Significance: The early detection of dysplasia in patients with Barrett’s esophagus could improve outcomes by enabling curative intervention; however, dysplasia is often inconspicuous using conventional white-light endoscopy.Aim: We sought to determine whether multispectral imaging (MSI) could be applied in endoscopy to improve detection of dysplasia in the upper gastrointestinal (GI) tract.Approach: We used a commercial fiberscope to relay imaging data from within the upper GI tract to a snapshot MSI camera capable of collecting data from nine spectral bands. The system was deployed in a pilot clinical study of 20 patients  to capture 727 in vivo image cubes matched with gold-standard diagnosis from histopathology. We compared the performance of seven learning-based methods for data classification, including linear discriminant analysis, Results: Validation of our approach using a Macbeth color chart achieved an image-based classification accuracy of 96.5%. Although our patient cohort showed significant intra- and interpatient variance, we were able to resolve disease-specific contributions to the recorded MSI data. In classification, a combined principal component analysis and Conclusions: MSI shows promise for disease classification in Barrett’s esophagus and merits further investigation as a tool in high-definition “chip-on-tip” endoscopes. HR-WLE actually represents a simple case of MSI, where tissue features are measured in three broad color bands: red . The proximal end of the imaging fiber was imaged and magnified using an objective lens . The light was split using a 90:10 plate beam splitter  and focused using an achromatic doublet lens , which provided illumination from 450 to 875 nm  . The SRDer-pixel  across ao 850 nm . The optThis distal end of the multispectral endoscope accessed the esophagus via the working channel of a therapeutic gastroscope, directed by the articulation of the gastroscope to collect diffuse reflectance images alongside standard-of-care imaging , thus caEndoscope settings were controlled using an interface developed in LabVIEW  running on a PC and a tablet . Images captured by the SRDA were saved as 8-bit the SRDA . For anaage cube  with a sspectra” . As highspectra” .2.2in vivo trials  prior to four of the o trials . The col2.3in vivo images. This prospective pilot cohort study was carried out at the Cambridge Clinical Research Centre, Cambridge University Hospitals, United Kingdom. Eligible patients were adults (at least 18 years old) with a previous diagnosis of BE with an endoscopic length of at least 2 cm if circumferential . The trial was registered at ClinicalTrials.gov (NCT03388047).The snapshot multispectral endoscope was deployed in a pilot clinical study to acquire 2.4Supplementary Material. Each procedure was performed by a single experienced endoscopist (MdP).The clinical procedure undertaken is summarized in Fig. S2 in the i.After local anesthesia and/or conscious sedation (midazolam ± fentanyl), the patient was intubated with HR-WLE . After cleaning the esophageal mucosa using a water jet, the endoscopist thoroughly inspected the mucosal surface of the esophagus. Cautery marks were placed around two regions of interest: one suspicious lesion and one region of inconspicuous BE as a control. In the absence of suspicious lesions, one or more random areas within the BE segment were selected depending on the length of the BE. The HR-WLE video stream was recorded using a recording unit .ii.The endoscopist inserted the snapshot multispectral endoscope through the working channel of a therapeutic endoscope . The use of the therapeutic scope was required as its accessory channel was sufficiently large (3.7 mm diameter) to allow easy insertion of the multispectral endoscope . The multispectral endoscope was used to image the regions of interest cautery marked in step (i). An endoscope cap was not used, as it can easily come into contact with lesions and induce contact bleeding. For the second half of the trial , an additional control region of distant squamous tissue was inspected with the multispectral endoscope following inspection of the two marked regions.iii.–The multispectral endoscope was withdrawn, and the endoscopist proceeded to an endoscopic mucosal resection or biopsy (depending on the endoscopic findings and the level of suspicion). Control areas received biopsies only. Pathological assessment of biopsies was performed by an expert GI pathologist with extensive experience in reporting BE-related neoplasia.For analysis, the most advanced disease present in each biopsy determined the label for the region such that three classes of spectra were acquired: (1) normal squamous; (2) nondysplastic BE (NDBE); and (3) neoplasia .2.5To enable matching of multispectral image data with the diagnosis from histopathology, the HR-WLE video stream and the video stream from the multispectral endoscope were synchronized and placed side-by-side for analysis. The HR-WLE video was carefully inspected to extract frames where the multispectral endoscope was sampling the marked regions of interest that were biopsied to give gold-standard diagnosis from histopathology. Since the esophageal lumen is quite featureless on MSI, the frames were identified using the cautery marks and other visible landmarks in the HR-WLE video stream to estimate the field of view of the multispectral endoscope. The tip of the multispectral endoscope was visible within the field of view of the HR-WLE endoscope, which facilitated identification of appropriate multispectral images that could be related to the gold-standard diagnosis made by histopathology.2.6Briefly, raw images were checked for saturation . This resulted in For classification, the spatial dimensions were binned into To quantify the variance in the data, standard deviations were calculated according to 2.7For classification, the multispectral image cubes were randomly split into 80% for training and 20% for testing. Spectra calculated per-pixel and per-image were classified using seven methods commonly used in spectral data classification.Finally, a neural network (NN) was used for classification. NNs perform classification by passing an input vector, in this case a nine-band spectrum, through a series of artificial neurons, with each neuron outputting some nonlinear function of its inputs with some weight that is adjusted during training. The output values of the final layer determine the classification. In contrast to LDA, NN classification does not make assumptions about the distribution of input data nor the shape of decision boundaries. The NN was implemented using a two-layer feedforward network, with a sigmoid transfer function in the hidden layer (10 neurons) and a linear transfer function in the output layer, using the MATLAB (MathWorks) Neural Network Pattern Recognition app. The 20% testing image cubes were randomly split into 50% for validation and 50% for testing . In summary, the seven classification methods compared were LDA, KNN, PCA-KNN, simple-SAM, SAM-LDA, SAM-KNN, and NN.Accuracy for per-pixel classification was calculated in three ways: per-pixel accuracy, the percentage of pixels classified correctly over all pixels; per-image accuracy, the average percentage of pixels classified correctly in an image; and majority-pixel-per-image, the percentage of correctly classified images based on a relative majority decision  of all pixels within an image . Accuracy for per-image-spectrum was the percentage of correctly classified mean-image-spectra.33.1Supplementary Material). All patients provided written informed consent. Of these, one subject was considered unfit for endoscopic procedure due to concomitant acute comorbidity and one was excluded as the visible lesion was too small for spectral imaging. Of the 18 subjects that underwent standard-of-care endoscopic procedures, three were excluded from analysis because of insufficient illumination for spectral imaging using the first prototype . To do this, cautery marks were made in two distinct regions of the esophagus, one deemed suspicious and one a control . The marked regions were inspected with the multispectral endoscope , then the regions were biopsied  and diagnosed based on the histopathologic analysis of the biopsies .The multispectral endoscope was deployed to acquire Supplementary Material). The mean exposure time was Data were collected in 15 subjects at 44 distinct regions: 9 regions of squamous tissue, 24 regions of NDBE, and 11 regions of neoplasia. Of the 35 BE tissue regions, 34 were confirmed with histopathological assessment from 45 collected samples . In patient number 12, the control region identified on endoscopy was diagnosed as dysplastic by histopathology, so spectra that were incidentally captured from another region of NDBE were taken as NDBE without confirmation from histopathology. Coregistration between imaging data and histopathological diagnosis was successful for 30 regions (20 NDBE and 10 neoplasia), yielding a total of 570 labeled image cubes for analysis, plus an additional 157 image cubes from nine squamous regions  and test data comprising of 146 image cubes . Seven classification methods were compared . Despitewith k=3 . Per-imawith k=3 . This isWe then created classification maps representing the three pathologies  to displSupplementary Material). For per-pixel classification PCA-KNN with To calculate sensitivity, specificity, positive predictive value, and negative predictive value for detection of neoplasia in BE, the classification models were retrained for two-way classification using only NDBE and neoplastic image cubes (Fig. S6 and Table S3 in the 4,Advanced optical imaging modalities have potential to impact the care of patients with BE, by enhancing contrast for early lesions that can be treated using minimally invasive endoscopic therapy. MSI enables both spatial and spectral information to be captured during endoscopy, which has the potential to achieve this goal by revealing changes in the distribution of optical absorbers and scatterers between different disease states. Diffusely reflected light collected in our multispectral endoscope is estimated to penetrate approximately in vivo. The SRDA-based snapshot multispectral endoscope was compatible with the clinical environment: it was deployed via the working channel of the standard-of-care endoscope allowing simultaneous standard-of-care imaging, illumination, articulation, insufflation, and washing capabilities; its deployment lengthened procedure time by To test the potential of MSI, we constructed and tested in a pilot clinical study an SRDA-based snapshot multispectral