Probing the Roles of Indium Oxides on Copper Catalysts for Enhanced Selectivity during CO2-to-CO Electrochemical Reduction.

The electrochemical CO2 reduction reaction (CO2RR) provides an alternative protocol to producing industrial chemicals with renewable electricity sources, and the highly selective, durable, and economic catalysts should expedite CO2RR applications. Here, we demonstrate a composite Cu-In2O3 catalyst in which a trace amount of In2O3 decorated on Cu surface greatly improves the selectivity and stability for CO2-to-CO reduction as compared to the counterparts (Cu or In2O3), realizing a CO faradaic efficiency (FECO) of 95% at -0.7 V (vs RHE) and no obvious degradation within 7 h. In situ X-ray absorption spectroscopy reveals that In2O3 undergoes the redox reaction and preserves the metallic state of Cu during the CO2RR process. Strong electronic interaction and coupling occur at the Cu/In2O3 interface which serves as the active site for selective CO2RR. Theoretical calculation confirms the roles of In2O3 in preventing oxidation and altering the electronic structure of Cu to assist COOH* formation and demote CO* adsorption at the Cu/In2O3 interface.

Exosomes Derived from Hypoxia-Cultured Human Adipose Stem Cells Alleviate Articular Chondrocyte Inflammaging and Post-Traumatic Osteoarthritis Progression.

Osteoarthritis (OA) is the most common age-related degenerative joint disease. Inflammaging, linking inflammation and aging, is found in senescent cells with the secretions of matrix-degrading proteins and proinflammatory cytokines. The senescence-associated secretory phenotype (SASP) plays a very important role in OA progression. However, there remains no effective way to suppress OA progression, especially by suppressing inflammaging and/or the chondrocyte SASP. Recent studies have shown that exosomes derived from hypoxia-cultured BMSCs can regenerate cartilage in OA animal models. Some reports have further indicated that exosomes secreted from MSCs contribute to the efficacy of MSC therapy in OA. However, whether hypoxia-cultured ADSC-secreted exosomes (hypoxia-ADSC-Exos) can alleviate the chondrocyte SASP or OA progression remains unclear. Accordingly, we hypothesized that hypoxia-ADSC-Exos have a beneficial effect on the normal functions of human articular chondrocytes (HACs), can attenuate the SASP of OA-like HACs in vitro, and further suppress OA progression in rats. Hypoxia-ADSC-Exos were derived from ADSCs cultured in 1% O2 and 10% de-Exo-FBS for 48 h. The molecular and cell biological effects of hypoxia-ADSC-Exos were tested on IL1-ß-induced HACs as OA-like HACs in vitro, and the efficacy of OA treatment was tested in ACLT-induced OA rats. The results showed that hypoxia-ADSC-Exos had the best effect on GAG formation in normal HACs rather than those cultured in normoxia or hypoxia plus 2% de-Exo-FBS. We further found that hypoxia-ADSC-Exos alleviated the harmful effect in OA-like HACs by decreasing markers of normal cartilage (GAG and type II collagen) and increasing markers of fibrous or degenerative cartilage (type I or X collagen), matrix degradation enzymes (MMP13 and ADAMT5), and inflammatory cytokines (TNFα and IL-6). More importantly, intra-articular treatment with hypoxia-ADSC-Exos suppressed OA progression, as evidenced by the weight-bearing function test and cartilage GAG quantification in ACLT rats. Moreover, through NGS and bioinformatic analysis, seven potential miRNAs were found in hypoxia-ADSC-Exos, which may contribute to regulating cellular oxidative stress and attenuating cell senescence. In summary, we demonstrated that hypoxia-ADSC-Exos, carrying potent miRNAs, not only improve normal HAC function but also alleviate HAC inflammaging and OA progression. The results suggest that hypoxia-ADSC-Exo treatment may offer another strategy for future OA therapy.

A smoking quitline integrated with clinician counselling at outpatient health facilities in Vietnam: a single-arm prospective cohort study.

