A bispecific antibody targeting HLA-DQ2.5-gluten peptides potently blocks gluten-specific T cells induced by gluten ingestion in patients with celiac disease.

The gluten-free diet for celiac disease (CeD) is restrictive and often fails to induce complete symptom and/or mucosal disease remission. Central to CeD pathogenesis is the gluten-specific CD4+ T cell that is restricted by HLA-DQ2.5 in over 85% of CeD patients, making HLA-DQ2.5 an attractive target for suppressing gluten-dependent immunity. Recently, a novel anti-HLA-DQ2.5 antibody that specifically recognizes the complexes of HLA-DQ2.5 and multiple gluten epitopes was developed (DONQ52). OBJECTIVE: To assess the ability of DONQ52 to inhibit CeD patient-derived T-cell responses to the most immunogenic gluten peptides that encompass immunodominant T cell epitopes. METHODS: We employed an in vivo gluten challenge model in patients with CeD that affords a quantitative readout of disease-relevant gluten-specific T-cell responses. HLA-DQ2.5+ CeD patients consumed food containing wheat, barley, or rye for 3 days with collection of blood before (D1) and 6 days after (D6) commencing the challenge. Peripheral blood mononuclear cells were isolated and assessed in an interferon (IFN)-γ enzyme-linked immunosorbent spot assay (ELISpot) testing responses to gluten peptides encompassing a series of immunodominant T cell epitopes. The inhibitory effect of DONQ52 (4 or 40 µg/mL) was assessed and compared to pan-HLA-DQ blockade (SPVL3 antibody). RESULTS: In HLA-DQ2.5+ CeD patients, DONQ52 reduced T cell responses to all wheat gluten peptides to an equivalent or more effective degree than pan-HLA-DQ antibody blockade. It reduced T cell responses to a cocktail of the most immunodominant wheat epitopes by a median of 87% (IQR 72-92). Notably, DONQ52 also substantially reduced T-cell responses to dominant barley hordein and rye secalin derived peptides. DONQ52 had no effect on T-cell responses to non-gluten antigens. CONCLUSION: DONQ52 can significantly block HLA-DQ2.5-restricted T cell responses to the most highly immunogenic gluten peptides in CeD. Our findings support in vitro data that DONQ52 displays selectivity and broad cross-reactivity against multiple gluten peptide:HLA-DQ2.5 complexes. This work provides proof-of-concept multi-specific antibody blockade has the potential to meaningfully inhibit pathogenic gluten-specific T-cell responses in CeD and supports ongoing therapeutic development.

Pancreatic fibrosis assessment and association with pancreatic cancer: comparison with the extracellular volume fraction.

AIMS: To compare the iodine washout rate (IWR) from multiphasic contrast-enhanced computed tomography (CT) with the extracellular volume fraction (fECV) for assessing pancreatic fibrosis and its association with pancreatic cancer. MATERIALS AND METHODS: The study included 51 individuals (33 men; median age: 69 years; 21 with pancreatic cancer, 30 with other diseases) who underwent multiphasic contrast-enhanced CT and histological evaluation for fibrotic changes in pancreas. The histological pancreatic fibrosis fraction (HPFF) was assessed on Azan-stained sections. Pancreatic parenchymal enhancement values were measured to calculate IWR and fECV. Statistical methods, such as Spearman's rho and Mann-Whitney U-test, were used. Linear regression models using IWR and fECV were constructed to predict HPFF, with the performance expressed as root mean squared error (RMSE) and Akaike information criterion (AIC). RESULTS: HPFF correlated with all CT parameters at the estimated transection line, strongest for IWRPPP-EP (r=-0.69, P<0.01). HPFF and fECV values were higher in the pancreatic cancer group than in controls (30% vs. 12.5%, P<0.01; 40.3% vs. 33.0%, P<0.01), whereas IWR values were lower (IWRPPP-EP: 43.3% vs. 55.0%, P<0.01; IWRPVP-EP: 25.0% vs. 33.5%, P<0.01). Linear regression models combining IWRPPP-EP + fECV and IWRPVP-EP + fECV were superior for predicting HPFF, with lower RMSE (9.23-9.35) and AIC (379.38-380.72) values than models with IWR or fECV alone. CONCLUSION: IWRPPP-EP, IWRPVP-EP, and fECV were reliable biomarkers for noninvasively assessing pancreatic fibrosis and were associated with pancreatic cancer risk. Linear regression combining these variables showed enhanced predictive accuracy for pancreatic fibrosis.

