Olanzapine Plus Triple Antiemetic Therapy for the Prevention of Carboplatin-Induced Nausea and Vomiting: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial.

PURPOSE: We evaluated the efficacy and safety of antiemetic therapy with olanzapine, a neurokinin-1 receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone for preventing chemotherapy-induced nausea and vomiting in patients receiving carboplatin-containing chemotherapy. PATIENTS AND METHODS: Chemotherapy-naïve patients scheduled to receive carboplatin (AUC ≥5) were randomly assigned to receive either olanzapine 5 mg once daily (olanzapine group) or placebo (placebo group) in combination with aprepitant, a 5-HT3 RA, and dexamethasone. The primary end point was the complete response (CR; no vomiting and no rescue therapy) rate in the overall phase (0-120 hours). Secondary end points included the proportion of patients free of nausea and safety. RESULTS: In total, 355 patients (78.6% male, median age 72 years, 100% thoracic cancer), including 175 and 180 patients in the olanzapine and placebo groups, respectively, were evaluated. The overall CR rate was 86.9% in the olanzapine group versus 80.6% in the placebo group. The intergroup difference in the overall CR rate was 6.3% (95% CI, -1.3 to 13.9). The proportions of patients free of chemotherapy-induced nausea in the overall (88.6% in the olanzapine group v 75.0% in the placebo group) and delayed (89.7% v 75.6%, respectively) phases were significantly higher in the olanzapine group than in the placebo group (both P < .001). Somnolence was observed in 43 (24.6%) and 41 (22.9%) patients in the olanzapine and placebo groups, respectively, and no events were grade ≥3 in severity. CONCLUSION: The addition of olanzapine was not associated with a significant increase in the overall CR rate. Regarding the prevention of nausea, adding olanzapine provided better control in patients receiving carboplatin-containing chemotherapy, which needs further exploration.

Xq22 deletion involving TCEAL1 in a female patient with early-onset neurological disease trait.

A 3.5-Mb microdeletion in Xq22 was identified in a female patient with early-onset neurological disease trait (EONDT). The patient exhibited developmental delay but no hypomyelination despite PLP1 involvement in the deletion. However, the clinical features of the patient were consistent with those of TCEAL1 loss-of-function syndrome. The breakpoint junction was analyzed using long-read sequencing, and blunt-end fusion was confirmed.

Characteristics of successful termination of atrial fibrillation by atrial antitachycardia pacing in patients with cardiac implantable electronic devices.

Asymptomatic paroxysmal atrial fibrillation (AF) is often found in patients implanted with cardiac implantable electronic devices (CIEDs). Second-generation atrial antitachycardia pacing (A-ATP) is effective in managing AF in patients implanted with CIEDs. The purpose of this study was to evaluate the efficacy and safety of A-ATP in patients implanted with CIEDs. This was a single-center retrospective study involving 91 patients (male 46 patients, mean age 74 ± 9 years) implanted with Reactive A-ATP equipped devices (84 patients with pacemakers, 6 with ICDs, and 1 with a CRT-D). The AF burden, rate of AF termination, and details of the activation of the A-ATP were analyzed in each patient. During a mean follow-up period of 21 ± 13 months, A-ATP was activated in 45 of 91 patients (49.5%). No patients had adverse events. Although the efficacy of the A-ATP varied among the patients, the median rate of AF termination was 44%. In comparison to the A-ATP start time, "0 min" had a higher AF termination rate by the A-ATP (39.4% vs. 24.4%, P = 0.011). The rate of termination by the A-ATP was high for AF with a long cycle length and a relatively regular rhythm. A-ATP successfully terminated AF episodes in some patients implanted with CIEDs. The optimal settings of the A-ATP will be determined in future studies.

Case report: An N-of-1 study using amplitude modulated transcranial alternating current stimulation between Broca's area and the right homotopic area to improve post-stroke aphasia with increased inter-regional synchrony.

