Light and temperature signals are integrated through a phyB-dependent gene regulatory network in rice.

Angiosperms are the most dominant land plant flora and have colonised most of the terrestrial habitats, thriving in different environmental conditions, among which light and temperature play a crucial role. In the eudicot Arabidopsis thaliana, light and temperature are integrated into a phytochrome B (phyB)-dependent signalling network that regulates development. However, whether this signal integration controls the development in other angiosperm lineages and if phyB is a conserved hub of this integratory network in angiosperms is unclear. We used a combination of phylogenetic, phenotypic, and transcriptomic analyses to understand the phyB-dependent light and temperature integratory network in the monocot Oryza sativa and infer its conservation in angiosperms. Here, we show that light and temperature co-regulate rice growth through a phyB-dependent regulatory network that shares conserved features between O. sativa and A. thaliana. Despite the conservation of the components of this regulatory network, the transcriptional regulation between the components has changed qualitatively since monocots and eudicots diverged (~192-145 MYA). The evolutionary flexibility of this integratory network might underlie the successful adaptation of plants to diverse ecological niches. Furthermore, our findings provide promising candidate genes whose activity and expression can be fine-tuned to improve plant growth and productivity in a warming planet.

Impact of Previous Cataract Surgery in Corneal Donors on the Outcome of Descemet Membrane Endothelial Keratoplasty.

PURPOSE: The aim of this study was to investigate differences between phakic, pseudophakic, and scarred stromal donor tissue for their influence on complication rates during preparation or implantation and on the postoperative outcome of Descemet membrane endothelial keratoplasty (DMEK). METHODS: We retrospectively compared 484 eyes undergoing DMEK, divided into 3 subgroups of donor tissue (1: phakic, 2: pseudophakic, and 3: scarred stromal). Visual acuity, central corneal thickness (CCT), and endothelial cell count were monitored preoperatively and postoperatively at 6 weeks and 3, 6, 12, and 24 months. The incidence of intraoperative and postoperative complications was analyzed. RESULTS: The risk of adherence and tearing during preparation was significantly higher in group 2 than in the other groups (p's < 0.001). No significant difference was found for visual acuity (p's ≥ 0.368) and long-term CCT, but CCT recovery took longer in group 2 (P = 0.003), normalizing after 3 months (p's ≥ 0.096). The overall mean endothelial cell count was lower in group 2 compared with the other groups (P = 0.011). No difference in the rebubbling rate was detected (P = 0.890). However, the risk of repeat keratoplasty for phakic grafts was lower compared with group 2 (P = 0.008). CONCLUSIONS: Pseudophakic donor grafts are more difficult to prepare and implant, resulting in longer recovery times and a higher risk of graft failure. However, when the preparation is uneventful and no graft failure occurs, pseudophakic grafts show a comparable outcome. Given the shortage of corneal donors and the high prevalence of pseudophakic corneal donors, they should not generally be excluded from corneal donation for DMEK.

Two new species of Microlaimidae (Nematoda: Microlaimida) from the Continental Shelf off Northeastern Brazil (Atlantic Ocean) with emended diagnosis and dichotomous key.

New species of the genera Spirobolbolaimus and Ixonema (Nematoda: Microlaimidae) have been found in sediment samples collected in the South Atlantic, along the Continental Shelf break off Northeastern Brazil. Different to other Spirobolbolaimus species, S. pernambucanus sp. nov. possesses six outer labial setae and four cephalic setae with approximately the same length. Ixonema gracieleae sp. nov. differs from other species of Ixonema in having somatic setae on peduncles. This is the first time that new species of these taxa have been described for the Brazilian coast. An amendment of the diagnosis and a dichotomous key are proposed for both genera.

High-confidence and high-throughput quantification of synapse engulfment by oligodendrocyte precursor cells.