endoscope capable of acquiring of nine-band multispectral image cubes Multispectral image cubes were successfully collected in 15 patients. Following MSI, biopsies were collected from the imaged regions, resulting in matched labeling from gold-standard diagnosis from histopathology. This resulted in the successful acquisition of 727 multispectral image cubes labeled with histopathological diagnosis from 39 distinct regions within 15 patients.in vivo imaging data has not yet been solved; as image segmentation becomes more detailed, so the coregistration of the image field with histopathology becomes more challenging. Careful consideration of these issues should be made in future studies aiming to use advanced spectral endoscopy methods to aid in BE surveillance. Additional variance could be attributed to variations in imaging geometry caused by peristalsis and the position of the lesion, though normalization should mitigate this effect. Nevertheless, the average spectra across patients showed clear differences between pathologies.We found substantial intra- and interpatient variation, which is likely due to the intrinsic spatial heterogeneity of the disease. In regions with diagnosis of multifocal disease, it is likely that some acquired image cubes include contributions from both focal neoplasia and the surrounding “sea” of NDBE, which was not possible to mitigate in this study. The challenge of coregistering small-scale disease heterogeneity with Seven classification methods were trained to classify the data as squamous tissue, NDBE, or neoplasia. PCA-KNN was found to provide the best performance in our dataset, classifying pathology with 74.2% accuracy per-pixel (While these results are very promising, this first experience of applying an SRDA-based multispectral endoscope in patients revealed several limitations that will inform future work. First, our classification algorithms were tested using a random per-image split. Future work with a larger dataset should employ a per-patient split on a dedicated test set to assess the classification performance when dealing with unseen patients, particularly in light of the large interpatient variation seen in this trial.,Second, our system was constructed using a commercial SRDA, selected for the even distribution of spectral bands across the near-infrared window of biological tissue. Though our findings are promising, the sensor was not optimized for the detection of disease-specific spectral signatures and the nine-band spectra of NDBE and neoplasia showed significant overlap. The spectral bands available on the SRDA in future studies could be customized using recently reported fabrication processesA third limitation of our multispectral endoscope is the use of an imaging fiber bundle to carry light to detectors outside the body. Though this afforded us a swift route to clinical translation, it limits acquisition to 10,000 spatial points per image cube and consequently, images are of low quality in comparison to the high-definition images captured by standard of care endoscopes. In addition, attenuation due to the imaging fiber bundle also decreases sensitivity. This is worsened by the low sensitivity of the SRDA, partly due to the low quantum efficiency of the underlying sensor (In summary, by combining the snapshot multispectral endoscope with machine learning techniques, we demonstrated a 74.2% accuracy per-pixel and 96.5% accuracy per-image for classifying squamous, NDBE, and neoplasia in a first-in-human trial. The next steps are to expand this work by testing custom SRDAs tailored to disease-specific spectral signatures. With further testing, multispectral endoscopy has the potential to improve detection of neoplasia during surveillance of BE.Click here for additional data file.


Results: After 6 weeks, participants showed significantly smaller absolute ankle joint reposition errors in dorsiflexion (p = 0.031), plantarflexion (p = 0.003) and eversion (p = 0.019) compared to the pre-training measurement. Furthermore, after training, a significantly slower average COP speed at pre-equilibrium during grand-plie movement (p = 0.003) and pre-equilibrium phase of releve en demi-pointe (p = 0.023) were observed. In addition, the maximum COP displacement in the medial-lateral direction was significantly smaller at pre-equilibrium phase during grand-plie (p = 0.044) and releve en demi-pointe movements (p = 0.004) after training. Conclusions: The 6-week integrated training program improved the ankle joint reposition sense and postural control in the medial-lateral direction during grand-plie and releve en demi-pointe movements.Objective: To investigate the effects of a 6-week integrated training program on the ankle joint reposition sense and postural stability in ballet dancers. Methods: Sixteen female ballet dancers participated in the study and underwent a 6-week integrated training program consisting of plyometric, proprioception and core stability exercises along with a home program involving additional ankle muscle strengthening and stretching. The ankle joint reposition tests and the parameters of the center of pressure (COP) while performing  Ballet requires intensive training to reach the demanded aesthetic standards. Consequently, ballet dancers are under intense physical and psychological demands during training, rehearsal and performance . The phyProprioception plays an essential role in ensuring a smooth and coordinated movement of the body by providing a conscious or unconscious awareness of the joint position . ProprioPlyometric exercise is an intensive exercise consisting of fast and powerful movements achieved via eccentric contraction of the muscles followed immediately by quick concentric contraction. The effects of plyometric exercise on performance and injury prevention have been widely studied in many sports, including soccer, basketball and volleyball ,12,13. BCore stability exercise (or core strengthening) is a widely used training program for improving athletic performance or preventing injury . A greatgrand-plie (deep squatting) and releve en demi-pointe movements before and after the training program, respectively. It is hypothesized that the ballet dancers will exhibit an improved ankle joint reposition sense and improved balance ability during ballet movements after receiving the proposed training program.As described above, the ankle joint in ballet dancers is subjected to intense physical demands during the execution of ballet movements. Consequently, effective training programs are essential to prevent injuries to the ankle joint (particularly strains) and improve the balance ability accordingly. Previous studies have shown that plyometric exercise, proprioception training and core stability strengthening are effective techniques for minimizing the risk of injury and improving performance in many different types of sports ,27,28. T2. All of the dancers had a classical ballet training history of at least seven years (10.72 ± 2.92 years).Sixteen female ballet dancers having ballet training history of minimum seven years and routine ballet training of minimum two hours per week were recruited from a college dance department to participate in this study. The mean age was 17.50 ± 1.37 years. The mean body height and body weight was 161.44 ± 4.22 cm and 51.03 ± 4.52 kg. The body mass index was 19.59 ± 1.82 kg/mParticipants with a history of balance and vestibular problems, or any other impairment which might potentially affect their balance, or any acute inflammation or pain that affected their performance at the physical screening stage, were excluded.In addition, four participants reported previous ankle sprain more than 4.5 years ago and did not have another onset of ankle sprain since then. The study was designed in accordance with ethical protocols and all the participants read and signed a formal consent form approved by the university Institutional Review Board (ER-95-190) prior to joining the study.The joint reposition sense of the ballet dancers was evaluated using a bi-axis electrogoniometer  placed around the ankle joint. The electrogoniometer signals were recorded by instruNet software through an analog-to-digital box .The absolute errors of active ankle joint reposition sense were measured in target angles of 10° dorsiflexion (DF), 20° plantarflexion (PF), 10° eversion (EV), 10° inversion (IV) and 20° inversion in the dominant leg. Note that the dominant leg was determined as the leg used preferentially by the participants in performing forward hops.In conducting the measurement process, the dancers sat on a custom-made chair with hip and knee flexion at 90° and trunk erected. The axis of motion in the sagittal plane  was taken as the line passing through the lateral and medial malleolus with the ankle in the neutral position. By contrast, the motion of the ankle in the frontal plane  was tested with the ankle in slight plantarflexion. The participants were asked to close their eyes during the tests to avoid visual cues. The participant’s ankle was placed passively to the target angle and maintained at the placed angle for 5 s. The ankle was then repositioned passively to the initial position by the same investigator. Once the ankle was restored to the initial position, the participant was instructed to reposition the ankle actively to the target angle and maintain the ankle in that position for 5 s.grand- plie and releve en demi-pointe. The three-dimensional trajectories of the reflective markers placed on the sacrum and heel posteriors of participants were captured at a sampling rate of 100 frames per second by a videographic acquisition system consisting of eight CCD cameras  in order to define the phases during movement. In addition, the center of pressure (COP) positions of the participants’ feet were detected by a force plate  at a rate of 1000 samples per second. The videographic data and force plate data were time-synchronized to 1000 Hz using a linear interpolation method. The participants were asked to stand on a large piece of paper in the ballet first position and the outlines of the feet were then drawn on the paper. The foot length was defined as the distance between the tip of the second toe and the mid-heel position. Similarly, the turnout angle was defined as the angle between the lines constructed by the second toes and mid-heels of the two feet [The balance ability test was measured during ballet dancing movements including two feet .releve en demi-pointe and 20-s grand-plie movements on the force plate. The ballet releve en demi-pointe movement commenced from the ballet first position and