Observation of room-temperature polar skyrmions.

Complex topological configurations are fertile ground for exploring emergent phenomena and exotic phases in condensed-matter physics. For example, the recent discovery of polarization vortices and their associated complex-phase coexistence and response under applied electric fields in superlattices of (PbTiO3)n/(SrTiO3)n suggests the presence of a complex, multi-dimensional system capable of interesting physical responses, such as chirality, negative capacitance and large piezo-electric responses1-3. Here, by varying epitaxial constraints, we discover room-temperature polar-skyrmion bubbles in a lead titanate layer confined by strontium titanate layers, which are imaged by atomic-resolution scanning transmission electron microscopy. Phase-field modelling and second-principles calculations reveal that the polar-skyrmion bubbles have a skyrmion number of +1, and resonant soft-X-ray diffraction experiments show circular dichroism, confirming chirality. Such nanometre-scale polar-skyrmion bubbles are the electric analogues of magnetic skyrmions, and could contribute to the advancement of ferroelectrics towards functionalities incorporating emergent chirality and electrically controllable negative capacitance.

Observation of polar vortices in oxide superlattices.

The complex interplay of spin, charge, orbital and lattice degrees of freedom provides a plethora of exotic phases and physical phenomena. In recent years, complex spin topologies have emerged as a consequence of the electronic band structure and the interplay between spin and spin-orbit coupling in materials. Here we produce complex topologies of electrical polarization--namely, nanometre-scale vortex-antivortex (that is, clockwise-anticlockwise) arrays that are reminiscent of rotational spin topologies--by making use of the competition between charge, orbital and lattice degrees of freedom in superlattices of alternating lead titanate and strontium titanate layers. Atomic-scale mapping of the polar atomic displacements by scanning transmission electron microscopy reveals the presence of long-range ordered vortex-antivortex arrays that exhibit nearly continuous polarization rotation. Phase-field modelling confirms that the vortex array is the low-energy state for a range of superlattice periods. Within this range, the large gradient energy from the vortex structure is counterbalanced by the corresponding large reduction in overall electrostatic energy (which would otherwise arise from polar discontinuities at the lead titanate/strontium titanate interfaces) and the elastic energy associated with epitaxial constraints and domain formation. These observations have implications for the creation of new states of matter (such as dipolar skyrmions, hedgehog states) and associated phenomena in ferroic materials, such as electrically controllable chirality.

Cabozantinib and Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer.

LESSONS LEARNED: Antitumor activity was observed in the study population. Dose modifications of cabozantinib improve long-term tolerability. Biomarkers are needed to identify patient populations most likely to benefit. Further study of cabozantinib with or without panitumumab in patients with metastatic colorectal cancer is warranted. BACKGROUND: The epidermal growth factor receptor (EGFR) antibody panitumumab is active in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), but nearly all patients experience resistance. MET amplification is a driver of panitumumab resistance. Cabozantinib is an inhibitor of multiple kinases, including vascular endothelial growth factor receptor 2 (VEGFR2) and c-MET, and may delay or reverse anti-EGFR resistance. METHODS: In this phase Ib clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of cabozantinib and panitumumab. We then treated an expansion cohort to further describe the tolerability and clinical activity of the RP2D. Eligibility included patients with KRAS WT mCRC (later amended to include only RAS WT mCRC) who had received prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab. RESULTS: Twenty-five patients were enrolled and treated. The MTD/RP2D was cabozantinib 60 mg p.o. daily and panitumumab 6 mg/kg I.V. every 2 weeks. The objective response rate (ORR) was 16%. Median progression free survival (PFS) was 3.7 months (90% confidence interval [CI], 2.3-7.1). Median overall survival (OS) was 12.1 months (90% CI, 7.5-14.3). Five patients (20%) discontinued treatment due to toxicity, and 18 patients (72%) required a dose reduction of cabozantinib. CONCLUSION: The combination of cabozantinib and panitumumab has activity. Dose reductions of cabozantinib improve tolerability.

