Miracle-dz/UniFAR-FTUs huggingface dataset:
Characteristics and Mechanisms of a Sphingolipid-associated Childhood Asthma Endotype.

RATIONALE A link between sphingolipids, 17q21 genetic variants and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such asthma endotype remain to be elucidated. OBJECTIVE To study the sphingolipid-associated childhood asthma endotype using multi-omics data. METHODS We used untargeted LC-MS plasma metabolomics profiles at age 6 months and 6 years from >500 children in the COPSAC2010 birth cohort focusing on sphingolipids, and integrated 17q21 genotype and nasal gene expression of serine palmitoyl-CoA transferase (SPT), i.e. the rate-limiting enzyme in the de novo sphingolipid synthesis, in relation to asthma development and lung function traits from infancy till age 6 years. Replication was sought in the independent VDAART cohort. MEASUREMENTS AND MAIN RESULTS Lower levels of ceramides and sphingomyelins at age 6 months were associated with increased risk of developing asthma before age 3, which was also observed in VDAART. At age 6 years, lower levels of key phosphosphingolipids, e.g. sphinganine-1-phosphate were associated with increased airway resistance. This relationship was dependent on 17q21 genotype and nasal SPT gene expression with significant interaction between genotype and phosphosphingolipids levels and between genotype and SPT expression, showing lower phosphosphingolipids and reduced SPT expression with increasing number of at-risk alleles. However, the findings did not pass FDR<0.05. CONCLUSIONS This exploratory study suggests the existence of a childhood asthma endotype with early onset and increased airway resistance that is characterized by reduced sphingolipid levels that is associated with 17q21 genetic variants and expression of the SPT enzyme.
Heat-stability study of various insulin types in tropical temperature conditions: New insights towards improving diabetes care

Strict storage recommendations for insulin are difficult to follow in hot tropical regions and even more challenging in conflict and humanitarian emergency settings, adding an extra burden to the management of people with diabetes. According to pharmacopeia unopened insulin vials must be stored in a refrigerator (2-8°C), while storage at ambient temperature (25-30°C) is usually permitted for the 4-week usage period during treatment. In the present work we address a critical question towards improving diabetes care in resource poor settings, namely whether insulin is stable and retains biological activity in tropical temperatures during a 4-week treatment period. To answer this question, temperature fluctuations were measured in Dagahaley refugee camp (Northern Kenya) using log tag recorders. Oscillating temperatures between 25 and 37°C were observed. Insulin heat stability was assessed under these specific temperatures which were precisely reproduced in the laboratory. Different commercialized formulations of insulin were quantified weekly by high performance liquid chromatography and the results showed perfect conformity to pharmacopeia guidelines, thus confirming stability over the assessment period (four weeks). Monitoring the 3D-structure of the tested insulin by circular dichroism confirmed that insulin monomer conformation did not undergo significant modifications. The measure of insulin efficiency on insulin receptor (IR) and Akt phosphorylation in hepatic cells indicated that insulin bioactivity of the samples stored at oscillating temperature during the usage period is identical to that of the samples maintained at 2-8°C. Taken together, these results indicate that insulin can be stored at such oscillating ambient temperatures for the usual four-week period of use. This enables the barrier of cold storage during use to be removed, thereby opening up the perspective for easier management of diabetes in humanitarian contexts and resource poor settings.
Are response function representations of the global carbon cycle ever interpretable?

Response function models are often used to represent the behaviour of complex, high order global carbon cycle (GCC) and climate models in applications which require short model run times. Although apparently black-box, these response function models need not necessarily be entirely opaque, but instead may also convey useful insights into the properties of the parent model or process. By exploiting a transfer function (TF) framework to analyse the Lenton GCC model, this paper attempts to demonstrate that response function representations of GCC models can sometimes also provide structural information on the parent model from which they are identified and calibrated. We take a fifth-order TF identified from the impulse response of the Lenton model atmospheric burden, and decompose this to show how it can be re-expresses in a generic five-box form in sympathy with the structure of the parent model.
Interpersonal Relationship Experiences in Adults Born With Cleft Lip and/or Palate: A Whole of Life Survey in the United Kingdom

