Effects of user experiences on continuance intention of using immersive three-dimensional virtual reality among institutionalized older adults.

AIM: To evaluate the acceptance of three-dimensional virtual reality programs and to explore the factors influencing the acceptance of the programs among the institutionalized older adults. DESIGN: A cross-sectional explanatory study. METHODS: A total of 71 residents completed the program successfully. They were invited to join a 9-week program included eight activities related to horticultural therapy in a virtual environment. Data were collected by structured questionnaires from August 2018 to February 2019. Ten association hypotheses were derived from the literature review. Partial least squares structural equation modelling was used to examine the proposed hypotheses. RESULTS: Program acceptance was defined as virtual reality practices and continuous usage intention. Frequency of practice was about 12 times during 9-week free-trial period, and the score of continuance usage intention was 13.06 (maximum value of 15). The findings indicated that virtual reality practices were significantly affected by presence and the presence was significantly affected by involvement and interactivity. Continuance usage intention was significantly affected by involvement; and involvement was significantly affected by interactivity. However, continuance usage intention was not significantly influenced by virtual reality practices. CONCLUSIONS: The findings supported that immersive three-dimensional virtual reality program was accepted by the institutionalized older adults. The acceptance, in terms of virtual reality practices and continuous usage intention, was influenced by different paths. The findings have a potential impact on the design of virtual reality technology for the care of institutionalized older adults. IMPACT: What problem did the study address? There were controversial findings about the acceptance of immersive 3D virtual reality program among older adults. What were the main findings? Interactivity advanced the sense of presence and, thus, resulted in a higher frequency of virtual reality practices. Interactivity enhanced perception of involvement, thus, contributing to an increased intention of continuous usage Where and on whom will the research have an impact? The immersive 3D virtual reality program was appropriate for older adults, even for first time users or individuals aged over 80 years. The findings revealed new insights for developing immersive 3D virtual reality programs for the older adults.

Effects of a Combination of Three-Dimensional Virtual Reality and Hands-on Horticultural Therapy on Institutionalized Older Adults' Physical and Mental Health: Quasi-Experimental Design.

BACKGROUND: Institutionalized older adults have limited ability to engage in horticultural activities that can improve their physical and mental health. OBJECTIVE: This study explored the effects of a combination of 3D virtual reality and horticultural therapy on institutionalized older adults' physical and mental health. METHODS: The study used a quasi-experimental design. A total of 106 older adults from 2 long-term care facilities were recruited and assigned to the experimental (n=59) or control (n=47) group. The experimental participants received a 9-week intervention. Both groups completed 3 assessments: at baseline, after the intervention, and 2 months later. The outcome variables included health status, meaning in life, perceived mattering, loneliness, and depression. RESULTS: The experimental group demonstrated significantly improved health status (P<.001), meaning in life (P<.001), and perceived mattering (P<.001) as well as significantly reduced depression (P<.001) and loneliness (P<.001) compared to the control group immediately after the intervention; these effects persisted for up to 2 months. CONCLUSIONS: This study verified the beneficial effects of a combination of 3D virtual reality and hands-on horticultural therapy on older adults' health. These results could support the future successful implementation of similar programs for institutionalized older adults on a larger scale.

Likelihood of a fecal occult blood test uptake among older adults: comparisons between health professionals and healthcare volunteers based on the health belief model.

BACKGROUND: Health professionals and healthcare volunteers play a critical role in promoting uptake of the fecal occult blood test (FOBT), which is an effective screening method for colorectal cancer. However, previous studies paid less attention to investigating both groups regarding their intention to undergo the test. This study used the Health Belief Model (HBM) to explore the likelihood of an FOBT uptake among health professionals and healthcare volunteers aged 50 years or older. METHODS: A cross-sectional survey was conducted at public health centers in a county in northern Taiwan. Health professionals and healthcare volunteers were invited to complete the questionnaires. Overall, 391 valid questionnaires were obtained (response rate = 93.10%). Structural equation modeling was used to examine the associations among the variables based on the HBM. RESULTS: The HBM explained 45, 44, and 50% of the variance in the likelihood of undergoing an FOBT in all participants, health professionals, and healthcare volunteers, respectively. The explained variance in healthcare volunteers outweighed that of professionals by 6%. Perceived benefits and self-efficacy significantly affected the likelihood of undergoing an FOBT. Self-efficacy significantly mediated the effects of perceived severity, benefits, and barriers on the likelihood of an FOBT uptake. A borderline significant difference in structural coefficients was found across groups. CONCLUSIONS: The HBM model was used to examine the likelihood of an FOBT uptake among health professionals and healthcare volunteers, and the results showed that self-efficacy was the optimal predictor of the likelihood of an FOBT uptake, followed by perceived benefits. Future multifactorial interventions to promote FOBT uptake among health professionals and healthcare volunteers aged 50-75 years could include these significant factors.

