Rhinoplasty Exclusively Utilizing Autologous Costal Cartilage for Patients with Prior Unilateral Cleft Lip Repair.

Background: Rhinoplasty in patients with previous unilateral cleft lip repair is a surgical challenge due to complex nasal deformities, including a horizontally positioned nasal wing, wide cleft side nostrils, nasal base defects, and a short and deviated nasal columella. To comprehensively address these complexities, we exclusively utilized autologous costal cartilage in rhinoplasty procedures, using various surgical techniques. Methods: This study presents a comprehensive case series of 39 patients who had previously undergone unilateral cleft lip surgery but still had nasal deformities. Rhinoplasty using autologous costal cartilage was performed at Cho Ray Hospital, Vietnam. Costal cartilage was partially crushed and then finely cut to shape the dorsal area and raise the nasal base on the cleft side. Partially crushed cartilage was also used to shape shield grafts, cap grafts, and alar batten grafts, whereas sliced cartilage was utilized for septal extension grafts. Evaluation was based on improvements in anthropometric indicators, patient satisfaction using Rhinoplasty Outcome Evaluation (ROE) scale and FACE-Q scores. Results: The average age of patients was 25.13 years. All postoperative anthropometric indicators showed significant improvements. Postsurgery, the total ROE score was three times higher than before surgery (P < 0.001), and the total FACE-Q score was 2.26 times higher (P < 0.001). No significant intraoperative or postoperative complications were observed. Conclusions: This procedure effectively addresses complex nasal deformities in patients with prior unilateral cleft lip repair, emphasizing the value of autologous costal cartilage in rhinoplasty for such individuals.

Atlantoaxial dislocation due to Os odontoideum in down syndrome: Literature review and case reports.

INTRODUCTION AND IMPORTANCE: Os odontoideum is a rare condition commonly associated with atlantoaxial instability (AAI) and leading to atlantoaxial dislocation. The incidence of Os odontoideum is higher in patients with Down syndrome. Similar to odontoid fractures, atlantoaxial dislocation in patients with Os odontoideum can result in neurological deficits, disability, and even mortality. CASE PRESENTATION: We present two cases of Os odontoideum accompanied by Down syndrome. Both patients were hospitalized due to progressive tetraparesis after falls several months prior. Upon examination, the patients exhibited myelopathy and were unable to walk or stand. MRI revealed spinal stenosis at the C1-C2 level due to atlantoaxial dislocation. C1-C2 fixation using Harms' technique was performed in both cases. One case experienced a complication involving instrument failure, necessitating revision surgery. CLINICAL DISCUSSION: Due to the characteristics of transverse ligament laxity, low muscle tone, excessive joint flexibility, and cognitive impairment, children with both Down syndrome and Os odontoideum are at a high risk of disability and even mortality from spinal cord injury. Most authors recommend surgical management when patients exhibit atlantoaxial instability. Additional factors such as low bone density, cognitive impairment, and a high head-to-body ratio may increase the risk of surgical instrument failure and nonunion postoperatively in patients with Down syndrome. CONCLUSION: Os odontoideum is a cause of AAI in patients with DS. Indication of surgery in the presence of AAI helps to resolve neurological injury and prevent further deterioration. The use of a cervical collar is considered to prevent instrument failure postoperatively.

Genome sequencing of correlated pathogenic Escherichia coli and Enterococcus associated with recurrent urinary tract infections.

Reported here are the sequences for 11 Escherichia coli and four Enterococcus strains isolated from post-menopausal women with a recurrent urinary tract infection. Each of the Enterococcus strains were isolated along with an E. coli strain. This provides a resource of high-quality complete genomes from polymicrobial infections.

Real-world analysis of afatinib as a first-line treatment for patients with advanced stage non-small-cell lung cancer with uncommon EGFR mutations: a multicenter study in Vietnam.

