Crystallization Pathways and Evolution of Morphologies and Structural Defects of α-MnO2 under Air Annealing.

Manganese dioxide nanomaterials have wide applications in many areas from catalysis and Li-ion batteries to gas sensing. Understanding the crystallization pathways, morphologies, and formation of defects in their structure is particularly important but still a challenging issue. Herein, we employed an arsenal of X-ray diffraction (XRD), scanning electron microscopy (SEM), neutron diffraction, positron annihilation spectroscopies, and ab initio calculations to investigate the evolution of the morphology and structure of α-MnO2 nanomaterials prepared via reduction of KMnO4 solution with C2H5OH prior to being annealed in air at 200-600 °C. We explored a novel evolution that α-MnO2 nucleation can be formed even at room temperature and gradually developed to α-MnO2 nanorods at above 500 °C. We also found the existence of H+ or K+ ions in the [1 × 1] tunnels of α-MnO2 and observed the simultaneous presence of Mn and O vacancies in α-MnO2 crystals at low temperatures. Increasing the temperature removed these O vacancies, leaving only the Mn vacancies in the samples.

Health Literacy, eHealth Literacy, Adherence to Infection Prevention and Control Procedures, Lifestyle Changes, and Suspected COVID-19 Symptoms Among Health Care Workers During Lockdown: Online Survey.

BACKGROUND: The COVID-19 pandemic has imposed a heavy burden on health care systems and governments. Health literacy (HL) and eHealth literacy (as measured by the eHealth Literacy Scale [eHEALS]) are recognized as strategic public health elements but they have been underestimated during the pandemic. HL, eHEALS score, practices, lifestyles, and the health status of health care workers (HCWs) play crucial roles in containing the COVID-19 pandemic. OBJECTIVE: The aim of this study is to evaluate the psychometric properties of the eHEALS and examine associations of HL and eHEALS scores with adherence to infection prevention and control (IPC) procedures, lifestyle changes, and suspected COVID-19 symptoms among HCWs during lockdown. METHODS: We conducted an online survey of 5209 HCWs from 15 hospitals and health centers across Vietnam from April 6 to April 19, 2020. Participants answered questions related to sociodemographics, HL, eHEALS, adherence to IPC procedures, behavior changes in eating, smoking, drinking, and physical activity, and suspected COVID-19 symptoms. Principal component analysis, correlation analysis, and bivariate and multivariate linear and logistic regression models were used to validate the eHEALS and examine associations. RESULTS: The eHEALS had a satisfactory construct validity with 8 items highly loaded on one component, with factor loadings ranked from 0.78 to 0.92 explaining 76.34% of variance; satisfactory criterion validity as correlated with HL (ρ=0.42); satisfactory convergent validity with high item-scale correlations (ρ=0.80-0.84); and high internal consistency (Cronbach α=.95). HL and eHEALS scores were significantly higher in men (unstandardized coefficient [B]=1.01, 95% CI 0.57-1.45, P<.001; B=0.72, 95% CI 0.43-1.00, P<.001), those with a better ability to pay for medication (B=1.65, 95% CI 1.25-2.05, P<.001; B=0.60, 95% CI 0.34-0.86, P<.001), doctors (B=1.29, 95% CI 0.73-1.84, P<.001; B 0.56, 95% CI 0.20-0.93, P=.003), and those with epidemic containment experience (B=1.96, 95% CI 1.56-2.37, P<.001; B=0.64, 95% CI 0.38-0.91, P<.001), as compared to their counterparts, respectively. HCWs with higher HL or eHEALS scores had better adherence to IPC procedures (B=0.13, 95% CI 0.10-0.15, P<.001; B=0.22, 95% CI 0.19-0.26, P<.001), had a higher likelihood of healthy eating (odds ratio [OR] 1.04, 95% CI 1.01-1.06, P=.001; OR 1.04, 95% CI 1.02-1.07, P=.002), were more physically active (OR 1.03, 95% CI 1.02-1.03, P<.001; OR 1.04, 95% CI 1.03-1.05, P<.001), and had a lower likelihood of suspected COVID-19 symptoms (OR 0.97, 95% CI 0.96-0.98, P<.001; OR 0.96, 95% CI 0.95-0.98, P<.001), respectively. CONCLUSIONS: The eHEALS is a valid and reliable survey tool. Gender, ability to pay for medication, profession, and epidemic containment experience were independent predictors of HL and eHEALS scores. HCWs with higher HL or eHEALS scores had better adherence to IPC procedures, healthier lifestyles, and a lower likelihood of suspected COVID-19 symptoms. Efforts to improve HCWs' HL and eHEALS scores can help to contain the COVID-19 pandemic and minimize its consequences.