Effect of Seasonal Change on Testicular Protein Expression in White Roman Geese.

The purpose of this study was to investigate the change in protein expression in the testes of ganders at various breeding stages. A total of nine 3-year-old male White Roman ganders were used. The blood and testis samples were collected at the nonbreeding, sexual reactivation, and breeding stages for sex hormone analysis and proteomic analysis, respectively. The testicular weight and serum testosterone observed for ganders at the breeding stage were higher than those for ganders at nonbreeding and sexual reactivation stages (P < 0.05). There were 124 protein spots differentially expressed in the testes of ganders at various reproductive stages. A total of 107 protein spots of 74 proteins was identified through mass spectrometry. Most of the differentially expressed proteins were responsible for the molecular functions of protein binding (24%) and catalytic activity (16%). A functional pathway analysis suggested that proteins involved in steroidogenesis, metabolism, and spermatogenesis pathways changed in the White Roman geese at various reproductive stages. In conclusion, ganders at various reproductive stages exhibited different levels of testosterone and protein expression in the testes. The varied levels of the proteins might be essential and unique key factors in seasonal reproduction in ganders.

A flexible loop for mannan recognition and activity enhancement in a bifunctional glycoside hydrolase family 5.

BACKGROUND: An array of glycoside hydrolases with multiple substrate specificities are required to digest plant cell wall polysaccharides. Cel5E from Clostridium thermocellum and Cel5A from Thermotoga maritima are two glycoside hydrolase family 5 (GH5) enzymes with high sequence and structural similarity, but notably possess different substrate specificities; the former is a bifunctional cellulase/xylanase and the latter is a cellulase/mannanase. A specific loop in TmCel5A, Tmloop, is one of the most structurally divergent regions compared to CtCel5E and interacts with substrates, suggesting the importance for mannan recognition. METHOD: A Tmloop inserted CtCel5E and its related mutants were produced to investigate the role of Tmloop in catalysis. Crystal structure of CtCel5E-TmloopF267A followed by site-direct mutagenesis reveals the mechanism. RtCelB, a homolog with Tmloop was identified to have mannanase activity. RESULT: Tmloop incorporation enables CtCel5E to gain mannanase activity. Tyr270, His277, and Trp282 in the Tmloop are indispensable for CtCel5E-Tmloop catalysis, and weakening hydrophobic environment near the Tmloop enhances enzyme kcat. Using our newly identified loop motif to search for structurally conserved homologs in other subfamilies of GH5, we identified RtCelB. This homolog, originally annotated as a cellulase also possesses mannanase and xylanase activities. CONCLUSION: Our studies show that Tmloop enhances GH5 enzyme promiscuity and plays a role in catalysis. GENERAL SIGNIFICANCE: The study identified a loop of GH5 for mannan recognition and catalysis. Weakening the hydrophobic environment near the loop can also enhance the enzyme catalytic rate. Our findings provide a new insight on mannan recognition and activity enhancement of GH5.

Interrogation of side chain biases for oligomannose recognition by antibody 2G12 via structure-guided phage display libraries.

