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Supplementary Data from CD20-Targeted Therapy Ablates De Novo Antibody Response to Vaccination but Spares Preestablished Immunity

To obtain a deeper understanding of poor responses to COVID-19 vaccination in patients with lymphoma, we assessed blocking antibodies, total anti-spike IgG, and spike-specific memory B cells in the peripheral blood of 126 patients with lymphoma and 20 age-matched healthy controls 1 and 4 months after COVID-19 vaccination. Fifty-five percent of patients developed blocking antibodies postvaccination, compared with 100% of controls. When evaluating patients last treated from days to nearly 18 years prior to vaccination, time since last anti-CD20 was a significant independent predictor of vaccine response. None of 31 patients who had received anti-CD20 treatment within 6 months prior to vaccination developed blocking antibodies. In contrast, patients who initiated anti-CD20 treatment shortly after achieving a vaccine-induced antibody response tended to retain that response during treatment, suggesting a policy of immunizing prior to treatment whenever possible.Significance:In a large cohort of patients with B-cell lymphoma, time since anti-CD20 treatment was an independent predictor of neutralizing antibody response to COVID-19 vaccination. Comparing patients who received anti-CD20 treatment before or after vaccination, we demonstrate that vaccinating first can generate an antibody response that endures through anti-CD20–containing treatment.This article is highlighted in the In This Issue feature, p. 85

Supplementary Figure from CD20-Targeted Therapy Ablates De Novo Antibody Response to Vaccination but Spares Preestablished Immunity

To obtain a deeper understanding of poor responses to COVID-19 vaccination in patients with lymphoma, we assessed blocking antibodies, total anti-spike IgG, and spike-specific memory B cells in the peripheral blood of 126 patients with lymphoma and 20 age-matched healthy controls 1 and 4 months after COVID-19 vaccination. Fifty-five percent of patients developed blocking antibodies postvaccination, compared with 100% of controls. When evaluating patients last treated from days to nearly 18 years prior to vaccination, time since last anti-CD20 was a significant independent predictor of vaccine response. None of 31 patients who had received anti-CD20 treatment within 6 months prior to vaccination developed blocking antibodies. In contrast, patients who initiated anti-CD20 treatment shortly after achieving a vaccine-induced antibody response tended to retain that response during treatment, suggesting a policy of immunizing prior to treatment whenever possible. Significance: In a large cohort of patients with B-cell lymphoma, time since anti-CD20 treatment was an independent predictor of neutralizing antibody response to COVID-19 vaccination. Comparing patients who received anti-CD20 treatment before or after vaccination, we demonstrate that vaccinating first can generate an antibody response that endures through anti-CD20–containing treatment. This article is highlighted in the In This Issue feature, p. 85

Background 5-aminosalicylic acid (5-ASA) is widely used as a first-line treatment for ulcerative colitis (UC), but intolerance sometimes occurs. 5-ASA-intolerance was considered a risk factor for colectomy in UC patients, but no reports have examined which treatment is suitable to avoid colectomy in 5-ASA-intolerant UC patients. This is the first report describing a treatment strategy for 5-ASA-intolerant UC. The aims of this study were to determine the optimal therapeutic strategy in 5-ASA-intolerant UC patients. Methods This retrospective cohort study involved patients who were newly diagnosed as having UC after January 2010 and who received oral 5-ASA agents. Patients were considered 5-ASA-intolerant when they fulfilled two or more of the following conditions: (1) paradoxical aggravation of colitis on introducing oral 5-ASA agents or allergic reactions to the agents; (2) obvious improvement of abdominal symptoms after discontinuation of 5-ASA agents; (3) positive drug-induced lymphocyte stimulation test (DLST) for at least two formulations of 5-ASA; (4) adverse events following re-challenge with 5-ASA agents; and (5) severe adverse events owing to 5-ASA agents. Results Of 950 UC patients with a history of 5-ASA administration, 213 (22.4%) were considered 5-ASA-intolerant. Five-year colectomy-free survival was significantly lower in 5-ASA-intolerant patients compared with 5-ASA-tolerant patients (73% vs. 84%, respectively). From the multivariate Cox proportional hazards model analysis in the 5-ASA-intolerant patient cohort, thiopurine use was shown to contribute to avoidance of colectomy in 5-ASA-intolerant patients (hazard ratio = 0.25; 95% confidence interval, 0.13–0.47; P < 0.001); however, 5-ASA-intolerant patients were also likely to be thiopurine-intolerant compared with 5-ASA-tolerant patients (27% vs. 15%, respectively; P = 0.04). Calcineurin inhibitor use was associated with an increased risk of colectomy (hazard ratio = 4.80; 95% confidence interval, 2.24–10.3; P < 0.001), while treatment with systemic corticosteroids and biologics did not affect the colectomy rate (hazard ratio = 1.07; 95% confidence interval, 0.60–1.91; P = 0.81). Conclusion Treatment with thiopurines demonstrated the potential to improve the prognosis in 5-ASA-intolerant patients. However, it should be noted that thiopurine intolerance was more frequent in 5-ASA-intolerant patients. Compared to biologics, calcineurin inhibitors may not contribute to avoidance of colectomy, and biologics may be preferred for intractable patients with 5-ASA intolerance. This is the first report describing a treatment strategy for 5-ASA-intolerant UC, and we believe it will have many implications in clinical practice.