Background: Afatinib is indicated for advanced-stage non-small-cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) and uncommon mutations. However, real-world studies on this topic are limited. This study aimed to evaluate afatinib as first-line therapy for locally advanced and metastatic NSCLC with uncommon EGFR mutations. Patients and methods: A retrospective study included 92 patients with advanced NSCLC with uncommon and compound EGFR mutations, treated with afatinib as first-line therapy. Patients were followed up and evaluated every 3 months or when symptoms of progressive disease arose. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and adverse events. Results: The G719X EGFR mutation had the highest occurrence rate (53.3% for both monotherapy and the compound). By contrast, the compound mutation G719X-S768I was observed at a rate of 22.8%. The ORR was 75%, with 15.2% of patients achieving complete response. The overall median TTF was 13.8 months. Patients with the G719X EGFR mutation (single and compound) had a median TTF of 19.3 months, longer than that of patients with other mutations, who had a median TTF of 11.2 months. Patients with compound EGFR mutations (G719X and S768I) demonstrated a median TTF of 23.2 months compared to that of 12.3 months for other mutations. Tolerated doses of 20 or 30 mg achieved a longer median TTF of 17.1 months compared to 11.2 months with 40 mg. Median TTF differed between patients with and without brain metastasis, at 11.2 and 16.9 months, respectively. Rash (55.4%) and diarrhea (53.3%) were the most common adverse events, primarily grades 1 and 2. Other side effects occurred at a low rate. Conclusion: Afatinib is effective for locally advanced metastatic NSCLC with uncommon EGFR mutations. Patients with G719X, compound G719X-S768I mutations, and tolerated doses of 20 or 30 mg had a longer median TTF than those with other mutations.

Understanding the impact of binding free energy and kinetics calculations in modern drug discovery.

INTRODUCTION: For rational drug design, it is crucial to understand the receptor-drug binding processes and mechanisms. A new era for the use of computer simulations in predicting drug-receptor interactions at an atomic level has begun with remarkable advances in supercomputing and methodological breakthroughs. AREAS COVERED: End-point free energy calculation methods such as Molecular Mechanics/Poisson Boltzmann Surface Area (MM/PBSA) or Molecular-Mechanics/Generalized Born Surface Area (MM/GBSA), free energy perturbation (FEP), and thermodynamic integration (TI) are commonly used for binding free energy calculations in drug discovery. In addition, kinetic dissociation and association rate constants (koff and kon) play critical roles in the function of drugs. Nowadays, Molecular Dynamics (MD) and enhanced sampling simulations are increasingly being used in drug discovery. Here, the authors provide a review of the computational techniques used in drug binding free energy and kinetics calculations. EXPERT OPINION: The applications of computational methods in drug discovery and design are expanding, thanks to improved predictions of the binding free energy and kinetic rates of drug molecules. Recent microsecond-timescale enhanced sampling simulations have made it possible to accurately capture repetitive ligand binding and dissociation, facilitating more efficient and accurate calculations of ligand binding free energy and kinetics.

Failure of Autophagy in Pompe Disease.

Autophagy is an evolutionarily conserved lysosome-dependent degradation of cytoplasmic constituents. The system operates as a critical cellular pro-survival mechanism in response to nutrient deprivation and a variety of stress conditions. On top of that, autophagy is involved in maintaining cellular homeostasis through selective elimination of worn-out or damaged proteins and organelles. The autophagic pathway is largely responsible for the delivery of cytosolic glycogen to the lysosome where it is degraded to glucose via acid α-glucosidase. Although the physiological role of lysosomal glycogenolysis is not fully understood, its significance is highlighted by the manifestations of Pompe disease, which is caused by a deficiency of this lysosomal enzyme. Pompe disease is a severe lysosomal glycogen storage disorder that affects skeletal and cardiac muscles most. In this review, we discuss the basics of autophagy and describe its involvement in the pathogenesis of muscle damage in Pompe disease. Finally, we outline how autophagic pathology in the diseased muscles can be used as a tool to fast track the efficacy of therapeutic interventions.

Improved Resolution and Image Quality of Musculoskeletal Magnetic Resonance Imaging using Deep Learning-based Denoising Reconstruction: A Prospective Clinical Study.

