Intrauterine twin environment and genetic factors subliminally affecting general movements in preterm infants.

BACKGROUND: Understanding background factors is beneficial for interpreting general movements (GMs). This study examines the factors involved in preterm-writhing GMs by comparing twins and singletons. METHOD: The subjects were 107 infants cared for at Oita University. The cohort consisted of very-low-birth-weight infants, including twins with a birth weight < 2000 g. The median gestational age (GA) was 29 weeks 1 day. The subjects consisted of 75 singletons, 32 twins (16 pairs), 20 monochorionic twins (M-twins), and 12 dichorionic twins (D-twins). GMs were scored according to the GMs optimality score (GMOS) and integrated into 6 items: the quality, neck-trunk and space, amplitude-speed, rotation, onset-offset and cramped, and tremulous score at 32-34 weeks, 35-36 weeks, and 37-42 weeks' GA. A hierarchical cluster analysis was performed using integrated GMOS, and the characteristics of clusters were examined according to clinical backgrounds. RESULTS: Three clusters were identified. Cluster 1 was characterized by good-quality GMs, cluster 2 by a poor repertoire but optimal space and rotatory components, and cluster 3 by overall poor-quality GMs, respectively. The mean GMOSs were 36.6, 31.8 and 24.3 in clusters 1, 2, and 3, respectively. There were no marked differences in proportions within clusters with respect to sex and twins. Small-for-gestational age (SGA) was significantly more frequent in cluster 3 at 32-34 weeks' GA than in other clusters. Perinatal brain injury had a significantly lower proportion in cluster 1 and a higher proportion in cluster 3 at 35-36 weeks' GA and 37-42 weeks' GA. M-twin pairs tended to belong to the same clusters at 35-36 weeks' GA. CONCLUSION: Preterm writhing GMs are associated with SGA and perinatal brain injury. Cluster matching in M-twins suggests that certain genetic factors may substantially influence GMs.

Immunogenicity after vaccination of COVID-19 vaccines in patients with cancer: a prospective, single center, observational study.

BACKGROUND: Patients with cancer, particularly those undergoing chemotherapy, are at risk from the low immunogenicity of Coronavirus Disease 19 (COVID-19) vaccines. METHODS: This prospective study assessed the seroconversion rate of COVID-19 vaccines among patients with cancer and hospital staff. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific IgG (S-IgG) concentrations were evaluated before the first vaccination, and 1-3 and 4-6 months after the second vaccination. The primary endpoint was the seroconversion rate measured 1-3 months after the second vaccine. RESULTS: In total, 590 patients and 183 healthy hospital staff were analyzed. At 1-3 months after the second vaccination, the S-IgG antibody concentration exceeded the cut-off value (20 BAU/mL) in 96.1% (567/590) of the patients with cancer and 100% (183/183) of the healthy controls (p = 0.0024). At 4-6 months after the second vaccination, the S-IgG antibody concentration exceeded the cut-off value (20 BAU/ml for S-IgG) in 93.1% (461/495) of the patients with cancer and 100% (170/170) of the healthy controls (p < 0.0001). Old age, being male, and low lymphocyte count were related to low SARS-CoV-2 S-IgG levels 1-3 months after the second vaccination among patients, while body mass index, smoking history, and serum albumin level were not. Patients undergoing platinum combination therapy and alkylating agent among cytotoxic drugs, and PARP inhibitor, mTOR inhibitor, and BCR-ABL inhibitor exhibited a low S-IgG antibody concentration compared to the no treatment group. CONCLUSIONS: COVID-19 vaccine immunogenicity was reduced among patients with cancer, especially under several treatment regimens.

Immunotherapy that leverages HPV-specific immune responses for precancer lesions of cervical cancer.

