Pelvic shape change in adult Japanese macaques and implications for childbirth at old age.

Pelvic morphology exhibits a particular sexual dimorphism in humans, which reflects obstetrical constraints due to the tight fit between neonates and mothers. Huseynov et al. [Proc. Natl. Acad. Sci. U.S.A. 113, 5227-5232 (2016)] showed that in humans, pelvic sexual dimorphism is greatest around the age of highest fertility, and it becomes less marked in association with menopause in females. They proposed that this reflects changes of obstetrical versus locomotor functional demands in females. It remains unknown whether such developmental adjustment of the pelvic morphology is unique to humans. Macaques exhibit human-like cephalopelvic proportions, but they lack menopause and usually maintain fertility throughout adulthood. Here, we track pelvic development in Japanese macaques from neonate to advanced ages using computed tomography-based data. We show that female pelvic morphology changes throughout adult life, reaching the obstetrically most favorable shape at advanced ages rather than around primiparity. We hypothesize that pelvic morphology in Japanese macaques is developmentally adjusted to childbirth at advanced ages, where obstetrical risks are potentially higher than at younger ages. Our data contribute to the growing evidence that the female primate pelvis changes its morphology during the whole lifespan, possibly adjusting for changing functional demands during adulthood.

Human shoulder development is adapted to obstetrical constraints.

In humans, obstetrical difficulties arise from the large head and broad shoulders of the neonate relative to the maternal birth canal. Various characteristics of human cranial development, such as the relatively small head of neonates compared with adults and the delayed fusion of the metopic suture, have been suggested to reflect developmental adaptations to obstetrical constraints. On the other hand, it remains unknown whether the shoulders of humans also exhibit developmental features reflecting obstetrical adaptation. Here we address this question by tracking the development of shoulder width from fetal to adult stages in humans, chimpanzees, and Japanese macaques. Compared with nonhuman primates, shoulder development in humans follows a different trajectory, exhibiting reduced growth relative to trunk length before birth and enhanced growth after birth. This indicates that the perinatal developmental characteristics of the shoulders likely evolved to ease obstetrical difficulties such as shoulder dystocia in humans.

Ramucirumab for advanced hepatocellular carcinoma in the current real world: a Japanese single-arm study post-REACH-2 (The R-evolution study).

This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study.

Sella turcica and facial bones: Morphological integration in the human fetal cranium.

OBJECTIVES: The cranial base plays a significant role in facial growth, and closer analyses of the morphological relationship between these two regions are needed to understand the morphogenesis of the face. Here, we aimed to study morphological integration between the sella turcica (ST) and facial bones during the fetal period using geometric morphometrics. MATERIALS AND METHODS: Magnetic resonance images of 47 human fetuses in the Kyoto Collection, with crown-rump lengths of 29.8-225 mm, were included in this study. Anatomical homologous landmarks and semilandmarks were registered on the facial bones and the midsagittal contour of the ST, respectively. The shape variations in the craniofacial skeleton and the ST were statistically investigated by reducing dimensionality using principal component analysis (PCA). Subsequently, the morphological integration between the facial bones and ST was investigated using two-block partial least squares (2B-PLS) analysis. RESULTS: PCA showed that small specimens represented the concave facial profile, including the mandibular protrusion and maxillary retrusion. The 2B-PLS showed a strong integration (RV coefficient = 0.523, r = .79, p < .01) between the facial bones and ST. The curvature of the anterior wall of the ST was highly associated with immature facial morphology characterized by a concave profile. CONCLUSION: The strong integration between the two regions suggested that the anterior ST may be associated with facial morphology. This result quantitatively confirms previous studies reporting ST deformities in facial anomalies and induces further research using postnatal subjects.

Reassessment of the phylogenetic relationships of the late Miocene apes Hispanopithecus and Rudapithecus based on vestibular morphology.

