Impact of the fundamental use of surgical energy certification on surgeons' behavior and awareness of safe use of energy devices: a cross-sectional survey research.

BACKGROUND: The Fundamental Use of Surgical Energy (FUSE) program was established to educate surgeons and trainees to promote awareness and behaviors for the safe use of surgical energy devices. Despite its implementation, the impact of FUSE certification on surgeons' behavior and safety awareness regarding practice of energy devices remains unclear. This study aimed to identify the perceived impact of FUSE certification on surgeons' behavior and awareness regarding the safe use of surgical energy devices. METHODS: We performed a descriptive cross-sectional survey study, using non probabilistic purposive sampling, and distributed 22-item web-based questionnaires among all 59 FUSE-certified surgeons in Japan, excluding operating room nurses and medical students. The questionnaire items covered demographics, surgical techniques using various energy devices, changes in behavior and safety awareness, communication with colleagues about surgical energy devices, and educational activities related to energy devices. RESULTS: Fifty-seven participants completed the questionnaire (response rate 96.6%). Most surgeons (91.3%) could apply material learned from the FUSE program in practice, especially material related to monopolar electrosurgery. Fifty-six surgeons (98.3%) reported increased awareness of surgical safety, and 35 (61.5%) reported increased communication with operating room personnel about the safe use of energy devices. Moreover, 56 participants (98.3%) indicated a need for systematic education in surgical energy, with participants recommending fellows (94.7% of participants specified that fellows should participate in further education), residents (75.4%), and attending surgeons (63.2%) as the target recipients of this training. Conclusions After FUSE certification, not only did surgeons' knowledge increase, but their energy-related surgical techniques in practice also improved. Furthermore, FUSE-certified surgeons felt that they were more aware of surgical-energy safety and were dedicated to its promotion.

The impact of the first peak of the COVID-19 pandemic on childhood myopia control practice patterns among ophthalmologists-an international pediatric ophthalmology and strabismus council global perspective.

BACKGROUND: The prevalence of myopia keeps increasing during the COVID-19 pandemic. We aimed to map the worldwide treatment preferences of ophthalmologists managing myopia control during the first wave of the pandemic. METHODS: An online questionnaire inquiring about pharmacological and optical treatment patterns during the first half of 2020 was sent to pediatric ophthalmology as well as general ophthalmology memberships worldwide. The results among pediatric ophthalmologists were compared to a previous study we performed before the pandemic. RESULTS: A total of 2269 respondents from 94 countries were included. Most respondents were pediatric ophthalmologists (64.6%), followed by ophthalmologists from other subspecialties (32.3%). The preferred modality for all geographical regions was a combination therapy of pharmacological and optical treatments. When evaluated independently, the pharmacological treatment was more popular than the optical treatment in most regions other than East Asia (P < 0.001). Compared to a pre-pandemic questionnaire, the participation of pediatric ophthalmologists affiliated with non-university hospitals increased. Additionally, the prevalence of respondents utilizing either any type of pharmacological treatment and those that using only evidence-based treatments increased globally. Although a decline in the use of optical treatment was evident worldwide, the use of evidence-based optical treatments increased. CONCLUSION: Ophthalmologists around the world preferred a combination therapy of pharmacological and optical treatments. More pediatric ophthalmologists treated myopia progression and preferred a better evidence-based approach to control myopia. These trends reflect a positive response and more awareness of the rising prevalence of myopia due to the increased burden of myopia imposed by the COVID-19 pandemic.

The Structural Abnormalities Are Deeply Involved in the Cause of RPGRIP1-Related Retinal Dystrophy in Japanese Patients.

Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophy. RPGRIP1-related LCA accounts for 5-6% of LCA. We performed whole-exome sequencing and whole-genome sequencing (WGS) on 29 patients with clinically suspected LCA and examined ophthalmic findings in patients with biallelic pathogenic variants of RPGRIP1. In addition to five previously reported cases, we identified five cases from four families with compound heterozygous RPGRIP1 variants using WGS. Five patients had null variants comprising frameshift variants, an Alu insertion, and microdeletions. A previously reported 1339 bp deletion involving exon 18 was found in four cases, and the deletion was relatively prevalent in the Japanese population (allele frequency: 0.002). Microdeletions involving exon 1 were detected in four cases. In patients with RPGRIP1 variants, visual acuity remained low, ranging from light perception to 0.2, and showed no correlation with age. In optical coherence tomography images, the ellipsoid zone (EZ) length decreased with age in all but one case of unimpaired EZ. The retinal structure was relatively preserved in all cases; however, there were cases with great differences in visual function compared to their siblings and a 56-year-old patient who still had a faint EZ line. Structural abnormalities may be important genetic causes of RPGRIP1-related retinal dystrophy in Japanese patients, and WGS was useful for detecting them.

The two-component response regulator OrrA confers dehydration tolerance by regulating avaKa expression in the cyanobacterium Anabaena sp. strain PCC 7120.

The cyanobacterium Anabaena sp. strain PCC 7120 exhibits dehydration tolerance. The regulation of gene expression in response to dehydration is crucial for the acquisition of dehydration tolerance, but the molecular mechanisms underlying dehydration responses remain unknown. In this study, the functions of the response regulator OrrA in the regulation of salt and dehydration responses were investigated. Disruption of orrA abolished or diminished the induction of hundreds of genes in response to salt stress and dehydration. Thus, OrrA is a principal regulator of both stress responses. In particular, OrrA plays a crucial role in dehydration tolerance because an orrA disruptant completely lost the ability to regrow after dehydration. Moreover, in the OrrA regulon, avaKa encoding a protein of unknown function was revealed to be indispensable for dehydration tolerance. OrrA and AvaK are conserved among the terrestrial cyanobacteria, suggesting their conserved functions in dehydration tolerance in cyanobacteria.

De novo heterozygous variants in KIF5B cause kyphomelic dysplasia.

Kyphomelic dysplasia is a heterogeneous group of skeletal dysplasias characterized by severe bowing of the limbs associated with other variable findings, such as narrow thorax and abnormal facies. We searched for the genetic etiology of this disorder. Four individuals diagnosed with kyphomelic dysplasia were enrolled. We performed whole-exome sequencing and evaluated the pathogenicity of the identified variants. All individuals had de novo heterozygous variants in KIF5B encoding kinesin-1 heavy chain: two with c.272A>G:p.(Lys91Arg), one with c.584C>A:p.(Thr195Lys), and the other with c.701G>T:p.(Gly234Val). All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein. All individuals had sharp angulation of the femora and humeri, distinctive facial features, and neonatal respiratory distress. Short stature was observed in three individuals. Three developed postnatal osteoporosis with subsequent fractures, two showed brachycephaly, and two were diagnosed with optic atrophy. Our findings suggest that heterozygous KIF5B deleterious variants cause a specific form of kyphomelic dysplasia. Furthermore, alterations in kinesins cause various symptoms known as kinesinopathies, and our findings also extend the phenotypic spectrum of kinesinopathies.

Assessment of physical activity and its facilitators and barriers among Syrian refugees living in Amman City, Jordan: a cross-sectional study.

