Nevin Manimala

PLoS One. 2025 May 13;20(5):e0322986. doi: 10.1371/journal.pone.0322986. eCollection 2025.

ABSTRACT

BACKGROUND: A decreasing age of menarche has been reported across the Western world. Early menarche is associated with unfavorable health outcomes.

AIM: The aims of this study were to describe the age at menarche in a general population sample in Norway and the associations between body mass index (BMI) categories at preschool (approximately 6 years of age) and age at menarche.

METHODS: We used self-reported age at menarche among girls who participated in the population-based study Fit Futures 1 (FF 2010-2011), mostly born in 1994, to calculate age at menarche. The preschool BMI from health records was divided into BMI categories according to validated cutoffs on the basis of age and sex from the International Obesity Task Force (IOTF). We estimated the effect of preschool BMI on age at menarche via a linear regression model adjusted for socioeconomic status (SES).

RESULTS: Among 500 girls with a mean age of 16.5 years (standard deviation (SD) ± 1.4), 497 (99%) had completed menarche. The mean age at menarche was 13.0 years (SD ± 1.2). According to the fitted linear regression model, preschool obesity was a statistically significant predictor of age at menarche and was associated with menarche 9.5 months earlier than a normal preschool BMI was. R2 estimated that preschool BMI could explain 3% of the variance in age at menarche.

CONCLUSION: The mean age at menarche in Northern Norway was 13.0 (SD ± 1.2) years, similar to previous Norwegian studies. Childhood obesity was associated with earlier age at menarche.

PMID:40359425 | DOI:10.1371/journal.pone.0322986

PLoS Comput Biol. 2025 May 13;21(5):e1013083. doi: 10.1371/journal.pcbi.1013083. Online ahead of print.

ABSTRACT

Accurate retrieval of the maintained information is crucial for working memory. This process primarily occurs during post-delay epochs, when subjects receive cues and generate responses. However, the computational and neural mechanisms that underlie these post-delay epochs to support robust memory remain poorly understood. To address this, we trained recurrent neural networks (RNNs) on a color delayed-response task, where certain colors (referred to as common colors) were more frequently presented for memorization. We found that the trained RNNs reduced memory errors for common colors by decoding a broader range of neural states into these colors through the post-delay epochs. This decoding process was driven by convergent neural dynamics and a non-dynamic, biased readout process during the post-delay epochs. Our findings highlight the importance of post-delay epochs in working memory and suggest that neural systems adapt to environmental statistics by using multiple mechanisms across task epochs.

PMID:40359421 | DOI:10.1371/journal.pcbi.1013083

PLoS One. 2025 May 13;20(5):e0321511. doi: 10.1371/journal.pone.0321511. eCollection 2025.

ABSTRACT

BACKGROUND: The Bacillus Calmette-Guérin (BCG) vaccine has shown potential non-specific protection against infectious diseases through “trained immunity”, which may offer cross-protection against viral infections. However, there is no consensus on whether BCG vaccination could prevent COVID-19 or reduce its symptoms.

METHODS: PubMed, Cochrane Library, Embase and Web of Science were searched for randomized controlled trials on BCG vaccination and COVID-19 prevention, covering studies from the inception of each database to 2 May 2024. We included studies where participants, not infected with COVID-19, were vaccinated with BCG or placebo. We excluded non-randomized trials, studies without full texts, unrelated interventions, and those not reporting relevant outcomes. Clinical data on COVID-19 infection, severity, hospitalization, mortality, and other adverse events, were extracted and analyzed. The DerSimonian-Laird random-effects model and the Cochrane Collaboration’s risk of Bias Tool were used for analysis and risk of bias assessment.