Late Miocene great apes are key to reconstructing the ancestral morphotype from which earliest hominins evolved. Despite consensus that the late Miocene dryopith great apes Hispanopithecus laietanus (Spain) and Rudapithecus hungaricus (Hungary) are closely related (Hominidae), ongoing debate on their phylogenetic relationships with extant apes (stem hominids, hominines, or pongines) complicates our understanding of great ape and human evolution. To clarify this question, we rely on the morphology of the inner ear semicircular canals, which has been shown to be phylogenetically informative. Based on microcomputed tomography scans, we describe the vestibular morphology of Hispanopithecus and Rudapithecus, and compare them with extant hominoids using landmark-free deformation-based three-dimensional geometric morphometric analyses. We also provide critical evidence about the evolutionary patterns of the vestibular apparatus in living and fossil hominoids under different phylogenetic assumptions for dryopiths. Our results are consistent with the distinction of Rudapithecus and Hispanopithecus at the genus rank, and further support their allocation to the Hominidae based on their derived semicircular canal volumetric proportions. Compared with extant hominids, the vestibular morphology of Hispanopithecus and Rudapithecus most closely resembles that of African apes, and differs from the derived condition of orangutans. However, the vestibular morphologies reconstructed for the last common ancestors of dryopiths, crown hominines, and crown hominids are very similar, indicating that hominines are plesiomorphic in this regard. Therefore, our results do not conclusively favor a hominine or stem hominid status for the investigated dryopiths.

Multivariate Analysis of Risk Factors for Complications in Pediatric Tissue Expansion.

BACKGROUND: Tissue expanders represent one of the main surgical options for skin reconstruction in cases of tumors, traumalike burn injury, scar contracture, and alopecia. However, the tissue expander device is also associated with complications such as infection and extrusion. The aim of this study was to analyze risk factors for major complications of use of tissue expanders in pediatric patients using multivariate analysis. METHODS: A retrospective, single-center observational study was performed over 10 years in pediatric patients who were treated with tissue expanders for tumors, nevus, scars, burn reconstruction, and alopecia from April 2012 to March 2022. The primary outcome was overall complications per operation and expander, including infection and extrusion. Ten predictor variables were included as risk factors based on previous studies and as new factors considered important from clinical experience. Univariate and multivariate logistic regression analyses were performed to identify risk factors for major complications such as expander infection or extrusion. RESULTS: The study included 44 patients who underwent 92 operations using 238 tissue expanders. The overall complication rate per expander was 14.3%. Univariate logistic regression analysis identified associations of younger age, number of expanders used per operation, history of infection, and tissue expander locations with a higher complication rate. In multivariate logistic regression analysis, younger age (odds ratio, 1.14; P = 0.043) was associated with a high likelihood of expander complications. CONCLUSIONS: Younger age is an independent risk factor for tissue expander complications in pediatric patients. This factor should be considered in preoperative planning and discussions with the patient's family.

Covariation of fetal skull and maternal pelvis during the perinatal period in rhesus macaques and evolution of childbirth in primates.

A large brain combined with an upright posture in humans has resulted in a high cephalopelvic proportion and frequently obstructed labor. Fischer and Mitteroecker [B. Fischer, P. Mitteroecker, Proc. Natl. Acad. Sci. U.S.A. 112, 5655-5660 (2015)] proposed that the morphological covariations between the skull and pelvis could have evolved to ameliorate obstructed labor in humans. The availability of quantitative data of such covariation, especially of the fetal skull and maternal pelvis, however, is still scarce. Here, we present direct evidence of morphological covariations between the skull and pelvis using actual mother-fetus dyads during the perinatal period of Macaca mulatta, a species that exhibits cephalopelvic proportions comparable to modern humans. We analyzed the covariation of the three-dimensional morphology of the fetal skull and maternal pelvis using computed tomography-based models. The covariation was mostly observed at the pelvic locations related to the birth canal, and the forms of the birth canal and fetal skull covary in such a way that reduces obstetric difficulties. Therefore, cephalopelvic covariation could have evolved not only in humans, but also in other primate taxa in parallel, or it could have evolved already in the early catarrhines.

Establishment of a keratinocyte and fibroblast bank for clinical applications in Japan.

Regenerative medicine products using allogeneic cells, such as allogeneic cultured epidermis (allo-CE), have become a more critical therapeutic method for the treatment of burns. However, there are no clinically available allo-CE products in Japan. Therefore, establishing a quality-controlled cell bank is mandatory to create regenerative medical products using allogeneic cells. In this study, we selected ten patients from the Department of Plastic Surgery of Kyoto University Hospital to become cell donors. We performed medical interviews and blood sampling for the donor to ensure virus safety. We examined the tissues and isolated cells by performing a nucleic acid test (NAT). To establish a master cell bank, quality evaluation was performed according to the International Conference of Harmonization (ICH) Q5A. Serological tests of the blood samples from the ten donors showed that two of them were ineligible. The cells registered in the cell bank were found to be compatible after virus testing was performed, and a master cell bank was constructed. Hence, we established a keratinocyte and fibroblast bank of clinically usable human cultured cells in Japan for the first time.