Oligodendrocyte precursor cells (OPCs) sculpt neural circuits through the phagocytic engulfment of synapses during development and adulthood. However, existing techniques for analyzing synapse engulfment by OPCs have limited accuracy. Here we describe the quantification of synapse engulfment by OPCs via a two-pronged cell biological approach that combines high-confidence and high-throughput methodologies. Firstly, an adeno-associated virus encoding a pH-sensitive, fluorescently tagged synaptic marker is expressed in neurons in vivo to differentially label presynaptic inputs, depending upon whether they are outside of or within acidic phagolysosomal compartments. When paired with immunostaining for OPC markers in lightly fixed tissue, this approach quantifies the engulfment of synapses by around 30-50 OPCs in each experiment. The second method uses OPCs isolated from dissociated brain tissue that are then fixed, incubated with fluorescent antibodies against presynaptic proteins, and analyzed by flow cytometry, enabling the quantification of presynaptic material within tens of thousands of OPCs in <1 week. The integration of both methods extends the current imaging-based assays, originally designed to quantify synaptic phagocytosis by other brain cells such as microglia and astrocytes, by enabling the quantification of synaptic engulfment by OPCs at individual and populational levels. With minor modifications, these approaches can be adapted to study synaptic phagocytosis by numerous glial cell types in the brain. The protocol is suitable for users with expertise in both confocal microscopy and flow cytometry. The imaging-based and flow cytometry-based protocols require 5 weeks and 2 d to complete, respectively.

Propofol-mediated loss of consciousness disrupts predictive routing and local field phase modulation of neural activity.

Predictive coding is a fundamental function of the cortex. The predictive routing model proposes a neurophysiological implementation for predictive coding. Predictions are fed back from the deep-layer cortex via alpha/beta (8 to 30 Hz) oscillations. They inhibit the gamma (40 to 100 Hz) and spiking that feed sensory inputs forward. Unpredicted inputs arrive in circuits unprepared by alpha/beta, resulting in enhanced gamma and spiking. To test the predictive routing model and its role in consciousness, we collected data from intracranial recordings of macaque monkeys during passive presentation of auditory oddballs before and after propofol-mediated loss of consciousness (LOC). In line with the predictive routing model, alpha/beta oscillations in the awake state served to inhibit the processing of predictable stimuli. Propofol-mediated LOC eliminated alpha/beta modulation by a predictable stimulus in the sensory cortex and alpha/beta coherence between sensory and frontal areas. As a result, oddball stimuli evoked enhanced gamma power, late period (>200 ms from stimulus onset) spiking, and superficial layer sinks in the sensory cortex. LOC also resulted in diminished decodability of pattern-level prediction error signals in the higher-order cortex. Therefore, the auditory cortex was in a disinhibited state during propofol-mediated LOC. However, despite these enhanced feedforward responses in the auditory cortex, there was a loss of differential spiking to oddballs in the higher-order cortex. This may be a consequence of a loss of within-area and interareal spike-field coupling in the alpha/beta and gamma frequency bands. These results provide strong constraints for current theories of consciousness.

Brazil towards malaria elimination: A time-series analysis of imported cases from 2007 to 2022.

Malaria is a global health challenge, and international efforts are underway to alleviate its impact by 2035. Within the 249 million global cases, 0.6 million occur in the Americas, mainly in Venezuela, Brazil, and Colombia. Considering Brazil's geographical proximity to malaria-endemic countries in South America, this study objective is to analyze the epidemiological characteristics and time trends of imported malaria cases in Brazil from 2007 to 2022, discussing their influence on the elimination process. This is an ecological time-series study that analyses malaria imported cases (infected in other countries) notified in Brazil, from 2007 to 2022. Brazil's Ministry of Health data were used. Descriptive statistics were employed to analyze sociodemographic and spatial patterns, while the impact of the Covid-19 pandemic on imported malaria trends was assessed using Prais-Winsten regression methods. In the study period there was a total of 109,914 imported cases (2.6% of Brazil's total malaria burden). There was an annual reduction of 515.3 cases (p = 0.001) prior to the Covid-19 pandemic. During the pandemics there was an overall reduction of -3,301.8 cases (p = 0.001). In the Amazon region P. vivax imported infections predominated, whereas in the extra-Amazon region P. falciparum imported infections were more prevalent. Most imported cases were males (67.8%), of Black ethnicity (47.5%), with incomplete primary education (45.1%), aged 20-39 (61.1%), and primarily gold miners (54.0%). Most cases are from French Guiana (31.7%), Venezuela (30.0%), and Guyana (17.9%). African nations, notably Angola and Nigeria, were primary sources of imported cases to the extra-Amazon region. The imported cases flux, predominantly from Latin America, threatens Brazil's elimination goals by potentially reintroducing the disease into previously cleared areas and sustaining the transmission in endemic areas. Strengthening epidemiological surveillance at the borders and fostering international cooperation are imperative steps in addressing this challenge.