Cervical cancer and its precursor lesion, cervical intraepithelial neoplasia (CIN), are caused by high-risk human papillomavirus (HPV) viral infection and are highly susceptible to host immunity targeting of HPV viral proteins, which include both foreign antigens and cancer antigens expressed by tumors. Immunotherapy that induces Th1 immunoreactivity against viral proteins is expected to take advantage of this immunological regression mechanism. However, although cancer immunotherapies for cervical cancer and CIN have been developed over the past several decades, none have been commercialized. Most of these immunotherapies target the viral cancer proteins E6 and E7, which are generally the same. The reasons for the underdevelopment of HPV-targeted immunotherapy differ depending on whether the target is invasive cancer or CIN. We here summarize the developmental history of cancer immunotherapy for CIN and discuss strategies for solving the problems that led to this underdevelopment. We note that CIN is a mucosal lesion and propose that inducing mucosal immunity may be the key.

Findings from a discontinued clinical trial of favipiravir in high-risk patients with early-onset COVID-19.

INTRODUCTION: Favipiravir terminates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. Accordingly, early administration of favipiravir to SARS-CoV-2-infected coronavirus disease 2019 (COVID-19) patients may be expected to suppress disease progression. METHODS: A randomized double-blind placebo-controlled trial was conducted to demonstrate efficacy of favipiravir in reducing disease progression in patients with mild COVID-19. The participants were unvaccinated patients with comorbidities and at risk of progression to severe disease. Patients were enrolled within 72 h of disease onset and randomized to receive either favipiravir (1800 mg/dose on Day 1 followed by 800 mg/dose) or matching placebo twice daily for 10 days. The primary endpoint was the proportion of patients requiring oxygen therapy within 28 days of randomization. RESULTS: The trial was discontinued after enrolling 84 patients due to slower than anticipated enrollment caused by rapid uptake of SARS-CoV-2-vaccines and the emergence of the Omicron variant. Results from the 84 patients demonstrated no significant difference in all clinical outcomes. In post-hoc analyses, favipiravir treatment showed higher efficacy in patients within 48 h of onset. No deaths or severe adverse events were documented in the favipiravir group. Plasma concentrations of favipiravir from Day 2 onward were maintained above 40 µg/mL. CONCLUSIONS: Conducting clinical trials for pathogens like SARS-CoV-2 that rapidly accumulate mutations leading to altered disease characteristics carries significant risks unless it can be done in a short period. Therefore, it would be important to prepare the comprehensive clinical trial platform that can appropriately and promptly evaluate drugs even under a pandemic.

Early infantile spontaneous movement in very low birthweight infants is associated with sensory characteristics at the corrected age of 3 years.

AIM: To clarify the relationship between early infantile spontaneous movement of very-low-birth-weight infants (VLBWIs) and sensory characteristics in childhood. STUDY DESIGN: Prospective cohort study. We investigated the association between the Motor Optimality Score-Revised (MOS-R), a detailed assessment of general movements (GMs) at the corrected age of 9-17 weeks and the Infant/Toddler Sensory Profile Japanese version (ITSP-J) at the corrected age of 3 years. A multiple regression analysis was performed to examine the correlation of ITSP-J and MOS-R with patient clinical background factors. SUBJECTS: Fifty-three VLBWIs (median gestational age: 28 weeks, 6 days; median birth weight: 997 g) who were managed at the NICU of Oita University from September 2013 to June 2019. RESULTS: A multiple regression analysis revealed that the ITSP-J subscale in the sensory section of visual score was significantly correlated with the age-adequate movement repertoire subscore of MOS-R, and in the sensory section of vestibular score was correlated with the fidgety subscore of MOS-R. For both visual and vestibular section scores, intraventricular hemorrhage (IVH) showed an independent association with the MOS-R subscore. CONCLUSION: Spontaneous movement characteristics in early infancy were associated with sensory characteristics in early childhood.

Phase I and II randomized clinical trial of an oral therapeutic vaccine targeting human papillomavirus for treatment of cervical intraepithelial neoplasia 2 and 3.