Many Brazilian forest industries use wood biomass as a sustainable energy source that generates a wood ash by-product. This residue is typically discarded in nearby planted forests. To evaluate the effects of wood ash rates on Pinus taeda L. growth, a study was established on a high clay soil in 2006. Five rates of wood ash (0, 10, 20, 40, and 80 T ha−1) were applied to a P. taeda system. Soil chemical properties were evaluated three times at different depths. Tree growth (i.e., height, diameter at breast height, and commercial volume) and nutrition (needle elemental composition) were determined. After 11 years, litter accumulation and soil mobilization (bioturbation) were also evaluated. Ash application did not affect tree growth/yield or litter accumulation. A small reduction in soil acidity and increased bases in the upper soil layer were observed two years after ash application; this effect reached deeper layers after six years but retreated to shallower depths at 11 years. A soil amount of 14.6 m3 ha−1 year−1 was relocated closer to the soil surface due to bioturbation by edaphic fauna. The application of wood ash to forest soils appears to be an ecologically sound alternative for disposal of this industrial by-product.

Background Intestinal Behçet's disease (BD) is a relapsing-remitting disease typically associated with punched-out ulcers in the ileocecal region. Optimal monitoring of disease activity is necessary; however, ileocolonoscopy cannot be performed on a regular basis as it is invasive, resource-intensive and causes considerable patient discomfort. Furthermore, there are risks of intestinal bleeding and perforation caused by pretreatment laxatives and air insufflation during the examination. Hence, other follow-up examinations are required. Intestinal ultrasonography (IUS) is a minimally invasive imaging method, but there are no previous reports of comparisons between IUS and endoscopy for intestinal BD. This study aimed to evaluate the usefulness of IUS in assessing the activity of ileocecal ulcers in intestinal BD. Methods This retrospective single-centre study included patients with intestinal BD who underwent colonoscopy and IUS within 2 weeks, from 2007 to 2020. Correlations between the corresponding endoscopic activity using the Sakita–Miwa classification and six IUS variables (bowel wall thickness [BWT], vascularity, bowel wall stratification, intramural and extramural abscesses, fistulas and mesenteric lymphadenopathy) were assessed and used to select the variables that should be included in the new simple score. IUS findings were also compared with biomarker (C-reactive protein [CRP]) concentrations and clinical severity indices (Crohn’s disease activity index and disease activity index for intestinal BD [DAIBD]). Results Seventy-nine IUS examinations from 53 patients were included. Univariate analysis revealed that CRP and DAIBD and the IUS findings BWT, vascularity and bowel wall stratification and intramural and extramural abscesses differed significantly according to endoscopic ulcer activity. Multivariate analysis using a logistic regression model revealed that only BWT and vascularity were statistically different; therefore, a new simple score ([2*BWT] + [5*vascularity]) was constructed. Receiver operating characteristic curve analysis revealed an area under the curve of 0.91 for detecting endoscopic activity, which was superior to those of CRP (0.80; P=0.069), Crohn’s disease activity index (0.69; P=0.002) and DAIBD (0.67; P Conclusion A new simple ultrasound activity index for intestinal BD comprising BWT and vascularity was constructed and correlated well with endoscopic disease activity. This is the first report describing the usefulness of IUS for intestinal BD, and we believe the findings will have many implications in clinical practice.

