KM Biologics (Japan)

Malnutrition is common among individuals with intellectual disabilities, and behavioral resistance may limit access to routine oral care. This study examined the association between refusal of oral care and poor nutritional status. In this cross-sectional study, conducted between February and March 2025, we assessed 55 adults with intellectual disabilities living in two designated residential support facilities for persons with disabilities in Fukuoka, Japan. Nutritional status was evaluated using the Mini Nutritional Assessment-Short Form. Oral care refusal was identified from staff records. Functional and body composition data were obtained using the Functional Independence Measure, Barthel Index, and bioelectrical impedance analysis. The at-risk/malnourished group had significantly lower BMI, fat mass, and functional scores, and a higher rate of oral care refusal (p=0.007). Logistic regression showed that oral care refusal [OR=9.23 (95% confidence interval (CI): 1.10-77.33], lower fat mass [OR=0.78 (0.66-0.92)] were independently associated with poor nutritional status (FIM-Eating [OR=0.86 (0.53-1.39)], gender [OR=0.44 (0.08-2.27)], age [OR=0.96 (0.90-1.02)]). AUC was 0.90 (0.81-0.98). Oral care refusal may indicate increased risk of malnutrition among adults with intellectual disabilities. Larger, longitudinal studies are needed to confirm these findings.

ABSTRACTIntroductionSafe and effective adeno‐associated virus (AAV) vectors are essential for gene therapy. Particle heterogeneity, specifically particle DNA of varying types and sizes, significantly affects recombinant adeno‐associated virus (rAAV) performance. Previous studies have identified particle‐associated DNAs; however, the specific DNA composition of these mixed populations remains poorly understood. This study aimed to investigate the DNA composition of the isolated subpopulations of rAAV particles obtained through anion exchange (AEX) chromatography.MethodsRAAV2‐ZsGreen1 particles were fractionated on an AEX column, resulting in 12 distinct fractions. We analyzed the DNA composition of these fractions using droplet digital PCR (ddPCR) and MiSeq to identify the incorporated DNA heterogeneity in them.ResultsOur findings illustrated a clear trend in which the DNA content increasing in fractions was associated with an increased rAAV genomic DNA ratio of total particle DNA. The particle DNA content increased significantly across fractions from Peak 1 to Peak 2, showing approximately 30,000‐ and 5000‐fold increases for ZsGreen1 (rAAV genome) and ampR (plasmid impurity), respectively. Notably, in the empty particle subpopulations, the rate of detectable DNA molecules was lower than one DNA fragment per 100 particles, with inverted terminal repeat (ITR) sequences being the most prevalent.ConclusionsWith the elucidated profile of particle DNAs, this study provides detailed information on particle heterogeneity, shedding light on empty and partial particle formation and impurity DNA incorporation.

Psychotropic drugs are associated with adverse outcomes in older adults. However, evidence on the effect of psychotropic use on walking ability in post-stroke patients is lacking. This study examined the association between psychotropic medication use and walking independence in post-stroke patients. This retrospective cohort study included stroke patients admitted for convalescent rehabilitation at a Japanese hospital between 2020 and 2022. Psychotropic medications (benzodiazepines, hypnotics, antipsychotics, and antidepressants) prescribed at admission were recorded. The primary outcome was walking independence at discharge, defined as a Functional Independence Measure (FIM) walk score ≥ 6. Logistic regression analyses examined the association between the number of psychotropic drugs and walking independence, adjusting for potential confounders. Of the 709 patients enrolled, 559 (mean age 75.5years, 52.8% male) were included in the analysis. At admission, 25.4% of patients used psychotropic drugs. In the adjusted analysis, the number of psychotropic medications was independently associated with lower walking independence at discharge (OR 0.620, 95% CI 0.428-0.897, P = 0.011). Hypnotic use specifically showed a negative impact on walking independence (OR 0.331, 95% CI 0.154-0.708, P = 0.004). However, psychotropic drug use was not significantly associated with improvement in FIM-motor scores. Psychotropic polypharmacy at admission, particularly with hypnotics, was associated with reduced likelihood of achieving walking independence after stroke rehabilitation. Judicious use of psychotropic medications may be warranted when ambulation is a critical goal for older post-stroke patients.