BACKGROUND: Although many human papillomavirus (HPV)-targeted therapeutic vaccines have been examined for efficacy in clinical trials, none have been translated into clinical use. These previous agents were mostly administered by intramuscular or subcutaneous injection to induce systemic immunity. We investigated the safety and therapeutic efficacy of an HPV-16 E7-expressing lacticaseibacillus-based oral vaccine. METHODS: In a double-blind, placebo-controlled, randomized trial, a total of 165 patients with HPV-16-positive high-grade cervical intraepithelial neoplasia 2 and 3 were assigned to orally administered placebo or low, intermediate, or high doses of IGMKK16E7 (lacticaseibacillus paracasei expressing cell surface, full-length HPV-16 E7). In the 4 groups, IGMKK16E7 or placebo was administered orally at weeks 1, 2, 4, and 8 postenrollment. The primary outcomes included histopathological regression and IGMKK16E7 safety. RESULTS: In per-protocol analyses, histopathological regression to normal (complete response) occurred in 13 (31.7%) of 41 high-dose recipients and in 5 (12.5%) of 40 placebo recipients (rate difference = 19.2, 95% confidence interval [CI] = 0.5 to 37.8). In patients positive for HPV-16 only, the clinical response rate was 40.0% (12 of 30) in high-dose recipients and 11.5% (3 of 26) in recipients of placebo (rate difference = 28.5, 95% CI = 4.3 to 50.0). There was no difference in adverse events that occurred in the high-dose and placebo groups (P = .83). The number of HPV-16 E7-specific interferon-γ producing cells within peripheral blood increased with level of response (stable disease, partial, and complete responses; P = .004). The regression to normal (complete response) rates among recipients with high levels of immune response were increased in a dose-dependent manner. CONCLUSION: This trial demonstrates safety of IGMKK16E7 and its efficacy against HPV-16-positive cervical intraepithelial neoplasia 2 and 3. IGMKK16E7 is the first oral immunotherapeutic vaccine to show antineoplastic effects. TRIAL REGISTRATION: jRCT2031190034.

Two Cases of Disseminated Alveolar Echinococcosis: The Diagnosis, Management, and Differential Considerations for Liver Lesions.

Alveolar echinococcosis (AE), caused by Echinococcus multilocularis, is an aggressive and potentially critical infestation that primarily affects the liver and can metastasize to any part of the body. We herein report two cases of echinococcosis, which could be differentiated from malignancy on imaging studies, with infections of the liver and mediastinal lymph nodes, and also associated with systemic disseminated lesions. AE is a very invasive infectious disease, and in order to detect such lesions at an early stage when they are still resectable, it is necessary to understand the characteristic imaging findings and determine the patient's current medical history.

Pathological roles of antimicrobial peptides and pro-inflammatory factors secreted from the cervical epithelium in Gardnerella vaginalis-abundant vaginal flora in pregnancy.

Bacterial vaginosis due to Gardnerella vaginalis (GV) is one of the main causes of preterm birth. Antimicrobial function of the cervical glands prevents ascending pathogen infection. This study investigated the effect of GV on the cervical gland cells. We examined the correlation between GV and neutrophil elastase in the cervical mucous obtained from pregnant women's clinical samples. Culture supernatants (sup) of GV and Lactobacillus crispatus (LC) were added to human immortalized cervical gland cells (EndoCx). Quantitative reverse transcription PCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) were used to examine the effects on the production of antimicrobial peptides (AMPs), secretory leukocyte peptidase inhibitor (SLPI), and Elafin. mRNA microarray analysis revealed the expression profile of GV-exposed EndoCx. Moreover, the antimicrobial activity of Elafin against LC and GV was investigated. In the clinical samples, neutrophil elastase was increased in the GV-positive cervical mucous. In an in vitro assay, RT-qPCR and ELISA showed that GV-sup enhanced the secretion of Elafin, but not SLPI, from EndoCx, whereas LC-sup did not. mRNA microarray assay and ELISA results demonstrated that GV-sup enhanced the proinflammatory pathway and interleukin (IL)- 8 secretion from EndoCx as well as cell adhesion and tight junction pathways. Moreover, GV-sup directly enhanced Elafin and IL-8 secretion from the cervical gland cells. In the GV-abundant vaginal flora, IL-8 level increased the neutrophil elastase activity and Elafin inhibited the elastase activity to protect from tissue damage and infection. Thus, the balance of IL-8-induced neutrophil and Elafin-induced antiprotease activities may be crucial in preterm labor.