Over one-third of stroke survivors develop aphasia, and language dysfunction persists for the remainder of their lives. Brain language network changes in patients with aphasia. Recently, it has been reported that phase synchrony within a low beta-band (14-19 Hz) frequency between Broca's area and the homotopic region of the right hemisphere is positively correlated with language function in patients with subacute post-stroke aphasia, suggesting that synchrony is important for language recovery. Here, we employed amplitude-modulated transcranial alternating current stimulation (AM-tACS) to enhance synchrony within the low beta band frequency between Broca's area and the right homotopic area, and to improve language function in a case of chronic post-stroke aphasia. According to an N-of-1 study design, the patient underwent short-term intervention with a one-time intervention of 15 Hz-AM-tACS with Broca's and the right homotopic areas (real condition), sham stimulation (sham condition), and 15 Hz-AM-tACS with Broca's and the left parietal areas (control condition) and long-term intervention with sham and real conditions (10 sessions in total, each). In the short-term intervention, the reaction time and accuracy rate of the naming task improved after real condition, not after sham and control conditions. The synchrony between the stimulated areas evaluated by coherence largely increased after the real condition. In the long-term intervention, naming ability, verbal fluency and overall language function improved, with the increase in the synchrony, and those improvements were sustained for more than a month after real condition. This suggests that AM-tACS on Broca's area and the right homotopic areas may be a promising therapeutic approach for patients with poststroke aphasia.

Reinforcement learning-based adaptive beam alignment in a photodiode-integrated array antenna module.

We successfully demonstrated an intelligent adaptive beam alignment scheme using a reinforcement learning (RL) algorithm integrated with an 8 × 8 photonic array antenna operating in the 40 GHz millimeter wave (MMW) band. In our proposed scheme, the three key elements of RL: state, action, and reward, are represented as the phase values in the photonic array antenna, phase changes with specified steps, and an obtained error vector magnitude (EVM) value, respectively. Furthermore, thanks to the Q-table, the RL agent can effectively choose the most suitable action based on its prior experiences. As a result, the proposed scheme autonomously achieves the best EVM performance by determining the optimal phase. In this Letter, we verify the capability of the proposed scheme in single- and multiple-user scenarios and experimentally demonstrate the performance of beam alignment to the user's location optimized by the RL algorithm. The achieved results always meet the signal quality requirement specified by the 3rd Generation Partnership Project (3GPP) criterion for 64-QAM orthogonal frequency division multiplexing (OFDM).

Blocking insulin-like growth factor 1 receptor signaling pathway inhibits neuromuscular junction regeneration after botulinum toxin-A treatment.

Botulinum toxin-A (BTX) administration into muscle is an established treatment for conditions with excessive muscle contraction. However, botulinum therapy has short-term effectiveness, and high-dose injection of BTX could induce neutralizing antibodies against BTX. Therefore, prolonging its effects could be beneficial in a clinical situation. Insulin-like growth factor-1 receptor (IGF1R) and its ligands, insulin-like growth factor (IGF) -I and II, regulate the physiological and pathological processes of the nervous system. It has been suggested that IGF1R is involved in the process after BTX administration, but the specific regeneration mechanism remains unclear. Therefore, this study aimed to determine how inhibition of IGF1R signaling pathway affects BTX-induced muscle paralysis. The results showed that anti-IGF1R antibody administration inhibited the recovery from BTX-induced neurogenic paralysis, and the synaptic components at the neuromuscular junction (NMJ), mainly post-synaptic components, were significantly affected by the antibody. In addition, the wet weight or frequency distribution of the cross-sectional area of the muscle fibers was regulated by IGF1R, and sequential antibody administration following BTX treatment increased the number of Pax7+-satellite cells in the gastrocnemius (GC) muscle, independent of NMJ recovery. Moreover, BTX treatment upregulated mammalian target of rapamycin (mTOR)/S6 kinase signaling pathway, HDAC4, Myog, Fbxo32/MAFbx/Atrogin-1 pathway, and transcription of synaptic components, but not autophagy. Finally, IGF1R inhibition affected only mTOR/S6 kinase translational signaling in the GC muscle. In conclusion, the IGF1R signaling pathway is critical for NMJ regeneration via specific translational signals. IGF1R inhibition could be highly beneficial in clinical practice by decreasing the number of injections and total dose of BTX due to the prolonged duration of the effect.

