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Objectives: CLCN4 variations have recently been identified as a genetic cause of X-linked neurodevelopmental disorders. This study aims to broaden the phenotypic spectrum of CLCN4-related condition and correlate it with functional consequences of CLCN4 variants. Methods: We described 13 individuals with CLCN4-related neurodevelopmental disorder. We analyzed the functional consequence of the unreported variants using heterologous expression, biochemistry, confocal fluorescent microscopy, patch-clamp electrophysiology, and minigene splicing assay. Results: We identified five novel (p.R41W, p.L348V, p.G480R, p.R603W, c.1576 + 5G > A) and three known (p.T203I, p.V275M, p.A555V) pathogenic CLCN4 variants in 13 Chinese patients. The p.V275M variant is found at high frequency and seen in four unrelated individuals. All had global developmental delay (GDD)/intellectual disability (ID). Seizures were present in eight individuals, and 62.5% of them developed refractory epilepsy. Five individuals without seizures showed moderate to severe GDD/ID. Developmental delay precedes seizure onset in most patients. The variants p.R41W, p.L348V, and p.R603W compromise the anion/exchange function of ClC-4. p.R41W partially impairs ClC-3/ClC-4 association. p.G480R reduces ClC-4 expression levels and impairs the heterodimerization with ClC-3. The c.1576 + 5G > A variant causes 22 bp deletion of exon 10. Conclusions: We further define and broaden the clinical and mutational spectrum of CLCN4-related neurodevelopmental conditions. The p.V275M variant may be a potential hotspot CLCN4 variant in Chinese patients. The five novel variants cause loss of function of ClC-4. Transport dysfunction, protein instability, intracellular trafficking defect, or failure of ClC-4 to oligomerize may contribute to the pathophysiological events leading to CLCN4-related neurodevelopmental disorder. [ABSTRACT FROM AUTHOR]

Honey bee viruses are serious pathogens that can cause poor colony health and productivity. We analyzed a multi-year longitudinal dataset of abundances of nine honey bee viruses (deformed wing virus A, deformed wing virus B, black queen cell virus, sacbrood virus, Lake Sinai virus, Kashmir bee virus, acute bee paralysis virus, chronic bee paralysis virus, and Israeli acute paralysis virus) in colonies located across Canada to describe broad trends in virus intensity and occurrence among regions and years. We also tested climatic variables (temperature, wind speed, and precipitation) as predictors in an effort to understand possible drivers underlying seasonal patterns in viral prevalence. Temperature was a significant positive predictor of the total number of viruses per sample, which was highest in British Columbia (mean = 5.0). Lake Sinai virus (LSV) was the most prevalent overall (at 89%) and had the highest infection intensity, at an average of 3.9 × 108 copies per bee. Acute bee paralysis virus was the least prevalent virus (at 4.7%) and had the lowest infection intensity (1.9 × 105 copies per bee). Surprisingly, including Varroa abundance as a covariate did not significantly improve model fit for any virus. All viruses, except Kashmir bee virus, varied by region, and one or more climatic variables were significant predictors for six of the nine viruses. Although climatic effects were often inconsistent among individual viruses, we show that climatic variables can be better predictors of virus intensity and occurrence than Varroa mite abundance, at least when infestation rates are low. [ABSTRACT FROM AUTHOR]

Metaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane. Mechanistically, NOS blockade leads to a decrease in the S-nitrosylation of c-Jun NH2-terminal kinase (JNK)/c-Jun complex to repress its transcriptional output, leading to enhanced tumor differentiation and associated chemosensitivity. As a result, combined NOS and PI3K inhibition with taxane targets MpBC stem cells and improves survival in patient-derived xenograft models relative to single-/dual-agent therapy. Similarly, biopsies from MpBC tumors that responded to L-NMMA+taxane therapy showed a post-treatment reversal of epithelial-to-mesenchymal transition and decreased stemness. Our findings suggest that combined inhibition of iNOS and PI3K is a unique strategy to decrease chemoresistance and improve clinical outcomes in MpBC. Metaplastic breast cancer is a highly chemoresistant breast cancer subtype with limited therapeutic options. Here, the authors report that the NOS inhibitor, L-NMMA, sensitises metaplastic breast cancer to a selective PI3K inhibitor, alpelisib, and taxane chemotherapy via repression of c-JUN mediated epithelial-to-mesenchymal transition. [ABSTRACT FROM AUTHOR]