Unusual Near-Horizon Cosmic-Ray-like Events Observed by ANITA-IV.

ANITA's fourth long-duration balloon flight in 2016 detected 29 cosmic-ray (CR)-like events on a background of 0.37_{-0.17}^{+0.27} anthropogenic events. CRs are mainly seen in reflection off the Antarctic ice sheets, creating a phase-inverted waveform polarity. However, four of the below-horizon CR-like events show anomalous noninverted polarity, a p=5.3×10^{-4} chance if due to background. All anomalous events are from locations near the horizon; ANITA-IV observed no steeply upcoming anomalous events similar to the two such events seen in prior flights.

Parathyroidectomy slows renal function decline in patients with primary hyperparathyroidism.

PURPOSE: Primary hyperparathyroidism has deleterious effects on health and causes nephrolithiasis and osteoporosis. However, it remains unclear whether parathyroidectomy benefits kidney function among patients with primary hyperparathyroidism. METHODS: In this retrospective study, patients with primary hyperparathyroidism receiving parathyroidectomy in a tertiary medical center between 2003 and 2017 were followed up until December 31 2017, death, or requiring renal replacement therapy. Impact of parathyroidectomy on kidney function was examined using longitudinal estimated glomerular filtration rate (eGFR) change scales: single, average, absolute difference, percent change, annual decline rate, and slope. We applied linear mixed-effect model to determine the effect of parathyroidectomy on kidney function. RESULTS: During study period, 167 patients with primary hyperparathyroidism were identified from 498 parathyroidectomized patients, and finally, 27 patients fulfilled our stringent criteria. Median follow-up duration was 1.50 years (interquartile range 1.05-1.81) before surgery and 2.47 years (1.37-6.43) after surgery. Although parathyroidectomy did not affect amount of proteinuria and distribution of eGFR, parathyroidectomy significantly slowed decline rate of eGFR compared with that before surgery (- 1.67 versus - 2.73 mL/min/1.73 m2/year, p < 0.001). More importantly, parathyroidectomy made more beneficial effects on kidney function in patients with age < 65 years and those without chronic kidney disease or hypertension. CONCLUSIONS: Our study showed that parathyroidectomy slows renal function decline irrespective of age or comorbidities, which offers novel insight into the revision of guidelines for surgical indications in primary hyperparathyroidism. Given small sample size, further large-scale controlled studies are warranted to confirm our findings.

Implementation of a Hepatic Artery Infusion Program: Initial Patient Selection and Perioperative Outcomes of Concurrent Hepatic Artery Infusion and Systemic Chemotherapy for Colorectal Liver Metastases.

BACKGROUND: Hepatic artery infusion (HAI) combined with systemic chemotherapy is a treatment strategy for patients with unresectable liver-only or liver-dominant colorectal liver metastases (CRLM). Although HAI has previously been performed in only a few centers, this study aimed to describe patient selection and initial perioperative outcomes during implementation of a new HAI program. METHODS: The study enrolled patients with CRLM selected for HAI after multi-disciplinary review November 2018-January 2020. Demographics, prior treatment, and perioperative outcomes were assessed. Objective hepatic response was calculated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. RESULTS: During a 14-month period, 21 patients with CRLM underwent HAI pump placement. Of these 21 patients, 20 (95%) had unresectable disease. Most of the patients had synchronous disease (n = 18, 86%) and had received prior chemotherapy (n = 20, 95%) with extended treatment cycles (median 16; interquartile range, 8-22; range, 0-66). The median number of CRLMs was 7 (range, 2-40). Operations often were performed with combined hepatectomy (n = 4, 19%) and/or colectomy/proctectomy (n = 11, 52%). The study had no 90-day mortality. The overall surgical morbidity was 19%. The HAI-specific complications included pump pocket seroma (n = 2), hematoma (n = 1), surgical-site infection (n = 1), and extrahepatic perfusion (n = 1). HAI was initiated in 20 patients (95%). The hepatic response rates at 3 months included partial response (n = 4, 24%), stable disease (n = 9, 53%), and progression of disease (n = 4, 24%), yielding a 3-month hepatic disease control rate (DCR) of 76%. CONCLUSION: Implementation of a new HAI program is feasible, and HAI can be delivered safely to selected patients with CRLM. The initial response and DCR are promising, even for patients heavily pretreated with chemotherapy.