Objectives: Previous research has suggested that adults with a cleft lip and/or palate (CL/P) may find their familial, friend, collegial, and/or romantic relationships impacted by their condition. Building on this prior work, this study examined the self-reported interpersonal experiences of a national sample of adults born with CL/P. Design: An online survey was designed by the Cleft Lip and Palate Association in collaboration with the Centre for Appearance Research. Data from 181 participants were included in the present study, collected between July and October 2018. Qualitative data were analyzed using inductive content analysis, while quantitative data were analyzed using descriptive statistics and independent t tests. Results: Most participants reported having good relationships with family members and existing friends with similar patterns of marriage as the general population. However, some experienced difficulties initiating new friendships and romantic relationships. Participants described bullying and discrimination in adulthood, most often in public settings and the workplace. Participants reported lower satisfaction with intimate relationships and less secure attachment compared to the general population. Concerns regarding the heritability of CL/P and its impact on the decision to have a family were also reported. Conclusions: Individuals with CL/P are at risk of negative social experiences, which if not appropriately addressed may impact psychological well-being in adulthood. The findings illustrate the importance of routine psychosocial support from childhood onward to help individuals with CL/P build social skills, self-esteem, and social confidence and to develop mutually fulfilling friendships and intimate relationships. Additionally, societal campaigns to raise awareness and target discrimination may be helpful.
ERK Inhibitor LY3214996-Based Treatment Strategies for RAS-Driven Lung Cancer

RAS gene mutations are the most frequent oncogenic event in lung cancer. They activate multiple RAS-centric signaling networks among them the MAPK, PI3K, and RB pathways. Within the MAPK pathway, ERK1/2 proteins exert a bottleneck function for transmitting mitogenic signals and activating cytoplasmic and nuclear targets. In view of disappointing antitumor activity and toxicity of continuously applied MEK inhibitors in patients with KRAS-mutant lung cancer, research has recently focused on ERK1/2 proteins as therapeutic targets and on ERK inhibitors for their ability to prevent bypass and feedback pathway activation. Here, we show that intermittent application of the novel and selective ATP-competitive ERK1/2 inhibitor LY3214996 exerts single-agent activity in patient-derived xenograft (PDX) models of RAS-mutant lung cancer. Combination treatments were well tolerated and resulted in synergistic (ERKi plus PI3K/mTORi LY3023414) and additive (ERKi plus CDK4/6i abemaciclib) tumor growth inhibition in PDX models. Future clinical trials are required to investigate if intermittent ERK inhibitor-based treatment schedules can overcome toxicities observed with continuous MEK inhibition and—equally important—to identify biomarkers for patient stratification.
The Impact of Modifying Empirical Antibiotic Therapy Based on Intestinal Colonization Status on Clinical Outcomes of Febrile Neutropenic Patients

