RNA-Activatable Near-Infrared Photosensitizer for Cancer Therapy.

Photodynamic therapy (PDT) has recently come to the forefront as an exceptionally powerful and promising method for the treatment of cancer. Existing photosensitizers are predominantly engineered to target diverse biomolecules, including proteins, DNA, lipids, and carbohydrates, and have proven to greatly enhance the efficacy or specificity of PDT. However, it is noteworthy that there exists a conspicuous scarcity of photosensitizers specifically designed to target RNAs. Recognizing the crucial and multifaceted roles played by RNAs in various cellular processes and disease states, we have ventured into the development of a novel RNA-targeting photosensitizer, named Se-718, designed specifically for PDT-based cancer therapy. Se-718 has been engineered to exhibit a high molar absorption coefficient in the NIR region, which is crucial for effective PDT. More importantly, Se-718 has demonstrated a distinct RNA-targeting capability, as evidenced through rigorous testing in both circular dichroism and fluorescence experiments. Furthermore, Se-718 has been shown to display both type I and type II photodynamic properties. This unique characteristic enables the efficient killing of cancer cells under a wide range of oxygen conditions, both normoxic (21% O2) and hypoxic (2% O2). The IC50 of Se-718 can be as low as 100 nM, and its light-to-dark toxicity ratio is an impressive 215 times higher, outperforming most photosensitizers currently available. Moreover, in vivo studies conducted with tumor-bearing mice have demonstrated the excellent antitumor effects and high safety profile of Se-718. Considering the outstanding PDT efficacy of Se-718, we are optimistic that the development of RNA-targeting photosensitizers may provide an innovative and highly effective option for cancer therapeutics in the near future.

Luciferase-Decorated Gold Nanorods as Dual-Modal Contrast Agents for Tumor-Targeted High-Performance Bioluminescence/Photoacoustic Imaging.

Gold nanorods (AuNRs) have been considered highly compelling materials for early cancer diagnosis and have aroused a burgeoning fascination among the biomedical sectors. By leveraging the versatile tunable optical properties of AuNRs, herein, we have developed a novel tumor-targeted dual-modal nanoprobe (FFA) that exhibits excellent bioluminescence and photoacoustic imaging performance for early tumor diagnosis. FFA has been synthesized by anchoring the recombinant bioluminescent firefly luciferase protein (Fluc) on the folate-conjugated AuNRs via the PEG linker. TEM images and UV-vis studies confirm the nanorod morphology and successful conjugation of the biomolecules to AuNRs. The nanoprobe FFA relies on the ability of the folate module to target the folate receptor-positive tumor cells actively, and simultaneously, the Fluc module facilitates excellent bioluminescent properties in physiological conditions. The success of chemical engineering in the present study enables stronger bioluminescent signals in the folate receptor-positive cells (Skov3, Hela, and MCF-7) than in folate receptor-negative cells (A549, 293T, MCF-10A, and HepG2). Additionally, the AuNRs induced strong photoacoustic conversion performance, enhancing the resolution of tumor imaging. No apparent toxicity was detected at the cellular and mouse tissue levels, manifesting the biocompatibility nature of the nanoprobe. Prompted by the positive merits of FFA, the in vivo animal studies were performed, and a notable enhancement was observed in the bioluminescent/photoacoustic intensity of the nanoprobe in the tumor region compared to that in the folate-blocking region. Therefore, this synergistic dual-modal bioluminescent and photoacoustic imaging platform holds great potential as a tumor-targeted contrast agent for early tumor diagnosis with high-performance imaging information.

Depression and posttraumatic stress disorder in adolescents with nonsuicidal self-injury: comparisons of the psychological correlates and suicidal presentations across diagnostic subgroups.

