The emergence of new structures can often be linked to the evolution of novel cell types that follows the rewiring of developmental gene regulatory subnetworks. Vertebrates are characterized by a ...complex body plan compared to the other chordate clades and the question remains of whether and how the emergence of vertebrate morphological innovations can be related to the appearance of new embryonic cell populations. We previously proposed, by studying mesoderm development in the cephalochordate amphioxus, a scenario for the evolution of the vertebrate head mesoderm. To further test this scenario at the cell population level, we used scRNA-seq to construct a cell atlas of the amphioxus neurula, stage at which the main mesodermal compartments are specified. Our data allowed us to validate the presence of a prechordal-plate like territory in amphioxus. Additionally, the transcriptomic profile of somite cell populations supports the homology between specific territories of amphioxus somites and vertebrate cranial/pharyngeal and lateral plate mesoderm. Finally, our work provides evidence that the appearance of the specific mesodermal structures of the vertebrate head was associated to both segregation of pre-existing cell populations, and co-option of new genes for the control of myogenesis.
Substance use disorder (SUD) is a global health problem with a significant impact on individuals and society. The presentation of SUD is diverse, involving various substances, ages at onset, comorbid ...conditions, and disease trajectories. Current treatments for SUD struggle to address this heterogeneity, resulting in high relapse rates. SUD often co-occurs with other psychiatric and mental health-related conditions that contribute to the heterogeneity of the disorder and predispose to adverse disease trajectories. Family and genetic studies highlight the role of genetic and environmental factors in the course of SUD, and point to a shared genetic liability between SUDs and comorbid psychopathology. In this study, we aimed to disentangle SUD heterogeneity using a deeply phenotyped SUD cohort and polygenic scores (PGSs) for psychiatric disorders and related traits. We explored associations between PGSs and various SUD-related phenotypes, as well as PGS-environment interactions using information on lifetime emotional, physical, and/or sexual abuse. Our results identify clusters of individuals who exhibit differences in their phenotypic profile and reveal different patterns of associations between SUD-related phenotypes and the genetic liability for mental health-related traits, which may help explain part of the heterogeneity observed in SUD. In our SUD sample, we found associations linking the genetic liability for attention-deficit hyperactivity disorder (ADHD) with lower educational attainment, the genetic liability for post-traumatic stress disorder (PTSD) with higher rates of unemployment, the genetic liability for educational attainment with lower rates of criminal records and unemployment, and the genetic liability for well-being with lower rates of outpatient treatments and fewer problems related to family and social relationships. We also found evidence of PGS-environment interactions showing that genetic liability for suicide attempts worsened the psychiatric status in SUD individuals with a history of emotional physical and/or sexual abuse. Collectively, these data contribute to a better understanding of the role of genetic liability for mental health-related conditions and adverse life experiences in SUD heterogeneity.
Neuropsychiatric symptoms (NPS) have been recently addressed as risk factors of conversion to Alzheimer's disease (AD) and other dementia types in patients diagnosed with Mild Cognitive Impairment ...(MCI). Our aim was to determine profiles based on the prominent NPS in MCI patients and to explore the predictive value of these profiles on conversion to specific types of dementia. A total of 2137 MCI patients monitored in a memory clinic were included in the study. Four NPS profiles emerged (classes), which were defined by preeminent symptoms: Irritability, Apathy, Anxiety/Depression and Asymptomatic. Irritability and Apathy were predictors of conversion to dementia (HR = 1.43 and 1.56, respectively). Anxiety/depression class showed no risk effect of conversion when compared to Asymptomatic class. Irritability class appeared as the most discriminant neuropsychiatric condition to identify non-AD converters (i.e., frontotemporal dementia, vascular dementia, Parkinson's disease and dementia with Lewy Bodies). The findings revealed that consistent subgroups of MCI patients could be identified among comorbid basal NPS. The preeminent NPS showed to behave differentially on conversion to dementia, beyond AD. Therefore, NPS should be used as early diagnosis facilitators, and should also guide clinicians to detect patients with different illness trajectories in the progression of MCI.
Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem ...when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia.
Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia.
The median (IQR) of meropenem AUC
in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L.