Significant and variable linear polarization during the prompt optical flash of GRB 160625B.

Newly formed black holes of stellar mass launch collimated outflows (jets) of ionized matter that approach the speed of light. These outflows power prompt, brief and intense flashes of γ-rays known as γ-ray bursts (GRBs), followed by longer-lived afterglow radiation that is detected across the electromagnetic spectrum. Measuring the polarization of the observed GRB radiation provides a direct probe of the magnetic fields in the collimated jets. Rapid-response polarimetric observations of newly discovered bursts have probed the initial afterglow phase, and show that, minutes after the prompt emission has ended, the degree of linear polarization can be as high as 30 per cent-consistent with the idea that a stable, globally ordered magnetic field permeates the jet at large distances from the central source. By contrast, optical and γ-ray observations during the prompt phase have led to discordant and often controversial results, and no definitive conclusions have been reached regarding the origin of the prompt radiation or the configuration of the magnetic field. Here we report the detection of substantial (8.3 ± 0.8 per cent from our most conservative simulation), variable linear polarization of a prompt optical flash that accompanied the extremely energetic and long-lived prompt γ-ray emission from GRB 160625B. Our measurements probe the structure of the magnetic field at an early stage of the jet, closer to its central black hole, and show that the prompt phase is produced via fast-cooling synchrotron radiation in a large-scale magnetic field that is advected from the black hole and distorted by dissipation processes within the jet.

Are biomechanics during gait associated with the structural disease onset and progression of lower limb osteoarthritis? A systematic review and meta-analysis.

OBJECTIVE: To evaluate if gait biomechanics are associated with increased risk of structurally diagnosed disease onset or progression of lower limb osteoarthritis (OA). METHOD: A systematic review of Medline and Embase was conducted from inception to July 2021. Two reviewers independently screened records, extracted data and assessed risk of bias. Included studies reported gait biomechanics at baseline, and either structural imaging or joint replacement occurrence in the lower limb at follow-up. The primary outcome was the Odds Ratio (OR) (95% confidence interval (CI)) of the association between biomechanics and structural OA outcomes with data pooled for meta-analysis. RESULTS: Twenty-three studies reporting 25 different biomechanical metrics and 11 OA imaging outcomes were included (quality scores ranged 12-20/21). Twenty studies investigated knee OA progression; three studies investigated knee OA onset. Two studies investigated hip OA progression. 91% of studies reported a significant association between at least one biomechanical variable and OA onset or progression. There was an association between frontal plane biomechanics with medial tibiofemoral and hip OA progression and sagittal plane biomechanics with patellofemoral OA progression. Meta-analyses demonstrated increased odds of medial tibiofemoral OA progression with greater baseline peak knee adduction moment (KAM) (OR: 1.88 [95%CI: 1.08, 3.29]) and varus thrust presence (OR: 1.97 [95%CI: 1.32, 2.96]). CONCLUSION: Evidence suggests that certain gait biomechanics are associated with an increased odds of OA onset and progression in the knee, and progression in the hip. REGISTRATION NUMBER: PROSPERO CRD42019133920.

Assessment of the cut-off value of quantitative liver-portal vein contrast ratio in the hepatobiliary phase of liver MRI.

