Symmetry-enforced nodal-line semimetals are immune to perturbations that preserve the underlying symmetries. This intrinsic robustness enables investigations of fundamental phenomena and applications utilizing diverse materials design techniques. The drawback of symmetry-enforced nodal-line semimetals is that the crossings of energy bands are constrained to symmetry-invariant momenta in the Brillouin zone. On the other end are accidental nodal-line semimetals whose band crossings, not being enforced by symmetry, are easily destroyed by perturbations. Some accidental nodal-line semimetals have, however, the advantage that their band crossings can occur in generic locations in the Brillouin zone, and thus can be repositioned to tailor material properties. We show that lattice engineering with periodic distributions of vacancies yields a hybrid type of nodal-line semimetals which possess symmetry-enforced nodal lines and accidental nodal lines, with the latter endowed with an enhanced robustness to perturbations. Both types of nodal lines are explained by a symmetry analysis of an effective model which captures the relevant characteristics of the proposed materials, and are verified by first-principles calculations of vacancy-engineered borophene polymorphs. Our findings offer an alternative path to relying on complicated compounds to design robust nodal-line semimetals; one can instead remove atoms from a common monoatomic material. Since then, band degeneracies are featured in various physical phenomena, from signaling quantum phase transitions2 to being the spectral signature of a semimetal4. According to the non-crossing rule by von Neumann and Wigner1, energy bands generally avoid each other, but symmetries entail the possibility of band crossings. A band crossing is symmetry-enforced if its existence is guaranteed by the underlying symmetry(ies) alone, and accidental if the band crossing requires also tuning parameters of the material . A special case occurs in three dimensions where the availability of sufficiently many tunable parameters  leads to accidental band crossings even in the absence of symmetries3. Symmetry-enforced band crossings arise from nonsymmorphic symmetries (point group transformations followed by a non-primitive translation), as first realized by Michel and Zak in 19995, and later applied to the research on topological semimetals (TSMs)8.The study of degeneracies between energy bands in the spectrum of a system dates back to the early days of quantum mechanics9 and chiral anomaly10, and promise diverse technological applications, notably in topological quantum computing4 and in quantum-device designs based on proximity effects11. TSMs with accidental band crossings are topologically protected only locally, being eventually destroyed by perturbations. In contrast, TSMs with symmetry-enforced band crossings are endowed with global topological protection, i.e. they are immune to symmetry-preserving perturbations7.The nontrivial topology of band crossings in TSMs underpins a variety of phenomena, e.g. Fermi arcs12 and honeycomb-Kagome lattices13, and PbFCl-type structures14, have been predicted to realize NLSMs. However, the frailty to perturbations, particularly to spin-orbit coupling (SOC), of the resulting accidental nodal lines (NLs) hinders possible applications and use of proximity effects11. Symmetry-enforced NLSMs are the natural candidates to overcome this challenge. Predicted realizations comprise 3D materials from hexagonal groups 15, and group P4/nmm16. A recent review gathers the most recent developments in the quest for 3D NLSMs17.Here we focus our attention on nodal-line semimetals (NLSMs), the TSMs with band crossings occurring along lines in the Brillouin zone (BZ). Two-dimensional (2D) structures, e.g. hexagonal lattices18 where their robustness was conjectured to be symmetry enforced since accidental NLs had so far been known to be easily destroyed by perturbations. However, these NLs can be moved inside the Brillouin zone (BZ) by varying the parameters of the material, contradicting a known feature of symmetry-enforced NLs, namely, that they are pinned at high-symmetry momenta in the BZ. Our movable, and yet unusually robust, NLs do not fit in either. one of the two known categories of NLs: robust and fixed symmetry-enforced NLs and fragile and movable accidental NLs. We thus uncover that the usual approach to distinguish NLs by their response to perturbations is inadequate when such band crossings appear simultaneously in the spectrum and have a common origin.As an alternative to naturally nonsymmorphic 3D crystals, we propose to engineer 2D symmetry-enforced NLSMs by turning symmorphic monoatomic sheets into nonsymmorphic ones through removing atoms. Quite surprisingly, besides symmetry-enforced NLs, vacancy-engineered materials exhibit also accidental NLs which survive under very strong SOC, with strength even exceeding the experimentally attainable values. These additional NLs were first noted in our previous reportIn this work, we develop a complete theoretical description of a 2D vacancy-engineered nonsymmorphic lattice which resolves the puzzle by demonstrating that, despite their unusual robustness, the NLs which are movable in the interior of the BZ are accidental, and that symmetry-enforced NLs also exist, but are pinned at an edge of the BZ. While the accidental NLs are not directly wielded by the nonsymmorphic symmetry per se, they are a direct consequence of the proposed mechanism of attaining nonsymmorphicity out of vacancies. The fact that these accidental NLs can move and change shape inside the BZ might enable manipulation of momentum-dependent scattering processes and, hence, of various responses of the material.7 and for a 2D two-band model8. It is well-known that a glide-plane symmetry enforces band degeneracies at the glide-invariant boundary of the BZ. But whether this band degeneracy is a nodal point or a NL is not guaranteed by the glide-plane symmetry. In Refs.8 the nonsymmorphic symmetry yields nodal points located at BZ corners. In contrast, our formalism is specifically focused on symmetry-enforced NLs along an edge of a 2D BZ. This fundamental difference is connected to the roles played by inversion and time-reversal symmetries in the effective models, which depend on dimensionality and number of bands. The NLs uncovered here are to be contrasted also with those predicted for 3D nonsymmorphic materials16. Symmetry-enforced NLs in 2D thus constitute a new case of band-degeneracy enforcement. The proposed mechanism of engineering nonsymmorphic 2D lattices from periodic configurations of vacancies offers an alternative path to fundamental investigations and materials design of NLSMs.Our analysis based on a 2D four-band effective model adds to the known proofs of band-degeneracy enforcement for a 1D two-band model33. In the first reported realizations, different borophene sheets were grown on a Ag (111) substrate through electron beam evaporation23 and molecular beam epitaxy24. Subsequent developments in the growth and stabilization of borophenes were compiled in a recent review 32. It reports a wealth of experimentally realized boron 2D lattices with periodic distributions of vacancies, and the agreement between first-principles predictions and experimental realizations for various vacancy concentrations. We can thus expect different robust NLSM-designs using borophene as a base material. Here we propose and investigate the two stable borophenes shown on Figure pmg nonsymmorphic wallpaper group34, feature periodic patterns of vacancies which are similar to the ones experimentally obtained in Ref.24.As a concrete example, we illustrate our idea in borophene, a 2D lattice of boron atoms. The character of boron bonding—with short covalent radius and possibility of mentclass2pt{minimPristine borophene without any vacancies is a symmorphic material; it possess two perpendicular reflection planes which entail the appearance of accidental Dirac cones in the spectrum, akin to those in graphene, silicene and germanene. Introducing vacancies at proper concentrations and configurations in pristine borophene yields that one of the reflection planes is replaced by a nonsymmorphic glide plane  (c (c\documthat Eq.  implies entclass1pt{minimat’s given in arbitrary units). The bands touch pairwise at some value of 6 shown on the left for comparison. Including higher-order hopping in Eq.  on onS11) oentclass1pt{minimaI isI in the basis constructed by the eigenstates of I from the center of the unit cell along the The invariance relation representing the symmetry of the lattice with respect to the inversion-point transformation entclass1pt{minimaI-symmetry implies that these hopping parameters must be real; c.f. Sect. 18, where the inversion-point combines with a last local constraint on the Hamiltonian to generate NLs at G and I imply R (c.f. Sect. 3 of the Supporting Information). Therefore, it is sufficient to analyze the constraints imposed by G and I on the band structure.Combining the constraints imposed by Eq.  with thoentclass1pt{minimaT, not considered in Ref.18 , the invariance relation is given byTurning to the time-reversal transformation Imposing Eq.  implies entclass1pt{minima18, to come from symmetry enforcement. The framework developed here conclusively resolves this puzzle and identifies the origin of such unusually robust, yet accidental, NLs.Here we discuss another feature of the band structure which is special to our scheme of engineering a nonsymmorphic symmetry out of vacancies: The appearance of unusually robust accidental NLs in the interior of the BZ. Accidental band crossings are usually very fragile to perturbations or change in material parameters. The appearance of NLs inside the BZ which survived extremely strong SOC and magnetic exchange field  was initially conjectured, in Ref.In a pristine monoatomic lattice in which the distance between neighboring atoms is the same in all directions (such as borophene), the hopping amplitudes are direction-independent. In such an isotropic environment , the crossings between energy bands are the ones associated only to the symmetries, as we have seen in the previous sections. Defects (including vacancies) break the isotropy of the hopping amplitudes, with the result that now bands can cross also in generic places of the BZ. For the particular band structure shown in Fig. We conclude that a nonsymmorphic 2D material created by vacancy-engineering possesses symmetry-enforced NLs at one edge of the BZ originated from a glide-plane symmetry , and also accidental NLs with enhanced robustness in the interior of the BZ from the vacancy-induced anisotropy and time-reversal symmetry.Figure Rashba SOC preserves the crystalline symmetries, as well as time-reversal symmetry. The NLs featured in the dispersions, shown in Fig. 