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Lysosomes have many roles, including degrading macromolecules and signalling to the nucleus 1 . Lysosomal dysfunction occurs in various human conditions, such as common neurodegenerative diseases and monogenic lysosomal storage disorders (LSDs) 2 – 4 . For most LSDs, the causal genes have been identified but, in some, the function of the implicated gene is unknown, in part because lysosomes occupy a small fraction of the cellular volume so that changes in lysosomal contents are difficult to detect. Here we develop the LysoTag mouse for the tissue-specific isolation of intact lysosomes that are compatible with the multimodal profiling of their contents. We used the LysoTag mouse to study CLN3, a lysosomal transmembrane protein with an unknown function. In children, the loss of CLN3 causes juvenile neuronal ceroid lipofuscinosis (Batten disease), a lethal neurodegenerative LSD. Untargeted metabolite profiling of lysosomes from the brains of mice lacking CLN3 revealed a massive accumulation of glycerophosphodiesters (GPDs)—the end products of glycerophospholipid catabolism. GPDs also accumulate in the lysosomes of CLN3-deficient cultured cells and we show that CLN3 is required for their lysosomal egress. Loss of CLN3 also disrupts glycerophospholipid catabolism in the lysosome. Finally, we found elevated levels of glycerophosphoinositol in the cerebrospinal fluid of patients with Batten disease, suggesting the potential use of glycerophosphoinositol as a disease biomarker. Our results show that CLN3 is required for the lysosomal clearance of GPDs and reveal Batten disease as a neurodegenerative LSD with a defect in glycerophospholipid metabolism. The lysosomal transmembrane protein CLN3 is required for the lysosomal clearance of glycerophosphodiesters in mice and in human cells, suggesting that the loss of CLN3 causes Batten disease in children due to defects in glycerophospholipid metabolism.

Antimicrobial resistance (AMR) in intensive care units (ICUs) is a critical issue, which has been exacerbated by the coronavirus disease 2019 (COVID-19) pandemic. This study investigated AMR prevalence and its associated factors among ICU patients in two Vietnamese hospitals from January 2020 to June 2022. Electronic medical records of 1,296 patients with 2,432 non-duplicate bacterial isolates were collected in Phu Tho Hospital (Northern, rural, non-COVID-19 treatment) and 175 Hospital (Southern, urban, COVID-19 treatment centre). Antibiotic susceptibility testing was conducted using VITEK2, BD Phoenix 100, and disk diffusion methods. Logistic regression with 1,000 bootstrap resampling and cross-validation was used to examine factors linked to AMR. Results revealed Acinetobacter spp. (27.5%) as leading strains in Phu Tho Hospital, while Klebsiella spp. (28.0%) predominated in 175 Hospital, except during 2021when Acinetobacter spp. reached the peak. Alarmingly, Acinetobacter spp., Klebsiella spp., and Pseudomonas aeruginosa demonstrated the highest AMR rates and multidrug resistance rates (83.8%–95.8%) in both hospitals. Resistance to cephalosporins, carbapenems, and fluoroquinolones ranged from 75% to 100%. Significant associated factors included age, sex, location, initial admission diagnosis, and bacterial isolation month. This study highlights the urgent need for controlling AMR in ICUs during the pandemic.

CLN3 disease is a neurodegenerative disorder with onset in childhood. It affects multiple functions at different developmental stages. Incomplete understanding of the pathophysiology hampers identification of cell and tissue biochemical compounds reflective of the disease process. As treatment approaches are being explored, more sensitive, objective, quantifiable, and clinically relevant biomarkers are needed. We collected prospective biosamples from 21 phenotyped individuals with CLN3. We measured neurofilament light chain (NEFL) levels, a marker of neuronal damage, in cross-sectional CSF and serum samples from individuals with CLN3 and in pediatric non-CLN3 controls using two different assays. Cerebrospinal fluid (CSF) and serum NEFL levels are significantly higher in CLN3 (CSF: 2096 ± 1202; serum: 29.0±18.0 pg/mL) versus similarly aged non-CLN3 (CSF: 345 ± 610; serum: 6.7±3.2 pg/mL) samples. NEFL levels correlate with Unified Batten Disease Rating Scale and adaptive behavior composite scores, and magnetic resonance (MR) spectroscopy markers. NEFL levels from CSF and serum are strongly correlated (rp = 0.83; p < 0.0001). CSF and serum NEFL levels increase in multiple neurologic conditions. Here, we show that CSF and serum NEFL levels also increase in CLN3 (versus non-CLN3) and correlate with other disease-relevant measures. These findings suggest NEFL as a relevant and feasible biomarker for applications in CLN3 clinical trials and management.