Post-transplant primary central nervous system lymphoma (PCNSL) is a rare complication of solid organ transplantation. The optimal therapy for post-transplant PCNSL is not well established and generally includes reduction of immunosuppression and chemotherapy. Progression after front-line chemotherapy is common, and whole-brain radiotherapy (WBRT) is a standard salvage treatment as there is a concern that localized treatment fields would not prevent out-of-field recurrences. However, WBRT is associated with neurotoxicity and morbidity in these patients with inherently poor prognoses. Here, we report a patient with local recurrence of post-transplant PCNSL who was treated with fractionated stereotactic radiotherapy (SRT). He had no clinical toxicity from treatment and maintained pre-treatment neurocognition and performance status. Local control was achieved for 20 months following SRT, at which point he developed an in-field recurrence. He restarted lymphoma therapy but died one month later from fungal pneumonia. For central nervous system (CNS) lymphoma, further data are needed to optimize tumor control and toxicity outcomes and identify patients in whom localized radiotherapy fields may be beneficial, avoiding the potential toxicity of WBRT.

We developed a CANDLES-III system to study the neutrino-less double beta (0$\nu\beta\beta$) decay of $^{48}$Ca. The proposed system employs 96 CaF$_{2}$ scintillation crystals (305 kg) with natural Ca ($^{\rm nat.}$Ca) isotope which corresponds 350\,g of $^{48}$Ca. External backgrounds were rejected using a 4$\pi$ active shield of a liquid scintillator surrounding the CaF$_2$ crystals. The internal backgrounds caused by the radioactive impurities within the CaF$_2$ crystals can be reduced effectively through analysis of the signal pulse shape. We analyzed the data obtained in the Kamioka underground for a live-time of 130.4\,days to evaluate the feasibility of the low background measurement with the CANDLES-III detector. Using Monte Carlo simulations, we estimated the background rate from the radioactive impurities in the CaF$_{2}$ crystals and the rate of high energy $\gamma$-rays caused by the (n, $\gamma$) reactions induced by environmental neutrons. The expected background rate was in a good agreement with the measured rate, i.e., approximately 10$^{-3}$ events/keV/yr/(kg of $^{\rm nat.}$Ca), in the 0$\nu\beta\beta$ window. In conclusion, the background candidates were estimated properly by comparing the measured energy spectrum with the background simulations. With this measurement method, we performed the first search for 0$\nu\beta\beta$ decay in a low background condition using a detector with a Ca isotope, in which the Ca present was not enriched, in a scale of hundreds of kg. The $^{48}$Ca isotope has a high potential for use in 0$\nu\beta\beta$ decay search, and is expected to be useful for the development of a next-generation detector for highly sensitive measurements.

BackgroundKnee joint disorder is one of the factors causing frailty in the elderly, which is associated with a decrease in walking speed.ObjectivesWe measured the walking speed of patients scheduled to undergo primary total knee arthroplasty (TKA) and examined factors correlated with walking speed.MethodsThe patients with knee disorders scheduled to undergo knee arthroplasty at our hospital between July 2020 and May 2021 were included. They were assessed for basic attributes, clinical assessment including Kness Society Score (KSS), degree of pain on walking by visual analogue scale (VAS), range of motion (ROM), and also leg skeletal muscle mass index (SMI; whole-body mode DXA), quadriceps strength by dynamometer with written consent (UMIN ID: 000040940). And Japanese Cardiovascular Health Study criteria for frailty, and sarcopenia by Asian Working Group for Sarcopenia 2019 criteria were evaluated.ResultsDemographic data of 83 patients (65 women, mean age 74.9 years) included in this study was shown in Table 1. The distribution in frailty is 36.2% and that in sarcopenia is 7.3%. Most of the patients with frailty with knee disorder did not suffer from sarcopenia. A multivariate analysis was conducted with walking speed as the objective variable and the dependent variables as age, gender, pain VAS on walking, KSS, leg SMI, quadriceps strength, and ROM. The results showed that age and ROM in flexion were significantly and independently associated with walking speed (P=0.01, 0.03). Gender, pain VAS on walking, KSS, leg SMI, quadriceps strength, and ROM in extension were not significantly associated with walking speed (P=0.92, 0.11, 0.11, 0.52, 0.85, 0.52).ConclusionAmong the patients with knee disorders immediately before arthroplasty, frailty was not caused by sarcopenia. Age was found to be the most correlated factor with walking speed, and walking speed became slower with age. In addition, poor flexion angle was also the factor for delayed walking speed, but it did not correlate with lower limb skeletal muscle mass or quadriceps strength. In this study pain on walking was not significant factor for walking speed, because it was observed in most of all cases.FactorGroup disease (n)osteoarthritis78 (94%) rheumatoid arthritis5 (6.0%)body mass index (kg/m2) 25.54 (4.11)pain VAS on walking 37.08 (26.35)total Knee Society Score 77.66 (27.85)range of motion (degree)flexion119.46 (12.88) extension-9.58 (6.59)quadriceps power (N) 122.00 [53.00, 350.00]waling speed (m/sec) 0.95 (0.33)grip power (kg) 20.24 (6.97)skeletal muscle mass index (kg/m2)appendicular6.50 [4.92, 9.85] lower limb5.06 [3.76, 7.56]Frailty (n)none10 (12.5%)Pre-frail41 (51.2%) frail29 (36.2%)Sarcopenia (n)none76 (92.7%)sarcopenia4 (4.9%) severe sarcopenia2 (2.4%)mean (standard deviation); median [min max]Disclosure of InterestsNone declared

