Background. Extensively drug‐resistant (XDR) tuberculosis (TB) is a major public health threat in South Korea. Methods. We analyzed baseline epidemiological data for 250 patients enrolled in an ...ongoing prospective observational study of TB at a large tertiary referral hospital in South Korea. Results. Twenty‐six subjects with XDR TB were identified; all were patients who had previously received TB therapy. Cumulative previous treatment duration (range, 18–34 months; odds ratio OR, 5.6; 95% confidence interval CI, 1.0–59), number of previously received second‐line anti‐TB drugs (OR, 1.3; 95% CI, 1.1–1.5), and female sex (OR, 3.2; 95% CI, 1.1–8.3) were significantly associated with XDR TB in crude analyses. After controlling for other factors in a multivariable model, cumulative previous treatment duration remained significantly associated with XDR TB (OR, 5.8; 95% CI, 1.0–61). Subjects with XDR TB were more likely to produce culture‐positive sputum at 6 months, compared with patients with non—multidrug resistant TB (risk ratio, 13; 95% CI, 5.1–53). Kanamycin resistance was found to be predictive of 6‐month culture positivity after adjustment for ofloxacin and streptomycin resistance (risk ratio, 3.9; 95% CI, 1.9–11). Conclusions. XDR TB was found to be associated with the cumulative duration of previous treatment with second‐line TB drugs among subjects in a tertiary care TB hospital. Patients with XDR TB were more likely to not respond to therapy, and successful conversion of sputum culture results to negative was correlated with initial susceptibility to both fluoroquinolones and kanamycin but not to streptomycin.
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BFBNIB, NUK, PNG, UL, UM, UPUK
Titanium dioxide nanoparticles (TiO
NPs) represent a scientific breakthrough in the areas of biological and medicinal applications. Interaction of TiO
NPs with components of innate immune system ...remains elusive.
This study explored in vitro immunotoxicity of murine macrophage RAW 264.7 to TiO
NPs (20 nm, negative charge) and its underlying molecular mechanism by way of immunoredox profiling.
In this study, chemically synthesized BSA-functionalized TiO
NPs (20 nm, negative charge) were characterized and immunotoxicity was investigated on RAW 264.7 cells.
We found that reactive oxygen species levels significantly increased with increasing nitric oxide production, whereas depleting endogenous antioxidant super oxide dismutase as well as nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels. Furthermore, NPs exposure increased the expression of apoptotic factors such as BAX, BIM, and PUMA with disruption of mitochondrial membrane potential (Δψ
) that lead to decrease in immunocytes. Molecular immune profiling revealed the activation of multiple toll-like receptors (TLRs) 4/9/12/13 simultaneously with the phosphorylation of p-p38MAPK and p-SAPK/c-Jun N-terminal kinase (JNK) compared to untreated control.
Collectively, this study shows that the molecular nature of TiO
NP-induced immunotoxicity in RAW 264.7 macrophage is simultaneous induction of immunocyte apoptosis and multiple TLRs signaling through oxidative stress-dependent SAPK/JNK and p38 mitogen-associated protein kinase activation. This is the first study to address newer molecular mechanism of TiO
NP-induced immunotoxicity.
Noradrenergic dysfunction may be associated with cognitive impairments in attention-deficit/hyperactivity disorder (ADHD), including increased response time variability, which has been proposed as a ...leading endophenotype for ADHD. The aim of this study was to examine the relationship between polymorphisms in the α-2A-adrenergic receptor (ADRA2A) and norepinephrine transporter (SLC6A2) genes and attentional performance in ADHD children before and after pharmacological treatment.One hundred one medication-naive ADHD children were included. All subjects were administered methylphenidate (MPH)-OROS for 12 weeks. The subjects underwent a computerized comprehensive attention test to measure the response time variability at baseline before MPH treatment and after 12 weeks. Additive regression analyses controlling for ADHD symptom severity, age, sex, IQ, and final dose of MPH examined the association between response time variability on the comprehensive attention test measures and allelic variations in single-nucleotide polymorphisms of the ADRA2A and SLC6A2 before and after MPH treatment.Increasing possession of an A allele at the G1287A polymorphism of SLC6A2 was significantly related to heightened response time variability at baseline in the sustained (P = 2.0 × 10) and auditory selective attention (P = 1.0 × 10) tasks. Response time variability at baseline increased additively with possession of the T allele at the DraI polymorphism of the ADRA2A gene in the auditory selective attention task (P = 2.0 × 10). After medication, increasing possession of a G allele at the MspI polymorphism of the ADRA2A gene was associated with increased MPH-related change in response time variability in the flanker task (P = 1.0 × 10).Our study suggested an association between norepinephrine gene variants and response time variability measured at baseline and after MPH treatment in children with ADHD. Our results add to a growing body of evidence, suggesting that response time variability is a viable endophenotype for ADHD and suggesting its utility as a surrogate end point for measuring stimulant response in pharmacogenetic studies.