OBJECTIVE: To prospectively evaluate a deep learning-based denoising reconstruction (DLR) for improved resolution and image quality in musculoskeletal (MSK) magnetic resonance imaging (MRI). METHODS: Images from 137 contrast-weighted sequences in 40 MSK patients were evaluated. Each sequence was performed twice, first with the routine parameters and reconstructed with a routine reconstruction filter (REF), then with higher resolution and reconstructed with DLR, and with three conventional reconstruction filters (NL2, GA43, GA53). The five reconstructions (REF, DLR, NL2, GA43, and GA53) were de-identified, randomized, and blindly reviewed by three MSK radiologists using eight scoring criteria and a forced ranking. Quantitative SNR, CNR, and structure's full width at half maximum (FWHM) for resolution assessment were measured and compared. To account for repeated measures, Generalized Estimating Equations (GEE) with Bonferroni adjustment was used to compare the reader's scores, SNR, CNR, and FWHM between DLR vs. NL2, GA43, GA53, and REF. RESULTS: Compared to the routine REF images, the resolution was improved by 47.61% with DLR from 0.39 ± 0.15 mm2 to 0.20 ± 0.06 mm2 (p < 0.001). Per-sequence average scan time was shortened by 7.93% with DLR from 165.58 ± 21.86 s to 152.45 ± 25.65 s (p < 0.001). Based on the average scores, DLR images were rated significantly higher in all image quality criteria and the forced ranking (p < 0.001). CONCLUSION: This prospective clinical evaluation demonstrated that DLR allows approximately two times finer resolution and improved image quality compared to the standard-of-care images.

Age-specific prevalence of IgG against measles/rubella and the impact of routine and supplementary immunization activities: A multistage random cluster sampling study with mathematical modelling.

BACKGROUND: Vietnam continues to have measles and rubella outbreaks following supplementary immunization activities (SIA) and routine immunization despite both having high reported coverage. To evaluate immunization activities, age-specific immunity against measles and rubella, and the number of averted Congenital Rubella Syndrome (CRS) cases, must be estimated. METHODS: Dried blood spots were collected from 2091 randomly selected individuals aged 1-39 years. Measles and rubella virus-specific immunoglobulin G (IgG) were measured by enzyme immunoassay. Results were considered positive at ≥120 mIU/mL for measles and ≥10 IU/mL for rubella. The number of CRS cases averted by immunization since 2014 were estimated using mathematical modelling. RESULTS: Overall IgG seroprevalence was 99.7% (95%CI: 99.2-99.9) for measles and 83.6% (95%CI: 79.3-87.1) for rubella. Rubella IgG seroprevalence was higher among age groups targeted in the SIA than in non-targeted young adults (95.4% [95%CI: 92.9-97.0] vs 72.4% [95%CI: 63.1-80.1]; P < 0.001). The estimated number of CRS cases averted in 2019 by immunization activities since 2014 ranged from 126 (95%CI: 0-460) to 883 (95%CI: 0-2271) depending on the assumed postvaccination reduction in the force of infection. CONCLUSIONS: The results suggest the SIA was effective, while young adults born before 1998 who remain unprotected for rubella require further vaccination.

Comparison of waist circumference and waist-to-height ratio as predictors of clustering of cardiovascular risk factors among middle-aged people in rural Khanh Hoa, Vietnam.

OBJECTIVE: Given the population-level variation in stature, a universal cut-off for waist circumference (WC) may not be appropriate for some populations. We compared the performance of WC and waist-to-height ratio (WHtR) to detect the clustering of cardiovascular disease (CVD) risk factors in rural Vietnam. METHODS: We obtained data from a baseline survey of the Khanh Hoa Cardiovascular Study comprising 2942 middle-aged residents (40-60 years). We used areas under the receiver operating characteristics curve (AUROC), net reclassification index (NRI), and integrated discrimination improvement (IDI) to compare the performance of WC and WHtR in predicting CVD risk clustering (≥2 of the following risk factors: hypertension, diabetes, dyslipidemia, and elevated C-reactive protein). RESULTS: The optimal cut-off values for WC were 81.8 and 80.7 cm for men and women, respectively. Regarding the clustering of CVD risk factors, the AUROC (95% CI) of WC and WHtR were 0.707 (0.676 to 0.739) and 0.719 (0.689 to 0.749) in men, and 0.682 (0.654 to 0.709) and 0.690 (0.663 to 0.717) in women, respectively. Compared with WC, WHtR had a better NRI (0.229; 0.102-0.344) and IDI (0.012; 0.004-0.020) in men and a better NRI (0.154; 0.050-0.257) in women. CONCLUSIONS: The optimal WC cut-off for Vietnamese men was approximately 10 cm below the recommended Asian cut-off. WHtR might perform slightly better in predicting the clustering of CVD risk factors among the rural population in Vietnam.