BACKGROUND: Physical inactivity is one of the major risk factors for non-communicable diseases. Few studies about physical activity have been conducted among refugees from neighbouring countries. Given changes in the situation of Syrians, assessment of physical activity among Syrian refugees is required to understand their situation. This study aimed to evaluate the degree of self-reported physical activity and to identify perceived facilitators of and barriers to physical activity among Syrian refugees living in Amman, Jordan, in 2017. METHODS: This community-based cross-sectional study was conducted using a structured questionnaire and the short form of the International Physical Activity Questionnaire. Participants were eligible for the study if they were Syrian refugees aged 18-64 years, living in Amman city, and were either registered with the United Nations High Commissioner for Refugees, waiting for their registration, or had a service card issued by the Jordanian Ministry of Interior. The relationship between physical activity level and sex was assessed using the chi-square test and Cochran-Armitage tests. The Mann-Whitney U test was performed to assess the relationship between the median metabolic equivalent scores of physical activity and gender. Backward stepwise logistic regression analysis was used to analyse the association between predictors of physical inactivity and physical activity level. RESULTS: Among the 173 participants, the majority (91.9%) reported moderate to a high level of physical activity, and 8.1% were physically inactive. The metabolic equivalent scores for the walking activity of males (median: 1039.5, IQR: 0, 2772) was significantly higher than that of females (median: 396, IQR: 0, 1188) (p < 0.01). "Perceived change in the amount of physical activity" was a significant predictor of physical inactivity (adjusted OR = 3.00; 95%CI: 1.27-7.26). Common facilitators of physical activity were "psychological wellbeing"(49.7%) and "prevent diseases"(46.8%). The greatest barriers to physical activity were "time limitation"(43.4%) and "high cost"(57.8%). CONCLUSION: This study revealed the physical activity level among Syrian refugees in Amman. The perceived facilitators and barriers to physical activity identified among Syrian refugees were similar to those in previous studies conducted among non-refugees. These results provide a valuable baseline for future examinations of physical activity level and to verify its possible facilitators and barriers.

[An improved driving ability after attention function training for safe driving via use of a day rehabilitation service in a patient with cerebral infarction].

In recent years, the assessment of and support for the safety of driving for people with higher brain dysfunction to allow them to resume car driving have become issues to be addressed in Japan. It is difficult to determine whether or not people with higher brain dysfunction may safely resume car driving; in addition, methods of supporting this resumption have not been established. To support people with higher brain dysfunction and allow them to live at home in areas where public means of transportation may be insufficient, initiatives promoting the resumption of car driving are necessary in healthcare sectors, including day rehabilitation facilities. We provided support to a patient with an attention disorder due to left thalamic infarction, with the aim of achieving sufficient independence to drive a car, in a day rehabilitation facility. We herein report this case from the perspective of a speech-language-hearing therapist. The patient was a right-handed man in his 60s who had higher brain dysfunction with attention disorder as the main symptom. No marked motor paralysis of the extremities was observed. Use of a day rehabilitation service was started approximately two months after the onset of symptoms. Rehabilitation and support aimed at the resumption of car driving were provided approximately one month after the start of the day rehabilitation service use. To determine whether or not the patient was fit to drive a car, higher brain function tests for the intellectual function, attention function, and frontal function, as well as a theoretical evaluation based on the Stroke Drivers' Screening Assessment Japanese Version (J-SDSA) and monitoring of daily behaviors were performed. In addition, after the patient was given permission from an attending physician to drive a car on the condition that the patient did not drive fast and the patient's wife always accompanied him while driving, a safety assessment was also performed. As a result, approximately 10 months later, the J-SDSA theoretical evaluation score showed a passing grade, in contrast to the failing grade he had previously earned. Furthermore, errors in performing household activities due to a decreased attention function became unremarkable with respect to daily behaviors; therefore, we determined, together with the attending physician, that the patient now had sufficient independence to drive a car. In our day rehabilitation facility, the number of requests for advice on car driving from people with higher brain dysfunction living in the community had been increasing. Multisectoral assessments, training, and instruction should be continued in collaboration with attending physicians, other facilities located within the community, and driving schools in order to support people with higher brain dysfunction and help them once again be able to drive a car.

Analysis of IKBKG/NEMO gene in five Japanese cases of incontinentia pigmenti with retinopathy: fine genomic assay of a rare male case with mosaicism.