RESULTS: A total of 12 RCTs involving 18,086 patients were finally included. For the prophylactic effect of BCG on COVID-19, pooled results showed no statistically significant difference between BCG and placebo (pooled RR 1.02; 95%CI: 0.91-1.14). There was no statistically significant difference between non-health care workers (pooled RR 0.91; 95%CI: 0.67-1.24) and health care workers (pooled RR 1.03; 95%CI: 0.93-1.15). Regarding COVID-19 severity, no significant difference were found for asymptomatic (pooled RR 1.18; 95%CI: 0.81-1.72), mild to moderate (pooled RR 0.99; 95%CI: 0.84-1.17), severe COVID-19 (pooled RR 1.25; 95%CI: 0.92-1.70), hospitalization (pooled RR 0.93; 95%CI: 0.58-1.50) or all-cause mortality (pooled RR 0.60; 95%CI: 0.18-1.95) between BCG and placebo groups. Subgroup analysis also showed no significant difference between BCG and placebo in non-health care workers or health care workers.

CONCLUSIONS: Vaccination of BCG could not effectively prevent COVID-19 infection or decrease COVID-19 symptoms both in non-health care workers and health care workers.

PMID:40359420 | DOI:10.1371/journal.pone.0321511

PLoS One. 2025 May 13;20(5):e0322663. doi: 10.1371/journal.pone.0322663. eCollection 2025.

ABSTRACT

Surveillance for food safety in the United States of America is a collaborative effort among public health agencies with additional partners worldwide contributing sequence data. Assemblies in GenBank and sequence reads in the Sequence Read Archive for surveilled species are received, rapidly analyzed, and results published publicly by an automated pathogen detection pipeline at the National Center for Biotechnology Information. The pipeline detects close isolates with a recent common ancestor by finding single nucleotide polymorphisms (SNPs) in genomes for pairs of isolates. Very few vertically transmitted SNPs are expected between a pair of close isolates; any genomic region with many SNPs compared to the number of SNPs in the rest of the genome is indicative of a horizontally transferred region that needs to be excluded for counting vertically transmitted SNPs. We developed dTOURS that adapted the ratio statistic for finding outliers to the problem of finding regions of high SNP density in a pair of genomes where isolates typically have fragmented genome assemblies. Simulations for deciding the dTOURS parameter are presented. We illustrate correctness of dTOURS using five published outbreaks, one each for five bacterial species that cause many foodborne outbreaks or lead to a high mortality rate. Comparison to Gubbins shows that while both Gubbins and dTOURS use the ratio statistic, the implementation in dTOURS is more robust for finding close isolates in outbreak analysis. Comparison with the method used by the Food and Drug Administration shows that their method is simple and fast but not sensitive.

PMID:40359413 | DOI:10.1371/journal.pone.0322663

PLoS Med. 2025 May 13;22(5):e1004472. doi: 10.1371/journal.pmed.1004472. Online ahead of print.

ABSTRACT

BACKGROUND: Parkinson disease (PD) is a chronic progressive neurodegenerative disorder leading to motor and non-motor impairment, often resulting in severe loss of quality of life. There are symptomatic treatments without effect on the progression of PD. A disease-modifying treatment that could ideally stop the neurodegenerative process is direly needed. Monosialotetrahexosylganglioside (GM1) is a promising molecule with neuroprotective effects in preclinical models of PD and has yielded encouraging results in patients with PD in a randomized placebo-controlled trial. Talineuren (TLN) is a liposomal formulation of GM1 that has been shown to cross the blood-brain barrier in animals. We assessed the safety and pharmacokinetics (PK) of TLN in patients with PD.