involved raising the heels up to demi-pointe within 5 s, maintaining this position for 10 s, and then returning to the initial position within 5 s  . In everParticipants received joint reposition sense tests and balance ability tests during ballet movements. They then underwent a six-week training program and home training program. The measurements  were performed again after a 6-week training.grand-plie and releve en demi-pointe movements.The COP-related parameters were used to represent the balance ability during grand-plie movement was divided into five phases, namely a 5 s lowering phase from the initiation of movement to the lowest sacrum position; a 10 s squatting phase  with the sacrum markers in the lowest position; and a 5 s rising phase from the squatting position to the original standing position. The releve en demi-pointe movement was similarly divided into five phases, namely rising, pre-equilibrium, equilibrium, post-equilibrium, and lowering based on the position of the sacrum marker.For analysis purposes, the turnout angle (θ) and average foot length (l) to eliminate the influence of inter-participant differences, i.e.,APNCOP denotes the normalized COP displacement in the anterior-posterior direction, while MLNCOP denotes the normalized COP displacement in the medial-lateral direction. The COP parameters for analysis included the average COP speed, the COP 95% ellipse area, the normalized maximal COP displacement, and the standard deviation (SD) of the COP displacement in the anterior-posterior and medial-lateral directions in each phase of the corresponding ballet movement. The SD of COP displacements throughout the ballet movement was calculated to assess the variability of COP displacement within a trial.The COP positions were determined from the virtual acting points of the ground reaction forces. The average speed of the COP in each phase of the movement was computed as the total trajectory length traveled by the COP divided by the corresponding time. The ellipse area was determined as the area enclosing 95% of the COP positions, and was formed by linear curve fitting of the axes. The COP displacements were normalized to the corresponding The variables of interest included the absolute errors of the active joint reposition sense of the ankle and the aforementioned COP measures. The Shapiro–Wilk test was used to test the normality of the outcome measures. The paired-t test was then performed to test the training effects on the errors of joint reposition sense and balance ability during ballet dance performance. The effect sizes were also calculated to evaluate the strength of comparison. The significance level was set as 0.05 in every case. All of the statistical analyses were performed using commercial SPSS software .p = 0.031), 20° plantarflexion (p = 0.003) and 10° eversion (p = 0.019) were improved significantly. However, no significant difference was observed between the pre- and post-training repositioning errors in 10° and 20° inversion , pre-equilibrium (p = 0.023) and equilibrium phases after training. Participants also showed a smaller maximum displacement in the medial-lateral direction during the pre-equilibrium phase (p = 0.004) and a smaller SD of the COP displacement in the anterior-posterior direction during the lowering phase (p = 0.034). However, no significant difference was observed in the 95% COP ellipse area, maximum displacement in the anterior-posterior direction, or SD of the displacements in the medial-lateral direction after training , pre-equilibrium (p = 0.003), equilibrium (p = 0.009) and post-equilibrium (p = 0.011) phases after training. Participants also showed smaller maximum displacements of the COP in the medial-lateral direction during the lowering (p = 0.004), pre-equilibrium (p = 0.044) and post-equilibrium (p = 0.011) phases. A smaller SD of the displacements in the medial-lateral direction during the lowering (p = 0.002), pre-equilibrium (p = 0.014), equilibrium (p = 0.046) and post-equilibrium (p = 0.017) phases were observed after training. However, no significant difference was observed between the pre- and post-training values of the 95% COP ellipse area, maximum displacement of the COP, and SD of the COP displacements in the anterior-posterior direction  on the foam mat or air discs. The execution of dorsiflexion movements on such unstable surfaces actively triggers the proprioceptive mechanoreceptors around the ankle joint and gives rise to an improved joint reposition sense as a result. Similarly, the plyometric training exercises involved continuous jump-landing tasks, in which the dancers were required to react quickly in the landing period, thereby actuating the proprioception function of ankle dorsiflexion to enhance the pre-stretching effect of the muscles and increase the contraction force for the following jump motion. Thus, it appears that both plyometric training and proprioception exercises are beneficial in improving the ankle joint reposition sense in ankle dorsiflexion.demi-pointe  or full pointe . Standing in these extreme positions requires full ankle plantarflexion combined with slight ankle eversion to maintain stability. Consequently, the medial side of the forefoot takes a larger proportion of the weight bearing. This in turn suppresses lateral deviation of the COP and reduces the risk of lateral ankle sprain. Overall, therefore, the improved reposition sense in ankle dorsiflexion, plantarflexion and eversion observed in both groups in the present study may be the natural result of regular ballet training rather than the integrated training program.Routine ballet training in itself  appears to be sufficient to improve the repositioning ability of the ankle in dorsiflexion, plantar flexion and eversion. A previous study investigated the ankle joint reposition ability of gymnasts and non-gymnasts and found that the gymnasts had a superior reposition ability performance . It was No improvement was observed in the ankle joint reposition sense in inversion following the training process. Notably, this contradicts the hypothesis of the present study that the training program can prevent episodes of ankle sprain. It is speculated that the insignificant training effect may be the natural result of regular ballet training. In particular, when performing heel-rise movements in ballet pointe shoes, ballet dancers are instructed to balance on the tips of two or three toes with the foot positioned away from the ankle inversion position. The dancers may apply the similar strategy during training sessions. Consequently, the ankles are routinely placed either neutrally or at slight eversion, and hence the effect of training on the ankle inversion reposition sense is inevitably reduced.turnout  are the primary muscles responsible for controlling postural stability in medial-lateral sway during grand-plie and releve en demi-pointe movements.Plyometric exercise involves two main adaptations, namely peripheral and central. In peripheral adaptation, the stretch sensitivity of the Golgi tendon organs (GTOs) is heightened, and hence the muscle spindle contributes more afferents to the central nervous system, together with better proprioception . The conturnout compared to quiet standing are a way to challenge proprioceptive awareness, as a previous study showed that quiet standing is less challenging for dancers [Central adaptation results from the anticipatory movements required to execute the plyometric exercises prescribed in the training program. For example, the preparation for serial jumping movements facilitates the activity of the central nervous system and hence enhances the sensitiveness of the muscle spindles to position changes. The facilitation of muscle spindles may improve the balance ability during ballet movements and joint reposition ability as a previous study showed that the ankle plantar flexor torques is associated with postural stability . The imp dancers .releve en demi-pointe and grand-plie movements. The dancers showed a slower COP average speed after the training program; thereby indicating a more stable posture. The improved postural stability may stem from a greater core stability and improved joint reposition sense. For example, a previous study investigated the transient effect of core stability exercises on postural sway, and found that core stability exercises reduce the range of COP displacements in the medial-lateral direction and decrease the COP speed during quiet standing [The effects of training on the postural stability of the ballet dancers were observed by measuring the speed and displacements of the COP during standing . Furtherstanding . In addistanding , and thureleve en demi-pointe and grand-plie movements. Previous studies have reported that improved postural stability in the medial-lateral direction but not in the anterior-posterior direction is associated with the use of different balance strategies in the two directions. In particular, in side-by-side stance, balance in the anterior-posterior direction is maintained mainly by the ankle joint, whereas in the medial-lateral direction, balance is maintained predominantly by the hip abductor/adductor [The dancers had both a lower absolute displacement of the COP in the medial-lateral direction and a smaller SD of the COP displacements after the training program during adductor . The corturnout position [A previous meta-analysis review reported that proprioception exercises can improve subjective instability and functional outcomes such as Star Excursion Balance test . Similarposition .In the present study, participants underwent assessments at pre- and post-training, however, this study did not have a control group to compare with the intervention effects. Hence, the intervention effectiveness is limited due to the training session including both the proposed training program and the regular ballet training.This study has investigated the effectiveness of an integrated training program involving proprioception, plyometric and core stability exercises on the joint reposition senses of the ankle joint, the balance ability during specific ballet movements.The integrated training program improved the neuromuscular control of the ankle joint, which may minimize the risk of ankle sprain during ballet movement by improving the joint reposition sense in dorsiflexion, plantarflexion, and eversion and the balance ability during specific ballet dance movements. Thus, the proposed integrated training program may be an option to be included in ballet dancers’ training program on improving the neuromuscular control of the ankle joint and the balance ability.


