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To evaluate the effect of acupoint stimulation compared to other interventions on pain control in neonates who underwent heel lance, we searched for randomized controlled trials across six databases (CINAHL, Cochrane Library, EMBASE, Medline, PubMed, and Web of Science) published up to January 2023. Studies comparing acupoint stimulation and other interventions for controlling heel lance pain in neonates were included. These reports measured at least one of the following variables: pain score, crying time, oxygenation saturation, heart rate, respiration rate, and duration of the procedure. The data were independently extracted by two authors, and the PRISMA guidelines for study selection were followed. A total of 79 articles were screened, and 10 studies, with results on 813 neonates, were included in the final selection. The pain scores recorded during the heel lance procedure were not significantly different between the acupoint stimulation cohort and the control cohort (SMD of −0.26, 95% confidence interval (CI) from −0.52 to 0.01; p = 0.06; I2 = 68%). After processing the subgroup analyses, significant differences were found in the comparisons of acupuncture vs. usual care (SMD of −1.25, 95% CI from −2.23 to 0.27) and acupressure vs. usual care (SMD of −0.62, 95% CI from −0.96 to −0.28); nonsignificant differences were found in other comparisons. Our results demonstrate that acupoint stimulation may improve pain score during the heel lance procedure.

Maternal infection during pregnancy may affect fetal brain development and increase the risk of developing neurological and mental disorders later in life in offspring. In this study, we used low-dose lipopolysaccharide (LPS) injection to mimic mild maternal infection at a critical time window for fetal dopamine (DA) and serotonin (5-HT) neuron development. The affected offspring exhibited reduction of dopaminergic and serotonergic neurons and anxiety- and depression-related behaviors in adulthood. In the current study, we evaluated whether dextromethorphan (DM, 30 mg/kg), an over-the-counter antitussive drug with anti-inflammatory and neuroprotective properties, could reduce the adverse effects of maternal infection mimicked by LPS exposure. We discovered that DM application did not change the baseline serum interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) levels in the LPS-exposed offspring. However, DM treatment could reduce the heightened immune responses induced by a postnatal LPS challenge test in prenatal LPS-exposed offspring. The neuroprotective effect of DM was only seen in DA neurons but not in 5-HT neurons. We concluded that DM treatment can partially protect the offspring against the adverse effects of LPS-induced maternal immune activation. The reduction in heightened immune responses and dopaminergic neuronal loss in LPS-exposed offspring could potentially reduce the risk of DA-related neurological and psychiatric disorders later in life.

C(sp3) radicals (R˙) are of broad research interest and synthetic utility.

Schizophrenia is associated with increased resting-state large-scale functional network connectivity in the gamma frequency. High-frequency transcranial random noise stimulation (hf-tRNS) modulates gamma-band endogenous neural oscillations in healthy individuals through the application of low-amplitude electrical noises. Yet, it is unclear if hf-tRNS can modulate gamma-band functional connectivity in patients with schizophrenia. We performed a randomized, double-blind, sham-controlled clinical trial to contrast hf-tRNS (N = 17) and sham stimulation (N = 18) for treating negative symptoms in 35 schizophrenia patients. Short continuous currents without neuromodulatory effects were applied in the sham group to mimic real-stimulation sensations. We used electroencephalography to investigate if a five-day, twice-daily hf-tRNS protocol modulates gamma-band (33–45 Hz) functional network connectivity in schizophrenia. Exact low resolution electromagnetic tomography (eLORETA) was used to compute intra-cortical activity from regions within the default mode network (DMN) and fronto-parietal network (FPN), and functional connectivity was computed using lagged phase synchronization. We found that hf-tRNS reduced gamma-band within-DMN and within-FPN connectivity at the end of stimulation relative to sham stimulation. A trend was obtained between the change in within-FPN functional connectivity from baseline to the end of stimulation and the improvement of negative symptoms at the one-month follow-up (r = −0.49, p = 0.055). Together, our findings suggest that hf-tRNS has potential as a network-level approach to modulate large-scale functional network connectivity pertaining to negative symptoms of schizophrenia.