Consequences of trisomy 21 for brain development in Down syndrome.

The appearance of cognitive deficits and altered brain morphology in newborns with Down syndrome (DS) suggests that these features are driven by disruptions at the earliest stages of brain development. Despite its high prevalence and extensively characterized cognitive phenotypes, relatively little is known about the cellular and molecular mechanisms that drive the changes seen in DS. Recent technical advances, such as single-cell omics and the development of induced pluripotent stem cell (iPSC) models of DS, now enable in-depth analyses of the biochemical and molecular drivers of altered brain development in DS. Here, we review the current state of knowledge on brain development in DS, focusing primarily on data from human post-mortem brain tissue. We explore the biological mechanisms that have been proposed to lead to intellectual disability in DS, assess the extent to which data from studies using iPSC models supports these hypotheses, and identify current gaps in the field.

Towards malaria elimination: a case-control study to assess associated factors to malaria relapses in the extra-Amazon Region of Brazil from 2008 to 2019.

BACKGROUND: Malaria is an infectious disease caused by the Plasmodium species and is a global burden. When not treated correctly, it can reemerge as a relapse or recrudescence. Malaria relapse cases can contribute to maintaining active transmission chains and can influence the patient to develop severe malaria, potentially leading to hospitalization or death. The objective of this study is to estimate the number of malaria relapse cases in the extra-Amazon region of Brazil and to investigate the associated factors. METHODS: This is a case-control study that analyses malaria infections caused by Plasmodium vivax, as reported in Notifiable Diseases Information System (Sinan) for the Brazilian extra-Amazon region (an area not endemic for the disease) from 2008 to 2019. For the identification of relapse cases, deduplication record linkage processes in R software were used. Malaria relapses were defined as the case group, and new malaria infections were defined as the control group. Logistic regression models were used to assess associated factors. RESULTS: Of the 711 malaria relapses, 589 (82.8%) were first relapses. Most relapses (71.6%) occurred between 30 and 120 days after the previous infection. Malaria relapses are spread throughout the extra-Amazon region, with a higher concentration near big cities. Driver occupation was found to be a common risk factor compared to other occupations, along with asymptomatic individuals. Other associated factors were: being infected in the Brazilian Amazon region, having follow-ups for malaria relapses, and having parasite density of the previous infection higher than 10,000 parasites per mm3. CONCLUSIONS: This study provides evidence that allows malaria health surveillance services to direct their efforts to monitor cases of malaria in the highest risk segments identified in this study, particularly in the period between 30 and 120 days after being infected and treated. Relapses were associated to driver occupation, absence of symptoms, infection in endemic areas of Brazil, being detected through active surveillance or routine follow-up actions, and with parasitaemia greater than 10,000 parasites per mm3 in the previous infection. Improving cases follow-up is essential for preventing relapses.

A Scoping Review of Non-Communicable Diseases among the Workforce as a Threat to Global Peace and Security in Low-Middle Income Countries.

Non-communicable diseases (NCDs) continue to pose a threat to public health. Although their impact on the workforce is widely recognized, there needs to be more understanding of how NCDs affect peace and security, particularly in low-middle-income countries. To address this, we conducted a scoping review and presented a narrative to explore how NCDs in the workforce threaten peace and security. Out of 570 papers screened, 34 articles, comprising 26 peer review and 8 grey literature, met the study criteria. Our findings reveal that while no study has drawn a direct relationship between NCDs in the workforce in LMICs and peace and security, several studies have demonstrated a relationship between NCDs and economic growth on one hand and economic growth and peace and security on the other. Therefore, using economic growth as a proximal factor, our findings show three pathways that link NCDs in the workforce to peace and security: (i) NCDs lead to low productivity and poor economic growth, which can threaten public peace and security; (ii) NCDs in the workforce can result in long-term care needs, which then puts pressure on public resources and have implications for public expenditure on peace and security; and (iii) household expenditures on caring for a family member with an NCD can destabilize families and create an unfavourable condition that threatens peace and security. This research highlights the dual threat of NCDs to health and security, as they impact human resources and community structures crucial for peace and security. The results underscore the importance of considering the workplace as a strategic setting for NCD prevention, which will have long-term implications for economic growth and peace and security.