BACKGROUND: Nonsuicidal self-injury (NSSI) combined with suicide ideation increases the risk of suicidal behaviors. Depression and posttraumatic stress disorder (PTSD) are comorbidities of NSSI compounding this relationship. The present study compared diagnostic subgroups of NSSI based on current depression and PTSD on psychological correlates (i.e., vulnerabilities and impairment) and suicidal presentations (i.e., suicidal cognitions and behaviors) in a psychiatric sample of adolescents. METHODS: Eighty-seven adolescents meeting DSM-5 criteria for NSSI and 104 age-range-matched nonclinical controls (NC) participated. Participants completed self-report measures on psychological vulnerabilities and impairment (e.g., emotion regulation difficulties, negative cognitions). Adolescents with NSSI also completed clinical interviews on psychiatric diagnoses and a recent self-injurious behavior (SIB). Scores on the psychological correlates of NSSI were compared between adolescents with NSSI and NC, and across three diagnostic subgroups of NSSI (A: NSSI+/depression-/PTSD-, n = 14; B: NSSI+/depression+/PTSD-, n = 57; C: NSSI+/depression+/PTSD+, n = 14). Differences between NSSI diagnostic subgroups were tested on the motives for SIB and accompanying suicidal presentations (e.g., desire, intent, motive, lethality). RESULTS: Common comorbidities of NSSI included depression, panic disorder, generalized anxiety disorder, and PTSD. The NSSI subgroup classification was significantly associated with panic disorder, which was controlled for in the subsequent group comparisons. Overall, adolescents who engage in NSSI with vs. without depression reported more psychological vulnerabilities and impairment and a greater degree of suicidal thoughts/desire in SIB (i.e., groups B, C >A), which remained significant after controlling for panic disorder. An increased odds of the suicidal motive for SIB was found in adolescents with all three conditions (i.e., group C: NSSI+/depression+/PTSD+) compared to those with NSSI but neither depression nor PTSD (i.e., group A: NSSI+/depression-/PTSD-); however, this was not significant after controlling for panic disorder. CONCLUSIONS: Psychological underpinnings of adolescent NSSI in clinical contexts may be largely associated with concurrent depression. Suicidal motives in adolescents who engage in NSSI in the presence of depression and PTSD may be confounded by the co-occurrence of panic disorder. This study warrants the importance of attending to the comorbid depression with NSSI in adolescents as it is related to an increase in suicidal desire accompanying SIB.

Interaction of sexual violence perpetration and victimization on suicide attempts in Korean adolescents on additive and multiplicative scales: a population-based cross-sectional study.

PURPOSE: To evaluate the associations and interaction between sexual violence perpetration and victimization on suicide attempts using a large representative sample of adolescents from South Korea. METHODS: Based on data from 515,247 adolescents aged 12-18 years from the Korea Youth Risk Behavior Web-Based Survey (2006-2012), a nationally representative repeated cross-sectional survey, we obtained self-reports of suicide attempts over the past year and of lifetime sexual violence perpetration and victimization. Using complex survey weights, weighted logistic regression models were employed to estimate the odds ratios (ORs). The interaction analyses were conducted on both additive and multiplicative scales. All analyses were conducted separately for boys and girls. RESULTS: Lifetime prevalence of sexual violence perpetration were 1.3% for boys and 0.4% for girls, and about 40% of those perpetrating sexual violence were also victims. After adjusting for several covariates, sexual violence perpetration was independently associated with suicide attempts in boys (ORadjusted for boys 1.80 [95% confidence intervals: 1.53, 2.11]), whereas in girls, the association was only marginally significant (ORadjusted for girls 1.27 [1.00, 1.63]). We found the negative multiplicative and additive interaction between the sexual violence perpetration and victimization on suicide attempts for both boys and girls (the ratio of ORs 0.30 [0.23, 0.39] for boys and 0.20 [0.12, 0.31] for girls; relative excess risk due to interaction - 1.20 [-1.91, - 0.50] for boys and - 2.33 [-3.00, - 1.66] for girls). CONCLUSION: Sexual violence perpetration and victimization were independently and interactively associated with suicide attempts in adolescents, with a sub-additive interaction found between these two variables. Public mental health services and policies should recognize the importance of actively involving adolescents who had sexually perpetrated others as key intervention targets.

Superior Capsular Reconstruction with the mini open key-hole Technique using Achilles allograft demonstrates favorable outcomes for patients with preoperative pseudoparalysis but worse outcome and strength with longer duration pseudoparalysis.