Chia-Yu Huang,1– 3 Ming-Cheng Huang,3,4 Mao-Feng Sun,3,4 Cheng-Li Lin,5,6 Mei-Yao Wu,4,7 Wu-Chou Lin,3,8,&ast; Hung-Rong Yen3,4,9,10,&ast; 1Department of Family Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, 427, Taiwan; 2School of Medicine, Tzu Chi University, Hualien, 970, Taiwan; 3Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 404, Taiwan; 4Department of Chinese Medicine, China Medical University Hospital, Taichung, 404, Taiwan; 5Management Office for Health Data, China Medical University Hospital, Taichung, 404, Taiwan; 6College of Medicine, China Medical University, Taichung, 404, Taiwan; 7School of Post-baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 404, Taiwan; 8Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, 404, Taiwan; 9Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung, 404, Taiwan; 10Chinese Medicine Research Center, China Medical University, Taichung, 404, Taiwan&ast;These authors contributed equally to this workCorrespondence: Hung-Rong Yen Tel +886-4-22053366 ext. 3313Email hungrongyen@mail.cmu.edu.twWu-Chou Lin Tel +886-4-22052121Email d0562@mail.cmuh.org.twBackground: Major depressive disorder is a significant public health concern, which often leads to loss of productivity, functional decline, and various complications. The aim of this study was to investigate the effectiveness of acupuncture in the risk reduction of coronary heart disease (CHD) in patients with depression.Methods: We enrolled patients diagnosed with depression between January 1, 1997, and December 31, 2010, through the Taiwanese National Health Insurance Research Database (NHIRD). Propensity score was used to match equal numbers (n=14,647) of acupuncture cohort and no-acupuncture cohort based on characteristics including sex, age, baseline comorbidity and medication. Patients were followed up until December 31, 2013, or withdrawn from the NHIRD. The Cox regression model was used to compare the hazard ratios (HRs) of CHD in the two cohorts.Results: The basic characteristics of the two groups were similar. A lower cumulative incidence of CHD was noted in the acupuncture cohort (Log rank test, p < 0.001). Over time, 1626 patients in the acupuncture cohort (21.05 per 1000 person-years) and 2412 patients in the no-acupuncture cohort (39.84 per 1000 person-years) developed CHD (adjusted HR=0.50, 95% CI 0.47– 0.53). The decreased CHD incidence was independent of age, sex, comorbidities, and medications used. The cumulative incidence of CHD was significantly lower in the acupuncture cohort than in the no-acupuncture cohort (Log rank test, p< 0.001).Conclusion: The results provided a real-world evidence that acupuncture may have beneficial effect on CHD risk reduction in patients with depression.Keywords: acupuncture, depression, coronary heart disease, National Health Insurance Research Database, real-world evidence

C(sp

The simple and efficient conversion of carbonyl compounds into functionalized alkanes via deoxygenation is highly enabling in chemical synthesis. This Review covers the recent methodology development in carbonyl and carboxyl deoxygenative functionalizations, highlighting some representative and significant contributions in this field. These advances are categorized based on the reactivity patterns of some oxygenated feedstock compounds, including aldehydes, ketones and carboxylic acids. Four types of reactive intermediates arising from aldehydes and ketones during the deoxygenation, namely, bis-electrophiles, carbenoids, bis-nucleophiles and alkyl radical equivalents, are presented, while the carboxylic acids mainly behave as tris-electrophiles when deoxygenated. In each subcategory, selected examples are organized according to the type of bond formation and discussed from a generalized mechanistic perspective.

