Tag: nevin manimala

Nat Med. 2022 Apr 4. doi: 10.1038/s41591-022-01755-w. Online ahead of print.

ABSTRACT

CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 ( NCT03140969 ), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit-risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.

PMID:35379979 | DOI:10.1038/s41591-022-01755-w

J Expo Sci Environ Epidemiol. 2022 Apr 4. doi: 10.1038/s41370-022-00427-8. Online ahead of print.

ABSTRACT

BACKGROUND: School districts across the world have been grappling with how to keep their schools open, students healthy, and prevent the spread of viruses in their communities.

OBJECTIVE: The aims of this study included assessing both (1) the effectiveness of enhanced classroom cleaning and disinfecting protocol on surface biocontamination and (2) the associations between surface biocontamination and student absence due to illnesses.

METHODS: Cleaning effectiveness was assessed using quantitative adenosine triphosphate (ATP) measurements during a 10-week study period in a sample of 34 public schools (15,814 students), of a district located in the Western US. The schools were randomly assigned to 17 intervention schools implementing enhanced cleaning and disinfecting protocol and 17 control schools cleaning as usual. General estimating equations (GEEs) were used for modeling associations between ATP levels and weekly aggregates of student absences due to respiratory and gastrointestinal illnesses, which were recorded by the schools according to district wide protocol.

RESULTS: The weekly average ATP levels on logarithmic scale were 5.02 (SD 0.53) and 5.26 (SD 0.48) in the intervention and control schools, respectively, where the difference is statistically significant (p < 0.001). The probability of weekly absence due to gastrointestinal illness was significantly associated with ATP levels (parameter estimate 1.16, 95% CI 1.01-1.34, per unit (log) increase of weekly average ATP), where the model accounts for student level, gender, ethnic group, and socioeconomic status as well as for school level attendance, total absence ratio, and ventilation adequacy in classrooms. Associations were not found between ATP levels and weekly probability of any absence, or absence due to respiratory illness.

SIGNIFICANCE: Enhanced cleaning resulted in a significantly lower level of biocontamination on desktops in the intervention group. In addition, a statistically significant association was established between ATP levels on classroom desks and probability of absence due to gastrointestinal illness.

IMPACT: We found that enhanced cleaning protocol, including bi-weekly cleaning of classroom desks, as well as training of custodians and teachers, monitoring of effectiveness, and feedback, yielded a moderate but statistically significantly lower level of biocontamination on desktops, indicated by quantitative ATP monitoring. Within the range of weekly average desktop ATP levels observed, the probability of reported absence due to gastrointestinal illness is estimated to increase from 0.021 to 0.026. Based on the results, enhanced surface cleaning and monitoring its effectiveness is a possible district, state, or even national level policy to support healthy school environments.

PMID:35379911 | DOI:10.1038/s41370-022-00427-8

Int J Obes (Lond). 2022 Apr 4. doi: 10.1038/s41366-022-01113-3. Online ahead of print.

ABSTRACT

BACKGROUND: Few studies have investigated the optimal anthropometric index associated with potential cardio-metabolic risk. Using direct measures of standing height, body mass, and waist circumference, we sought to identify the optimal index for detecting cardio-metabolic risk associated with diabetes and hypertension in a nationally representative sample of US adults.

METHODS: Complete (non-missing) cross-sectional data from 8375 US adults aged 18-80+ years were obtained from the 2015-16 and 2017-March 2020 (pre-pandemic) cycles of the National Health and Nutrition Examination Survey. The cardio-metabolic risk was identified using blood pressure and glycohemoglobin (A1c). Allometric models were used to identify the optimal anthropometric indices associated with cardio-metabolic risk. Receiver operating characteristics curves were used to verify the discriminatory ability of the identified index in comparison with other anthropometric measures.

RESULTS: The optimal anthropometric index associated with cardio-metabolic risk was waist circumference divided by body mass to the power of 0.333 (WC/M^0.333). The ability for this new index to discriminate those with diabetes (area under the ROC curve: 0.73 [95%CI: 0.71-0.74]) and hypertension (area under the curve: 0.70 [95%CI: 0.69-0.72]) was superior to all other anthropometric measure/indices investigated in this study (body mass index, waist circumference, waist-to-height ratio, and waist/height^0.5).