BACKGROUND: Limited evidence is available about the combination of multiple smoking cessation modalities in low- and middle-income countries. The study aimed to assess the feasibility of a smoking cessation intervention that integrates follow-up counselling phone calls and scheduled text messages with brief advice from physicians in Vietnam. METHODS: This was a single-arm intervention study. Smokers were referred to the study Quitline after brief advice by physicians at three rural district hospitals in Hanoi, Vietnam. Following referral, participants received nine counselling phone calls in 12 months and a scheduled text message service that lasted for three months. Participants who reported smoking cessation for at least 30 days at the 12-month follow-up were invited for a urinary cotinine test to confirm cessation. RESULTS: The Quitline centre had 431 referrals from participating hospitals. Among them, 221 (51.3%) were enrolled. After the baseline phone call, 141 (63.8%) participated in all 4 follow-up calls within the first month and 117 (52.9%) participated in all phone calls in 12 months. The median number of successful phone calls was 8 (interquartile range: 6 - 8). At the end of the study, 90 (40.7%) self-reported abstinence from smoking over the previous 30 days. Among them, 22 (24.4%) submitted a sample for cotinine test, of which 13 (59.1% of those tested) returned a negative result. The proportion of biochemically-verified quitters was 5.9%. CONCLUSIONS: The integration of brief advice and referral from healthcare facilities, Quitline counselling phone calls, and scheduled text messaging was feasible in rural health facilities in northern Vietnam. TRIAL REGISTRATION: ACTRN12619000554167 .

Smoking behaviour among adult patients presenting to health facilities in four provinces of Vietnam.

BACKGROUND: Attendance at healthcare facilities provides an opportunity for smoking cessation interventions. However, the smoking behaviours of patients seeking healthcare in Vietnam are not well-understood. We aimed to evaluate behaviours related to smoking among patients presenting to health facilities in Vietnam. METHODS: We conducted a cross-sectional study in 4 provinces of Vietnam. Consecutive patients aged ≥15 years presenting to 46 health facilities were assessed. Current smokers were randomly selected to complete a full survey about smoking behaviour, quit attempts, and preparedness to quit. RESULTS: Among 11,245 patients who sought healthcare, the prevalence of current smoking was 18.6% (95% CI: 17.8-19.4%) overall, 34.6% (95% CI: 33.2-36.0%) among men and 1.1% (95% CI: 0.8-1.3%) among women. Current smokers who were asked about smoking by healthcare providers in the last 12 months were more likely to make quit attempts than those not asked (40.6% vs 31.8%, p = 0.017). Current smokers who attempted to quit in the past 12 months made limited use of cessation aids: counselling (1.9%) and nicotine replacement therapy (10%). A higher proportion of patients wanted to quit in the next month at national/provincial hospitals (30.3%) than those visiting district hospitals (11.3%, p < 0.001) and commune health centres (11.1%, p = 0.004). CONCLUSIONS: Smoking is common among male patients presenting to healthcare facilities in Vietnam. Formal smoking cessation supports are generally not used or offered. This population is likely to benefit from routine smoking cessation interventions that are integrated within the routine healthcare delivery system.

Mouse Models of Achromatopsia in Addressing Temporal "Point of No Return" in Gene-Therapy.

Achromatopsia is characterized by amblyopia, photophobia, nystagmus, and color blindness. Previous animal models of achromatopsia have shown promising results using gene augmentation to restore cone function. However, the optimal therapeutic window to elicit recovery remains unknown. Here, we attempted two rounds of gene augmentation to generate recoverable mouse models of achromatopsia including a Cnga3 model with a knock-in stop cassette in intron 5 using Easi-CRISPR (Efficient additions with ssDNA inserts-CRISPR) and targeted embryonic stem (ES) cells. This model demonstrated that only 20% of CNGA3 levels in homozygotes derived from target ES cells remained, as compared to normal CNGA3 levels. Despite the low percentage of remaining protein, the knock-in mouse model continued to generate normal cone phototransduction. Our results showed that a small amount of normal CNGA3 protein is sufficient to form "functional" CNG channels and achieve physiological demand for proper cone phototransduction. Thus, it can be concluded that mutating the Cnga3 locus to disrupt the functional tetrameric CNG channels may ultimately require more potent STOP cassettes to generate a reversible achromatopsia mouse model. Our data also possess implications for future CNGA3-associated achromatopsia clinical trials, whereby restoration of only 20% functional CNGA3 protein may be sufficient to form functional CNG channels and thus rescue cone response.