Generation and characterization of fully human monoclonal antibodies against human Orai1 for autoimmune disease.

Calcium entry into T cells following antigen stimulation is crucial for nuclear factor of activated T cells (NFAT)-mediated T cell activation. The movement of calcium is mediated by calcium release-activated calcium (CRAC) channels. There are two key components of this channel: Orai1 is the pore-forming subunit located in the plasma membrane, and stromal interaction molecule 1 (STIM1) functions as a Ca(2+) sensor in the endoplasmic reticulum. A subset of human patients carry mutations in either STIM1 or Orai1 that affect protein function or expression, resulting in defective store-operated Ca(2+) influx and CRAC channel function, and impaired T cell activation. These patients suffer from a hereditary form of severe combined immune deficiency syndrome, highlighting the importance of the CRAC channel for T lymphocyte function in humans. Since autoreactive T cells play an important role in the development of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and organ transplantation, Orai1 becomes an attractive therapeutic target for ameliorating autoimmune disease. We developed a novel approach to inhibiting CRAC function by generating high-affinity fully human monoclonal antibodies to human Orai1. These antibodies inhibited ICRAC current, store-operated Ca(2+) influx, NFAT transcription, and cytokine release. These fully human antibodies to human Orai1 may represent a novel therapeutic approach for the treatment of autoimmunity.

Variational quantum metrology for multiparameter estimation under dephasing noise.

We present a hybrid quantum-classical variational scheme to enhance precision in quantum metrology. In the scheme, both the initial state and the measurement basis in the quantum part are parameterized and optimized via the classical part. It enables the maximization of information gained about the measured quantity. We discuss specific applications to 3D magnetic field sensing under several dephasing noise models. Indeed, we demonstrate its ability to simultaneously estimate all parameters and surpass the standard quantum limit, making it a powerful tool for metrological applications.

Exploring the Sub-nanoscale Structure of Cobalt Molybdenum Sulfide and the Role of a Cobalt Promoter in Catalytic Hydrogen Evolution.

Cobalt-promoted molybdenum sulfide (CoMoS) is known as a promising catalyst for H2 evolution reaction and hydrogen desulfurization reaction. This material exhibits superior catalytic activity as compared to its pristine molybdenum sulfide counterpart. However, revealing the actual structure of cobalt-promoted molybdenum sulfide as well as the plausible contribution of a cobalt promoter is still challenging, especially when the material has an amorphous nature. Herein, we report, for the first time, on the use of positron annihilation spectroscopy (PAS), being a nondestructive nuclear radiation-based method, to visualize the position of a Co promoter within the structure of MoS at the atomic scale, which is inaccessible by conventional characterization tools. It is found that at low concentrations, a Co atom occupies preferably the Mo-vacancies, thus generating the ternary phase CoMoS whose structure is composed of a Co-S-Mo building block. Increasing the Co concentration, e.g., a Co/Mo molar ratio of higher than 1.12/1, leads to the occupation of both Mo-vacancies and S-vacancies by Co. In this case, secondary phases such as MoS and CoS are also produced together with the CoMoS one. Combining the PAS and electrochemical analyses, we highlight the important contribution of a Co promoter to enhancing the catalytic H2 evolution activity. Having more Co promoter in the Mo-vacancies promotes the H2 evolution rate, whereas having Co in the S-vacancies causes a drop in H2 evolution ability. Furthermore, the occupation of Co to the S-vacancies leads also to the destabilization of the CoMoS catalyst, resulting in a rapid degradation of catalytic activity.

Impacts of Digital Healthy Diet Literacy and Healthy Eating Behavior on Fear of COVID-19, Changes in Mental Health, and Health-Related Quality of Life among Front-Line Health Care Workers.