Real-world Data on the Incidence of Coronavirus Disease (COVID-19) in Patients With Advanced Thoracic Cancer During the Early Phase of the Pandemic in Japan.

BACKGROUND/AIM: The severity and associated mortality of coronavirus disease 2019 (COVID-19) are higher in patients with thoracic cancer than in healthy populations and those with other cancer types. Here, we investigated real-world data on the incidence of COVID-19 and false-negative cases using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) real-time reverse-transcription polymerase chain reaction (rRT-PCR) testing in patients with thoracic cancer. PATIENTS AND METHODS: We retrospectively reviewed patients with advanced thoracic cancer at the National Cancer Center Hospital between March 2020-May 2021. Blood samples were collected and evaluated for IgM and IgG antibodies specific for nucleocapsid (N) and spike (S) protein SARS-CoV-2 before and after rRT-PCR testing. False-negative cases were assessed based on anti-SARS-CoV-2 antibody levels before and after rRT-PCR testing. RESULTS: A total of 2,107 patients with thoracic cancer were identified between March 2020 and May 2021, 7 (0.3%) of whom developed COVID-19. Among the 218 patients who underwent at least one rRT-PCR test because of suspected COVID-19 symptoms or as a screening test at our institute, the most common diagnosis was non-COVID-19 pneumonia (34.4%), followed by tumor fever (30.7%). Furthermore, of the 218 patients, 120 paired serum samples before and after rRT-PCR testing were available. Seroconversion was identified in all three patients with positive SARS-CoV-2 rRT-PCR results but was only observed in 1 out of the 117 patients who tested negative; the rate of false-negative cases was low (0.9%). CONCLUSION: COVID-19 incidence among patients with advanced thoracic cancer was low during the early phase of the pandemic in Japan.

Molecular Dynamics Study on the Structure-Property Relationship of Self-Assembled Gear-Shaped Amphiphile Molecules with/without Methyl Groups.

Gaining insight into the encapsulation mechanism is important for controlling the encapsulation rate toward the self-assembly of gear-shaped amphiphile molecules (GSAs). To this aim, we conducted molecular dynamics (MD) simulations for three different hexameric nanocubes (1612+, 2612+, and 3612+) of GSAs (12+, 22+, and 32+, respectively) to elucidate the quantitative structure-property relationship between the stability of the nanocubes and the rate of encapsulation of a guest molecule. The 12+, 22+, and 32+ monomers differ from each other in the number of methyl groups, having three, zero, and two methyl groups, respectively. The 3612+ hexamer has methyl groups only on the equatorial region. In the cases of the simulations of 1612+ and 3612+, the cubic structures are maintained due to a tight triple-π stacking around the equator region. Meanwhile, 2612+ deforms easily due to the occurrence of a large fluctuation. These results indicate that the methyl groups on the equator are crucial to stabilize the nanocubes. The encapsulation of an iodide ion as a guest molecule is revealed to occur through the pole region via a gap that is easily formed in the nanocubes without methyl groups on the poles. Our study clearly suggests that self-assembled nanocubes can be designed to attain a specific stability and encapsulation efficiency simultaneously.

SARS-CoV-2 Antibody Response to Symptoms Indicative of COVID-19 in a Non-Infected Population in Japan: a Cross-Sectional Study.

This study was aimed at investigating differences in antibody titers indicative of the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between those who had experienced symptoms of coronavirus disease 2019 (COVID-19) and those who had not. We used data from a cross-sectional survey conducted at the National Cancer Center, Japan, of 434 individuals with no previous COVID-19 infection. The participants self-reported symptoms from the start of 2020. A generalized linear model was used to compare the mean SARS-CoV-2-specific IgG nucleocapsid protein (N-IgG) titer with estimated confidence intervals according to the onset of symptoms indicative of COVID-19. We observed a tendency toward an association between higher mean N-IgG titers and occurrence of high fever within the past 8 months (P = 0.053). The mean N-IgG titer was higher in those with prior symptoms (P = 0.03) and those with over three symptoms (P < 0.01) than in those without symptoms. The mean N-IgG titer was higher in those with symptoms and those with more symptoms that might indicate COVID-19 relative to those without symptoms, suggesting that transient but contained SARS-CoV-2 infection had occurred.

