Nickel-Catalyzed Hydrofluorination in Unactivated Alkenes: Regio- and Enantioselective C-F Bond Formation.

Catalytic formation of a regio- and enantioselective C-F bond chiral center from readily available alkenes is a crucial goal, yet it continues to pose significant challenges in organic synthesis. Here, we report the regioselective formation of C-F bonds facilitated by NiH catalysis and a coordination directing strategy that enables precise hydrofluorination of both terminal and internal alkenes. Notably, we have optimized this methodology to achieve high enantioselectivity in creating aliphatic C-F stereogenic centers especially with ß,γ-alkenyl substrates, using a tailored chiral Bn-BOx ligand. Another pivotal finding in our research is the identification of the (+)-nonlinear effect under optimized conditions, allowing for high enantioselectivity even with moderately enantiomerically enriched chiral ligands. Given the significant role of fluorine in pharmaceuticals and synthetic materials, this research offers essential insights into the regioselective and enantioselective formation of C-F bond chiral centers, paving the way for the efficient production of valuable fluorinated compounds.

Quantitative risk factor analysis of prior disease condition and socioeconomic status with the multiple myeloma development: nationwide cohort study.

Early diagnosis and following management are important determinants of the prognosis of multiple myeloma (MM). However, screening for MM is not routinely performed because it is rare disease. In this study, we evaluated the association of prior disease condition and socioeconomic status (SES) with MM diagnosis and developed a simple predictive model that can identify patients at high risk of developing MM who may need screening using nationwide database from South Korea. According to multivariate logistic regression analysis, eight prior disease conditions and SES before diagnosis were shown to be predictors of MM development and selected for score development. Total prediction scores were categorized into four groups: patients without any risk (≤ 0) intermediate-1 (0.5-9), intermediate-2 (9-14), and high risk (> 14). The odds ratios for developing MM in the intermediate-1, intermediate-2, and high-risk groups were 1.29, 3.07, and 4.62, respectively. The association of prior disease conditions and SES with MM diagnosis were demonstrated and the simple scoring system to predict the MM risk was developed. This scoring system is also provided by web-based application and could be a useful tool to support clinicians in identifying potential candidates for MM screening.

Combined translational pharmacometrics approach to support the design and conduct of the first-in-human study of DWP16001.

AIMS: The objective of this study was to characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of DWP16001, a novel sodium-glucose cotransporter 2 inhibitor, and predict efficacious doses for the first-in-human study using various translational approaches. METHODS: A mechanistic PK/PD model was developed for DWP16001 using nonlinear mixed-effect modelling to describe animal PK/PD properties. Using allometry and in silico physiologically based equations, human PK parameters were predicted. Human PD parameters were scaled by applying interspecies difference and in vitro drug-specific factors. Human parameters were refined using early clinical data. Model-predicted PK and PD outcomes were compared to observations before and after parameter refinement. RESULTS: The PK/PD model of DWP16001 was developed using a 2-compartment model with first-order absorption and indirect response. Efficacious doses of 0.3 and 2 mg of DWP16001 were predicted using human half-maximal inhibitory concentration values translated from Zucker Diabetic Fatty rats and normal rats, respectively. After parameter refinement, doses of 0.2 and 1 mg were predicted to be efficacious for each disease model, which improved the prediction results to within a 1.2-fold difference between the model prediction and observation. CONCLUSIONS: This study predicted efficacious human doses of DWP16001 using population PK/PD modelling and a combined translational pharmacometrics approach. Early clinical data allowed the methods used to translate in vitro and in vivo findings to clinical PK/PD values for DWP16001 to be optimized. This study has shown that a refinement step can be readily applied to improve model prediction and further support the study design and conduct of a first-in-human study.

A Bayesian Analysis of a Cognitive-Behavioral Therapy Intervention for High-Risk People on Probation.