PurposePulmonary disease is the major cause of morbidity and mortality in osteogenesis imperfecta (OI). We investigated the contribution of intrinsic lung factors to impaired pulmonary function in children and young adults with OI types III, IV, VI.MethodsPatients with type III (n=8), IV (n=21), VI (n=5), VII (n=2) or XIV (n=1) OI (mean age 23.6 years) prospectively underwent pulmonary function tests (PFTs) and thoracic CT and radiographs.ResultsPFT results were similar using arm span or ulnar length as height surrogates. PFTs were significantly lower in type III than type IV or VI OI. All patients with type III and half of type IV OI had lung restriction; 90% of patients with OI had reduced gas exchange. Patients with COL1A1 variants had significantly lower forced expiratory flow (FEF)25%–75% compared with those with COL1A2 variants. PFTs correlated negatively with Cobb angle or age. CT scans revealed small airways bronchial thickening (100%, 86%, 100%), atelectasis (88%, 43%, 40%), reticulations (50%, 29%, 20%), ground glass opacities (75%, 5%, 0%), pleural thickening (63%, 48%, 20%) or emphysema (13%, 19%, 20%) in type III, IV or VI OI, respectively.ConclusionBoth lung intrinsic and extrinsic skeletal abnormalities contribute to OI pulmonary dysfunction. Most young adult patients have restrictive disease and abnormal gas exchange; impairment is greater in type III than type IV OI. Decreased FEF25%–75% and thickening of small bronchi walls indicate a critical role for small airways. Lung parenchymal abnormalities (atelectasis, reticulations) and pleural thickening were also detected. Clinical interventions to mitigate these impairments are warranted.Trial registration number NCT03575221.

Background Antimicrobial resistance (AMR) is a critical global health issue, with inconsistent adherence to antimicrobial stewardship contributing to its worsening. This study aims to assess physicians’ awareness and attitudes towards AMR and appropriate antimicrobial use across different medical specialties in Japan. Methods An online cross-sectional survey was conducted from January 31 to February 5, 2024, among 280 physicians from three specialties (internal medicine, pediatrics, and otorhinolaryngology) who were working in outpatient clinics in Japan. Participants were asked about their familiarity with the National Action Plan (NAP) on AMR and the manuals of Ministry of Health and Labor Welfare (MHLW) on prudent antimicrobial use. Their opinions on AMR facts and antibiotic use were also surveyed using five-point Likert scales. Data were analyzed using descriptive statistics, multilevel mixed-effects ordered logistic regression and generalized linear models to examine factors influencing NAP/manuals adherence. Results Most respondents were male (85%) and predominantly aged 50 and above (73.9%), Familiarity with the AMR Action Plan varied, with 36.4% of respondents reported understanding its content, while 37.5% only knew its name. Similarly, 27.1% of respondents used the MHLW manuals, whereas 48.6% were aware of them but did not use them. Internal medicine physicians showed the highest adherence to antimicrobial stewardship and most concern about AMR facts, while pediatricians demonstrated the highest adherence to MHLW manuals (AOR = 2.4, p  = 0.000 compared to internal medicine doctors). Otorhinolaryngologists reported higher awareness of NAP (AOR = 2.6, p  = 0.006 compared to internal medicine doctors) but had the lowest adherence to NAP and MHLW manuals. Younger physicians (< 50 years) were more proactive in addressing AMR and adhering to antimicrobial stewardship than older physicians. Messages emphasizing the prevention of drug resistance and societal impacts of AMR were most associated with positive attitudes from physicians in outpatient clinics. Conclusions This study highlights significant variability in AMR awareness and adherence across specialties and age groups. Internal medicine physicians showed the highest adherence, while pediatricians were the most familiar with AMR manuals. Otorhinolaryngologists demonstrated strong awareness but lower adherence. Targeted educational interventions, particularly focusing on older physicians and specific specialties, are needed to improve antimicrobial use and combat the growing threat of resistance.