A protease activity-based machine-learning approach as a complementary tool for conventional diagnosis of diarrhea-predominant irritable bowel syndrome.

Irritable bowel syndrome (IBS) has no clinically accepted biomarkers even though it affects a large number of individuals worldwide. To address this lack of understanding, we evaluated peptidase activity in fecal samples from 35 patients with diarrheal IBS without symptom exacerbation (IBS-n) and 35 healthy subjects using a library of 384 fluorescent enzymatic substrate probes. IBS-n patients had high trypsin-like peptidase activity for cleavage of C-terminal lysine and arginine residues and low elastase-like activity for cleavage of C-terminal serine and glycine residues. These fluorescent probe library data, together with diagnostic machine-learning techniques, were able to accurately predict IBS-n. This approach can be used to diagnose diseases where no clinically accepted biomarkers exist, in which fecal enzyme activity is altered and also suggests that the development of new therapies targeting enzyme activities is possible.

The Prognostic Nutritional Index before durvalumab after chemoradiation predict the overall survival in patients with stage III non-small cell lung cancer.

BACKGROUND: Adjuvant durvalumab after chemoradiation has become the standard of care for patients with stage III NSCLC, according to the PACIFIC trial. Whether biomarkers before durvalumab for patients with stage III NSCLC showed predictive and prognostic effects remains unknown. METHODS: This is a retrospective study in the Fujieda Municipal General Hospital between October 2018 and March 2022. We assessed the predictive value of the Prognostic Nutritional Index (PNI) in stage III non-small cell lung cancer (NSCLC) patients treated with durvalumab after chemoradiation. RESULTS: After applying the inclusion and exclusion criteria, the study included 56 patients for further analysis. The median follow-up period was 17.6 months (range, 3.0-45.4 months). According to receiver operating characteristic curve results, the PNI cutoff value to predict overall survival (OS) was 37.9, with sensitivity and specificity at 67.9% and 67.9%. Accordingly, the patients were divided into low- and high-PNI groups. Patients with the low-PNI group had a significantly shorter progression-free survival compared to the high-PNI group (median, 9.1 vs. 21.3 months, p = 0.032). OS was also shorter in the low-PNI group (median, 19.0 months vs. not reached, p < 0.001). In the multivariate Cox hazards regression analyses, the high-PNI was an independent prognostic factor for OS (hazard ratio, 0.187; 95% confidence interval, 0.046-0.760; p = 0.019).It seems that PNI could be used as a predictor for OS in patients with stage III NSCLC treated with durvalumab after chemoradiation.KEY MESSAGESInadequate immunocompetence and nutritional status after chemoradiation therapy may result in poor antitumor efficacy of ICIs.Pretreatment immune and nutritional assessment using PNI could be considered an independent predictor for the survival of stage III NSCLC patients treated with durvalumab after chemoradiation therapy.

Analysis of the ratio of urinary beta-2-microglobulin to total protein concentration in children with isolated tubulointerstitial disease.