This analysis employs a Bayesian framework to estimate the impact of a Cognitive-Behavioral Therapy (CBT) intervention on the recidivism of high-risk people under community supervision. The study relies on the reanalysis of experimental datal using a Bayesian logistic regression model. In doing so, new estimates of programmatic impact were produced using weakly informative Cauchy priors and the Hamiltonian Monte Carlo method. The Bayesian analysis indicated that CBT reduced the prevalence of new charges for total, non-violent, property, and drug crimes. However, the effectiveness of the CBT program varied meaningfully depending on the participant's age. The probability of the successful reduction of drug offenses was high only for younger individuals (<26 years old), while there was an impact on property offenses only for older individuals (>26 years old). In general, the probability of the successful reduction of new charges was higher for the older group of people on probation. Generally, this study demonstrates that Bayesian analysis can complement the more commonplace Null Hypothesis Significance Test (NHST) analysis in experimental research by providing practically useful probability information. Additionally, the specific findings of the reestimation support the principles of risk-needs responsivity and risk-stratified community supervision and align with related findings, though important differences emerge. In this case, the Bayesian estimations suggest that the effect of the intervention may vary for different types of crime depending on the age of the participants. This is informative for the development of evidence-based correctional policy and effective community supervision programming.

Effect of Attenuated Light Through Translucent Zirconia on the Interfacial Adaptation and Polymerization of Resin Cements.

PURPOSE: The first objective was to determine if dual-curing of resin cement with reduced light could affect interfacial adaptations of zirconia restoration. The second objective was to examine whether cement type and pretreatment method of universal adhesive affected interfacial adaptation. The final objective was to compare the polymerization degree of cement under different reduced-light conditions. MATERIALS AND METHODS: Inlay cavities were prepared on extracted third molars. Translucent zirconia restorations were milled using Katana UTML (Kuraray Noritake) in three groups with restoration thicknesses of 1, 2, and 3 mm, respectively. Each group had three subgroups using different cementation methods. For subgroup 1, restorations were cemented with self-adhesive cement. For subgroup 2, universal adhesive was applied and light cured. After the restoration was seated with conventional resin cement, light curing was performed. For subgroup 3, after adhesive was applied, the restoration was seated with conventional resin cement. Light curing was performed for the adhesive and cement simultaneously. After thermocycling, interfacial adaptation at the restoration-tooth interface was investigated using swept-source optical coherence tomography imaging. Finally, polymerization shrinkage of the cement was measured using a linometer and compared under the conditions of different zirconia thicknesses and light-curing durations. RESULTS: Interfacial adaptation varied signficantly depending on the zirconia thickness, pretreatment, polymerization mode and cements used (p < 0.05). The effects of the adhesive and polymerization shrinkage differed signficantly, depending on the reduced light under the zirconia (p < 0.05). CONCLUSION: Lower curing-light irradiance may lead to inferior adaptation and lower polymerization of the cement. Polymerization of resin cement can differ depending on the light irradiance and exposure duration.

A multicenter, retrospective comparison of pregnancy outcomes between groups of preterm labor nulliparous mothers treated with atosiban vs. ritodrine in singleton and multiple pregnancies.

OBJECTIVE: To evaluate the safety and efficacy of atosiban and ritodrine in pregnant women who were hospitalized for threatened preterm labor (TPL). MATERIALS AND METHODS: Diagnosis records of preterm labor and subsequent pregnancy-related records and medical records of newborns were extracted from the Clinical Data Warehouse of the Catholic Medical Center's affiliated hospital. Since 2009, cases of preterm labor diagnosed before 34 weeks of pregnancy for first-time mothers who delivered at any one of three hospitals and who received drug treatment for more than 2 days to delay delivery were included in the dataset. Based on characteristics of Korea's national health insurance system, the drug treatment after diagnosis of preterm labor could be classified into cases using only ritodrine (571 women), cases using only atosiban (244 women), and cases where ritodrine treatment was started and then changed to atosiban (275 women). Demographic factors, obstetric outcomes, neonatal outcomes of the two groups were analyzed. RESULTS: The duration and maintenance of pregnancy were found to be similar between the two groups, although the initial cervical length was significantly shorter in the atosiban cohort (AC). Only in multifetal pregnancies, the maintenance of pregnancy was significantly longer in the AC. The total duration of pregnancy did not show any significant difference between the two groups regardless of singleton or multiple pregnancy. However, the distribution graph showed non-responders in the ritodrine cohort (RC). Our study showed a difference in neonatal birth weight of singleton between the two groups. The length of hospitalization and the NICU admission rate were also significantly higher in the RC for singleton. Although not significant, the proportion of numbers with an Apgar score less than 7 was higher in the RC. Neonatal death was more common in the RG (8 cases in AC and 18 cases in RC). CONCLUSIONS: Using atosiban for TPL is more effective than using ritodrine for maintaining pregnancy in the case of a multifetal pregnancy. In singleton pregnancies, neonatal outcomes of the atosiban group were superior to those of the ritodrine group. There seems to be a non-responder group when using ritodrine for TPL. Further studies are needed to determine causes of non-responders of ritodrine and effects of ritodrine on the fetus.