The potential role of Tai Chi in improving sarcopenia and frailty has been shown in randomized controlled trials (RCTs). This systematic review and meta-analysis aimed to examine the effect of Tai Chi on muscle mass, muscle strength, physical function, and other geriatric syndromes in elderly individuals with sarcopenia and frailty.Systematic searches of the PubMed, Cochrane Library, PEDro, EMBASE, Web of Science, CINAHL, and Medline databases for RCTs published between 1989 and 2022 were conducted; the database searchers were supplemented with manual reference searches. The inclusion criteria were as follows: (1) the study was designed as a RCT; (2) Tai Chi was one of the intervention arms; (3) the participants had a minimum age of ≥ 60 years and were diagnosed with frailty or sarcopenia, and the diagnostic guidelines or criteria were mentioned; (4) the number of participants in each arm was ≥ 10; and (5) the outcome reports included ≥ 1 item from the following primary or secondary outcomes. The exclusion criteria were as follows: (1) non-RCT studies; (2) nonhuman subjects; (3) participants aged 60 years; (4) no description of the diagnostic guidelines or criteria for frailty or sarcopenia in the text; and (5) reported outcomes not among the following primary or secondary outcomes. The primary outcomes were muscle mass, grip strength and muscle performance (gait speed, 30-second chair stand test (30CST), sit-to-stand test (SST), Timed up and go test (TUGT), balance, and the Short Physical Performance Battery (SPPB)). The secondary outcomes included the number of falls and fear of falling (FOF), diastolic blood pressure (DBP), Mini-Mental State Examination (MMSE) score, and depression and quality of life (QOL) assessments.Eleven RCTs were conducted from 1996 to 2022 in 5 countries that investigated 1676 sarcopenic or frail elderly individuals were included in the review. There were 804 participants in the Tai Chi exercise cohort and 872 participants in the control cohort (nonexercised (n = 5)/ exercise (n = 8)). The mean age of participants was 70-89.5 years and the numbers of participants from each arm in each study were 10-158. The majority of the participants practiced Yang-style Tai Chi (n = 9), and the numbers of movement ranged from 6 to 24. The prescriptions of training were 8-48 weeks, 2-7 sessions per weeks, and 30-90 min per session. Most studies used Tai Chi expert as instructor (n = 8). The lengths of follow-up period were 8-48 weeks. The results from our meta-analysis revealed significant improvements for Tai Chi compared to control group (nonexercise/ exercise) on measures of the 30CST (weighted mean difference (WMD): 2.36, 95% confidence interval (CI) 1.50-3.21, p 0.00001, IOur results demonstrated that patients with frailty or sarcopenia who practiced Tai Chi exhibited improved physical performance in the 30-second chair stand test, the Timed up and go test, number of falls and fear of falling. However, there was no difference in muscle mass, grip strength, gait speed, or Short Physical Performance Battery score between the Tai Chi and control groups. Improvements in the sit-to-stand test, balance, diastolic blood pressure, Mini-Mental State Examination score, and depression and quality of life assessments were found when comparing the Tai Chi cohort to the nonexercise control cohort rather than the exercise control cohort. To explore the effectiveness of Tai Chi in sarcopenic and frail elderly individuals more comprehensively, a standardized Tai Chi training prescription and a detailed description of the study design are suggested for future studies.

Reduced left-lateralized electroencephalographic (EEG) frontal alpha asymmetry (FAA), a biomarker for the imbalance of interhemispheric frontal activity and motivational disturbances, represents a neuropathological attribute of negative symptoms of schizophrenia. Unidirectional high-frequency transcranial random noise stimulation (hf-tRNS) can increase the excitability of the cortex beneath the stimulating electrode. Yet, it is unclear if hf-tRNS can modulate electroencephalographic FAA in patients with schizophrenia. We performed a randomized, double-blind, sham-controlled clinical trial to contrast hf-tRNS and sham stimulation for treating negative symptoms in 35 schizophrenia patients. We used electroencephalography to investigate if 10 sessions of hf-tRNS delivered twice-a-day for five consecutive weekdays would modulate electroencephalographic FAA in schizophrenia. EEG data were collected and FAA was expressed as the differences between common-log-transformed absolute power values of frontal right and left hemisphere electrodes in the alpha frequency range (8–12.5 Hz). We found that hf-tRNS significantly increased FAA during the first session of stimulation (p = 0.009) and at the 1-week follow-up (p = 0.004) relative to sham stimulation. However, FAA failed to predict and surrogate the improvement in the severity of negative symptoms with hf-tRNS intervention. Together, our findings suggest that modulating electroencephalographic frontal alpha asymmetry by using unidirectional hf-tRNS may play a key role in reducing negative symptoms in patients with schizophrenia.