BACKGROUND: Proteinuria is broadly classified into glomerular and tubular proteinuria. Urinary beta-2-microglobulin (ß2-MG) is known as a marker for detecting tubulointerstitial diseases. However, tubulointerstitial damage can also lead to an increase in urinary ß2-MG level in some patients with glomerular diseases. This study aimed to determine the ratio of urinary ß2-MG to total protein (TP) concentration in patients with both isolated tubulointerstitial and glomerular disease. METHODS: This multicenter, retrospective study included children with Dent disease or lupus nephritis in five facilities. Their urinary ß2-MG levels were > 1000 µg/L. Urinary ß2-MG and TP concentrations were obtained, and the ratio of urinary ß2-MG to TP concentration (µg/mg) was calculated. The Mann-Whitney U test was performed to compare this ratio between these children. The optimal cutoff value of the ratio for considering the presence of glomerular disease was obtained from the receiver operating characteristic (ROC) curve. RESULTS: We obtained information on 23 children with Dent disease and 14 children with lupus nephritis. The median ratios of urinary ß2-MG to TP concentrations in children with Dent disease and lupus nephritis were 84.85 and 1.59, respectively. The ROC curve yielded the optimal cutoff value of this ratio for distinguishing between these diseases, and the cutoff value was found to be 22.3. CONCLUSION: In children with tubulointerstitial diseases, the urinary ß2-MG concentration may be approximately 8.5% of the TP concentration. The possibility of presenting with glomerular disease should be considered in patients with a ratio of urinary ß2-MG to TP concentration of < 22.3 (µg/mg).

Case report: Backward gait training combined with gait-synchronized cerebellar transcranial alternating current stimulation in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is characterized by recurrent falls caused by postural instability, and a backward gait is considered beneficial for postural instability. Furthermore, a recent approach for rehabilitation combined with gait-oriented synchronized stimulation using non-invasive transcranial patterned stimulation could be promising for balance function. Here, we present a case of PSP with backward gait training combined with gait-synchronized transcranial alternating current stimulation (tACS). A 70-year-old woman with PSP-Richardson's syndrome underwent backward gait training combined with synchronized cerebellar tACS. Initially, she underwent short-term intervention with combined training of backward gait with synchronized cerebellar tACS, asynchronized, or sham stimulation according to the N-of-1 study design. Synchronized tACS training demonstrated a decrease in postural instability, whereas asynchronized or sham stimulation did not. The additional long-term interventions of combined backward gait training with synchronized cerebellar tACS demonstrated further decrease in postural instability with improvements in gait speed, balance function, and fall-related self-efficacy in daily life. The present case describes a novel approach for motor symptoms in a patient with PSP. Backward gait training with synchronized cerebellar tACS may be a promising therapeutic approach.

Case report: A novel approach of closed-loop brain stimulation combined with robot gait training in post-stroke gait disturbance.

Most post-stroke patients have long-lasting gait disturbances that reduce their daily activities. They often show impaired hip and knee joint flexion and ankle dorsiflexion of the lower limbs during the swing phase of gait, which is controlled by the corticospinal tract from the primary motor cortex (M1). Recently, we reported that gait-synchronized closed-loop brain stimulation targeting swing phase-related activity in the affected M1 can improve gait function in post-stroke patients. Subsequently, a gait-training robot (Orthobot®) was developed that could assist lower-limb joint movements during the swing phase of gait. Therefore, we investigated whether gait-synchronized closed-loop brain stimulation combined with robot-assisted training targeting the swing phase could enhance the recovery of post-stroke gait disturbance. A 57-year-old female patient with chronic post-stroke hemiparesis underwent closed-loop brain stimulation combined with robot-assisted training for 10 min 2 years after left pons infarction. For closed-loop brain stimulation, we used transcranial oscillatory electrical current stimulation over the lesioned M1 foot area with 1.5 mA of DC offset and 0-3 mA of sine-wave formed currents triggered by the paretic heel contact to set the maximum current just before the swing phase (intervention A; two times repeated, A1 and A2). According to the N-of-1 study design, we also performed sham stimulation (intervention B) and control stimulation not targeting the swing phase (intervention C) combined with robot-assisted training in the order of A1-B-A2-C interventions. As a result, we found larger improvements in gait speed, the Timed Up and Go test result, and muscle strength after the A1 and A2 interventions than after the B and C interventions. After confirming the short-term effects, we performed an additional long-term intervention twice a week for 5 weeks, for a total of 10 sessions. Gait parameters also largely improved after long-term intervention. Gait-synchronized closed-loop brain stimulation combined with robot-assisted training targeting the swing phase of gait may promote the recovery of gait function in post-stroke patients. Further studies with a larger number of patients are necessary.