PURPOSE: The purpose of this study was to analyze whether unique SCR with key-hole technique using Achilles allograft can improve pseudoparalysis in patients with irreparable rotator cuff tears and additionally to identify preoperative factors that influence clinical outcomes. METHODS: Between January 2018 and October 2021, patient data from SCR with our institution's unique key-hole technique using Achilles were retrospectively collected (minimum 2-years follow up). The patients were categorized into pseudoparalysis group (P group) and no pseudoparalysis group (NP group). Active range of motion (ROM) of shoulder, clinical scores (constant and pain visual analog scale scores) and muscle strength was assessed preoperatively and at 2-years postoperatively. And the correlation between preoperative and postoperative clinical data was analyzed through simple linear regression in the P group. RESULTS: 69 patients who underwent SCR with key-hole technique using Achilles, were included in the study. Group P and NP had 24 and 45 cases, respectively. Preoperative ROM (FE, ER), constant score and muscle strength (FE, ER) were significantly lower in P group than NP group. At 2-year follow-up the active ROM (FE, p<0.001, ER, p<0.001), constant score, VAS, muscle strength (FE, p<0.001, ER, p<0.001) were improved in the P group. In P group, pseudoparalysis recovered in 21 out of 24 patients (87.5%) at 2-year after surgery. The minimum clinically important difference of patient reported outcomes (Constant Score / VAS) were 8.15/1.05 for the P group and 9.47/0.92 for the NP group. Among the 3 cases of recovery failed, 2 cases were due to graft failure, and 1 case had delayed recovery. Prolonged preoperative pseudoparalysis and weaker preoperative external rotation strength were associated with worse clinical outcomes. CONCLUSIONS: Superior capsular reconstruction with mini open key-hole technique using Achilles allograft demonstrates favorable outcomes for patients with preoperative pseudoparalysis. However, for SCR with the pseudoparalyis patients the careful attention is needed because the longer pseudoparalysis duration and the weaker external rotation strength could have the tendency of worse postoperative outcomes.

Change in Femoral Cartilage Cross-Sectional Area After Aerobic and Resistance Exercise.

We compared the immediate response and recovery of femoral cartilage morphology following aerobic or resistance exercise to a control condition. Fifteen healthy young males (23.9 years; 170.1 cm; 69.7 kg) visited the laboratory three separate days and randomly performed one of the 30-min exercise aerobic exercises (treadmill running), resistance exercises (leg presses, back squats, and knee extensions), or seated rest as the control, each followed by the 50-min recovery. Ultrasonographic images of the femoral cartilage cross-sectional area (CSA) were obtained before and after exercise and every 5 min thereafter. To test exercise effects over time, a mixed model analysis of variance and Tukey-Kramer post-hoc tests were performed (p<0.05). The femoral cartilage CSA was different (condition×time: F34,742=4.30, p<0.0001) and the femoral cartilage CSA was decreased after the aerobic (-5.8%, p<0.0001) and the resistance (-3.4%, p=0.04) exercises compared to the pre-exercise levels. Deformed femoral cartilage CSA took 35 and 10 min to return to the pre-exercise levels after aerobic and resistance exercises (p+>+0.09), respectively. Thirty minutes of moderate exertion performing aerobic or resistance exercises immediately reduced the femoral cartilage CSA. A rest period ranging from 10 to 35 min was required for cartilage recovery after weight-bearing exercises.

Ultrasound-Guided Modified Thread Carpal Tunnel Release for Carpal Tunnel Syndrome: A Pilot Study.

PURPOSE: This study aimed to investigate the effectiveness and safety of modified thread carpal tunnel release (mTCTR) using Smartwire-01 in patients with carpal tunnel syndrome (CTS). MATERIALS AND METHODS: Patients with CTS who required CTR were enrolled. Symptom severity and functional status were assessed using the Boston Carpal Tunnel Syndrome Questionnaire-Symptom Severity Scale (BCTQ-SSS) and Functional Status Scale (BCTQ-FSS), and pain was assessed using a numerical rating scale (NRS) at 4, 8, and 12 weeks after mTCTR. The scores were compared with the pre-procedural scores. The electrophysiologic study and median nerve cross-sectional area (CSA) measurements at the wrist before and 12 weeks after mTCTR were compared. RESULTS: A total of 11 patients were included. No adverse effects were reported throughout the study period. The NRS, BCTQ-SSS, and BCTQ-FSS scores significantly improved at 4 weeks after mTCTR, and this improvement persisted throughout the follow-up period (NRS and BCTQ-SSS, P < 0.001; BCTQ-FSS, P = 0.012). After 12 weeks, the latency and velocity of the median sensory nerve action potential significantly improved, compared with those before mTCTR (latency, 5.4 ± 1.3 to 4.7 ± 1.1 ms, P = 0.01; velocity 27.8 ± 6.8 to 31.8 ± 7.4 m/s, P = 0.019). No significant change was observed in the median nerve CSA before and after mTCTR. CONCLUSION: mTCTR using Smartwire-01 is a safe and effective procedure and a possible alternative to surgery.