Purpose Growth deficiency is a cardinal feature of osteogenesis imperfecta (OI) types III and IV, caused by pathogenic variants in type I collagen. OI-specific longitudinal growth charts are needed for patient care. Methods We compiled longitudinal length, weight, head circumference, and body mass index (BMI) data from 100 children with types III and IV OI and known type I collagen pathogenic variants. Effects of gender, OI type, and pathogenic variant were examined using multilevel modeling. OI-specific centile curves were constructed using generalized additive model for location, scale, and shape (GAMLSS). Results OI type and gender, but not the specific mutated collagen gene, significantly affect stature, but only OI type affects weight. Head circumference was not significantly different by gender, type, or mutated gene. In both genders, length curves for types III and IV OI overlap and the type IV 95th centile curve overlaps the lower US Centers for Disease Control and Prevention (CDC) curves for the general population. A pubertal growth spurt is generally absent or blunted in types III/IV OI. The body mass index 50th and 95th centile curves are distinctly shifted above respective US CDC curves in both genders. Conclusions OI type is a stronger contributing factor than gender for OI growth, while curves do not differ for COL1A1 versus COL1A2 pathogenic variants. Types III and IV OI-specific growth curves are presented.

There has been no report on the situation of socioeconomic inequalities in the full vaccination coverage among Vietnamese children. This study aims to assess the trends and changes in the socioeconomic inequalities in the full vaccination coverage among Vietnamese children aged 12–23 months from 2000 to 2014. Data were drawn from Multiple Indicator Cluster Surveys (2000, 2006, 2011, and 2014). Concentration index (CCI) and concentration curve (CC) were applied to quantify the degree of the socioeconomic inequalities in full immunization coverage. The prevalence of children fully receiving recommended vaccines was significantly improved during 2000–2014, yet, was still not being covered. The total CCI of full vaccination coverage gradually decreased from 2000 to 2014 (CCI: from 0.241 to 0.009). The CC increasingly became close to the equality line through the survey period, indicating the increasingly narrow gap in child full immunization amongst the poor and the rich. Vietnam witnessed a sharp decrease in socioeconomic inequality in the full vaccination coverage for over a decade. The next policies towards children from vulnerable populations (ethnic minority groups, living in rural areas, and having a mother with low education) belonging to lower socioeconomic groups may mitigate socioeconomic inequalities in full vaccination coverage.

Background In contrast to high-income countries where physical activity (PA), particularly leisure-time PA, has been shown to be protective against hypertension, few studies have been conducted in low- and middle-income countries. We examined the cross-sectional association between PA and hypertension prevalence among rural residents in Vietnam. Methods We used data collected in the baseline survey of a prospective cohort study, among 3000 people aged 40–60 years old residing in rural Khánh Hòa, Vietnam. Hypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or the use of antihypertensive medication. We assessed occupational PA and leisure-time PA using the Global Physical Activity Questionnaire. A robust Poisson regression model was used to investigate the associations, with adjustment for covariates. Results The prevalence of hypertension was 39.6%. After adjusting for socio-demographic and lifestyle-related variables, leisure-time PA was positively associated with hypertension prevalence (prevalence ratio [PR]: 1.03 per 10 MET-hour/week, 95% confidence interval [CI] 1.01–1.06). Occupational PA was inversely associated with hypertension prevalence (PR: 0.98 per 50 MET-hour/week, 95% CI = 0.96–0.996). After adjusting for BMI and other health-related variables, the association related to occupational PA became statistically non-significant, while the association related to leisure-time PA remained statistically significant. Conclusion In contrast to previous studies in high-income countries, we found that leisure-time PA was positively associated with hypertension prevalence and occupational PA was associated with a lower hypertension prevalence. This suggests that the association between PA and hypertension might differ depending on the context.