Steroid- and immunosuppressant-based protocol of Henoch-Schönlein purpura nephritis without angiotensin inhibitors in the acute phase.

BACKGROUND: The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest initially using angiotensin-converting-enzyme inhibitors (ACE-Is) and/or angiotensin receptor blockers (ARBs) to treat Henoch-Schönlein purpura nephritis (HSPN). However, these guidelines might overlook the potential benefits of aggressive therapy. Therefore, we evaluated the efficacy of an HSPN protocol that primarily uses steroids and immunosuppressants, without ACE-Is or ARBs. METHODS: We determine treatment intensity based on International Study of Kidney Diseases in Children (ISKDC) grading. Fifty-one patients were treated with our protocol that primarily uses steroids and immunosuppressants. ACE-Is and ARBs were not used in the acute phase, including before renal biopsy. We evaluated the proteinuria disappearance rate, duration to proteinuria disappearance, and estimated glomerular filtration rate (eGFR) at the time of last observation and compared them to those in previous reports. RESULTS: Proteinuria disappeared in 49 patients (96%) within a median of 5 months. The median eGFR was 116.0 mL/min/1.73 m2 at the time of last observation. Six of 51 patients had acute kidney injury (eGFR<90 mL/min/1.73 m2) before treatment, but all recovered during the observation period (median 52 months). CONCLUSIONS: Our steroid- and immunosuppressant-based protocol without ACE-Is or ARBs in the acute phase of HSPN had almost equivalent efficacy to that in previous studies that used ACE-Is and/or ARBs with steroids and immunosuppressants.

Eculizumab for paediatric patients with atypical haemolytic uraemic syndrome: full dataset analysis of post-marketing surveillance in Japan.

BACKGROUND: Eculizumab was approved for atypical haemolytic uraemic syndrome (aHUS) in Japan in 2013. Post-marketing surveillance (PMS) was mandated by regulatory authorities to assess the safety and effectiveness of eculizumab in patients with aHUS in a real-world setting. METHODS: Paediatric patients in the PMS cohort who were <18 years of age at the first administration of eculizumab and diagnosed with aHUS [excluding Shiga toxin-producing Escherichia coli HUS, thrombotic thrombocytopaenic purpura and secondary thrombotic microangiopathy (TMA)] were included in the effectiveness and safety analysis. Clinical endpoints of effectiveness [complete TMA response, TMA event-free status, platelet (PLT) count and lactate dehydrogenase (LDH) normalization, serum creatinine (sCr) decrease and estimated glomerular filtration rate (eGFR) improvement] were analysed in patients treated with at least one dose of eculizumab. Serious adverse events (SAEs) were also evaluated. RESULTS: A total of 40 paediatric patients (median age 5 years) were included. The median eculizumab treatment duration was 66 weeks. PLT count, LDH and eGFR significantly improved at 10 days post-treatment. Complete TMA response, haematologic normalization, sCr decrease, eGFR improvement and TMA event-free status were achieved by 73.3%, 73.3%, 70.0%, 78.3% and 77.5% of patients, respectively. Discontinuation criteria were met by 18 patients: 13 patients maintained treatment discontinuation at the end of observation and 5 patients, including 1 patient with aHUS relapse, continued the treatment but extended the treatment interval. During eculizumab treatment, 59 SAEs (0.66/person-year) were reported. Although four deaths were reported, none of them were related to eculizumab. CONCLUSION: Eculizumab was well tolerated and effective for paediatric patients with aHUS in the real-world setting in Japan.