Dual Chemotherapeutic Loading in Oxalate Transferrin-Conjugated Polymersomes Incorporated into Chitosan Hydrogels for Site-Specific Targeting of Melanoma Cells.

In this work, we developed a smart drug delivery system composed of poly (ethylene glycol)-block-poly (ε-caprolactone) (PEG-PCL)-based polymersomes (Ps) loaded with doxorubicin (DOX) and vemurafenib (VEM). To enhance targeted delivery to malignant melanoma cells, these drug-loaded nanovesicles were conjugated to the oxalate transferrin variant (oxalate Tf) and incorporated into three-dimensional chitosan hydrogels. This innovative approach represents the first application of oxalate Tf for the precision delivery of drug-loaded polymersomes within a semi-solid dosage form based on chitosan hydrogels. These resulting semi-solids exhibited a sustained release profile for both encapsulated drugs. To evaluate their potency, we compared the cytotoxicity of native Tf-Ps with oxalate Tf-Ps. Notably, the oxalate Tf-Ps demonstrated a 3-fold decrease in cell viability against melanoma cells compared to normal cells and were 1.6-fold more potent than native Tf-Ps, indicating the greater potency of this nanoformulation. These findings suggest that dual-drug delivery using an oxalate-Tf-targeting ligand significantly enhances the drug delivery efficiency of Tf-conjugated nanovesicles and offers a promising strategy to overcome the challenge of multidrug resistance in melanoma therapy.

Comparative study of the reproductive and growth performance of the Hamra and Rumbi ovine breeds.

Growth and reproductive performance traits are important economic indicators for analyzing the overall performance of breeding systems. This study aims to evaluate the comparative performance of two Algerian sheep (Rumbi and Hamra) in terms of growth and reproductive performance, and the effect of factors such as breed, season of birth, mode of birth and age of the mother on this performance in a semi-intensive breeding system. The reproductive performance of 577 Rumbi ewes and 1328 Hamra ewes bred at the Tiaret and Saïda experimental stations respectively, was analyzed using performance monitoring data. Fertility rates for the Rumbi and Hamra breeds of 87.14% and 78.8% respectively were practically similar (p > 0,05). Litter size at birth and weaning was significantly higher in the Hamra breed than in the Rumbi breed (p < 0,05). Weaning mortality was significantly higher in the Hamra breed than in the Rumbi breed, with an average of 22.60% versus 14.94% (p < 0,05). The effect of factors showed that there was a highly significant effect of the mother's age and season of birth on the reproductive performance of the Hamra and Rumbi breeds with a p < 0.0001 on fertility, litter size at birth, litter size at weaning and fertility. There was a significant effect of the year factor on reproductive performance with p = 0,013 for the Hamra breed and p = 0,031 for the Rumbi breed. The results of this study showed that Rumbi lambs were heavier at birth than Hamra lambs. The values observed were 4,86 kg versus 3,10 kg for the Hamra breed, with a highly significant difference (p < 0,0001), so that the average daily pre-weaning weight gains of Rumbi lambs were higher than those of Hamra lambs, at 0,195 kg/day versus 0,113 kg/day for Hamra lambs, with a high significance (p < 0,0001). The effect of factors showed that there was a significant effect of the mother's age on the ADGs (0-30), (30-70) and (70-90) of the Hamra and Rumbi breeds with a p = 0,034 and p = 0,02 respectively. There was also a highly significant effect of the birth mode effect on ADGs (0-30), (30-70) and (70-90) only for the Hamra breed with a p = 0,004. The effect of the birth weight on ADGs was not significant for both Hamra and Rumbi breeds with a p > 0,05. According to the findings of this study, the Hamra breed had superior reproductive potential and the Rumbi breed had superior growth. The Hamra breed showed better maternal skills in terms of fertility and prolificacy, while the Rumbi breed showed better lamb growth performance. Consequently, these results could be used for selective sheep breeding, taking into account the random effects of the environment and the potential of each breed.

Impact of a tailored exercise regimen on physical capacity and plasma proteome profile in post-COVID-19 condition.