METHODS AND FINDINGS: We prospectively enrolled 12 patients with PD into a single-center, open-label phase I trial to assess the safety and tolerability of weekly infusions with TLN. The maximum suitable dose of TLN was determined by dose escalation in three patients. All three patients tolerated the predetermined maximal dose of 720 mg. Subsequently, these and nine additional patients received weekly infusions at the maximum suitable dose of 720 mg TLN over two months (1 patient stopped prematurely). PK were determined for the additional nine patients as a secondary outcome measure. Cmax was reached 4 h after infusion start for all but one participant, who reached Cmax after 1 h, while the median plasma half-life was reached at 12.6 h. All adverse events were continuously assessed as the primary objective and coded according to the Medical Dictionary for Regulatory Activities (MedDRA). Clinical manifestations of PD were assessed as secondary outcomes using the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), including a levodopa challenge test at baseline and end. In addition to weekly history taking, scales to measure mood, behavior, quality of life, sleepiness, non-motor symptoms of PD, and cognition were used as further secondary outcomes as well as assessing the Levodopa-equivalent daily dose (LEDD). Overall, 304 adverse events (mean: 25.33; 6-75 events per patient) occurred, 267 of which were mild (mean: 22.25; 3-72 events per patient). 23 were considered related to the study treatment (0-8 events per patient). Very mild-to-severe acute infusion reactions at the second, third, or fourth administration of TLN within the first minutes of the infusion occurred in seven patients. All reported back or neck pain. Other acute infusion reactions were urticaria, plethora, nausea, and chest pain. These adverse reactions disappeared within minutes of stopping the infusion and did not recur when TLN administration was resumed at a very low rate. Beyond the fourth administration, infusions could be given at increased rates up to 370 ml/h, and no acute reaction occurred anymore. The mechanism of this acute infusion reaction remains unclear. Some patients reported mild dizziness for a few hours after TLN following many but not all administrations throughout the study. Non-motor symptoms of PD, motor parkinsonian signs off medication, and quality of life improved significantly during the treatment phase, including the MDS-UPDRS total score (mean decrease -11.09; 95% confidence interval [CI]; -18, -4.1; p = 0.006), the Parkinson’s disease Questionnaire-39 (PDQ-39) summary index(mean decrease -2.91; 95% CI; -4.4, -1.4; p = 0.005), and the Non-Motor Symptoms Questionnaire (NMS-Quest) (mean decrease -4.27; 95% CI; -6.5, -2.1; p = 0.009). No statistically significant improvements were seen in the Montreal Cognitive Assessment (MoCA) (mean decrease -0.73; 95% CI; -2.1, 0.62; p = 0.255), Epworth Sleepiness Scale (mean increase 0.09; 95% CI; -2.6, 2.8; p > 0.999), Beck Depression Inventory (BDI) (mean decrease -1.27; 95% CI; -3.8, 1.3; p = 0.257), and the Starkstein Apathy Scale (mean increase 0.36; 95% CI; -1.6, 2.4; p = 0.822). Dopaminergic medications remained stable during the study (LEDD mean increase 8.18; 95% CI; -7.7, 24; p = 0.423). While clinical improvements indicate a benefit associated with TLN treatment, the trial design does not allow for definite conclusions regarding efficacy. A randomized, placebo-controlled trial will be required to corroborate our exploratory findings.

CONCLUSION: TLN is safe and well-tolerated in general. This prospective phase I trial revealed non-allergic habituating acute infusion reactions at the second, third, or fourth treatment that can be prevented by a slower rate of infusion. Importantly, the exploratory results suggest a consistent improvement of signs and symptoms of PD.

TRIAL REGISTRATION: The NEON trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT04976127 and in the Swiss National Clinical Trials Portal (SNCTP000004631).

PMID:40359409 | DOI:10.1371/journal.pmed.1004472

Pain. 2025 May 13. doi: 10.1097/j.pain.0000000000003651. Online ahead of print.

ABSTRACT

Neuropathic pain (NP) is a common challenging problem, and there is a growing need to develop safe and effective nonopioid treatments. Sleep disturbance is commonly associated with NP because pain intensity of NP conditions is often worse at night. Some evidence suggests that the pineal hormone, melatonin, may reduce pain in clinical settings. We conducted a clinical trial to evaluate the efficacy of melatonin for NP. Using a double-blind, placebo-controlled, crossover design, 31 adults with NP were randomly allocated to 1 of 2 sequences of treatment with melatonin and placebo. During each of 2 treatment periods, participants took capsules containing melatonin or placebo for 4 weeks, followed by a 7-day washout period. The primary outcome was mean daily pain intensity (0-10) at maximally tolerated doses (MTD) during each period. Secondary outcomes, assessed at MTD, included adverse events, and measures of sleep, mood, and quality of life. Thirty-one participants were recruited, and 30 participants completed both treatment periods of the trial. The mean maximal tolerated dose of melatonin in this trial was 11.9 mg/day. Treatment-emergent adverse events with melatonin were infrequent and not statistically different from placebo. At MTD, mean daily pain (standard error) was 4.1 (0.3) for melatonin and 4.2 (0.3) for placebo (P = 0.8). There were no statistically significant differences between placebo and melatonin for any secondary outcomes. Overall, the results of this trial do not provide any evidence to suggest promise for melatonin as an effective treatment for NP.