AIM: To calculate the quantitative liver-portal vein contrast ratio (Q-LPC) cut-off value based on tumour detectability by using receiver operating characteristic (ROC) curves. MATERIALS AND METHODS: Seventy-four patients with tumours (46 men and 28 women; age, 71 ± 8.1 years), who underwent liver magnetic resonance imaging (MRI) using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) were enrolled. Some patients were found to have multiple tumours. In total, 102 tumour images were evaluated for quantitative liver-spleen contrast ratio (Q-LSC) and Q-LPC 10 minutes after the administration of Gd-EOB-DTPA. Q-LPC and Q-LSC were compared to assess the cut-off values and usefulness. The ROC curve was evaluated using the method for continuously distributed test results, with a free scale of 50 mm. A score of ≥30 out of 50 points was considered good. Cut-off values of Q-LPC and Q-LSC were then calculated. The areas under the ROC curve (AUCs) were also examined and compared. RESULTS: The AUC-ROC for Q-LPC was 0.858 (95% confidence interval [CI], 0.783-0.933). The cut-off value was determined to be at 1.462. Sensitivity was 0.747, and specificity was 0.852 at the cut-off value. The AUC-ROC for Q-LSC was 0.710 (95% CI, 0.597-0.822). The cut-off value was at 1.543, the sensitivity was 0.560, and the specificity was 0.778 at the cut-off value. A significant difference was noted between the AUCs (p=0.0016). CONCLUSION: Q-LPC can be used for hepatobiliary phase MRI evaluation.

Circular polarization in the optical afterglow of GRB 121024A.

Gamma-ray bursts (GRBs) are most probably powered by collimated relativistic outflows (jets) from accreting black holes at cosmological distances. Bright afterglows are produced when the outflow collides with the ambient medium. Afterglow polarization directly probes the magnetic properties of the jet when measured minutes after the burst, and it probes the geometric properties of the jet and the ambient medium when measured hours to days after the burst. High values of optical polarization detected minutes after the burst of GRB 120308A indicate the presence of large-scale ordered magnetic fields originating from the central engine (the power source of the GRB). Theoretical models predict low degrees of linear polarization and no circular polarization at late times, when the energy in the original ejecta is quickly transferred to the ambient medium and propagates farther into the medium as a blast wave. Here we report the detection of circularly polarized light in the afterglow of GRB 121024A, measured 0.15 days after the burst. We show that the circular polarization is intrinsic to the afterglow and unlikely to be produced by dust scattering or plasma propagation effects. A possible explanation is to invoke anisotropic (rather than the commonly assumed isotropic) electron pitch-angle distributions, and we suggest that new models are required to produce the complex microphysics of realistic shocks in relativistic jets.

Leak-free million-fold DNA amplification with locked nucleic acid and targeted hybridization in one pot.

An isothermal cascade reaction that exponentially amplifies pre-designed, single-stranded DNA as a sensor and signal amplifier module for DNA-based computing and molecular robotics was developed. Taking advantage of the finding that locked nucleic acid can suppress problematic ab initio DNA synthesis, up to million-fold amplification rates and concurrent hybridization were achieved at a physiological temperature in a single reactor. Although the effect of locked nucleic acid introduction to the templates was complicated, undesired leak DNA amplification was generally suppressed in the amplification reaction for distinct DNA sequences. The present reaction that senses one DNA as an input and generates a large amount of another DNA as an output, exhibiting a high correlation between the molecular concentration and the amplification time, is applicable for nucleic acid quantification.

Stretch dependent electronic structure and vibrational energy of the bipyridine single molecule junction.

We have studied the stretch dependence of the electronic structure and vibrational energy for the 4,4'-bipyridine (BPY) single molecule junction, which was fabricated by the mechanically controllable break junction (MCBJ) using the highly stable nano MCBJ electrodes. The electronic structure and vibrational energy of the single molecule junction were studied by the current-voltage (I-V) curve and surface enhanced Raman scattering (SERS), respectively. The simultaneous SERS and I-V curve measurements revealed the lowest unoccupied molecular orbital (LUMO) and vibrational energy of the C-C stretching mode decreased with an increase in the metal-molecule distance. The molecular orbital energy shift and vibrational energy shift can be explained by the change in the degree of the hybridization of molecular and metal orbitals.

Highly polarized light from stable ordered magnetic fields in GRB 120308A.