Cross-coupling reaction between two C-H bonds has become a fundamental strategy in synthetic organic chemistry. With its increasing importance in green chemistry, atom economy, and step economy, its development has sky-rocketed within the last 20 years, with the term "cross-dehydrogenative coupling (CDC)" popularized and progressed by the group of Li and others to describe direct Y-Z bond formations from Y-H and Z-H bonds under oxidative conditions. Among all types of CDC reactions, the C-C bond formations are of prime importance in building up the molecular complexity but their categorization currently remains disarray due to a wide diversity, resulting in frequent display in separate topics. In this Perspective, a contemporary categorization via C-H activation strategies is presented herein, which could be vital for future CDC designs. With this mechanism-based categorization and discussion, we wish that this minireview will help more synthetic chemists gain insight into the design of CDC reactions and inspires more ideas on this topic.

Minisci alkylation is of prime importance for its applicability in functionalizing diverse heteroarenes, which are core structures in many bioactive compounds. In alkyl radical generation processes, precious metal catalysts, high temperatures and excessive oxidants are generally involved, which lead to sustainability and safety concerns. Herein we report a new strategy using diacetyl (2,3-butanedione) as an abundant, visible light-sensitive and “traceless” hydrogen atom abstractor to achieve metal-free cross-dehydrogenative Minisci alkylation under mild conditions. Mechanistic studies supported hydrogen atom transfer (HAT) between an activated C(sp3)–H substrate and diacetyl. Moreover, with the assistance of di-tert-butyl peroxide (DTBP), the scope of the reaction could be extended to strong aliphatic C–H bonds via diacetyl-mediated energy transfer. The robustness of this strategy was demonstrated by functionalizing complex molecules such as quinine, fasudil, nicotine, menthol and alanine derivatives.

Microplastics (MPs) pollution has become a serious environmental issue worldwide, but its potential effects on health remain unknown. The administration of polystyrene MPs (PS-MPs) to mice for eight weeks impaired learning and memory behavior. PS-MPs were detected in the brain especially in the hippocampus of these mice. Concurrently, the hippocampus had decreased levels of immediate-early genes, aberrantly enhanced synaptic glutamate AMPA receptors, and elevated neuroinflammation, all of which are critical for synaptic plasticity and memory. Interestingly, ablation of the vagus nerve, a modulator of the gut-brain axis, improved the memory function of PS-MPs mice. These results indicate that exposure to PS-MPs in mice alters the expression of neuronal activity-dependent genes and synaptic proteins, and increases neuroinflammation in the hippocampus, subsequently causing behavioral changes through the vagus nerve-dependent pathway. Our findings shed light on the adverse impacts of PS-MPs on the brain and hippocampal learning and memory.

Objective: Chinese herbal medicine (CHM) is quite popular in Asia. The purpose of this study is to investigate the benefits of decreasing the risk of cirrhosis in patients with non-alcoholic fatty ...

Carboxylic acids are readily available, structurally diverse and shelf-stable; therefore, converting them to the isoelectronic boronic acids, which play pivotal roles in different settings, would be highly enabling. In contrast to the well-recognised decarboxylative borylation, the chemical space of carboxylic-to-boronic acid transformation via deoxygenation remains underexplored due to the thermodynamic and kinetic inertness of carboxylic C-O bonds. Herein, we report a deoxygenative borylation reaction of free carboxylic acids or their sodium salts to synthesise alkylboronates under metal-free conditions. Promoted by a uniquely Lewis acidic and strongly reducing diboron reagent, bis(catecholato)diboron (B2cat2), a library of aromatic carboxylic acids are converted to the benzylboronates. By leveraging the same borylative manifold, a facile triboration process with aliphatic carboxylic acids is also realised, diversifying the pool of available 1,1,2-alkyl(trisboronates) that were otherwise difficult to access. Detailed mechanistic studies reveal a stepwise C-O cleavage profile, which could inspire and encourage future endeavours on more appealing reductive functionalisation of oxygenated feedstocks., Converting a carboxylic acid into a boronic acid, which makes a useful chemical handle from a feedstock chemical, currently relies on decarboxylation and requires metal catalysts and prior functionalization. Here the authors show a simplified procedure via deoxygenation, using diboron and free carboxylic acids.