Introduction: Reactive arthritis (ReA) is a chronic inflammatory disease usually caused by a preceding gastrointestinal or genitourinary bacterial infection. ReA usually occurs in the lower limbs causing joint pain and joint swelling. Physiotherapy-led exercise is recommended to prevent muscle atrophy. The purpose of this case report is to describe the outcome after 12 weeks of low-load blood flow restricted resistance training (BFR-RT) as a rehabilitation method for a young male suffering from ReA.Methods and materials: A 17-year-old male suffered from ReA in the both knee joints and the left hip joint. 36 months after the incident, he suffered from another ReA incident in his right knee. Non-steroid anti-inflammatory drugs and a new arthrocentesis added with corticosteroid injection was unsuccessful in treating the ReA. The patient performed 12 weeks of BFR-RT on the right lower limb with a low amount of supervision after the first week of training. Assessment of unilateral 30-sec chair stand test (u30-sec CST), low-thigh circumference above apex patella, The Knee Injury and Osteoarthritis Outcome Score (KOOS), The Forgotten Knee Joint Score (FJS), and Numeric Ranking Scale for pain (NRS) was performed at baseline and after 3,6,9, and 12 weeks of BFR-RT.Results: The patient completed all planned exercise sessions. u30-sec CST improved with 7 repetitions (reps) on the right limb and 5 reps on the left leg. Low-thigh circumference decreased 1.1 cm on the right leg and 1.0 on the left leg. KOOS symptoms, ADL, quality of life and FJS demonstrated a clinically relevant change on 10, 14 and 23 points.Conclusion: The present case study indicates that even with low amounts of supervision BFR-RT could increase functional performance, reduce knee joint swelling and improve key patient-reported outcome. Reactive arthritis (ReA) is a chronic inflammatory disease usually occurring in the lower limb. ReA is often caused by a gastrointestinal or genitourinary bacterial infection which leads to a local immune reaction  with loads corresponding to >75% of the one repetition maximum (1RM) is usually applied to promote skeletal muscle hypertrophy and skeletal muscle strength gains  with no family history of inflammatory joint- or connective tissue diseases. Further, the patient did not suffer from any cardiovascular diseases. After a week of sickness due to a gastrointestinal infection the patient developed ReA in both of his knee joints as well as the left hip joint, hence resulting in hip- and knee joint pain as well as joint swelling, ultimately reducing his physical activity level and quality of life. The ReA of hip joint as well as the knee joints was successfully treated with arthrocentesis, with full recovery in knee joint mobility and only small reduction in hip flexion and hip internal rotation as compared with the right hip joint. At the physical examination at the hospital, the range of motion was not quantified, but only compared between each limb. Thirty-six months after the first ReA, the patient suffered a relapse in his right knee. Similar to the episode, he suffered from knee joint pain and knee joint swelling which resulted in a reduced physical activity-level as well as a reduced quality of life. Treatment with non-steroid anti-inflammatory drugs (NSAID) did not reduce symptoms and a new arthrocentesis and aorticosteroid injection only reduced the knee swelling temporary. After 3 months without improvements, the patient was offered 12 weeks of BFR-RT to (i) improve his functional capacity, (ii) reduce swelling of the knee joint, and (iii) reduce knee symptoms . The patThe BFR-RT was performed at home every second day for 12 weeks, and consisted of squat and lunges . The loaOne physiotherapist collected outcome measures at baseline and after 3, 6, 9, and 12 weeks of BFR-RT and included unilateral 30-Sec chair-stand test (u30-sec CST)  was used to quantify the level of pain prior to each testing session  and relative change in percent  and all planned outcome assessments sessions (100% adherence).Pre-to-post improvements in u30-sec CST was demonstrated for both the right and the left lower limb. However, a two-fold relative improvement in lower limb function was observed for the right lower limb . Low-thiKOOS subscales Symptoms, Activities of daily living (ADL), and Quality of Life (QOL) displayed a ≥10-point change from baseline to after 12 weeks of BFR-RT. Furthermore, a 23-point reduction in the FJS was demonstrated .After 12 weeks of BFR-RT every second day, the young male patient suffering from ReA reported and also demonstrated increased functional capacity, a reduction of knee symptoms, increased ability to perform ADL-activities, an improved QOL in line with reducing his awareness of the knee joint after 12 weeks of BFR-RT. Also, 12 weeks of BFR-RT did not provoke additional knee pain or increase knee joint swelling during the exercise period. Therefore, BFR-RT performed as home-based, body weight exercises seems both feasible, safe, and clinically relevant for patients suffering from ReA.To our best knowledge, this is the first study to demonstrate that 12 weeks of bodyweight BFR-RT every second day was safe and feasible as an exercise method for increasing function and reduce knee joint swelling in a patient suffering from ReA. The reduction in knee swelling was lower than the findings in a RCT performed by Hughes et al.  who repoAfter the intervention period, the patient had improved lower limb function (improved u30-sec CST), suggesting that the exercise method increased lower limb strength and muscular power  demonstrate that BFR-RT was feasible as home-based exercise rehabilitation and (ii) improved functional performance and patient-reported outcomes. Furthermore, the exercise protocol utilized in the present study withholds some limitations that needs to be addressed. First, we decided to include a bilateral exercise (squat) while only restriction blood flow to the right lower limb. As the BFR accelerates the fatigue during an exercise compared to performing the same exercise without BFR  for the publication of any potentially identifiable images or data included in this article.IM: contributed to conception, design of the study, organized the database, and wrote sections of the manuscript. SJ: performed the statistical analysis and wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In this dataset, experimental fatigue testing results have been presented for the additive-manufactured 3D-printed Polylactic acid (PLA) biomaterials under fully-reversed rotating-bending loadings. For such an objective, a fused deposition modeling (FDM) 3D-printer was utilized to fabricate the standard cylindrical samples with different printing parameters in the horizontal direction. For the demonstration of printing parameter effects on the PLA fatigue lifetime, the nozzle diameters were from 0.2 to 0.6 mm, the extruder temperatures were from 180 to 240 °C, and finally, the printing speeds were from 5 to 15 mm/s. Then after 3D-printing of specimens, fatigue testing was performed on various samples under fully-reversed rotating-bending loadings. Then, the fatigue data were presented in tables through the high-cycle fatigue regime, under the load-controlled condition. For further works, these dataset tables could be used to draw the S-N (stress-lifetime) diagram, to find the fatigue strength coefficient and exponent. Having a dataset on the fatigue lifetime for such parts, could be helpful and also useful.•The benefit of these data is to find the effect of different parameters in the 3D-printing technique on the quality in general and on the fatigue lifetime and strength (as a specific criterion) of PLA biomaterials. This experimental fatigue data could help design engineers to further investigations, based on a known behavior of the material.•Using these fatigue datasets could increase the knowledge of the PLA biomaterial behavior, fabricated by fused deposition modeling (FDM) 3D-printers. The data could be utilized to demonstrate the S-N (stress-lifetime) of the material under different fabrication variables in order to find the superior condition of 3D-printing.•The main concern in this dataset is the fatigue strength and lifetime of PLA biomaterials. Such data could be rarely found in articles and this could be one novelty of the presented experimental results. Several articles were presented on the tensile properties of PLA; however, fatigue properties are still rare, especially under various parameters of the 3D-printing process.•These fatigue datasets could be reused for further developments of experiments, as the initial analysis of the fatigue lifetimes for PLA biomaterials. In the future, the fatigue strength of the novel materials could be compared to these data. The novel material could be introduced by reinforcing PLA with fibers or other improvement techniques for the material strength and lifetime.1Raw data for additive-manufactured PLA biomaterials could be seen in 2For the material, the transparent PLA filaments were used with 1.75 mm of diameter, made by YouSu Company. Then, the FDM 3D-printer  was utilIn this dataset, 3 parameters of FDM 3D-printing were considered as the nozzle diameter, the printing temperature, and the printing speed. Then, different standard samples were fabricated to consider all mentioned variables, which change in 3 levels. These descriptions could be seen in Due to the horizontal printing direction, the support has been used to provide the possibility of printing overhangs. In addition, a raft layer has been considered for proper adhesion of the initial layers to the print platform. Removing these materials affects the surface quality and consequently fatigue properties. Thus, post-processing was performed by polishing with sandpaper number of 120 to increase the surface quality for all samples.After fabricating PLA samples, fatigue testing was done under the load-controlled loading condition. For such an objective, the rotary bending fatigue test device , “HCF testing raw data on 3D-printed PLA polymers”, Mendeley Data, V1, DOI: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