Mass spectrometry (MS)-based proteomics aims to characterize comprehensive proteomes in a fast and reproducible manner. Here we present the narrow-window data-independent acquisition (nDIA) strategy consisting of high-resolution MS1 scans with parallel tandem MS (MS/MS) scans of ~200 Hz using 2-Th isolation windows, dissolving the differences between data-dependent and -independent methods. This is achieved by pairing a quadrupole Orbitrap mass spectrometer with the asymmetric track lossless (Astral) analyzer which provides >200-Hz MS/MS scanning speed, high resolving power and sensitivity, and low-ppm mass accuracy. The nDIA strategy enables profiling of >100 full yeast proteomes per day, or 48 human proteomes per day at the depth of ~10,000 human protein groups in half-an-hour or ~7,000 proteins in 5 min, representing 3× higher coverage compared with current state-of-the-art MS. Multi-shot acquisition of offline fractionated samples provides comprehensive coverage of human proteomes in ~3 h. High quantitative precision and accuracy are demonstrated in a three-species proteome mixture, quantifying 14,000+ protein groups in a single half-an-hour run. A new mass spectrometry strategy combines the advantages of data-dependent and data-independent acquisition. [ABSTRACT FROM AUTHOR]

Work has not examined if acculturation or enculturation may predict endorsed benefits, barriers, and intentions to seek mental health services for depression, specifically among Latino students enrolled in a rural and majority Latino immigrant institution of higher education. An improved understanding of factors informing mental health help-seeking is needed to identify possible intervention points to address gaps in accessing depression treatment. Participants (N = 406) read a vignette depicting a person with depressive symptoms. Participants were asked if they would seek help for depression if in the situation described in the vignette. Participants provided text responses about their preferences for managing depression symptoms and their mental health help-seeking history. Additionally, participants completed a self-report depression symptom screener, demographic surveys, acculturation assessment, and questionnaires on perceived benefits and barriers to seeking mental health services. Path analysis was used to test the link between acculturation status and intent to seek services for depression, with benefits and barriers as mediators. The results revealed that higher perceived benefits and lower barriers were directly associated with greater intentions to seek help. Furthermore, an indirect effect of acculturation on help-seeking intentions via higher perceived benefits of seeking care was observed. These findings persisted after controlling for age, gender, depression, and history of seeking care for depression. Future work should test the replicability of this finding with diverse college students living in predominantly immigrant communities. Universities might consider tailoring outreach initiatives to provide information on the range and accessibility of mental health services, the location of mental health service centers, and the procedures for accessing such services. [ABSTRACT FROM AUTHOR]

Every person should feel accepted at work. Organizations can signal that all identities are welcomed and protected through affirming factors in their environment, known as identity-safety cues. However, there are also things organizations can do to signal that certain identities are not welcome. Thus, the current study aims to identify the factors that can impact identity safety perceptions among transgender and gender expansive employees of color, as the past literature on transgender and gender expansive identity-safety cues predominately includes White-majority samples. This study analyzes the intersection of marginalized racial/ethnic and gender identities, and how these combined identities impact the perceptions of identity safety. Researchers conducted 21 semi-structured interviews through Zoom, which were analyzed by hand and through Dedoose software using reflexive thematic analysis. Results found that minimal, partial, or incomplete identity support may signal some identity safety, but the ideal inclusion is support for all identities, and the intersection of those identities. Indeed, limited identity support, insufficient organizational systems, performativity, and discrimination can restrict perceptions of identity safety, while interpersonal support, intersectional representation, and inclusive organizational policies can signal identity safety. Overall, results indicated that it is not sufficient for organizations to signal identity safety for one identity, or for each identity separately; but rather, intersectional support is needed to allow transgender and gender expansive employees of color to feel safe at work. [ABSTRACT FROM AUTHOR]