Visuomotor adaptation is a form of motor learning that enables accurate limb movements in the presence of altered environmental or internal conditions. It requires updating the mapping between visual input and motor output, and can occur when learning a new device/tool or during rehabilitation after neurological injury. In either case, it is desirable to stabilize, or consolidate, this visuomotor memory for long-term usage. However, reactivation of a consolidated memory, whether it is motor-based or not, is thought to render it temporarily fragile again, and thus susceptible to interference or modification. Here, we determined if visuomotor memories demonstrate long-term retention but are fragile once reactivated. We used prism lenses to create a novel visuomotor mapping, which participants learned while having to walk and step to the center of targets. We re-tested this memory after one week and one year. We found that the mapping is retained for at least one year, regardless of whether participants were exposed to an interfering (i.e., opposing) mapping in the first session. We also found that presenting an opposing mapping in a block of trials following reactivation of the memory one year later did not disrupt subsequent performance when we re-tested the original memory. Our results suggest that these visuomotor memories are stored for extended periods of time and have limited fragility. Taken together, our results highlight the robustness of visuomotor memories associated with walking.

Plasmonic metamaterials based on random metallic nanostructures on mirror were proposed to tune the optical properties due to the surface plasmon (SP) resonance in a flexible manner. The SP resonance peaks were enhanced and dramatically sharpened, and flexibly tuned by optimizing the thickness of the spacer layer between the metal hemisphere and the metal substrate. We verified both experimentally and numerically that structures enable tuning of the localized SP resonance in the deep UV and near IR wavelength regions, respectively. Plasmonic metamaterials proposed here is envisaged to lead to the development of new applications and technologies in the field of plasmonics and nanophotonics.

A 1280×960 floating diffusion storage global shutter image sensor is implemented in a 3D stacked back illuminated indirect time of flight sensor (iToF). The sensor, achieves 18,000e- full well capacity and 32% quantum efficiency (QE) with a pyramid surface for diffraction (PSD) structure [1], utilizing a 3.5µm pixel. Low power consumption is also achieved, due to low leakage current for the iToF pixel and low resistance Cu-Cu connection metal wiring. These device architectures enable high resolution and wide dynamic range 3D depth sensing for both near and far objects.

Previous work has shown that humans account for and learn novel properties or the arm's dynamics, and that such learning causes changes in both the predictive (i.e., feedforward) control of reaching and reflex (i.e., feedback) responses to mechanical perturbations. Here we show that similar observations hold in old-world monkeys (Macaca fascicularis). Two monkeys were trained to use an exoskeleton to perform a single-joint elbow reaching and to respond to mechanical perturbations that created pure elbow motion. Both of these tasks engaged robust shoulder muscle activity as required to account for the torques that typically arise at the shoulder when the forearm rotates around the elbow joint (i.e., intersegmental dynamics). We altered these intersegmental arm dynamics by having the monkeys generate the same elbow movements with the shoulder joint either free to rotate, as normal, or fixed by the robotic manipulandum, which eliminates the shoulder torques caused by forearm rotation. After fixing the shoulder joint, we found a systematic reduction in shoulder muscle activity. In addition, after releasing the shoulder joint again, we found evidence of kinematic aftereffects (i.e., reach errors) in the direction predicted if failing to compensate for normal arm dynamics. We also tested whether such learning transfers to feedback responses evoked by mechanical perturbations and found a reduction in shoulder feedback responses, as appropriate for these altered arm intersegmental dynamics. Demonstrating this learning and transfer in non-human primates will allow the investigation of the neural mechanisms involved in feedforward and feedback control of the arm's dynamics.