18. These materials thus possess symmetry-enforced NLs and unusually robust accidental NLs in the spectrum. It is worth mentioning that the proposed structures fall within the stability range reported in Ref.22, x is a measure of concentration of vacancies.We note that the phenomena uncovered here are not exclusive to BWe have shown how vacancy-engineering turns a monoatomic symmorphic 2D material into a nonsymmorphic one with a glide-plane symmetry. By carrying out a symmetry analysis and applying it to an effective model, we have demonstrated that the synthesized glide plane enforces two pairs of nodal points in the spectrum of the material. When the glide-plane symmetry is combined with inversion-point and time-reversal symmetries, the nodal points of each pair are connected through enforced NLs pinned at one edge of the BZ. We have also uncovered anisotropy-induced accidental NLs which can be moved around in the interior of the BZ by varying the anisotropic parameters, an interesting and potentially very useful byproduct of introducing vacancies.32, another reason for choosing borophene as our test-material is the possible implications for topological superconductivity. Indeed, for an efficient braiding or fusion of Majorana states, necessary to utilize their non-Abelian statistics in topological quantum computing38, it is important to have a 2D topological superconductor. Such a 2D realization overcomes the need for fine-tuned material parameters to realize topological superconductivity in commonly studied 1D systems41, besides removing the 1D geometrical constraint, by that enabling braiding and fusion43. Since boron becomes superconducting when squeezed, fascinating prospects are thus opened starting from a borophene-made NLSM and enhancing its superconductivity by proximity effects and/or pressure. Finally, borophene is flexible and transparent, which might also encourage technological applications of our proposal.DFT results for vacancy-engineered borophenes confirm the analytical predictions for the enforced NLs, and also convey that these materials have accidental NLs inside the BZ which survive under very strong Rashba SOC and intrinsic SOC. This enhanced robustness is consistent with an anisotropy-origin, and should be contrasted to the usual frailty of common accidental NLs. Besides the availability of various already realized borophenes with periodic distributions of vacancies11, at the same time that the ability to move the NLs might, conceivably, affect momentum-dependent scattering processes, or even suppresses them, which can be used to manipulate various susceptibilities of the material. Some guidance in such a design of nodal regions can be inferred from the example of unconventional superconductors: The change in the BZ location of the gap closing modifies the electric, magnetic, thermal, and optical responses of the material48. For example, in addition to the common Meissner effect, which is linear in the applied magnetic field, the presence of NLs is responsible for the nonlinear Meissner effect, whose angular dependence can then be modified by changing the position of the NLs. The presence of NLs and their location can be probed through the higher-harmonic generation for an applied harmonic magnetic field50. Finally, our proposal relies only on crystal symmetries, being applicable to general 2D materials, and possibly also to 3D materials51. The basic principle of creating a nonsymmorphic symmetry by introducing vacancies in a symmorphic crystal offers fresh opportunities for fundamental and applied research on NLSMs.For possible applications, enhanced robustness of the accidental NLs is particularly desirable. An accidental NL which is robust across the experimentally available ranges of perturbations’ strengths is at least as good as a symmetry-enforced one, with the advantage that the former can be moved around in the BZ. In fact, the enhanced robustness would allow the resulting NLSM to survive strong perturbations while being modified by various proximity effects52. The kinetic energies cutoff for wave function (ecutwfc) and for charge density (ecutrho) are set to 600 and 60 Ry, respectively. Perdew, Burke and Ernzerhof (PBE) form of the generalized gradient approximation (GGA) is adopted for the exchange-correlation energy53. Numerical integrations in the Brillouin zone are evaluated with the Monkhorst-Pack mesh of The band structures of B54. This maps the ground-state wave functions from the density functional theory output file onto a maximally localized Wannier function basis To incorporate Rashba SOC, we develop a tight-binding (TB) model using the package Wannier90k-mesh strategy to build the TB Hamiltonian, We employ an adaptive p the momentum, s at site i, i and j in the lattice, 55.Borophene BSupplementary Information.


The first cases of COVID-19 infection were reported as pneumonia of unknown cause in China in December 2019. While respiratory complications remain the hallmark of the disease, multisystem involvement has been well documented. Cardiovascular involvement with potentially lethal myocarditis has been extensively reported in the literature. Reports of conduction system disturbances are much rarer, especially in patients without other signs of cardiac involvement. We present a case of an 88-year-old male with no prior cardiac history who presented to the hospital with obstipation. He was diagnosed with a small bowel obstruction and underwent a lysis of adhesions. During the hospitalization, he developed intermittent bradycardia with a high-degree atrioventricular (AV) block. A decision was made to implant a permanent pacemaker. During a pre-procedure COVID-19 screen, he was found to be positive for the presence of SARS-CoV-2 RNA. He had no signs of myocardial injury, a transthoracic echocardiogram showed no abnormalities, and he remained free of any respiratory symptoms. While the involvement of the cardiac conduction system has been documented in patients with symptomatic COVID-19 infection, our patient only exhibited conduction abnormalities and remained free of other COVID-19 symptoms. The sole involvement of the conduction system by COVID-19 is rare, especially in patients with otherwise asymptomatic infections. There is no long-term data to suggest whether such conduction abnormalities are temporary or permanent. As such, patients might benefit from the implantation of a permanent pacemaker. The first cases of COVID-19 infection were reported as pneumonia of unknown cause in Wuhan City, China, in December 2019 . Dagher An 88-year-old male with a past medical history of hypertension, diabetes mellitus, and hyperlipidemia presented to the hospital with a five-day history of obstipation.The patient was ultimately diagnosed with a small bowel obstruction due to intestinal adhesions. As a part of a routine preadmission assessment, the patient was tested negative for the presence of SARS-CoV-2 RNA using a nasopharyngeal swab. His admission electrocardiogram (ECG) revealed a normal sinus rhythm with normal PR 188 ms) and QRS (86 ms) intervals without acute ST-T abnormalities  and no regional wall motion abnormalities to suggest ischemic heart disease. The patient did not receive any medications with known negative chronotropic effects.At his six-month follow-up visit after the pacemaker implantation, the patient reported no symptoms of dizziness or syncope. His 12-lead ECG demonstrated an atrial-sensed, ventricular-paced rhythm with a PR interval of 274 ms Figure . His devWe present a case of a patient with COVID-19 who developed recurrent paroxysmal high-degree AV block necessitating implantation of a permanent pacemaker. The cardiovascular effects of SARS-CoV-2 have been well documented in critically ill patients. Our patient did not exhibit any respiratory symptoms attributable to COVID-19. He had two troponin I levels eight days apart within the normal reference range. His transthoracic echocardiogram was unrevealing with a normal LVEF and no regional wall motion abnormalities. The telemetry strip and an ECG demonstrated a 2:1 AV block without an associated decrease in sinus node activity, suggesting an AV nodal rather than a vagus nerve involvement. In our patient, whether the AV block was permanent or temporary was uncertain, driving the decision to implant a permanent pacemaker. The pacemaker was interrogated six months later, demonstrating the patient to be ventricularly paced 59% of the time despite the paced and sensed atrioventricular delay being set to >250 ms.Given that the patient remained asymptomatic during the episodes of bradycardia, we cannot exclude the possibility of latent AV block before the discovery on telemetry. However, given no signs of bradycardia during the first six days of hospitalization, followed by frequent episodes of high-degree AV block, conduction disturbance can be attributed to the newly acquired SARS-CoV-2 infection.At present, data regarding the involvement of the cardiac conduction system by SARS-CoV-2 is limited, especially in patients with asymptomatic infections. It is unclear whether these disturbances are permanent or temporary. As such, implantation of permanent pacemakers may be warranted as demonstrated by the prolonged pacing requirement in our patient.


COVID-19, was declared a pandemic by World Health Organisation on March 11, 2020. Older people with dementia or those with multimorbidity are more vulnerable to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the development of COVID-19. Given absence of a vaccine or treatment, prevention is the fundamental aspect of COVID-19 control. This requires early identification of contagious people with COVID-19 and isolation keeping them apart from non infected group of people. Early identification of infection in elderly with dementia or functional psychiatric condition is often difficult, due to difficulty in obtaining history or evaluating medical symptoms.1) To establish the current standards of interventions provided at the unit to control COVID-19, with current recommendation by Government guidance. 2) To address difficulties in early identification of people of COVID-19 in Old Age Psychiatry wards. 3) To introduce sustainable interventions aimed at controlling COVID-19 risk, targeted to this group.Trust guidance for COVID-19 testing on the ward and guidance of isolation were reviewed. Literature review of currently available scientific evidence for testing for controlling COVID-19 was conducted.We have created a bi-weekly mass testing guidance for Old Age Psychiatry inpatient wards with clear guidane of when to start isolation and when to stop isolation.There is no specific interventions to target older adult within our service currently and it was felt that it is necessary to develop a sustainable mass testing programme for this group of people for control of COVID-19.