Incontinentia pigmenti (IP) is an X-linked dominant genodermatosis that is usually lethal in utero in males, though exceptionally they survive very rarely either with Klinefelter syndrome or a somatic mosaicism. We performed genomic analysis of five Japanese IP patients including a rare boy case, all of whom were definite cases with retinopathy. Four patients including the boy revealed the recurrent exon 4-10 deletion in the sole known causative gene IKBKG/NEMO, which was confirmed by various specific PCR techniques. The boy's saliva DNA showed a mosaicism consisting of the deletion and intact alleles, but his blood DNA did not. Relative quantification analysis of the real-time PCR data by ∆∆CT method estimated the mosaicism ratio of the boy's saliva as 45:55 (deletion:intact). A genomic analysis for the recurrent deletion at the nucleotide sequence level has been performed directly using patient's DNA and it has been clarified that the breakpoints are within two MER67B repeats in the intron 3 and downstream of exon 10. This is the first report of the assay for the mosaicism ratio of a male IP case with a recurrent exon 4-10 deletion of IKBKG/NEMO and the sequencing analysis of the breakpoints of the recurrent deletion directly using patient's sample.

Increased Stress Concentration in Prosthesis, Adhesive Cement, and Periodontal Tissue with Zirconia RBFDPs by the Reduced Alveolar Bone Height.

PURPOSE: To investigate the risk of debonding of resin-bonded fixed dental prosthesis frameworks and the effects on the periodontal tissue in patients with reduced alveolar bone levels. MATERIALS AND METHODS: The abutment teeth were the upper central incisor and the canine. Resin-bonded fixed dental prosthesis framework fabricated using zirconia was set to models with five different alveolar bone levels. A 200-N load (the maximum clenching force of the anterior teeth) was applied to the center of the pontic to analyze the internal stress on the framework, adhesive cement, and periodontal tissue using finite element analysis. RESULTS: The mean maximum principal stress generated in the framework was 25.33 and 29.35 MPa in the models with the normal and the lowest alveolar bone level, respectively. Regarding shear stress on the adhesive cement, stress concentration was observed on the connector side in all models, and it increased on the cervical side of the central incisor as the alveolar bone level decreased. In addition, the mean maximum and minimum principal strains generated on the periodontal ligament of the central incisor and canine tended to increase as alveolar bone loss progressed. Furthermore, the mean maximum principal stress on the cortical bone was the greatest in the model with the most significant bone loss at 5.10 MPa. CONCLUSIONS: This study suggested that the risk of debonding and periodontal tissue damage might be higher when resin-bonded fixed dental prosthesis frameworks were used in patients with reduced alveolar bone levels compared to those in a healthy state.

[A patient with mesenteric lymphoma who developed amyotrophic lateral sclerosis and sepsis].

We treated a patient with mesenteric lymphoma who concomitantly developed amyotrophic lateral sclerosis (ALS). The patient died of urinary tract infection nine months after the onset of ALS. We herein report the changes in the patient's condition and the sequence of events until death from the viewpoint of a physiotherapist. The patient was a 69-year-old woman who developed mesenteric lymphoma in September of X year and perceived weakness in the toes in November of X year. She showed signs of upper and lower motor neuron disorders, and electrophysiologic testing revealed denervation in three areas of the spinal cord. In March of X+1 year, she was diagnosed with definite ALS based on the Awaji criteria. In April of X+1 year, she began to receive continuous home healthcare, specifically outpatient rehabilitation. No remarkable bulbar palsy was observed soon after the initiation of rehabilitation; however, manual muscle testing revealed strengths in the lower and upper limbs of 1 and 3-5, respectively, indicating muscle weakness and muscle atrophy. She developed exacerbation of neurological symptoms in the upper limbs, bulbar palsy, and respiratory muscle paralysis during rehabilitation. The ALS Functional Rating Scale-Revised indicated a decreased tendency to X [please define X]. In July of X+1 year, the mesenteric lymphoma had enlarged, resulting in the development of ureteric obstruction and ultimately causing hydronephrosis. Urinary tract infection and sepsis were diagnosed, and she was hospitalized. Although her fever temporarily subsided following ceftriaxone administration, she ultimately died due to a systemic inflammatory response syndrome three days after hospitalization. The mean period between the ALS onset and death is reportedly 40.6±33.1 months. The rate of ALS progression differs among individuals. Malignant tumors and paraneoplastic neurological syndrome may be involved in rapidly worsening neurological symptoms. Patients who concomitantly develop motor neuron disorders and malignant tumors are likely to have a higher risk of developing serious conditions associated with the exacerbation of neurological symptoms and complications. Our patient had several diseases that affected her survival prognosis; however, the sharing of information regarding her condition among healthcare professionals may have been insufficient. The primary physician responsible for treating each disease should cooperate with physiotherapists and other paramedical staff who have frequent opportunities to talk to patients in daily clinical practice. In geriatric patients in particular, such an environment is essential.