Sero and Carriage Epidemiology of Pertussis in Urban and Rural Regions in Vietnam.

The underestimation of the pertussis burden prompted our study to investigate the prevalence of recent pertussis infection, its associated factors, and antibody titer changes in the same individuals in Vietnam. Two cross-sectional surveys were conducted in Nha Trang in 2017 and Quang Ngai in 2019, representing high- and low-vaccine-coverage areas, respectively. Serum anti-pertussis toxin immunoglobulin-G (anti-PT IgG) ≥ 62.5 IU/mL by ELISA indicated infection in the previous 12 months. In Nha Trang, the participants of the 2017 survey were followed up in 2019. Logistic regression was used to determine the odds ratios for the characteristics associated with anti-PT IgG ≥ 62.5. The age-stratified prevalence in patients aged >2 years ranged from 2.1% (age 26-35) to 9.6% (3-5) in Nha Trang (2017) and from 7.2% (age 26-35) to 11.4% (6-15) in Quang Ngai. The prevalence tended to be higher in Quang Ngai across all age groups. Cough, recent antibiotic use, and smoking in Nha Trang were positively associated with an anti-PT IgG of ≥62.5, and having been diagnosed with pertussis and persistent cough with paroxysms/whoop in Quang Ngai were positively associated with an anti-PT IgG of ≥62.5. No nasopharyngeal swabs were positive for Bordetella pertussis using real-time PCR. The geometric mean of the IgG titer ratio from 2019 to 2017 was 1.45 in the paired samples. This study emphasizes Bordetella pertussis circulation across all age groups in both low- and high-vaccine-coverage settings in Vietnam, underscoring the need for continuous and standardized surveillance for a comprehensive understanding of its epidemiology.

A real-world cohort study of first-line afatinib in patients with EGFR-mutant advanced non-small cell lung cancer in Vietnam.

BACKGROUND: This study aimed to evaluate the efficacy and side effects of first-line afatinib treatment in a real-world setting in Vietnam. METHODS: This retrospective study was conducted across nine hospitals in Vietnam. Advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients who received afatinib as first-line therapy between April 2018 and June 2022 were included, and patient medical records were reviewed. Key outcomes were overall response rate (ORR), time-to-treatment failure (TTF), and tolerability. RESULTS: A total of 343 patients on first-line afatinib were eligible for the study. EGFR exon 19 deletion (Del19) alone was detected in 46.9% of patients, L858R mutation alone in 26.3%, and other uncommon EGFR mutations, including compound mutations, in 26.8%. Patients with brain metastases at baseline were 25.4%. Patients who received 40 mg, 30 mg, and 20 mg as starting doses of afatinib were 58.6%, 39.9%, and 1.5%, respectively. The ORR was 78.1% in the overall population, 82.6% in the Del19 mutation subgroup, 73.3% in the L858R mutation subgroup, and 75.0% in the uncommon mutation subgroup (p > 0.05). The univariate and multivariate analyses indicate that the ORR increased when the starting dose was 40 mg compared to starting doses below 40 mg (83.9% vs. 74.3%, p = 0.034). The median TTF (mTTF) was 16.7 months (CI 95%: 14.8-18.5) in all patients, with a median follow-up time of 26.2 months. The mTTF was longer in patients in the common EGFR mutation subgroup (Del19/L858R) than in those in the uncommon mutation subgroup (17.5 vs. 13.8 months, p = 0.045) and in those without versus with brain metastases at baseline (17.5 vs. 15.1 months, p = 0.049). There were no significant differences in the mTTF between subgroups based on the starting dose of 40 mg and < 40 mg (16.7 vs. 16.9 months, p > 0.05). The most common treatment-related adverse events (any grade/grade ≥ 3) were diarrhea (55.4%/3.5%), rash (51.9%/3.2%), paronychia (35.3%/5.0%), and stomatitis (22.2%/1.2%). CONCLUSIONS: Afatinib demonstrated clinical effectiveness and good tolerability in Vietnamese EGFR-mutant NSCLC patients. In our real-world setting, administering a starting dose below 40 mg might result in a reduction in ORR; however, it might not have a significant impact on TTF.