Effect of hyperthermia on improving neutrophil restoration after intraperitoneal chemotherapy.

Purpose: Intraperitoneal (IP) chemotherapy has several benefits but also can have severe hematologic side effects. We compared the effects of hyperthermic intraperitoneal chemotherapy (HIPEC) and conventional IP chemotherapy on bone marrow suppression and evaluated whether HIPEC increased neutrophil recovery.Methods: HIPEC or IP chemotherapy was administered to ovarian cancer-bearing mice. Bone marrow progenitor cell colony-forming unit (CFU) count, serum cytokine levels, and peripheral leukocyte count after HIPEC and IP chemotherapy were compared.Results: Peripheral neutrophil count, cytokine (G-CSF and CXCL1/KC) levels, and bone marrow progenitor cell CFU count were significantly higher after HIPEC than after IP chemotherapy.Conclusions: Hyperthermia increased the serum neutrophil-recruiting cytokine levels and reduced the magnitude of chemotherapy-induced neutropenia. Thus, HIPEC improved neutrophil and bone marrow recovery compared with conventional IP chemotherapy.

Tellimagrandin II, A Type of Plant Polyphenol Extracted from Trapa bispinosa Inhibits Antibiotic Resistance of Drug-Resistant Staphylococcus aureus.

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has become a critical global concern. Identifying new candidates of anti-S. aureus agents is urgently required because the therapeutic strategies for infected patients are limited currently. Therefore, the present study investigated whether Tellimagrandin II (TGII), a pure compound extracted from the shells of Trapa bispinosa, exhibits antibacterial effects against MRSA. We first showed that TGII exerted potent inhibitory activity against MRSA with a minimum inhibitory concentration of 128 µg/mL. The obtained fractional inhibitory concentration suggested that TGII could alone exert antistaphylococcal activity, and TGII combined with low doses of antibiotics displayed synergistic effects against MRSA. Moreover, we found that TGII exerted bactericidal activity by reducing the expression of mecA followed by the negative regulation of the penicillin-binding protein 2a (PBP2a) of MRSA. Transmission electron microscopy (TEM) images further confirmed that TGII destroyed the integrity of the cell wall of MRSA and caused the loss of cytoplasm content. In conclusion, we evidenced the antibacterial effects of TGII against MRSA, which enables the effective dose of current antibiotics to be reduced and the predicament of drug-resistant S. aureus isolates to be overcome.

InGaN light emitting diodes with a nanopipe layer formed from the GaN epitaxial layer.

A Si-heavy doped GaN:Si epitaxial layer is transformed into a directional nanopipe GaN layer through a laser-scribing process and a selectively electrochemical (EC) etching process. InGaN light-emitting diodes (LEDs) with an EC-treated nanopipe GaN layer have a high light extraction efficiency. The direction of the nanopipe structure was directed perpendicular to the laser scribing line and was guided by an external bias electric field. An InGaN LED structure with an embedded nanopipe GaN layer can enhance external quantum efficiency through a one-step epitaxial growth process and a selective EC etching process. A birefringence optical property and a low effective refractive index were observed in the directional-nanopipe GaN layer.

A 15-Year Nationwide Epidemiological Analysis of Guillain-Barré Syndrome in Taiwan.

BACKGROUND: Guillain-Barré syndrome (GBS) is a potentially life-threatening disease that typically occurs after a preceding infectious disease. An accurate estimation of GBS incidence would be useful for investigating the potential causal relationships between risk factors and GBS. Here we described the nationwide incidence of GBS in Taiwan. METHODS: The cases of GBS were obtained from all admission records of the National Health Insurance Research Database. We identified all of the first-admitted GBS patients by a code of ICD-9-CM 357.0 presented at the discharge diagnoses in admission records between 1997 and 2011. Calendar year, age, and sex-specific incidence, and seasonal variation were estimated. RESULTS: A total of 5,998 patients were identified. The male-to-female rate ratio was 1.54. The crude incidence rate was 1.65 per 100,000 person-years. The incidence of GBS was lowest in people aged less than 20 and increased with age, especially in people older than 50 years. In spring, the incidence was 10% higher than in other seasons. CONCLUSIONS: The overall incidence is in line with previous large-scale studies. A significant higher rate in spring is also shown. The potential reasons for the seasonality and higher incidence among older patients should be further investigated.