Anesthetic management of a patient with trisomy 18 undergoing esophageal banding and preceding gastrostomy-A case report.

A patient diagnosed with trisomy 18 is at great risk of perioperative morbidity and mortality, especially with complex congenital cardiac anomalies. Here, we report successful anesthetic management of palliative esophageal-banding and gastrostomy for trachea-esophageal fistula in a patient who had a complex congenital heart disease with trisomy 18.

Early Clinical Remission Is a Predictor of Long-Term Remission with the Use of Vedolizumab for Ulcerative Colitis.

Vedolizumab (VDZ) is an α4ß7 integrin-antibody used to manage refractory ulcerative colitis (UC). This retrospective multicenter study aimed to identify predictors of efficacy or the time points when evaluation of VDZ therapy for UC would be most useful. We compiled data on 87 patients with moderate to severe active UC that was treated with VDZ. Overall clinical remission (CR) rates at 6 weeks and 52 weeks after VDZ administration were 44.4% (bio-naïve 44.2%, bio-failure 44.8%) and 52.8% (bio-naïve 53.5%, bio-failure 51.7%) respectively. Also, 83.3% (bio-naïve 81.3%, bio-failure 85.7%) of patients achieved mucosal healing at week 52. Among patients with a CR at week 52, 73.3% had a CR at week 6. In contrast, of patients who discontinued VDZ, 82.4% had not reached a CR at week 6. Our study demonstrated that VDZ was effective in a large percentage of UC patients, with a high mucosal healing rate even after prior biological exposures. This suggests that VDZ can be a treatment option even in bio-failure cases. Additionally, it was considered that early CR can predict long-term remission and that week 6 can be a helpful evaluation point for treatment decisions when using VDZ for UC.

Exploratory evaluation of an eye-tracking system in patients with advanced spinal muscular atrophy type I receiving nusinersen.

Objective: This study evaluated the feasibility of a matching-pair test using eye-tracking technology to assess nusinersen effectiveness in patients with advanced spinal muscular atrophy (SMA) type I. Methods: This prospective, observational study enrolled patients with 5q-SMA type I who had lost gross motor function. Three different levels of matching-pair tests were conducted using the eye-gaze system (My Tobii; TobiiDynavox Inc.) at baseline, and after 9 and 24 weeks of nusinersen treatment. The primary endpoint was the change from baseline in matching-pair test scores and response times (i.e., the time to answer matching-pair test) at 24 weeks from baseline. Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), Pediatric Quality of Life inventory for patients with Neuromuscular Disease (PedsQL-NM) and Numerical Rating Scale (NRS) scores were also assessed as secondary endpoints. Analysis of ocular fixation was performed as an additional analysis. This study was registered at https://www.umin.ac.jp/ctr/ (UMIN000033935). Results: Seven patients (one male, six female) aged 5-21 years (median 11 years) were enrolled; all patients were bedridden and six patients were ventilated. All seven patients were able to conduct level 1 matching-pair tests at each assessment; five patients were also able to conduct levels 2 and 3. Two patients (those with the highest CHOP-INTEND scores) were able to complete all tests correctly within 60 s. There was a non-significant trend toward improvement in CHOP-INTEND, PedsQL-NM, and NRS scores over the 6-month period. There were no significant differences in the number of actions, errors, correct answers, or response times between baseline and Week 9 or 24 at any level. However, the result of an additional analysis suggests that detection of eye movement would be useful to evaluate for advanced SMA. Conclusions: Eye-tracking systems are possibly feasible for the assessment of treatment efficacy in patients with advanced SMA type I.

Severe Hypokalemia and Metabolic Alkalosis Caused by Licorice Discovered During the Treatment of Intraoperative Hypoxemia.