Background: Medical image processing tasks represented by multi-object segmentation are of great significance for surgical planning, robot-assisted surgery, and surgical safety. However, the exceptionally low contrast among tissues and limited available annotated data makes developing an automatic segmentation algorithm for pelvic CT challenging. Methods: A bi-direction constrained dual-task consistency model named PICT is proposed to improve segmentation quality by leveraging free unlabeled data. First, to learn more unmarked data features, it encourages the model prediction of the interpolated image to be consistent with the interpolation of the model prediction at the pixel, model, and data levels. Moreover, to constrain the error prediction of interpolation interference, PICT designs an auxiliary pseudo-supervision task that focuses on the underlying information of non-interpolation data. Finally, an effective loss algorithm for both consistency tasks is designed to ensure the complementary manner and produce more reliable predictions. Results: Quantitative experiments show that the proposed PICT achieves 87.18%, 96.42%, and 79.41% mean DSC score on ACDC, CTPelvic1k, and the individual Multi-tissue Pelvis dataset with gains of around 0.8%, 0.5%, and 1% compared to the state-of-the-art semi-supervised method. Compared to the baseline supervised method, the PICT brings over 3–9% improvements. Conclusions: The developed PICT model can effectively leverage unlabeled data to improve segmentation quality of low contrast medical images. The segmentation result could improve the precision of surgical path planning and provide input for robot-assisted surgery. Preoperative pelvic Computed Tomography (CT) segmentation is a key technology in computer-assisted surgery and minimally invasive surgical robot navigation ,2,3,4,5.However, developing an automatic segmentation algorithm for soft and hard tissue of pelvic CT faces many challenges. The major challenge is the similarity of gray-scale features and local texture between tissues. As shown in In the past years, the convolutional neural network (CNN), with its strong non-linear modeling capability  and captAn alternative solution to reduce the labeled data burden is the semi-supervised learning (SSL) method . In receA bi-directional constrained dual-task consistency method is proposed; the PICT enhances the ability to learn data features by resisting subtle differences at pixel, model, and task level, and can effectively capture and infer the tissue semantic feature in the low contrast area of pelvic CT.A pseudo-supervision module was designed as an auxiliary supervision task to learn the underlying information of original unlabeled data without perturbations, so as to constrain some false predictions of interpolation.A multi-object pelvic dataset annotated by experts was developed, which contains 100 CT and subdivides the muscles, tissues, and bones with extremely low contrast into seven categories. PICT achieves state-of-the-art performance in three challenging medical datasets: ACDC, CTPelvic1k, and the individual dataset Multi-tissue Pelvic.Specifically, the proposed interpolation-based pseudo-supervision (PICT) consists of two consistency tasks: the interpolation consistency task and the pseudo-supervision task. The former task encourages the teacher model predictions of pairwise unlabeled interpolation data to be consistent with the student model interpolation prediction of unlabeled data, which is a pixel-level and model-level consistency. The latter task utilizes the unlabeled predictions of the teacher model as pseudo-labels to conduct supervision on student unlabeled outputs and further encourages consistency between the two network predictions, which is both the model-level and task-level consistency. The two joint tasks act in a complementary manner and successfully tackle both low-contrast tissues and high-similar feature problems. The contributions of this paper are summarized as follows:The SSL method can be roughly grouped into four categories: adversarial learning method, self-training method, co-training method, and consistency regularization method .The adversarial method is a process in which two networks compete against each other . One is The self-training method usually uses a pre-trained model to generate pseudo-labels of unlabeled data to expand the limited labeled dataset and then train the model until the performance improvement can be ignored . HoweverThe co-training method usually trains two models with different initializations simultaneously and encourages them to take each other’s predictions as pseudo-supervision signals ; ref. 2 put forwThe consistency regularization method follows the assumption that the predictions of the same input should be consistent, which is a method of expanding dataset and avoiding overfitting through technical means, such as noise perturbations , data auHowever, the existing consistency methods basically enforce consistency on the unlabeled perturbations data, and do not make use of the original unlabeled data structure characteristics. The main disadvantage is that some perturbations may not be in the adversarial direction, in which the network is liable to misclassify the pixels, leading to the loss of generalization ability ,35. ThusThe overall framework is illustrated in function  as a balThe supervision part conducted the combination of pixel-wise Dice Loss , . α and β are the hyper-parameters of the interpolation factor, which controls the strength of interpolation between data pairs; The interpolation task considers two unlabeled image data-point and interpolates the two unlabeled image data-pointt with β , followit with β  so that To resist the feature interference caused by some interpolation perturbations, an auxiliary task of pseudo-label supervision was introduced to focus on the feature structure of the original data without perturbations:This section introduces information about the test datasets: Multi-tissue Pelvic dataset, CTPelvic1k dataset , and AutTo evaluate the anatomical segmentation performance of proposed PITC methods for pelvic CT, 100 slices with the size of 512 × 512 pixels from the total of 6251 slices were randomly selected to form the Multi-tissue Pelvic dataset. The window width of all slices was set to 60 HU, the window level was set to 500 HU, and then a median filtering algorithm was used to reduce noise. Under the medical annotation software Pair, seven categories in each slice were manually delineated by three experienced radiologists. The seven categories were background, miscellaneous intra-pelvic content (MIPC), bone, muscle, subcutaneous adipose tissue (SAT), inter-muscular adipose tissue (IMAT), and intra-pelvic gas (IPG). An authoritative radiologist finally checked the labeled data to minimize the individual errors.In the preprocessing phase, the image edges were randomly cropped according to pelvic region of ground-truth, randomly splitting the Multi-tissue Pelvic dataset into 80 images for training, 15 images for testing, and 5 images for validation.The CTPelvic1k dataset comes from a public pelvic 3D CT dataset. Selecting the first 70 pelvic fracture CT from subset-6 with mean size of 512 × 512 × 345 voxels to form the dataset. The pelvic regions were annotated as five categories in the ground-truth: background, sacrum, left hip (LH), right hip (RH), and lumbar spine (LS). A random 50 CT were assigned to the training set, 10 to the validation set, and 10 to the test set. Finally, a centering crop was used to reduce the size of the 3D CT volume..The ACDC dataset is hosted in MICCAI 2017 open challenge and contains of 200 3D short-axis MRI scans from 100 patients, along with the expert annotations for three cardiac regions: myocardium (Myo), left ventricle (LV), and right ventricle (RV). Following existing work , this exFor all experiments on the same dataset, the U-Net  model wa−4 and a poly-learning rate strategy with an initial learning rate of 0.01. The hyper-parameter All the experiments were implemented with PyTorch under an NVIDIA GeForce RTX 3090 and trained by the Stochastic Gradient Descent (SGD) optimizer with a momentum of 0.9 and weight decay of 10t to 0.2 . For semTo alleviate the over-fitting of networks, we employed the random flip, rotation data, and random clipping augmentation techniques ,42. The To quantitatively evaluate the segmentation performance, the experiments followed the two commonly used complementary evaluation metrics for the ACDC dataset:  as HD95 ,21,38.For the CTPelvic1k dataset, experiment performances are evaluated by using the region based metrics For the Multi-tissue Pelvic dataset experiments, the three metrics used include Under the experimental setup with a batch size of eight and three labeled samples, two evaluation metrics are shown in From the experiment results, the PICT with the best DSC score outperforms all the related works. The diagram illustration of the related work is shown in The second section discusses the influence of pseudo-loss function. The experiment results show that when using the same CE loss as CPS, the optimization effect is not apparent, as shown in PICT (CE). When the PICT (CE + Dice) uses such a supervised loss manner in the combination of CE loss and Dice loss as the pseudo-supervision loss, the performance of Taking the examples of seven labeled cases, three common models  , Mean TeAs shown in The blurry edges caused by fracture are the major challenge for the accurate segmentation of pelvic CT. In order to investigate the performance of the proposed technique, we set three comparisons with different labeled levels on the fracture dataset CTPelvic1k, as seen in The 3D visualization of the segmentation results is convenient for doctors to know the fracture types at a glance. This paper further studied the segmentation performance of the proposed method on Multi-tissue Pelvic. To demonstrate superiority, this section quantitatively studied the performance under different labeled ratios; the mean ork with , which aTo further investigate the feasibility of the proposed method, the comparison of each category’s performance with 40 labeled as an example are listed in The proposed algorithm improves consistently over almost every category under every labeled–unlabeled ratio. The segmentation performance results show the ability of PICT in 2D pelvic CT analysis with multi tissues.Finally, we list the time spent on three datasets during training processes in Based on the above quantitative and qualitative results, it can be found that PICT achieves state-of-the-art performance and efficiently reduces the costs of medical image research. The ablation experiments on the open ACDC dataset showed that the combination of the interpolation module and pseudo-supervision module is effective. The pseudo-supervision module can constrain some ineffective interpolation perturbations where pixels are prone to misclassify. The data augmentation of pixel interpolation can make up for the unstable quality of the pseudo-label. This idea is also confirmed on two pelvic datasets: CTPelvic1k and Multi-tissue dataset.Facing medical image segmentation with different types and tasks, the PICT proposed in this paper still has certain advantages. These results show that the proposed method is progressive and generalizable. This has clinical significance for exploring pelvic data analysis and other medical data analysis.However, the proposed PICT also has a limitation. Manually annotating a multi-tissue 3D pelvic CT dataset is associated with difficulties, even when training in a semi-supervised manner. In future work, we plan to develop a 3D pelvic dataset containing multiple tissue and organs. For the semi-supervised model, we plan to automatically balance the weights of the interpolation consistency part and pseudo-supervision part.This paper proposed a bi-direction constrained dual-task consistency semi-supervision method named PICT for few-label medical images, consisting of an interpolation consistency regularization task and a pseudo-supervision task. It can leverage free unlabeled data to capture more tissue semantic feature in the low contrast area and is sensitive to fracture margins with low time cost. The experiments on ACDC 2018, CTPelvic1k, and Multi-tissue datasets proved that the proposed PICT achieves state-of-the-art performance in comparison to the latest semi-supervised methods. This model can be used to visualize the anatomical morphology of soft hard tissue in computer-assisted surgery and can promote some automatic operations such as automatic path planning and postoperative evaluation, which is of great significance to promoting the application of machine learning in the clinical treatment of pelvic fractures.