Effects of adding a neurokinin-1 receptor antagonist to 5 mg olanzapine, a 5-hydroxytryptamine-3 receptor antagonist, and dexamethasone for preventing carboplatin-induced nausea and vomiting: a propensity score-matched analysis.

BACKGROUND: Olanzapine has been reported to be an effective antiemetic in patients receiving carboplatin-based chemotherapy. However, the efficacy of a neurokinin-1 receptor antagonist (NK1RA) added to olanzapine, a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA), and dexamethasone (DEX) has not been proven. This study aimed to assess the efficacy and safety of NK1RA, in combination with three-drug antiemetic regimens containing olanzapine, in preventing nausea and vomiting induced by carboplatin-based chemotherapy. METHODS: Data were pooled for 140 patients receiving carboplatin-based chemotherapy from three multicenter, prospective, single-arm, open-label phase II studies that evaluated the efficacy and safety of olanzapine for chemotherapy-induced nausea and vomiting. The propensity score of the co-administration of NK1RA was estimated for each patient using a logistic regression model that included age, sex, and carboplatin dose. We analyzed a total of 62 patients, who were treated without NK1RA (non-NK1RA group: 31 patients) and with NK1RA (NK1RA group: 31 patients). The patients were selected using propensity score matching. RESULTS: The complete response rate (without emetic episodes or with no administration of rescue medication) in the overall period (0-120 h post carboplatin administration) was 93.5% in the non-NK1RA group and 96.8% in the NK1RA group, with a difference of -3.2% (95% confidence interval, -18.7% to 10.9%; P = 1.000). In terms of safety, there was no significant difference between the groups in daytime sleepiness and concentration impairment, which are the most worrisome adverse events induced by olanzapine. CONCLUSIONS: The findings suggest that antiemetic regimens consisting of olanzapine, 5HT3RA, and DEX without NK1RA may be a treatment option for patients receiving carboplatin-based chemotherapy.

Mortality outcomes and clinical background of children on maintenance dialysis without receiving kidney transplantation.

BACKGROUND: Some pediatric patients on maintenance dialysis may need end-of-life care in the future because of being excluded from the indication of kidney transplantation and experiencing difficulty in continuation of their dialysis. This study aimed to thoroughly elucidate mortality outcomes of children on maintenance dialysis including the cause of death and clinical background of exclusion from indication of transplantation. PATIENTS AND METHODS: This single-center retrospective study enrolled 53 children who received kidney transplantation (5) or maintenance peritoneal dialysis (PD, 48) as initial renal replacement therapy (RRT). We examined the selected RRT modalities, mortality outcomes, clinical backgrounds of cause of death, and risk factors of excluding from future the indication of transplantation. RESULTS: Nine (17%) of all 53 patients, all receiving PD (9/48, 19%), were finally excluded from next RRT indication-7 were excluded due to severe extrarenal complications that indicated high risk for transplantation and 2 were excluded due to severe psychomotor retardation and at the guardians' discretion. Patients who were excluded from the indication had a younger age at PD induction and higher proportion of cerebral and cardiac complications or psychomotor retardation than patients who were included in the indication. Of the nine patients, seven died; of which, one patient died due to fatal progression of extrarenal complications and six died due to infectious or noninfectious dialysis-related complications. CONCLUSION: Patients with severe extrarenal complications or psychomotor retardation tend to be excluded from the indication of transplantation. Their condition becomes fatal because of the complications of long-term dialysis and progression in extrarenal complications.

Serum albumin level is associated with mycophenolic acid concentration in children with idiopathic nephrotic syndrome.