Impact of the village health center project on contraceptive behaviors in rural Jordan: a quasi-experimental difference-in-differences analysis.

BACKGROUND: Appropriate contraceptive use remains a major health challenge in rural Jordan. The Japan International Cooperation Agency implemented a project aimed at enhancing the capacity of village health centers (VHCs) to improve the quality and quantity of family planning (FP) services in rural Jordan in 2016-2018. Facility- and community-based approaches were integrated into the interventions. We evaluated the project's impacts on contraceptive behaviors and the effectiveness of the two approaches. METHODS: We used a difference-in-differences analysis based on the project baseline and endline surveys, and logistic regression analysis to assess associations between eight primary outcomes and three secondary outcomes (impacts). The unit of intervention was five target VHCs; the unit of analysis was currently married women of reproductive age (15-49 years) in five intervention and five control villages. RESULTS: Overall, 2061 married women participated; 83.8% were in need of FP. Compared with the control villages, significant effects, ranging from + 0.4% points (pp) to + 11.5 pp., were observed in the intervention villages for six primary outcomes in these categories: increasing the use of FP services at VHCs, participation in health promotion activities, and changing the sources of reproductive health information. There was a trend toward improved secondary outcomes in the intervention villages, but no significant differences were observed between the intervention and control villages regarding modern contraceptive use (mCU; + 4.3 pp), traditional contraceptive use (tCU; - 0.5 pp), and spousal agreement on contraception (+ 5.1 pp). mCU was positively associated with five primary outcomes: obtaining contraceptives at VHCs [adjusted odds ratio (AOR) 3.44, 95% confidence interval (CI) 1.26-9.40], education sessions at VHC (AOR 7.41, 95% CI 1.60-34.39), health activities in communities (AOR 7.41, 95% CI 3.28-16.78), counseling by private doctor/clinic (AOR 0.62, 95% CI 0.40-0.97), and information gained through TV (AOR 0.50, 95% CI 0.32-0.76). Spousal agreement on contraception showed similar positive trends. tCU was associated only with TV. CONCLUSIONS: The project had impacts on increased mCU and husbands' perception of contraception in rural Jordan. The integration of facility- and community-based approaches may be effective in shifting from tCU to mCU in other rural areas.

X-linked Retinitis Pigmentosa in Japan: Clinical and Genetic Findings in Male Patients and Female Carriers.