To generate a novel oncolytic vaccinia virus with improved safety and productivity, the genome of smallpox vaccine strain LC16m8 was modified by a bacterial artificial chromosome system. By using LC16m8, a replicating virus homologous to the target virus, as a helper virus for the bacterial artificial chromosome system, we successfully recovered genome-edited infectious viruses. Oncolytic viruses with limited growth in normal cells were obtained by deleting the genes for vaccinia virus growth factor (VGF), extracellular signal-regulated kinase-activating protein (O1L), and ribonucleotide reductase (RNR) present in the viral genome. Furthermore, the amino acid residues of seven proteins involved in extracellular enveloped virus virion formation were replaced to the IHD-J strain sequence, which is known to highly express extracellular enveloped virus. In cultured cancer cells (HeLa), these modified viruses showed cytotoxicity and increased productivity, but it was confirmed that the cytotoxicity was suppressed in normal cells (normal human dermal fibroblasts). For in vivo safety evaluation, a modified virus (MD-RVV-ΔRR-EEV6) in which the VGF, O1L, and RNR genes of LC16m8 were deleted and the genes of six extracellular enveloped virus-associated proteins were replaced with sequences derived from IHD-J strain, and another modified virus (MD-RVV) lacking only the VGF and O1L were administered intravenously to severe combined immunodeficiency mice. In the MD-RVV administration, animals in all dose groups died by 40 days after virus administration. On the other hand, after MD-RVV-ΔRR-EEV6 administration, 3 out of 5 animals in the high and medium dose groups and all animals in the low dose group were still alive by day 71, the end of the observation period. These results demonstrate that genome editing of oncolytic vaccinia virus can delete genes involved in viral replication to improve safety in normal cells, while replacing genes involved in maturation improves proliferative potential in cancer cells.

Although respiratory syncytial virus (RSV) vaccine development initiatives have existed for half a century, no candidate has been approved for application at all ages from neonates to children. Developing an effective and safe RSV vaccine for pediatric use is challenging owing to RSV-associated disease and vaccine-enhanced disease (VED). We aimed to design an RSV vaccine, KD-409, by structurally incorporating the F ectodomain and G protein central conserved domain without the CX3C chemokine motif and test its efficacy and safety. KD-409 formed rosette particles or trimmers. KD-409 immunization of mice mainly induced anti-RSV F protein IgG. The induced anti-F antibodies had a higher IgG2a/IgG1 ratio than pre-fusion F, suggesting that they induced Th1-dominant immunity. Active and passive immunities were assessed by analyzing the viral titers in BALB/c mice intranasally challenged with RSV after intramuscular KD-409 immunization and pups derived from mothers who were intramuscularly vaccinated with KD-409 twice, respectively. KD-409 was more effective than post-fusion F and had a lower minimum effective dose than pre-fusion F. Thus, KD-409 demonstrated great potential as a novel RSV vaccine candidate, outperforming existing RSV F-based candidates. Our findings provide a promising strategy to overcome RSV-associated acute lower respiratory infections without the risk of VED associated with traditional approaches.

Abstract The use of fibrin glue for hernia mesh fixation has been suggested to be effective in preventing hematomas and reducing postoperative pain. The effect of fibrin glue can vary significantly based on the device used. This study assessed the efficacy of fibrin glue based on the type of devices used in an ex vivo system. The rabbit’s abdominal wall was trimmed to a size of 3.0 × 6.0 cm and was secured at the edges with metal fixtures. To measure the maximum tensile strength at the point of adhesion failure, the hernia mesh was fixed to the rabbit’s abdominal wall using fibrin glue in a 2-cm square area, left for 3 min, and then pulled at a speed of 50 cm/min. The test was conducted 10 times for each group. The median (minimum–maximum) tensile strength values using the spraying, two-liquid mixing, and sequential layering methods were 3.58 (1.99–4.95), 0.51 (0.27–1.89), and 1.32 (0.63–1.66) N, respectively. The spraying method had predominantly higher tensile strength values than the two-liquid mixing and sequential layering methods (P < 0.01). In conclusion, in hernia mesh fixation, the spraying method can be adopted to achieve appropriate adhesive effects.