Association of green tea consumption with prediabetes, diabetes and markers of glucose metabolism in rural Vietnam: a cross-sectional study.

The literature on green tea consumption and glucose metabolism has reported conflicting findings. This cross-sectional study examined the association of green tea consumption with abnormal glucose metabolism among 3000 rural residents aged 40-60 years in Khánh Hòa province in Vietnam. Multinomial logistic regression analysis was conducted to examine the association of green tea consumption (0, < 200, 200-< 400, 400-< 600 or ≥ 600 ml/d) with prediabetes and diabetes (based on the American Diabetes Association criteria). Linear regression analysis was performed to examine the association between green tea consumption and the log-transformed homeostatic model assessment of insulin resistance (HOMA-IR) (a marker of insulin resistance) and the log-transformed homeostatic model assessment of ß-cell function (HOMA-ß) (a marker of insulin secretion). The OR for prediabetes and diabetes among participants who consumed ≥ 600 ml/d v. those who did not consume green tea were 1·61 (95 % CI = 1·07, 2·42) and 2·04 (95 % CI = 1·07, 3·89), respectively. Higher green tea consumption was associated with a higher level of log-transformed HOMA-IR (Pfor trend = 0·04) but not with a lower level of log-transformed HOMA-ß (Pfor trend = 0·75). Higher green tea consumption was positively associated with the prevalence of prediabetes, diabetes and insulin resistance in rural Vietnam. The findings of this study indicated prompting the need for further research considering context in understanding the link between green tea consumption and glucose metabolism, especially in rural settings in low- and middle-income countries.

Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes.

Mutations that cause familial Alzheimer's disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, that together produce amyloid ß-peptide (Aß). Nevertheless, whether Aß is the primary disease driver remains controversial. We report here that FAD mutations disrupt initial proteolytic events in the multistep processing of APP substrate C99 by γ-secretase. Cryoelectron microscopy reveals that a substrate mimetic traps γ-secretase during the transition state, and this structure aligns with activated enzyme-substrate complex captured by molecular dynamics simulations. In silico simulations and in cellulo fluorescence microscopy support stabilization of enzyme-substrate complexes by FAD mutations. Neuronal expression of C99 and/or presenilin-1 in Caenorhabditis elegans leads to synaptic loss only with FAD-mutant transgenes. Designed mutations that stabilize the enzyme-substrate complex and block Aß production likewise led to synaptic loss. Collectively, these findings implicate the stalled process-not the products-of γ-secretase cleavage of substrates in FAD pathogenesis.

Sex differences in the association between socioeconomic status and untreated hypertension among residents with hypertension in rural Khánh Hòa, Vietnam: a post-hoc analysis.

BACKGROUND: Several studies have examined the association between socioeconomic status (SES) and the proportion of untreated hypertension, but have produced conflicting findings. In addition, no study has been conducted to determine sex differences in the association between SES and untreated hypertension. Thus, the aim of this study was to examine whether the associations between SES and the proportion of untreated hypertension differed by sex in Vietnam. METHODS: This study was conducted using the data of 1189 individuals (558 males and 631 females) who were judged to have hypertension during the baseline survey of a prospective cohort study of 3000 residents aged 40-60 years in the Khánh Hòa Province. A multilevel Poisson regression model with a robust variance estimator was used to examine whether sex and SES indicators (household income and educational attainment) interacted in relation to untreated hypertension. RESULTS: The proportion of untreated hypertension among individuals identified as hypertensive was 69.1%. We found significant interaction between sex and SES indicators in relation to untreated hypertension (education: p < 0.001; household income: p < 0.001). Specifically, the association between SES and untreated hypertension was inverse among males while it was rather positive among females. CONCLUSIONS: Our finding suggests that the role of SES in the proportion of untreated hypertension might differ by sex.