BACKGROUND: We aimed to examine the impacts of digital healthy diet literacy (DDL) and healthy eating behaviors (HES) on fear of COVID-19, changes in mental health, and health-related quality of life (HRQoL) among front-line healthcare workers (HCWs). METHODS: An online survey was conducted at 15 hospitals and health centers from 6-19 April 2020. Data of 2299 front-line HCWs were analyzed-including socio-demographics, symptoms like COVID-19, health literacy, eHealth literacy, DDL, HES, fear of COVID-19, changes in mental health, and HRQoL. Regression models were used to examine the associations. RESULTS: HCWs with higher scores of DDL and HES had lower scores of FCoV-19S (regression coefficient, B, -0.04; 95% confidence interval, 95% CI, -0.07, -0.02; p = 0.001; and B, -0.10; 95% CI, -0.15, -0.06; p < 0.001); had a higher likelihood of stable or better mental health status (odds ratio, OR, 1.02; 95% CI, 1.00, 1.05; p = 0.029; and OR, 1.04; 95% CI, 1.00, 1.07; p = 0.043); and HRQoL (OR, 1.02; 95% CI, 1.01, 1.03; p = 0.006; and OR, 1.04; 95% CI, 1.02, 1.06; p = 0.001), respectively. CONCLUSIONS: DDL and HES were found as independent predictors of fear of COVID-19, changes in mental health status, and HRQoL in front-line HCWs. Improving DDL and HES should be considered as a strategic approach for hospitals and healthcare systems.

Negative Impacts of COVID-19 Induced Lockdown on Changes in Eating Behavior, Physical Activity, and Mental Health as Modified by Digital Healthy Diet Literacy and eHealth Literacy.

Background: The COVID-19-induced lockdown has been implemented in many countries, which may cause unfavorable changes in lifestyles and psychological health. People's health literacy, healthy diet, and lifestyles play important roles in mitigating the negative impacts of the pandemic. Therefore, we aimed to examine associations of COVID-19 lockdown with changes in eating behavior, physical activity, and mental health; and the modification effects by digital healthy diet literacy (DDL) and eHealth literacy (eHEALS) on the associations. Methods: We conducted an observational study on 4,348 outpatients from 7th April to 31st May 2020. Data from 11 hospitals in Vietnam included demographic characteristics, DDL, eHEALS, eating behavior, physical activity, and mental health changes. Multiple logistic regression and interaction models were performed to examine associations. Results: Patients under lockdown had a lower likelihood of having "unchanged or healthier" eating behavior (odds ratio, OR, 0.38; 95% confidence interval, 95%CI, 0.29 to 0.51; p < 0.001), "unchanged or more" physical activity (OR, 0.79; 95% CI, 0.69 to 0.90; p < 0.001), and "stable or better" mental health (OR, 0.77; 95% CI, 0.67 to 0.89; p < 0.001), as compared to those after lockdown. In interaction models, as compared to patients after lockdown and with the lowest DDL score, those under lockdown and with a one-score increment of DDL had a higher likelihood of having "unchanged or healthier" eating behavior (OR, 1.05; 95% CI, 1.02 to 1.07; p < 0.001), and "stable or better" mental health (OR, 1.02; 95% CI, 1.01 to 1.04; p < 0.001). Similarly, as compared to patients after lockdown and with the lowest eHEALS score, those under lockdown and with a one-score increment of eHEALS had a higher likelihood of having an "unchanged or more" physical activity (OR, 1.03; 95% CI, 1.01 to 1.05; p < 0.001). Conclusion: The COVID-19 lockdown measure could negatively affect eating behavior, physical activity, and mental health among outpatients. Better DDL and eHEALS were found to mitigate the negative impacts of the lockdown, which may empower outpatients to maintain healthy lifestyles and protect mental health. However, this study holds several limitations that may undermine the certainty of reported findings.

Negative Impact of Fear of COVID-19 on Health-Related Quality of Life Was Modified by Health Literacy, eHealth Literacy, and Digital Healthy Diet Literacy: A Multi-Hospital Survey.