Monoclonal antibodies (mAbs) are essential reagents for deciphering gene or protein function and have been a fruitful source of therapeutic and diagnostic agents. However, developing anticarbohydrate antibodies to target glycans for those purposes has been less successful because the molecular basis for glycan-mAb interactions is poorly understood relative to protein- or peptide-binding mAbs. Here, we report our investigation on glycan-mAb interactions by using the unique architectural scaffold of 2G12, an antibody that targets oligomannoses on the HIV-1 glycoprotein gp120, as the template for engineering highly specific mAbs to target glycans. We first analyzed 24 different X-ray structures of antiglycan mAbs from the Protein Data Bank to determine side chain amino acid distributions in of glycan-mAb interactions. We identified Tyr, Arg, Asn, Ser, Asp, and His as the six most prevalent residues in the glycan-mAb contacts. We then utilized this information to construct two phage display libraries ("Lib1" and "Lib2") in which positions on the heavy chain variable domains of 2G12 were allowed to vary in restricted manner among Tyr, Asp, Ser, His, Asn, Thr, Ala and Pro to interrogate the minimal physicochemical requirements for oligomannose recognition. We analyzed the sequences of 39 variants from Lib1 and 14 variants from Lib2 following selection against gp120, the results showed that there is a high degree of malleability within the 2G12 for glycan recognitions. We further characterized five unique phage clones from both libraries that exhibited a gp120-specific binding profile. Expression of two of these variants as soluble mAbs indicated that, while specificity of gp120-binding was retained, the affinity of these mutants was significantly reduced relative to WT 2G12. Nonetheless, the results indicate these is some malleability in the identity of contact residues and provide a novel insight into the nature of glycan-antibody interactions and how they may differ from protein-antibody binding interactions.

A mechanism-based fluorescence transfer assay for examining ketosynthase selectivity.

Since their discovery, polyketide synthases have received massive attention from researchers hoping to harness their potential as a platform for generating new and improved therapeutics. Despite significant strides toward this end, inherent specificities within the enzymes responsible for polyketide production have severely limited these efforts. We have developed a mechanism-based, fluorescence transfer assay for a key enzyme component of all polyketide synthases, the ketosynthase domain. As demonstrated, this method can be used with both ketosynthase-containing didomains and full modules. As proof of principle, the ketosynthase domain from module 6 of the 6-deoxyerythronolide synthase is examined for its ability to accept a variety of simple thioester substrates. Consistent with its natural hexaketide substrate, we find that this ketosynthase prefers longer, α-branched thioesters and its ability to distinguish these structural features is quite remarkable. Substrate electronics are also tested via a variety of p-substituted aromatic groups. In all, we expect this technique to find considerable use in the field of polyketide biosynthesis and engineering due to its extraordinary simplicity and very distinct visible readout.

Structural tuning intra- versus inter-molecular proton transfer reaction in the excited state.

A series of 2-pyridyl-pyrazole derivatives 1-4 possessing five-membered ring hydrogen bonding configuration are synthesized, the structural flexibility of which is strategically tuned to be in the order of 1 > 2 > 3 > 4. This system then serves as an ideal chemical model to investigate the correlation between excited-state intramolecular proton transfer (ESIPT) reaction and molecular skeleton motion associated with hydrogen bonds. The resulting luminescence data reveal that the rate of ESIPT decreases upon increasing the structural constraint. At sufficiently low concentration where negligible dimerization is observed, ESIPT takes place in 1 and 2 but is prohibited in 3 and 4, for which high geometry constraint is imposed. The results imply that certain structural bending motions associated with hydrogen bonding angle/distance play a key role in ESIPT. This trend is also well supported by the DFT computational approach, in which the barrier associated with ESIPT is in the order of 1 < 2 < 3 < 4. Upon increasing the concentration in cyclohexane, except for 2, the rest of the title compounds undergo ground-state dimerization, from which the double proton transfer takes place in the excited state, resulting in a relatively blue shifted dimeric tautomer emission (cf. the monomer tautomer emission). The lack of dimerization in 2 is rationalized by substantial energy required to adjust the angle of hydrogen bond via twisting the propylene bridge prior to dimerization.

The empirical correlation between hydrogen bonding strength and excited-state intramolecular proton transfer in 2-pyridyl pyrazoles.