Characteristics and distribution of chronic pain after mastectomy and breast reconstruction: a long-term prospective cohort study.

PURPOSE: Chronic pain following breast surgery is a concern for breast cancer survivors; however, few studies have investigated the localization of persistent postoperative pain. We conducted this study to identify the location of pain following breast reconstruction. METHODS: A total of 213 Japanese women undergoing mastectomy only or breast reconstruction with a tissue expander/implant (TE/Imp) or a deep inferior epigastric perforator (DIEP) flap were enrolled in the study. Questionnaires related to pain location were sent to patients at the end of postoperative year (POY) 1 and POY 5. Multiple comparisons of the types of operation and cross-tabulation were made between the two time points. RESULTS: Surveys were completed by 107 of the women. Severe pain in the upper medial breast was significantly more common in POY 1 after DIEP reconstruction than after mastectomy only (P = 0.01), whereas abdominal pain was worse in POY 5 after DIEP reconstruction than after mastectomy only (P = 0.04). Pain in the medial arm and axilla had resolved better after TE/Imp (P = 0.03) and DIEP reconstruction (P = 0.01) than after mastectomy only by POY 5, but the difference between TE/Imp and DIEP reconstruction was not significant. CONCLUSIONS: These results show that localization of prolonged postoperative pain following breast reconstruction differs depending on the surgical strategy.

Patient-Reported Outcomes After Autologous Fat Grafting in Prosthetic Breast Reconstruction: Prospective Cohort Study Using a Multivariate Analysis.

INTRODUCTION: There is widespread recognition of the importance of assessment of patient satisfaction and well-being after breast reconstruction. However, few studies of fat grafting performed simultaneously with implant-based breast reconstruction (IBBR) have accounted for confounding factors, such as patient background and information bias. The aim of this study was to examine patient satisfaction and well-being using multivariate analysis of BREAST-Q scores in patients treated with IBBR combined with fat grafting. METHODS: Seventy-one consecutive patients who underwent IBBR with silicone breast implants were enrolled for a prospective cohort study. Among these patients, 56 responded to the BREAST-Q questionnaire, including 24 who underwent fat grafting at the same time as IBBR (FAT+ group) and 32 who underwent IBBR alone (FAT- group). The BREAST-Q questionnaire was completed 1 year after surgery. Statistical analysis was performed using descriptive and summary statistics to identify differences between the 2 groups. RESULTS: Logistic regression analysis showed that the FAT+ group was significantly more likely than the FAT- group to have satisfaction with breasts (P = 0.0201) and satisfaction with outcome (P = 0.0364). CONCLUSIONS: Multivariate analysis with consideration of confounding factors indicated that addition of fat grafting to IBBR improves outcomes of breast reconstruction. These results suggest that a minor surgical procedure of fat grafting can improve patient satisfaction and outcomes after breast reconstruction.

Free superficial circumflex iliac artery perforator flow-through flap transfer for reconstruction after excision of arteriovenous malformations of the hand: A case report.

The management of arteriovenous malformations (AVMs) of the hand remains challenging. When radical excision results in large defects of both soft tissue and vessels, flow-through flap transfer is useful; however, flow-through flap options for hand and digit reconstructions are limited. Herein, we describe the use of a superficial circumflex iliac artery perforator (SCIP) flow-through flap after excision of an AVM of the hand. A 44-year-old female patient with an AVM of the hand required simultaneous reconstruction of soft tissue, vascular, and bone defects after radical excision of vascular lesions. A 6 × 15 cm SCIP flow-through flap was transferred, and flow-through vascular reconstruction was performed with flap vessels: the deep branch of the superficial circumflex iliac artery, superficial inferior epigastric artery, and superficial circumflex iliac vein. In addition, three bone holes in the proximal phalanx of the index finger were filled with iliac bone grafts. The postoperative course was uneventful, with good functional results 1 year after surgery. An SCIP flow-through flap is an option for reconstruction after excision of AVMs of the hand because of its advantages, including minimal donor-site morbidity, availability of multiple vessels suitable for anastomosis with hand vessels, and simultaneous availability of iliac bone grafts.

Real-world outcomes of molecular targeted agents for patients with hepatocellular carcinoma over 80 years old.