Background This paper aimed to inspect factors affecting febrile neutropenia patients with hematologic malignancies. The intestinal colonization rate of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) and carbapenem-resistant Enterobacteriaceae (CRE) was assessed. The rate of subsequent ESBL-E and CRE bacteremia correlated with corresponding bacterial colonization was evaluated. Further, the risk factors for ESBL-E and CRE intestinal colonization were examined. Finally, the impact of rectal swab screening combined with adapted empirical antibiotic therapy on the mortality rate of patients with febrile neutropenia was assessed. Materials and Methods Febrile neutropenia patients underwent rectal swabs and collection of blood culture specimens upon admission. Empirical treatment was subsequently modified according to rectal swab results if necessary. Bacteremia patients were treated according to blood culture results. Explorative forward-stepwise logistic regression analyses were used to identify risk factors for ESBL-E and CRE fecal carriage and mortality. Results In total, 201 rectal swabs and 402 blood samples were collected from 163 patients during 201 febrile neutropenia episodes. Of these episodes, 38 (18.90%) were colonized with ESBL-E and 30 (14.92%) with CRE. Bloodstream infections developed in 29/201 (14.42%) episodes. Only bacteremia episodes caused by Gram-negative bacilli were included in our analysis. The development of Gram-negative-rod bacteremia was observed in eight out of 38 (21.05%) ESBL-E colonized episodes and four out of 30 (13.33%) CRE-colonized episodes. A BSI developed in three out of 38 (7.89%) ESBL-E colonized episodes, and two out of 30 (6.66%) CRE-colonized episodes developed BSI with the respective organism. Multivariate analysis identified previous quinolone use as the only independent risk factor for fecal colonization of multi-drug-resistant (MDR) Enterobacteriaceae (ESBL-E and CRE) (odds ratio, 17.09; 95% confidence interval, 5.29 - 55.18; P <0.0001). No significant association was observed between ESBL-E and CRE carriage and increased risk of developing subsequent bacteremia. No significant differences were detected between groups receiving modified and non-modified treatments in duration of hospitalization or antibiotic therapy (univariate analysis) and 28-day mortality rate (logistic regression). Conclusion Quinolone exposure was a major risk factor for ESBL-E and CRE fecal carriage. Performing rectal swab screening for MDR Enterobacteriaceae and modifying empirical antibiotic therapy accordingly did not improve clinical outcomes of febrile neutropenia patients.
Substâncias húmicas, atividade microbiana e carbono orgânico lábil em agregados de um Latossolo Vermelho distrófico sob duas coberturas vegetais

Organic matter is an indicator of the soil quality. Knowledge about its different components, explaining the influence of management practices on organic matter and soil aggregation, is essential for the sustainability of agricultural systems. In the present work, we evaluated humic substances, microbial activity and labile organic carbon in a Dystrophic Red Latosol from Minas Gerais state, Brazil, under natural vegetation (Cerradao) or under 30-years of conventional corn cultivation. Soil samples were collected from depths of 5-10 and 15-20 cm at four different sites. Then the samples were dried and fractioned in aggregate classes (diameter 4.75-2.0; 2.0-1.0; 1.0-0.5; 0.5-0.25; 0.25-0.105; and less than 0.105 mm). Furthermore, organic carbon of fulvic acid (AF), humic acids (AH) and humins (HUM) fractions, and labile organic carbon (COL) using KMnO4 15.6 and 33.0 mmol L-1 of the samples were determined. The material was further subjected to a respirometry test, in which CO2 production values were adjusted to logistic equations [Y = a/1 + e-(b + cx)] to estimate the time needed to achieve half of the maximum CO2 (t1/2), production. Results showed higher mean organic carbon contents in the AH fraction and COL with KMnO4 33.0 mmol L-1 of soil aggregates under conventional tillage. For AF and HUM fractions and COL with KMnO4 15.6 mmol L-1 this behavior was only observed in the 15-20 cm layer. The highest CO2 production was observed in the aggregates of the soil under Cerradao. The smaller aggregates tended to present higher organic carbon contents in the AF and AH fractions and COL. These were responsible for the highest CO2 production and constituted favorable sites of organic matter storage, due to the physical and chemical protection, as well as for mineralization, since microorganisms prefer these sites. The coefficients of the logistic equation (a, b, c) and the t1/2 can be considered important indicators of organic matter quality and lability under different managements.
Rapid Changes in Serum Testosterone in Men With Newly Diagnosed Type 2 Diabetes With Intensive Insulin and Metformin

OBJECTIVE To investigate the effect of metformin on testosterone levels in men with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Seventy men with newly diagnosed drug-naive T2DM and HbA1c >9.0% (75 mmol/mol) were treated with intensive insulin pump therapy for 5 days to achieve glucose normalization. They were randomized to control (continued on intensive insulin only) and metformin (plus metformin) groups (1:1) for 1 month. Testosterone was measured at baseline, randomization, and after 1-month treatment. RESULTS Total, free, and bioavailable testosterone increased significantly within 5 days (all P < 0.001). After 1 month, compared with the control group, the metformin group had lower total (12.7 vs. 15.3 nmol/L), free (0.20 vs. 0.24 nmol/L), and bioavailable (4.56 vs. 5.31 nmol/L) testosterone (all P < 0.05). CONCLUSIONS In men with T2DM, 1-month oral metformin may decrease serum testosterone levels independent of blood glucose control. The effects of long-term metformin on testosterone in men need further study.
‘Online therapy’ to reduce caregiver’s distress and to stimulate post-severe acquired brain injury motor and cognitive recovery: A Sicilian hospital experience in the COVID era