Key summary points Aim We share our strategies for preventing a COVID-19 outbreak in a nursing home in Taiwan and evaluate the efficacy of these strategies. Findings (1) Our strategies are useful for decreasing the numbers of outpatient department visits, days of prescription from the outpatient department, number of emergency department visits, number of admissions, and days of admission to treat respiratory tract infections in the nursing home residents. (2) Nursing home staff also had lower numbers of outpatient department visits and days of prescription from the outpatient department to treat respiratory tract infections through executing our preventive measures for a COVID-19 outbreak. Message Our preventive strategies for the COVID-19 outbreak are helpful for decreasing the incidence and severity of respiratory tract infections in the nursing home residents and staff. Taiwan’s experience could also be a benchmark for other countries. However, these strategies still require weeks to achieve their estimated results. Supplementary Information The online version contains supplementary material available at 10.1007/s41999-021-00459-7., Purpose We share our strategies for preventing the COVID-19 outbreak in a nursing home in Taiwan. Methods We compared the number of outpatient department visits, the days of prescription from the outpatient department, the number of emergency department visits of the nursing home residents and staff, the number of admissions, and the days of admission of the residents for respiratory tract infection treatment between 2019 and 2020 to examine the effect of our preventive measures in the nursing home. Residents and staff who continuously lived and worked in the nursing home from 2019 to 2020 were included. The differences in outcomes between 2019 and 2020 were examined using paired sample t tests. The multivariate analyses were presented through generalized estimating equation analysis. Results A cohort of 183 residents and 127 staff was included and their electronic medical documentation was analyzed in two periods: January–September 2019 and January–September 2020. These residents had lower numbers of outpatient department visits (P

Aim of the Study: The purpose of this study is to demonstrate that Chinese herbal medicine is beneficial for survival improvement in patients with multiple myeloma. Materials and Methods: We performed a 1:1 propensity score–matched cohort study to analyze patients with multiple myeloma diagnosed between January 1, 2002, and December 31, 2012, through the Taiwanese National Health Insurance Research Database. Patients who received Chinese herbal medicine therapy from the initial date of diagnosis of multiple myeloma to December 31, 2012, were included in the Chinese herbal medicine group. Patients who were not treated with Chinese herbal medicine during the same interval were categorized in the non-Chinese herbal medicine group. A Cox regression model was used to adjust for sex, age, comorbidities, and drug use. Hazard ratios were also compared between the 2 groups. Results: A total of 312 patients were identified after 1:1 propensity score matching. The patients had similar basic characteristics. A better survival status was found in the Chinese herbal medicine cohort (log-rank test, P < .0001). Finally, 49 patients in the Chinese herbal medicine cohort and 96 patients in the non-Chinese herbal medicine cohort died (adjusted hazard ratio = 0.35, 95% confidence interval = 0.24-0.51). The effect of survival improvement from Chinese herbal medicine in patients with multiple myeloma could be observed when prescriptions had the duration of ≥30 days. Conclusions: Our results showed that patients with multiple myeloma could benefit from Chinese herbal medicine treatment, which could improve the survival rate in Taiwan. The findings offer important ideas for further study.

Direct conversion of aldehydes and ketones into alkylboronic esters via deoxygenative borylation represents an unknown yet highly desirable transformation. Herein, we present a one-step and metal-free method for carbonyl deoxy-borylation under mild conditions. A wide range of aromatic aldehydes and ketones are tolerated and successfully converted into the corresponding benzylboronates. By the same deoxygenation manifold with aliphatic aldehydes and ketones, we also enable a concise synthesis of 1,1,2-tris(boronates), a family of compounds that currently lack efficient synthetic methods. Given its simplicity and versatility, we expect that this novel borylation approach could show great promise in organoboron synthesis and inspire more carbonyl deoxygenative transformations in both academic and industrial settings.