Background: Individuals affected by the post-covid condition (PCC) show an increased fatigue and the so-called post-exertion malaise (PEM) that led health professionals to advise against exercise although accumulating evidence indicates the contrary. The goal of this study is to determine the impact of a closely monitored 8-week mixed exercise program on physical capacity, symptoms, fatigue, systemic oxidative stress and plasma proteomic profiles of PCC cases. Methods: Twenty-five women and men with PCC were assigned sequentially to exercise (n = 15) and non-exercise (n = 10) groups. Individuals with no PCC served as a control group. The exercise program included cardiovascular and resistance exercises. Physical capacity, physical activity level and the presence of common PCC symptoms were measured before and after the intervention. Fatigue was measured the day following each exercise session. Plasma and PBMC samples were collected at the beginning and end of the training program. Glutathione and deoxyguanosine levels in PBMC and plasma proteomic profiles were evaluated. Results: Bicep Curl (+15% vs 4%; p = 0.040) and Sit-to-Stand test (STS-30 (+31% vs +11%; p = 0.043)) showed improvement in the exercise group when compared to the non-exercise group. An interaction effect was also observed for the level of physical activity (p =0.007) with a positive effect of the program on their daily functioning and without any adverse effects on general or post-effort fatigue. After exercise, glutathione levels in PBMCs increased in women but remained unchanged in men. Discernable changes were observed in the plasma proteomics profile with certain proteins involved in inflammatory response decreasing in the exercise group. Conclusions: Supervised exercise adapted to the level of fatigue and ability is safe and effective in PCC patients in improving their general physical capacity and wellbeing. Systemic molecular markers that accompany physical improvement can be monitored by analyzing plasma proteomics and markers of oxidative stress. Large-scale studies will help identify promising molecular markers to objectively monitor patient improvement.

Outcomes at 6 months after isolated or non-isolated surgery for temporal bone cerebrospinal fluid leak in adults: A STROBE analysis.

AIM: The main aim of this study was to evaluate 6-month closure success in surgery for isolated or non-isolated temporal bone osteomeningeal breach (OMB). Secondary objectives were to analyze complications of closure and correlations between success and breach, treatment and patient data. MATERIAL AND METHOD: This was a single-center retrospective observational study of patients who underwent surgery for temporal bone OMB via a middle cranial fossa or transmastoid approach in a French university teaching hospital between 2007 and 2022, with follow-up of at least 6months. Patients with superior semicircular canal dehiscence were excluded. Study data comprised gender, age, body mass index, OMB etiology, mode of discovery, audiometric and radiological data, surgical technique, length of hospital stay and postoperative complications. The primary endpoint was absence of a cerebrospinal fluid leak on MRI at 6months. Fisher's exact test or Chi2 test were used for qualitative data and Student t-test for quantitative data. RESULTS: The closure success rate was 87%: 81% (3 recurrences) in the middle cranial fossa group of 16 patients and 93% in the transmastoid group of 14 patients. Postoperative audiometry showed significant improvement (P=0.0016) for air conduction in the middle cranial fossa group. Five patients (17%) operated on via the middle cranial fossa approach and 1 (7%) operated on via the transmastoid approach had postoperative complications. OMB was in the tegmen mastoideum in 8 patients (29%), tegmen tympani in 7 (25%), tegmen antri in 4 (14%), tegmina antri and tympani in 3 (11%), antri and mastoideum in 1 (8%) and in the whole tegmen in 5 (18%). Eleven OMBs were lateral to the superior semicircular canal, 13 medial and 4 on either side. CONCLUSION: The transmastoid approach is indicated in case of associated middle-ear procedures, patients aged over 75years or OMB lateral to the superior semicircular canal. The middle cranial fossa approach is reserved for OMB located medial to the superior semicircular canal patients under 75years of age without associated ossicular procedures. For patients with OMB medial to the superior semicircular canal who require middle-ear surgery, a combined approach can be used.

Correlates of low resilience and physical and mental well-being among black youths in Canada.