A total of 80 geographically distinct clusters are delineated within the Agogo district of the Asante Akim region in Ghana. Clusters are randomized to the intervention arm receiving Vi-TT or a control arm receiving the meningococcal A conjugate vaccine. The primary study endpoint is the total protection of Vi-TT against blood-culture-confirmed typhoid fever. Total, direct, and indirect protection are measured as secondary outcomes. Blood-culture-based enhanced surveillance enables the estimation of incidence rates in the intervention and control clusters. Evaluation of the real-world impact of TCVs and evidence synthesis improve the uptake of prequalified/licensed safe and effective typhoid vaccines in public health programs of high burden settings. This trial is registered at the Pan African Clinical Trial Registry, accessible at Pan African Clinical Trials Registry (ID: PACTR202011804563392).Typhoid fever remains a significant health problem in sub-Saharan Africa, with incidence rates of >100 cases per 100,000 person-years of observation. Despite the prequalification of safe and effective typhoid conjugate vaccines (TCV), some uncertainties remain around future demand. Real-life effectiveness data, which inform public health programs on the impact of TCVs in reducing typhoid-related mortality and morbidity, from an African setting may help encourage the introduction of TCVs in high-burden settings. Here, we describe a cluster-randomized trial to investigate population-level protection of TYPBAR-TCV Salmonella enterica subspecies enterica serovar Typhi (S. Typhi), is one of the most common causes of bacteremia in several low- and middle-income countries and caused an estimated 10.9 million cases and 116,000 deaths globally in 2017 [Typhoid fever (TF), caused by the  in 2017 ,4,5. RecS. Typhi strains, resistant to first-line antimicrobials chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole; fluoroquinolones; and third generation cephalosporins, in many countries reduce the number of viable treatment options and necessitate increasingly complicated and costly alternatives [Most typhoid cases are effectively treated with antibiotics, although the case fatality rate remains at about 1% [rnatives . Improvernatives . Howeverrnatives . Additiornatives , which w®, a Vi-polysaccharide conjugated to a tetanus-toxoid protein carrier (Vi-TT), was prequalified by the WHO in January 2018 and Gavi the Vaccine Alliance has committed an $85 million funding window to support the roll out of TCV in eligible countries between 2019 and 2020.In October 2017, the WHO has recommended the use of TCV in typhoid-endemic countries from the age of 6 months onwards, administered as a single dose and programmatic administration in combination with other childhood vaccines at 9 months of age or in the second year of life . A positOverall, TCVs have been shown to have a reassuringly safety profile across age groups including infants and children ,15,16,17As of January 2021, Vi-TT is licensed for use in nine countries worldwide including Tanzania, Ghana, Kenya, and Zambia. However, large-scale effectiveness data of TCVs in many African settings are still limited. Effectiveness data provide critical input to decision making by national and regional stakeholders to drive country and regional uptake in Africa, where the epidemiology of typhoid fever differs from South Asia. Nonetheless, there are no cluster-randomized trials currently ongoing on the continent and population-level protection data are largely lacking. Herein, we present the design of the first cluster-randomized trial assessing the real-world vaccine effectiveness of TCVs in preventing typhoid fever on the African continent. The data generated will be used in estimating the budgetary impact and in understanding the value of the money invested in the potential introduction of TCV in Ghana.The Typhoid Conjugate Vaccine Effectiveness in Ghana (TyVEGHA) study is a participant- and observer-blinded, cluster-randomized phase IV trial with clusters randomized to receive Vi-TT or the control vaccine MenAfriVac ) to evaluate the effectiveness and safety of Vi-TT in Ghanaian children and adolescents. The cluster-randomized design was selected in order to assess both the individual-level effectiveness (on vaccinees) and population-level effectiveness (on both vaccinees and non-vaccinees) including herd protection of vaccination of children and adolescents aged 9 months to <16 years living in the Asante Akim District in Ghana for a period of 3 years. The first vaccination was conducted through a cluster level mass vaccination of age eligible children (Year 1), followed by annual catch-up vaccinations (Year 2 and 3) for age-eligible children and adolescents at the trial sites. Enhanced passive surveillance was conducted in parallel in the trial catchment area to identify blood-culture-confirmed TF cases.www.pactr.org (ID: PACTR202011804563392).This trial is registered at the Pan African Clinical Trial Registry, accessible at The TyVEGHA study population was recruited from a geographically defined catchment area in the Asante Akim District of Ghana  socioeconomic information of the households, including profession, household income, and level of education and (2) healthcare-seeking behavior and to access to water, sanitation, and hygiene (WaSH) infrastructure. Household verbal consent for the census was provided by the head or a key informant of the household.A total of 23,000 eligible children and adolescents will be vaccinated—11,500 each in the Vi-TT and MCV-A arms. A subset for immunogenicity assessment will include 600 children and adolescents aged 9 months to <16 years , and a subset for safety monitoring will include 3000 children and adolescents aged 9 months to <16 years   at the time of vaccination, voluntarily provide consent via their parents or legally authorized representative (LAR), and live within the study cluster at the time of vaccination.Individuals will not be enrolled if they, or a parent or LAR, report a history of allergic reactions to any vaccine component, ongoing acute and/or chronic illness, or any coagulopathies ; if there are any compelling medical or social reasons in the judgment of a physician; if they are pregnant (including self- or parent-/LAR-reported or positive urine testing) or are lactating; or if they received a typhoid vaccination (proven by presentation of a vaccine card or parent-/LAR-reported) in the last 5 years prior to presentation.Participants will be temporarily excluded if, at the time point of vaccination, the parent/LAR reported fever (elevated tympanic (≥38 °C) or axillary temperature (≥37.5 °C)) in the child within 24 h and/or the use of antipyretics within 4 h prior to vaccination or if they received any other vaccination during the previous 4 weeks (confirmed by vaccine card or parent-/LAR-reporting). Females ≥11 years of age with self- or parent-/LAR-reported irregular menstruation or who did not know their last menstruation date will be reassessed and consented at or after their next menstrual period. A reassessment at least 48 h after the initial screening of resolving the condition of temporary exclusion criteria will be conducted to ensure these temporary exclusion criteria no longer existed.The trial staff identified potential participants living in the 80 clusters of Asante Akim North, Ghana. Trial staff, including community health volunteers, will systematically approach each household in the area to identify households with children and adolescents that will be age-eligible at the time of vaccination. Once a household with a potential participant will be identified, the parent/LAR of the child will be given basic information about the trial and invited to attend the nearest study vaccination clinic.After arrival at the study clinic, participants and their parents/LAR will be provided with an explanation of study objectives and invited to participate following written informed consent. Assent will be sought for participants ≥11 years of age. Once consent and assent (as appropriate) will be obtained, trial staff will screen volunteers according to the inclusion/exclusion criteria and conduct a medical examination, including measuring baseline temperature to assess for temporary exclusion criteria. Demographic information (including age and address) and participant/parent/LAR contact details will be updated during this visit. Participants or their parent/LAR meeting at least one temporary exclusion criteria after the medical assessment will be informed of the reason and asked to return in ≥48 h after resolving the condition of temporary exclusion criteria for repeat assessment and re-consenting.Consented participants will be randomized by cluster to receive either Vi-TT or MCV-A. The randomization list by cluster will be computer-generated prior to the start of the vaccination campaign and will be provided to the staff assigned for randomization to reduce discriminatory practices or unfair assignment of vaccines. Based on the cluster randomization, the appropriate vaccine will be administered by a trained member of the study team. The site of vaccination will be recorded. If the participant’s parent/LAR consent to participation