A series of 2-pyridyl pyrazoles 1a and 1-5 with various functional groups attached to either pyrazole or pyridyl moieties have been strategically designed and synthesized in an aim to probe the hydrogen bonding strength in the ground state versus dynamics of excited-state intramolecular proton transfer (ESIPT) reaction. The title compounds all possess a five-membered-ring (pyrazole)N-H···N(pyridine) intramolecular hydrogen bond, in which both the N-H bond and the electron density distribution of the pyridyl nitrogen lone-pair electrons are rather directional, so that the hydrogen bonding strength is relatively weak, which is sensitive to the perturbation of subtle chemical substitution and consequently reflected from the associated ESIPT dynamics. Various approaches such as (1)H NMR (N-H proton) to probe the hydrogen bonding strength and absorption titration to assess the acidity-basicity property were made for all the title analogues. The results, together with supplementary support provided by a computational approach, affirm that the increase of acidity (basicity) on the hydrogen bonding donor (acceptor) sites leads to an increase of hydrogen-bonding strength among the title 2-pyridyl pyrazoles. Luminescence results and the associated ESIPT dynamics further reveal an empirical correlation in that the increase of the hydrogen bonding strength leads to an increase of the rate of ESIPT for the title 2-pyridyl pyrazoles, demonstrating an interesting relationship among N-H acidity, hydrogen bonding strength, and the associated ESIPT rate.

Effects of Swimming Pool Conditions and Floor Types on White Roman Geese's Physical Condition Scores and Behaviors in an Indoor Rearing System.

Biosecurity problems, including the continual risk of avian influenza spread by wild birds, have severely affected traditional free-range waterfowl production systems. Regulations and techniques for indoor goose production require more considerations for animal welfare. This study investigated the effects of swimming pool conditions and different floor types on the physical condition scores and behaviors of indoor-reared White Roman geese. A total of 48 male and 48 female White Roman geese reared from the age of 15 to 84 days were randomly allocated to pens with or without a swimming pool and with either mud or perforated plastic floors. Providing a swimming pool improved geese's eye and feather cleanliness and breast blister scores at the age of 84 days. Compared with geese reared on a mud floor, those reared on a perforated plastic floor had better feather cleanliness and higher breast blister scores at the age of 56 and 84 days. Providing a swimming pool to indoor-reared geese may reduce the proportion of abnormal behaviors, such as injurious feather pecking, by increasing water-related behaviors. This study suggests a more appropriate environment design for better balancing commercial goose production with animal welfare in an indoor rearing system.

Fine tuning the energetics of excited-state intramolecular proton transfer (ESIPT): white light generation in a single ESIPT system.

Using 7-hydroxy-1-indanone as a prototype (I), which exhibits excited-state intramolecular proton transfer (ESIPT), chemical modification has been performed at C(2)-C(3) positions by fusing benzene (molecule II) and naphthalene rings, (molecule III). I undergoes an ultrafast rate of ESIPT, resulting in a unique tautomer emission (λ(max) ∼530 nm), whereas excited-state equilibrium is established for both II and III, as supported by the dual emission and the associated relaxation dynamics. The forward ESIPT (normal to proton-transfer tautomer species) rates for II and III are deduced to be (30 ps)(-1) and (22 ps)(-1), respectively, while the backward ESIPT rates are (11 ps)(-1) and (48 ps)(-1). The ESIPT equilibrium constants are thus calculated to be 0.37 and 2.2 for II and III, respectively, giving a corresponding free energy change of 0.59 and -0.47 kcal/mol between normal and tautomer species. For III, normal and tautomer emissions in solid are maximized at 435 and 580 nm, respectively, achieving a white light generation with Commission Internationale de l'Eclairage (CIE) (0.30, 0.27). An organic light-emitting diode based on III is also successfully fabricated with maximum brightness of 665 cd m(-2) at 20 V (885 mA cm(-2)) and the CIE coordinates of (0.26, 0.35). The results provide the proof of concept that the white light generation can be achieved in a single ESIPT system.

pH-Dependent spectroscopic and luminescent properties, and metal-ion recognition studies of Re(I) complexes containing 2-(2'-pyridyl)benzimidazole and 2-(2'-pyridyl)benzimidazolate.