After the initial burst of γ-rays that defines a γ-ray burst (GRB), expanding ejecta collide with the circumburst medium and begin to decelerate at the onset of the afterglow, during which a forward shock travels outwards and a reverse shock propagates backwards into the oncoming collimated flow, or 'jet'. Light from the reverse shock should be highly polarized if the jet's magnetic field is globally ordered and advected from the central engine, with a position angle that is predicted to remain stable in magnetized baryonic jet models or vary randomly with time if the field is produced locally by plasma or magnetohydrodynamic instabilities. Degrees of linear polarization of P ≈ 10 per cent in the optical band have previously been detected in the early afterglow, but the lack of temporal measurements prevented definitive tests of competing jet models. Hours to days after the γ-ray burst, polarization levels are low (P < 4 per cent), when emission from the shocked ambient medium dominates. Here we report the detection of P =28(+4)(-4) per cent in the immediate afterglow of Swift γ-ray burst GRB 120308A, four minutes after its discovery in the γ-ray band, decreasing to P = 16(+5)(-4) per cent over the subsequent ten minutes. The polarization position angle remains stable, changing by no more than 15 degrees over this time, with a possible trend suggesting gradual rotation and ruling out plasma or magnetohydrodynamic instabilities. Instead, the polarization properties show that GRBs contain magnetized baryonic jets with large-scale uniform fields that can survive long after the initial explosion.

Effects of postoperative dietary intake on functional recovery of patients undergoing cardiac surgery.

BACKGROUND AND AIM: Among elderly patients undergoing cardiac surgery, malnutrition is very common and related to muscle wasting known as sarcopenia. Cardiac surgery causes a further decline of nutritional status due to reduced dietary intake (DI); however, the impact of postoperative DI on functional recovery is unclear. METHODS AND RESULTS: We enrolled 250 consecutive patients undergoing cardiac surgery. Daily DI was measured between postoperative days 3 and 7. Patients were categorized as having sufficient or insufficient DI based on whether their DI met or was less than estimated total energy requirements. Functional capacity was measured using the 6-minute walking distance (6MWD) preoperatively and at discharge. Mean postoperative DI was 22.4 ± 3.0 kcal/kg/day, and postoperative DI was insufficient in 92 patients (36.8%). The prevalence of sarcopenia was not different by postoperative DI. Although there was no significant difference in preoperative 6MWD results (P = 0.65), the sufficient DI group had longer 6MWD at discharge than the insufficient DI group (P = 0.04). In multivariate regression analysis, preoperative poor nutritional status (ß = -0.29), duration of surgery (ß = -0.18), and postoperative DI (ß = 0.40) remained statistically significant predictors for improvement of 6MWD (P < 0.0001, adjusted R2 = 0.41). CONCLUSIONS: Postoperative DI was independently associated with functional recovery, but preoperative sarcopenia was not. Regardless of preoperative nutritional status or the presence of sarcopenia, aggressive nutritional intervention in the early stage after surgery helps support functional recovery.

A case of under-dosing after raltegravir formulation change in an elderly patient treated for HIV.

Our case was a 70-year-old male (height: 168 cm, weight: 74.3 kg) with polypharmacy (total 15 drugs including 10 tablets) who was treated for HIV infection. His dosing schedule of raltegravir was changed from BID (a 400 mg tablet, twice) to QD (2x600 mg tablet, once). After a month, we found that he miss-took raltegravir for 1x600 mg tablet at once. His HIV-1 RNA increased from undetectable levels to < 20 copies per mL. Pharmaceutical companies should therefore carefully consider swallowing difficulties in old patients, such as by reformulating medications so that only one dosing is required per day and decreasing the size of tablets to 7-8 mm in diameter or orally distinguish tablet.

The presence of multiple NS5A RASs is associated with the outcome of sofosbuvir and ledipasvir therapy in NS5A inhibitor-naïve patients with chronic HCV genotype 1b infection in a real-world cohort.