BACKGROUND: The COVID-19 pandemic has been disseminating fear in the community, which has affected people's quality of life, especially those with health problems. Health literacy (HL), eHealth literacy (eHEAL), and digital healthy diet literacy (DDL) may have potential impacts on containing the pandemic and its consequences. This study aimed to examine the association between the fear of COVID-19 scale (FCoV-19S) and the health-related quality of life (HRQoL), and to examine the effect modification by HL, eHEAL, and DDL on this association. METHODS: A cross-sectional study was conducted in 11 hospitals across Vietnam from 7 April to 31 May 2020. Data were collected on 4348 outpatients, including demographic characteristics, HL, eHEAL, DDL, FCoV-19S, and HRQoL. Multiple linear regression and interaction models were used to explore associations. RESULTS: Patients with higher FCoV-19S scores had lower HRQoL scores (unstandardized coefficient, B = -0.78, p < 0.001). HL (B = 0.20, p < 0.001), eHEAL (B = 0.24, p < 0.001), and DDL (B = 0.20, p < 0.001) were positively associated with higher HRQoL scores. The negative impact of FCoV-19S on HRQoL was significantly attenuated by higher eHEAL score groups (from one standard deviation (SD) below the mean, B = -0.93, p < 0.001; to the mean, B = -0.85, p < 0.001; and one SD above the mean, B = -0.77, p < 0.001); and by higher DDL score groups (from one SD below the mean, B = -0.92, p < 0.001; to the mean, B = -0.82, p < 0.001; and one SD above the mean, B = -0.72, p < 0.001). CONCLUSIONS: eHealth literacy and digital healthy diet literacy could help to protect patients' health-related quality of life from the negative impact of the fear of COVID-19 during the pandemic.

Fear, anxiety and depression among pregnant women during COVID-19 pandemic: impacts of healthy eating behaviour and health literacy.

INTRODUCTION: The COVID-19 pandemic has been influencing people's psychological health, especially in pregnant women. We aimed to examine associated factors of fear of COVID-19, anxiety and depression among pregnant women during the pandemic where the impacts of healthy eating behaviour (HES) and health literacy (HL) were emphasized. METHODS: A cross-sectional study was conducted between 14 February 2020 and 31 May 2020 in 18 health centres and hospitals across Vietnam. Data of 518 pregnant women were analysed, including socio-demographics, pregnant-related factors, HES, HL, health-related behaviours, fear of COVID-19 scale (FCoV-19S), anxiety (using the generalized anxiety disorder (GAD-7)) and depression (using the patient health questionnaire with 9 items (PHQ-9)). Regression analysis was utilized to explore the associations. RESULTS: Pregnant women with higher scores of HES and HL had lower likelihood of anxiety (odds ratio, OR, 0.79; 95% confidence interval (95%CI), 0.73, 0.87; p < .001; and OR, 0.94; 95%CI, 0.90, 0.99; p = .018) and depression (OR, 0.84; 95%CI, 0.78, 0.91; p < .001; and OR, 0.96; 95%CI, 0.91, 0.99; p = .044), respectively. Pregnant women being employed had a lower FCoV-19S score (regression coefficient, B, -1.46; 95%CI, -2.51, -0.40; p = .007). Besides, other significant predictors of anxiety were eating healthier during the pandemic, unchanged or more physical activity, elevated gestational age and smoking. Other significant predictors of depression were eating healthier during the pandemic, elevated gestational age and smoking. CONCLUSIONS: Among others, HES and HL had positive impacts on protecting pregnant women against anxiety and depression. Improving HES and HL should be addressed as a strategic approach to improve reproductive health during the pandemic.KEY MESSAGEThe COVID-19 pandemic influences antenatal mental disorders with the higher level as opposed to that before the pandemic.Healthy eating behaviour and better health literacy (HL) had critical roles in lowering prenatal anxiety and depression during the COVID-19 crisis.Strategic approaches for improving healthy eating and HL should be recommended for protecting pregnant women from mental health problems during the pandemic.

Associations of Underlying Health Conditions With Anxiety and Depression Among Outpatients: Modification Effects of Suspected COVID-19 Symptoms, Health-Related and Preventive Behaviors.

Objectives: We explored the association of underlying health conditions (UHC) with depression and anxiety, and examined the modification effects of suspected COVID-19 symptoms (S-COVID-19-S), health-related behaviors (HB), and preventive behaviors (PB). Methods: A cross-sectional study was conducted on 8,291 outpatients aged 18-85 years, in 18 hospitals and health centers across Vietnam from 14th February to May 31, 2020. We collected the data regarding participant's characteristics, UHC, HB, PB, depression, and anxiety. Results: People with UHC had higher odds of depression (OR = 2.11; p < 0.001) and anxiety (OR = 2.86; p < 0.001) than those without UHC. The odds of depression and anxiety were significantly higher for those with UHC and S-COVID-19-S (p < 0.001); and were significantly lower for those had UHC and interacted with "unchanged/more" physical activity (p < 0.001), or "unchanged/more" drinking (p < 0.001 for only anxiety), or "unchanged/healthier" eating (p < 0.001), and high PB score (p < 0.001), as compared to those without UHC and without S-COVID-19-S, "never/stopped/less" physical activity, drinking, "less healthy" eating, and low PB score, respectively. Conclusion: S-COVID-19-S worsen psychological health in patients with UHC. Physical activity, drinking, healthier eating, and high PB score were protective factors.