CONCLUSIONS: We identified WC/M^0.333 as the optimal anthropometric index for identifying US adults with hypertension and diabetes. Instead of using body mass index (kg/m²), we recommend using WC/M^0.333 in clinical and public health practice to better identify US adults at potential cardio-metabolic risk associated with hypertension and diabetes.

PMID:35379906 | DOI:10.1038/s41366-022-01113-3

Commun Biol. 2022 Apr 4;5(1):306. doi: 10.1038/s42003-022-03243-w.

ABSTRACT

Bayesian networks (BNs) are disciplined, explainable Artificial Intelligence models that can describe structured joint probability spaces. In the context of understanding complex relations between a number of variables in biological settings, they can be constructed from observed data and can provide a guiding, graphical tool in exploring such relations. Here we propose BNs for elucidating the relations between driver events in large cancer genomic datasets. We present a methodology that is specifically tailored to biologists and clinicians as they are the main producers of such datasets. We achieve this by using an optimal BN learning algorithm based on well established likelihood functions and by utilising just two tuning parameters, both of which are easy to set and have intuitive readings. To enhance value to clinicians, we introduce (a) the use of heatmaps for families in each network, and (b) visualising pairwise co-occurrence statistics on the network. For binary data, an optional step of fitting logic gates can be employed. We show how our methodology enhances pairwise testing and how biologists and clinicians can use BNs for discussing the main relations among driver events in large genomic cohorts. We demonstrate the utility of our methodology by applying it to 5 cancer datasets revealing complex genomic landscapes. Our networks identify central patterns in all datasets including a central 4-way mutual exclusivity between HDR, t(4,14), t(11,14) and t(14,16) in myeloma, and a 3-way mutual exclusivity of three major players: CALR, JAK2 and MPL, in myeloproliferative neoplasms. These analyses demonstrate that our methodology can play a central role in the study of large genomic cancer datasets.

PMID:35379892 | DOI:10.1038/s42003-022-03243-w

Sci Rep. 2022 Apr 4;12(1):5629. doi: 10.1038/s41598-022-09709-5.

ABSTRACT

When asked to estimate the number of items in the visual field, neurotypical adults are more precise and rapid if the items are clustered into subgroups compared to when they are randomly distributed. It has been suggested that this phenomenon, termed “groupitizing”, relies on the recruitment of arithmetical calculation strategies and subitizing. Here the role of arithmetical skills in groupitizing was investigated by measuring the groupitizing effect (or advantage) in a sample of children and adolescents with and without math learning disability (dyscalculia). The results showed that when items were grouped, both groups of participants showed a similar advantage on sensory precision and response time in numerosity estimates. Correlational analyses confirmed a lack of covariation between groupitizing advantage and math scores. Bayesian statistics on sensory precision sustained the frequentist analyses providing decisive evidence in favor of no groups difference on groupitizing advantage magnitude (LBF = – 0.44) and no correlation with math scores (LBF = – 0.57). The results on response times, although less decisive, were again in favor of the null hypothesis. Overall, the results suggest that the link between groupitizing and mathematical abilities cannot be taken for granted, calling for further investigations on the factors underlying this perceptual phenomenon.

PMID:35379895 | DOI:10.1038/s41598-022-09709-5

Sci Rep. 2022 Apr 4;12(1):5603. doi: 10.1038/s41598-022-09531-z.