Lipid nanoparticle-encapsulated DNA vaccine robustly induce superior immune responses to the mRNA vaccine in Syrian hamsters.

DNA vaccines for infectious diseases and cancer have been explored for years. To date, only one DNA vaccine (ZyCoV-D) has been authorized for emergency use in India. DNA vaccines are inexpensive and long-term thermostable, however, limited by the low efficiency of intracellular delivery. The recent success of mRNA/lipid nanoparticle (LNP) technology in the coronavirus disease 2019 (COVID-19) pandemic has opened a new application for nucleic acid-based vaccines. Here, we report that plasmid encoding a trimeric spike protein with LNP delivery (pTS/LNP), similar to those in Moderna's COVID-19 vaccine, induced more effective humoral responses than naked pTS or pTS delivered via electroporation. Compared with TSmRNA/LNP, pTS/LNP immunization induced a comparable level of neutralizing antibody titers and significant T helper 1-biased immunity in mice; it also prolonged the maintenance of higher antigen-specific IgG and neutralizing antibody titers in hamsters. Importantly, pTS/LNP immunization exhibits enhanced cross-neutralizing activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and protects hamsters from the challenge of SARS-CoV-2 (Wuhan strain and the Omicron BA.1 variant). This study indicates that pDNA/LNPs as a promising platform could be a next-generation vaccine technology.

Electroretinogram (ERG) to Evaluate the Retina in Cases of Retinitis Pigmentosa (RP).

Electroretinogram (ERG) captures the electrical responses of photoreceptors, the summation of action potentials from all neurons in the retina elicited by illumination. ERG testing is an incredibly useful tool in obtaining more specific information regarding a retinal dystrophy. Specifically, ERGs are typically used to test photoreceptors and inner retinal function in humans and animals, to diagnose retinal dystrophies, and to monitor disease progression. In this chapter, we will introduce the components of ERGs and the standard ERG protocols for clinical examination. We will also introduce the various specialized ERG tests, which can help to differentiate retinitis pigmentosa (RP) from other retinal disorders. Lastly, we will elaborate on how to use ERGs to predict visual prognosis in RP.

Electroretinogram (ERG) to Evaluate the Retina Using Mouse Models.

Electroretinogram (ERG) is a sensitive and useful tool for the measurement of the retina's electrical response to flash stimuli. It provides a functional evaluation of the photoreceptors and downstream associated retinal cells. Similar to those conducted on humans, mouse ERGs include the amplitudes of a- and b-waves as well as the implicit time from those ERGs. Applications of ERGs include identification of retinal phenotypes, measurement of retinal function (at one and various time points), and evaluation of treatment efficacy. However, there are some differences between the manifestation of disease in patients as compared to mouse models that should be taken into consideration when implementing mouse ERGs. Herein, this chapter will introduce how to perform and obtain mouse ERGs.

Association of malignant ascites with systemic inflammation and muscle loss after treatment in advanced-stage ovarian cancer.