Health Literacy and Preventive Behaviors Modify the Association between Pre-Existing Health Conditions and Suspected COVID-19 Symptoms: A Multi-Institutional Survey.

People with pre-existing health conditions (PEHC) are vulnerable to viral infection while health literacy (HL) and preventive behaviors (PB) have been shown to benefit people during the COVID-19 pandemic. The aim of this study was to examine the association between PEHC and suspected COVID-19 symptoms (S-COVID-19-S), and to investigate the modification effect of HL and PB. A cross-sectional study was conducted on 8291 participants visiting outpatient departments at 18 hospitals and health centers across Vietnam from 14 February to 31 May 2020. Data were collected regarding participant's characteristics, HL, PB, PEHC, and S-COVID-19-S. Regression models were used for analyzing the associations. Results showed that people with PEHC had a 3.38 times higher likelihood of having S-COVID-19-S (odds ratio, OR, 3.38; 95% confidence interval, 95% CI, 3.01, 3.79; p < 0.001). In comparison to participants without PEHC and with the lowest HL score, those with PEHC and one HL score increment had a 7% lower likelihood of having S-COVID-19-S (OR, 0.93; 95% CI, 0.92, 0.94; p < 0.001). In comparison to participants without PEHC and not adhering to mask wearing, those with PEHC and adhering to mask wearing had a 77% lower likelihood of having S-COVID-19-S (OR, 0.23; 95% CI, 0.16, 0.32; p < 0.001). Higher HL and adherence to mask wearing can protect people from having S-COVID-19-S, especially in those with PEHC.

Impacts and interactions of COVID-19 response involvement, health-related behaviours, health literacy on anxiety, depression and health-related quality of life among healthcare workers: a cross-sectional study.

OBJECTIVES: We examined impacts and interactions of COVID-19 response involvement, health-related behaviours and health literacy (HL) on anxiety, depression, and health-related quality of life (HRQoL) among healthcare workers (HCWs). DESIGN: A cross-sectional study was conducted. Data were collected 6 April to 19 April 2020 using online-based, self-administered questionnaires. SETTING: 19 hospitals and health centres in Vietnam. PARTICIPANTS: 7 124 HCWs aged 21-60 years. RESULTS: The COVID-19 response-involved HCWs had higher anxiety likelihood (OR (95% CI)=4.41 (3.53 to 5.51)), higher depression likelihood (OR(95% CI)=3.31 (2.71 to 4.05)) and lower HRQoL score (coefficient, b(95% CI)=-2.14 (-2.89 to -1.38)), compared with uninvolved HCWs. Overall, HCWs who smoked or drank at unchanged/increased levels had higher likelihood of anxiety, depression and lower HRQoL scores; those with unchanged/healthier eating, unchanged/more physical activity and higher HL scores had lower likelihood of anxiety, depression and higher HRQoL scores. In comparison to uninvolved HCWs who smoked or drank at never/stopped/reduced levels, involved HCWs with unchanged/increased smoking or drinking had lower anxiety likelihood (OR(95% CI)=0.34 (0.14 to 0.83)) or (OR(95% CI)=0.26 (0.11 to 0.60)), and lower depression likelihood (OR(95% CI)=0.33 (0.15 to 0.74)) or (OR(95% CI)=0.24 (0.11 to 0.53)), respectively. In comparison with uninvolved HCWs who exercised at never/stopped/reduced levels, or with those in the lowest HL quartile, involved HCWs with unchanged/increased exercise or with one-quartile HL increment reported lower anxiety likelihood (OR(95% CI)=0.50 (0.31 to 0.81)) or (OR(95% CI)=0.57 (0.45 to 0.71)), lower depression likelihood (OR(95% CI)=0.40 (0.27 to 0.61)) or (OR(95% CI)=0.63 (0.52 to 0.76)), and higher HRQoL scores (b(95% CI)=2.08 (0.58 to 3.58)), or (b(95% CI)=1.10 (0.42 to 1.78)), respectively. CONCLUSIONS: Physical activity and higher HL were found to protect against anxiety and depression and were associated with higher HRQoL. Unexpectedly, smoking and drinking were also found to be coping behaviours. It is important to have strategic approaches that protect HCWs' mental health and HRQoL.