Background We investigated whether the availability of a tap water supply system is associated with lowering the admission rate 30 days after burn injury. Methods We analysed data from the Longitudinal Health Insurance Database 2000 from the National Health Research Institutes. It contains a random sample of 1,000,000 subjects out of 22 million beneficiaries of the National Health Insurance of Taiwan from 1996 to 2010. The included patients were diagnosed twice with burn injuries in local medical departments. The odds ratios and 95% confidence intervals were estimated by logistic regression model to evaluate the correlations of baseline characteristics and comorbidities. Results A total of 5,996 patients were identified after 1:1 propensity score matching. They had similar basic characteristics. Ultimately, 96 patients in the case cohort (1.10 per 1,000 person-years) and 58 patients in the control cohort (0.66 per 1,000 person-years) were admitted 30 days after a burn injury (adjusted hazard ratio 1.67, 95% confidence interval 1.21–2.32). A lower incidence of admission because of burn injury was found in the control cohort (log-rank test, p = 0.019). The advantageous effect of a well-equipped tap water system on a lower admission rate in burn patients was independent of comorbidities. Conclusions The results of this study demonstrated the association between lowering the admission rate at 30 days in burn patients in Taiwan and using a well-equipped tap water system. It also could offer important information to the government for enhancing the availability of tap water system in those areas lack adequate tap water supply which is useful to protect burn patients from following admission.

China’s port facility construction projects in the Indian Ocean (IO) region, particularly those in Gwadar and Djibouti, have led to a heated debate among strategists over whether the country has been carrying out a ‘string of pearls’ strategy, an alleged Chinese scheme to challenge America’s military predominance in South Asia. Although Beijing has denied the existence of such a strategy, it has enhanced its strategic ties with littoral countries in the IO region over the past few years. This article discusses the evolution of Beijing’s IO strategy and examines the nature of these Chinese port projects. It argues that rather than simply copying the American model of developing military bases overseas, China has been deliberating a more sophisticated plan for its physical presence there—creating a new set of ‘overseas strategic pivots’. These ‘pivots’ are designed to help Beijing sustain its anti-piracy campaign and serve as forward stations for the transportation of China’s imported energy and merchandise while, with a relatively low-key stance, reducing any unnecessary opposing actions by rival powers. In addition, their political and economic functions are to a certain extent greater than their military functions despite the fact that they appear to be military bases. More importantly, these ‘pivots’ can help China create closer partnerships with littoral governments in the IO region, which suggests that the country is trying to create a friendly international environment favouring its plan to step into the global maritime domain.

The International Commission on Radiological Protection (ICRP) recommended that the equivalent dose limit for the lens of the eye be decreased from 150 mSv/y ( ICRP, 2007 ) to 20 mSv/y averaged over five years ( ICRP, 2011 ). How to accurately measure the eye-lens dose has, therefore, been an issue of interest recently. Interventional radiologists are at a higher risk of radiation-induced eye injury, such as cataracts, than all other occupational radiation workers. The main objective of this study is to investigate the relationship between the doses to the eye lenses of interventional radiologists measured by different commercial eye-lens dosimeters. This study measured a reference eye-lens dose, which involved placing thermoluminescent dosimeter (TLD) chips at the surface of the eye of the Rando Phantom, and the TLD chips were covered by a 3-mm-thick tissue-equivalent bolus. Commercial eye-lens dosimeters, such as a headband dosimeter and standard personnel dose badges, were placed at the positions recommended by the manufacturers. The results show that the personnel dose badge is not an appropriate dosimeter for evaluating eye-lens dose. Dose deviations for different dosimeters are discussed and presented in this study.