Molecular Dynamics Activation of γ-Secretase for Cleavage of the Notch1 Substrate.

γ-Secretase is an intramembrane aspartyl protease complex that cleaves the transmembrane domain of over 150 peptide substrates, including amyloid precursor protein (APP) and the Notch family of receptors, via two conserved aspartates D257 and D385 in the presenilin-1 (PS1) catalytic subunit. However, while the activation of γ-secretase for cleavage of APP has been widely studied, the cleavage of Notch by γ-secretase remains poorly explored. Here, we combined Gaussian accelerated molecular dynamics (GaMD) simulations and mass spectrometry (MS) analysis of proteolytic products to present the first dynamic models for cleavage of Notch by γ-secretase. MS showed that γ-secretase cleaved the WT Notch at Notch residue G34, while cleavage of the L36F mutant Notch occurred at Notch residue C33. Initially, we prepared our simulation systems starting from the cryoEM structure of Notch-bound γ-secretase (PDB: 6IDF) and failed to capture the proper cleavages of WT and L36F Notch by γ-secretase. We then discovered an incorrect registry of the Notch substrate in the PS1 active site through alignment of the experimental structure of Notch-bound (PDB: 6IDF) and APP-bound γ-secretase (PDB: 6IYC). Every residue of the APP substrate was systematically mutated to the corresponding Notch residue to prepare a resolved model of Notch-bound γ-secretase complexes. GaMD simulations of the resolved model successfully captured γ-secretase activation for proper cleavages of both WT and L36F mutant Notch. Our findings presented here provided mechanistic insights into the structural dynamics and enzyme-substrate interactions required for γ-secretase activation for cleavage of Notch and other substrates.

Deep Learning Dynamic Allostery of G-Protein-Coupled Receptors.

G-protein-coupled receptors (GPCRs) make up the largest superfamily of human membrane proteins and represent primary targets of ∼1/3 of currently marketed drugs. Allosteric modulators have emerged as more selective drug candidates compared with orthosteric agonists and antagonists. However, many X-ray and cryo-EM structures of GPCRs resolved so far exhibit negligible differences upon the binding of positive and negative allosteric modulators (PAMs and NAMs). The mechanism of dynamic allosteric modulation in GPCRs remains unclear. In this work, we have systematically mapped dynamic changes in free energy landscapes of GPCRs upon binding of allosteric modulators using the Gaussian accelerated molecular dynamics (GaMD), deep learning (DL), and free energy prOfiling Workflow (GLOW). GaMD simulations were performed for a total of 66 µs on 44 GPCR systems in the presence and absence of the modulator. DL and free energy calculations revealed significantly reduced dynamic fluctuations and conformational space of GPCRs upon modulator binding. While the modulator-free GPCRs often sampled multiple low-energy conformational states, the NAMs and PAMs confined the inactive and active agonist-G-protein-bound GPCRs, respectively, to mostly only one specific conformation for signaling. Such cooperative effects were significantly reduced for binding of the selective modulators to "non-cognate" receptor subtypes. Therefore, GPCR allostery exhibits a dynamic "conformational selection" mechanism. In the absence of available modulator-bound structures as for most current GPCRs, it is critical to use a structural ensemble of representative GPCR conformations rather than a single structure for compound docking ("ensemble docking"), which will potentially improve structure-based design of novel allosteric drugs of GPCRs.

Determination of the crystalline size of hexagonal La1-xSrxMnO3 (x = 0.3) nanoparticles from X-ray diffraction - a comparative study.