BACKGROUND: Malignant ascites is prevalent in advanced-stage ovarian cancer and may facilitate identification of the drivers of muscle loss. This study aimed to evaluate the association of ascites with changes in systemic inflammation and muscle after treatment of advanced-stage ovarian cancer. METHODS: We evaluated 307 patients with advanced-stage (III/IVA) ovarian cancer who underwent primary debulking surgery and adjuvant platinum-based chemotherapy between 2010 and 2019. The changes in skeletal muscle index (SMI) and radiodensity (SMD) were measured using pre-surgery and post-chemotherapy portal-venous phase contrast-enhanced computed tomography scans at L3. Systemic inflammation was measured using albumin levels, prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR). Primary endpoint was the changes in SMI and SMD after treatment. Linear regression analysis was used to test associations between muscle change and other covariates. Mediation analysis was used to determine the mediator. RESULTS: The median (range) age was 53 (23-83) years. The median duration (range) of follow-up was 5.2 (1.1-11.3) years. Overall, 187 (60.9%) patients had ascites. The changes in muscle and systemic inflammatory markers after treatment were significantly different between patients with and without ascites (SMI: -3.9% vs. 2.2%, P < 0.001; SMD: -4.0% vs. -0.4%, P < 0.001; albumin: -4.4% vs. 2.1%, P < 0.001; PNI: -8.4% vs. -0.1%, P < 0.001; NLR: 20.6% vs. -29.4%, P < 0.001; and PLR: 1.7% vs. -19.4%, P < 0.001). The changes in SMI and SMD were correlated with the changes in albumin, PNI, NLR, and PLR (all P < 0.001). In multiple linear regression, ascites and NLR changes were negatively while albumin change was positively correlated with SMI change (ascites: ß = -3.19, P < 0.001; NLR change: ß = -0.02, P = 0.003; albumin change: ß = 0.37, P < 0.001). Ascites and NLR changes were negatively while PNI change was positively correlated with SMD change (ascites: ß = -1.28, P = 0.02; NLR change: ß = -0.02, P < 0.001; PNI change: ß = 0.11, P = 0.04). In mediation analysis, ascites had a direct effect on SMI change (P < 0.001) and an indirect effect mediated by NLR change (indirect effects = -1.61, 95% confidence interval [CI]: -2.22 to -1.08) and albumin change (indirect effects = -2.92, 95% CI: -4.01 to -1.94). Ascites had a direct effect on SMD change (P < 0.001) and an indirect effect mediated by NLR change (indirect effects = -1.76, 95% CI: -2.34 to -1.22) and PNI change (indirect effects = -2.00, 95% CI: -2.79 to -1.36). CONCLUSIONS: Malignant ascites was associated with enhanced systemic inflammation and muscle loss after primary debulking surgery and adjuvant chemotherapy in advanced-stage ovarian cancer. The association between ascites and muscle loss may be mediated by systemic inflammation.

Spatiotemporal control of genome engineering in cone photoreceptors.

BACKGROUND: Cones are essential for color recognition, high resolution, and central vision; therefore cone death causes blindness. Understanding the pathophysiology of each cell type in the retina is key to developing therapies for retinal diseases. However, studying the biology of cone cells in the rod-dominant mammalian retina is particularly challenging. In this study, we used a bacterial artificial chromosome (BAC) recombineering method to knock in the "CreERT2" sequence into the Gnat2 and Arr3 genes, respectively and generated three novel inducible CreERT2 mice with different cone cell specificities. RESULTS: These models (Gnat2CreERT2, Arr3T2ACreERT2, and Arr3P2ACreERT2) express temporally controllable Cre recombinase that achieves conditional alleles in cone photoreceptors. Cre-LoxP recombination can be induced as early as postnatal day (PD) two upon tamoxifen injection at varying efficiencies, ranging from 10 to 15% in Gnat2CreERT2, 40% in Arr3T2ACreERT2, and 100% in Arr3P2ACreERT2. Notably, knocking in the P2A-CreERT2 cassette does not affect cone cell morphology and functionality. Most cone-phototransduction enzymes, including Opsins, CNGA3, etc. are not altered except for a reduction in the Arr3 transcript. CONCLUSIONS: The Arr3P2ACreERT2 mouse, an inducible cone-specific Cre driver, is a valuable line in studying cone cell biology, function, as well as its relationship with rod and other retinal cells. Moreover, the Cre activity can be induced by delivering tamoxifen intragastrically as early as PD2, which will be useful for studying retinal development or in rapid degenerative mouse models.

A DNA vaccine candidate delivered by an electroacupuncture machine provides protective immunity against SARS-CoV-2 infection.