Pre-vaccine SARS-CoV-2 seroprevalence data from Germany are scarce outside hotspots, and socioeconomic disparities remained largely unexplored. The nationwide representative RKI-SOEP study  investigated seroprevalence and testing in a supplementary wave of the Socio-Economic-Panel conducted predominantly in October–November 2020. Self-collected oral-nasal swabs were PCR-positive in 0.4% and Euroimmun anti-SARS-CoV-2-S1-IgG ELISA from dry-capillary-blood antibody-positive in 1.3% . Seroprevalence was 1.7% (95% CI 1.2–2.3%) when additionally correcting for antibody decay. Overall infection prevalence including self-reports was 2.1%. We estimate 45% (95% CI 21–60%) undetected cases and lower detection in socioeconomically deprived districts. Prior SARS-CoV-2 testing was reported by 18% from the lower educational group vs. 25% and 26% from the medium and high educational group . Symptom-triggered test frequency was similar across educational groups. Routine testing was more common in low-educated adults, whereas travel-related testing and testing after contact with infected persons was more common in highly educated groups. This countrywide very low pre-vaccine seroprevalence in Germany at the end of 2020 can serve to evaluate the containment strategy. Our findings on social disparities indicate improvement potential in pandemic planning for people in socially disadvantaged circumstances. In spring 2020, case counts in Germany were relatively low, but the proportion of the population infected was supposed to be much higher due to asymptomatic or mild symptomatic cases that might not have been captured by the predominantly symptom-triggered testing. The seroprevalence of SARS-CoV-2 became of high interest since it can be used to estimate the prevalence of past infection in a population, including unrecognized infections or infections that were not confirmed by RT-PCR testing. The seroprevalence is not a perfect estimate of the proportion which already had contact to the virus and is thus likely to have some degree of immunity, but it is the best estimate available at the population level. Seroepidemiological studies are also an important empirical input for analyses and predictions of the pandemic using mathematical models. One of the first highly publicized seroepidemiological studies worldwide was carried out in the small German hotspot of Gangelt2. This study reported that 16% of the Gangelt population had been infected by early April 2020 and concluded that undetected cases account for about 80% of total cases. Several studies from other hotspot areas in Germany reported a SARS-CoV-2 seroprevalence around ten percent in the spring and summer 20204. Although far from representing the German population, these initial reports of high seroprevalence in local hotspots raised the expectation of an already high, albeit unknown, nationwide proportion of the population with antibodies against SARS-CoV-2. In contrast, a still low seroprevalence outside hotspots was suggested by testing blood donors6 and by a population-based cohort from the city of Bonn, which all showed a SARS-CoV-2 IgG seroprevalence below one percent by June 20207. In line with this, a study conducted in Munich, in the more highly affected south of Germany, found that seroprevalence by the beginning of summer was at only 1.8%8.The first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Germany was reported on January 27th 2020. In line with the National Pandemic Response Plan, early on in 2020 testing capacities were improved, a containment strategy with regulations on physical distancing and movement as well as closures of daycare facilities, schools and in the retail sector were establishedTo obtain national estimates of cumulative SARS-CoV-2 infections in Germany in the late fall of 2020, the Robert Koch Institute (RKI) initiated a large nationwide study as part of its seroepidemiological studies program CORONA MONITORING. In recognition of the importance of the socio-economic determinants and consequences of the pandemic, the nationwide RKI-SOEP study was based on the dynamic cohort German Socio-Economic Panel (SOEP). The SOEP provides a representative picture of the population living in private households in Germany and offers comprehensive longitudinal data on the sociodemographic background and the living conditions of its participants.to estimate the SARS-CoV-2 infection prevalence and antibody seroprevalence,to estimate the proportion of undetected cases,to examine the frequency of and occasions for SARS-CoV-2 testing andto investigate demographic and socioeconomic disparities in these aspects among the adult population in Germany before vaccination rollout, which began in January 2021.The aims of the present analysis of the RKI-SOEP study are.9. In brief, the study methods were guided by the World Health Organization protocol for population-based age-stratified seroepidemiological investigations for coronavirus 2019 (COVID-19) infection10. The study was designed as an extraordinary wave of a dynamic population-based cohort study, the Socio-Economic Panel (SOEP). The SOEP is a nationwide longitudinal multidisciplinary household survey. Due to its two-stage sampling design , which also takes into account the socio-demographic structure of the population , the SOEP allows for representative statements about private households in Germany. In this study, persons in private households have been asked annually about a variety of topics since 1984. These include socio-demographic characteristics, income, labor market participation and family situation, health, and their basic orientations, concerns and satisfactions. Adults from the entire SOEP gross sample in 2020  were invited to participate in the RKI-SOEP study. This gross sample covers all 401 districts in Germany. Approval was obtained from the ethics committee of the Berlin Doctors’ Council (reference ID Eth-33/20). The RKI-SOEP study was carried out in accordance with the Declaration of Helsinki. All participants provided informed consent.The study design, its population and recruitment of participants are described in detail in the study protocol9. Study participants were asked to take several dried blood spots (DBS) by capillary finger prick and an ONS9. Both samples were sent by mail to the RKI. From ONS, RNA was extracted with the QIAamp Viral RNA Mini Kit  and tested by real-time reverse transcription polymerase chain reaction (PCR), targeting the E gene and the orf1ab region of SARS-CoV-211. The PCR was regarded positive when both targets tested positive. Standardized punches of DBS  were extracted according to the manufacturer’s protocol  and tested for SARS-CoV-2 anti-S1 IgG antibodies using lots E200518BC  and E200831BC  of the Anti-SARS-CoV-2-ELISA (IgG) . For defining seropositivity, the ratio cutpoint provided by the manufacturer was adapted from 1.1 to 0.94 for DBS testing , a self-sampling kit for an oral-nasal swab (ONS) sample for PCR testing, illustrated instructions and a link to video material on self-sampling and Frequently Asked QuestionsSelf-reported questionnaire information on pre-study SARS-CoV-2 testing refers to tests based on nasal or oral swabs, excluding self-tests. By excluding self-tests and since antigen tests became more widely available only at the end of the study period, we assume that these positive test results refer to PCR tests and hence to notified cases. Participants reporting a positive test are thus described as having “notified infections” in this paper, participants reporting a negative or no test have “unnotified infections”. The overall infection status was considered positive if at least one of the three indicators  was positive. It was considered negative when all available results were negative. At least one of the three indicators had to be available; sensitivity analyses requiring complete data yielded similar results.12. This is a composite index of area-based socioeconomic indicators, measuring relative deprivation in the domains of education, employment and income. The GISD was classified into low (quintile one), medium (quintiles two to four) and high (quintile five) deprivation12.Household composition was classified based on the total number of household members and, for participants aged < 60 years, whether or not there were children ≤ 16 years living in the household. Socioeconomic position was assessed by the participants’ individual school education and by regional socioeconomic deprivation at the participants’ place of residence. School education was classified as low , medium  or high , which was available from previous SOEP waves. Regional socioeconomic deprivation was measured at the level of Germany’s 401 districts using the German Index of Socioeconomic Deprivation (GISD)Due to the relatively small number of seropositive participants, it was not feasible to perform a regional stratification by federal state. Therefore, place of residence was classified into four incidence strata by grouping districts with a similar temporal pattern of notified SARS-CoV-2 cases, as described in Supplement 13.Unless stated otherwise, all analyses are weighted to allow generalizing the findings to the adult population in Germany and to counteract non-response bias. For example, smokers and persons with non-German nationality participated significantly less often than non-smokers and persons with a German nationality. The weighting factors result from complex modelling of contactability and participation probabilities. A total of about 400 characteristics at the person and household level (taken from previous waves of the SOEP) were reviewed for inclusion in the different weighting steps. The characteristics reviewed include socio-demographic characteristics, characteristics on health status, housing situation and attitudes . Furthermore, the weights were calibrated to national statistics at the person level (age and gender distribution of adult persons in private households) and at the household level . The sampling and weighting have been described in detail14 using the initial values described in Supplement Descriptive analyses include absolute frequencies, unweighted proportions and population-weighted proportions, overall and stratified by sex, age group, household composition, school education, district incidence stratum and the regional socio-economic deprivation index. IgG seroprevalence was corrected for test characteristics (i.e. sensitivity and specificity)15, in order to account for weighting and for within-household correlation. The CIs were calculated on the logit scale and then back-transformed. p-values for global F-tests were obtained using the Rao-Scott approximation as implemented in standard procedures for survey data analysis15, again to account for weighting and within-household correlation. CIs for the seroprevalence with correction for test characteristics were derived by transforming the uncorrected confidence limits according to the correction formula14, ignoring the variability in the estimates of sensitivity and specificity.We calculated 95% confidence intervals (CI) for proportions using cluster-robust standard errors (with the household as cluster) as implemented in standard procedures for survey data analysis15. The table shows the odds ratios in comparison to a reference category with their 95% CI and the p-value for the global test of each variable. The model included all stratification variables mentioned above, plus date of study participation (as a linear variable) and sampling batch. Age was included as a natural cubic spline. Analyses were performed with SAS 9.4 .For infection status as a target variable Table , we fit The number of infections missed by the mandatory notification system was estimated in two ways: first by looking at the proportion of seropositive cases with an unnotified infection (according to self-reports) in our study sample Table , and secFigure 16). DBS specimens yielding valid laboratory test results were available from 14,781 participants  and ONS from 97.1% of participants. Questions on pre-study SARS-CoV-2 testing (PCRpre-study) were answered by 98.6% of participants. The study sample included 146 participants with a self-reported pre-study positive SARS-CoV-2 test.According to the nationwide sampling design, 31,675 adults from 19,569 households were invited to participate in the study and 