AIM: There is insufficient evidence regarding the safety and efficacy of molecular targeted agents (MTAs) for elderly patients with hepatocellular carcinoma (HCC), who are likely to be vulnerable to adverse events (AEs) of therapy. The aim of this study was to compare sorafenib and lenvatinib use in elderly patients with HCC from the viewpoint of overall survival (OS) and rate of AE-induced MTA discontinuation. METHODS: This retrospective study included patients with HCC over 80 years old who received first-line molecular targeted therapy (MTT) at four hospitals between June 2009 and September 2019. They were divided into three groups according to the era and type of first-line MTA: E1-Sora (sorafenib, between 2009 and 2016), E2-Sora (sorafenib, between 2017 and 2019), and E2-Len (lenvatinib, between 2017 and 2019). RESULTS: The study included 173 patients (E1-Sora, n = 79; E2-Sora, n = 50; E2-Len, n = 44) with a median age of 81.9 years (range, 80-93 years). Median OS was 15.1 months in the entire cohort (E1-Sora, 12.7 months; E2-Sora, 20.5 months; E2-Len, 10.3 months). The rate of treatment discontinuation due to AEs was high in the entire cohort, especially in E1-Sora and E2-Len (49.4% in E1-Sora, 28.0% in E2-Sora, and 54.6% in E2-Len, p = 0.0753). More E2-Sora patients received subsequent MTT than E2-Len patients (E2-Sora, 50%; E2-Len, 28.6%; p = 0.0111). CONCLUSION: Both sorafenib and lenvatinib were effective and feasible for elderly patients with HCC. In terms of discontinuation due to AEs and subsequent MTT, sorafenib might be more desirable for elderly patients with HCC over 80 years.

Preliminary report of de novo adipogenesis using novel bioabsorbable implants and image evaluation using a porcine model.

Our bioabsorbable poly-L-lactic acid (PLLA) mesh implants containing collagen sponge are replaced with adipose tissue after implantation, and this is an innovative method for breast reconstruction. In this preliminary study, we investigated the formation of adipose tissue and evaluated the process via multimodal images in a porcine model using an implant aggregate to generate the larger adipose tissue. The implant aggregate consists of PLLA mesh implants containing collagen sponge and a poly-glycolic acid woven bag covering them. We inserted the implant aggregates under the porcine mammary glands. Magnetic resonance imaging (MRI), ultrasonography (USG), and 3-dimensional (3D) surface imaging and histological evaluations were performed to evaluate the formation of adipose tissue over time. The volume of the implant aggregate and the formed adipose tissue inside the implant aggregate could be evaluated over time via MRI. The space within the implant aggregate was not confirmed on USG due to the acoustic shadow of the PLLA threads. The change in volume was not confirmed precisely using 3D surface imaging. Histologically, the newly formed adipose tissue was confirmed on the skin side of the implant aggregate. This implant aggregate has the ability to regenerate adipose tissue, and MRI is an appropriate method for the evaluation of the volume of the implant aggregation and the formation of adipose tissue.

Protection of rat artery grafts from tissue damage by voltage-applied supercooling.

Supercooling preservation below 0 °C allows the storage of the transplantable sources in an unfrozen state. This can improve the safety and efficacy of storage by improving the inhibition of metabolism and organ preservation in comparison with conventional preservation at 4 °C. We have developed a supercooling technique using a voltage-applied apparatus without perfusion. We examined the preservation effects of our supercooling preservation technique in a rat model of artery transplantation. Our technique produces a supercooled state at - 2 °C with application of 1000 V. The viability of tissue cells from rat arteries was found to be higher with storage using the proposed method than that under ordinary conditions. Damage to the vascular endothelium of the femoral artery preserved by voltage-applied supercooling at - 2 °C was reduced compared to storage under ordinary conditions. Artery graft revival was successfully achieved with graft patency after supercooling preservation, and 1 week outcomes for post-transplanted grafts, including thrombosis, were better with supercooling preservation than with conventional 4 °C preservation. Supercooling artery preservation at - 2 °C with 1000 V promises to greatly prolong preservation time and improve post-transplant outcomes.

Mapping molar shapes on signaling pathways.