Varus-valgus alignment of humeral short stem in reverse total shoulder arthroplasty: does it really matter?

BACKGROUND: The utilization of short humeral stems in reverse total shoulder arthroplasty has gained attention in recent times. However, concerns regarding the risk of misalignment during implant insertion are associated with their use. METHODS: Eight fresh-frozen cadaveric shoulders were prepared for dissection and biomechanical testing. A bespoke humeral implant was fabricated to facilitate assessment of neutral, varus, and valgus alignments using a single stem, and 10° was established as the maximum permissible angle for misalignments. Shift in humerus position and changes in deltoid length attributable to misalignments relative to the neutral position were evaluated using a Microscribe 3DLx system. The impingement-free range of motion, encompassing abduction, adduction, internal rotation, and external rotation (ER), was gauged using a digital goniometer. The capacity for abduction was evaluated at maximal abduction angles under successive loading on the middle deltoid. A specialized traction system coupled with a force transducer was employed to measure anterior dislocation forces. RESULTS: Relative to the neutral alignment, valgus alignment resulted in a more distal (10.5 ± 2.4 mm) and medial (8.3 ± 2.2 mm) translation of the humeral component, whereas the varus alignment resulted in the humerus shifting more superiorly (11.2 ± 1.3 mm) and laterally (9.9 ± 0.9 mm) at 0° abduction. The valgus alignment exhibited the highest abduction angle than neutral alignment (86.2°, P < .001). Conversely, the varus alignment demonstrated significantly higher adduction (18.4 ± 7.4°, P < .001), internal rotation (68.9 ± 15.0°, P = .014), and ER (45.2 ± 10.5°, P = .002) at 0° abduction compared to the neutral alignments. Anterior dislocation forces were considerably lower (23.8 N) in the varus group compared to the neutral group at 0°ER (P = .047). Additionally, abduction capability was markedly higher in varus alignment at low deltoid loads than the neutral alignment (5N, P = .009; 7.5 N, P = .007). CONCLUSIONS: The varus position enhances rotational range of motion (ROM) but increases instability, while the valgus position does not significantly impact ROM or instability compared to the neutral position.

Synthesis and Evaluation of Chloride-Substituted Ramalin Derivatives for Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-beta plaques and hyperphosphorylated tau proteins, leading to cognitive decline and neuronal death. However, despite extensive research, there are still no effective treatments for this condition. In this study, a series of chloride-substituted Ramalin derivatives is synthesized to optimize their antioxidant, anti-inflammatory, and their potential to target key pathological features of Alzheimer's disease. The effect of the chloride position on these properties is investigated, specifically examining the potential of these derivatives to inhibit tau aggregation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) activity. Our findings demonstrate that several derivatives, particularly RA-3Cl, RA-4Cl, RA-26Cl, RA-34Cl, and RA-35Cl, significantly inhibit tau aggregation with inhibition rates of approximately 50%. For BACE-1 inhibition, Ramalin and RA-4Cl also significantly decrease BACE-1 expression in N2a cells by 40% and 38%, respectively, while RA-23Cl and RA-24Cl showed inhibition rates of 30% and 35% in SH-SY5Y cells. These results suggest that chloride-substituted Ramalin derivatives possess promising multifunctional properties for AD treatment, warranting further investigation and optimization for clinical applications.

Custom fabricated three-dimensional printed surgical guide for trephine bur in autogenous bone graft: A technique report.

This technique presents a workflow that designs the custom surgical guide to cover a trephine bur using simple slicer software and three-dimensional (3D) printing to perform the semilunar technique. This method in autogenous bone grafting surgery harvests a thin layer of cortical bone in the donor site with a trephine bur. Its biologically favorable, round shape can be used as a shell to reconstruct the ridge with a 3D contour acceptable for future implant placement. A 78-year-old female patient required vertical and horizontal bone grafting for future implant placement due to the infection caused by the vertically fractured root of a premolar. The patient's cone beam computed tomography (CBCT) file was translated into a standard tessellation language (STL) file, and recipient and donor site models were created. Simulated surgery was done using the software first to detect any possible complications during surgery. The trephine bur planned for use in surgery was measured in necessary dimensions, and the values were added to create a guide for surgery in slicer software. Then, it was 3D-printed with a stereolithography (SLA) printer. After testing the fit of the guide, it was further tested on a fused filament fabrication (FFF) printed donor site model to check if the desired shape and size of the plate were acquired after harvest. Then, the plates were used for model surgery on the recipient site model. After no issues from the previous steps, the final patient surgery was approved and completed with success. This technique utilizes the SLA printing method to create the custom surgical guide for a trephine bur without using commercially available products. Moreover, it could be tested on FFF 3D-printed anatomical models to ensure its validity. With this innovative technique, clinicians can efficiently perform a semilunar technique, facilitating the surgery and improving patient care.