Healthy Dietary Intake Behavior Potentially Modifies the Negative Effect of COVID-19 Lockdown on Depression: A Hospital and Health Center Survey.

Background: The COVID-19 pandemic causes a huge burden for affected countries. Several public health interventions were applied to contain the infection. However, the pandemic itself and the lockdown measure negatively influence people's lifestyles and psychological health. Purpose: To explore determinants of healthy dietary intake and depression, and examine the interaction between healthy dietary intake and COVID-19 lockdown on depression. Methods: A cross-sectional study was conducted at 18 hospitals and health centers from February 14 to May 31, 2020. Data of 8,291 outpatients were collected including patients' characteristics, clinical parameters, health literacy, healthy dietary intake (using the healthy eating score, HES), other health-related behaviors, and depression (using the patient health questionnaire, PHQ). Depression was defined as PHQ score ≥ 10. Results: Protective factors of healthy dietary intake and depression were higher education, better medication payment ability, higher social status, more physical activity, and higher health literacy, whereas older age, ever married, own business or other types of occupation, lockdown, suspected COVID-19 symptoms, and comorbidity were associated with lower HES scores and a higher depression likelihood. Besides, overweight/obesity and alcohol drinking were associated with lower HES scores. As compared with patients not under lockdown and with lowest HES score, those who were under lockdown and with lowest HES score had 10.6 times higher depression likelihood (odds ratio, OR, 10.60; 95% CI 6.88, 16.32; p < 0.001), whereas people with higher HES score had 15% lower depression likelihood (OR 0.85; 95% CI 0.82, 0.89; p < 0.001). Conclusions: Healthy dietary intake and depression were determined by several sociodemographic, clinical, and behavioral factors. Lockdown measure affects people's dietary intake behavior and depression. Importantly, healthy dietary intake potentially modifies the negative effect of lockdown on depression.

Synthesis and activity of substituted carbamates as potentiators of the alpha4beta2 nicotinic acetylcholine receptor.

The synthesis and structure-activity relationship of a series of carbamate potentiators of alpha4beta2 nAChR is reported herein. These compounds were highly selective for alpha4beta2 over other nAChR subtypes. In addition, compounds increased the response of alpha4beta2 nAChRs to acetylcholine, as measured with patch-clamp electrophysiology.

Discovery and optimization of substituted piperidines as potent, selective, CNS-penetrant alpha4beta2 nicotinic acetylcholine receptor potentiators.

The discovery of a series of small molecule alpha4beta2 nAChR potentiators is reported. The structure-activity relationship leads to potent compounds selective against nAChRs including alpha3beta2 and alpha3beta4 and optimized for CNS penetrance. Compounds increased currents through recombinant alpha4beta2 nAChRs, yet did not compete for binding with the orthosteric ligand cytisine. High potency and efficacy on the rat channel combined with good PK properties will allow testing of the alpha4beta2 potentiator mechanism in animal models of disease.

Inhibition of CRAC with a human anti-ORAI1 monoclonal antibody inhibits T-cell-derived cytokine production but fails to inhibit a T-cell-dependent antibody response in the cynomolgus monkey.

ORAI1 is the pore-forming component of calcium release-activated calcium (CRAC) channels. CRAC channels are the primary route for calcium ion (Ca(2+)) entry into T-cells following antigen stimulation. This Ca(2+) entry induces proliferation and cytokine production through activation of calcineurin and the nuclear factor of activated T-cells (NFAT) transcription factor along with subsequent cytokine-related genes. It was hypothesized that the in vivo inhibition of T-cell function by blocking ORAI1 or calcineurin would lead to similar functional consequences. To test this hypothesis the activity of 2C1.1, a fully human anti-ORAI1 monoclonal antibody, and cyclosporin A (CsA) were tested in vivo for their suppressive effect on T-cell-derived cytokine production and a T-cell-dependent antibody response (TDAR) using sheep red blood cells (SRBC) in cynomolgus monkeys. Despite showing similar inhibition of ex vivo interleukin (IL)-2 production by stimulated T-cells, both molecules exhibited different pharmacologic effects on the SRBC antibody response. CsA blocked the development of SRBC-specific antibodies, while 2C1.1 failed to inhibit the antigen-specific antibody response. These surprising observations suggest that full inhibition of the CRAC channel is required to inhibit a functional immune response, consistent with findings from human patients with loss of function mutations in ORAI1.