The short-term effects of fixed copayment policy on elderly health spending and service utilization: evidence from South Korea's age-based policy using exact date of birth.

A large number of the poor elderly in Korea have been exposed to the risk of insufficient proper medical treatments because of financial restrictions. South Korea launched policies to reduce the cost-sharing burden on the elderly, including one compelling the elderly to pay a fixed out-of-pocket amount for outpatient treatments. The impacts of such policies, however, have yet to be elucidated. In this paper, we estimate the short-term effects of the fixed outpatient copayment policy on the health-related behavior of the elderly. We employed a regression discontinuity design by using the exact days before and after the sample's 65th birthdate as the assignment variable, along with the restricted individual-level 2012 and 2013 National Health Insurance claims data. Results show that the policy increased the elderly's health service utilization numbers and reduced out-of-pocket spending for insured services. Moreover, the effects on prescription spending and the insurer's burden differed depending on beneficiaries' characteristics.

Establishing Rationale for the Clinical Development of Cell Therapy Products: Consensus between Risk and Benefit.

Despite long-term research achievements, the development of cell therapy (CT) products remains challenging. This is because the risks experienced by the subject and therapeutic effects in the clinical trial stage are unclear due to the various uncertainties of CT when administered to humans. Nevertheless, as autologous cell products for systemic administration have recently been approved for marketing, CT product development is accelerating, particularly in the field of unmet medical needs. The human experience of CT remains insufficient compared with other classes of pharmaceuticals, while there are countless products for clinical development. Therefore, for many sponsors, understanding the rationale of human application of an investigational product based on the consensus and improving the ability to apply it appropriately for CT are necessary. Thus, defining the level of evidence for safety and efficacy fundamentally required for initiating the clinical development and preparing it using a reliable method for CT. Furthermore, the expertise should be strengthened in the design of the first-in-human trial, such as the starting dose and dose-escalation plan, based on a sufficiently acceptable rationale. Cultivating development professionals with these skills will increase the opportunity for more candidates to enter the clinical development phase.

Pharmacokinetic properties of a new sustained-release pregabalin tablet in subjects with reduced renal function.

A new sustained-release (SR) pregabalin tablet, YHD1119, was formulated for once-daily dosing. In the current study, we aimed to evaluate the pharmacokinetics of YHD1119 tablets in patients with reduced renal function. Subjects were grouped by creatinine clearance: > 60 mL/min/1.73m2 (Cohort A) and 30-60 mL/min/1.73m2 (Cohort B). Eight subjects in Cohort A received a YHD1119 75 mg tablet (Y75T) and a YHD1119 150 mg tablet (Y150T) in each period, and eight subjects in Cohort B received a Y75T. Non-compartment analysis and population pharmacokinetic analysis using a one-compartment model with first-order elimination and first-order absorption with lag time were performed. Sixteen subjects completed the study. The geometric mean ratio (GMR) (90% confidence intervals [CI]) for maximum concentration (Cmax), and area under the concentration-time profile from 0 to the last measurable time (AUClast) after Y75T of Cohort B to those of Y75T of Cohort A were 1.2273 (1.0245-1.4701), and 2.4146 (1.8142-3.2138), respectively. The GMR (90% CI) for Cmax, and AUClast after Y75T of Cohort B to those of Y150T of Cohort A were 0.6476 (0.5229-0.8021), and 1.1471 (0.8418-1.5632), respectively. Simulated steady-steady pregabalin concentrations after once-daily Y75T dosing in subjects with eGFR 45 mL/min/1.73 m2 were within the range of steady-state concentrations simulated after once-daily Y150T dosing in subjects with eGFR 90 mL/min/1.73 m2. The total pregabalin exposure of Y75T in patients with moderate renal impairment was comparable with that of Y150T in subjects with near-normal renal function. Trial Registration: ClinicalTrials.gov Identifier: NCT05012436.

