Delgocitinib ointment in pediatric patients with atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and a subsequent open-label, long-term study.

BACKGROUND: Delgocitinib 0.5% ointment, a topical Janus kinase inhibitor, has been approved in Japan for adult patients with atopic dermatitis (AD). OBJECTIVE: To evaluate the efficacy and safety of delgocitinib ointment in pediatric patients with AD. METHODS: Part 1 of this study was a 4-week double-blind period in which Japanese patients aged 2 through 15 years were randomized in a 1:1 ratio to delgocitinib 0.25% ointment or vehicle ointment. Part 2 was a 52-week extension period. Eligible patients entered part 2 to receive 0.25% or 0.5% delgocitinib ointment. RESULTS: At the initiation of the study, approximately half of the patients had moderate AD. At the end of treatment in part 1, the least-squares mean percent change from baseline in modified Eczema Area and Severity Index score, the primary efficacy endpoint, was significantly greater for delgocitinib ointment than for vehicle (-39.3% vs +10.9%, P < .001). In part 2, improvements in AD were also seen through week 56. Most adverse events were mild and unrelated to delgocitinib across the study periods. LIMITATIONS: Only Japanese patients were included. In part 2, no control group was included and rescue therapy was allowed. CONCLUSION: Delgocitinib ointment was effective and well tolerated when applied to Japanese pediatric patients with AD for up to 56 weeks.

Efficacy of combined bland embolization and chemoembolization for huge (≥10 cm) hepatocellular carcinoma.

INTRODUCTION: To assess the efficacy of combined therapy involving bland transarterial embolization using gelatin sponge particles (bland GS-TAE) followed by transarterial chemoembolization using lipiodol mixed with anticancer agents and GS particles (Lip-TACE) to reduce the adverse events and increase the therapeutic effect of Lip-TACE in the treatment of huge (≥10 cm) hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Twenty-one consecutive patients with huge HCCs (≥10 cm in diameter) were enrolled in this study. First, bland GS-TAE was performed to reduce the tumor volume, and then Lip-TACE was performed to control the remaining tumor at intervals of around three weeks. Tumor response, survival, and adverse events of this combined therapy were assessed. RESULTS: The tumor response was assessed three months after combined TACE, with complete response in 38.1% and partial response in 57.1% of cases. Severe adverse events were seen in two patients, acute cholecystitis and tumor rupture. The median survival time was 2.7 years, and the one-, two-, three-, and five-year overall survival rates were 76.2%, 66.7%, 42.9%, and 25.0%, respectively. CONCLUSION: Combined therapy involving bland GS-TAE followed by Lip-TACE can be performed safety and may improve survival in patients with huge HCCs.

Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study.

BACKGROUND: Previous studies showed the potential effectiveness of delgocitinib ointment, a novel topical Janus kinase inhibitor, in atopic dermatitis (AD). OBJECTIVE: This study aimed to evaluate the efficacy and safety of delgocitinib 0.5% ointment. METHODS: In part 1, a 4-week double-blind period, Japanese patients aged 16 years or older with moderate or severe AD were randomly assigned in a 2:1 ratio to delgocitinib 0.5% ointment or vehicle ointment. Eligible patients entered part 2, a 24-week extension period, to receive delgocitinib 0.5% ointment. RESULTS: At the end of treatment in part 1, the least-squares mean percent changes from baseline in the modified Eczema Area and Severity Index score, the primary efficacy endpoint, were significantly greater in the delgocitinib group than in the vehicle group (-44.3% vs 1.7%, P < .001). The improvement in modified Eczema Area and Severity Index score was maintained in part 2. Most adverse events were mild and unrelated to delgocitinib across the study periods. LIMITATIONS: Only Japanese patients were included. The vehicle-controlled period lasted only 4 weeks. In part 2, topical corticosteroids were allowed for the treatment of worsening of AD. CONCLUSION: Delgocitinib ointment was effective and well tolerated in Japanese adult patients with moderate to severe AD for up to 28 weeks.