Comparable efficacy and safety of brodalumab in obese and nonobese patients with psoriasis: analysis of two randomized controlled trials.

BACKGROUND: Obesity is associated with psoriasis and negatively affects response to therapy. OBJECTIVES: To evaluate the efficacy and safety of brodalumab in nonobese vs. obese patients with psoriasis. METHODS: This is a post hoc analysis of the prospective, phase III, multicentre, randomized, placebo- and active-comparator-controlled AMAGINE-2 and AMAGINE-3 trials, in which patients were randomized to treatment with brodalumab 210 mg every 2 weeks, ustekinumab or placebo for a 12-week induction phase. At week 12, patients who received brodalumab 210 mg every 2 weeks continued brodalumab, those treated with ustekinumab continued ustekinumab, and those who received placebo switched to brodalumab 210 mg every 2 weeks. Patients were categorized by body mass index (BMI) category (< 30 or ≥ 30 kg m-2 ) and efficacy was evaluated using the physician-rated Psoriasis Area and Severity Index and static Physician's Global Assessment instruments. RESULTS: In total, 281 of 687 patients (40·9%) were obese. Skin clearance was comparable across BMI subgroups in brodalumab-treated patients. Psoriasis Area and Severity Index 100% improvement rates in nonobese and obese patients at week 12 were 54·1% and 49·5%, respectively, and at week 52 they were 72·6% and 64·8%, respectively. Week 12 ustekinumab responses were lower than brodalumab responses and were 6-17% lower in obese than in nonobese patients. No appreciable differences in overall safety were observed between nonobese and obese patients. CONCLUSIONS: The efficacy and safety of brodalumab did not differ between patients with moderate-to-severe psoriasis who had a BMI < 30 kg m-2 or a BMI ≥ 30 kg m-2 .

The interferon-γ-induced protein 10/CXCR3 axis is associated with human herpesvirus-6 reactivation and the development of sequelae in drug reaction with eosinophilia and systemic symptoms.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a condition caused by a drug-induced immune response. Previous reports have found that CXCL10, also known as interferon-γ-induced protein (IP)-10, may participate in the pathogenesis of cutaneous adverse drug reactions. However, the exact role of IP-10 in DRESS and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) has remained unknown. OBJECTIVES: This comparative prospective cohort study aimed to ascertain the roles of the IP-10/CXCR3 axis in DRESS and SJS/TEN. METHODS: Plasma IP-10 levels were analysed, and univariate analyses were conducted to assess the relationship between IP-10, human herpesvirus (HHV)-6 reactivation and the development of long-term sequelae. We also performed immunohistochemical staining using skin specimens and flow cytometry to determine the expression of CXCR3 in peripheral blood mononuclear cells (PBMCs). RESULTS: Significantly higher plasma IP-10 levels were observed in patients with DRESS with long-term sequelae (effect size 0·81) and also in those with HHV-6 reactivation (effect size 0·83). By immunohistochemistry, more abundant IP-10+ and CXCR3+ cells were demonstrated in the skin lesions of patients with DRESS with HHV-6 reactivation. The percentages of CLA+  CXCR3+  CD4+ cells and CLA+  CXCR3+  CD8+ cells were also higher in the PBMCs of HHV-6-reactivated patients with DRESS than in those of patients with SJS/TEN. CONCLUSIONS: Higher plasma IP-10 levels are associated with the development of long-term sequelae in DRESS. Higher IP-10/CXCR3 expression in skin and more abundant CLA+  CXCR3+  CD4+ cells and CLA+  CXCR3+  CD8+ cells were observed in patients with DRESS with HHV-6 reactivation. The IP-10/CXCR3 axis is associated with HHV-6 reactivation and development of long-term sequelae in DRESS. What is already known about this topic? Elevated levels of interferon-γ-induced protein-10 (IP-10) have been observed in patients with drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Patients with DRESS tend to develop long-term autoimmune sequelae, including type 1 diabetes and autoimmune thyroiditis. IP-10 has been associated with these autoimmune diseases in previous studies. What does this study add? The patients with DRESS with HHV-6 reactivation exhibited higher levels of IP-10 in the plasma and skin than the patients with DRESS without HHV-6 reactivation and the patients with SJS/TEN. Patients with DRESS with higher plasma IP-10 levels tended to develop sequelae during long-term follow-up. What is the translational message? IP-10 is a useful biomarker to predict the development of long-term sequelae in patients with DRESS. Linked Comment: Belloón and Kardaun. Br J Dermatol 2020; 183:804-805.