Mycophenolate mofetil is effective for the treatment of pediatric idiopathic nephrotic syndrome (INS). The dosage of mycophenolate mofetil is adjusted according to the serum concentration of mycophenolic acid (MPA). Kidney function or cyclosporine (CsA) concentrations affect serum MPA levels. However, few studies have focused on the association between serum concentrations of MPA and albumin. This retrospective observational study aimed to evaluate the relationship between the serum concentrations of MPA and albumin in INS children. Subjects were children with INS who underwent the therapeutic drug monitoring of CsA and MPA. We obtained the serum albumin (sAlb) concentration, estimated glomerular filtration rate (eGFR), age, and MPA and CsA areas under concentration-time curves from 0 to 12 h (AUC0-12). Multiple linear regression analysis and generalized estimating equations were performed to predict values for MPA AUC0-12. We obtained information for 51 INS children with 261 MPA AUC0-12 measurements. The standardized regression coefficients of sAlb, eGFR, CsA AUC0-12, and age were 0.54, - 0.21, - 0.07, and 0.04, respectively. Furthermore, MPA AUC0-12 levels positively correlated with sAlb concentrations (p < 0.001) and were inversely correlated with eGFR values (p = 0.005) but not with CsA AUC0-12 (p = 0.24) and age (p = 0.65).Conclusion: Serum albumin concentration was strongly associated with total MPA concentration compared with kidney function or CsA values. Although patients with INS may have a low serum concentration of total MPA in the presence of low sAlb concentration, close attention should be paid to the interpretation of the low MPA values. What is Known: • The dosage of mycophenolate mofetil is adjusted according to the serum concentration of total mycophenolic acid. • Kidney function, cyclosporin concentrations, or serum albumin concentrations influence serum mycophenolic acid levels. What is New: • Serum albumin concentration is more strongly associated with total mycophenolic acid concentration than kidney function or cyclosporin values. • In children with nephrotic syndrome, the total mycophenolic acid concentration may not increase in the presence of severe hypoalbuminemia.

Metabolic Effects of Bee Larva-Derived Protein in Mice: Assessment of an Alternative Protein Source.

Food crises caused by growing global population or environmental changes are predicted in the near future; therefore, sustainable solutions are needed. Edible insects, which are rich in protein and can save feed and environmental resources, have the potential to be a sustainable alternative protein source. However, there is limited evidence on the impact on health. In this study, we investigated the biological effects of ingesting bee larva by examining their effects on amino acid, lipid, and glucose metabolism in animal models. In our animal experiments, the replacement of casein as a protein source, with edible insects, did not seem to cause any deficiency in murine amino acid levels in the plasma and liver. Metabolomic analysis of plasma metabolites showed decreased 3-methylhistidine and increased nicotinamide in the bee larva-derived protein-fed mice. Decreased levels of plasma 3-metylhistidine, an indicator of muscle degradation, implies that replacement to bee-larva protein from casein did not cause muscle degradation in vivo. We further investigated effects of increased plasma nicotinamide on peripheral tissue and found an increase in expression levels of genes involved in glucose uptake in muscle and thermogenesis in adipose tissue. These data imply that bee larva is a potential sustainable, safe and healthy alternative protein source.

Genotype-Phenotype Correlation in WT1 Exon 8 to 9 Missense Variants.

INTRODUCTION: WT1 missense mutation in exon 8 or 9 causes infantile nephrotic syndrome with early progression to end-stage kidney disease (ESKD), Wilms tumor, and 46,XY female. However, some patients with missense mutations in exon 8 or 9 progress to ESKD in their teens or later. Therefore, we conducted a systematic review and functional analysis of WT1 transcriptional activity. METHODS: We conducted a systematic review of 174 cases with WT1 exon 8 or 9 missense variants from our cohort (n=13) and previous reports (n=161). Of these cases, mild and severe genotypes were selected for further in vitro functional analysis using luciferase assay. RESULTS: The median age of developing ESKD was 1.17 years. A comparative study was conducted among three WT1 genotype classes: mutations of the DNA-binding site (DBS group), mutations outside the DNA-binding site but at sites important for zinc finger structure formation by 2 cysteines and 2 histidines (C2H2 group), and mutations leading to other amino acid changes (Others group). The DBS group showed the severest phenotype and the C2H2 group was intermediate, whereas the Others group showed the mildest phenotype (developing ESKD at 0.90, 2.00, and 3.92 years, respectively, with significant differences). In vitro functional analysis showed dominant-negative effects for all variants; in addition, the DBS and C2H2 mutations were associated with significantly lower WT1 transcriptional activity than the other mutations. CONCLUSION: Not only the DNA-binding site but also C2H2 zinc finger structure sites are important for maintaining WT1 transcriptional activity, and their mutation causes severe clinical symptoms.