Phase 2 clinical study of delgocitinib ointment in pediatric patients with atopic dermatitis.

BACKGROUND: Topical delgocitinib (JTE-052), a novel Janus kinase inhibitor, had been shown to be clinically effective in adults with atopic dermatitis (AD). However, the efficacy of topical delgocitinib in pediatric patients with AD remained unclear. OBJECTIVE: We sought to evaluate the efficacy and safety of delgocitinib ointment in pediatric patients with AD. METHODS: In this phase 2 clinical study (JapicCTI-173553) Japanese patients aged 2 through 15 years with AD were randomized in a 1:1:1 ratio to receive 0.25% or 0.5% delgocitinib ointment or vehicle ointment twice daily for 4 weeks. The primary efficacy end point was the percentage change from baseline in the modified Eczema Area and Severity Index score at the end of treatment (EOT). RESULTS: At EOT, modified Eczema Area and Severity Index scores in both delgocitinib groups were significantly reduced compared with that in the vehicle group. The least-squares mean percentage change from baseline was -54.2% in the 0.25% group and -61.8% in the 0.5% group versus -4.8% in the vehicle group (P < .001 for both comparisons). Similarly, all other efficacy parameters, including Investigator's Global Assessment and pruritus scores, in both delgocitinib groups were significantly improved compared with those in the vehicle group at EOT. Adverse events in both delgocitinib groups were mild in severity, and no serious adverse events were reported. CONCLUSIONS: Delgocitinib ointment improved clinical signs and symptoms in pediatric patients with AD and was well tolerated. These study results indicate that delgocitinib ointment can be a promising therapeutic option for pediatric patients with AD.

Three-dimensional analyses of aging-induced alterations in facial shape: a longitudinal study of 171 Japanese males.

We sought to generate data to facilitate forensic facial comparisons. Specifically, we conducted a longitudinal study of alterations in face shape induced by aging. We obtained two three-dimensional facial shape measurements in 171 Japanese males at intervals of approximately 10 years. With this data, we created a homologous model consisting of 10,741 data points for each face based on 33 anatomical landmarks. We averaged the movements of corresponding data points between the two homologous models for each individual and used this data to predict up to 30 years of face aging in an average Japanese male. We clearly identified aging-induced shape changes, such as drooping and denting of the facial folds, drooping of the upper lip, and projection of the lower eyelid, in the virtually aged model. A quantitative comparison of aging-induced shape alterations among three age groups (individuals in their 20's, 30's, and 40-50's) showed that these alterations accelerated more quickly as age increased. Using our predictive model, we conducted a preliminary study focused on facial shape alterations induced by reductions in body weight. Our findings indicated that our proposed method would also be valid for this purpose.

Complete and partial spontaneous regression of metastases of lung cancer in a patient: Serial CT and 18F-fluodeoxyglucose PET/CT findings.

Spontaneous regression of cancer is a rare biological phenomenon and the mechanisms underlying it are poorly understood. There have been few reports of temporal changes in morphology and metabolism associated with spontaneous regression. Here, we report an 80-year-old man who presented with right upper quadrant pain. He was diagnosed with stage IVA lung cancer, but without treatment, rib metastasis disappeared 4 months after the diagnosis. Although mediastinal lymph node metastasis regressed partially it began to grow 10 months after the diagnosis. In this case, complete and partial spontaneous tumor regressions were observed in the patient, allowing for a comparison of morphological and metabolic changes during each occurrence by serial computed tomography (CT) and 18F-fluodeoxyglucose positron emission tomography with computed tomography (FDG-PET/CT). We observed that the rib metastasis with high FDG uptake on initial PET/CT was composed of cancer cells as well as intratumoral immune cells, whereas recurrent mediastinal lymph node metastasis with high FDG uptake on follow-up PET/CT was composed of cancer cells with few immune cells. Our findings suggest that hypermetabolism within the rib metastasis on initial PET/CT reflected immune activation, whereas hypermetabolism within the mediastinal lymph node on follow-up PET/CT reflected tumor activation.

Analytic second derivatives of the energy in the fragment molecular orbital method.