Increased incidence and recurrence rates of acute diverticulitis in patients with irritable bowel syndrome.

AIM: Acute diverticulitis (AD) is commonly diagnosed in outpatient and emergency departments and is associated with severe complications such as perforation and fistula. Symptoms of irritable bowel syndrome (IBS), such as abdominal pain, constipation and diarrhoea, are also common with AD. This study aimed to evaluate the strength of a possible association between IBS and AD. METHOD: This retrospective study analysed records from Taiwan's National Health Insurance Research Database and involved a total of 25 810 patients, including 12 905 IBS patients diagnosed between 2000 and 2012. The IBS and non-IBS cohorts were matched by propensity score for age, gender, comorbidities and medication, then compared for confounding variables by the chi-square test or Student's t-test. The association between AD and IBS was determined using Cox proportional hazards models. Kaplan-Meier curves assessed the cumulative incidence of AD in IBS patients. RESULTS: The overall incidence of AD was 3.95-fold higher in the IBS cohort than in the non-IBS cohort (63.34 vs 16.02 per 100 000 person-years, respectively) and IBS was an independent risk factor for subsequent diagnosis of AD in multivariate Cox proportional hazards regression model adjusted hazards ratio (aHR = 3.84, 95% CI = 2.29-6.44, P < 0.001) and Kaplan-Meier (log-rank test, P < 0.001) analysis. IBS was also associated with a high recurrence rate of AD (aHR = 8.30, 95% CI = 1.07-64.30, P = 0.04). CONCLUSION: The epidemiological evidence in this study demonstrates that patients with IBS are associated with a higher incidence of AD and also its recurrence.

Appearance of pediatric choroidal neovascular membranes on optical coherence tomography angiography.

PURPOSE: Compared with fluorescein angiography (FA), the gold standard for diagnosing choroidal neovascularization (CNV) activity, optical coherence tomography angiography (OCTA) is non-invasive without risks associated with fluorescein dye use, and may be especially advantageous in the diagnosis and monitoring of children with CNV. METHODS: Eight eyes from eight patients aged 12 months to 18 years were imaged with the investigational Spectralis OCTA (version 6.9, Heidelberg Engineering, Heidelberg, Germany) and the RTVue XR Avanti (Optovue Inc., Fremont, CA, USA). Two patients were imaged during examination under anesthesia while six patients were imaged in the clinic. Demographic information, ocular characteristics, treatment history, and imaging studies (color photos, fluorescein angiography, OCT) were collected and reviewed. RESULTS: Three eyes had active CNV while five had quiescent CNV at the time of imaging. CNV was idiopathic or secondary to trauma, retinal vascular dysgenesis versus retinopathy of prematurity, pigmentary retinopathy, Best vitelliform macular dystrophy, panuveitis, morning glory disc anomaly, and optic disc drusen. OCTA of two active CNV demonstrated presence of a main trunk with multiple fine capillaries, vessel loops, and anastomoses. OCTA was repeated after treatment for two CNV and demonstrated a decrease in size with loss of fine capillaries, vessel loops, and anastomoses. For the third active CNV, OCTA verified flow in the CNV complex despite the uncertainty of FA hyperfluorescence in the setting of grossly abnormal retinal vasculature. The five quiescent CNV all lacked fine capillaries, vessel loops, and anastomoses on OCTA. CONCLUSION: OCTA demonstrates morphological differences between active and quiescent pediatric CNV.