Pharmacokinetic Model Based on Stochastic Simulation and Estimation for Therapeutic Drug Monitoring of Tacrolimus in Korean Adult Transplant Recipients.

BACKGROUND: Tacrolimus shows high variability in inter- and intraindividual pharmacokinetics (PK); therefore, it is important to develop an appropriate model for accurate therapeutic drug monitoring (TDM) procedures. This study aimed to develop a pharmacokinetic model for tacrolimus that can be used for TDM procedures in Korean adult transplant recipients by integrating published models with acquired real-world TDM data and evaluating clinically meaningful covariates. METHODS: Clinical data of 1829 trough blood samples from 269 subjects were merged with simulated data sets from published models and analyzed using a nonlinear mixed-effect model. The stochastic simulation and estimation (SSE) method was used to obtain the final parameter estimates. RESULTS: The final estimated values for apparent clearance, the volume of distribution, and absorption rate were 21.2 L/h, 510 L, and 3.1/h, respectively. The number of postoperative days, age, body weight, and type of transplant organs were the major clinical factors affecting tacrolimus PK. CONCLUSIONS: A tacrolimus PK model that can incorporate published PK models and newly collected data from the Korean population was developed using the SSE method. Despite the limitations in model development owing to the nature of TDM data, the SSE method was useful in retrieving complete information from the TDM data by integrating published PK models while maintaining the variability of the model.

Risk of secondary nonhematologic malignancies after allogeneic stem cell transplantation: A nationwide case-control cohort study.

Our study investigated the incidence of secondary nonhematologic malignancies in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT) and explored its risk compared to the general population. A population-based case cohorts with adult patients who received allo-SCT between January 2002 and December 2018 and a control cohort with matched general population were extracted from the Korean National Health Insurance Service database. Each case and control cohort included 5177 patients. With a median follow-up of 2374 days for the case cohort and 2269 days for the control cohort, the 10-year cumulative incidence rate of nonhematologic malignancy was significantly higher in the case cohort compared to the control cohort (4.23% vs 2.3%, hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.32-2.25, P < .001). The sub-class analysis according to cancer-site revealed significantly higher risks of 10-year cumulative incidence for cancers of head, neck and esophagus (HR 3.19, 95% CI 1.34-7.59, P = .003); cancers involving upper gastrointestinal tract (HR 3.74, 95% CI 1.58-8.85, P < .001), colorectal cancer (HR 2.02, 95% CI 1.04-3.91, P = .029), thyroid cancer (HR 2.09, 95% CI 1.1-3.97, P = .012), gynecological cancer (HR 2.69, 95% CI 1.04-6.96, P = .048) in the case cohort compared to the control cohort. No significant differences were detected for cancers involving lung, mediastinum and heart, breast cancer in female, cancers of the hepatobiliary and pancreatic system and cancers associated with urological system. These findings suggest the need for enhanced screening for nonhematologic malignancies in allo-SCT recipients compared to the general population.

Urinary Profile of Endogenous Gamma-Hydroxybutyric Acid and its Biomarker Metabolites in Healthy Korean Females: Determination of Age-Dependent and Intra-Individual Variability and Identification of Metabolites Correlated With Gamma-Hydroxybutyric Acid.