15,122 adults aged 18–99 years, 54% women, from 9781 households in 400 districts participated as shown in Fig. We compared the observed and the expected proportion of self-reported laboratory-confirmed COVID-19 infections, and they were rather similar ; Table We estimated a very similar proportion of undetected cases of 45% (95% CI 21–60%) in a separate analysis which compared the cumulative incidence of notified cases in Germany, sampling-density adjusted as described in Supplement A quarter of participants reported at least one SARS-CoV-2 test prior to the study  Fig. . These t17. We estimate that in this first year of the pandemic, approximately a quarter of all adults had at least one SARS-CoV-2 test and that slightly more than half of SARS-CoV-2 infections have been detected and notified. Corresponding with our finding that testing for SARS-CoV-2 was more common among more advantaged socioeconomic groups, we found a higher rate of undetected cases among residents in socioeconomically deprived districts.This nationwide SARS-CoV-2 seroepidemiological study (RKI-SOEP study), among adults in private households in Germany, shows that by November 2020 only about two percent of adults in Germany had a SARS-CoV-2 infection. This finding expands on an early analysis of the RKI-SOEP data which estimated a nationwide seroprevalence of 1.3% in adults but had not yet accounted for test characteristics and antibody decay over time18. Mostly, these were regional or local studies. The Rhineland study, testing from April to June 2020, found a seroprevalence of less than one percent in two districts of the city of Bonn7, the STAAB-COVID program (June to mid-October) a seroprevalence of 1.3% in the city of Würzburg19, and the KoCo-19 study representative of Munich showed 1.8% in the first (April to June 2020) and 3.3% in the second round (November to mid-December)20. In the SaarCoPS study (until mid-October 2020), which is representative for the federal state of Saarland, the seroprevalence was around 1%21. The MuSPAD study showed prevalences between 1.3 and 2.8% in different German regions between July and December 202022. Of note, Munich, Saarland and some of the MuSPAD study locations tend to be more severely affected regions. There is only one Germany-wide study besides ours, Corona-BUND (August to mid-November 2020), with a seroprevalence of about 1% in the adult population. In its first round (July to August 2020), the study estimated that there were 1.8 times as many infections as reported by health authorities23. While first local seroepidemiological studies in Germany, which were mainly conducted in hotspot areas, indicated underascertainment ratios of four to five26, starting with the second half of 2020 underascertainment ratios were lower, in the majority of studies underascertainment was around two31. The Robert Koch Institute as the national Public Health Institute systematically tracks seroepidemiological studies in the general population as well as in special population groups conducted in Germany (http://www.rki.de/covid-19-serostudies-germany). Internationally, Germany can be classified among the countries with low seroprevalence in 2020, similar to Norway 32, Denmark 33, and, earlier, Iceland 34. Somewhat higher seroprevalences were found in nationwide population studies in Slovenia 35, Spain 37, the Netherlands 38, and England 39 and a much higher seroprevalence of 28% in October–November was estimated for the Czech Republic40. In Norway, the estimated ratio between seroprevalence and cumulative incidence was 1.132, the study from Iceland showed a ratio of 1.834, and the Danish study a ratio of six in May and two in December33. There is a wide range of response rates among these nationwide studies, with higher rates e. g. in the Spanish (75%) and the Slovenian (47%) and lower in the Norwegian (30%) and the Dutch study (21%). A recent systematic review of seroepidemiological studies worldwide with search between January and December 2020 showed an overall seroprevalence of 4.5%, the estimates being a median of 18.1 times higher than the corresponding SARS-CoV-2 cumulative incidence41.Our results on the low pre-vaccine SARS-CoV-2 seroprevalence in Germany are in line with other seroepidemiological studies based on random samples from the general population in Germany—not including hotspot studies—up to November 2020, which also indicate relatively low seroprevalence rates44. A previous analysis of our RKI-SOEP data used information on vocational and academic qualifications in addition to the level of secondary school graduation  to assess the participants’ educational level, and found higher SARS-CoV-2 seropositivity in adults with lower education17. Taking this finding together with our present result that secondary school education alone was not associated with seropositivity, it can be suggested that professional education  is more crucial for the risk of infection than secondary school education. Occupational working conditions may be an important mediator in this relationship. For instance, lower-skilled workers in essential jobs may have had fewer opportunities to reduce occupational contact and mobility by working remotely during the pandemic than highly qualified academics45. In this context, area-based patterns of infections need to be considered, as well. Previous ecological studies from Germany showed that notified SARS-CoV-2 infections shifted from more affluent districts at the very beginning of the pandemic to socioeconomically deprived districts in more advanced stages of the pandemic47. Especially in the second pandemic wave, accordingly, Germany’s most deprived districts had the highest rates of notified infections46.With regard to social disparities in infections with SARS-CoV-2, previous findings from national seroprevalence studies in the pre-vaccine era of the pandemic are inconsistent and sometimes contradictoryThe strengths of the RKI-SOEP study include the nationwide sampling covering 400 out of 401 districts in Germany, the embedding in a long-standing dynamic cohort with ample data that allows for sophisticated weighting and thus higher generalizability to the adult population, the high response rate, the user-friendly self-sampling methods accompanied by methodological studies for cutpoint adjustments and the perspective of a longitudinal follow-up. However, we could not include persons with limited German language skills, nor persons who are not community-dwelling (e.g. living in elder care homes). We assume that among community-dwelling adults those severely ill and multimorbid were less likely to participate, and we see some under-representation of persons with pre-study COVID-19 infection in the highest age group. Due to the relatively small number of seropositive cases, the possibilities for stratified analyses are limited. Of note, the clustered structure of the sample  is accounted for by weighting both at household and individual level and by the analysis which takes the correlation within households into account. Therefore, the household-based sample does not introduce bias into the estimation of the seroprevalence and its variance.48. The assessment of IgG antibody serum levels as a marker of a SARS-CoV-2 infection in serological surveys is limited by different long-term kinetics of SARS-CoV-2 antibodies depending on the target structure to which the antibodies are directed51, the applied laboratory assay53, the severity of the disease55 and the time interval between exposure to the antigen (infection or vaccination) and blood sampling. Until now, long-term studies using the Euroimmun assay cover periods up to 9-months. Euroimmun assay-measured antibodies against the S1 subunit of the surface glycoprotein Spike-S show a decrease in antibody titers over time. Six to nine months after initial IgG seroconversion, results indicate a maintained seropositivity between 50% and over 80%59. The maintained seropositivity of 62% after a median time of 70 days (interquartile range 33–193 days) in our study is lower, which may be due to the population sample with more asymptomatic and less severe cases than in a clinical sample. Still, this estimate relies on self-reported notified infections and may itself be somewhat too high when considering all infections, including the undetected ones, which would include even more asymptomatic cases. Therefore, our seroprevalence estimate allowing for antibody decay may still be biased downward. On the other hand, using this estimate, we obtained results regarding the underascertainment ratio and the proportion of undetected cases that were very similar to the results obtained by comparing our estimated seroprevalence to the number of notified cases in Germany under the assumption that there are no more antibodies detectable 6 months after infection, which is an extreme scenario considering the literature results cited above. Therefore, the downward bias should not be too strong.It has been suggested that without a correction for the proportion of seroreversion, serological surveys underestimate the cumulative prevalence of infected persons in a population62 with regularly updated guidance on testing criteria63 (version history available at: https://edoc.rki.de/handle/176904/6459 and https://edoc.rki.de/handle/176904/6484.11). Rapid antigen tests started to become available towards the end of the fieldwork of our study. These dynamic changes have been a challenge for comprehensive evaluation of the effectiveness of the strategies, thus seroepidemiological studies may help to reduce these knowledge gaps. The social gradient in utilization of tests found in our study is in line with ecological evidence from Switzerland and from Massachusetts, where testing was associated with neighborhood socioeconomic position64 or neighborhood socioeconomic vulnerability index65.Adapting the testing strategy to varying needs in different phases of the pandemic has played a major role in Germany’s response to the pandemic47. Although direct test costs to individuals were not involved in Germany, testing capacities were limited at the beginning of the pandemic and other barriers to testing access may exist (e.g. time and transport constraints), language or health literacy-related barriers. In addition, the distribution of the test frequency by federal state may reflect differences in the incidence, but also the different strategies of the federal states responsible for infectious disease control in Germany. In line with this, Supplemental Fig. Our findings of a lower test frequency and a higher underascertainment of cases in the socioeconomically most deprived districts of Germany suggest that testing-related disparities may have masked the magnitude of the social gradient in SARS-CoV-2 infections as found in previous ecological analyses of notification datahttp://www.rki.de/covid-19-serostudies-germany). We conclude that after one year of SARS-CoV-2 pandemic and shortly before the start of the German vaccination program, only about two percent of adults in Germany had contact with the virus and more than half of these cases had been detected and notified. Although our estimate may be somewhat too low because of healthy participant bias and since some unrecognized infections might still be missed due to antibody decay, this study confirms that Germany is among the countries with a low seroprevalence before the start of vaccinations. Recent analyses with worldwide data have shown that stringent public health and social measures were associated with lower seroprevalence66.The results of this representative study from Germany at the end of 2020 are in line with a living systematic review of seroepidemiological SARS-CoV-2 studies in Germany . The study reveals social disparities not only in infections but also in detection. This is a clear lesson for pandemic preparedness and underlines the importance of surveillance instruments that can capture social disparities.As a further conclusion, the study confirms that representative data can be collected in crisis situations in large countries like Germany provided that an appropriate research infrastructure is in place. Rapid access to a representative sample, preferably with already collected ample pre-pandemic information, as well as agile implementation of new methods such as self-sampling is essential.Supplementary Information.