in the immunogenicity substudy, a blood sample will be collected prior to vaccination by a trained staff member. The participant will be considered enrolled in the study at the point in that any medical procedure took place .A study card will be provided during the annual update census, which contains the name of the study, the participant ID, and contact details for the study team will be given to all participants/parents/LAR for use if they have any concerns or if their child is admitted to hospital at any time during the study. The study card will also contain instructions for attending the study health care facilities or sentinel sites if the participant develops a fever at any time over the follow-up period of three years.n = 3000, 1:1 assignment to intervention and control group) using study diary cards, and 3 years of passive hospital-level febrile and severe adverse event (SAE) surveillance. An independent Safety Monitoring Committee (SMC) was established to assess safety results and to correspond with the Data Safety Monitoring Board (DSMB). Randomization lists for these subsets will be generated prior to the vaccination campaign by an independent statistician who is not part of the study. The selection of these participants were age-stratified  (A subset of 600 participants will be selected on a 2:1 ratio (Vi-TT vs. MCV-A) to have blood samples collected at baseline (Day (D) 0) and at D28, D365, D730 and D1095 post-vaccination to assess vaccine immunogenicity. Safety assessments will include an active safety follow-up contact on day 7 to monitor adverse events following immunization in participants in the safety substudy ( of 1:1) . ParticiS. Typhi (anti-Vi IgM and IgG) and invasive non-typhoidal Salmonella after Vi-TT administration will be determined at defined timepoints.The primary outcome of interest is the total protection of single-dose Vi-TT vaccination, measured as the incidence of blood-culture-confirmed typhoid fever in vaccinated children and adolescents, comparing intervention with the control clusters. Secondary outcomes include the occurrence of adverse events reported from participants receiving Vi-TT compared with MCV-A through active safety follow-up in a subset (safety subgroup) within the first 7 days post-vaccination and passive safety follow-up of serious adverse events within 6 months of vaccination determined by self-reporting at follow-up contact. The incidence of blood-culture-confirmed symptomatic TF, clinical TF (cases with fever persisting for >72 h), and severe TF, defined as blood-culture-confirmed TF with any one systemic complication of TF detected at presentation, will be assessed in all residents , comparing intervention clusters with control clusters as well as in vaccinated individuals  and in unvaccinated individuals (indirect protection) . The shoS. Typhi, incidence of acute abdominal surgery and surgical procedure on intestinal perforations, and all-cause hospitalization rates in all residents and in vaccinees of the intervention cluster compared with the control clusters. The analysis of mortality rates assessed through verbal autopsy in the study area differentiates between all-cause mortality, mortality with fever, and mortality with fever and abdominal pain between the intervention clusters compared with the control vaccine clusters. In addition, the prevalence of antimicrobial-resistant S. Typhi pre- and post-vaccination will be compared between the intervention and control clusters, and the corresponding antimicrobial prescription patterns were observed in participating health care facilities that are part of the existing surveillance system.Exploratory outcome measures include the assessment of incidence of clinically diagnosed intestinal perforations that are associated with The sample size was calculated by assuming an expected cumulative incidence rate of typhoid fever in control clusters over 3 years of 36 cases per 10,000 person-years in a catchment population of 21,213 i.e., 45,961.5 person-years of risk. Based on a preliminary analysis of survey data from the target population, we assumed that 50% of febrile illness cases seek healthcare at Agogo Presbyterian Hospital . A totalFollowing Hayes and Moulton, a total sample size of 13,200 person-years, which was obtained by sampling 80 clusters (40 in each arm) with an average cluster size ranging from 145 to 180, achieved >80% power to detect a total effectiveness of 80% between the intervention event rate 0.0007 and the control event rate 0.0036 . The betn = 200) or control vaccine (n = 100) with an assumption of a 90% reference seroconversion rate, −10% of non-inferiority margin, and 25% drop-out rate.For the immunogenicity substudy, a total of 600 children and adolescents will be enrolled, stratified by age (<5 years and ≥5 years). Each age stratum was randomized 2:1 to receive the intervention  and gender . The subgroup analysis was not powered to evaluate the primary outcome, and any observed patterns were interpreted cautiously, owing to the large study population and increased chance of type I error.The primary outcome measure is blood-culture-positive TF detected during passive surveillance see  at the sFor safety assessment in the subset for active follow-up, solicited and unsolicited adverse events (AEs) at day 7 post-vaccination will be assessed. The frequency and proportion of participants who experience solicited AE and unsolicited AE post-vaccination will be presented with the 95% CI. Additionally, the number of participants and number of occurrences of AEs by vaccine arm for each age strata as well as overall ages were assessed. The occurrence of any SAE within 6 months follow-up post-dose will be also summarized and listed.An immunogenicity analysis will be presented as the geometric mean titre (GMT) with 95% CI at baseline (D 0), D 28, D 365 D 730, and D 1095, and as a proportion of four-fold increase from baseline (seroconversion rate) with 95% CI at D 28, D 365, D 730, and D 1095.Data defined by the study protocol will be captured in a clinical study database using REDCap . All cliS. Typhi isolated from a positive blood culture. Patients enrolled in SETA Plus received appropriate initial treatment, with follow-up of blood-culture-positive cases including informing patients of the results and adjustment of treatment based on laboratory findings in accordance with hospital guidelines.Surveillance for enteric fever and clinically suspected perforations was integrated within the Severe Typhoid Fever in Africa (SETA) Program . This eshttps://office.microsoft.com/excel), which was used to estimate the costs of TCV vaccination in India [versus geographically targeted) against the current situation of no vaccination. In-country immunization managers will be consulted to gather information on vaccination strategies included in the analysis.Health economics studies are planned to transform evidence generated from TyVEGHA to support decision making during the introduction of TCVs in Ghana. As a first step, we will project the TCV delivery cost in Ghana based on the country’s immunization practices using a Microsoft Excel-based tool  between 9 months up to 16 years of age see . The genThe survey on water, sanitation, and hygiene (WaSH) factors showed that the main drinking water sources were at the community level, including unprotected systems such as boreholes and wells (29%) or surface water (3%) see . Few houn = 7327) were latrines (29.1%) and open defecation (19%).Regarding access to sanitation facilities, adults from 59.4% of the surveyed households reported using latrines. The main sanitation option reported from households with children (www.thecaproject.net). The first population census conducted in 2019 defined the baseline cohort profile, including demographic characteristics and key baseline WaSH indicators. We observed that access to safe water and hygiene practices was poor while access to sanitation facilities was reported in two thirds of adults and a one third of children. Over 40% of the catchment population was found to be younger than 16 years, those who are considered eligible for vaccination in the trial.This protocol described a cluster-randomized study designed to measure population-based vaccine effectiveness of the Vi-TT vaccine in Ghana, embedded in a blood-culture-based typhoid fever surveillance system. The TyVEGHA trial constitutes one arm of the Typhoid Conjugate Vaccine Introduction in Africa (THECA) program  in 2018 and Vi-CRM197  in 2020 [Our study complements the efforts on effectiveness evaluation of WHO-prequalified TCVs and those under clinical development to support introduction in public health programs. To date, two TCVs have been WHO prequalified for use in children–Vi-TT (Typbar-TCV in 2020 ,32. Addi in 2020 ,17,33. TData generated from TyVEGHA describing the real-world effectiveness of one of the WHO prequalified vaccines will be of particular importance to policy makers in high-burden countries and will provide them with a clearer view of the full public health value of TCVs deployed at this scale as they develop typhoid control and elimination strategies. Furthermore, it paves the way for more impact evaluation studies of different TCVs in high-burden settings. Health economic studies including vaccine delivery cost estimation, budget impact analysis, and cost-effectiveness analyses provide an evidence summary that is directly applicable to Ghana and readily usable for making decisions on TCV introductions. The results of TyVEGHA may be transferable to similar settings on the African continent and may provide evidence to promote further uptake of TCVs by health authorities in typhoid-endemic countries.