Assessment of Macular Microvasculature in Healthy Eyes of Infants and Children Using OCT Angiography.

PURPOSE: To assess macular vasculature in healthy infants and children using OCT angiography (OCTA). DESIGN: Prospective cross-sectional study. PARTICIPANTS: One hundred thirty-five normal maculae of 89 healthy infants and children (mean age, 8.5±5.3 years; range, 9 weeks-17 years) treated at the Duke University Eye Center. METHODS: We imaged 135 maculae of 89 pediatric patients using the standard Spectralis tabletop and investigational Spectralis with Flex module devices, both equipped with investigational OCTA software (Heidelberg Engineering, Heidelberg, Germany). OCT angiography images of the superficial vascular complex (SVC) and deep vascular complex (DVC) were analyzed for foveal avascular zone (FAZ) area and superficial and deep vessel density. We assessed effects of age, gender, race, axial length (AL), and central subfield thickness on FAZ and vessel density. Patients with both eyes imaged were assessed for agreement between the FAZ and vessel densities of the left and right eyes. MAIN OUTCOME MEASURES: The FAZ area, as well as vessel area density (VAD) and vessel length density (VLD) in the SVC and DVC. RESULTS: The FAZ varied significantly with race; white patients showed a significantly smaller FAZ than black patients (mean difference, 0.11 mm2; P = 0.004). The FAZ did not vary with age, gender, or AL (P > 0.05). In the SVC, VAD and VLD varied significantly with age (P < 0.001) and AL (R2 = 0.46; P < 0.001) but not gender (P > 0.05). The SVC VLD was significantly different between races and ethnicities (P = 0.037), but VAD was not (P < 0.05). In the DVC, VAD and VLD also varied significantly with age (P < 0.001) and AL (R2 = 0.46; P < 0.001) but not gender or race (P > 0.05). There was excellent agreement between the right and left eyes for FAZ (intraclass correlation [ICC], 0.97), SVC VLD (ICC, 1.00), and DVC VLD (ICC, 1.00). CONCLUSIONS: Quantitative studies of pediatric perifoveal vasculature should consider age, race, and AL. In eyes with unilateral disease, the perifoveal vasculature in the unaffected eye may be used as a control comparison because there is excellent agreement between eyes.

Randomized trial of oral versus enteral feeding for patients with postoperative pancreatic fistula after pancreatoduodenectomy.

BACKGROUND: Whether continued oral feeding may have a negative impact on healing of postoperative pancreatic fistula (POPF) is unclear. The aim was to test the hypothesis that oral feeding is non-inferior to enteral feeding in closure of POPF after pancreatoduodenectomy, and to clarify the effects of oral feeding on the duration and grade of POPF. METHODS: This multicentre, non-inferiority randomized trial of oral or enteral feeding of patients with POPF after pancreatoduodenectomy recruited patients between August 2013 and September 2016. The primary efficacy outcome was the 30-day fistula closure rate. The prespecified non-inferiority margin was 15 per cent. Other efficacy outcomes included grade of fistula, and hospital stay and costs. RESULTS: A total of 114 patients were included, and received oral (57) or enteral (57) feeding. The two groups were balanced in baseline characteristics and no patient was lost to follow-up. In intention-to-treat analysis, oral feeding was non-inferior to enteral feeding in terms of 30-day fistula closure rate (88 versus 89 per cent respectively; difference -1·8 per cent, lower limit of 95 per cent c.i. -14·4 per cent; P = 0·020 for non-inferiority). Compared with enteral feeding, oral feeding significantly reduced hospital costs and duration of stay. No significant differences were noted in the number of patients whose POPF evolved into grade B/C, or other outcomes. CONCLUSION: Oral feeding in patients with POPF after pancreatoduodenectomy did not increase the duration or grade of POPF, and was associated with reduced duration of stay and hospital costs. Registration number: NCT01755260 (http://www.clinicaltrials.gov).