BACKGROUND: Resilience has gained considerable attention in the mental health field as a protective factor that enables individuals to overcome mental health issues and achieve positive outcomes. A better understanding of resilience among Black youth is important for supporting the strengths and capacities within this population. This study seeks to investigate the correlates of resilience among Black youths in Canada. METHODS: The survey was conducted online through REDCap between November 2022 and March 2023. The Brief Resilience Scale (BRS) was utilized to measure the capacity of participants to recover from or bounce back from stress. The BRS comprises six five-point Likert scale items. Data were analyzed employing a bivariate analysis followed by a multivariable binary logistic regression. RESULTS: A total of 933 Black youths participated in the study across all Canadian provinces, of which 51.8% (483) identified as female and 46.7% (436) as male. Most respondents 51.3% (479) were between the ages of 16 and 20 years, with 28% (261) between the ages of 21 and 25 years, and 20.2% (188) between the ages of 26 and 30 years. In terms of employment, 62.0% (578) were working part-time, 23.7%, (220) were unemployed, and 9.8% (91) were working full-time. Over a third of participants (39.3%, 331) rated their mental health over the last month as good, with 34% (317) giving a rating of poor and 20.9% (195) giving a rating of fair. Black youths who were working part-time had four times greater odds of expressing low resilience (OR: 4.02; 95% CI: 1.82-11.29) than those who were not working. Black youth who ranked their mental health as poor were about nine times (OR: 8.65; 95% CI: 1.826-21.978) more likely to express low resilience. CONCLUSION: In this study, the Black youth participants reported relatively low resilience scores. Employment, physical health, and mental health status were factors that contributed to low resilience. Further studies are needed to examine the causal link between resilience and its dynamic effect on health outcomes among Black youth. More interventions are needed to make mental health services accessible to Black youth in a more culturally sensitive way with cross-culturally trained professionals.

Impact of preoperative age-adjusted sagittal imbalance on radiographic and clinical outcomes following 1-level minimally invasive transforaminal lumbar interbody fusion for degenerative spondylolisthesis.

OBJECTIVE: Prior studies investigating the use of minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) for treatment of degenerative lumbar conditions and concomitant sagittal deformity have not stratified patients by preoperative pelvic incidence (PI)-lumbar lordosis (LL) mismatch, which is the earliest parameter to deteriorate in mild sagittal deformity. Thus, the aim of the present study was to determine the impact of preoperative PI-LL mismatch on clinical outcomes and sagittal balance restoration among patients undergoing MI-TLIF for degenerative spondylolisthesis (DS). METHODS: Consecutive adult patients undergoing primary 1-level MI-TLIF between April 2017 and April 2022 for DS with ≥ 6 months radiographic follow-up were included. Patient-reported outcome measures (PROMs) included the Oswestry Disability Index, visual analog scale (VAS), 12-Item Short-Form Health Survey (SF-12), and Patient-Reported Outcomes Measurement Information System at preoperative, early postoperative (< 6 months), and late postoperative (≥ 6 months) time points. The minimal clinically important difference (MCID) for PROMs was also evaluated. Radiographic parameters included PI, LL, pelvic tilt (PT), and sagittal vertical axis (SVA). Patients were categorized into balanced and unbalanced groups based on preoperative PI-LL mismatch according to age-adjusted alignment goals. Changes in radiographic parameters and PROMs were evaluated. RESULTS: Eighty patients were included (L4-5 82.5%, grade I spondylolisthesis 82.5%, unbalanced 58.8%). Mean clinical and radiographic follow-up were 17.0 and 8.3 months, respectively. The average preoperative PI-LL was 18.8° in the unbalanced group and -3.3° in the balanced group. Patients with preoperative PI-LL mismatch had significantly worse preoperative PT (26.2° vs 16.4°, p < 0.001) and SVA (53.2 vs 9.0 mm, p = 0.001) compared with balanced patients. Patients with preoperative PI-LL mismatch also showed significantly worse PI-LL (16.0° vs 0.54°, p < 0.001), PT (25.9° vs 18.7°, p < 0.001), and SVA (49.4 vs 22.8 mm, p = 0.013) at long-term follow-up. No significant radiographic improvement was observed among unbalanced patients. All patients demonstrated significant improvements in all PROMs (p < 0.05) except for SF-12 mental component score. Achievement of MCID for VAS back score was significantly greater among patients with preoperative PI-LL mismatch (85.7% vs 65.5%, p = 0.045). CONCLUSIONS: Although 1-level MI-TLIF did not restore sagittal alignment in patients with preoperative PI-LL mismatch, patients presenting with DS can expect significant improvement in PROMs following 1-level MI-TLIF regardless of preoperative alignment or extent of correction. Thus, attaining good clinical outcomes in patients with mild sagittal imbalance may not require addressing imbalance directly.