A major challenge in evolutionary developmental biology is to understand how genetic mutations underlie phenotypic changes. In principle, selective pressures on the phenotype screen the gene pool of the population. Teeth are an excellent model for understanding evolutionary changes in the genotype-phenotype relationship since they exist throughout vertebrates. Genetically modified mice (mutants) with abnormalities in teeth have been used to explore tooth development. The relationship between signaling pathways and molar shape, however, remains elusive due to the high intrinsic complexity of tooth crowns. This hampers our understanding of the extent to which developmental factors explored in mutants explain developmental and phenotypic variation in natural species that represent the consequence of natural selection. Here we combine a novel morphometric method with two kinds of data mining techniques to extract data sets from the three-dimensional surface models of lower first molars: i) machine learning to maximize classification accuracy of 22 mutants, and ii) phylogenetic signal for 31 Murinae species. Major shape variation among mutants is explained by the number of cusps and cusp distribution on a tooth crown. The distribution of mutant mice in morphospace suggests a nonlinear relationship between the signaling pathways and molar shape variation. Comparative analysis of mutants and wild murines reveals that mutant variation overlaps naturally occurring diversity, including more ancestral and derived morphologies. However, taxa with transverse lophs are not fully covered by mutant variation, suggesting experimentally unexplored developmental factors in the evolutionary radiation of Murines.

Real-world efficacy and safety of 12-week sofosbuvir/velpatasvir treatment for patients with decompensated liver cirrhosis caused by hepatitis C virus infection.

AIM: This study aimed to evaluate the real-world efficacy and safety of 12-week sofosbuvir/velpatasvir (SOF/VEL) treatment for patients with decompensated liver cirrhosis caused by hepatitis C virus (HCV) infection. METHODS: A total 72 of patients with Child-Pugh (CP) class B or C were enrolled. We evaluated the sustained virologic response at 12 weeks after the end of treatment (SVR12), adverse events (AEs), and changes in the liver function. RESULTS: All participants had genotype 1 or 2 HCV infection. At baseline, the numbers of patients with CP class B and C were 59 and 13, respectively. The overall SVR12 rate was 95.8% (69/72); 94.9% (56/59) in CP class B and 100% (13/13) in CP class C. The serum albumin level, prothrombin time and ascites were significantly improved (P < 0.01); however, the serum bilirubin level and encephalopathy did not improve. Among patients who achieved SVR12, 75.0% showed an improvement in their CP score, while 5.9% showed a worsening. The presence of large portosystemic shunt (diameter ≥6 mm) and hyperbilirubinemia (≥2.0 mg/dL) were independent factors that interfered with the improvement in the CP score (P < 0.05). The most common AEs were encephalopathy (15.3%) and skin symptoms (7.9%). Two patients discontinued SOF/VEL due to AEs. CONCLUSIONS: Treatment with SOF/VEL for 12 weeks was relatively safe and effective for patients with decompensated cirrhosis. An SVR provided an improvement of the liver function in the majority of patients. However, large portosystemic shunt and hyperbilirubinemia were independent factors that interfered with the improvement in the CP score.

Clinical and virologic features of hepatitis E virus infection at a university hospital in Japan between 2000 and 2019.

The clinical and virologic features of hepatitis E virus (HEV) infection seem to vary among regions even in developed countries. However, we have little information on the diversity of HEV infection. Here, we investigated the characteristics of 26 patients in our hospital located in Tochigi prefecture, 90 km north of Tokyo, between 2000 and 2019. The reported number of patients with acute hepatitis E is increasing in Japan because measurement of IgA-class anti-HEV antibody was commercially available from 2011. In contrast, the numbers at our hospital were 1.5/y and 1.0/y in 2000 to 2011 and 2012 to 2019, respectively. This is attributed to the fact that we have been investigating HEV as a cause of unknown hepatitis before 2011. Among isolated HEV subgenotypes, including 3a, 3b, 4b, 4c, and 4d, all three patients with subgenotype 4c infection presented acute liver failure. Four HEV strains shared more than or equal to 99% identity within the 412-nucleotide partial sequence, in which the time and place of HEV infection varied, except for one intrafamilial infection. In addition, some strains were similar to HEV strains isolated far from Tochigi prefecture. In conclusion, the number of patients with acute hepatitis E was not increasing at Jichi Medical University Hospital and some strains were found to circulate in Japan.

Metameric variation of upper molars in hominoids and its implications for the diversification of molar morphogenesis.