Cutting Off H+ Leaks on the Inner Mitochondrial Membrane: A Proton Modulation Approach to Selectively Eradicate Cancer Stem Cells.

Cancer stem cells (CSCs) are associated with the invasion and metastatic relapse of various cancers. However, current cancer therapies are limited to targeting the bulk of primary tumor cells while remaining the CSCs untouched. Here, we report a new proton (H+) modulation approach to selectively eradicate CSCs via cutting off the H+ leaks on the inner mitochondrial membrane (IMM). Based on the fruit extract of Gardenia jasminoides, a multimodal molecule channel blocker with high biosafety, namely, Bo-Mt-Ge, is developed. Importantly, in this study, we successfully identify that mitochondrial uncoupling protein UCP2 is closely correlated with the stemness of CSCs, which may offer a new perspective for selective CSC drug discovery. Mechanistic studies show that Bo-Mt-Ge can specifically inhibit the UCP2 activities, decrease the H+ influx in the matrix, regulate the electrochemical gradient, and deplete the endogenous GSH, which synergistically constitute a unique MoA to active apoptotic CSC death. Intriguingly, Bo-Mt-Ge also counteracts the therapeutic resistance via a two-pronged tactic: drug efflux pump P-glycoprotein downregulation and antiapoptotic factor (e.g., Bcl-2) inhibition. With these merits, Bo-Mt-Ge proved to be one of the safest and most efficacious anti-CSC agents, with ca. 100-fold more potent than genipin alone in vitro and in vivo. This study offers new insights and promising solutions for future CSC therapies in the clinic.

Comparison of the acid suppression effects between low-dose esomeprazole and famotidine in healthy subjects.

OBJECTIVE: Famotidine, an H2 receptor antagonist (H2RA), is mainly prescribed to alleviate the early symptoms of gastritis. Our aim was to explore the possibilities of low-dose esomeprazole as a treatment of gastritis as well as the pharmacodynamic (PD) properties of esomeprazole and famotidine. MATERIALS AND METHODS: A randomized, multiple-dose, 6-sequence, 3-period crossover study was conducted with a 7-day washout between periods. For each period, the subjects were administered one dose of esomeprazole 10 mg or famotidine 20 mg or esomeprazole 20 mg each day. To evaluate the PDs, the 24-hour gastric pH was recorded after single and multiple doses. The mean percentage of time during which the gastric pH was above 4 was evaluated for PD assessment. To confirm the pharmacokinetic (PK) characteristics of esomeprazole, blood was collected for up to 24 hours after multiple doses. RESULTS: 26 subjects completed the study. Following the multiple doses of esomeprazole 10 mg, esomeprazole 20 mg, and famotidine 20 mg, the mean percentages of time during which the gastric pH was above 4 over the course of 24 hour were 35.77 ± 19.56%, 53.75 ± 20.55%, and 24.48 ± 17.36%, respectively. After multiple doses, the time of peak plasma concentration at steady state (tmax,ss) was 1.00 and 1.25 hours for 10 and 20 mg of esomeprazole, respectively. The geometric mean ratio and its 90% confidence interval of area under the plasma drug concentration-time curve in steady state (AUCT,ss) and maximum concentration of drug in plasma in steady state (Cmax,ss) for esomeprazole 10 mg compared to 20 mg were 0.3654 (0.3381 - 0.3948) and 0.5066 (0.4601 - 0.5579), respectively. CONCLUSION: The PD parameters of esomeprazole 10 mg were comparable to those of famotidine after multiple doses. These findings provide support for further evaluating the use of 10 mg of esomeprazole as a treatment option for gastritis.

Cosmetic Open Rhinoplasty in Acute Nasal Bone Fracture With Pre-Existing Deformity.