Gamma-hydroxybutyric acid (GHB), used as a therapeutic and an illegal anesthetic, is a human neurotransmitter produced during gamma-aminobutyric acid (GABA) biosynthesis and metabolism. Potential biomarker metabolites of GHB intoxication have been identified previously; however, reference concentrations have not been set due to the lack of clinical study data. Urinary profiling of endogenous GHB and its biomarker metabolites in urine samples (n = 472) of 206 healthy females was performed based on differences in age and time of sample collection using liquid chromatography-tandem mass spectrometry following validation studies. The unadjusted and creatinine-adjusted urinary concentrations ranges were obtained after urinary profiling. The creatinine-adjusted concentrations of glutamic and succinic acids and succinylcarnitine significantly increased, whereas that of glycolic acid significantly decreased with advancing age. Significant inter-day variation of GABA concentration and intra-day variation of 3,4-dihydroxybutyric acid and succinylcarnitine concentrations were observed. The urinary concentrations of 2,4-dihydroxybutyric acid, succinic acid, and 3,4-dihydroxybutyric acid showed the highest correlation with that of GHB. Data from this study suggest population reference limits to facilitate clinical and forensic decisions related to GHB intoxication and could be useful for identification of biomarkers following comparison with urinary profiles of GHB-administered populations.

DallphinAtoM: Physiologically based pharmacokinetics software predicting human PK parameters based on physicochemical properties, in vitro and animal in vivo data.

BACKGROUND AND OBJECTIVES: In silico experiments and simulations using physiologically based pharmacokinetic (PBPK) and allometric approaches have played an important role in pharmaceutical research and drug development. These methods integrate diverse data from preclinical and clinical development, and have been widely applied to in vitro-in vivo extrapolation (IVIVE) of absorption, distribution, metabolism, and excretion (ADME). METHODS: To develop a user-friendly open tool predicting human PK, we assessed various references on PBPK and allometric methods published so far. They were integrated into a software system named "DallphinAtoM" (Drugs with ALLometry and PHysiology Inside-Animal to huMan), which has a user-friendly platform that can handle complex PBPK models and allometric models with a relatively small amount of essential information of the drug. The models of DallphinAtoM support the integration of data gained during the nonclinical development phase, enable translation from animal to human, and allow the prediction of concentration-time profiles with predicted PK parameters. RESULTS: We presented two illustrative applications using DallphinAtoM: (1) human PK simulation of an orally administered drug using PBPK method; and (2) simulation of intravenous infusion following a two-compartment model using the allometric scaling method. CONCLUSIONS: We conclude that this is a straightforward and transparent tool allowing fast and reliable human PK simulation based on the latest knowledge on biochemical processes and physiology and provides valuable information for decision making during the early-phase drug development.

Metabolic Disease Incidence After Allogeneic Stem Cell Transplantation: A Nationwide Korean Case-Control Study.

CONTEXT: There have been no large-scale reports elucidating the relative risks of developing metabolic diseases in adult allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients compared to the general population. OBJECTIVE: This work aimed to investigate the relative risk of developing metabolic diseases and cerebrovascular or cardiovascular disease (CVA) in allo-HSCT recipients compared to the general population in a real-world setting, using a large Korean cohort under long-term observation. METHODS: We conducted a population-based case-control study and analyzed data of 8230 adult allo-HSCT recipients and 32 920 healthy individuals matched for age, sex, and index date in a 1:4 ratio, using a nationwide database of the Korean National Health Insurance Service. Thereafter, we established 4 substudies to investigate the relative risks of metabolic disease development following allo-HSCT: hypertension (cohort A study), diabetes (cohort B study), dyslipidemia (cohort C study), and CVA (cohort D study). RESULTS: The 10-year cumulative incidence of metabolic disease in each experimental cohort was statistically significantly higher than that in the control cohort (overall P value < .001 for all): cohort A study, 17.6% vs 11.8%; cohort B study, 23.5% vs 14.4%; cohort C study for dyslipidemia, 44.5% vs 32.1%; and cohort D study for CVA, 4.2% vs 3.2%. In comparison to the incidence of metabolic diseases in the general population, allo-HSCT recipients presented adjusted hazard ratios of 1.58 for hypertension, 2.06 for diabetes, 1.62 for dyslipidemia, and 1.45 for CVA. CONCLUSION: Recipients of allo-HSCT need to be rigorously monitored for the development of metabolic diseases, including hypertension, diabetes, dyslipidemia, and CVA, based on an enhanced lifelong health care policy including a robust screening program compared to the general population.