It is unclear whether multiple nonstructural (NS) 5A resistance-associated substitutions (RASs) correlate with the outcome of sofosbuvir (SOF) and ledipasvir (LDV) therapy. We investigated the effects of multiple NS5A RASs in NS5A inhibitor-naïve patients with chronic hepatitis C virus genotype 1b infection treated with SOF/LDV. In 313 patients treated with SOF/LDV, we assessed the effects of multiple NS5A RASs on the sustained virological response (SVR). RASs at L28, R30, L31, Q54, P58, Q62, A92, and Y93 in the NS5A region were examined by direct sequencing. The prevalence of RASs was as follows: 2.6% at L28, 8.7% at R30, 6.1% at L31, 48.7% at Q54, 9.9% at P58, 9.9% at Q62, 5.1% at A92, 13.8% at Y93, and 19.2% at L31 or Y93. A total of 133 patients had no RASs. SVR was achieved in 98.7% of the patients. SVR rates significantly differed between patients with and without the L31 or Y93 RAS (93.0% [53/57] vs 100% [250/250], P = .0011). In addition, among patients with the L31 or Y93 RAS, 29.8%, 45.6% and 24.6% had one, two and three or more NS5A RASs, respectively. The SVR rate was significantly lower in patients with the L31 or Y93 RAS with more than three NS5A RASs compared to those with fewer than three NS5A RASs (71.4% [10/14] vs 100% [43/43], P = .0025). Although the prevalence of multiple NS5A RASs at baseline was low in NS5A inhibitor-naïve patients, the presence of multiple NS5A RASs was associated with the effectiveness of SOF/LDV therapy.

Transcriptome characterization of male accessory glands in ants to identify molecules involved in their reproductive success.

In insects, seminal fluid proteins that are produced by male accessory glands and transferred to females during mating have key functions in sperm competition and sperm physiology that lead to male reproductive success. In ants, male reproductive success also depends on the longevity of sperm stored in the queen's spermatheca because their sexual offspring are usually produced only after a prolonged storage period. We identified genes that were up-regulated in the male accessory glands relative to the bodies of Crematogaster osakensis to characterize the reproductive molecules associated with male reproductive success in ants. We found novel genes that had no hits in a homology search and that were predominantly expressed in the accessory glands. These reproductive proteins may have evolved under rapid positive selection for reproductive success in the species. Furthermore, we discovered that three spermatheca-specific genes of C. osakensis queens were also enriched in the accessory glands relative to the bodies of males. These genes may be important for maintaining the sperm quality continuously from ejaculation by males to prolonged storage by queens. This research provides crucial information about the molecular mechanisms of sperm maintenance and sexual selection in ants, and also insight into the evolution of reproductive strategies in insects.

Visual criterion for evaluating hepatobiliary phase image acquisition of gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid-enhanced MRI.

AIM: To evaluate the hepatobiliary phase (HBP) of liver magnetic resonance imaging (MRI) using gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid, and report a visual criterion based on the portal vein (PV), which can be used as a substitute for the quantitative liver-spleen contrast ratio (Q-LSC). MATERIALS AND METHODS: In HBP images of 167 patients, a visual criterion was established based on the sufficient contrast between the liver parenchyma (LP) and PV. The Q-LSC was calculated for patients to assess whether the cut-off value of 1.5 was exceeded. The correlation between the signal intensities in the PV and tumours were determined and comparisons were made. The contrast between LP and the tumour was visually assessed with scores ranging from 1 to 3 defined as poor, fair, and good, respectively. The correlation between Q-LSC and quantitative liver-PV contrast ratio (Q-LPC) was also assessed. RESULTS: The Q-LSC was <1.5 in all patients who did not meet the visual criterion. There was a strong correlation between the signal intensities in the PV and tumours (r=0.72), and no significant differences (p=0.99) were found between the signal intensities in PV and tumours by Wilcoxon's signed-rank test. Significant differences of all the combinations were found using Steel-Dwass multiple comparisons in the visual assessments of contrasts between LP and tumour. The correlation between Q-LSC and Q-LPC was strong (r=0.82). CONCLUSIONS: The visual criterion based on the PV was suitable for the assessment of HBP images as a substitute for Q-LSC.

Association between health risks and frailty in relation to the degree of housing damage among elderly survivors of the great East Japan earthquake.