The simultaneous reduction of nasal bone fracture and cosmetic rhinoplasty is a challenging procedure, because of fracture severity and skeletal instability. Our aim was to investigate the surgical strategy and outcomes of cosmetic rhinoplasty according to the pre-existing nasal deformity when performing simultaneous reduction of nasal bone fracture and cosmetic rhinoplasty. In total, 71 patients who underwent cosmetic rhinoplasty were included. All patients were categorized according to pre-existing deformity, dorsal hump and irregularities, and deviation of the nose, wide nose, and flat nasal dorsum. The authors performed individual maneuvers to correct each deformity. Autologous tissue was used in all maneuvers for graft. Photoanalysis was performed to measure the deviation, nasal length, radix height, dorsal height, tip projection, nasofrontal angle, and nasolabial angle. Subjective evaluation of the functional and esthetic problems was confirmed through rhinoplasty outcome evaluation. In the analysis of the photographs, most patients presented improved scores ( P <0.05). The scores of satisfaction were significantly higher in the postoperative state ( P <0.05). As a postoperative complication, 2 cases of deviated tip occurred due to septal instability and were successfully revised with septoplasty and columellar strut graft. The authors created a harmonious face by evaluating, categorizing, and treating each deformity of the nose in patients with nasal fractures according to our algorithm.

Cancer therapeutics based on diverse energy sources.

Light-based phototherapy has been developed for cancer treatment owing to its non-invasiveness and spatiotemporal control. Despite the unique merits of phototherapy, one critical disadvantage of light is its limited penetration depth, which restricts its application in cancer treatment. Although many researchers have developed various strategies to deliver light into deep-seated tumors with two-photon and near-infrared light irradiation, phototherapy encounters the peculiar limitations of light. In addition, high oxygen dependency is another limitation of photodynamic therapy to treat hypoxic tumors. To overcome the drawbacks of conventional treatments, various energy sources have been developed for cancer treatment. Generally, most energy sources, such as ultrasound, chemiluminescence, radiation, microwave, electricity, and magnetic field, are relatively free from the restraint of penetration depth. Combining other strategies or therapies with other energy-source-based therapies improves the strength and compensates for the weakness. This tutorial review focuses on recent advances in the diverse energy sources utilized in cancer treatment and their future perspectives.

Transparent Air Filters with Active Thermal Sterilization.

The worldwide proliferation of COVID-19 poses the urgent need for sterilizable and transparent air filters to inhibit virus transmission while retaining ease of communication. Here, we introduce copper nanowires to fabricate transparent and self-sterilizable air filters. Copper nanowire air filter (CNAF) allowed visible light penetration, thereby can exhibit facial expressions, helpful for better communication. CNAF effectively captured particulate matter (PM) by mechanical and electrostatic filtration mechanisms. The temperature of CNAF could be controlled by Joule-heating up to 100 °C with thermal stability. CNAF successfully inhibited the growth of E. coli because of the oligodynamic effect of copper. With heat sterilization, the antibacterial efficiency against G. anodireducens was greatly improved up to 99.3% within 10 min. CNAF showed high reusability with stable filtration efficiency and thermal antibacterial efficacy after five repeated uses. Our result suggests an alternative form of active antimicrobial air filter in preparation for the current and future pandemic situations.

Validation and development of Voice Handicap Index-Throat (VHI-T) for Koreans.

INTRODUCTION: This study aimed to develop, validate, and analyze the reliability of the Korean version of the Voice Handicap Index-Throat (VHI-Tk). METHODS: This prospective study included 103 patients in the case group with voice problems (18 with functional dysphonia, 44 with mass in the larynx, 18 with neurological voice disorder, 23 with throat problems) and 27 in the control group without voice problems. All participants completed these questionnaires at their initial visit: the Korean version of the Voice Handicap Index (K-VHI), VHI-Tk, and the Korean version of the Voice Symptom Scale (K-VoiSS). Case group patients in the case group re-completed the VHI-Tk questionnaire to assess test-retest reliability. Finally, a one-way analysis of variance was implemented to assess differences in VHI-Tk scores among the four diagnosis types in the case group. RESULTS: The VHI-Tk scores in the case group were significantly higher than in the control group. The VHI-Tk was significantly correlated with the subscales of K-VHI and K-VoiSS. The VHI-Tk has significant test-retest reliability, and its internal consistency is good to excellent (Cronbach's alpha correlation coefficient range: 0.895-0.901). There was significant difference in the mean VHI-Tk scores according to the four diagnosis types (throat problems group > neurological voice disorder group). CONCLUSION: We validated the VHI-T questionnaire to measure self-perceived voice and throat problems among Koreans. A large sample size and various diagnosis types are required in future studies to fully validate the VHI-T for use in multiple cultures.

Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment (ICON8): overall survival results from an open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Standard-of-care first-line chemotherapy for epithelial ovarian cancer is carboplatin and paclitaxel administered once every 3 weeks. The JGOG 3016 trial reported significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly (ie, once every 3 weeks) carboplatin. However, this benefit was not observed in the previously reported progression-free survival results of ICON8. Here, we present the final coprimary outcomes of overall survival and updated progression-free survival analyses of ICON8. METHODS: In this open-label, randomised, controlled, phase 3 trial (ICON8), women aged 18 years or older with newly diagnosed stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma (here collectively termed ovarian cancer, as defined by International Federation of Gynecology and Obstetrics [FIGO] 1988 criteria) and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 117 hospitals with oncology departments in the UK, Australia and New Zealand, Mexico, South Korea, and Ireland. Patients could enter the trial after immediate primary surgery (IPS) or with planned delayed primary surgery (DPS) during chemotherapy, or could have no planned surgery. Participants were randomly assigned (1:1:1), using the Medical Research Council Clinical Trials Unit at University College London randomisation line with stratification by Gynecologic Cancer Intergroup group, FIGO disease stage, and outcome and timing of surgery, to either 3-weekly carboplatin area under the curve (AUC)5 or AUC6 and 3-weekly paclitaxel 175 mg/m2 (control; group 1), 3-weekly carboplatin AUC5 or AUC6 and weekly paclitaxel 80 mg/m2 (group 2), or weekly carboplatin AUC2 and weekly paclitaxel 80 mg/m2 (group 3), all administered via intravenous infusion for a total of six 21-day cycles. Coprimary outcomes were progression-free survival and overall survival, with comparisons done between group 2 and group 1, and group 3 and group 1, in the intention-to-treat population. Safety was assessed in all patients who started at least one chemotherapy cycle. The trial is registered on ClinicalTrials.gov, NCT01654146, and ISRCTN registry, ISRCTN10356387, and is closed to accrual. FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 patients were randomly assigned to group 1 (n=522), group 2 (n=523), or group 3 (n=521). The median age was 62 years (IQR 54-68), 1073 (69%) of 1566 patients had high-grade serous carcinoma, 1119 (71%) had stage IIIC-IV disease, and 745 (48%) had IPS. As of data cutoff (March 31, 2020), with a median follow-up of 69 months (IQR 61-75), no significant difference in overall survival was observed in either comparison: median overall survival of 47·4 months (95% CI 43·1-54·8) in group 1, 54·8 months (46·6-61·6) in group 2, and 53·4 months (49·2-59·6) in group 3 (group 2 vs group 1: hazard ratio 0·87 [97·5% CI 0·73-1·05]; group 3 vs group 1: 0·91 [0·76-1·09]). No significant difference was observed for progression-free survival in either comparison and evidence of non-proportional hazards was seen (p=0·037), with restricted mean survival time of 23·9 months (97·5% CI 22·1-25·6) in group 1, 25·3 months (23·6-27·1) in group 2, and 24·8 months (23·0-26·5) in group 3. The most common grade 3-4 adverse events were reduced neutrophil count (78 [15%] of 511 patients in group 1, 183 [36%] of 514 in group 2, and 154 [30%] of 513 in group 3), reduced white blood cell count (22 [4%] in group 1, 80 [16%] in group 2, and 71 [14%] in group 3), and anaemia (26 [5%] in group 1, 66 [13%] in group 2, and 24 [5%] in group 3). No new serious adverse events were reported. Seven treatment-related deaths were reported (two in group 1, four in group 2, and one in group 3). INTERPRETATION: In our cohort of predominantly European women with epithelial ovarian cancer, we found that first-line weekly dose-dense chemotherapy did not improve overall or progression-free survival compared with standard 3-weekly chemotherapy and should not be used as part of standard multimodality front-line therapy in this patient group. FUNDING: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.

Cooperative sequence clustering and decoding for DNA storage system with fountain codes.