An experience on the model-based evaluation of pharmacokinetic drug-drug interaction for a long half-life drug.

Fixed-dose combinations development requires pharmacokinetic drugdrug interaction (DDI) studies between active ingredients. For some drugs, pharmacokinetic properties such as long half-life or delayed distribution, make it difficult to conduct such clinical trials and to estimate the exact magnitude of DDI. In this study, the conventional (non-compartmental analysis and bioequivalence [BE]) and modelbased analyses were compared for their performance to evaluate DDI using amlodipine as an example. Raw data without DDI or simulated data using pharmacokinetic models were compared to the data obtained after concomitant administration. Regardless of the methodology, all the results fell within the classical BE limit. It was shown that the model-based approach may be valid as the conventional approach and reduce the possibility of DDI overestimation. Several advantages (i.e., quantitative changes in parameters and precision of confidence interval) of the model-based approach were demonstrated, and possible application methods were proposed. Therefore, it is expected that the model-based analysis is appropriately utilized according to the situation and purpose.

Association between Dementia and Clinical Outcome after COVID-19: A Nationwide Cohort Study with Propensity Score Matched Control in South Korea.

OBJECTIVE: Despite a high prevalence of dementia in older adults hospitalized with severe acute respiratory syndrome coronavirus 2 infection (SARS-CoV-2), or so called COVID-19, research investigating association between preexisting diagnoses of dementia and prognosis of COVID-19 is scarce. We aimed to investigate treatment outcome of patients with dementia after COVID-19. METHODS: We explored a nationwide cohort with a total of 2,800 subjects older than 50 years who were diagnosed with COVID-19 between January and April 2020. Among them, 223 patients had underlying dementia (dementia group). We matched 1:1 for each dementia- non-dementia group pair yielding 223 patients without dementia (no dementia group) using propensity score matching. RESULTS: Mortality rate after COVID-19 was higher in dementia group than in no dementia group (33.6% vs. 20.2%, p=0.002). Dementia group had higher proportion of patients requiring invasive ventilatory support than no dementia group (34.1% vs. 22.0%, p=0.006). Multivariable analysis showed that dementia group had a higher risk of mortality than no dementia group (odds ratio=3.05, p<0.001). We also found that patients in dementia group had a higher risk of needing invasive ventilatory support than those in no dementia group. CONCLUSION: Our results suggest that system including strengthen quarantines are required for patients with dementia during the COVID- 19 pandemic.

Pre-transplant Dementia is Associated with Poor Survival After Hematopoietic Stem Cell Transplantation: A Nationwide Cohort Study with Propensity Score Matched Control.

OBJECTIVE: No previous study examined impact of dementia in the outcome of allogeneic hematopoietic stem cell transplantation (HSCT). We aimed to investigate overall survival (OS) of patients with dementia after receiving HSCT. METHODS: Among 8,230 patients who underwent HSCT between 2002 and 2018, 5,533 patients younger than 50 years were first excluded. Remaining patients were divided into those who were and were not diagnosed with dementia before HSCT (dementia group: n = 31; no dementia: n = 2,666). Thereafter, among 2,666 participants without dementia, 93 patients were selected via propensity-matched score as non-dementia group. Patients were followed from the day they received HSCT to the occurrence of death or the last follow-up day (December 31, 2018), whichever came first. RESULTS: With median follow-up of 621 days for dementia group and 654 days for non-dementia group, 2 year-OS of dementia group was lower than that of non-dementia group (53.3% [95% confidence interval, 95% CI, 59.0-80.2%] vs. 68.8% [95% CI, 38.0-68.2%], p = 0.076). In multivariate analysis, dementia had significant impacts on OS (hazard risk = 2.539, 95% CI, 1.166-4.771, p = 0.017). CONCLUSION: Our results indicated that patients diagnosed with dementia before HSCT have 2.539 times higher risk of mortality after transplantation than those not having dementia. With number of elderly needing HSCT is increasing, further work to establish treatment guidelines for the management of HSCT in people with dementia is needed.

Printable Nanocomposite Metalens for High-Contrast Near-Infrared Imaging.