X-linked retinitis pigmentosa (XLRP) is a type of severe retinal dystrophy, and female carriers of XLRP demonstrate markedly variable clinical severity. In this study, we aimed to elucidate the clinical findings of male patients with and female carriers of XLRP in a Japanese cohort and demonstrate the genetic contribution. Twelve unrelated families (13 male patients, 15 female carriers) harboring pathogenic mutations in RPGR or RP2 were included, and comprehensive ophthalmic examinations were performed. To identify potential pathogenic mutations, targeted next-generation sequencing was employed. Consequently, we identified 11 pathogenic mutations, of which five were novel. Six and five mutations were detected in RPGR and RP2, respectively. Only one mutation was detected in ORF15. Affected male patients with RP2 mutations tended to have lower visual function than those with RPGR mutations. Female carriers demonstrated varying visual acuities and visual fields. Among the female carriers, 92% had electroretinographical abnormalities and 63% had a radial autofluorescent pattern, and the carriers who had higher myopia showed worse visual acuity and more severe retinal degeneration. Our results expand the knowledge of the clinical phenotypes of male patients with and female carriers of XLRP and suggest the possibility that RP2 mutations are relatively highly prevalent in Japan.

Purification and structural analysis of volatile sesquiterpenes produced by Escherichia coli carrying unidentified terpene synthase genes from edible plants of the family Araliaceae.

A simple method to purify volatile sesquiterpenes from recombinant Escherichia coli was developed using the cells that carried known sesquiterpene synthase (Tps) genes ZzZss2 (ZSS2) and ZoTps1. This method was applied for the purification and structural analyses of volatile sesquiterpenes produced by E. coli cells that carried unidentified Tps genes, which were isolated from the Aralia-genus edible plants belonging to the family Araliaceae. Recombinant cells carrying each Tps gene were cultured in the two-layer medium (n-octane/TB medium), and volatile sesquiterpenes trapped in n-octane were purified through two-phase partition, silica gel column chromatography, and reversed-phase preparative high-performance liquid chromatography, if necessary. Further, their structures were confirmed by nuclear magnetic resonance, [α]D, and gas chromatography-mass spectrometry analyses. Herein, the products of E. coli cells that carried two Tps gene (named AcTps1 and AcTps2) in Araria cordata "Udo" and a Tps gene (named AeTps1) in Aralia elata "Taranoki" were studied resulting in identifying functionalities of these cryptic Tps genes.

Validity and reliability of the Japanese version of the Care Transitions Measure.

OBJECTIVE: To evaluate the validity and reliability of the Japanese Version of the Care Transitions Measure (J-CTM-15). DESIGN: Questionnaire items were translated, and a longitudinal study was conducted. SETTING: Three urban hospitals: a special functioning hospital, a regional-designated cancer care hospital, and a private hospital in the northern part of Japan. PARTICIPANTS: Patients, aged 20 years and older, who were discharged from hospitals. MAIN OUTCOME MEASURE: Reliability was measured using Cronbach α and item-total correlations. Convergent validity was measured using a Pearson correlation with the Self-Care Agency Questionnaire. Construct validity was examined by an exploratory factor analysis. Predictive validity was examined by the ability to discriminate negative post hospital experiences, including anxiety, problems at home, readmission, emergency visit, consultation via telephone, poor health condition without consultation, and by the correlation with the 12-item Short Form Health Survey (SF-12v2). RESULTS: A total of 223 and 158 participants were selected for data analyses. The Cronbach α was 0.90. The J-CTM-15 differed from the original factor model, but significantly correlated with Self-Care Agency Questionnaire and SF-12v2 scores. The J-CTM-15 also significantly discriminated between patients who did and did not display anxiety, problems at home, and poor health condition, but did not discriminate for readmission, emergency visits, and consultation via telephone. CONCLUSION: The J-CTM-15 is a valid and reliable measure of the quality of care transitions. However, insufficient levels of predictive validity and a lack of generalizability are limitations of the current study.

Total Synthesis of Biselyngbyaside.

The first total synthesis of biselyngbyaside, an 18-membered macrolide glycoside, was achieved. The glycoside bond was introduced using the Schmidt method before construction of the 18-membered ring due to the instability of the conjugated diene and the ß-hydroxy ester moiety. The macrolactone ring was constructed using the Mitsunobu reaction followed by intramolecular the Stille coupling reaction.

[A Case of Merkel Cell Carcinoma Complicated with Severe Thrombocytopenia Treated with Carboplatin/Etoposide Regimen after Surgery].