A phase Ib study of capecitabine and ziv-aflibercept followed by a phase II single-arm expansion cohort in chemotherapy refractory metastatic colorectal cancer.

BACKGROUND: Patients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC. METHODS: All patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS). RESULTS: A total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1-14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60-84%). Median PFS and OS were 3.9 months (95% CI, 2.3-4.5) and 7.1 months (95% CI: 5.8-10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes. CONCLUSION: The combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study. TRIAL REGISTRATION: This clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.

Efficacy and safety of brodalumab in patients with psoriasis who had inadequate responses to ustekinumab: subgroup analysis of two randomized phase III trials.

BACKGROUND: Brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, has demonstrated superior efficacy and safety over ustekinumab as induction therapy for moderate-to-severe psoriasis. OBJECTIVES: To evaluate the efficacy and safety of brodalumab through week 52 in patients who had inadequate responses to ustekinumab. METHODS: A subgroup analysis of the phase III AMAGINE-2/-3 double-blind randomized controlled trials was performed. Participants were aged 18-75 years and had a Psoriasis Area and Severity Index (PASI) ≥ 12, static Physician's Global Assessment score ≥ 3 and involvement of ≥ 10% body surface area. The studies were registered at ClinicalTrials.gov: AMAGINE-2, NCT01708603; AMAGINE-3, NCT01708629. RESULTS: At baseline, patients with or without prior biologic experience who had an adequate response at week 16 on ustekinumab or brodalumab had lower rates of involved body surface area, PASI, prior biologic use, psoriatic arthritis and body mass index than patients who experienced inadequate response at or after week 16. Among patients who experienced inadequate response to ustekinumab, those rescued with brodalumab had PASI ≥ 75%, ≥ 90% and 100% improvement response rates of 72·6%, 58·1% and 36·3%, respectively, at week 52 compared with 61·7%, 25·5% and 5·4%, respectively, in patients who continued ustekinumab. Exposure-adjusted rates of treatment-emergent adverse events were similar among patients rescued with brodalumab (377·3 adverse events per 100 patient-years) and those who remained on ustekinumab (389·9 adverse events per 100 patient-years). CONCLUSIONS: Among patients who experienced inadequate responses to ustekinumab, rescue with brodalumab improved skin clearance outcomes compared with continuing ustekinumab.

Phase coexistence and electric-field control of toroidal order in oxide superlattices.

Systems that exhibit phase competition, order parameter coexistence, and emergent order parameter topologies constitute a major part of modern condensed-matter physics. Here, by applying a range of characterization techniques, and simulations, we observe that in PbTiO3/SrTiO3 superlattices all of these effects can be found. By exploring superlattice period-, temperature- and field-dependent evolution of these structures, we observe several new features. First, it is possible to engineer phase coexistence mediated by a first-order phase transition between an emergent, low-temperature vortex phase with electric toroidal order and a high-temperature ferroelectric a1/a2 phase. At room temperature, the coexisting vortex and ferroelectric phases form a mesoscale, fibre-textured hierarchical superstructure. The vortex phase possesses an axial polarization, set by the net polarization of the surrounding ferroelectric domains, such that it possesses a multi-order-parameter state and belongs to a class of gyrotropic electrotoroidal compounds. Finally, application of electric fields to this mixed-phase system permits interconversion between the vortex and the ferroelectric phases concomitant with order-of-magnitude changes in piezoelectric and nonlinear optical responses. Our findings suggest new cross-coupled functionalities.

Hepatitis B virus infection in Taiwan: The role of NTCP rs2296651 variant in relation to sex.