An increase in the dose of meropenem administered by CI achieved a higher exposure in the plasma and ELF. The use of the highest licensed dose of 6 g/day may be necessary to achieve an optimal coverage in ELF for all susceptible isolates (MIC ≤ 2 mg/L) in patients with conserved renal function. An alternative therapy should be considered when the presence of microorganisms with a MIC greater than 2 mg/L is suspected.
The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT-no. 2016-002796-10). Registered on 27 December 2016.
Despite treatment, prognosis of unresectable squamous cell carcinoma of the head and neck (SCCHC) is dismal. Cetuximab therapy has proven to increase the clinical activity of radiation therapy and ...chemotherapy in patients with locoregional advanced disease with an acceptable toxicity profile. We designed a phase 2 trial to evaluate the efficacy of docetaxel, cisplatin, and 5-fluorouracil (TPF) plus cetuximab (C-TPF) as an induction regimen in patients with unresectable SCCHN.
A single-arm phase 2 trial was conducted. Eligible patients included those with untreated unresectable SCCHC, World Health Organization performance status of 0 to 1, 18 to 70 years of age. Treatment consisted of four 21-day cycles of TPF (docetaxel, 75 mg/m(2) day 1; cisplatin, 75 mg/m(2) day 1; 5-fluorouracil 5-FU, 750 mg/m(2) day 1-5) and cetuximab, 250 mg/m(2) weekly (loading dose of 400 mg/m(2)). Prophylactic granulocyte colony-stimulating factor and antibiotic support were given. After induction, sequential accelerated radiation therapy with concomitant boost (69.9 Gy) and weekly cetuximab therapy were delivered in the absence of disease progression. The primary endpoint was objective response rate (ORR) to C-TPF.
Fifty patients were enrolled across 8 centers. Median age was 54 years; disease was stage IV; oropharynx and hypopharynx were the most common primary sites. Eighty-two percent received 4 cycles of C-TPF, and 86% started sequential treatment based on radiation therapy and cetuximab. ORR after C-TPF was 86% (95% confidence interval CI: 73%-94%) and 24% had complete response (CR). With a median follow-up of 40.7 months, median overall survival (OS) was 40.7 months. The 2-year actuarial locoregional control (LRC) rate was 57%. The most common drug-related grade 3 or 4 toxicities during induction were neutropenia (24%), neutropenic fever (24%), and diarrhea (20%). There were 3 treatment-related deaths (6%).
C-TPF yields high ORR and CR as induction treatment in unresectable SCCHN. However, hematologic toxicity is too high to recommend this regimen at the current dose.
Waterproofed vegetable leather is desired for its “greenness” in front of chromium-tanned waterproofed leather. However, conferring waterproofing capabilities to vegetable tanned leather maintaining ...light color and a soft touch is a fact of great concern for leather goods producers. Sustainable and technical requirements are currently demanded by high-quality brands in order to pass the threshold established by Leather Working Group (LWG) initiatives to earn their environmental audit seal. The research work has focused on testing various mineral salts and hydrophobic products compatible with vegetable tanned leather. According to the obtained results, acrylic copolymers along with zirconium salts are necessary to achieve the desired leather properties. The present study provides the environmental comparison of a new vegetable tanning process to give waterproofing capabilities with the conventional vegetable tanning process. The comparison comprises both wastewater analysis and environmental impacts in a life cycle assessment (LCA) framework. The paper also outlines the comparison using different life cycle impact assessment (LCIA) methods. Further, the study provides specific data on leather vegetable tanning processes. Comparative analysis has been focused on the two diverging stages for both conventional and waterproofing vegetable tanning processes, namely retanning and fatliquoring. Conventional process environmental impacts are lower than waterproofing process impacts according to LCA methodology. However, wastewater analysis shows no major differences between both processes. Main contributors to these results are the zirconium salts, dispersing agents and acrylic copolymers used along with an increase in energy consumption due to processing times. Alternative methods used in the impact assessment lead to similar results, revealing no major differences in the comparative results between methods in this case.
•Waterproofing process in vegetable leather requires the use of zirconium salts.•Waterproofing process entails an increase on the GWP impact.•Zirconium salts and acrylic copolymers increase environmental impact.•Comparison between LCIA methods in different databases.•The study will serve future research for improvement and comparison of results.