Introduction Severe acquired brain injury(SABI) often results in the deterioration of physical, cognitive and emotional functions in the patient and a significant caregiver's distress syndrome, which is now amplified by the social isolation, depression and financial difficulties related to the COVID-19 pandemic. The use of web-based online-therapy has been shown to be useful to overcome caregiver's distress syndrome and further stimulate cognitive-motor recovery of SABI-patients. Our study aimed to investigate whether a systematic online Skype-therapy(OLST) may be of support in favoring global cognitive and sensory-motor recovery in SABI-patients and reducing caregiver distress. Methods Twenty-five SABI-subjects in inpatient regimen were provided with intensive OLST with the caregiver for 12 weeks in addition to standard neurorehabilitation. Each subject and caregiver was evaluated before and after the treatment by administering an ad hoc battery. Furthermore, 18 of 27 patients were provided with EEG recording in resting state. Results We found a significant reduction in caregiver's anxiety (p<0.0001) and burden(p<0.0001). Patients showed significant improvement in trunk control (p<0.0001), functional independence (p = 0.005), functional (p = 0.01) and global communication (p = 0.004), cognitive functioning (p = 0.001), and behavioral responsiveness (p = 0.0004). The training yielded a significant connectivity change within the fronto-centro-parietal areas in the delta frequency band (p<0.0001) and the centro-parieto-occipital areas in the alpha range (p = 0.004). Discussion OLST may be a useful and complementary treatment to optimize global cognitive and functional recovery in SABI-subjects and reduce caregivers' concerns in the Covid-era. OLST can foster cognitive-motor recovery potentially by favoring the plasticity-dependent functional recovery. Therefore, OLST could be proposed as a tool allowing social conversations also in the hospital setting.
Evaluation of Discipline-Specific Outcomes Through a Multidisciplinary Team Clinic for Patients With Isolated Cleft Palate

Objective: To describe the incidence and timing of provider-specific interventions for children with isolated cleft palate. Design: This was a retrospective cohort study involving review of medical records. Setting: Multidisciplinary team care clinic at a tertiary academic children’s hospital between January 2000 and July 2019. Patients: Patients with isolated nonsyndromic cleft palate seen by an American Cleft Palate-Craniofacial Association-approved team; 138 children were included. Main Outcome Measures: Study outcomes included incidence of secondary velopharyngeal management, tympanostomy tube insertion, speech therapy, hearing loss, dental/orthodontic treatment, and psychology interventions. Provider-specific outcomes were calculated for patients at ages 0 to 3, 3 to 5, and >5 years. Results: Median follow-up time was 7.0 years (interquartile range: 3.3-11.8 years). At their last team assessment, 42% of patients still had conductive hearing loss. The rate of tympanostomy tube insertions not done alongside a palatoplasty was highest for ages 3 to 5 and dropped after new American Academy of Otolaryngology-Head and Neck Surgery Foundation guidelines in 2013 (P = .015); 54% of patients received speech-language therapy during follow-up. Palatoplasty, psychology, and dental/orthodontic treatment were all less common than speech or ENT treatment (P < .01). Secondary palatoplasty was performed in 31 patients (22%). Patients who received speech, dental/orthodontic, or psychology intervention followed up longer than those who did not (9.8 vs 2.1 years, P < .001). Conclusion: Half of the patients terminated team follow-up by age 7, suggesting that burden of care outweighed perceived benefits of continued follow-up for many families. These results can be used to adjust protocols for children with isolated cleft palate.
A Meta-analysis of Dynamic Prevalence of Cognitive Deficits in the Acute, Subacute, and Chronic Phases After Traumatic Brain Injury.