The Care Block of Bogotá, Colombia, is an urban program that offers services for low-income unpaid caregivers. This study aimed to (i) characterize unpaid caregivers' subjective well-being, mental health symptoms, physical activity levels, and use of public spaces linked to the Care Block; (ii) identify caregivers' perceived built and social environment facilitators and barriers to accessing the Care Block facility; and (iii) document the community-led advocacy process to improve the Care Block program. The quantitative component included a subjective well-being and mental health symptoms survey, and the System for Observing Play and Recreation in Communities (SOPARC) instrument. The qualitative component included the Our Voice citizen science method augmented with portable virtual reality equipment to engage participants in advocacy for changes. Participants (median age of 53 years) dedicated a median of 13.8 h a day to unpaid caregiving, had an average subjective well-being score of 7.0, and 19.1% and 23.8% reported having depression and generalized anxiety symptoms respectively. Caregivers reported that the program fosters their perception of purpose, enjoyment, resilience, and cognitive and emotional awareness. SOPARC evaluation showed that most women engaged in moderate to vigorous physical activity. The caregivers highlighted education, physical activity services, and integration of facilities as facilitators to accessing the Care Block program. Poor quality and lack of sidewalks and roads, limited personal safety, and the risk of pedestrian-vehicle collisions were identified as barriers. Virtual Reality sparked compelling dialogue between participants and stakeholders, allowing stakeholders to reflect on an urban program facilitating unpaid care work. [ABSTRACT FROM AUTHOR]

Environmental stresses are responsible for limiting soybean yield. To mitigate the impacts generated by water deficit, molecular biology tools are being used to develop genetically modified plants. Previous studies showed that two independent events (B1 and B3) of soybean transgenic plants expressing a Solanum nigrum osmotin (SnOLP) had an increment in drought tolerance. The present study aims to investigate the modulated pathways that results in the drought tolerance promoted by osmotin overexpression in soybean. Transgenic and non-transgenic (NT) plants in the vegetative stage were submitted to water deficit by irrigation suppression for seven days. Control plants were kept irrigated. Physiological variables were monitored and confirmed that the transgenic plants present better performance when compared to the NT plants. The total RNA extracted from leaves was sequenced and data was normalized by DESeq2. A total of 2044 and 1505 differentially expressed genes (DEGs) were identified in B1 and B3 events, respectively. Regarding the B1 event, 769 genes were upregulated and 1275 downregulated. For B3, 541 genes were upregulated and 964 genes were downregulated. Excluding common differentially expressed genes (DEGs) between transgenic and non-transgenic (NT) plants yielded 395 upregulated and 234 downregulated genes, which were shared by B1 and B3 events. The metabolic pathways and gene ontology categories identified are known to be involved in plant responses to drought. Hormonal, photosynthetic, carbohydrate and amino acid metabolism, reactive oxygen species, and post-translational modifications pathways were significantly modulated in transgenic plants. Altogether, the results suggest that osmotin promotes tolerance through an increment in the plant responses elicited by drought. [ABSTRACT FROM AUTHOR]

The remarkable increase in superconducting transition temperature (Tc) observed at the interface of one-unit-cell FeSe films on SrTiO3 substrates (1 uc FeSe/STO)1 has attracted considerable research into the interface effects2–6. Although this high Tc is thought to be associated with electron–phonon coupling (EPC)2, the microscopic coupling mechanism and its role in the superconductivity remain elusive. Here we use momentum-selective high-resolution electron energy loss spectroscopy to atomically resolve the phonons at the FeSe/STO interface. We uncover new optical phonon modes, coupling strongly with electrons, in the energy range of 75–99 meV. These modes are characterized by out-of-plane vibrations of oxygen atoms in the interfacial double-TiOx layer and the apical oxygens in STO. Our results also demonstrate that the EPC strength and superconducting gap of 1 uc FeSe/STO are closely related to the interlayer spacing between FeSe and the TiOx terminated STO. These findings shed light on the microscopic origin of the interfacial EPC and provide insights into achieving large and consistent Tc enhancement in FeSe/STO and potentially other superconducting systems. Phonons at the FeSe/STO interface are imaged at atomic scale, uncovering new optical phonon modes that couple strongly with electrons, shedding light on the microscopic origin of the interfacial EPC and providing insights into achieving superconducting transition temperature enhancement. [ABSTRACT FROM AUTHOR]