PMID:40359364 | DOI:10.1097/j.pain.0000000000003651

PLoS One. 2025 May 13;20(5):e0323237. doi: 10.1371/journal.pone.0323237. eCollection 2025.

ABSTRACT

OBJECTIVE: Ureterorenoscopy (URS) is a common procedure performed for renal or upper ureteric stones. Nevertheless, the efficacy and safety of URS in the elderly is unclear. We conducted the first meta-analysis of literature comparing outcomes of URS between elderly and non-elderly patients.

METHODS: Embase, PubMed, Web of Science, and Scopus databases were searched for studies relevant to the review. The last date was 2nd September 2024. The elderly were defined as ≥ 65 or 60 years of age. Outcomes compared were stone-free rates (SFR), complications, and length of hospital stay (LOS).

RESULTS: Nine studies met the inclusion criteria. Pooled analysis showed that there was no difference in SFR between elderly and non-elderly groups after URS (OR: 0.96 95% CI: 0.81, 1.14 I2 = 3%). Meta-analysis failed to show any statistical significant in all complication rates (OR: 1.04 95% CI: 0.77, 1.40 I2 = 51%) as well as infectious (OR: 1.27 95% CI: 0.84, 1.92 I2 = 0%), medical (OR: 2.01 95% CI: 0.23, 17.57 I2 = 93%), surgical (OR: 1.18 95% CI: 0.68, 2.03 I2 = 0%) or Clavein Dindo grade ≥2 (OR: 1.02 95% CI: 0.60, 1.75 I2 = 0%) complications between elderly and non-elderly groups. Meta-analysis showed that the elderly had significantly longer LOS as compared to non-elderly patients (MD: 0.75 95% CI: 0.05, 1.45 I2 = 90%).

CONCLUSIONS: URS seems to efficacious and safe in the elderly. Patients ≥60 or 65 years of age have similar SFR and complication rates as younger patients. However, LOS may be increased in the elderly. More robust studies taking into account baseline characteristics and importantly presenting rates are needed to validate the current results.

PMID:40359352 | DOI:10.1371/journal.pone.0323237

Biopsychosoc Sci Med. 2025 May 9. doi: 10.1097/PSY.0000000000001399. Online ahead of print.

ABSTRACT

OBJECTIVE: Due to population aging, the increasing prevalence of Alzheimer’s Disease (AD) and related dementias are major public health concerns. Dietary consumption of antioxidant nutrients, in particular the carotenoid β-carotene, has been associated with lower age-related neurocognitive decline. What is unclear, however, is the extent to which antioxidant nutrients may exert neuroprotective effects via their influence on established indicators of age-related changes in brain tissue. This study thus tested associations of circulating β-carotene and other nutrients with a structural neuroimaging indicator of brain age derived from cross-validated machine learning models trained to predict chronological age from brain tissue morphology in independent cohorts.

METHODS: Midlife adults (N=132, aged 30.4 to 50.8 years, 59 female at birth) underwent a structural magnetic resonance imaging (MRI) protocol and fasting phlebotomy to assess plasma concentrations of β-carotene, retinol, γ-tocopherol, ⍺-tocopherol, and β-cryptoxanthin.