ABSTRACT BACKGROUND: Reports regarding prevalence of post-traumatic brain injury (TBI) cognitive deficits were inconsistent. We aimed to synthesize the prevalence of cognitive deficits after TBI in the acute, subacute, and chronic phases. METHODS: PubMed, EMBASE, and ProQuest Dissertations and Theses A&I databases were searched from the inception to April 27, 2020. Studies with prospective, retrospective, and cross-sectional designs reporting the prevalence of cognitive deficits after TBI in adults were included. RESULTS: A total of 15 articles were included for prevalence estimation. The pooled prevalence of memory and attention deficits after mild TBI was 31% and 20% in the acute phase and 26% and 18% in the subacute phase, respectively, and 49% and 54% in the subacute phase and 21% and 50% in the chronic phase after moderate-to-severe TBI. The overall prevalence of information processing speed deficits after mild TBI in the acute and subacute phases was 21% and 17%, respectively, and 57% in the chronic phase after moderate-to-severe TBI. The overall prevalence of executive dysfunction in the subacute and chronic phases was 48% and 38%, respectively, after moderate-to-severe TBI. CONCLUSION: Cognitive deficits are prevalent in the acute to chronic phases after TBI. Healthcare providers should design effective intervention targeting cognitive impairment after TBI as early as possible.
The Topical Nanodelivery of Vismodegib Enhances Its Skin Penetration and Performance In Vitro While Reducing Its Toxicity In Vivo

Vismodegib is a first-in-class inhibitor for advanced basal cell carcinoma treatment. Its daily oral doses present a high distribution volume and several side effects. We evaluated its skin penetration loaded in diverse nanosystems as potential strategies to reduce side effects and drug quantities. Ultradeformable liposomes, ethosomes, colloidal liquid crystals, and dendrimers were able to transport Vismodegib to deep skin layers, while polymeric micelles failed at this. As lipidic systems were the most effective, we assessed the in vitro and in vivo toxicity of Vismodegib-loaded ultradeformable liposomes, apoptosis, and cellular uptake. Vismodegib emerges as a versatile drug that can be loaded in several delivery systems for topical application. These findings may be also useful for the consideration of topical delivery of other drugs with a low water solubility.
Droplet digital PCR of viral ‎DNA/RNA, current progress, challenges, and future perspectives

High‐throughput droplet‐based digital PCR (ddPCR) is a refinement of the conventional polymerase chain reaction (PCR)‎ methods. In ddPCR, DNA/RNA is encapsulated stochastically inside the microdroplets as reaction chambers. A small percentage of the reaction chamber contains one or fewer copies of the DNA or RNA. After PCR amplification, concentrations are determined based on the proportion of nonfluorescent partitions through the Poisson distribution. Some of the main features of ddPCR include high sensitivity and specificity, absolute quantification without a standard curve, high reproducibility, good tolerance to PCR inhibitor, and high efficacy compared to conventional molecular methods. These advantages make ddPCR a valuable addition to the virologist's toolbox. The following review outlines the recent technological advances in ddPCR methods and their applications in viral identification.
Age differences in functional network reconfiguration with working memory training

Demanding cognitive functions like working memory (WM) depend on functional brain networks being able to communicate efficiently while also maintaining some degree of modularity. Evidence suggests that aging can disrupt this balance between integration and modularity. In this study, we examined how cognitive training affects the integration and modularity of functional networks in older and younger adults. Twenty three younger and 23 older adults participated in 10 days of verbal WM training, leading to performance gains in both age groups. Older adults exhibited lower modularity overall and a greater decrement when switching from rest to task, compared to younger adults. Interestingly, younger but not older adults showed increased task‐related modularity with training. Furthermore, whereas training increased efficiency within, and decreased participation of, the default‐mode network for younger adults, it enhanced efficiency within a task‐specific salience/sensorimotor network for older adults. Finally, training increased segregation of the default‐mode from frontoparietal/salience and visual networks in younger adults, while it diffusely increased between‐network connectivity in older adults. Thus, while younger adults increase network segregation with training, suggesting more automated processing, older adults persist in, and potentially amplify, a more integrated and costly global workspace, suggesting different age‐related trajectories in functional network reorganization with WM training.