Sodium taurocholate cotransporting polypeptide (NTCP) is a functional receptor for hepatitis B virus (HBV) infection. NTCP rs2296651 is believed to be an Asian-specific variant responsible for HBV susceptibility. We investigated the relationship between rs2296651 and HBV infection in Taiwan based on stratification by gender and menopausal status. We recruited 10 017 Taiwan Biobank participants aged 30-70 years with complete genetic data and sociodemographic information. Gender-stratified multivariate logistic regression models were used to determine the relationship between NTCP variant and HBV infection. Among individuals with HBV infection, the genotype frequencies of GG, AG and AA in women were 0.85, 0.15 and 0 while those in men were 0.82, 0.18 and 0, respectively. The multivariate-adjusted odds ratios (OR) of HBV infection were 0.77 (95% CI 0.59-0.99) in women and 0.98 (95% CI 0.79-1.20) in men. The adjusted OR was 0.87 (CI 0.63-1.19) in premenopausal and 0.59 (0.36-0.97) in postmenopausal women. We found that genetic variation in the HBV receptor gene (NTCP) was significantly associated with a decreased risk of HBV infection in Taiwanese women.

Improvement in itch and other psoriasis symptoms with brodalumab in phase 3 randomized controlled trials.

BACKGROUND: Patients with psoriasis have lesional symptoms, including itch, which can reduce quality of life. The efficacy and safety of brodalumab, an interleukin-17 receptor A antagonist, in treating moderate-to-severe psoriasis have been reported in three randomized, controlled, phase 3 trials (AMAGINE-1/-2/-3). OBJECTIVE: The effect of brodalumab on lesional symptoms was assessed using the psoriasis symptom inventory (PSI), a validated patient-reported instrument. METHODS: Patients were randomized to receive brodalumab (140 or 210 mg every 2 weeks [Q2W]), placebo (AMAGINE-1/-2/-3), or ustekinumab (AMAGINE-2/-3) during a 12-week induction phase, followed by a maintenance phase through week 52. Patients electronically rated the severity of PSI items (itch, burning, stinging, pain, redness, scaling, cracking and flaking) during the previous 24 h on a scale of 0 (not at all severe) to 4 (very severe). At each visit, the PSI total score responder status was assessed, with responders defined as having an average weekly total inventory score ≤8 with no item score >1 at week 12. RESULTS: Across AMAGINE-1/-2/-3, brodalumab was associated with improvements in PSI total scores and itch scores vs. placebo from week 2 through week 12 (P < 0.001 in both domains). In AMAGINE-2/-3, brodalumab 210 mg Q2W demonstrated faster onset of PSI total score and itch responses (week 2, 22.1% and 36.4%, respectively) vs. ustekinumab (week 2, 6.9% and 17.1%, respectively) and was associated with improved itch responses vs. ustekinumab after 52 weeks of constant treatment. CONCLUSION: Brodalumab demonstrated rapid, robust improvements in symptoms assessed by the PSI, including itch, vs. placebo and ustekinumab.

Pre-stroke physical activity is associated with fewer post-stroke complications, lower mortality and a better long-term outcome.

BACKGROUND AND PURPOSE: Physical activity is associated with a reduced incidence of first-time stroke. However, few studies have examined the effect of pre-stroke physical activity on post-stroke complications and clinical outcomes. METHODS: A total of 39 835 cases of stroke registered in the nationwide stroke registry system of Taiwan between 2006 and 2009 were analyzed according to five levels of severity as determined by National Institutes of Health Stroke Scale score upon hospital admission. Pre-stroke physical activity was defined in the Taiwan Stroke Registry as dedicated leisure-time physical activity for at least 30 min/day for 3 days/week for more than 6 months. A Cox model was used to compare complications and outcomes between active and inactive groups. RESULTS: The active and inactive groups were similar in age distribution and stroke type distribution, but the active group had better National Institutes of Health Stroke Scale scores upon admission. The active group also had significantly fewer post-stroke complications. Active patients had lower hospital mortality and better functional outcomes upon discharge as per the modified Rankin Scale. Improved functional status in the active group was significant at 1, 3 and 6 months post-stroke. CONCLUSION: Dedicated leisure-time physical activity for at least 30 min/day, at least three times per week for more than 6 months was associated with decreased stroke severity, fewer post-stroke complications, lower mortality and better outcomes.