Information and communication technology (ICT)-based training devices for older adults' care related to dementia are being developed to enhance older adults' cognitive functions. Older adults who ...require bicycle training devices can improve muscle strength and balance of lower limbs by continuously contracting and relaxing lower-limb muscles and improving cognitive function to prevent dementia. This study was conducted to investigate the effects of an ICT-based multicomponent program on body composition and cognitive function in older adults.
In a randomized controlled intervention test on 20 people over the age of 60 (exercise group: n = 10; control: n = 10), the multicomponent program was applied to the exercise group twice per week, once per day for 12 weeks, at 30 min per session, whereas the control group was advised to maintain their usual daily activities.
Comparing body composition changes and cognitive function changes before and after intervention exhibited statistically significant differences in skeletal muscle mass (
=0.01) and modified Alzheimer's disease assessment scale-cognitive score (
=0.01) between the two groups.
It can be difficult to be engaged in a simple repetitive exercise program. Therefore, to meet older adults' interests and expectations, a customized ICT-based multicomponent program, which can improve body composition and cognitive function in older adults and is believed to help prevent dementia, is recommended.
UMIN000042129 (https://www.umin.ac.jp/english/).
Phase 3, randomized, controlled, multicenter, equivalence trial.
Recruitment of participants occurred between 04Februray2020 and 15July2020 at four centers in the Philippines: University of the East ...– Ramon Magsaysay Memorial Medical Center Inc., Quezon City; University of Philippines Manila – National Institute of Health, Ermita Manila; Asian Hospital and Medical Center, Metro Manila, Philippines Study; and Medical Research Unit, Tropical Disease Foundation, Makati City, Metro Manila, Philippines.
1800 adults and children 6-months to 45-years of age.
Participants received a single injection of multidose (MD) or single dose (SD) Vi-DT as test vaccines or meningococcal conjugate vaccine as a comparator.
To evaluate immune equivalence of SD and MD formulations of Vi-DT, and to assess the safety of both formulations compared with comparator vaccine.
Blood draw for immunogenicity was performed at baseline prior to vaccine receipt and at four weeks after vaccination for a subset of participants to determine anti-Vi IgG geometric mean titers (GMT) and seroconversion rates. The primary outcome was comparison of anti Vi-IgG seroconversion and GMT between the two formulations of Vi-DT at 4 weeks following vaccine administration. Immune equivalence of MD and SD formulations was confirmed when the two-tailed 95% confidence interval (CI) of the GMT ratio is within 0.67, 1.5 at a two-sided significance level of 0.05. All participants were followed for safety events for six months after vaccine administration.
Participants were randomized to receive SD Vi-DT, MD Vi-DT, or meningococcal conjugate vaccines in 2.5:2.5:1 allocation ratio.
Study participants and observers were blinded to treatment assignment.
Immune equivalence of SD (n=252) and MD (n=247) formulations was confirmed by anti-Vi IgG GMT ratio of 1.14 (95%CI: 0.91, 1.43) with respective GMTs in the MD and SD groups of 640.62 IU/mL (95%CI: 546.39, 751.11) and 562.57 IU/mL (95%CI: 478.80, 661.00) (p=0.259). Similarly, anti-Vi IgG seroconversion rate difference between the two formulations of ‒0.43% (95%CI: –4.42, 3.56) confirmed immune equivalence with corresponding seroconversion rates of 98.38% (95%CI: 95.91, 99.37) and 98.81% (95%CI: 96.56, 99.59) in MD and SD Vi-DT formulations, respectively (p=0.722). Both formulations of Vi-DT had a satisfactory safety profile – all five serious adverse events reported during the study were unrelated to the investigational product.