We developed the analytic second derivatives of the energy for the fragment molecular orbital (FMO) method. First we derived the analytic expressions and then introduced some approximations related to the first and second order coupled perturbed Hartree-Fock equations. We developed a parallel program for the FMO Hessian with approximations in GAMESS and used it to calculate infrared (IR) spectra and Gibbs free energies and to locate the transition states in SN2 reactions. The accuracy of the Hessian is demonstrated in comparison to ab initio results for polypeptides and a water cluster. By using the two residues per fragment division, we achieved the accuracy of 3 cm(-1) in the reduced mean square deviation of vibrational frequencies from ab initio for all three polyalanine isomers, while the zero point energy had the error not exceeding 0.3 kcal/mol. The role of the secondary structure on IR spectra, zero point energies, and Gibbs free energies is discussed.

Free hemiback flap with surgical delay for reconstruction of extensive soft tissue defect: a case report.

A delay procedure allows for reliable tissue transfer in random pattern flaps and axial pattern flaps. However, delay procedures have not been studied in free flaps. In this report, we present a case involving the use of a free extended latissimus dorsi musculocutaneous flap (hemiback flap) that included half of the total back skin and was based on thoracodorsal vessels for reconstruction of an extensive soft tissue defect of the flank and waist. The flap was tailored in combination with a delay procedure. Intraoperative indocyanine green fluorescence angiography indicated profuse perfusion except for the most inferomedial part of the flap, which was discarded. The flap survived. A free hemiback flap may offer a valuable option for reconstruction of extensive soft tissue defects. To our knowledge, this is the first report to demonstrate a free flap made in combination with a delay procedure.

Delayed distally based sural flap with temporary venous supercharging.

The distally based sural flap has become popular for reconstruction of the foot and leg. However, this flap often fails due to venous congestion. In this report, we developed a new modification of the distally based sural flap. The procedure comprised three stages. In the first stage, the flap was raised cephalad to the midpoint of the posterior aspect of the leg, involving reanastomosis of the short saphenous vein (SSV) at the proximal end of the flap. In the second stage, ligature of the SSV was performed. In the third stage, the entire flap was raised. We treated eight patients with the flap. All flaps survived completely. Duplex scanning indicated that venous drainage of the flap was provided by the tenuous venae comitantes (VCs) surrounding the SSV. Reanastomosis of the SSV may prevent rapid venous overloading of the VCs. Our new modification may be useful to avoid venous congestion.

Reading man flap: application to plantar defects.

The plantar surface of the foot has highly specialized, densely adherent, glabrous skin, making functional replacement difficult. Glabrous skin defects should be replaced with similar skin to restore function and aesthetics. An innovative technique, the "reading man flap," was developed for closure of circular skin defects. At locations such as the face, trunk, thigh, and calf, the "reading man" procedure provides tension-free closure with minimal additional healthy skin excision, and it does not cause "dog ear" formation. The potential exists for replacement of plantar defects with skin of the same quality using this procedure. In the present study, we report on 2 clinical cases in which intermediate-size plantar defects were reconstructed using the reading man flap. This method can provide tissue as durable, yet as sensitive, as skin that matches the unique characteristics of the plantar skin.

Development of a novel artificial intelligence algorithm to detect pulmonary nodules on chest radiography.

BACKGROUND: In this study, we aimed to develop a novel artificial intelligence (AI) algorithm to support pulmonary nodule detection, which will enable physicians to efficiently interpret chest radiographs for lung cancer diagnosis. METHODS: We analyzed chest X-ray images obtained from a health examination center in Fukushima and the National Institutes of Health (NIH) Chest X-ray 14 dataset. We categorized these data into two types: type A included both Fukushima and NIH datasets, and type B included only the Fukushima dataset. We also demonstrated pulmonary nodules in the form of a heatmap display on each chest radiograph and calculated the positive probability score as an index value. RESULTS: Our novel AI algorithms had a receiver operating characteristic (ROC) area under the curve (AUC) of 0.74, a sensitivity of 0.75, and a specificity of 0.60 for the type A dataset. For the type B dataset, the respective values were 0.79, 0.72, and 0.74. The algorithms in both the type A and B datasets were superior to the accuracy of radiologists and similar to previous studies. CONCLUSIONS: The proprietary AI algorithms had a similar accuracy for interpreting chest radiographs when compared with previous studies and radiologists. Especially, we could train a high quality AI algorithm, even with our small type B data set. However, further studies are needed to improve and further validate the accuracy of our AI algorithm.