The continued success of the COVID-19 vaccination programme in the UK will depend on widespread uptake of booster vaccines. However, there is evidence of hesitancy and unwillingness to receive the booster vaccine, even in fully vaccinated adults. Identifying factors associated with COVID-19 booster vaccine intentions specifically in this population is therefore critical.We used data from 22,139 fully vaccinated adults who took part in the UCL COVID-19 Social Study. Multinomial logistic regression examined predictors of uncertainty and unwillingness (versus willingness) to receive a COVID-19 booster vaccine (measured 22 November 2021 to 6 December 2021), including (i) socio-demographic factors, (ii) COVID-19 related factors , and (iii) initial intent to receive a COVID-19 vaccine in the four months following the announcement in the UK that the vaccines had been approved (2 December 2020 to 31 March 2021).4% of the sample reported that they were uncertain about receiving a COVID-19 booster vaccine, and a further 4% unwilling. Initial uncertainty and unwillingness to accept the first COVID-19 vaccine in 2020-21 were each associated with over five times the risk of being uncertain about and unwilling to accept a booster vaccine. Healthy adults  were also more likely to be uncertain or unwilling to receive a booster vaccine. In addition, low levels of current stress about catching or becoming seriously ill from COVID-19, consistently low compliance with COVID-19 government guidelines during periods of strict restrictions , lower levels of educational qualification, lower socio-economic position, and age below 45 years were all associated with uncertainty and unwillingness.Our findings highlight that there are a range of factors that predict booster intentions, with the strongest predictor being previous uncertainty and unwillingness. Two other concerning patterns also emerged from our results. First, administration of booster vaccinations may increase social inequalities in experiences of COVID-19 as adults from lower socio-economic backgrounds are also most likely to be uncertain or unwilling to accept a booster vaccine as well as most likely to be seriously affected by the virus. Second, some of those most likely to spread COVID-19  are most likely to be uncertain and unwilling. Public health messaging should be tailored specifically to these groups.The Nuffield Foundation [WEL/FR-000022583], the MARCH Mental Health Network funded by the Cross-Disciplinary Mental Health Network Plus initiative supported by UK Research and Innovation [ES/S002588/1], and the Wellcome Trust [221400/Z/20/Z and 205407/Z/16/Z]. Widespread uptake of COVID-19 booster vaccines is essential for maintaining the progress made in managing the pandemic. However, little is known about which factors relate specifically to accepting a COVID-19 booster vaccine amongst adults who have been fully vaccinated. We searched PubMed for English language scientific articles published 1 January 2020 to 10 December 2021 using the MeSH terms “COVID-19 Vaccines” AND “Vaccination/psychology” OR “Vaccination refusal”. The search yielded 424 results. Identified studies focused on socio-demographic, behavioural, and COVID-19 related factors in relation to uncertainty and unwillingness to accept a first dose of a COVID-19 vaccine, but not COVID-19 booster vaccines.This is the first study, to our knowledge, to examine socio-demographic and COVID-19 related predictors of COVID-19 booster vaccine hesitancy. Using a sample of fully vaccinated adults, our analyses build on this prior research and demonstrate that the strongest predictors of booster vaccine hesitancy were initial uncertainty and unwillingness to accept a COVID-19 vaccine, poor compliance with government guidelines, younger age, and indicators of lower socio-economic status .Initial uncertainty and unwillingness to accept a COVID-19 vaccine will be a significant barrier to widespread uptake of booster vaccines. Other factors associated with initial COVID-19 vaccine hesitancy also appear to predict booster vaccine uncertainty and unwillingness: lower levels of education and income, low levels of compliance with behavioural guidelines to control the pandemic, and younger age.Alt-text: Unlabelled box,,,Although highly effective in preventing severe disease and death,,,,,Although COVID-19 vaccine uptake in the UK has, overall, been high,Recent data from the Opinions and Lifestyle Survey (OPN) in the UK suggest a considerable proportion of the general population who have received two doses of a COVID-19 vaccine are either unwilling  or unsure  about accepting a booster vaccine.Therefore, the aims of this study were to identify associations between socio-demographic and COVID-19 related factors  and initial intent to receive the COVID-19 vaccine following the announcement in the UK that the vaccines had been approved (2 December 2020 to 31 March 2021) with uncertainty and unwillingness to receive a COVID-19 booster vaccine in adults who had been fully vaccinated.https://osf.io/jm8ra/). The study commenced on 21 March 2020 and involves online weekly data collection from participants for the duration of the COVID-19 pandemic in the UK. The study is not random and therefore is not representative of the UK population. But it does contain a well-stratified sample that was recruited using three primary approaches. First, convenience sampling was used, including promoting the study through existing networks and mailing lists , print and digital media coverage, and social media. Second, more targeted recruitment was undertaken focusing on groups who were anticipated to be less likely to take part in the research via our first strategy, including (i) individuals from a low-income background, (ii) individuals with no or few educational qualifications, and (iii) individuals who were unemployed. Third, the study was promoted via partnerships with third sector organisations to vulnerable groups, including adults with pre-existing mental health conditions, older adults, carers, and people experiencing domestic violence or abuse. The study was approved by the UCL Research Ethics Committee [12467/005] and all participants gave informed consent. Participants were not compensated for participation.Data were drawn from the COVID-19 Social Study; a large population-based panel study of the psychological  and social experiences  of over 70,000 adults (aged 18+) in the UK during the COVID-19 pandemic. See the study User Guide for a complete listing of study questions and modules  data on intent to receive a COVID-19 booster vaccine , (ii) data on initial intent to receive a first COVID-19 vaccine (collected 2 December 2020 to 31 March 2021), (iii) received at least two doses of a COVID-19 vaccine at follow-up, and (iv) complete data on other study variables.A total of 32,096 participants met the first criterion, and of these, 26,619 also had data on initial COVID-19 vaccine intent, and 25,821 also met the third criterion of having had at least two doses of a COVID-19 vaccine at follow-up. 3,682 individuals were excluded due to missing data on other study variables, for example those who had selected “other/prefer not to say” in response to gender or “prefer not to say” on ethnicity or income, due to insufficient statistical power and an inability to create statistical weights for these individuals, leaving a total analytical sample of 22,139. See Supplemental Table S1 for a comparison of excluded and included participants on study variables.On 14 September 2021, the UK Joint Committee on vaccination and Immunisation (JCVI) announced that booster vaccinations were available to vulnerable groups , provided they had had their second COVID vaccination at least six months ago. On 29 November 2021, in response to the rise of the Omicron variant, the UK government accelerated the booster programme by announcing that all adults over the age of 18 would be eligible to receive a booster vaccine at least three months after their second dose.Intention to receive a COVID-19 booster vaccine was measured in the November COVID-19 Social Study with a study developed item (“How likely do you think you are to get a COVID-19 booster vaccine if/when you are offered one?”). Response options ranged from 1 “very unlikely” to 6 “very likely”, as well as 7 “I have already had one/accepted one”. An ordinal variable was coded: (0) intend to receive the booster vaccine (responses of 5-7), (1) unsure about whether to receive the booster vaccine (responses of 3-4), and (2) unwilling to receive the booster vaccine (responses of 1-2). Participants who had already received or accepted a booster vaccine were included in the comparison group in order to maximise sample size and ensure that older and vulnerable groups were part of analyses, under the assumption that uptake of the booster vaccine so early in the programme indicated a willingness to receive it. To examine how their inclusion may have affected results, a sensitivity analysis which excluded these people was carried out. See Supplemental Table S2 for a listing of all question wording for study developed items.Socio-demographic factors were collected at baseline  and included gender , age group  ethnicity , education  or vocational training, and up to GCSE  [equivalent to education to age 16]), income , smoking status (non-smoker vs former or current smoker), employment status , area of dwelling , living arrangement , and government's identified key worker status (not a key worker vs key worker). The latter included people with jobs deemed essential during the pandemic  and who were required to leave home to carry out this work during lockdowns.Participant reports at baseline on whether they had received a clinical diagnosis of a mental health condition  or chronic physical health condition  were used to create two binary variables (yes/no) to indicate the presence or absence of pre-existing physical and mental health conditions.Initial intent to receive a COVID-19 vaccine was measured with a study developed item administered 2 December 2020 to 31 March 2021. Many participants had vaccine intention data for all four months during this period, but because we were interested in their first recorded intention to receive the vaccine after its authorisation was announced in the UK on 2 December 2020, we coded initial intent in this way. In a sensitivity analysis, participants’ last recorded COVID-19 vaccine intention during the period 2 December 2020 to 31 March 2021 was used.Ever having had COVID-19 was operationalised from a study developed item administered at follow-up which was coded as: yes, confirmed by a test (either a positive COVID-19 test or an antibody test), yes, suspected by either a doctor or the participant, and no.Confidence in government and the health service to handle the pandemic were assessed with one study developed question each at follow-up. Response options ranged from 1  to 7 (lots). Two binary variables were created to indicate a lot of (5-7) versus low (1-4) confidence in the government and health system.Self-reported compliance with government COVID-19 guidelines was measured with one study developed question with response options ranging from 1  to 7 (very much so). We analyse this as an binary variable reflecting patterns of compliance whilst restrictions were in place across the pandemic. As most of our sample resides in England, we used dates for which there were strict COVID-19 restrictions in England . See Supplemental Table S3 for a listing of these dates. The binary variable was coded as: consistently high compliance  vs consistently low compliance . Sensitivity analyses using a variable reflecting average compliance across the entirety of the pandemic were conducted.Self-reported