A major challenge in the use of DNA vaccines is efficient DNA delivery in vivo. Establishing a safe and efficient electric transfer method is the key to developing rapid DNA vaccines against emerging infectious diseases. To overcome the complexity of designing new electric transfer machines for DNA delivery, a clinically approved electric transfer machine could be considered as an alternative. Here, we report an electroacupuncture machine-based method for DNA vaccine delivery after intramuscular injection of the COVID-19 DNA vaccine. The S gene of SARS-CoV-2 in the pVAX1 plasmid (pSARS2-S) was used as an antigen in this study. We optimized the clinically used electroacupuncture machine settings for efficient induction of the neutralizing antibody titer after intramuscular injection of pSARS2-S in mice. We found that pSARS2-S immunization at 40 Vpp for 3-5 s could induce high neutralizing antibody titers and Th1-biased immune responses. IFN-γ/TNF-α-secreting CD4+ and CD8+ T cells were also observed in the DNA vaccination group but not in the recombinant protein vaccination group. T-cell epitope mapping shows that the major reactive epitopes were located in the N-terminal domain (a.a. 261-285) and receptor-binding domain (a.a. 352-363). Importantly, pSARS2-S immunization in hamsters could induce protective immunity against SARS-CoV-2 challenge in vivo. In the preclinical toxicology study, blood biochemistry, hematology, and DNA persistence analysis reveal that the DNA delivery method is safe. Furthermore, the raised antisera could also cross-neutralize different variants of concern. These findings suggest that DNA vaccination using an electroacupuncture machine is feasible for use in humans in the future.

Stepped treatment algorithm using budesonide-formoterol for chronic respiratory diseases: A single arm interventional study.

BACKGROUND: While the safety and efficacy of inhaled budesonide-formoterol, used as-needed for symptoms, has been established for patients with asthma, it has not been trialed in undifferentiated patients with chronic respiratory diseases. We aimed to assess the feasibility of a pragmatic intervention that entails a stepped algorithm using inhaled budesonide-formoterol (dry powder inhaler, 160µg/4.5µg per dose) for patients presenting with chronic respiratory diseases to three rural district hospitals in Hanoi, Vietnam. METHODS: We recruited patients with evidence of airflow obstruction on spirometry and/or symptoms consistent with asthma. The algorithm consisted of three steps: 1. as-needed inhaled budesonide-formoterol for symptoms, 2. maintenance plus as-needed inhaled budesonide-formoterol, and 3. referral to a higher-level healthcare facility. All participants started at step 1, with escalation to the next step at review visits if there had been exacerbation(s) or inadequate symptom control. Patients were followed for 12 months. RESULTS: Among 313 participants who started the treatment algorithm, 47.2% had ≥ 1 episode of acute respiratory symptoms requiring a visit to hospital or clinic and 35.4% were diagnosed with an exacerbation. Twelve months after enrolment, 50.7% still adhered to inhaled budesonide-formoterol at the recommended treatment step. The mean and median number of doses per day was 1.5 (standard deviation 1.2) doses and 1.3 (interquartile range 0.7-2.3) doses, respectively. The proportion of patients taking more than 800µg budesonide per day was 3.8%. CONCLUSION: This novel therapeutic algorithm is feasible for patients with chronic respiratory diseases in a rural setting in Vietnam. Further studies are required to establish the effectiveness, safety and cost-effectiveness of similar approaches in different settings. TRIAL REGISTRATION: ACTRN12619000554167.

InGaN light emitting diodes with a laser-treated tapered GaN structure.

InGaN light-emitting diode (LED) structures get an air-void structure and a tapered GaN structure at the GaN/sapphire interface through a laser decomposition process and a lateral wet etching process. The light output power of the treated LED structure had a 70% enhancement compared to a conventional LED structure at 20 mA. The intensities and peak wavelengths of the micro-photoluminescence spectra were varied periodically by aligning to the air-void (461.8nm) and the tapered GaN (459.5nm) structures. The slightly peak wavelength blueshift phenomenon of the EL and the PL spectra were caused by a partial compressed strain release at the GaN/sapphire interface when forming the tapered GaN structure. The relative internal quantum efficiency of the treated LED structure (70.3%) was slightly increased compared with a conventional LED (67.8%) caused by the reduction of the piezoelectric field in the InGaN active layer.

Cardiovascular outcomes and healthcare costs of liraglutide versus basal insulin for type 2 diabetes patients at high cardiovascular risk.