Ensuring a healthy lifestyle for the increasing number of Vietnamese migrants living in Japan is a key public health issue, including infectious disease responses such as tuberculosis (TB). To develop risk communication in relation to the TB response, this study aimed to explore the health issues and health-related behaviors of Vietnamese migrants living in Japan using a mixed method. A survey was conducted on Vietnam-born migrants, aged 18 years and over, in Tokyo. The survey consisted of questions on the following components: (1) demographics; (2) health-related issues and behavior; and (3) health-seeking behavior, information, and communication. A total 165 participants participated in the survey. The majority of the participants were young adults. 13% of the participants responded that they were concerned about their health. Moreover, 22% and 7% of the participants reported weight loss and respiratory symptoms, respectively. 44% of the participants answered they had no one to consult about their health in Japan when they needed it, and 58% answered they had no awareness of any Vietnamese-language health consultation services. Logistic regression analysis revealed that people who contact family members living in Vietnam or overseas using social networking services (SNSs) when they needed to consult someone about their health (adjusted odds ratio (AOR) = 6.09, 95% confidence interval (CI) 1.52–24.43) were more likely to present with one or more of the typical TB symptoms, compared to those who did not consult someone in this manner. Current smokers (OR = 3.08, 95% CI 1.15–8.23) were more likely to have health problems compared to non-smokers. The key informant interviews revealed that individual factors, the health system, and socio-environmental factors may hinder Vietnamese migrants’ health-seeking and health-information-seeking behaviors in Japan. TB risk communication approaches for migrants need to be developed considering their health-related behaviors while addressing their health needs.

Background Niemann-Pick disease, type C1 (NPC1) is a rare lysosomal disorder with progressive neurological manifestations, historically recognized as a pediatric disease. However, awareness of the adult-onset (AO) subtype is increasing, often with non-specific symptoms leading to delayed and misdiagnosis. Dysphagia, commonly recognized as a clinical morbidity in NPC1, raises concerns for swallowing safety and aspiration risk. This study aims to characterize swallowing function in AO NPC1, addressing the gap in understanding and clinical management. Methods Fourteen AO NPC1 individuals in a prospective natural history study (NCT00344331) underwent comprehensive assessments, including history and physical examinations utilizing the NPC1 severity rating scale, videofluoroscopic swallowing studies with summary interpretive analysis, and cerebrospinal fluid (CSF) collection for biomarker evaluation at baseline visit. Descriptive statistics and multivariate statistical modeling were employed to analyze NPC1 disease covariates, along with the American Speech-Language-Hearing Association National Outcome Measure (ASHA-NOMS) and the NIH Penetration Aspiration Scale (NIH-PAS). Results Our cohort, comprised of 14 predominately female ( n  = 11, 78.6%) individuals, had an average age of 43.1 ± 16.7 years at the initial visit. Overall, our AO patients were able to swallow independently with no/minimal cueing, with 6 (43%) avoiding specific food items or requiring more time. Upon risk analysis of aspiration, the cohort demonstrated no obvious aspiration risk or laryngeal aspiration in 8 (57%), minimal risk with intermittent laryngeal penetration and retrograde excursion in 5(36%), and moderate risk (7%) in only one. Dietary modifications were recommended in 7 (50%), particularly for liquid viscosities ( n  = 6, 43%) rather than solids ( n  = 3, 21%). No significant correlations were identified between swallowing outcomes and NPC1-related parameters or CSF biomarkers. Conclusion Despite the heterogeneity in NPC1 presentation, the AO cohort displayed functional swallowing abilities with low aspiration risk with some participants still requiring some level of dietary modifications. This study emphasizes the importance of regular swallowing evaluations and management in AO NPC1 to address potential morbidities associated with dysphagia such as aspiration. These findings provide clinical recommendations for the assessment and management of the AO cohort, contributing to improved care for these individuals.