Metameric variation of molar size is in part associated with the dietary adaptations of mammals and results from slight alterations of developmental processes. Humans and great apes exhibit conspicuous variation in tooth morphology both between taxa and across tooth types. However, the manner in which metameric variation in molars emerged among apes and humans via evolutionary alterations in developmental processes remains largely unknown. In this study, we compare the enamel-dentine junction of the upper molars of humans-which closely correlates with morphology of the outer enamel surface and is less affected by wear-with that of the other extant hominoids: chimpanzees, bonobos, gorillas, orangutans, and gibbons. We used the morphometric mapping method to quantify and visualize three-dimensional morphological variation, and applied multivariate statistical analyses. Results revealed the following: 1) extant hominoids other than humans share a common pattern of metameric variation characterized by a largely linear change in morphospace; this indicates a relatively simple graded change in metameric molar shape; 2) intertaxon morphological differences become less distinct from the mesial to distal molars; and 3) humans diverge from the extant ape pattern in exhibiting a distinct metameric shape change trajectory in the morphospace. The graded shape change and lower intertaxon resolution from the mesial to distal molars are consistent with the concept of a 'key' tooth. The common metameric pattern observed among the extant nonhuman hominoids indicates that developmental patterns underlying metameric variation were largely conserved during ape evolution. Furthermore, the human-specific metameric pattern suggests considerable developmental modifications in the human lineage.

Lusutrombopag is effective and safe in patients with chronic liver disease and severe thrombocytopenia: a multicenter retrospective study.

BACKGROUND: Chronic liver disease (CLD) is often complicated by severe thrombocytopenia (platelet count < 50,000/µL). Platelet transfusion has been a gold standard for increasing the platelet count to prevent hemorrhagic events in such patients. Lusutrombopag, a thrombopoietin receptor agonist, can increase the platelet count in such patients when invasive procedures are scheduled. Former studies on lusutrombopag included patients with a platelet count of > 50,000/µL at baseline: the proportions of patients who did not require platelet transfusion were 84-96%, which might be overestimated. METHODS: The efficacy and safety of lusutrombopag were retrospectively investigated in CLD patients with platelet count of < 50,000/µL, a criterion for platelet transfusion, in real-world settings. We examined the proportion of patients who did not require platelet transfusion in 31 CLD patients, which exceeded a minimum required sample size (21 patients) calculated by 80% power at a significance level of 5%. Lusutrombopag, 3 mg once daily, was administered 8-18 days before scheduled invasive procedures. RESULTS: Among 31 patients who received lusutrombopag, 23 patients (74.2%) patients showed a platelet count of ≥ 50,000/µL (Group A) and did not require platelet transfusion. The remaining 8 patients (25.8%) did not reached platelet ≥ 50,000/µL (Group B). The means of platelet increase were 38,000/µL and 12,000/µL in groups A and B, respectively. A low platelet count at baseline was a characteristic of patients in group B. Among 13 patients who repeatedly used lusutrombopag, lusutrombopag significantly increased the platelet count as the initial treatment. When all repeated uses of lusutrombopag were counted among these 13 patients, platelet transfusion was not required in 82.1% (23/28) of treatments. Although one patient showed portal thrombosis after lusutrombopag treatment, the thrombosis was disappeared by anticoagulant treatment for 35 days. The degree of platelet increase with lusutrombopag was larger than that in their previous platelet transfusion. CONCLUSIONS: The proportion of patients who did not require platelet transfusion was 74.2%, which is smaller than that in former studies which included CLD patients with a platelet count of > 50,000/µL. However, lusutrombopag is effective and safe for CLD patients with a platelet count of < 50,000/µL.

Variation of bony labyrinthine morphology in Mio-Plio-Pleistocene and modern anthropoids.

OBJECTIVES: The bony labyrinth of the inner ear has special relevance when tracking phenotypic evolution because it is often well preserved in fossil and modern primates. Here we track the evolution of the bony labyrinth of anthropoid primates during the Mio-Plio-Pleistocene-the time period that gave rise to the extant great apes and humans. MATERIALS AND METHODS: We use geometric morphometrics to analyze labyrinthine morphology in a wide range of extant and fossil anthropoids, including New World and Old World monkeys, apes, and humans; fossil taxa are represented by Aegyptopithecus, Microcolobus, Epipliopithecus, Nacholapithecus, Oreopithecus, Ardipithecus, Australopithecus, and Homo. RESULTS: Our results show that the morphology of the anthropoid bony labyrinth conveys a statistically significant phylogenetic signal especially at the family level. The bony labyrinthine morphology of anthropoids is also in part associated with size, but does not cluster by locomotor adaptations. The Miocene apes examined here, regardless of inferred locomotor behaviors, show labyrinthine morphologies distinct from modern great apes. DISCUSSION: Our results suggest that labyrinthine variation contains mixed signals and alternative explanations need to be explored, such as random genetic drift and neutral phenotypic evolution, as well as developmental constraints. The observed pattern in fossil and extant hominoids also suggests that an additional factor, for example, prenatal brain development, could have potentially had a larger role in the evolutionary modification of the bony labyrinth than hitherto recognized.