Printable metalenses composed of a silicon nanocomposite are developed to overcome the manufacturing limitations of conventional metalenses. The nanocomposite is synthesized by dispersing silicon nanoparticles in a thermally printable resin, which not only achieves a high refractive index for high-efficiency metalenses but also printing compatibility for inexpensive manufacturing of metalenses. The synthesized nanocomposite exhibits high refractive index >2.2 in the near-infrared regime, and only 10% uniform volume shrinkage after thermal annealing, so the nanocomposite is appropriate for elaborate nanofabrication compared to commercial high-index printable materials. A 4 mm-diameter metalens operating at the wavelength of 940 nm is fabricated using the nanocomposite and one-step printing without any secondary operations. The fabricated metalens verifies a high focusing efficiency of 47%, which can be further increased by optimizing the composition of the nanocomposite. The printing mold is reusable, so the large-scale metalenses can be printed rapidly and repeatedly. A compact near-infrared camera combined with the nanocomposite metalens is also demonstrated, and an image of the veins underneath human skin is captured to confirm the applicability of the nanocomposite metalens for biomedical imaging.

Pre-transplant depression decreased overall survival of patients receiving allogeneic hematopoietic stem cell transplantation: a nationwide cohort study.

Studies investigating association of depression with overall survival (OS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) yielded conflicting results. A nationwide cohort study, which included all adult patients [n = 7,170; depression group, 13.3% (N = 956); non-depression group, 86.7% (N = 6,214)] who received allo-HSCT from 2002 to 2018 in South Korea, analyzed risk of pre-transplant depression in OS of allo-HSCT. Subjects were followed from the day they received allo-HSCT, to occurrence of death, or last follow-up day (December 31, 2018). Median age at allo-HSCT for depression and non-depression groups were 50 and 45 (p < 0.0001), respectively. Two groups also differed in rate of females (depression group, 55.8%; non-depression group, 43.8%; p < 0.0001) and leukemia (depression group, 61.4%; non-depression group, 49.7%; p < 0.0001). After a median follow-up of 29.1 months, 5-year OS rate was 63.1%. Cox proportional-hazard regression evaluated an adjusted risk of post-transplant mortality related to depression: OS decreased sequentially from no depression (adjusted hazard ratio [aHR] = 1) to pre-transplant depression only (aHR = 1.167, CI: 1.007-1.352, p = 0.04), and to having both depression and anxiety disorder (aHR = 1.202, CI: 1.038-1.393, p = 0.014) groups. Pre-transplant anxiety (anxiety only) did not have significant influence in OS. Additional medical and psychiatric care might be necessary in patients who experienced depression, especially with anxiety, before allo-HSCT.

A partial imputation EM-algorithm to adjust the overestimated shape parameter of the Weibull distribution fitted to the clinical time-to-event data.

BACKGROUND AND OBJECTIVES: Typical clinical data can suffer routine information loss when event times are rounded to the nearest day and right-censored at the end of follow-up. Because of the daily basis recording system, for the first 24 h, there are no events, which can damage the estimation of the Weibull survival model. Its estimation bias is inevitable since, for this short period, massive events might have occurred, the data is missing, and the fitted Weibull model is to show a steep slope. This phenomenon of estimation bias caused by the information loss caused by the problem of measurement resolution has not been properly discussed so far. METHODS: We propose a partial imputation Expectation Maximization (PIEM)-algorithm to estimate missing lifetimes only for day 1 at the mode among the whole clinical follow-up days. Based on various Weibull distributions, we simulated clinical sets after rounding and censoring raw event times and prepared chimera sets by partially substituting the imputed lifetimes only for the 24 h at the mode among the entire clinical sets. RESULTS: For shape parameter ≤ 1, almost all the 95% prediction intervals (PIs) of both parameters in the chimera sets include their true values, while those in the clinical sets miss most of the true shape parameters and some of the true scale parameters. Estimating a small proportion of missing data only for the 24 h period, while keeping the rest as they are, greatly reduces biases of both scale and shape parameters. For shape parameter >1, the chimera sets consistently outperform the clinical sets. CONCLUSIONS: The PIEM-algorithm may be applied as an intuitive tool for time-to-event modeling of survival data with this kind of information loss.