Efficacy and safety of Butantan-DV in participants aged 2-59 years through an extended follow-up: results from a double-blind, randomised, placebo-controlled, phase 3, multicentre trial in Brazil.

BACKGROUND: A single-dose dengue vaccine that protects individuals across a wide age range and regardless of dengue serostatus is an unmet need. We assessed the safety and efficacy of the live, attenuated, tetravalent Butantan-dengue vaccine (Butantan-DV) in adults, adolescents, and children. We previously reported the primary and secondary efficacy and safety endpoints in the initial 2 years of follow-up. Here we report the results through an extended follow-up period, with an average of 3·7 years of follow-up. METHODS: In this double-blind, randomised, placebo-controlled, phase 3, multicentre trial in Brazil, healthy participants (aged 2-59 years) who had not previously received a dengue vaccine were enrolled and randomly assigned 2:1 (stratified by age 18-59 years, 7-17 years, and 2-6 years) using a central electronic randomisation system to receive 0·5 mL of Butantan-DV (containing approximately 103 plaque-forming units of each of the four vaccine virus strains) or placebo, administered subcutaneously. Syringes containing vaccine or placebo were prepared by an unmasked trial pharmacist who was not involved in any subsequent participant assessments; other site staff and the participants remained unaware of the group allocations. Vaccine efficacy was calculated with the accrual of virologically confirmed dengue (VCD) cases (by RT-PCR) at least 28 days after vaccination up until the cutoff (at least 2 years of follow-up from the last participant enrolled). The primary endpoint was vaccine efficacy against VCD after day 28 by any dengue virus (DENV) serotype regardless of dengue serostatus at baseline in the per-protocol population. The primary and secondary safety endpoints up until day 21 were previously reported; secondary safety endpoints include the frequency of unsolicited vaccine-related adverse events after day 22. Safety analyses were done on all participants as treated. This trial is registered with ClinicalTrials.gov (NCT02406729) and is ongoing. FINDINGS: Of 16 363 participants assessed for eligibility, 16 235 were randomly assigned between Feb 22, 2016, and July 5, 2019, and received single-dose Butantan-DV (10 259 participants) or placebo (5976 participants). 16 162 participants (Butantan-DV n=10 215; placebo n=5947) were included in the per-protocol population and 16 235 (Butantan-DV n=10 259; placebo n=5976) in the safety population. At the data cutoff (July 13, 2021), participants had 2-5 years of follow-up (mean 3·7 years [SD 1·0], median 4·0 years [IQR 3·2-4·5]). 356 VCD cases were captured through the follow-up (128 in the vaccine group and 228 in the placebo group). Vaccine efficacy against VCD caused by any DENV serotype was 67·3% (95% CI 59·4-73·9); cases caused by DENV-3 or DENV-4 were not observed. The proportions of participants who had serious adverse events were similar between treatment groups (637 [6·2%] in the vaccine group and 395 [6·6%] in the placebo group) up until the cutoff. INTERPRETATION: A single dose of Butantan-DV was generally well tolerated and efficacious against symptomatic VCD (caused by DENV-1 and DENV-2) for a mean of 3·7 years. These findings support the continued development of Butantan-DV to prevent dengue disease in children, adolescents, and adults regardless of dengue serostatus. FUNDING: Instituto Butantan and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. TRANSLATIONS: For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Molecular signatures of Haemonchus contortus infection in sheep: A comparative serum proteomic study on susceptible and resistant sheep breeds.