We aimed to compare the (1) clinical outcomes including composite cardiovascular outcomes, cardiovascular death, and all-cause death, and (2) healthcare costs of using liraglutide and basal insulin as an initial treatment for patients with type 2 diabetes mellitus (T2DM) and high cardiovascular diseases (CVD) risk. This is a retrospective cohort study using Taiwan's Health and Welfare Database. A total of 1057 patients treated with liraglutide were identified and matched with 4600 patients treated with basal insulin. The liraglutide group had a lower risk of a composite CVD outcome (hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.50-0.85; p < 0.01), all-cause mortality (HR 0.40; 95% CI 0.28-0.59; p < 0.0001), and nonfatal stroke (HR 0.54; 95% CI 0.34-0.87; p = 0.01). Compared to the basal insulin group, the liraglutide group had lower median per-patient-per-month (PPPM) inpatient, emergency room (ER), and total medical costs, but higher median PPPM outpatient, total pharmacy, and total costs (all p < 0.0001). In conclusion, compared to basal insulin, liraglutide was found to be associated with reduced risk of a composite CVD outcome, nonfatal stroke, and all-cause mortality among high CVD risk patients with T2DM. In addition, liraglutide users had lower inpatient, ER, and total medical costs, but they had higher outpatient and total pharmacy costs.

Conditional Deletion of Activating Rearranged During Transfection Receptor Tyrosine Kinase Leads to Impairment of Photoreceptor Ribbon Synapses and Disrupted Visual Function in Mice.

Purpose: The rearranged during transfection (RET) receptor tyrosine kinase plays a key role in transducing signals related to cell growth and differentiation. Ret mutant mice show abnormal retinal activity and abnormal levels and morphology of bipolar cells, yet die on the 21st day after birth as a result of renal underdevelopment. To extend the observation period, we generated the Ret conditional knockout Chx10-Cre;C-Ret lx/lx mouse model and analyzed the retinal function and morphological changes in mature and aging Chx10-Cre;C-Ret lx/lx mice. Methods: Retina-specific depletion of Ret was achieved using mice with floxed alleles of the Ret gene with CHX10-driven Cre recombinase; floxed mice without Cre expression were used as controls. Retinal function was examined using electroretinography (ERG), and 2-, 4-, 12-, and 24-month-old mice were analyzed by hematoxylin staining and immunohistochemistry to evaluate retinal morphological alterations. The ultrastructure of photoreceptor synapses was evaluated using electron microscopy. Results: The results of the ERG testing showed that b-wave amplitudes were reduced in Chx10-Cre;C-Ret lx/lx mice, whereas a-waves were not affected. A histopathological analysis revealed a thinner and disorganized outer plexiform layer at the ages of 12 and 24 months in Chx10-Cre;C-Ret lx/lx mice. Moreover, the data provided by immunohistochemistry showed defects in the synapses of photoreceptor cells. This result was confirmed at the ultrastructural level, thus supporting the participation of Ret in the morphological changes of the synaptic ribbon. Conclusion: Our results provide evidence of the role of Ret in maintaining the function of the retina, which was essential for preserving the structure of the synaptic ribbon and supporting the integrity of the outer plexiform layer.

A syndromic approach to assess diagnosis and management of patients presenting with respiratory symptoms to healthcare facilities in Vietnam.

BACKGROUND: The aim of the study was to establish syndromic diagnoses in patients presenting with respiratory symptoms to healthcare facilities in Vietnam and to compare the diagnoses with facility-level clinical diagnoses and treatment decisions. METHODS: A representative sample of patients aged ≥5 years, presenting with dyspnoea, cough, wheezing, and/or chest tightness to healthcare facilities in four provinces of Vietnam were systematically evaluated. Eight common syndromes were defined using data obtained. RESULTS: We enrolled 977 subjects at 39 facilities. We identified fixed airflow limitation (FAL) in 198 (20.3%) patients and reversible airflow limitation (RAL) in 26 (2.7%) patients. Patients meeting the criteria for upper respiratory tract infection (URTI) alone constituted 160 (16.4%) patients and 470 (48.1%) did not meet the criteria for any of the syndromes. Less than half of patients with FAL were given long-acting bronchodilators. A minority of patients with either RAL or FAL with eosinophilia were prescribed inhaled corticosteroids. Antibiotics were given to more than half of all patients, even among those with URTI alone. CONCLUSION: This study identified a substantial discordance between prescribed treatment, clinician diagnosis and a standardised syndromic diagnosis among patients presenting with respiratory symptoms. Increased access to spirometry and implementation of locally relevant syndromic approaches to management may help to improve patient care in resource-limited settings.