Purpose : With the growing demand for shared decision-making and patient-centered care, optimal informed consent (IC) has gained relevance. Virtual reality (VR) has seen significant technological advancements, and its medical applications currently include surgical planning and medical education. This pilot study investigates the feasibility of VR-enhanced informed consent (VR-IC) in neurosurgery to improve preoperative IC and patient satisfaction. Methods: We included patients aged 18 to 75 years who were scheduled for skull base meningioma or brain aneurysm surgery between May and December 2023. Exclusion criteria were visual/auditory impairments and severe cognitive/psychiatric disorders. Patients received standard IC followed by VR-IC using patient-specific VR models of their pathology. After an initial demonstration by the surgeon, the patients used the VR station independently. A questionnaire with 18 questions on a 5-point Likert scale assessed the subjective impression of VR-IC. Results: Ten patients participated in the study, with six (60%) undergoing aneurysm clipping and four (40%) undergoing skull base meningioma resection. The mean age of the participants was 58 years (± 15, range 27 to 75 years), with four female patients (40%). Patients overall rated the VR-informed consent (VR-IC) positively with a mean of 4.22 (± 0.84). There was a better understanding of their pathology (mean 4.30 ± 0.92) and the planned procedure (mean 3.95 ± 1.04). Trust in the surgeon was rated with a mean of 3.47 (± 0.94). Only minimal side effects from the VR experience including dizziness or discomfort were noted (mean 4.60 ± 0.22). None of the participants dropped out of the study. Conclusion: VR-enhanced informed consent is feasible and improves patient understanding and satisfaction without significant side effects. These findings will guide the planning of a randomized controlled trial to validate the benefits of VR-IC in neurosurgery further. [ABSTRACT FROM AUTHOR]

High-throughput screening techniques are pivotal to unlocking the mysteries of biology. Yet, the promise of droplet microfluidics in enabling single-cell resolution, ultra-high-throughput screening remains largely unfulfilled. Droplet sorting errors caused by polydisperse droplet sizes that are often inevitable in multi-step assays have severely limited the effectiveness and utility of this technique, especially when screening large libraries. Even a relatively low 1% sorting error results in 10,000 false calls in a 1,000,000 droplet screen, imposing an unreasonably large burden on downstream validation. Here, we present NOVAsort (Next-generation Opto-Volume-based Accurate droplet sorter), a device capable of discerning droplets based on both size and fluorescence intensity. With a 1000- and 10,000-fold reduction in false positives and false negatives, respectively. NOVAsort addresses the challenges of conventional droplet sorting approaches and sets standards for accuracy and throughput in droplet microfluidic assays. Droplet microfluidic tools with single-cell resolution and high-throughput screening capacities remain scarce. Here, the authors propose NOVAsort, a next-generation droplet sorter that can discern droplets based on both size and fluorescence, which can overcome common problems with conventional sorters. [ABSTRACT FROM AUTHOR]

Background: Concrete, data-driven guidelines for breast cancer screening among the transgender and gender diverse (TGD) population is lacking. The present study evaluates possible associations of gender-affirming hormone therapy (GAHT) on incidental breast pathology findings in trans-masculine patients to inform decision making about breast cancer screening. Patients and Methods: This was a retrospective cohort study of patients who had gender-affirming mastectomy or breast reduction at a single center from July 2019 to February 2024. A total of 865 patients met the inclusion criteria. Gender-affirming testosterone therapy and length of exposure were evaluated to seek differences in post-operative pathology findings. Results: The median age at the time of surgery was 27 years [interquartile range (IQR) 21–30]. Most participants identified as female to male (658, 75.6%). A significant portion of the participants (688, 79.2%) were undergoing testosterone therapy at the time of surgery, with the median duration of testosterone use prior to surgery being 14 months (IQR 4–29). High risk or malignant findings were noted in pathology results for 12 of 1730 breasts (0.7%). Ordered logistic regression found that duration of testosterone therapy was not associated with increasing severity of incidental breast pathology. Additionally, patients under 25 years of age were 70% less likely to have any incidental finding on pathological evaluation than older patients [odds ratio (OR) 0.3, p < 0.01, confidence interval (CI) 0.18–0.50]. Conclusions: The present study found that patients undergoing GAHT should not be screened for breast cancer with increased frequency compared with cis-gender women. Additionally, it may be appropriate for trans women under the age of 25 with normal breast cancer risk to forego pathological breast tissue examination. [ABSTRACT FROM AUTHOR]