MOTIVATION: In DNA storage systems, there are tradeoffs between writing and reading costs. Increasing the code rate of error-correcting codes may save writing cost, but it will need more sequence reads for data retrieval. There is potentially a way to improve sequencing and decoding processes in such a way that the reading cost induced by this tradeoff is reduced without increasing the writing cost. In past researches, clustering, alignment and decoding processes were considered as separate stages but we believe that using the information from all these processes together may improve decoding performance. Actual experiments of DNA synthesis and sequencing should be performed because simulations cannot be relied on to cover all error possibilities in practical circumstances. RESULTS: For DNA storage systems using fountain code and Reed-Solomon (RS) code, we introduce several techniques to improve the decoding performance. We designed the decoding process focusing on the cooperation of key components: Hamming-distance based clustering, discarding of abnormal sequence reads, RS error correction as well as detection and quality score-based ordering of sequences. We synthesized 513.6 KB data into DNA oligo pools and sequenced this data successfully with Illumina MiSeq instrument. Compared to Erlich's research, the proposed decoding method additionally incorporates sequence reads with minor errors which had been discarded before, and thus was able to make use of 10.6-11.9% more sequence reads from the same sequencing environment, this resulted in 6.5-8.9% reduction in the reading cost. Channel characteristics including sequence coverage and read-length distributions are provided as well. AVAILABILITY AND IMPLEMENTATION: The raw data files and the source codes of our experiments are available at: https://github.com/jhjeong0702/dna-storage.

Subcortical volumetric alterations as potential predictors of methylphenidate treatment response in youth with attention-deficit/hyperactivity disorder.

BACKGROUND: Patients with attention-deficit/hyperactivity disorder (ADHD) show structural alterations in the subcortical and dopaminergic regions of the brain. Methylphenidate is a first-line treatment for ADHD, and it is known to affect the subcortical and dopaminergic systems. The degree of pretreatment structural alterations in patients with ADHD may be an important factor in predicting methylphenidate treatment outcomes. The present study examined whether pretreatment volumetric alterations in the subcortical and dopaminergic regions predicted treatment response in youth with ADHD. METHODS: This study included 67 youth with ADHD and 25 healthy controls. Youth with ADHD received 8 weeks of methylphenidate treatment. They completed baseline (pretreatment) T 1-weighted structural MRI scans and underwent clinical assessments before and after methylphenidate treatment. The healthy controls also completed baseline structural MRI scans. We assessed volumetric alterations using relative volumes (volume of each region of interest/intracranial volume). RESULTS: Among 67 youth with ADHD, 44 were treatment responders and 23 were nonresponders based on post-treatment scores on the Clinical Global Impression Scale-Improvement. Nonresponders had larger volumes in the bilateral amygdala and right thalamus than responders. Nonresponders also had larger volumes in amygdalar subregions (i.e., the bilateral lateral nucleus and right basal nucleus) and hippocampal subregions (i.e., the right hippocampal head and right molecular layer) relative to responders. LIMITATIONS: We did not collect post-treatment structural T 1-weighted images, so volumetric changes related to methylphenidate treatment in youth with ADHD were undetermined. CONCLUSION: These findings suggest that pretreatment volumetric alterations in subcortical regions may serve as biomarkers for predicting methylphenidate treatment response in youth with ADHD.

Application of the New Preoperative Frailty Risk Score in Elderly Patients Undergoing Emergency Surgery.

BACKGROUND: Predicting preoperative frailty risk in emergency surgery is difficult with limited information because preoperative evaluation is not commonly performed properly. A recent study attempted to predict preoperative frailty risk using only diagnostic and surgical codes that can be extracted from the electronic medical records system. OBJECTIVE: This study aimed to validate whether the prediction model of preoperative frailty risk presented in the previous study is well applied to other medical hospitals' data. METHODS: This is a retrospective cohort study including 1,557 patients (≥75 years old) who were admitted to a single institution for emergency operations between January 1, 2010, and December 31, 2019, for study analysis. The Charlson comorbidity index, Hospital Frailty Risk Score, and the recently developed Operation Frailty Risk Score (OFRS) were calculated using the patient's diagnostic and operation codes. The predictive performances of these calculated risk scores and the American Society of Anesthesiologists-Physical Status classification for postoperative 90-day mortality were compared by using the receiver operating characteristic curve analysis. FINDINGS: The predictive performance of the OFRS, Charlson comorbidity index, American Society of Anesthesiologists-Physical Status, and Hospital Frailty Risk Score for postoperative 90-day mortality was 0.81, 0.630, 0.699, and 0.549 on a c-statistics basis, respectively. CONCLUSIONS: The OFRS using diagnostic and operation codes may show the best predictive performance for 90-day mortality compared to other risk scores, and it can be the clinically applicable model to evaluate the preoperative frailty risk in elderly patients undergoing emergency surgery.