Thrombocytopenia is often caused by myelosuppression during chemotherapy. However, when platelet transfusions are required, pathological conditions such as idiopathic thrombocytopenic purpura(ITP)and thrombotic thrombocytopenic purpura( TTP)also occur. We report a case of Merkel cell carcinoma complicated with severe thrombocytopenia treated with carboplatin/etoposide regimen after surgery. The patient's platelet count did not increase in spite of platelet transfusions. However, the platelet count increased after steroid treatment was chosen under the diagnosis of ITP. Subsequent examinations revealed that the patient had HLA antibody, which caused the platelet transfusion refractoriness. When the platelet count does not increase in spite of platelet transfusions during chemotherapy, the possibility that the platelet transfusion refractoriness is due to the presence of HLA antibody should be considered.

Novel HPS6 mutations identified by whole-exome sequencing in two Japanese sisters with suspected ocular albinism.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, platelet dysfunction and ceroid deposition. We report suspected ocular albinism in two Japanese sisters, caused by mutations in the HPS6 (Hermansky-Pudlak syndrome 6) gene. Trio-based whole-exome sequencing (WES) identified novel compound heterozygous mutations in HPS6 (c.1898delC: mother origin and c.2038C>T: father origin) in the two sisters. To date, 10 associated mutations have been detected in HPS6. Although we detected no general manifestations, including platelet dysfunction, in the sisters, even in long-term follow-up, we established a diagnosis of HPS type 6 based on the HPS6 mutations and absence of dense bodies in the platelets, indicating that WES can identify cases of HPS type 6. To the best of our knowledge, this is the first report of HPS6 mutations in Japanese patients.

[A Pancreatic Cancer Patient in Whom Pegfilgrastim Prophylaxis Did Not Prevent Severe Neutropenia Caused by the FOLFIRINOX Regimen].

Recently, newer agents in regimens such as FOLFIRINOX have shown promising activity, being superior to gemcitabine as a single agent for unresectable pancreatic cancer patients with good performance status. Herein, we report a case of pancreatic cancer treated with the FOLFIRINOX regimen and pegfilgrastim prophylaxis as second-line treatment in a patient who failed this regimen. He previously received gemcitabine/nab-paclitaxel combination chemotherapy as first-line treatment. It was reported that grade 3-4 neutropenia frequently occurred in many patients receiving the FOLFIRINOX regimen. Prophylactic use of pegfilgrastim is recommended for cancer patients who are at high risk of neutropenic events. However, severe neutropenia occurred with the FOLFIRINOX regimen in spite of pegfilgrastim prophylaxis. We emphasize the importance of occasional serious adverse effects with the FOLFIRINOX regimen and pegfilgrastim prophylaxis.

The mammalian circadian clock protein period counteracts cryptochrome in phosphorylation dynamics of circadian locomotor output cycles kaput (CLOCK).

The circadian transcription factor CLOCK exhibits a circadian oscillation in its phosphorylation levels. Although it remains unclear whether this phosphorylation contributes to circadian rhythm generation, it has been suggested to be involved in transcriptional activity, intracellular localization, and degradative turnover of CLOCK. Here, we obtained direct evidence that CLOCK phosphorylation may be essential for autonomous circadian oscillation in clock gene expression. Importantly, we found that the circadian transcriptional repressors Cryptochrome (CRY) and Period (PER) showed an opposite effect on CLOCK phosphorylation; CRY impaired BMAL1-dependent CLOCK phosphorylation, whereas PER protected the phosphorylation against CRY. Interestingly, unlike PER1 and PER2, PER3 did not exert a protective action, which correlates with the phenotypic differences among mice lacking the Per genes. Further studies on the regulatory mechanism of CLOCK phosphorylation would thus lead to elucidation of the mechanism of CRY-mediated transcriptional repression and an understanding of the true role of PER in the negative feedback system.