Essential tremor (ET) is a prevalent movement disorder that impairs gait function, including gait speed - a critical marker of mobility disability and adverse outcomes. This meta-analysis aimed to quantify differences in gait speed between individuals diagnosed with ET compared to people without a movement disorder diagnosis. Electronic databases were searched for studies comparing gait speed in ET patients and controls. Effect sizes were calculated using standardized mean differences (Hedges’ g) and pooled using a random-effects model. Eight studies (390 ET, 227 controls) were included. ET patients exhibited significantly slower gait speeds than controls. The effect size (Hedges’ g = -1.06, 95% CI -1.47 to -0.65, p <.001) indicates a large, clinically significant difference. Substantial study heterogeneity was observed (I2 = 76.9%). These findings suggest that gait speed deficits are a significant feature of ET, potentially reflecting cerebellar dysfunction. This highlights the need for gait assessment and targeted interventions in ET management to reduce fall risk and improve quality of life. Understanding the moderating factors such as medication type and state, disorder severity, and age could provide significant benefits in the treatment and management of ET. [ABSTRACT FROM AUTHOR]

The Large Area Detector (LAD) is one of the science payloads of the enhanced X-ray Timing and Polarimetry (eXTP) mission. The LAD is a spectral-timing instrument with a broad energy response, covering a range from 2 to 30 keV, a good timing resolution of better than 10 µs, and an expected energy resolution of 260 eV at 6 keV. The LAD consists of 640 large-area multi-anode Silicon Drift Detectors (SDDs). Given the large number of detectors, the LAD uses a modular design. Each module comprises sixteen detectors, and each detector is equipped with dedicated Front-End Electronics (FEE), interfacing with two separate Module Back-End Electronics (MBEEs). Each MBEE is designed to process the data from 1,792 anode channels in 8 FEEs (224 anode channels per FEE), performing the energy reconstruction and time tagging for X-ray events. The MBEE uses the European Field Programmable Gate Array (FPGA) from NanoXplore™, based on a pipeline concept, which reduces dead time, making the LAD suitable for higher flux X-ray detection, and it can handle a sustained flux of >500 mCrab and a continuous flux of >15 Crab for up to 300 minutes (Feroci et al. 2018). Additionally, the MBEE serves as the central hub for configuring the module's electronics, including the FEEs, the Power Supply Unit (PSU), and the MBEE itself, and it is also responsible for collecting housekeeping data to monitor the system's status. The prototype MBEE was designed, manufactured, and programmed with FPGA firmware using VHDL. The basic functional test was conducted in this paper, and the results indicated that the MBEE could be operated in different modes to perform the functions mentioned above. Analysis and testing show that it can transmit event packets-containing timing tag, event type, position ID, and energy information-at a baud rate of 2 Mbps with an event loss fraction of 1.5%. [ABSTRACT FROM AUTHOR]

Background: Food insecurity (FI) is prevalent among children with chronic kidney disease (CKD), but its impact on health outcomes, and feasibility of prescribed diet restrictions is unknown. Accordingly, this study aims to explore associations of FI and CKD outcomes, and understand its role in following prescribed kidney diet recommendations. Methods: We performed a mixed-methods single-center cohort study of children with advanced CKD or kidney failure. Demographics, socioeconomic status, and health outcomes were compared across FI status; associations between FI and CKD outcomes were explored using multivariable regression. A qualitative sub-analysis of de-identified caregiver interview transcripts was analyzed for themes around diet restrictions. Results: There was a trend that FI patients were more likely to be of Black race (33% vs. 20%); have public insurance (67% vs. 48%); need more blood pressure medications (2 [0.75,3] vs. 1 [0,3]); and have a higher likelihood of emergency department (42% vs. 25%) or intensive care unit encounters (25% vs. 14%). There were no associations of FI and outcomes of interest. Major themes that emerged from caregiver interviews include (1) understanding of the kidney diet focuses on foods to avoid; (2) adapting to suggested dietary restrictions requires changes in meal preparation; and (3) challenges to adherence include social stigma, growth, budget, and time. Conclusions: The impact of FI on children's medical needs with CKD remains inconclusive but trends suggest a higher risk. Regardless of FI status, adhering to prescribed diet restrictions in kidney disease involves significant dedication. Challenges involve food availability, a child's response to restrictions, and social stigma. [ABSTRACT FROM AUTHOR]