A series of Re(I) complexes, [Re(CO)(3)Cl(HPB)] (1), [Re(CO)(3)(PB)H(2)O] (2), [Re(CO)(3)(NO(3))(PB-AuPPh(3))] (3), and [Re(CO)(3)(NO(3))(PB)Au(dppm-H)Au](2) (4) [HPB = 2-(2'-pyridyl)benzimidazole; dppm = 2,2'-bis(diphenylphosphinomethane)], have been synthesized and characterized by X-ray diffraction. Complex 1, which exhibits interesting pH-dependent spectroscopic and luminescent properties, was prepared by reacting Re(CO)(5)Cl with an equimolar amount of 2-(2'-pyridyl)benzimidazole. The imidazole unit in complex 1 can be deprotonated to form the imidazolate unit to give complex 2. Addition of 1 equiv of AuPPh(3)(NO(3)) to complex 2 led to the formation of a heteronuclear complex 3. Addition of a half an equivalent of dppm(Au(NO(3)))(2) to complex 2 yielded 4. In both 3 and 4, the imidazolate unit acts as a multinuclear bridging ligand. Complex 4 is a rare and remarkable example of a Re(2)Au(4) aggregate in combination with µ(3)-bridging 2-(2'-pyridyl)benzimidazolate. Finally, complex 2 has been used to examine the Hg(2+)-recognition event among group 12 metal ions. Its reversibility and selectivity toward Hg(2+) are also examined.

Novel potent anti-STEAP1 bispecific antibody to redirect T cells for cancer immunotherapy.

BACKGROUND: The prognosis for metastatic Ewing sarcoma family of tumors (EFT) is still poor despite high-dose chemotherapy and radiation treatment. Immunotherapies hold promise, but cancer antigen-targeting immunotherapies have largely failed to induce effective T cell receptor-mediated antitumor response. However, T cell-engaging bispecific antibodies (T-BsAbs) have yet to be adequately explored. METHODS: Rehumanized STEAP1-IgG was used to build T-BsAb (named BC261) using the 2+2 IgG-[L]-scFv platform carrying the anti-CD3 huOKT3 scFv as the second specificity. Its binding epitope mapping, species cross-reactivity, tumor cell line staining, and in vitro cytotoxicity were investigated thoroughly. Its potency in driving tumor-infiltrating lymphocytes (TILs) was quantified using bioluminescence, correlated with in vivo antitumor response against cell line-derived or patient-derived xenografts (CDXs or PDXs) and compared with anti-STEAP1 T-BsAbs built on representative antibody platforms. RESULTS: BC261 binding epitope was mapped to its second extracellular domain of STEAP1 shared among canine and primate orthologs. BC261 induced potent cytotoxicity against panels of EFT, prostate cancer, and canine osteosarcoma cell lines despite their low antigen density. BC261 drove significantly more TILs into tumors (30-fold) and exerted superior antitumor effects compared with the other standard BsAb platforms. The antitumor efficacy of BC261 was consistent against EFT and prostate cancer CDXs and PDXs. CONCLUSIONS: BC261 was highly efficient in driving T cell infiltration and tumor ablation. Either as stand-alone therapeutics or for ex vivo armed T cells, this novel anti-STEAP1 T-BsAb BC261 has therapeutic potential.

Effects of Different Swimming Pool Conditions and Floor Types on Growth Performance and Footpad Dermatitis in Indoor-Reared White Roman Geese.

Footpad dermatitis (FPD) is a major foot disease in modern poultry production, and it affects both poultry health and animal welfare. It refers to inflammation and necrotizing lesions on the plantar surface of the footpads and toes. We investigated the effects of providing a swimming pool and different floor types on growth performance and FPD score in indoor-reared White Roman geese. Forty-eight male and 48 female White Roman geese were randomly allocated to pens with or without a swimming pool and with either mud or perforated plastic floor and reared from 15 to 84 days of age. Growth performance measurements included feed intake (FI), weight gain (WG), and feed conversion ratio (FCR). FI, WG, and FCR were significantly decreased at various growth periods in geese provided with a pool. Lower WG and bodyweight for the perforated plastic floor group were found at 15-28 and 28 days of age, respectively. The geese reared on the perforated plastic floors without a pool had higher FPD scores at 70 and 84 days of age than those with other rearing conditions. A higher incidence of FPD score 1 was observed in geese raised without a pool. In conclusion, providing a pool can improve footpad health in indoor-reared White Roman geese but may not benefit growth performance.

Diphenyl(1-naphthyl)phosphine ancillary for assembling of red and orange-emitting Ir(III) based phosphors; strategic synthesis, photophysics, and organic light-emitting diode fabrication.