The MD and SD formulations of Vi-DT elicited robust and equivalent immune responses following one dose vaccination, and both formulations demonstrated a favorable safety profile.
ClinicalTrials.gov: NCT04204096.
This study was funded by the Bill & Melinda Gates Foundation (OPP 1115556).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The objectives of this study were to 1) in patients without pulmonary function, determine resting energy expenditure (REE) in venovenous extracorporeal membrane oxygenation (ECMO) acute respiratory ...distress syndrome (ARDS) patients by paralysis status and 2) determine the threshold tidal volume (TV) associated with meaningful gas exchange as determined by measurable end-tidal carbon dioxide elimination (etV̇co
).
Retrospective observational study.
A tertiary high ECMO volume academic institution.
Ten adult ARDS patients on venovenous ECMO.
None.
The modified Weir equation, Fick principle, Henderson-Hasselbalch equation, ECMO flow, hemoglobin, and pre and post oxygenator blood gases were used to determine ECMO carbon dioxide production (V̇co
), ECMO oxygen consumption, and REE. REE values were matched to patients' paralysis status based on medication flowsheets and compared using a paired
test. Linear regression was performed to determine the threshold TV normalized to ideal body weight (IBW) associated with measurable ventilator etV̇co
, above which meaningful ventilation occurs. When lungs were not functioning, patients had significantly lower mean REE when paralyzed (23.4 ± 2.8 kcal/kg/d) than when not paralyzed (29.2 ± 5.8 kcal/kg/d) (
= 0.02). Furthermore, mean REE was not similar between patients and varied as much as 1.7 times between patients when paralyzed and as much as 1.4 times when not paralyzed. Linear regression showed that ventilator V̇co
was measurable and increased linearly when TV was greater than or equal to 0.7 mL/kg.
REE is patient-specific and varies significantly with and without patient paralysis. When TV exceeds 0.7 mL/kg IBW, ventilator V̇co
increases measurably and must be considered in determining total REE.
Research on psychostimulants, analysis of animal models and genetic association studies all suggest that the brain-derived neurotrophic factor gene (BDNF) may be a good candidate for pharmacogenetic ...studies of attention deficit hyperactivity disorder (ADHD). Yet to date there have been no pharmacogenetic studies of BDNF in ADHD. A total of 102 drug-naive ADHD children (8.7±2.1 yr) were treated with osmotic release oral system-methylphenidate (OROS-MPH) for 12 wk, and four kinds of response criteria were applied, based first, on a combined threshold of the ADHD Rating Scale – IV (ARS) and the Clinical Global Impression – Improvement scale (CGI-I); second, on scores of 1 or 2 vs. 3–7 on the CGI – Severity scale; third, on a >50% reduction in ARS scores; and fourth, on satisfaction of all of the aforementioned criteria. The Val66Met polymorphism of BDNF and six single nucleotide polymorphisms from the SLC6A2, ADRA2A and NTF-3 genes were tested for association with each criterion. Relative to other genotypes, homozygosity for the Val allele of the BDNF Val66Met polymorphism was associated with a greater relative frequency of good response under all four response criteria (after controlling for baseline ARS score, age, gender, final dose (mg/kg) of OROS-MPH at 12 wk, and level of academic functioning). This association was significant at the uncorrected level for the first and third response criteria (p=0.013 and p=0.018, respectively) and significant at a Bonferroni-corrected level for the second and fourth response criteria (p=0.0002, p=0.0003, respectively). Our findings support an association between homozygosity for the Val allele of BDNF and better response to OROS-MPH in Korean ADHD children as assessed by four different response criteria.
