagnostically confirmed malaria cases. Allocation of subsidy dollars between testing and treatment for test-positive individuals may present a better use of programmatic resources than unconditional private sector subsidies.S1 Text(DOCX)Click here for additional data file.S2 Text(DOCX)Click here for additional data file.S1 Protocol(PDF)Click here for additional data file.S1 CONSORT checklist(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 TableAL, artemether lumefantrine.(DOCX)Click here for additional data file.S5 TableRD, risk difference.(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.S7 Table(DOCX)Click here for additional data file.S8 Table(DOCX)Click here for additional data file.


Ganglionic tuberculosis is the most common extrapulmonary localization in Morocco. It is still a diagnostic and therapeutic problem especially when the infection is concomitant to the management of a cancer.Here, we report the uncommon case of a fortuitous discovery of ganglionic tuberculosis in the anatomopathological analysis of an axillary node dissection after conservative treatment of breast cancer for a 29-year-old patient without medical history. Her file was discussed in a multidisciplinary consultation meeting during which several decisions were made. We decided to start her antituberculosis treatment then after three weeks her adjuvant chemotherapy with radiotherapy and hormone therapy. Furthermore, giver her young age, she had an oncogenetic consultation. Despite difficulties of therapeutic compliance, the patient completed her cancer treatments after two years, she also cured of her tuberculosis. Being in remission, she is still on hormone therapy and consults every 3-months as part of her follow-up.Cancer and tuberculosis presenting simultaneously creates clinical and histopathological difficulties for differential diagnosis and for therapeutic decisions. Anticancer chemotherapy is not an obstacle in anti-tuberculosis treatment but the compliance of patients to receive both at the same time with the associated side effects is one to consider. According to the World Health Organization, tuberculosis is a global public health problem and about one-third of the world’s population is infected . In MoroWe hereby present the rare case of a 29-year-old white woman married for 5 years gravida 1 para 1 without significant personal or family history who found during breast self-examination a left breast mass. Then she went to a high medical center where she received breast ultrasound and a mammogram that revealed the presence of a left breast cancer classified 5 in the Breast Imaging Reporting And Data System of the American College Of Radiology, that is to say highly suggestive of malignancy (more than 95%). The radiological report noticed a mammary nodule at the level of the supero-external quadrant of the left breast of 2 cm long axis with the presence of two homolateral axillary lymphadenopathies of 1.2 cm and 0.8 cm. Then she was referred to us and admitted to the National Institute of Oncology in Rabat. The clinical examination confirmed the presence of a mobile mammary mass at the level of the supero-external quadrant of the left breast of 2 cm long, without inflammatory or cutaneous signs, nor mammalian flow, with just one mobile axillary homolateral suspicious ganglion of 1 cm.First, we performed a micro biopsy with pistol to confirm histologically the presence of the cancer which turned out to be a non-specific infiltrating carcinoma grade 3  of the Elston-Ellis modified Scarff-Bloom and Richardson staging with no intraductal component nor intravascular tumor emboli. She then had a thoraco-abdominopelvic computed tomography as part of her extension assessment, which was negative. Taking into consideration all these elements, we were able to classify the tumor cT1N1M0. We therefore decided to offer conservative treatment to the patient as soon as possible given the diagnosis of cancer at a relatively early stage, which she accepted.Three weeks later, the patient underwent lumpectomy with ipsilateral axillary dissection. The one-month follow-up showed that the wound had healed well. There was no significant complication in the short term. The histopathology report confirmed the presence of infiltrating ductal carcinoma WHO 2003) measuring 2.2 cm long axis, grade 3  of the Elston-Ellis modified Scarff-Bloom and Richardson staging, with no intraductal component nor intravascular tumor emboli, with healthy exeresis limits: non-tumorous deep plane at 0.8 cm, healthy lateral margins closest to 0.2 cm; and at the level of axillary dissection 12 N(−)/12 N. The pathological staging of the tumor was therefore pT2N0M0. On the other hand, the histological examination of the axillary dissection revealed the presence of several epitheloid and gigantocellular granulomas centred by a caseous necrosis, typical of follicular ganglionic tuberculosis. The immunohistochemical profile of the tumor could be elaborated and revealed a strong expression of hormone receptors (oestrogen and progesterone), a 30% ki67 without overexpression of HER 2. According to the genomic classification of breast cancer, we could therefore classify this tumor as a luminal tumor A [ measurinHer file was discussed in a multidisciplinary consultation meeting during which several decisions were made. First, TB case was notified and Directly Observed Treatment Short course was given.She received her anti-tuberculosis treatment with a course of 6 months according to the latest WHO recommendations of 2HRZE/4HR  [Despite difficulties of therapeutic compliance, after 2 years the patient completed her cancer treatment and she cured of her tuberculosis. Being in remission, she is still on hormone therapy and consults every 3-months as part of her follow-up.According to the American Cancer Society, breast cancer makes up 25% of all cancer diagnoses in women globally . UnfortuFurthermore, several recent studies have compared conservative with radical treatment and they have demonstrated comparable survival rates and recurrences, while conservative treatment would provide a better quality of life –10.Tuberculosis is also a global public health problem and more than 9 million new cases of tuberculosis occur each year . The diaMycobacterium tuberculosis within the macrophage of granulomas. However, in our case the fortuitous discovery of tuberculosis was earlier than any treatment and almost concomitant with the discovery of cancer itself. Its occurrence is fortunately independent, since chemotherapy could have boosted the tuberculosis spread.Calarasu et al.  reportedSafdar et al.  describeIn terms of treatment, most authors recommend starting TB treatment before initiating chemotherapy , 19. VenThe specificity of our case turns out to be the chronology of the diagnoses. Indeed, the management of the breast cancer led to the fortuitous discovery of ipsilateral ganglionic tuberculosis. The cause-and-effect relationship that has been revealed in the few studies that have examined the association between both cannot be established in our case. In fact, there is no immunodepression induced by chemotherapy or cancer itself that would explain a reactivation of latent tuberculosis. Furthermore, this turn of events allowed us to take the necessary steps, namely to start antituberculous treatment 3 weeks before starting the adjuvant chemotherapy as recommended in the literature .Cancer and tuberculosis presenting simultaneously creates clinical and histopathological difficulties for differential diagnosis and for therapeutic decisions. The authors suggest also that there is a high index of suspicion for ganglionic TB during investigation of lymph nodes in breast cancer patients, more so in LMICs/developing countries which have a high burden of TB. Anticancer chemotherapy is not an obstacle in anti-tuberculosis treatment but the compliance of patients to receive both at the same time with the associated side effects is one to consider. Education and rigorous follow-up of patients and family are necessary for a successful outcome.