Treatment of a series of dinuclear Ir(III) complexes [(fnazo)(2)Ir(µ-Cl](2), [(fpiq)(2)Ir(µ-Cl](2), and [(fppy)(2)Ir(µ-Cl](2) with diphenyl(1-naphthyl)phosphine (dpnH) in decalin at 100 °C afforded the simple adducts, trans-N,N'-[(fnazo)(2)Ir(dpnH)Cl] (1a), trans-N,N'-[(fpiq)(2)Ir(dpnH)Cl] (1b), and trans-N,N'-[(fppy)(2)Ir(dpnH)Cl] (1c), for which the C(∧)N cyclometalating reagents, that is, fnazoH, fpiqH and fppyH, stands for 4-(4-fluorophenyl)quinazoline, 1-(4-fluorophenyl)isoquinoline and 4-fluorophenylpyridine, respectively. Single crystal X-ray diffraction study on 1a revealed existence of two trans-N,N' cyclometalates, with both chloride and dpnH donors located at the positions opposite to the phenyl substituents. Subsequent heating of 1a-1c at higher temperature afforded the second isomer (2a-2c), showing formation of cis-N,N' orientation for the aforementioned cyclometalates. Further thermolysis of either trans or cis-Ir(III) complexes 1 or 2 in presence of sodium acetate, which serves as both activator and chloride scavenger, gave successful isolation of a mixture of two fully cyclometalated Ir(III) complexes trans-N,N'-[(C(∧)N)(2)Ir(dpn)] (3a-3c) and cis-N,N'-[(C(∧)N)(2)Ir(dpn)] (4a-4c). Structural and photophysical properties of complexes 3a-3c and 4a-4c were measured and compared. Time-dependent density functional theory (DFT) studies suggested that, upon changing the C(∧)N cyclometalates from quinazolinyl, isoquinolinyl, and, finally, to pyridyl fragment, the lowest unoccupied molecular orbitals (LUMOs) are gradually shifted from the cyclometalating nitrogen heterocycles to the 1-naphthyl group of the phosphine chelate and, concomitantly altered the photophysical properties. An organic light-emitting diode (OLED) using orange-red phosphors 4a and 4b has been successfully fabricated. At the practical brightness of 500 cd·m(-2), decent external quantum efficiency of 10.6% and 12.5% could be reached for 4a and 4b, respectively, revealing the usefulness of relevant molecular architecture in designing triplet OLED emitters.

Excited-state intramolecular proton transfer (ESIPT) fine tuned by quinoline-pyrazole isomerism: pi-conjugation effect on ESIPT.

A series of quinoline/isoquinoline-pyrazole isomers (I-III), in which the pyrazole moiety is in a different substitution position, was strategically designed and synthesized, showing a system with five-membered intramolecular hydrogen bonding. Despite the similarity in molecular structure, however, only I undergoes excited-state intramolecular proton transfer, as evidenced by the distinct 560 nm proton-transfer emission and its associated relaxation dynamics. The experimental results support a recent theoretical approach regarding the conjugation effect on a proton (or hydrogen atom) transfer reaction (J. Phys. Chem. A 2009, 113, 4862-4867). The concept simply predicts that more extended pi conjugation, i.e., resonance, for proton-transfer tautomer species could allow for efficient delocalization of excess charge in the reaction center, resulting in a larger thermodynamic driving force for proton transfer.

Exploring prior diseases associated with incident late-onset Alzheimer's disease dementia.

Studies have identified prior conditions associated with late-onset Alzheimer's disease dementia (LOAD), but all prior diseases have rarely been screened simultaneously in the literature. Our objective in the present study was to identify prior conditions associated with LOAD and construct pathways for them. We conducted a population-based matched case-control study based on data collected in the National Health Insurance Research database of Taiwan and the Catastrophic Illness Certificate database for the years 1997-2013. Prior diseases definitions were based on the first three digits of the codes listed in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Inclusion criteria required that each ICD-code existed for at least 1 year and incurred at least 2 outpatient visits or inpatient diagnosis. The case group comprised 4,600 patients newly diagnosed with LOAD in 2007-2013. The LOAD patients were matched by sex and age to obtain 4,600 controls. Using stepwise multivariate logistic regression analysis, diseases were screened for 1, 2 …, 9 years prior to the first diagnosis of LOAD. Path analysis was used to construct pathways between prior diseases and LOAD. Our results revealed that the following conditions were positively associated with the incidence of LOAD: anxiety (ICD-code 300), functional digestive disorder (ICD code 564), psychopathology-specific symptoms (ICD-code 307), disorders of the vestibular system (ICD-code 386), concussion (ICD-code 850), disorders of the urethra and urinary tract (ICD-code 599), disorders of refraction and accommodation (ICD-code 367), and hearing loss (ICD-code 389). A number of the prior diseases have previously been described in the literature in a manner identical to that in the present study. Our study supports the assertion that mental, hearing, vestibular system, and functional digestive disorders may play an important role in the pathogenesis of LOAD.