•Patients with psychogenic nonepileptic seizures show improved cognition after an accurate diagnosis.•Specifically, executive functions, language, attention, and psychomotor speed improve in PNE ...patients.•Reduction in number of antiseizure medication is associated with improved cognition in PNES patients.•Patients with temporal lobe epilepsy had a cognitive stability at one year of follow-up.
Much remains to be elucidated about the cognitive profile of patients with psychogenic nonepileptic seizures (PNES) and about how this changes over time and compares to that of patients with epilepsy. The aim of this study was to study the neuropsychological profile of patients with PNES and an age-matched group of patients with temporal lobe epilepsy (TLE) during admission to a video electroencephalography monitoring unit (VEMU) and 1 year after discharge.
Patients diagnosed with PNES or TLE at a VEMU were prospectively recruited. Neuropsychological, demographic, clinical, and treatment variables were collected at baseline and 1 year. To minimize multiple comparisons, scores from different cognitive tests were computed for attention and psychomotor speed, verbal memory, visual memory, language, and executive function. A global cognitive impairment index (GCII) was also created. Post hoc analyses were conducted to identify clinical variables that might mediate the differences observed in cognition over time between the groups. These included seizure frequency, number of antiseizure medication (ASM), number of psychotropic drugs, depression, and quality of life.
We studied 24 patients with PNES and 24 patients with TLE. The groups performed similarly in the baseline neuropsychological tests. There was a significant time (baseline to 1-year follow-up) by group (PNES vs TLE) interaction for the GCII (p = 0.006), language (p = 0.04), and executive function (p = 0.013), with PNES patients showing improvement and TLE patients remaining stable. The time by group interaction for attention and psychomotor speed showed a trend toward significance (p = 0.056), Reduction in number of ASM was associated with improved cognition in PNES patients at 1 year.
PNES patients showed improved cognition at 1 year of follow-up, particularly in language and executive functions. This finding shows the potential benefits of an early, accurate diagnosis, which range from improved cognition to better management.
Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability ...(MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues.
Blood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers.
The hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic
carriers (n=5) compared with
carriers (n=15). The hs-MSI analysis did not detect a difference between LS and control blood samples (p=0.564).
The hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.
Bolivia has the highest prevalence of Chagas disease (CD) in the world (6.1%), with more than 607,186 people with Trypanosoma cruzi infection, most of them adults. In Bolivia CD has been declared a ...national priority. In 2009, the Chagas National Program (ChNP) had neither a protocol nor a clear directive for diagnosis and treatment of adults. Although programs had been implemented for congenital transmission and for acute cases, adults remained uncovered. Moreover, health professionals were not aware of treatment recommendations aimed at this population, and research on CD was limited; it was difficult to increase awareness of the disease, understand the challenges it presented, and adapt strategies to cope with it. Simultaneously, migratory flows that led Bolivian patients with CD to Spain and other European countries forced medical staff to look for solutions to an emerging problem.
In this context, thanks to a Spanish international cooperation collaboration, the Bolivian platform for the comprehensive care of adults with CD was created in 2009. Based on the establishment of a vertical care system under the umbrella of ChNP general guidelines, six centres specialized in CD management were established in different epidemiological contexts. A common database, standardized clinical forms, a and a protocolized attention to adults patients, together with training activities for health professionals were essential for the model success. With the collaboration and knowledge transfer activities between endemic and non-endemic countries, the platform aims to provide care, train health professionals, and create the basis for a future expansion to the National Health System of a proven model of care for adults with CD.
From 2010 to 2015, a total of 26,227 patients were attended by the Platform, 69% (18,316) were diagnosed with T. cruzi, 8,567 initiated anti-parasitic treatment, more than 1,616 health professionals were trained, and more than ten research projects developed. The project helped to increase the number of adults with CD diagnosed and treated, produce evidence-based clinical practice guidelines, and bring about changes in policy that will increase access to comprehensive care among adults with CD. The ChNP is now studying the Platform's health care model to adapt and implement it nationwide.
This strategy provides a solution to unmet demands in the care of patients with CD, improving access to diagnosis and treatment. Further scaling up of diagnosis and treatment will be based on the expansion of the model of care to the NHS structures. Its sustainability will be ensured as it will build on existing local resources in Bolivia. Still human trained resources are scarce and the high staff turnover in Bolivia is a limitation of the model. Nevertheless, in a preliminary two-years-experience of scaling up this model, this limitations have been locally solved together with the health local authorities.
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