Citrin deficiency is an autosomal recessive disorder caused by a defect of citrin resulting from mutations in the SLC25A13 gene. Intrahepatic cholestasis and various metabolic abnormalities, including hypoglycemia, galactosemia, citrullinemia, and hyperammonemia may be present in neonates or infants in the "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD) form of the disease. Because at present, newborn screening (NBS) for citrin deficiency using citrulline levels in dried blood spots (DBS) can only detect some of the patients, we tried to develop a new evaluation system to more reliably detect newborns with citrin deficiency utilizing parameters already in place in present NBS methods. To achieve this goal, we re-analyzed NBS profiles of amino acids and acylcarnitines in 96 NICCD patients, who were diagnosed through selective screening or positive family history. Hereby, we identified the combined evaluation of arginine (Arg), citrulline (Cit), isoleucine+leucine (Ile + Leu), tyrosine (Tyr), free carnitine (C0) / glutarylcarnitine (C5-DC) ratio in DBS as potentially sensitive to diagnose citrin deficiency in pre-symptomatic newborns. In particular, a scoring system using threshold levels for Arg (≥9 μmol/L), Cit (≥ 39 μmol/L), Ile + Leu (≥ 99 μmol/L), Tyr (≥ 96 μmol/L) and C0/C5-DC ratio (≥327) was significantly effective to detect newborns who later developed NICCD, and could thus be implemented in existing NBS programs at no extra analytical costs whenever citrin deficiency is considered to become a novel target disease.

AimYLB113 biosimilar was evaluated in an open‐label extension single‐arm study to assess long‐term safety, efficacy, and immunogenicity in patients with rheumatoid arthritis (RA). We also report post‐hoc results on the incidence of injection‐site reactions (ISRs) and injection‐site erythema (ISE) from a phase III study.MethodParticipants from the phase III, double‐blind, randomized, 96 week equivalence study who completed the final visit received 50 mg YLB113 subcutaneously every 2 weeks. Key safety end points were assessed through adverse events (AEs), ISRs, ISE, and anti‐drug antibody (ADA) incidence. The efficacy end point was change from baseline in Disease Activity Score 28‐joint count (DAS28) over time.ResultsOf 201 participants, 184 (91.5%) completed the study. Treatment‐emergent AEs were experienced by 93.5% and severe AEs by 10.0% of participants. The discontinuation rate due to AEs was 2.0%. Overall, 20.0% of participants reported an incidence of ISRs throughout the open‐label extension study. Two participants developed ADAs, and none developed neutralizing ADAs at any time after study drug administration. The overall DAS28 (mean ± SD) change was 2.22 ± 0.95 at the study transition, 2.10 ± 0.91 at week 72, and 2.06 ± 0.89 at the end of the study. In the post‐hoc analysis, YLB113 showed a statistically significant lower incidence of ISRs (10 [3.8%], P < 0.0001) and ISE (5 [1.9%], P < 0.0001) compared with the reference product Enbrel®.ConclusionYLB113 demonstrated long‐term safety and sustained efficacy for up to 96 weeks. Patients on YLB113 experienced significantly lower ISRs and ISE in a post‐hoc analysis of the phase III study when compared with reference product.

Decellularized tissues are widely used as promising materials in tissue engineering and regenerative medicine. Research on the microstructure and components of the extracellular matrix (ECM) was conducted to improve the current understanding of decellularized tissue functionality. The presence of matrix-bound nanovesicles (MBVs) embedded within the ECM was recently reported. Results of a previous experimental investigation revealed that decellularized tissues prepared using high hydrostatic pressure (HHP) exhibited good in vivo performance. In the current study, according to the hypothesis that MBVs are one of the functional components in HHP-decellularized tissue, we investigated the extraction of MBVs and the associated effects on vascular endothelial cells. Using nanoparticle tracking assay (NTA), transmission electron microscopy (TEM), and RNA analysis, nanosized (100–300 nm) and membranous particles containing small RNA were detected in MBVs derived from HHP-decellularized small intestinal submucosa (SIS), urinary bladder matrix (UBM), and liver. To evaluate the effect on the growth of vascular endothelial cells, which are important in the tissue regeneration process, isolated SIS-derived MBVs were exposed to vascular endothelial cells to induce cell proliferation. These results indicate that MBVs can be extracted from HHP-decellularized tissues and may play a significant role in tissue remodeling.