RESULTS: In regression analyses adjusting for chronological age, sex at birth, smoking status, MRI image quality, season of testing, annual income, and education, greater circulating levels of β-carotene were associated with a lower (i.e., younger) predicted brain age (β=-0.23, 95% CI=-0.40 to -0.07, P=0.006). Other nutrients were not statistically associated with brain age, and results persisted after additional covariate control for body mass index, cortical volume, and cortical thickness.

CONCLUSIONS: These cross-sectional findings are consistent with the possibility that dietary intake of β-carotene may be associated with slower biological aging at the level of the brain, as reflected by a neuroimaging indicator of brain age.

PMID:40359351 | DOI:10.1097/PSY.0000000000001399

Laryngoscope. 2025 May 13. doi: 10.1002/lary.32258. Online ahead of print.

ABSTRACT

OBJECTIVE: This study examined patterns of cellular and neural degeneration in the peripheral vestibular system following head trauma, comparing cases with and without skull/temporal bone fractures.

METHODS: We analyzed 26 temporal bones (17 cases) with head trauma with fractures (six cases, nine ears) and ones without fractures (11 cases, 17 ears). Appropriate age-matched control groups comprising temporal bones without temporal bone pathology were included for comparative purposes. Histopathological analyses included counts of Scarpa’s ganglion cells (ScGCs) in the superior and inferior vestibular nerves (SVN and IVN), and counts of vestibular hair cells (HCs) in the utricle, saccule, lateral semicircular canal (LSCC), and posterior semicircular canal (PSCC). Mann-Whitney U tests were used for statistical analyses.

RESULTS: The group without fractures showed a significant reduction in total ScGCs (SVN + IVN) compared to controls (p = 0.040), with a pronounced decrease in the SVN (p = 0.014). Significant reductions in type I and type II HCs were observed in the utricle (p = 0.008 and p = 0.035) and in type I HCs in the LSCC (p = 0.037). In the group with fractures, only type I HCs in the utricle were significantly reduced (p = 0.038).

CONCLUSION: Head trauma without fractures is associated with more severe vestibular cell degeneration and greater loss of ganglion cells in the SVN in our specimens. These findings suggest that head trauma without fractures may pose a higher risk for vestibular cell damage compared with trauma with fractures.

LEVEL OF EVIDENCE: NA.

PMID:40359321 | DOI:10.1002/lary.32258

Elife. 2025 May 13;13:RP101369. doi: 10.7554/eLife.101369.

ABSTRACT

Bulk transcriptomic analyses of high-grade serous ovarian cancer (HGSOC) so far have not uncovered potential drug targets, possibly because subtle, disease-relevant transcriptional patterns are overshadowed by dominant, non-relevant ones. Our aim was to uncover disease-outcome-related patterns in HGSOC transcriptomes that may reveal novel drug targets. Using consensus-independent component analysis, we dissected 678 HGSOC transcriptomes of systemic therapy naïve patients-sourced from public repositories-into statistically independent transcriptional components (TCs). To enhance c-ICA’s robustness, we added 447 transcriptomes from non-serous histotypes, low-grade serous, and non-cancerous ovarian tissues. Cox regression and survival tree analysis were performed to determine the association between TC activity and overall survival (OS). Finally, we determined the activity of the OS-associated TCs in 11 publicly available spatially resolved ovarian cancer transcriptomes. We identified 374 TCs, capturing prominent and subtle transcriptional patterns linked to specific biological processes. Six TCs, age, and tumor stage stratified patients with HGSOC receiving platinum-based chemotherapy into ten distinct OS groups. Three TCs were linked to copy-number alterations affecting expression levels of genes involved in replication, apoptosis, proliferation, immune activity, and replication stress. Notably, the TC identifying patients with the shortest OS captured a novel transcriptional pattern linked to synaptic signaling, which was active in tumor regions within all spatially resolved transcriptomes. The association between a synaptic signaling-related TC and OS supports the emerging role of neurons and their axons as cancer hallmark-inducing constituents of the tumor microenvironment. These constituents might offer a novel drug target for patients with HGSOC.

PMID:40359002 | DOI:10.7554/eLife.101369