Background Current consensus statements recommend at least 3–6 months of preconception steroid-free remission for women with inflammatory bowel disease, as determined by experts. However, little data is available on the appropriate preconception remission period in women with ulcerative colitis (UC). We explored the effect of the preconception steroid-free remission period on disease activity during pregnancy and birth outcomes in women with UC. Methods Data were obtained from a retrospective chart review of 141 consecutive pregnant women with UC at our inflammatory bowel disease centre and a related clinic from 2000–2020. Women who were diagnosed with UC more than 6 months before conception and who were judged to have been accurately assessed for disease activity during the 6-month preconception period and at each trimester during pregnancy were included. We categorized the women into four subgroups according to their preconception steroid-free remission periods (≥6 months, 3–6 months, Results The rate of active disease during pregnancy was 63% in the ≥6 months preconception steroid-free remission group, 50% in the 3–6 months preconception steroid-free remission group, 71% in the 0.05). Conclusion The largest risk factor for disease activity during pregnancy appears to be active disease at conception. A shorter preconception steroid-free remission period than the recommended 3–6 months might reduce the risk of disease activity during pregnancy.

Background Serrated polyps are recognized as precursors of colorectal cancer in general population and have recently been reported in patients with ulcerative colitis (UC). However, their prevalence and detailed characteristics remain unclear. Methods The prevalence and clinicopathological and biological characteristics of serrated polyps in patients with UC were retrospectively examined in a single tertiary inflammatory bowel disease centre in Japan from 2000 to 2020. Results In total, 252 neoplasms, including 36 serrated polyps (26 in colitis-affected segments, 10 in colitis-unaffected segments), were identified in 187 patients with UC. The proportion of serrated polyps was significantly higher from 2010 to 2020 (35/213, 17%) than from 2000 to 2009 (1/39, 3%; p = 0.023). Serrated polyps in colitis-affected segments were common in patients with extensive colitis (88%), a history of persistent active colitis (58%), and a long duration of UC (12.1 years). Serrated polyps in colitis-affected segments were more common in men (88%). Of 26 serrated polyps in colitis-affected segments, 15, 6, and 5 were categorized as sessile serrated lesion (SSL)-like dysplasia, traditional serrated adenoma (TSA)-like dysplasia, and serrated dysplasia not otherwise specified (SD NOS), respectively. SSL-like dysplasia was common in the proximal colon (67%) and with BRAF mutation (62%), whereas TSA-like dysplasia and SD NOS were common in the distal colon (100% and 80%) and with KRAS mutations (100% and 75%). CpG island hypermethylation phenotype-positive status was observed in 60% cases of TSA-like dysplasia but in only 25% cases of SSL-like dysplasia and SD NOS. Conclusion Serrated polyps have recently been increasing in patients with UC. Serrated polyps in colitis-affected segments were common in men with extensive and longstanding colitis, suggesting that chronic inflammation is involved in the development of serrated polyps in patients with UC.

A CpG-stimulated autologous tumor cell vaccine for patients with MCL is safe and feasible and induces detectable antitumor T cell immune responses. Patients who received the CpG-MCL vaccination demonstrated freedom from MRD at 1 yr after ASCT that surpassed previously reported rates., Here, we report on the results of a phase I/II trial (NCT00490529) for patients with mantle cell lymphoma who, having achieved remission after immunochemotherapy, were vaccinated with irradiated, CpG-activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT). The primary endpoint was detection of minimal residual disease (MRD) within 1 yr after ASCT at the previously validated threshold of ≥1 malignant cell per 10,000 leukocyte equivalents. Of 45 evaluable patients, 40 (89%) were found to be MRD negative, and the MRD-positive patients experienced early subsequent relapse. The vaccination induced antitumor CD8 T cell immune responses in 40% of patients, and these were associated with favorable clinical outcomes. Patients with high tumor PD-L1 expression after in vitro exposure to CpG had inferior outcomes. Vaccination with CpG-stimulated autologous tumor cells followed by the adoptive transfer of vaccine-primed lymphocytes after ASCT is feasible and safe.