Introduction: Bacillus Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) patients are in great need of effective immunotherapies. STING (Stimulator of Interferon Genes) plays a central role in mounting innate and adaptive immune responses to tumor cells. Activation of the STING pathway leads to the induction of inflammatory cytokines (IFN-α/β, TNF-α, IL-6 and CXCL10), maturation and activation of dendritic cells (DC), and induction of anti-tumor T cells. Our group has developed a novel STING agonist, VB-85247. Here we use a murine NMIBC model to report the potent antitumor effect of VB-85247 compared to standard of care BCG and anti-PD1 checkpoint inhibitor therapy currently used in the management of NMIBC. Methods: We developed a mouse model of Non-Muscle Invasive Bladder Cancer (NMIBC) utilizing orthotopically implanted MB49-Luc cells, permitting BLI (Bioluminescence) measurement of tumor growth by In Vivo Imaging Systems (IVIS). Results: VB-85247 was found to bind to mouse STING and all major variants of human STING protein. VB-85247 induced high levels of IFN-β and other cytokines across cells from different species, including primary human bladder epithelial cells. VB-85247 treatment by intravesical instillation in the mouse model of NMIBC resulted in dose dependent tumor regression starting after the first treatment, achieving up to a 100% complete response rate at the 40 µg dose level after 5 weekly treatments. The treatment was well tolerated, eliciting strong and durable anti-tumor immune responses without any mortality. All cured mice rejected a re-challenge with MB49-Luc cells with no further treatment, demonstrating long-lasting anti-tumor immunity. By contrast, BCG treatment in the same model was not efficacious. Combination with anti-PD1 treatment reduced the dose of VB-85247 needed to achieve 100% complete responses to 20 µg, whereas anti-PD1 treatment alone resulted in only 25% complete responses. In addition, a single dose of 40 µg VB-85247 by bladder instillation in the NMIBC model induced systemic immune responses including serum cytokines demonstrating Type I IFN responses plus DC mobilization and activation in the blood, draining lymph nodes, and spleen within 24 hours. Conclusions: The STING agonist VB-85247 was well tolerated and displayed robust efficacy by bladder instillation in a mouse orthotopic tumor model of NMIBC, achieving up to 100% complete responses. All cured mice rejected fresh inoculations of tumor cells with no further treatment, demonstrating induction of immunologic memory. Treatment with BCG was not efficacious in the model. These results suggest the potential utility of the VB-85247 STING agonist in the treatment of BCG unresponsive NMIBC patients. Based on these data, VB-85247 is being advanced to clinical development. Citation Format: Miglena Prabagar, Venu Bommireddy, Rachael Siegel, Haihua Zheng, Lee Pellegrino, Stanley Nawoschik, Albert Uveges, Steven Paget, Ku Lu, Krista Saufler, Axel Metzger, David Diller, Jason Trama, Grant Gallagher, Chia-Yu Huang, Brian McGuinness, James R. Beasley, Michael McQueney, Martin Adelson, Gary L. Schieven, Eli Mordechai, Rukiye-Nazan Eraslan. The novel STING agonist VB-85247 induces robust durable antitumor immune responses by intravesical administration in a non-muscle invasive bladder cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 524.

We have developed a colorimetric sensing strategy employing gold nanoparticles and a paper-based analytical platform for the diagnosis of tuberculosis (TB). By utilizing the surface plasmon resonance effect, we were able to monitor changes in the color of a gold nanoparticle colloid based on the effects of single-stranded DNA probe molecules hybridizing with targeted double-stranded TB DNA. The hybridization event changes the surface charge density of the nanoparticles, causing them to aggregate to various degrees, which modifies the color of the solution in a manner that can be readily measured to determine the concentration of the targeted DNA analyte. In order to adapt this TB diagnosis method to resource-limited settings, we extended this label-free oligonucleotide and unmodified gold nanoparticle solution-based technique to a paper-based system that can be measured using a smartphone to obtain rapid parallel colorimetric results with low reagent consumption and without the need for sophisticated analytical equipment. In this study, we investigated various assay conditions, including the denaturing temperature and time, different oligonucleotide probe sequences, as well as the ratio of single stranded probe and double stranded target DNA. After optimizing these variables, we were able to achieve a detection limit of 1.95 × 10