One of the causes of preoperative hypokalemia is the prolonged use of herbal medicines, especially licorice. Licorice can induce pseudo-aldosteronism, hypertension, metabolic alkalosis, and hypokalemia. An 87-year-old woman with a history of knee osteoarthritis was scheduled to undergo a total knee arthroplasty (TKA) under spinal anesthesia. She had also been prescribed herbal medicine for osteoarthritis of the knee two years before the surgery. During the surgery, the pulse oximeter showed hypoxemia. After the surgery was completed, arterial blood sampling showed hypoxemia, hypokalemia with electrocardiography (ECG) abnormalities, and metabolic alkalosis. The symptoms improved after the discontinuation of herbal medicines and administering potassium chloride. It is necessary to suspect electrolyte abnormalities as one of the causes of hypoxemia, hypertension, or ECG abnormalities in patients prescribed herbal medicines. Therefore, it is also important to ensure that patients on such drugs have their blood potassium levels assessed frequently in the perioperative period.

Animal models of chronic and recurrent Pseudomonas aeruginosa lung infection: significance of macrolide treatment.

Animal models of human diseases are invaluable and inevitable elements in identifying and testing novel treatments for serious diseases, including severe infections. Planning and conducting investigator-initiated human trials are generally accepted as being enormously challenging. In contrast, it is often underestimated how much planning, including background and modifying experiments, is needed to establish a relevant infectious disease animal model. However, representative animal infectious models, well designed to test generated hypotheses, are useful to improve our understanding of pathogenesis, virulence factors and host response and to identify novel treatment candidates and therapeutic strategies. Such results can subsequently proceed to clinical testing if suitable. The present review aims at presenting all the pulmonary Pseudomonas aeruginosa infectious models we have knowledge of and the detailed descriptions of established animal models in our laboratory focusing on macrolide therapy are presented.

An Algorithm for the Detection of General Movements of Preterm Infants Based on the Instantaneous Heart Rate.

Video recording and editing of general movements (GMs) takes time. We devised an algorithm to automatically extract the period of GMs emergence to assist in the assessment of GMs. The algorithm consisted of δHR: subtracting the moving average heart rate (HR) for the past 60 s from the average instantaneous HR; and %δHR: the percentage of the instantaneous HR to the moving average HR. Ten-second sections in which δHR was positive for three consecutive sections and contained at least one section with %δHR > 105% were extracted. Extracted periods are called automated extraction sections (AESs). We evaluated the concordance rate between AESs and GMs in three periods (gestational age 24−32, 33−34, and 35−36 weeks). The records of 84 very low birth weight infants were evaluated. Approximately 90% of AESs were accompanied by GMs at any period in both the supine and prone positions. The proportion of full-course (beginning to end) GMs among GMs in the AES was 80−85% in the supine position and 90% in the prone position in all periods. We could extract a sufficient number of assessable GMs with this algorithm, which is expected to be widely used for assisting in the assessment of GMs.

Fidgety Movements Assessment Accuracy Survey in Japan.

To investigate the accuracy of fidgety movements (FMs) assessment in Japanese assessors. Sixty specialists participated in the first survey. Of the participants, 18 were assessors certified by the GMs basic-training course. The surveys were composed of FMs assessment of 20 video clips. The correct assessment rates (CARs) were investigated. The survey videos were judged into three types: normal (F + +, F +), abnormal (AF) and absent (F + -, F -). After the first survey, each participant performed a self-learning exercise using clips of the first survey. The follow-up survey was conducted three months after the first survey. The median CAR of the first survey was 65% in certified assessors and 50% in noncertified assessors. The median CARs of certified assessors were significantly higher than that of noncertified assessors for all clips and for normal FMs and AF clips (p < 0.01). After 3 months of self-learning exercise the CARs in each judgement type improved in 28 follow-up survey participants. Their median CAR improved from 60% in the first survey to 84% in the follow-up survey. To practise general movements assessment (GMA), course certification is required. The self-learning exercise with the confirmed judgement FMs clips may be effective for improving the ability of FMs judgement.