Previous work has shown that humans account for and learn novel properties or the arm’s dynamics, and that such learning causes changes in both the predictive (i.e., feedforward) control of reaching and reflex (i.e., feedback) responses to mechanical perturbations. Here we show that similar observations hold in old-world monkeys (macaca fascicularis). Two monkeys were trained to use an exoskeleton to perform a single-joint elbow reaching and to respond to mechanical perturbations that created pure elbow motion. Both of these tasks engaged robust shoulder muscle activity as required to account for the torques that typically arise at the shoulder when the forearm rotates around the elbow joint (i.e., intersegmental dynamics). We altered these intersegmental arm dynamics by having the monkeys generate the same elbow movements with the shoulder joint either free to rotate, as normal, or fixed by the robotic manipulandum, which eliminates the shoulder torques caused by forearm rotation. After fixing the shoulder joint, we found a systematic reduction in shoulder muscle activity. In addition, after releasing the shoulder joint again, we found evidence of kinematic aftereffects (i.e., reach errors) in the direction predicted if failing to compensate for normal arm dynamics. We also tested whether such learning transfers to feedback responses evoked by mechanical perturbations and found a reduction in shoulder feedback responses, as appropriate for these altered arm intersegmental dynamics. Demonstrating this learning and transfer in non-human primates will allow the investigation of the neural mechanisms involved in feedforward and feedback control of the arm’s dynamics.

Generating pure elbow rotation requires contracting muscles at both the shoulder and elbow joints to counter torques that arise at the shoulder when the forearm rotates (i.e., intersegmental dynamics). Previous work has shown that human participants learn to reduce their shoulder muscle activity if the same elbow movement is performed after the shoulder joint is mechanically locked, which is appropriate because locking the shoulder joint eliminates the torques that arise at the shoulder when the forearm rotates. However, this learning is slow (i.e., it unfolds over hundreds of trials) and incomplete (i.e., shoulder activity is not fully eliminated). Here we investigated whether and how the addition of explicit strategies and biofeedback modulate this type of learning. Three groups of human participants (N = 55) performed voluntary pure elbow rotations using a robotic exoskeleton that permits shoulder and elbow rotation in a horizontal plane. Participants did the task with the shoulder free to move (baseline), then with the shoulder joint locked by the robotic manipulandum (adaptation), and then with the shoulder free to move again (post-adaptation). The first group of participants performed this protocol and received no instructions about what to do after their shoulder was locked. The second group of participants received visual feedback about their shoulder muscle activity after each movement and was instructed to reduce their shoulder activity to zero. The third group of participants also received visual biofeedback, but it was removed part way through the experiment. We found that, although all groups learned, the rate and magnitude of learning was not reliably different across the groups. Taken together, our results suggest that learning new arm dynamics, unlike other motor learning paradigms, unfolds independent of explicit instructions, biofeedback and task instructions.

© 2020 Elsevier Inc. Learning a new motor task modifies feedforward (i.e., voluntary) motor commands and such learning also changes the sensitivity of feedback responses (i.e., reflexes) to mechanical perturbations [1–9]. For example, after people learn to generate straight reaching movements in the presence of an external force field or learn to reduce shoulder muscle activity when generating pure elbow movements with shoulder fixation, evoked stretch reflex responses to mechanical perturbations reflect the learning expressed during self-initiated reaching. Such a transfer from feedforward motor commands to feedback responses is thought to take place because of shared neural circuits at the level of the spinal cord, brainstem, and cerebral cortex [10–13]. The presence of shared neural resources also predicts the transfer from feedback responses to feedforward motor commands. Little is known about such a transfer presumably because it is relatively hard to elicit learning in reflexes without engaging associated voluntary responses following mechanical perturbations. Here, we demonstrate such transfer by leveraging two approaches to elicit stretch reflexes while minimizing engagement of voluntary motor responses in the learning process: applying very short mechanical perturbations [14–19] and instructing participants to not respond to them [20–26]. Taken together, our work shows that transfer between feedforward and feedback control is bidirectional, furthering the notion that these processes share common neural circuits that underlie motor learning and transfer.

Previous work has demonstrated that when learning a new motor task, the nervous system modifies feedforward (ie. voluntary) motor commands and that such learning transfers to fast feedback (ie. reflex) responses evoked by mechanical perturbations. Here we show the inverse, that learning new feedback responses transfers to feedforward motor commands. Sixty human participants (34 females) used a robotic exoskeleton and either 1) received short duration mechanical perturbations (20 ms) that created pure elbow rotation or 2) generated self-initiated pure elbow rotations. They did so with the shoulder joint free to rotate (normal arm dynamics) or locked (altered arm dynamics) by the robotic manipulandum. With the shoulder unlocked, the perturbation evoked clear shoulder muscle activity in the long-latency stretch reflex epoch (50-100ms post-perturbation), as required for countering the imposed joint torques, but little muscle activity thereafter in the so-called voluntary response. After locking the shoulder joint, which alters the required joint torques to counter pure elbow rotation, we found a reliable reduction in the long-latency stretch reflex over many trials. This reduction transferred to feedforward control as we observed 1) a reduction in shoulder muscle activity during self-initiated pure elbow rotation trials and 2) kinematic errors (ie. aftereffects) in the direction predicted when failing to compensate for normal arm dynamics, even though participants never practiced self-initiated movements with the shoulder locked. Taken together, our work shows that transfer between feedforward and feedback control is bidirectional, furthering the notion that these processes share common neural circuits that underlie motor learning and transfer.