Paper- and paperboard-based materials are alternatives to petroleum-based plastics in food packaging but unsuitable for their poor moisture and oil resistance. In this sense, fluorinated compounds improve water and grease repellency, though their use is controversial. This Perspective discusses main techniques to combine fluorinated compounds with paper and paperboard, including water and oil contact angles and grease resistance values, and summarizes main legal aspects in Europe and the United States. [ABSTRACT FROM AUTHOR]

Social interactions promote vocal learning, but the impact of social feedback on this process and its neural circuitry is not well understood. We studied song imitation in juvenile male zebra finches raised either in the presence or absence of adult females. Juveniles learned songs more accurately with a female present, suggesting her presence improves imitation. When female calls correlated with practice, tutees’ songs better resembled the tutor’s, hinting toward the possibility that females provide practice-specific vocalizations. Intracellular recordings of HVC projection neurons revealed that a subset of these neurons in both juveniles and adults is sensitive to female calls during listening, suggesting a consistent neural mechanism for processing important vocalizations, regardless of age. However, call-related neural responses during singing were observed only in juveniles. These findings highlight how vocalizations, beyond those of the tutor, influence the neural circuits for vocal learning and production.Juvenile male zebra finches learn their songs from adult male tutors, but the role of females in this process is less clear. Here the authors show that the presence of adult females enhances song imitation in young males, with female calls influencing both the behavior and neural activity linked to vocal learning. [ABSTRACT FROM AUTHOR]

An increasing adoption of electric vehicles (EVs) is expected in the coming decades mainly due to the need to achieve carbon neutrality until 2050. However, predicting electric mobility's future is challenging due to three main factors: technological advancements, regulatory policies, and consumer behaviour. The projections presented in this study are based on several scenarios driven mainly from reports published by public entities and consultants. It considers the evolution of electric road mobility by defined targets in the electrification of the transport sector. Therefore, the gathered data addresses different horizon times regarding EV penetration in the World, Europe, Portugal, Denmark, Greece, and Slovenia. Thus, an extensive literature review and estimating approach for EV forecast was conducted concerning EV markets, charging infrastructure, and electricity demand. Also, the dataset aims to provide a demand projection by 2050 and serving as a critical input to further work on EV mass deployment in the context of the project Electric Vehicles Management for carbon neutrality in Europe (EV4EU) and other works related to this field. [ABSTRACT FROM AUTHOR]

There is an urgent need for strategies to reduce the negative impacts of a warming climate on human health. Cooling urban neighborhoods by planting trees and vegetation and increasing albedo of roofs, pavements, and walls can mitigate urban heat. We used synoptic climatology to examine how different tree cover and albedo scenarios would affect heat-related morbidity in Los Angeles, CA, USA, as measured by emergency room (ER) visits. We classified daily meteorological data for historical summer heat events into discrete air mass types. We analyzed those classifications against historical ER visit data to determine both heat-related and excess morbidity. We used the Weather Research and Forecasting model to examine the impacts of varied tree cover and albedo scenarios on meteorological outcomes and used these results with standardized morbidity data algorithms to estimate potential reductions in ER visits. We tested three urban modification scenarios of low, medium, and high increases of tree cover and albedo and compared these against baseline conditions. We found that avoiding 25% to 50% of ER visits during heat events would be a common outcome if the urban environment had more tree cover and higher albedo, with the greatest benefits occurring under heat events that are moderate and those that are particularly hot and dry. We conducted these analyses at the county level and compared results to a heat-vulnerable, working-class Los Angeles community with a high concentration of people of color, and found that reductions in the rate of ER visits would be even greater at the community level compared to the county. [ABSTRACT FROM AUTHOR]