Unmet needs in patients with cancer and their carers are common but poorly identified and addressed. The Needs Assessment Tool-Cancer (NAT-C) is a structured consultation guide to identify and triage patient and carer unmet needs. The NAT-C is validated, but its effectiveness in reducing unmet patient and carer needs in primary care is unknown.Cluster randomised controlled trial with internal pilot and embedded process evaluation to test the clinical and cost effectiveness of the NAT-C in primary care for people with active cancer in reducing unmet patient and carer need, compared with usual care. We will recruit 1080 patients with active cancer (and carers if relevant) from 54 general practices in England.Participating practices will be randomised 1:1 to either deliver an NAT-guided clinical consultation plus usual care or to usual care alone. Consenting participants with active cancer and their carers (if nominated) will be asked to complete study questionnaires at baseline, 1 and 3 months for all, 6 months except for those recruited outside of the last 3 months of recruitment, and attend an NAT-C appointment if allocated to an intervention practice. An internal pilot will assess: site and participant recruitment, intervention uptake and follow-up rates. The primary outcome, the proportion of patients with an unmet need on the Supportive Care Needs Survey Short Form 34 at 3 months postregistration, will be analysed using a multilevel logistic regression. Mixed-methods process evaluation informed by Normalisation Process Theory will use quantitative survey and interview data from clinicians and key stakeholders in cancer care to develop an implementation strategy for nationwide rollout of the NAT-C if the intervention is cost-effective.Ethical approval from London-Surrey REC (20/LO/0312). Results will be peer-reviewed, published and made available to research participants.ISRCTN15497400. We are testing the clinical and cost-effectiveness of the Needs Assessment Tool-Cancer, which has been validated and shown to be acceptable to patients and clinicians during feasibility testing.Feasibility testing led to modifications of intervention delivery and informed trial design, making successful completion of the trial more likely.CANASSESS is a cluster randomised controlled trial of 54 general practices across 2 regions in England, making it likely that findings will be generalisable nationwide.By necessity, participants, health professionals delivering the intervention and study researchers will be aware of treatment allocation; potential bias will be monitored during the trial.COVID-19 presents unique challenges in terms of safely conducting clinical trials in primary care.Unmet needs in people with cancer and their carers are common but poorly identified and addressed. Many people with cancer experience unmet needs across multiple domains.4Tools are available to assist clinicians caring for people with cancer,14–16The Needs Assessment Tool-Cancer (NAT-C) was developed in Australia, where it has been shown to reduce unmet needs of patients in oncology clinics.Our phase II feasibility study found that a randomised trial is feasible in terms of recruitment, data quality and intervention delivery.The CANAssess trial aims to evaluate the clinical effectiveness and cost effectiveness of the NAT-C in reducing unmet needs of patients and carers in primary care carer compared with usual care alone.CANAssess is a multicentre, two-arm, pragmatic, cluster randomised controlled trial (cRCT) with 12-month internal pilot, embedded process evaluation and cost-effectiveness evaluation. A cRCT design reflects that the intervention would be implemented at general practice level and reduces contamination in the control group.The trial opened to recruitment on 1 October 2020, recruitment is expected to cease on 1 June 2022 and participant follow-up will end on 1 September 2022.Trial objectives and outcomes are reported in Box 1To test the effectiveness of the Needs Assessment Tool-Cancer (NAT-C) compared with usual care in reducing unmet patient need as measured using the Supportive Care Needs Survey Short Form 34 (SCNS-SF34)To evaluate the effectiveness of the NAT-C compared with usual care with regard to:Patient unmet need on psychological, health system information, physical and daily activity, patient care and support, and sexuality domains of the SCNS-SF34 at 1, 3 and 6 months.Patient performance status, measured using the Australian-modified Karnofsky Performance StatusPatient severity of symptoms, measured using the Revised Edmonton Symptom Assessment SystemPatient mood and quality of life as measured by the European Organisation for Research and Treatment of Cancer Quality of Life-C15-Palliative questionnaireCarers’ ability to care and carer well-being as measured using the Carer Experience ScaleTo evaluate intervention delivery, uptake and fidelity of the NAT-C as measured by:NAT-C training of general practitioners and nurses in each general practice.Completed NAT-C consultations by patient and general practice .Length of NAT-C consultations.Referral patterns and actions taken to meet identified unmet need  from the completed NAT-C.To assess sufficiency of numbers of general practices and patients at 12 months post start of recruitment, we will proceed with the trial unchanged if we have 80% (43) sites open and are recruiting to 80% (48 participants per month) of target. We will assess intervention uptake, follow-up rates and potential for selection bias.Service utilisation, referral patterns and cost-effectiveness measured using:Bespoke Resource Use Questionnaire for capturing patient healthcare service utilisation and referral patterns at 1, 3 and 6 months.The EQ-5D-5L,To assess the adequacy of NAT-C training, intervention fidelity, possible mechanisms of action and issues regarding implementation in practice if the intervention is effective.The study aims to recruit patients and their carers from 54 general practices (clusters) from four geographical regions (recruitment ‘hubs’) in Yorkshire, East Midlands and the North East of England. Locations were selected to ensure a range of multi-ethnic, rural and urban populations to maximise generalisability of findings.Site identification and recruitment is detailed in Where practice manager agreement is obtained, capacity and capability confirmed, and initial read-code search completed, participating general practices  will be randomised sequentially via an automated system at the clinical trials research unit (CTRU). General practice randomisation will be 1:1 to: implement the NAT-C in addition to usual care, or usual care alone, using a computer-generated minimisation programme incorporating a random element to ensure arms are balanced for stratification factors:Locality: Urban or rural area.19 20List size: <5000, 5000–10000, >10000.20A GP training practice (obtained from site feasibility questionnaire): yes, no.General practices and research nurses providing participant recruitment and follow-up support across multiple surgeries will, by necessity, be aware of treatment allocation. However, no member of the research team will be involved with intervention delivery to minimise performance bias. A structured risk of bias assessment is presented in 10.1136/bmjopen-2021-051394.supp1Supplementary dataEligibility criteria are shown in box 2Box 2Adults (aged 18 years and above).Diagnosis of active cancer .Willing and able to complete questionnaires at the trial follow-up schedule.Provision of written or observed verbal informed consent.Sufficient knowledge of the English language to provide informed consent and complete trial questionnaires. The use of an appropriate translator/interpreter is allowed.Patients in complete remission .Patients with basal cell carcinoma.Patients living in a care home or other institutional setting.Patients within 1 month of receiving their initial cancer diagnosis.Adults (aged 18 and above).Nominated by participant.Able to complete trial measures.Written or observed verbal informed consent.Sufficient knowledge of the English language to provide informed consent and complete trial questionnaires. The use of an appropriate translator/interpreter is allowed.Employed to look after the participant.General practices will identify eligible patients by searching cancer registers and screening for eligibility. Eligible patients will be sent a letter with a patient information sheet and expression of interest form. General practices may also send an SMS text message or amended letter to patients inviting them to express interest in the study on the CANAssess website. Patients will provide informed consent  ahead of10.1136/bmjopen-2021-051394.supp2Supplementary dataThe NAT-C comprises five sections: priority referral for further assessment, patient well-being, ability of carer or family to care for patient, carer/family well-being and resulting referrals (if required). Clinicians will be encouraged to use the tool as an aide memoire, conducting a holistic patient assessment as usual, but referring to the NAT-C to ensure all domains are addressed during a consultation. The NAT-C will be completed using either the electronic medical record template  or on paper. Completed paper copies of the NAT-C will be uploaded to the patient record.At least two clinicians per practice will be trained to use the NAT-C either face to face, via webinar or online using a training package piloted during feasibility work.Participating patients at intervention arm surgeries will be offered a 20 min appointment or home visit depending on clinical need, guided by an NAT-C trained clinician using the tool within approximately 2 weeks of study registration. Appointments will take place either at the practice, at patients’ homes or remotely via phone or video according to clinical judgement and coronavirus guidelines. Participating carers will be welcome to accompany patients to their appointment, however, the NAT-C allows assessment of carer need through patient response.Usual care is defined as management normally provided for patients with cancer registered at the general practice concerned.21Required data, assessment tools, collection time points and processes are summarised in Clinical data including comorbidities, cancer stage and treatments will be collected at baseline by the research nurse from the participant’s medical record. Demographic information will be collected on participants, including age, sex, participant ethnicity and living arrangements, during the researcher baseline discussion. For carers, age, sex, relationship status and living arrangements will be collected.Self-reported participant and carer outcome measures will be collected via questionnaires at baseline, 1-month and 3-month postregistration. Questionnaires will also be collected at 6 months for participants and carers registered before 3 months prior to the end of participant recruitment.Participants will be able to complete questionnaires using paper forms sent by post, online via Research Electronic Data Capture (REDCap) or with a researcher over the phone or face-to-face, as appropriate. Only CTRU data and statistical staff will have direct access to the dataset.Researchers will telephone participants to confirm questionnaire receipt and assess and collect performance (AKPS) and COVID-19 status.A research nurse will collect information on NAT-C intervention delivery and content, including the timing, duration, mode of delivery, referrals and subsequent appointments from the participant’s medical record.In this population, it is expected that episodes of acute illness, infection, new medical problems and deterioration of existing medical problems will occur and could result in prolonged hospitalisation, hospital readmission, significant or permanent disability or incapacity, or death.Only serious adverse events fulfilling the definition of a related unexpected serious adverse event resulting from administration of any research procedure, and participant deaths during the trial period, will be recorded. Survival status of participants will be ascertained by research nurses from general