We report a very rare case of pulmonary chromomycosis caused by Scedosporium prolificans that developed after lung transplantation and was successfully treated with endobronchial topical amphotericin B instillation. The subject was a woman in her 50s with a history of bilateral lobar lung transplantation from living donors for idiopathic pulmonary hypertension. Eight years after the lung transplantation, chest radiography X-ray and computed tomography showed an abnormal shadow in the right lung. Bronchoscopic findings showed obstruction by a fungal component at the laterobasal bronchus B9. She was diagnosed with pulmonary chromomycosis after S. prolificans was detected in the bronchial aspirate. Systemic antifungal treatment with itraconazole was ineffective. Therefore, we administered topical amphotericin B weekly via endobronchial instillation and replaced oral itraconazole with voriconazole. The endobronchial procedure was safe and tolerable. Bronchial obstruction improved after three 3 instillations. We continued topical amphotericin B instillation once every 3 months for 2 years, and the abnormal shadow nearly disappeared. This case report describes infection by S. prolificans, which rarely becomes an etiologic agent in lung transplant patients, and shows that endobronchial topical amphotericin B instillation is a therapeutic option when systemic antifungal treatment is ineffective.

Korrespondenz zu 10.1200/JCO.2018.78.5246

Background: Patients with B-cell lymphoma have poor clinical outcomes to SARS-CoV-2 infection (COVID-19) and are also more likely to have suboptimal responses to immunization. An understanding of which lymphoma patients are at greatest risk of poor COVID-19 vaccine response and what aspects of immunity are most impaired is critical for developing strategies to protect these patients from a potentially fatal infection. Methods: We enrolled 149 participants, including 129 with lymphoma and 20 age-matched controls, who received a complete COVID-19 vaccination series to assess how B- and T-cell vaccine responses vary among clinically relevant subgroups and over time. This cohort included 99 patients with prior anti-CD20 treatment, ranging from 1 week to 17 years prior, allowing us to assess relationships between timing and intensity of anti-CD20 exposure and vaccine response. The cohort also included 18 patients who began treatment with an anti-CD20-containing regimen after being fully vaccinated, in whom we are assessing the potential efficacy of a pre-therapy vaccination strategy. Peripheral blood samples were taken on average 28 days and 4 months after last vaccine dose. B-cell responses are being profiled by measuring anti-Spike serum IgG, RBD-ACE2 blocking activity, and spike-specific memory B cells. T cell assessments include quantitation of spike-specific activation and cytokine production via interferon-gamma ELISPOTs and multiparameter flow cytometry. Results: The 129 participants with lymphoma had a median age of 68, were 59% male, and 70% had either diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Thirteen percent had no therapy prior to vaccination, half had not been treated in the past six months and 36% had been treated recently or were currently being treated. Ninety-three percent received an mRNA COVID-19 vaccine. Although we did not detect a statistically significant difference in vaccine response between previously untreated lymphoma patients and controls, 3/17 were negative for blocking antibodies post-vaccine, compared to 0/20 controls (Fishers exact test p=0.09, Figure 1A). Lymphoma patients with any history of treatment had impaired serologic responses to the vaccine compared to previously untreated patients (p=0.01). Responses did not vary by specific lymphoma histology. Blocking antibodies were evident in only 45% and 3% of patients recently/currently treated with a BTK inhibitor or an anti-CD20 antibody, respectively (Figure 1A). Closely evaluating all patients who had ever received anti-CD20 antibody therapy, we found a strong linear correlation between time since last anti-CD20 treatment and RBD-ACE2 binding inhibition (p Conclusions: Treatment with anti-CD20 antibodies significantly impaired COVID-19 vaccine-induced humoral responses in patients with lymphoma in a manner dependent on the time elapsed since last anti-CD20 treatment. Vaccination at least six months after anti-CD20 treatment, likely co-incident with recovery of the B-cell compartment, was associated with positive blocking antibody titers. These data suggest that booster vaccination strategies are more likely to succeed in lymphoma patients who have not received anti-CD20 treatment for at least 6 months and that those patients with recent anti-CD20 treatment may benefit most from passive immunization strategies. Forthcoming results from the pre-therapy vaccination cohort will also help inform sequencing of additional vaccine doses, passive immunization, and anti-cancer treatments. Figure 1 Figure 1. Disclosures Shree: Gilead: Other: Spouse's employment. Beygi: Kite/Gilead: Current Employment. Advani: Astellas/Agensys: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Cell Medica: Membership on an entity's Board of Directors or advisory committees; Forty Seven: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutical: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millenium: Research Funding; Pharmacyclics: Consultancy, Research Funding; Portola Pharmaceuticals: Consultancy; Regeneron: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Khodadoust: CRISPR Therapeutics, Nutcracker Therapeutics: Research Funding; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator. Kurtz: Roche: Consultancy; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Genentech: Consultancy. Alizadeh: Bristol Myers Squibb: Research Funding; Gilead: Consultancy; Celgene: Consultancy, Research Funding; Janssen Oncology: Honoraria; Roche: Consultancy, Honoraria; Foresight Diagnostics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; CAPP Medical: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cibermed: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Levy: GigaGen: Membership on an entity's Board of Directors or advisory committees; Teneobio: Membership on an entity's Board of Directors or advisory committees; Nurix: Membership on an entity's Board of Directors or advisory committees; Dragonfly: Membership on an entity's Board of Directors or advisory committees; Apexigen: Membership on an entity's Board of Directors or advisory committees; Viracta: Membership on an entity's Board of Directors or advisory committees; Spotlight: Membership on an entity's Board of Directors or advisory committees; Immunocore: Membership on an entity's Board of Directors or advisory committees; Walking Fish: Membership on an entity's Board of Directors or advisory committees; Kira: Membership on an entity's Board of Directors or advisory committees; Abintus Bio: Membership on an entity's Board of Directors or advisory committees; Khloris: Membership on an entity's Board of Directors or advisory committees; Virsti: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; Quadriga: Membership on an entity's Board of Directors or advisory committees.