The electronic, magnetic, optical and elastic properties of nanomaterials are governed partially by the crystallite size and crystal defects. Here, the crystalline size of hexagonal La1-xSrxMnO3 (x = 0.3) nanoparticles was determined using various methods. Single-phase La0.7Sr0.3MnO3 nanopowders were produced after 10 h of milling in a commercial high-energy SPEX 8000D shaker mill, and then they were heated at 700 °C and 800 °C to study the effect of calcined temperature on the crystallization of nanoparticles. The modified Scherrer, Williamson-Hall, size-strain, and Halder-Wagner methods were used to determine the crystallite sizes and the elastic properties, such as intrinsic strain, stress, and energy density, from the X-ray diffraction peak broadening analysis. The obtained results were then compared with one another. The difference in crystallite sizes calculated from the different methods was due to the different techniques.

Structural basis of agonist specificity of α1A-adrenergic receptor.

α1-adrenergic receptors (α1-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists for all α1 subtypes has limited our understanding of the physiological roles of different α1-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of α1A-AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the α1A-AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between α1A-AR and α1B-AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer α1A-AR mutants that are not responsive to A61603, and α1B-AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for α1-ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists.

1 Year-follow-up of transforaminal surgical approach in the management of migrated disc herniation: a cross-sectional study.

Transforaminal percutaneous endoscopic lumbar discectomy (TPELD) recently confirms its superiority compared to typical open discectomy in the treatment of very high-grade migrated disk herniation. In Vietnam, this technique has been applied in recent years; however; lack of reports and evidence. Objectives: In this study, the authors would like to share their surgical experience and report the initial results in their center, after successfully performing TPELD for very high-grade migrated disk herniation in 40 patients. Patients and methods: Forty patients, who underwent TPELD to remove the nucleus of very high-grade migrated disk herniation, were enrolled in this study. The study was carried out from April 2019 to April 2021. Preoperative and postoperative MRI were compared to demonstrate the removed disk. Postoperative visual analog score, oswestry disability index, and modified Macnab criteria were obtained after 1 month, 6 months, and 1 year and were compared. Results: There were no major complications related directly to this technique. Seven patients were operated at L3-4, 28 patients at L4-5, and 5 patients at l5-S1. Mean visual analog score for leg pain improved from 7.36±0.64 preoperatively to 1.22±1.16 at 6 months postoperatively and 1.34±1.47 at 1 year postoperatively (P<0.01). The mean preoperative oswestry disability index improved from 67.1±8.79 preoperatively to 12.1±13.48 at 1 year postoperatively (P<0.01). Excellent or good global outcomes were obtained in 95%. Conclusions: TPELD is a minimally invasive treatment with effective and safe results of very high-grade migrated disk herniation. Improvement of several pain scores can be observed in the 12-month follow-up after surgery.

Information needs of informal caregivers in caring and rehabilitation for dioxin victims in Vietnam.

BACKGROUND: Health outcomes among Agent Orange/dioxin (dioxin) victims are significant due to many individuals requiring daily assistance, informal care, and rehabilitation support. This study aimed to identify the information needs of informal caregivers of dioxin victims in Vietnam. METHODS: A cross-sectional study was conducted in Quynh Phu district, Thai Binh province - an area with a large number of dioxin victims, from June 2019 to June 2020. Quantitative data were collected from 124 caregivers of victims via structured interviews. Qualitative data were collected using semi-structured interview guides with in-depth interviews (IDI) (n = 36) and two focus group discussions (FGD) (n = 12). RESULTS: The results demonstrated that all caregivers of dioxin victims were family members, predominantly older (71.8%), 61.5 years old on average, living on low incomes (87.9%), and were farmers (80.7%). Almost all participants (96.8%) reported having information needs, particularly concerning dioxin's harms, nutrition, dioxin-related policies and rehabilitation, and psychological support for patients. Caregivers reported that they would like to receive information via health staff counselling (85.0%), television (75.0%), and community loudspeaker (65.8%). Notably, the majority of caregivers reported the need for information regarding psychological support (70.0%). These findings are consistent with qualitative data, which identify an urgent need to provide information, especially through health staff and digital resources. CONCLUSION: Many families with dioxin victims lived with little support and information, highlighting their high demand for information about care and rehabilitation. Thus, the healthcare system should promote information support, policy, and psychological support for caregivers and victims. An online support system for caregivers and victims is also recommended.