Exploring chemistry with the fragment molecular orbital method.

The fragment molecular orbital (FMO) method makes possible nearly linear scaling calculations of large molecular systems, such as water clusters, proteins and DNA. In particular, FMO has been widely used in biochemical applications involving protein-ligand binding and drug design. The method has been efficiently parallelized suitable for petascale computing. Many commonly used wave functions and solvent models have been interfaced with FMO. We review the historical background of FMO, and summarize its method development and applications.

Analysis of solute-solvent interactions in the fragment molecular orbital method interfaced with effective fragment potentials: theory and application to a solvated griffithsin-carbohydrate complex.

Based on the proposed new expression of the polarization energy for the fragment molecular orbital (FMO) method interfaced with effective fragment potentials (EFPs), we develop an analysis of the solute(FMO)-solvent(EFP) interactions by defining individual fragment contributions for both solute and solvent. The obtained components are compared to all-electron calculations where water is treated as FMO fragments in the pair interaction energy decomposition analysis. The new energy expression is shown to be accurate, and the developed energy analysis is applied to the solvated griffithsin-carbohydrate complex. The details of the ligand recognition are revealed in the context with their interplay with the solvent effects. Tyr residue fragments are shown to reduce the desolvation penalty for Asp, which strongly binds the ligand.

Analytic gradient for second order Møller-Plesset perturbation theory with the polarizable continuum model based on the fragment molecular orbital method.

A new energy expression is proposed for the fragment molecular orbital method interfaced with the polarizable continuum model (FMO/PCM). The solvation free energy is shown to be more accurate on a set of representative polypeptides with neutral and charged residues, in comparison to the original formulation at the same level of the many-body expansion of the electrostatic potential determining the apparent surface charges. The analytic first derivative of the energy with respect to nuclear coordinates is formulated at the second-order Møller-Plesset (MP2) perturbation theory level combined with PCM, for which we derived coupled perturbed Hartree-Fock equations. The accuracy of the analytic gradient is demonstrated on test calculations in comparison to numeric gradient. Geometry optimization of the small Trp-cage protein (PDB: 1L2Y) is performed with FMO/PCM/6-31(+)G(d) at the MP2 and restricted Hartree-Fock with empirical dispersion (RHF/D). The root mean square deviations between the FMO optimized and NMR experimental structure are found to be 0.414 and 0.426 Å for RHF/D and MP2, respectively. The details of the hydrogen bond network in the Trp-cage protein are revealed.

Unrestricted Hartree-Fock based on the fragment molecular orbital method: energy and its analytic gradient.

A consideration of the surrounding environment is necessary for a meaningful analysis of the reaction activity in large molecular systems. We propose an approach to perform unrestricted Hartree-Fock (UHF) calculations within the framework of the fragment molecular orbital (FMO) method (FMO-UHF) to study large systems with unpaired electrons. Prior to an energy analysis one has to optimize geometry, which requires an accurate analytic energy gradient. We derive the FMO-UHF energy and its analytic gradient and implement them into GAMESS. The performance of FMO-UHF is evaluated for a solvated organic molecule and a solvated metal complex, as well as for the active part of a protein, in terms of energy, gradient, and geometry optimization.

Hemiforehead flap for reconstruction of composite facial defects.