It is well known that the performance of the turbomachinery (losses, vibrations, noise, and erosion) is often affected by the trailing vortex from the blade tip (Tip Leakage Vortex; TLV) of the impeller or propeller, and sometimes cavitation occurs in the center of the vortex core (Tip Vortex Cavitation; TVC). Many researches on the vortex characteristics of isolated hydrofoil by numerical simulations or experiments have been done so far, however, the research on understanding the mechanism of the vortex control technique is not enough, and it is important to mitigate the effect of TLV or TVC, to enhance the performance of turbomachinery. In this study, numerical simulation and experimental investigation were carried out to clarify the effect of winglet, attached to the elliptical hydrofoil (NACA16020). Five different winglet patterns were tested, changing bending angle and direction. Experiments were carried out using the high-speed cavitation tunnel in Ecole Polytechnique Fédérale de Lausanne (EPFL). As for numerical simulation, it was carried out in the same condition of the experiment. As a result, it was clarified that TVC decreased as increasing the bending angle of winglet, and disappeared in the case of 90 degree bent toward pressure side. And it is clarified that the vortex strength, in other word, vortex core pressure is affected by the interaction of the leading edge vortex and the tip vortex, and in case of pressure side 90 degree bended winglet, both vortices were mutually affected and cancelled the strength of these vortices.

As we walk, we must accurately place our feet to stabilize our motion and to navigate our environment. We must also achieve this accuracy despite imperfect sensory feedback and unexpected disturbances. In this study we tested whether the nervous system uses state estimation to beneficially combine sensory feedback with forward model predictions to compensate for these challenges. Specifically, subjects wore prism lenses during a visually guided walking task, and we used trial-by-trial variation in prism lenses to add uncertainty to visual feedback and induce a reweighting of this input. To expose altered weighting, we added a consistent prism shift that required subjects to adapt their estimate of the visuomotor mapping relationship between a perceived target location and the motor command necessary to step to that position. With added prism noise, subjects responded to the consistent prism shift with smaller initial foot placement error but took longer to adapt, compatible with our mathematical model of the walking task that leverages state estimation to compensate for noise. Much like when we perform voluntary and discrete movements with our arms, it appears our nervous systems uses state estimation during walking to accurately reach our foot to the ground. NEW & NOTEWORTHY Accurate foot placement is essential for safe walking. We used computational models and human walking experiments to test how our nervous system achieves this accuracy. We find that our control of foot placement beneficially combines sensory feedback with internal forward model predictions to accurately estimate the body's state. Our results match recent computational neuroscience findings for reaching movements, suggesting that state estimation is a general mechanism of human motor control.