Focal Loss for Dense Object Detection.

The highest accuracy object detectors to date are based on a two-stage approach popularized by R-CNN, where a classifier is applied to a sparse set of candidate object locations. In contrast, one-stage detectors that are applied over a regular, dense sampling of possible object locations have the potential to be faster and simpler, but have trailed the accuracy of two-stage detectors thus far. In this paper, we investigate why this is the case. We discover that the extreme foreground-background class imbalance encountered during training of dense detectors is the central cause. We propose to address this class imbalance by reshaping the standard cross entropy loss such that it down-weights the loss assigned to well-classified examples. Our novel Focal Loss focuses training on a sparse set of hard examples and prevents the vast number of easy negatives from overwhelming the detector during training. To evaluate the effectiveness of our loss, we design and train a simple dense detector we call RetinaNet. Our results show that when trained with the focal loss, RetinaNet is able to match the speed of previous one-stage detectors while surpassing the accuracy of all existing state-of-the-art two-stage detectors. Code is at: https://github.com/facebookresearch/Detectron.

Collocation of avian and mammal antibodies to develop a rapid and sensitive diagnostic tool for Russell's Vipers Snakebite.

Russell's vipers (RVs) envenoming is an important public health issue in South-East Asia. Disseminated intravascular coagulopathy, systemic bleeding, hemolysis, and acute renal injury are obvious problems that develop in most cases, and neuromuscular junction blocks are an additional problem caused by western RV snakebite. The complex presentations usually are an obstacle to early diagnosis and antivenom administration. Here, we tried to produce highly specific antibodies in goose yolks for use in a paper-based microfluidic diagnostic kit, immunochromatographic test of viper (ICT-Viper), to distinguish RVs from other vipers and even cobra snakebite in Asia. We used indirect ELISA to monitor specific goose IgY production and western blotting to illustrate the interaction of avian or mammal antibody with venom proteins. The ICT-Viper was tested not only in prepared samples but also in stored patient serum to demonstrate its preliminary efficacy. The results revealed that specific anti-Daboia russelii IgY could be raised in goose eggs effectively without inducing adverse effects. When it was collocated with horse anti-Daboia siamensis antibody, which broadly reacted with most of the venom proteins of both types of Russell's viper, the false cross-reactivity was reduced, and the test showed good performance. The limit of detection was reduced to 10 ng/ml in vitro, and the test showed good detection ability in clinical snake envenoming case samples. The ICT-Viper performed well and could be combined with a cobra venom detection kit (ICT-Cobra) to create a multiple detection strip (ICT-VC), which broadens its applications while maintaining its detection ability for snake envenomation identification. Nonetheless, the use of the ICT-Viper in the South-East Asia region is pending additional laboratory and field investigations and regional collaboration. We believe that the development of this practical diagnostic tool marks the beginning of positive efforts to face the global snakebite issue.

Exploiting Signaling Pathways and Immune Targets Beyond the Standard of Care for Ewing Sarcoma.

Ewing sarcoma (ES) family of tumors includes bone and soft tissue tumors that are often characterized by a specific translocation between chromosome 11 and 22, resulting in the EWS-FLI1 fusion gene. With the advent of multi-modality treatment including cytotoxic chemotherapy, surgery, and radiation therapy, the prognosis for patients with ES has substantially improved. However, a therapeutic plateau is now reached for both localized and metastatic disease over the last two decades. Burdened by the toxicity limits associated with the current frontline systemic therapy, there is an urgent need for novel targeted therapeutic strategies. In this review, we discuss the current treatment paradigm of ES, and explore preclinical evidence and emerging treatments directed at tumor signaling pathways and immune targets.