practices ahead of sending study follow-up questionnaires.The date and cause of all deaths occurring during the trial period (to last participants 3-month follow-up assessment) will be collected by the researcher from participant’s medical record.The study has been powered to detect improvement in patients’ level of unmet need as measured by proportion of patients reporting at least one moderate or high need in domains of the Supportive Care Needs Survey Short Form 34 (SCNS-SF34).22Assuming that the proportion of patients with an unmet need on any SCNS-SF34 domain will be similar to that observed pre-intervention by Waller 2012The sample size assumes: a 20% loss to follow-up rate by 3 months, to account for eligible patients who are, or are nearing, end of life; an intracluster correlation coefficient (ICC) of 0.05; an average general practice size of 20; and an adjustment to account for variable practice sizes of 4–40. Given heterogeneity in the design of palliative care services and availability of resources through general practices, and median ICCs reported for outcome variables (0.03) and primary care settings (0.045), an ICC of 0.05 will be used.23The internal pilot will end 12 months from recruitment of the first general practice. Data from participants in the internal pilot will be included in the main study analysis.Progression criteria for recruitment are shown in There are no planned interim analyses; outcome data will be analysed once only. All analyses will be conducted on the intention-to-treat (ITT) population, in which all general practices and participants will be included in the analysis according to the group which the GP practice was randomised, and regardless of non-adherence to the intervention or withdrawal from the study. A two-sided 5% significance level will be used for statistical endpoint comparisons.The flow of patients and general practices through the trial will be presented in a Consolidated Standards of Reporting Trials diagram.As appropriate for cluster trials recruiting participants after randomisation,Analyses of primary  and secondary outcomes  will use multilevel logistic or linear regression (as appropriate) with participants nested within general practices, and general practices treated as a random effect. The model will be adjusted for the following fixed effects: GP practice-level stratification factors, important participant-level covariates , and other relevant known predictors of outcome. Results will be expressed as point estimates, p values, ICCs and 95% CIs.Reasons for attrition and missing participant data will be summarised and mechanisms for missing data we explored according to participant characteristics, intervention and control groups.Quantitative summaries for AKPS score and corresponding change from baseline will be presented at baseline and months 1, 3 and 6 by treatment group. Intervention delivery will be summarised overall and by general practice to evaluate uptake of the NAT-C, adherence to the processes and quality of intervention delivery.Within-trial health economic evaluation will be undertaken to assess cost-effectiveness of NAT-C vs usual care. The cost–utility analysis will be conducted alongside the trial and follow National Institute for Health and Clinical Excellence reference case for health technology appraisals.We will fully cost intervention delivery and measure service utilisation using a bespoke RUQ and measure outcomes using the EQ-5D-5L, ICECAP-SCM and CES at 1, 3 and 6 months.A patient-completed RUQ will gather data on community-based , specialist palliative care  and hospital-based  healthcare resource utilisation at follow-up. Participants will be given a diary planner to keep to note any healthcare attendances to facilitate completion of the RUQ. Costs will be estimated using UK NHS reference unit costs, data from the Personal Social Services Research Unit and British National Formulary. The primary perspective is the health and personal social service provider but a secondary analysis will adopt a wider perspective to incorporate costs and productivity loss incurred by patients and carers.Results will be presented as incremental cost-effectiveness ratio (ICERs). Results will also be presented as expected net monetary benefit and cost-effectiveness acceptability curves based on non-parametric bootstrapping.A mixed-methods substudy will use normalisation process theory (NPT) to structure data collection and analysis of: (1) implementation of the NAT-C in trial general practices and (2) clinicians’ and staff perspectives on the usefulness and effectiveness of the NAT-C, how this relates to usual care and how, if effective, the NAT-C could be implemented nationwide.NPT is a well-established framework for understanding the dynamics involved in implementing, embedding and integrating a new intervention. We will draw on quantitative and qualitative elements to identify issues related to implementation in terms of (1) a quantitative NPT survey to elicit the views of clinicians who have undergone NAT-C training and (2) qualitative interviews/focus groups with general practice staff, clinicians and external stakeholders with key roles in health policy and commissioning, relevant to cancer care in primary care.The NPT survey (NoMAD instrument) is a 23-item instrument for measuring implementation processes from the perspective of professionals directly involved in the work of implementing complex interventions. During feasibility testing, we adapted the NoMAD instrument in to a 17-point checklist to specifically address the NAT-C. Clinicians will be invited to complete the NoMAD survey either on paper or online following completion of NAT-C training (survey 1). Using results from survey 1, emerging qualitative findings and experiences, the NoMAD will be adapted to include questions regarding emerging issues and concerns. At the end of a practices’ involvement with the study, clinicians who have used the NAT-C will be asked to complete the adapted NoMAD survey (survey 2).Clinicians will be asked questions on a Likert scale in relation to issues such as: attitudes to the NAT-C, NAT-C training and implementation concerns. Completion of the survey will imply informed consent. Data collection and management for surveys 1 and 2 will be delivered by the University of Hull (UoH). All survey data will be anonymised.Opinion regarding NAT-C training, the role and place of the NAT-C within routine practice will be sought from clinicians who received NAT-C training and experts from a range of stakeholder groups . Semistructured interviews and focus groups using a priori topic guides  will be conducted at various time points post-NAT-C use and up to the end of study. Interviews/focus groups with clinicians and key stakeholders will focus on structural and policy issues relevant to potential implementation of the NAT-C in general practices nationwide, should trial results be positive.Maximum variation purposive sampling will be used to optimise exploration of a range of clinicians, practice staff and key stakeholder perspectives. An initial purposive sampling grid for clinicians  will be expanded with further criteria identified from implementation study survey responses.A sample of 15–20 clinicians and general practice staff and 10–15 experts from a range of stakeholders will be sought through interviews or focus group.Potential interviewees will be provided with a study invitation, a study information sheet and asked to provide informed written consent prior to study procedures. All interviews and focus group discussions will be audiorecorded.Free-text responses in survey 1 will be monitored by the implementation study researcher to enable rapid feedback to inform subsequent training at other sites.29Once all surveys 1 and 2 are completed, free-text responses will be subject to thematic analysis and descriptive statistics will be used to analyse Likert scale responses including: (1) the extent to which the intervention fits with current practice in relation to the components of NPT; (2) the potential relevance of the NAT-C to individuals’ roles; (3) adequacy of NAT-C training and (4) clinician attitudes to the NAT-C at baseline and at the end of the trial from survey 1 and 2.Qualitative data will be analysed using thematic analysis,We will synthesise key aspects of process evaluation data, with effectiveness of the NAT-C within clusters according to randomisation strata, to improve understanding using NPT about how and if the NAT-C should be implemented into clinical practice using critical interpretative synthesis.31Kirkpatrick’s model for training evaluation will be used to evaluate NAT-C training in terms of: reaction to the training, learning and skills improvement, behavioural change and results.CANAssess is sponsored by the UoH coordinated by Leeds CTRU and UoH. The sponsor had no direct input in to the design or conduct of the study. The Trial Management Group consists (TMG) of coapplicants, trial coordinators, four GP-hub leads and a public–patient representative. The TMG is responsible for clinical setup, ongoing management, promotion of the trial, and for the interpretation and publishing of the results. A TSC will meet annually and on request to provide independent oversight of the trial and reports to the Sponsor.A Data Monitoring and Ethics Committee is not needed due to the nature of the study. The TSC will adopt a safety monitoring role, with the constitution of a subcommittee to review safety issues where necessary.An experienced lay representative was part of our funding application. She also reviewed and edited public-facing study documentation, and sits on our TMG, with public–patient involvement as a standing item. A further lay representative forms part of our TSC.If trial results are positive, the NAT-C has the potential to become the gold standard cancer care delivery in primary care as the only valid tool subjected to formal effectiveness testing.Findings will be presented and discussed at a final dissemination meeting, to which a wide range of stakeholders will be invited, including trial clinicians, participants and those involved in the stakeholder engagement.Results of the study will be published in peer-review publications and will be presented at national and international conferences. A lay summary of our findings will be published on study and organisational websites, sent to participating general practices and will be accessible to participants.The trial received ethical approval from the London-Surrey REC (20/LO/0312). Any future amendments to the trial will be submitted to the REC and participants will be informed of any changes which may affect them.The COVID-19 outbreak in England occurred just as ethical approval for the study had been obtained and the process of site identification had begun. We halted site identification and adapted the trial processes to allow remote intervention delivery as per practice procedure for remote consultations, telephone consent and data collection, and online patient study responses and online completion of follow-up questionnaires. Amidst concerns that patient recruitment may be affected by social distancing measures, the Leeds CTRU also highlighted how their secure online computer systems would allow online informed consent provision and data collection. We; therefore, submitted an amendment to allow all study activity to be completed remotely through phone or videoconference.Following COVID-19-related delays, the trial team is in place, incorporating employed trial-specific research nurses and Clinical Research Network support. Recruitment of GP practices and participants is underway. Our first study site was opened for recruitment on 21 October 2020 and we now have seven general practices recruiting participants. The first participant was recruited on 1 December 2020. As of 25 January 2022, we have 27 general practices open to recruitment and have recruited 333 patient participants and 102 carer participants. This manuscript has been prepared in accordance with study protocol V.3, 24 June 2020. A copy of the full protocol is available on request from JC.