knowledge of COVID-19 was measured at follow-up with one study developed question and rated on a 7-point scale from 1 (very poor knowledge) to 7 (very good knowledge). Responses of 1-4 were categorised as low compared to high (5-7) COVID-19 knowledge. The presence or absence of worry about either contracting COVID-19 or becoming seriously ill from it were captured from two multiple choice questions asked at follow-up. A binary variable was created to indicate not having endorsed either as a source of stress vs having endorsed one or both.Two multinomial regression models were fitted to examine associations between socio-demographic and COVID-19 related factors and uncertainty and unwillingness to receive a COVID-19 booster vaccine. The first model included only socio-demographic variables whilst the second additionally included COVID-19 related variables. The outcome variable in these two models was coded such that those who were uncertain or unwilling were compared to those who were very likely to receive the COVID-19 booster vaccine or had already accepted one. Multinomial regression coefficients were exponentiated and presented as relative risk ratios (RRR) with corresponding 95% confidence intervals (CI).To account for the non-random nature of the sample and increase representativeness of the UK general population, all data were weighted to the proportions of gender, age, ethnicity, country, and education obtained from the Office for National Statistics.Unweighted and weighted sample characteristics are presented in 4% of the weighted sample expressed unwillingness to receive a COVID-19 booster vaccine , whilst 4% were uncertain (a score of 3-4) . DescripOf those who were initially willing to accept a COVID-19 vaccine when it became available, 5% said they were either uncertain (3%) or unwilling (2%) to accept a booster . 73% of Results from the multinomial regression model predicting uncertainty and unwillingness to receive a COVID-19 booster vaccine from socio-demographic factors are shown in For booster uncertainty, the same three factors continued to be predictors. Relative to adults aged 60 and above, adults aged 18-29 were over five times more likely to be uncertain , adults aged 30-44 were over four times more likely , and even adults aged 45-59 were 1·6 times more likely to be uncertain . Education up to GCSE was additionally associated with a 1·7 times increased risk of being uncertain  relative to having a degree, but the association for adults with A-levels or vocational qualifications was not present. As for unwillingness, healthy adults were also at increased risk of being uncertain  to receive the booster compared to individuals with a long-term physical health condition. For uncertainty, two further socio-demographic factors emerged as predictors too. Adults who were employed (vs unemployed/retired/students/not working) were more than three times more likely to be uncertain . There were mixed results for income, with some evidence that household income levels below £60,000 and below £16,000 per year were associated with increased risk of being uncertain  relative to higher income households. But no further socio-demographic factors were associated with uncertainty, including ethnicity, living arrangement, smoking status, keyworker status and having a mental health condition.The strongest predictor of booster uncertainty and unwillingness was original intention to be vaccinated when the vaccines were first approved . Adults The second highest predictor of unwillingness was consistently low compliance with COVID-19 guidelines during strict restriction periods  which also predicted uncertainty . Not having said that catching or falling seriously ill from COVID-19 was a source of stress in the past week at follow-up also predicted unwillingness  and uncertainty  about boosters. Low self-reported knowledge of COVID-19 also predicted uncertainty but not unwillingness to get a booster . Confidence in government, confidence in the health system, and past experience of having COVID-19 were not predictors of booster intentions.Sensitivity analyses conducted using participants’ last recorded (rather than first recorded) COVID-19 vaccine intention during the period 2 December 2020 to 31 March 2021 , from the model which included a variable indicating average low vs high levels of compliance with guidelines across the entirety of the pandemic (rather than only during periods of strict restrictions) , and from the model which included only sample participants who had had exactly two doses of a COVID-19 vaccine at follow-up  resulted in substantively similar findings. However, amongst adults who had had exactly two doses of a COVID-19 vaccine at follow-up, age was no longer a predictor of booster uncertainty , whilst education up to A-levels or vocational and age 30-44 were no longer predictors of booster unwillingness .The funders had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. All researchers listed as authors are independent from the funders and all final decisions about the research were taken by the investigators and were unrestricted. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.,,,This is the first study, to our knowledge, to examine associations between socio-demographic and COVID-19 related factors, and previously measured initial intent to receive a COVID-19 vaccine with future uncertainty and unwillingness to receive a COVID-19 booster vaccine in fully vaccinated adults. The proportions in our sample who were uncertain about receiving (4%) and unwilling (4%) to receive a COVID-19 booster vaccine are similar to those in the OPN .Previous vaccine attitudes and intentions are logical predictors of attitudes to booster vaccines, and prior research has highlighted a range of reasons for initial hesitancy, including high levels of mistrust in vaccines and concerns about unforeseen future side effects,,,,It is also concerning that some we found a socio-economic gradient in intentions to take up the booster vaccine, as some of the same socio-demographic groups most at risk of uncertainty and unwillingness to receive the COVID-19 booster vaccine are also at increased risk for severe illness and death from COVID-19, including those with low incomes and who have low levels of education.,,,,Worryingly, some of those who are most likely to spread the virus are also the least likely to say they will accept a booster vaccine. First, the most important socio-demographic determinant of both uncertainty and unwillingness to receive a COVID-19 booster vaccine in our study was age, which has been found in prior work.Interestingly, though, having been previously infected with COVID-19 was not a predictor of either unwillingness or uncertainty about accepting a booster vaccine, which was also found in a large multi-national survey in relation to COVID-19 vaccine intent.Finally, it is notable that we found that some people willing to accept a booster had initially been uncertain or unwilling to have a vaccination when the vaccines were first approved in 2020. As our sample was restricted to people who had received two vaccinations, it only covers individuals who had overcome initial uncertainty or unwillingness to be vaccinated. Nonetheless, 73% of those who were initially uncertain and 65% of those who were initially unwilling to be vaccinated but who had still received two vaccinations were willing to accept a booster. This highlights that previous vaccination attitudes can be changed not just for single vaccinations but for multiple courses of vaccination. It supports previous research suggesting that people who were initially uncertain rather than unwilling may be easier to convince to vaccinate than the latter, and therefore a promising group to engage in health communication programmes.Strengths of the current study are that it is a large sample well-stratified on major demographic characteristics and analyses were weighted to increase representativeness of the general UK population. Analyses of initial COVID-19 vaccine intentions with outcomes were also longitudinal and included rich information on a range of socio-demographic and COVID-19 related factors. We focused on initial COVID-19 vaccine attitudes in the four months following the day their approval was announced in the UK in 2019 as well as gathering new data on booster vaccine attitudes to allow comparisons of attitudes over the past twelve months. However, there were some limitations. First, our sample is not nationally representative of the general UK population. We used a heterogeneous and large sample in our analyses and weighted our responses to population proportions, but it is possible that more extreme views towards booster vaccines may therefore not be represented. Second, our recruitment strategy could have resulted in clustering , and attitudes may be more similar within households. However, this would be considered a minimal risk given the large sample and we used robust standard errors. Third, due to small sub-group sample sizes we were unable to examine specific associations of different ethnicities with booster vaccine attitudes and we treated this socio-demographic characteristic as binary. This could have led to oversimplification of the diverse opinions and experiences held by different ethnicity subgroups.Findings suggest initial uncertainty and unwillingness about receiving a COVID-19 booster vaccine will be a barrier to maintaining the progress that has been made thus far in controlling the COVID-19 pandemic through vaccines. There is therefore an urgent need for public health messaging emphasising the safety and importance of COVID-19 booster vaccines even for fully vaccinated adults, in particular focusing on individuals from lower socio-economic backgrounds and individuals at greatest risk of spreading the virus. Finally, in light of evidence showing that existing COVID-19 vaccines offer protection for limited time periods and therefore will likely need to be updated on a regular period moving forwards, there is a need for more research into ongoing attitudes to COVID-19 vaccinations and boosters.Both authors declare no conflicts of interest.


Ageist attitudes and loneliness negatively impact both younger and older adults . This study utilized a randomized waitlist-control design to investigate the effects of a six-week intergenerational e-mail pen pal program on loneliness in younger and older adults and ageism in younger adults. Thirty-three younger adults (18-30 years) and 28 older adults (over age 65) completed an online survey assessing ageist attitudes, loneliness, well-being, and other individual differences. One week after completing a baseline survey, 17 email pen pal pairs began the six-week e-mail intervention. Participants repeated the survey one week after the completion of the intervention (which was eight weeks after the baseline for the control participants). Analyses showed that at baseline, younger adults  reported higher levels of loneliness compared to older adults , t(59) = 3.85, p < .001. Repeated measures ANOVAs showed that the intervention did not have a significant effect on ageism or loneliness in either younger or older adults. However, the effect size of the intervention for loneliness among older adults was moderate to large (η2= .07). Descriptive statistics indicated that older adults in both the intervention and control groups experienced an increase of loneliness during the post-test. However, the older adults in the intervention group experienced less of an increase compared to older adults in the control group. This suggests that the intervention may have buffered the increase in loneliness that older adults may experience during the winter months and during the onset of the COVID-19 pandemic.