ABSTRACT

Color vision tests use estimative of threshold color discrimination or number of correct responses to evaluate performance in chromatic discrimination tasks. Both approaches have advantages and disadvantages. In the present investigation, we compared the number of errors during color discrimination task in normal trichromats and participants with color vision deficiency (CVD) using pseudoisochromatic stimuli at fixed saturation levels. We recruited 28 normal trichromats and eight participants with CVD. Cambridge Color Test was used to categorize their color vision phenotype, and those with a phenotype suggestive of color vision deficiency had their L- and M-opsin genes genotyped. Pseudoisochromatic stimuli were shown with target chromaticity in 20 vectors radiating from the background chromaticity and saturation of 0.06, 0.04, 0.03, 0.02, 0.01, and 0.005 u’v’ units. Each stimulus condition appeared in four trials. The number of errors for each stimulus condition was considered an indicator of the participant’s performance. At high chromatic saturation, there were fewer errors from both phenotypes. The errors of the normal trichromats had no systematic variation for high saturated stimuli, but below 0.02 u’v’ units, there was a discrete prevalence of tritan errors. For participants with CVD, the errors happened mainly in red-green chromatic vectors. A three-way ANOVA showed that all factors (color vision phenotype, stimulus saturation, and chromatic vector) had statistically significant effects on the number of errors and that stimulus saturation was the most important main effect. ROC analysis indicated that the performance of the fixed saturation levels to identify CVD was better between 0.02 and 0.06 u’v’ units reaching 100%, while saturation of 0.01 and 0.005 u’v’ units decreased the accuracy of the screening of the test. We concluded that the color discrimination task using high saturated stimuli separated normal trichromats and participants with red-green color vision deficiencies with high performance, which can be considered a promising method for new color vision tests based in frequency of errors.

PMID:35379850 | DOI:10.1038/s41598-022-09531-z

Sci Rep. 2022 Apr 4;12(1):5588. doi: 10.1038/s41598-022-08942-2.

ABSTRACT

Battery electric vehicles (BEVs) have emerged as a promising alternative to traditional internal combustion engine (ICE) vehicles due to benefits in improved fuel economy, lower operating cost, and reduced emission. BEVs use electric motors rather than fossil fuels for propulsion and typically store electric energy in lithium-ion cells. With rising concerns over fossil fuel depletion and the impact of ICE vehicles on the climate, electric mobility is widely considered as the future of sustainable transportation. BEVs promise to drastically reduce greenhouse gas emissions as a result of the transportation sector. However, mass adoption of BEVs faces major barriers due to consumer worries over several important battery-related issues, such as limited range, long charging time, lack of charging stations, and high initial cost. Existing solutions to overcome these barriers, such as building more charging stations, increasing battery capacity, and stationary vehicle-to-vehicle (V2V) charging, often suffer from prohibitive investment costs, incompatibility to existing BEVs, or long travel delays. In this paper, we propose Peer-to-Peer Car Charging (P2C2), a scalable approach for charging BEVs that alleviates the need for elaborate charging infrastructure. The central idea is to enable BEVs to share charge among each other while in motion through coordination with a cloud-based control system. To re-vitalize a BEV fleet, which is continuously in motion, we introduce Mobile Charging Stations (MoCS), which are high-battery-capacity vehicles used to replenish the overall charge in a vehicle network. Unlike existing V2V charging solutions, the charge sharing in P2C2 takes place while the BEVs are in-motion, which aims at minimizing travel time loss. To reduce BEV-to-BEV contact time without increasing manufacturing costs, we propose to use multiple batteries of varying sizes and charge transfer rates. The faster but smaller batteries are used for charge transfer between vehicles, while the slower but larger ones are used for prolonged charge storage. We have designed the overall P2C2 framework and formalized the decision-making process of the cloud-based control system. We have evaluated the effectiveness of P2C2 using a well-characterized simulation platform and observed dramatic improvement in BEV mobility. Additionally, through statistical analysis, we show that a significant reduction in carbon emission is also possible if MoCS can be powered by renewable energy sources.

PMID:35379831 | DOI:10.1038/s41598-022-08942-2

Nat Commun. 2022 Apr 4;13(1):1789. doi: 10.1038/s41467-022-29426-x.