BACKGROUND: Many survivors of the Great East Japan Earthquake that occurred in 2011 were at risk of deteriorating health, especially elderly people living in disaster-stricken areas. The objectives of this prospective study were: a) to clarify the different lifestyle and psychosocial factors associated with frailty by sex among the non-disabled elderly survivors, and b) to describe the differences in characteristics stratified by the degree of disaster-related housing damage. METHODS: We followed 2261 Japanese survivors aged ≥65 years (45.3% male; mean age, 71.7 years) without disability or frailty who completed a self-administered questionnaire at baseline. All participants completed a baseline questionnaire in 2011 and at least one identical follow-up questionnaire between 2012 and 2015 regarding lifestyle (smoking status, alcohol intake, physical activity, sedentary lifestyle, and dietary intake) and psychosocial factors (self-rated health, standard of living, psychological distress, and social networks). Frailty was defined as a score of ≥5 on the Kihon Checklist, which is used by the Japanese government to certify the need for long-term care insurance. Adjusted odds ratios and 95% confidence intervals with frailty as the dichotomous dependent variable and health factors as the independent variables were calculated using a multilevel model for repeated measures by sex, followed by stratification analyses by the degree of housing damage. RESULTS: Over the 4-year study period, 510 participants (22.6%) developed frailty. In the post-disaster setting, many of the psychosocial factors remained more prevalent 4 years later among survivors with extensive housing damage. The presence of risk factors regarding the development of frailty differed by the degree of housing damage. Among men, psychological distress, in parallel with a poor social network, was related to frailty among only the participants with extensive housing damage and those living in temporary housing, whereas among women, worsening psychological distress was associated only with no damage and no displaced survivors. Among women with extensive damage and displacement, health outcomes such as overweight and diabetes and poor social networks were strongly related to frailty. CONCLUSIONS: Lifestyle and psychosocial factors associated with the risk of frailty differ by sex and the degree of housing damage.

Practices for Supporting and Confirming Decision-Making Involved in Kidney and Liver Donation by Related Living Donors in Japan: A Nationwide Survey.

This nationwide survey investigated the actual practices for supporting and confirming the decision-making involved in related living-organ donations in Japan, focusing on organ type and program size differences. Answers to a questionnaire survey were collected from 89 of the 126 (71%) kidney and 30 of the 35 (86%) liver transplantation programs in Japan that were involved in living-donor transplantations in 2013. In 70% of the kidney and 90% of the liver transplantation programs, all donors underwent "third-party" interviews to confirm their voluntariness. The most common third parties were psychiatrists (90% and 83%, respectively). Many programs engaged in practices to support decision-making by donor candidates, including guaranteeing the right to withdraw consent to donate (70% and 100%, respectively) and prescribing a set "cooling-off period" (88% and 100%, respectively). Most donors were offered care by mental health specialists (86% and 93%, respectively). Third parties were designated by more of the larger kidney transplant programs compared with the smaller programs. In conclusion, the actual practices supporting and confirming the decision to donate a living organ varied depending on the organ concerned and the number of patients in the program.

The prevalence of patellofemoral osteoarthritis: a systematic review and meta-analysis.

OBJECTIVE: To determine the prevalence of radiographic patellofemoral osteoarthritis (OA) from population- and symptom-based cohorts and to evaluate if knee pain, physical function and quality of life (QOL) differ between people with isolated patellofemoral OA, isolated tibiofemoral OA and combined patellofemoral and tibiofemoral OA. METHOD: Terms associated with "patellofemoral OA", "prevalence" and "clinical features" were used to search Medline, EMBASE, CINAHL, SCOPUS, AMED and Web of Science databases with no language restriction' from inception to August 2014. Two independent reviewers screened papers for eligibility. Studies were included if they reported prevalence of compartmental patterns of radiographic knee OA in population- or symptom-based cohorts. Studies were excluded if they evaluated a targeted sample (e.g., occupation-specific participants) or repeated already reported data from the same cohorts. Point prevalence estimates of patellofemoral OA were extracted from eligible studies, pooled and quantitatively analysed. A critical appraisal tool was used to evaluate methodological quality. RESULTS: The search yielded 1891 records. The inclusion criteria were met by 32 studies. The crude prevalence of patellofemoral OA was 25% in the population-based cohorts (aged >20 years) and 39% in the symptom-based cohorts (aged >30 years). Eight studies reported knee pain, physical function and QOL in people with different compartmental disease; however no significant differences were found. CONCLUSION: These findings confirm the substantial prevalence of patellofemoral OA, demonstrating the need to specifically consider the patellofemoral joint in knee OA research and clinical settings.