Anticoagulation with warfarin in Asian patients with atrial fibrillation (AF) often has been decreased as an international normalized ratio (INR) of prothrombin time 1.6-2.6 due to fear of bleeding, ...although universal criteria recommend an INR of 2.0-3.0. In this randomized, open-label trial, low-intensity anticoagulation (INR 1.6-2.6) was compared with standard-intensity anticoagulation (INR 2.0-3.0) with warfarin. A total 616 patients with AF and at least 1 risk factor for stroke were randomized to low-intensity anticoagulation (n = 308) and standard-intensity anticoagulation (n = 308) groups. The intention-to-treat analysis was performed to determine differences. The baseline characteristics of the two groups were comparable. New-onset stroke occurred in 2 patients (0.44% per year) in the low-intensity group and 5 patients (1.05% per year) in the standard-intensity group (HR 0.42, 95% CI 0.08-2.15). Major bleeding occurred in 4 patients (0.89% per year) in the low-intensity group and 5 patients (1.06% per year) in the standard-intensity group (HR 0.84, 95% CI 0.22-3.11). The rate of the net clinical outcome (composite of stroke, systemic embolism, major bleeding, and death) was 1.33% per year in the low-intensity group compared with 2.12% per year in the standard-intensity group (HR 0.63, 95% CI 0.23-1.72). In Asian patients with AF, clinical outcomes were not different between low-intensity and standard-intensity anticoagulation with warfarin.
The angiotensin receptor antagonist fimasartan lowered blood pressure (BP) in a previous large population study. The purpose of this study was to evaluate whether fimasartan treatment for 3 months ...affects clinical and home BP variability in addition to reducing BP.
The study enrolled 1,396 patients (mean age 56.2±10.0 years; males 53.6%) with mild-to-moderate hypertension who had a complete set of home BP measurements (morning and evening) and metabolic risk evaluation. During the 3 months of study, fimasartan alone was used to control BP at a daily dose of 30-120 mg. Clinical and home BP measurements were performed before and after the 3-month treatment. BP variability included beat-to-beat variability (clinical) and day-to-day variability (home).
Fimasartan reduced BP after 3 months of treatment. The average reduction of clinical systolic BP (c-SBP) was 15.08±18.36 mmHg (P<0.0001), and the average reduction of morning home SBP (m-SBP) was 11.49±19.33 mmHg (P<0.0001). Beat-to-beat variability as standard deviation (SD) of c-SBP was reduced from 4.56±3.22 to 4.24±3.11 mmHg (P=0.0026). Day-to-day variability as SD of m-SBP was reduced from 7.92±6.74 to 6.95±4.97 mmHg (P<0.0001). Multiple regression analysis revealed an independent association between the change in the SD of c-SBP and the change in c-SBP (P=0.0268) and, similarly, between the change in the SD of m-SBP and the change in m-SBP (P=0.0258), after adjusting for age, sex, body mass index, and change in mean BP.
This study indicated that 3 months of fimasartan treatment reduced day-to-day BP variability independent of BP reduction in patients with hypertension.
Community-genotype methicillin-resistant Staphylococcus aureus (MRSA) clones have emerged in the community worldwide and recently have been spreading into the hospitals. To identify predictors of ...sequence type 72-MRSA-SCCmec type IV (ST72-MRSA-IV) in patients with community-onset (CO) S. aureus infection, a case-control study was conducted among CO S. aureus infections, including healthcare-associated infections.
Eighty-four patients with CO infections caused by ST72-MRSA-IV strains in Korea between 2007 and 2009 were selected as cases. Members of the control group were those with CO methicillin-susceptible S. aureus infections and they were matched by the admission date in a 1 : 1 ratio.
The most common type of infection was skin and soft tissue infection in both groups (48.8% versus 52.4%), followed by pneumonia. Female sex (OR 2.55, 95% CI 1.30-5.04), severe sepsis or septic shock (OR 3.05, 95% CI 1.09-8.55), prior hospitalization within the previous year (OR 2.18, 95% CI 1.10-4.32) and surgical site infection (SSI) (OR 4.63, 95% CI 1.38-15.59) were associated with ST72-MRSA-IV infections in multivariate analyses.
Female sex, SSI, severe sepsis or septic shock and prior hospitalization within the previous year were predictors of ST72-MRSA-IV among patients with CO S. aureus infection.
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