ABSTRACT

The metabolic principles underlying the differences between follicular and marginal zone B cells (FoB and MZB, respectively) are not well understood. Here we show, by studying mice with B cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that glutathione synthesis affects homeostasis and differentiation of MZB to a larger extent than FoB, while glutathione-dependent redox control contributes to the metabolic dependencies of FoB. Specifically, Gclc ablation in FoB induces metabolic features of wild-type MZB such as increased ATP levels, glucose metabolism, mTOR activation, and protein synthesis. Furthermore, Gclc-deficient FoB have a block in the mitochondrial electron transport chain (ETC) due to diminished complex I and II activity and thereby accumulate the tricarboxylic acid cycle metabolite succinate. Finally, Gclc deficiency hampers FoB activation and antibody responses in vitro and in vivo, and induces susceptibility to viral infections. Our results thus suggest that Gclc is required to ensure the development of MZB, the mitochondrial ETC integrity in FoB, and the efficacy of antiviral humoral immunity.

PMID:35379825 | DOI:10.1038/s41467-022-29426-x

Ann Transplant. 2022 Apr 5;27:e935604. doi: 10.12659/AOT.935604.

ABSTRACT

BACKGROUND Liver transplantation (LT) has been validated widely all over the world as the curative treatment for hepatocellular carcinoma (HCC). Statins have been reported to prevent the progression of HCC. There are many factors that affect recurrence of HCC, but the precise role of statins is unknown. Therefore, we examined whether statin therapy is associated with decreased HCC recurrence in patients who underwent living-donor LT (LDLT) for HCC. MATERIAL AND METHODS We retrospectively analyzed 844 HCC patients who underwent primary adult-to-adult LDLT in our center between January 2007 and December 2016. Statin therapy was defined as administration of statins for more than 30 cumulative defined daily doses (cDDDs) after LT. We compared HCC recurrence and patient survival between non-statin (n=334) and statin (n=52) groups. RESULTS The recurrence rate was higher in the non-statin group; however, time-dependent multivariate analysis with Kaplan-Meier curves showed that statin users did not significantly benefit in terms of HCC recurrence-related survival or overall survival. Further, risk factor analysis of HCC recurrence and patient survival confirmed multiple regional treatments (≥3 times), high alpha fetoprotein level (≥100 ng/mL), large tumor size (≥3 cm), and microvascular invasion as risk factors for HCC recurrence, but statin treatment was not associated with a significantly lower recurrence rate of HCC or reduced mortality after adjusting for other risk factors. CONCLUSIONS Statin use might be associated with prevention of HCC progression, but no significant decrease in HCC recurrence rates in LDLT patients was recorded in this study.

PMID:35379768 | DOI:10.12659/AOT.935604

Transl Psychiatry. 2022 Apr 4;12(1):140. doi: 10.1038/s41398-022-01910-4.

ABSTRACT

The effects of microglial activation on the associations between depression and Alzheimer’s disease (AD) are still unclear. TREM2 gene plays a pivotal role in microglial activation, has been identified as a risk factor for AD. In this work, we aimed to assess the interrelationships of soluble TREM2 (sTREM2) level in cerebrospinal fluid (CSF), minimal depressive symptoms (MDSs), and CSF amyloid markers. The linear regression analyses were conducted on 796 cognitively unimpaired participants from the CABLE (Chinese Alzheimer’s Biomarker and LifestylE) study. Causal mediation analyses with 10,000 bootstrapped iterations were used to test the mediation effects. In addition, similar statistical analyses were performed in subgroups stratified by sex, age, and APOE ε4 carrier status. In total subjects, MDSs were associated with lower CSF sTREM2 levels (p < 0.0001), lower CSF amyloid markers (p < 0.0001), and poorer cognitive performance (MMSE, p = 0.0014). The influence of MDSs on CSF amyloid markers was partially mediated by CSF sTREM2 (proportion from 2.91 to 32.58%, p < 0.0001). And we found that the sTREM2-amyloid pathway partially mediated the effects of MDSs on cognition. Of note, exploratory subgroup analyses showed that the above influences of CSF sTREM2 were pronounced in the APOE ε4 (-) group. These results suggest that early depression is associated with amyloid pathology, which might be partly mediated by microglial activation, especially in the absence of APOE ε4.

PMID:35379792 | DOI:10.1038/s41398-022-01910-4