Due to the negative impact of Haemonchus contortus in the tropics and subtropics, the detection of serum protein profiles that occur in infected sheep is of high relevance for targeted selective treatment strategies (TST). Herein, we integrated proteomics with phenotypic traits to elucidate physiological mechanisms associated to H. contortus infection in susceptible (Dorper - D) and resistant (Santa Inês - S) sheep breeds. Naïve female lambs were infected with H. contortus third-stage larvae on day zero (D0), and samples were collected weekly, for 28 days. Feces were used for individual fecal egg counts (FEC) blood for packed cell volume (PCV) and serum for specific antibody quantification through ELISA. Sera was collected on D0 (-) and D21 (+), and analyzed using a LC-MS/MS based proteomics approach. FEC, PCV, and anti-H. contortus antibody levels confirmed the absence of infection on D0. On D28 there was a significant difference between the two breeds for logFEC means (D = 3774 and S = 3141, p=0.033) and PCV means (D = 16.3 % and S = 24.3 %, p=0.038). From a total of 754 proteins identified, 68 differentially abundant proteins (DAPs) were noted. Phosphopyruvate hydratase (ENO3) was a DAP in all comparisons, while S+ vs D+ and S- vs D- shared the highest number of DAPs (8). Each of the four experimental groups clustered separately in a principal component analysis (PCA) of protein profile. Among the DAPs, proteins associated with the innate and adaptive immune system were detected when comparing S- vs D- and S+ vs D+. In D-, some proteins were linked to stress response to handling, sampling and heat. Focusing on the consequences of infection in each breed, in the D+ vs D- comparison, upregulated proteins were associated with inflammation control and immune response, where downregulated proteins pointed to a negative impact of infection on tissue anabolism, compromising muscle growth and fat deposition. In the S+ vs S- comparison, upregulated proteins were related to immune response, while the downregulated proteins were possibly linked to muscular development and growth, impaired by infection. Collectively, it can be concluded that ENO3 regulation emerges as a potential factor underlying the differential immune response observed between Santa Inês and Dorper sheep infected with H. contortus. In turn, detected acute phase proteins (APPs) reinforce their relation with infection, inflammation and stress conditions, whereas THEMIS-like may contribute to the immune system in Dorper. GSDMD, Guanylate-binding protein and ACAN warrant further investigation as possible biomarkers for TST strategy development.

A [2.2]Isoindolinophanyl-Based Carbene (iPC) Ligand: Synthesis, Electronic and Photophysical Properties, and Application in Photocatalysis.

Cyclic amino(alkyl) and cyclic amino(aryl) carbenes (cAACs/cAArCs) have been established as very useful ligands for catalytic and photonic applications of transition metal complexes. Herein, we describe the synthesis of a structurally related sterically demanding, electrophilic [2.2]isoindolinophanyl-based carbene (iPC) that bears a [2.2]paracyclophane moiety. The latter leads to more delocalized frontier orbitals and intense green fluorescence of (HiPC)OTf (2) from an intra-ligand charge transfer (1ILCT) state in the solid state. Base-promoted synthesis of the free carbene led to an unusual ring expansion and subsequent dimerization reaction, but the beneficial ligand properties can be exploited by trapping in situ at a metal center. The iPC ligand is a very potent π-chromophore, which participates in low energy metal-to-ligand (ML)CT transitions in [RhCl(CO)2(iPC)] (4) and IL-"through-space"-CT transitions in [Au(iPC)2]OTf (5). The steric demand of the iPC leads to high stability of 5 against air, moisture, or solvent attack, and ultralong-lived green phosphorescence with a lifetime of 185 µs is observed in solution. The beneficial photophysical and electronic properties of the iPC ligand, including a large accessible π surface area, were exploited by employing highly efficient energy transfer (EnT) photocatalysis in a [2+2] styrene cycloaddition reaction using 5, which outperformed other established photocatalysts in comparison.

Pharmacokinetics in regional anesthesia.

PURPOSE OF REVIEW: Pharmacokinetics of local anesthetics are one of the main determinants of success and safety of regional anesthesia and comprise local and systemic distribution phases. This review aims to summarize the latest research findings on this topic in the context of various regional blocks performed for different surgeries and patient populations. RECENT FINDINGS: Research into local kinetics and systemic absorption of local anesthetics has chiefly been focused on novel fascial plane blocks, especially the erector spinae plane block, as these are increasingly adopted for regional anesthesia and pain management. As their clinical efficacy is very dependent on injection of large volumes of local anesthetic, doses over typically recommended limits are often administered. SUMMARY: Fascial plane blocks are the regional anesthesia techniques in need of the most pharmacokinetic characterization, not only to better understand their complex mechanisms of action but also to avoid harm from excessive doses of local anesthetics. Further mapping of risk factors for systemic toxicity from administration in different block sites is crucial. Extremes of age and pregnancy are vulnerable patient populations but in whom regional anesthesia, including novel techniques, has been performed with few complications.