Efficacy and safety of 5 mg olanzapine for nausea and vomiting management in cancer patients receiving carboplatin: integrated study of three prospective multicenter phase II trials.

BACKGROUND: The efficacy of olanzapine as an antiemetic agent in cancer chemotherapy has been demonstrated. However, few high-quality reports are available on the evaluation of olanzapine's efficacy and safety at a low dose of 5 mg among patients treated with carboplatin regimens. Therefore, in this study, we investigated the efficacy and safety of 5 mg olanzapine for managing nausea and vomiting in cancer patients receiving carboplatin regimens and identified patient-related risk factors for carboplatin regimen-induced nausea and vomiting treated with 5 mg olanzapine. METHODS: Data were pooled for 140 patients from three multicenter, prospective, single-arm, open-label phase II studies evaluating the efficacy and safety of olanzapine for managing nausea and vomiting induced by carboplatin-based chemotherapy. Multivariable logistic regression analyses were performed to determine the patient-related risk factors. RESULTS: Regarding the endpoints of carboplatin regimen-induced nausea and vomiting control, the complete response, complete control, and total control rates during the overall study period were 87.9, 86.4, and 72.9%, respectively. No treatment-related adverse events of grade 3 or higher were observed. The multivariable logistic regression models revealed that only younger age was significantly associated with an increased risk of non-total control. Surprisingly, there was no significant difference in CINV control between the patients treated with or without neurokinin-1 receptor antagonist. CONCLUSIONS: The findings suggest that antiemetic regimens containing low-dose (5 mg) olanzapine could be effective and safe for patients receiving carboplatin-based chemotherapy.

Serum S100A8 and S100A9 as prognostic biomarkers in acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a devastating and life-threatening condition during its clinical course. Biomarkers for precisely anticipating the prognosis of AE-IPF remain to be fully established. The objective of this study was to clarify whether S100A8 and S100A9, which are calcium-binding proteins mainly produced by activated neutrophils, are significant prognostic biomarkers in AE-IPF. METHODS: Thirty-seven patients with AE-IPF who were diagnosed and treated at our hospital were retrospectively evaluated. The serum levels of S100A8 and S100A9 were measured using enzyme-linked immunosorbent assay, and the relationships between these levels and clinical parameters or prognosis were evaluated. RESULTS: The serum levels of S100A8 (median 386.5 ng/mL) and S100A9 (median 60.2 ng/mL) in patients with AE-IPF were significantly higher than those in age-matched healthy controls and in patients at IPF diagnosis (p < 0.001 for all combinations). The serum levels of S100A8 negatively correlated with percent forced vital capacity (r = -0.356, p = 0.049) and positively correlated with peripheral white blood cell number (r = 0.509, p = 0.002). Immunohistochemical staining of autopsy lung specimens showed that neutrophils, present mainly in the alveolar septum, were positive for S100A8 and S100A9. Patients with AE-IPF with higher levels of S100A8 or S100A9 showed significantly worse 3-month survival than those with lower levels (log-rank test, both p = 0.028). Finally, in multivariate analysis, the serum levels of both S100A8 and S100A9 were significant prognostic factors (hazard ratio 4.032, p = 0.023 and hazard ratio 4.327, p = 0.012). CONCLUSION: The serum levels of S100A8 and S100A9 at AE were significant prognostic biomarkers in patients with AE-IPF.