Performance of Clinical Algorithms for Smear-Negative Tuberculosis in HIV-Infected Persons in Ho Chi Minh City, Vietnam.

Background. Tuberculosis (TB) disease diagnosis in Vietnam relies on symptom screening, chest radiography (CXR), and acid fast bacilli (AFB) sputum smear which have a poor sensitivity in HIV patients. We evaluated the performance of clinical algorithms in screening and diagnosing AFB smear-negative TB in HIV patients. Methods. We enrolled 399 HIV-positive patients seeking care at a HIV clinic in Ho Chi Minh City (HCMC), Vietnam. Participants' demographics, medical history, common TB symptoms, CXR, and laboratory tests were collected. Results. Of 399 HIV patients, 390 had initial AFB-negative smears and 22/390 patients had positive cultures. Symptom screening missed 54% (12/22) of smear-negative pulmonary TB (PTB) cases. Multivariate analysis found CD4+ cell level and CXR were significant PTB predictors. An algorithm combining four TB symptoms and TST presented a high sensitivity (100%), but poorly specific (24%) diagnostic performance for smear-negative PTB. Conclusion. Up to 54% of PTB cases in the HIV-infected population may be missed in the routine screening and diagnostic procedures used in Vietnam. Symptom screening was a poor overall diagnostic measure in detecting smear-negative TB in HIV patients. Our study results suggest that routine sputum cultures should be implemented to achieve a more accurate diagnosis of TB in HIV patients.

Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL.

RANKL is a TNF family member that mediates osteoclast formation, activation, and survival by activating RANK. The proresorptive effects of RANKL are prevented by binding to its soluble inhibitor osteoprotegerin (OPG). Recombinant human OPG-Fc recognizes RANKL from multiple species and reduced bone resorption and increased bone volume, density, and strength in a number of rodent models of bone disease. The clinical development of OPG-Fc was discontinued in favor of denosumab, a fully human monoclonal antibody that specifically inhibits primate RANKL. Direct binding assays showed that denosumab bound to human RANKL but not to murine RANKL, human TRAIL, or other human TNF family members. Denosumab did not suppress bone resorption in normal mice or rats but did prevent the resorptive response in mice challenged with a human RANKL fragment encoded primarily by the fifth exon of the RANKL gene. To create mice that were responsive to denosumab, knock-in technology was used to replace exon 5 from murine RANKL with its human ortholog. The resulting "huRANKL" mice exclusively express chimeric (human/murine) RANKL that was measurable with a human RANKL assay and that maintained bone resorption at slightly reduced levels versus wildtype controls. In young huRANKL mice, denosumab and OPG-Fc each reduced trabecular osteoclast surfaces by 95% and increased bone density and volume. In adult huRANKL mice, denosumab reduced bone resorption, increased cortical and cancellous bone mass, and improved trabecular microarchitecture. These huRANKL mice have potential utility for characterizing the activity of denosumab in a variety of murine bone disease models.

Discovery and optimization of a novel series of N-arylamide oxadiazoles as potent, highly selective and orally bioavailable cannabinoid receptor 2 (CB2) agonists.

The CB2 receptor is an attractive therapeutic target for analgesic and anti-inflammatory agents. Herein we describe the discovery of a novel class of oxadiazole derivatives from which potent and selective CB2 agonist leads were developed. Initial hit 7 was identified from a cannabinoid target-biased library generated by virtual screening of sample collections using a pharmacophore model in combination with a series of physicochemical filters. 7 was demonstrated to be a selective CB2 agonist (CB2 EC50 = 93 nM, Emax = 98%, CB1 EC50 > 10 microM). However, this compound exhibited poor solubility and relatively high clearance in rat, resulting in low oral bioavailability. In this paper, we report detailed SAR studies on 7 en route toward improving potency, physicochemical properties, and solubility. This effort resulted in identification of 63 that is a potent and selective agonist at CB2 (EC50 = 2 nM, Emax = 110%) with excellent pharmacokinetic properties.