Composite defects overlap 2 or more facial units. It is difficult to reconstruct composite defects with adequate shape, color, and texture. Because it is non-hair bearing, is relatively thin, and has a color and texture similar to that of the rest of the face, the skin of the forehead possesses excellent characteristics for nasal reconstruction and repair of other facial areas. The authors developed an extended thin forehead flap (hemiforehead flap) that includes half of the total forehead skin and is based on supratrochlear vessels. In the patient reported here, a hemiforehead flap was used to reconstruct composite defects of the lower lid, cheek, nose, and upper lip. Acceptable aesthetic and functional results were achieved. This flap may serve as an alternative for reconstruction of composite facial defects.

Long-Term Habitual Exercise and Combination of ß-Hydroxy-ß-Methylbutyrate plus Black Ginger Alter the Autophagy and Mitochondria Related Genes in SAMP8 Mice.

Muscle mass and strength decrease with aging; however, habitual exercise can maintain muscle health. ß-Hydroxy-ß-methyl butyrate calcium (HMB) and black ginger (BG) improve muscle protein metabolism and energy production. Combining these two molecules, which have similar effects, may have a synergistic effect. Senescence-accelerated mouse-prone 8 (SAMP8) is a useful model of muscle aging. Therefore, we explored how the combination of habitual exercise, HMB, and BG affected muscle aging. We used 28-wk-old (28w) SAMP8 mice divided into six groups: 28 wk (28w), 44 wk (44w, Con), exercise (Ex), Ex+BG, Ex+HMB, and Ex+BG+HMB (Ex+Comb). Mice were required to run on a treadmill for 16 wk for 5 d per week. In 28w and 44w mice, grip strength tests and dissection were conducted. Muscle weight was measured, and qPCR and immunoblotting were conducted. Muscle mass and strength were declined in the 44w group. Exercise with HMB or BG alone had no effect, whereas muscle mass and strength were augmented in the Ex+Comb group. Similarly, levels of mitochondrial function- and biogenesis-related genes were increased. Autophagy-related protein (Atg3, 7, 16L1 and Beclin1) were altered in the Ex+Comb group. These results suggest that Ex+Comb affects autophagy. Overall, the combination of habitual exercise and HMB+BG may enhance muscle mass and strength by affecting the mitochondrial and autophagy systems in SAMP8.

Analytic energy gradient for second-order Møller-Plesset perturbation theory based on the fragment molecular orbital method.

The first derivative of the total energy with respect to nuclear coordinates (the energy gradient) in the fragment molecular orbital (FMO) method is applied to second order Møller-Plesset perturbation theory (MP2), resulting in the analytic derivative of the correlation energy in the external self-consistent electrostatic field. The completely analytic energy gradient equations are formulated at the FMO-MP2 level. Both for molecular clusters (H(2)O)(64) and a system with fragmentation across covalent bonds, a capped alanine decamer, the analytic FMO-MP2 energy gradients with the electrostatic dimer approximation are shown to be complete and accurate by comparing them with the corresponding numeric gradients. The developed gradient is parallelized with the parallel efficiency of about 97% on 32 Pentium4 nodes connected by Gigabit Ethernet.

A combined effective fragment potential-fragment molecular orbital method. II. Analytic gradient and application to the geometry optimization of solvated tetraglycine and chignolin.

The gradient for the fragment molecular orbital (FMO) method interfaced with effective fragment potentials (EFP), denoted by FMO∕EFP, was developed and applied to polypeptides solvated in water. The structures of neutral and zwitterionic tetraglycine immersed in water layers of 2.0, 2.5, 3.0, 3.5, 4.0, and 4.5 Å are investigated by performing FMO∕EFP geometry optimizations at the RHF∕cc-pVDZ level of theory for the solutes. The geometries optimized with FMO-RHF∕EFP are compared to those from the conventional RHF∕EFP and are found to be in very close agreement. Using the optimized geometries, the stability of the hydrated zwitterionic and neutral structures is discussed structurally and in terms of energetics at the second-order Møller-Plesset theory (MP2)∕cc-pVDZ level. To demonstrate the potential of the method for proteins, the geometry of hydrated chignolin (protein data bank ID: 1UAO) was optimized, and the importance of the inclusion of water was examined by comparing the solvated and gas phase structures of chignolin with the experimental NMR structure.