Few studies have reported the cost and cost-effectiveness of workplace interventions to reduce sedentary time. The purpose of this study was to complete an economic evaluation of a multilevel intervention to reduce sitting time and increase light-intensity physical activity (LPA) among employees.We conducted a retrospective within-trial cost and cost-effectiveness analysis (CEA) to compare a 12-month multilevel intervention with (STAND+) and without (MOVE+) a sit-stand workstation, across 24 worksites (N=630 employee participants) enrolled in a cluster randomized clinical trial. We estimated the intervention costs using activity-based costing strategy. The intervention costs were further expressed as per person and per worksite. CEA was conducted using an incremental cost-effectiveness ratio (ICER) metric, expressed as costs for additional unit of sitting time (minute/day), LPA (minutes/day), cardiometabolic risk score, and quality-adjusted life years (QALY) increased/decreased at 12 months. We assessed the cost analysis and CEA from the organizational  perspective with a one-year time horizon.Total intervention costs were $134 and $72 per person, and $3939 and $1650 per worksite for the STAND+  and MOVE+  interventions, respectively. The ICER was $1 (95% CI $0.8–1.4) for each additional minute reduction of workplace sitting time (standardized to 8-hour workday); and $4656 per QALY gained at 12 months. There was a modest and non-significant change of loss of work productivity improvement , which was associated with a $0.34 return for every $1 invested.The multi-level intervention with sit-stand workstations has the potential to be widely implemented to reduce workplace sitting time. Future research into work productivity outcomes in terms of cost-benefits for employers is warranted. Sedentary behaviors (SB), ie, sitting/lying at low energy expenditure while awake, are established modifiable risk factors of all-cause mortality and cardiometabolic outcomes  –3, and sIn response, an increasing number of multi-level/multi-component workplace SB interventions have been developed targeting individual, social, and environmental factors of SB. These types of interventions are distinct from physical activity interventions and target reductions in sitting time rather than increases in physical activity. Several reviews have suggested that workplace SB interventions, particularly those that implement the use of sit-stand workstations, can effectively reduce workplace SB by >60 minutes per 8-hour workday in 3–9 months . WorkplaCost-effectiveness analyses (CEA) of multilevel workplace SB reduction interventions may be critical for workplace adoption decision-making, program implementation, and sustainability. Notably, Gao et al  applied Recently, the Stand & Move at Work (SMW) trial examined SB and cardiometabolic risk following a multi-level behavioral intervention that incorporated workplace policy, environmental, social, and individual-level strategies with (STAND+) and without (MOVE+) a sit-stand workstation . The SMWUsing retrospective data collected during the SMW trial (January 2016 to December 2017), we estimated the costs of implementing the multi-level SB intervention. We conducted a CEA following the recommendations of the Trial-Based Economic Evaluations in Occupational Health , and ConThe design and outcomes related to the overall study have been described in detail elsewhere , 24, 25.SMW was a workplace intervention designed to accompany sit-stand workstations to reduce sedentary time and increase LPA. It was grounded in a social-ecological framework incorporating individual , social , environmental , and organizational  strategies. The implementation of SMW was dependent on the identification and engagement of worksite administrators and managers to enact policy-level changes, implement environmental changes , and model and promote behavior change . Thus, wWe assessed the cost analysis and CEA of the SMW program from the organizational  perspective given that the employers make the decision of whether or not to adopt or sustain the program after the grant funding ceases. We conducted the analyses over a one-year time horizon and thus the costs and effects were not discounted.Following the cost assessment procedure of behavioral interventions proposed by Ritzwoller et al , the cosWe divided intervention delivery costs into labor costs and non-labor costs. We estimated labor costs based on time spent on each intervention activity. Specifically, we utilized a micro-costing approach with an activity-based costing strategy  for costNon-labor costs including workstations ($300/unit), wireless keyboards ($20/unit), material printing , and footrests ($4.50/unit) were based on actual amounts spent and were tracked from receipts and payment invoices from the worksites. We did not consider the overhead or space costs given all the SMW intervention activities occurred at workplaces where the participating employees regularly performed their daily work activities. In addition, we annuitized costs of the sit-stand workstations using a 5-year straight-line approach.The activPAL3c micro accelerometer  was used to objectively measure workplace and overall sitting time and workplace LPA. Work periods were standardized to an 8-hour workday . We also collected fasting glucose, insulin, triglycerides, HDL and LDL cholesterol, waist circumference, and resting blood pressure to calculate a summary metabolic risk score (CMR)  by summiHealth utility (EQ-5D)  was mappThe Work Productivity and Activity Impairment (WPAI) Questionnaire  was asseWe used linear mixed models to evaluate within-group changes and between-group differences of SF-12 quality of life scores , presenteeism, sickness absence, and overall work productivity using the baseline and 12-month outcomes. The group randomized design was accounted for using a random effect for site nested within treatment (MOVE+ versus STAND+). Models were adjusted for baseline values of the respective outcome and a priori selected covariates: age, sex, race/ethnicity, and baseline body mass index (BMI), as performed for the primary outcomes of the trial .We conducted the CEA using an incremental cost-effectiveness ratio (ICER) which was calculated as the incremental costs per additional unit increase in effectiveness outcomes between MOVE+ and STAND+ regardless of the significance of the between-group differences. This was based on the justification that adoption decisions should be based on the mean net benefits irrespective of whether differences are statistically significant (arbitrary rules of inference) . We calcWe calculated the return on investment analysis according to the employer’s perspective as: benefit-cost ratio (BCR)=benefits/costs. If BCR is >1, the financial return of the investment was positive. Specifically, costs were defined as SMW intervention delivery costs, whereas benefits were defined as the difference in lost productivity costs  between MOVE+ and STAND+ at the 12-month follow-up, with positive benefits indicating reduced spending/productivity gain. The lost productivity costs were defined as the costs associated with time lost from paid work  due to a health problem, and the human capital approach using a national average hourly wage was applied for the estimation. We extrapolated the adjusted difference in the lost work productivity in the past two weeks (results of linear mixed models) between STAND+ and MOVE+, over a 52-week  time period. To derive the overall cost of lost work productivity over a one-year time period, we then multiplied the overall lost work productivity (measured in hours) with a value of $27.07 per hour  or Microsoft Excel.STAND+ significantly reduced workplace sitting time compared to MOVE+  as well as total sitting time  at 12-months. However, there were no statistically significant differences in the outcomes of workplace LPA and CMR scores between study conditions regardless of the positive direction observed [the full account of effectiveness outcomes have been published elsewhere ]. STAND+The CEA results in terms of effectiveness outcomes regardless of significance are reported in activities led by an advocate, as the estimates range from $1447–1853 per site, following conduct workspace inventory for worksites. In addition to cost variations resulting from labor activities, the other potential cost uncertainty was the cost of the sit-stand workstation and footrest, estimated at $61 per participant per year (for STAND+ only), with a 5-year depreciation, and the associated installation and training (~45 minutes), estimated at $12 per person.The one-way sensitivity analysis results are presented in To the best of our knowledge, this is the first study to examine the cost-effectiveness of the addition of sit-stand workstations relative to a multi-level intervention to reduce workplace SB. Other studies that have assessed the cost-effectiveness of multi-level interventions have either had no intervention  or a usuThe cost and cost-effectiveness analysis of SMW was completed to inform the adoption decision-making process for workplaces interested in reducing SB. Our cost analysis results showed an employer would need to invest a fixed baseline cost of $1650 for the one-year intervention regardless of how many employees participated, and a variable cost of $73 per person . The variable costs of a sit-stand workstation may be further reduced through bulk orders, shared-use, and so forth . FurtherAlthough workplace SB interventions were mostly multi-component interventions, they varied in degrees of intensity, which may impact the observed effect size. In the current study, the magnitude of the effect of the reduction of workplace sitting time was estimated at 59.2 minutes per workday, which is comparable to the 46.8 and 41.3 minutes in Gao et al  and MuniFor the ability to compare across studies, we described the intervention cost as a unit cost (per participant) as the total intervention costs differed in study scope and size, resulting in great variability . Interve2 and only ~19% of participants reported having a previous diabetes diagnosis or a fasting blood glucose ≥100 mg/dL (In contrast to the ICER findings and different from the positive return on investment (amount of money return per $1 invested) reported in Munir et al ($5.2)  and Ben 00 mg/dL . It mighIn addition, our results indicated that the ICER was $2737 for an additional CMR score reduction. A unit change in the CMR score was one standard deviation (SD). Other similar metrics of cardiometabolic health, in large population-based cohorts, have demonstrated that a 1 SD reduction was associated with 1.8 lower odds of incidence of cardiovascular disease and 5.1 lower odds of incidence of type 2 diabetes . The redDespite the fact that QALY is recognized as a standard metric of health outcome in CEA, the data may not be widely available from the randomized trials of the interventions. Moreover, worksite decision-makers may see it challenging to conceptualize QALY and the associated interpretation. Accordingly, in addition to ICER, presenting other generic cost-effectiveness outcomes  simultaneously, may improve the uptake of the program adoption or maintenance by increasing decision makers’ comprehension of the CEA results.First, the present study may suffer from issues related to recall bias, given all the cost data were collected retrospectively by interviewing the advocates, project coordinator and staff. Moreover, because participants were generally in good health and able to safely reduce sitting and increase LPA (one of the eligibility criteria), we may underestimate the effect of absenteeism and presenteeism. Participants may not have been able to recall the events of sickness absence or have a higher self-rated efficiency score at work. Second, given that the SMW trial was a cluster randomized controlled trial, where the worksite was the unit of randomization, employees within a worksite were free to choose whether to participate in the intervention program. It is likely that the addition of a sit-stand workstation may influence employees’ willingness to participate in the program . Third, although we derived the presenteeism and absenteeism data using the validated questionnaires, there is still bias associated the self-reported nature, and the retrospective survey questions assessing for the preceding period of past 2 weeks, completed three times across 12-month period. Fourth, we used the past 2-week productivity change between baseline and 12-month follow up to estimate the productivity gain between the intervention groups across entire 12-month period, as opposed to derived from employer data  , 18 due In the study, we presented a detailed costing process of the multi-level intervention on SB to facilitate future comparative cost analysis. Furthermore, the multi-level intervention with sit-stand workstations holds the potential to be widely implemented within worksites and was effective in reducing workplace sitting time. Future research examining work productivity outcomes in terms of cost-benefits for employers is warranted.