Patients with heterotaxy syndrome and congenital heart disease (CHD) experience inferior cardiac surgical outcomes. Heart transplantation outcomes are understudied, however, particularly compared to non-CHD patients. Data from UNOS and PHIS were used to identify 4803 children (< 18 years) undergoing first-time heart transplant between 2003 and 2022 with diagnoses of heterotaxy (n = 278), other-CHD (n = 2236), and non-CHD cardiomyopathy (n = 2289). Heterotaxy patients were older (median 5 yr) and heavier (median 17 kg) at transplant than other-CHD (median 2 yr and 12 kg), and younger and lighter than cardiomyopathy (median 7 yr and 24 kg) (all p < 0.001). UNOS status 1A/1 at listing was not different between groups (65–67%; p = 0.683). At transplant, heterotaxy and other-CHD patients had similar rates of renal dysfunction (12 and 17%), inotropes (10% and 11%), and ventilator-dependence (19 and 18%). Compared to cardiomyopathy, heterotaxy patients had comparable renal dysfunction (9%, p = 0.058) and inotropes (46%, p = 0.097) but more hepatic dysfunction (17%, p < 0.001) and ventilator-dependence (12%, p = 0.003). Rates of ventricular assist device (VAD) were: heterotaxy-10%, other-CHD-11% (p = 0.839 vs. heterotaxy), cardiomyopathy-37% (p < 0.001 vs. heterotaxy). The 1-year incidence of acute rejection post-transplant was comparable between heterotaxy and others (p > 0.05). While overall post-transplant survival was significantly worse for heterotaxy than others (p < 0.05 vs. both), conditional 1-year survival was comparable (p > 0.3 vs. both). Children with heterotaxy syndrome experience inferior post-heart transplant survival, although early mortality appears to influence this trend, with 1-year survivors having equivalent outcomes. Given similar pre-transplant clinical status to others, heterotaxy patients are potentially under risk-stratified. Increased VAD utilization and pre-transplant end-organ function optimization may portend improved outcomes. [ABSTRACT FROM AUTHOR]

Approximately 3.9 billion people are at risk of infection with dengue fever, a group of viruses transmitted by mosquitoes (Halstead in Annu Rev Entomol 53:273–291, 2008. https://doi.org/10.1146/annurev.ento.53.103106.0933262008; WHO in WHO | Dengue and severe dengue, Geneva, 2018). In 2019, Central America suffered a severe dengue epidemic (Salinas Maldonado in Un brote de dengue pone en alerta a Centroamérica | Sociedad | EL PAÍS, El País, 2019). Costa Rica witnessed an almost doubling of the number of dengue cases in the first 24 epidemiological weeks of 2019 compared to the same period in the previous year (Ávalos in Costa Rica casi duplica número de enfermos de dengue en lo que va del año, con respecto al 2018, La Nación, 2019). In the Americas, forest cover is thought to diminish anthropogenic habitats for mosquitoes while also increasing the presence of their predators (Vasilakis et al. in Nat Rev Microbiol 9:532–541, 2011. https://doi.org/10.1038/nrmicro2595; Weterings et al. in Basic Appl Ecol 15:486–495, 2014a. https://doi.org/10.1016/J.BAAE.2014.07.006). In this study, we estimate the marginal effects of increasing forest cover on dengue prevalence in Costa Rica using econometric models to relate hospital admission records to forest cover maps from 2001 and 2011. We find that increasing the percentage of forest cover significantly decreases both the number of hospital admissions for dengue and the probability of an outbreak. Using the same models, we predict that if forest cover had been increased by three percentage points during 10 years (0.29% per year), 29 dengue hospital admissions per year might have been avoided (around 1.4% of cases in the country, depending on the year). This represents average savings between USD 7230 and 82,207 per year, depending on the severity of the impact on individuals with dengue. Our study demonstrates that forest conservation can serve as a public health investment, enhancing social welfare by mitigating illness and reducing associated healthcare expenditures. Our results must be interpreted with caution, however, as the characteristics of our data prevent us from confirming that the estimated negative effect of forest cover on dengue represents a causal impact. [ABSTRACT FROM AUTHOR]

Satellite imagery allows us to view landscapes from a bird’s eye view, providing a new dimension in appreciating the environments we inhabit. This alternative perspective has the potential to shape individual perceptions of landscapes and play a pivotal role in land management decision-making and communication. However, the interpretation and appreciation of landscapes seen in satellite imagery may vary among observers. This study investigates the relationship between individuals’ ability to interpret images from eye-level and satellite perspectives, their familiarity with the landscape, and their appreciation of land cover from this viewpoint. To achieve this, a survey was conducted presenting respondents with images of land cover classes captured at eye level and from satellite imagery of the Yungay municipality in Chile. Participants were asked to interpret the primary land use land cover (LULC) depicted in the imagery and indicate their appreciation of that landscape. Variation in the interpretation of LULC was observed between the image source and land cover type. For instance, forest classes seen in eye-level imagery were more accurately interpreted compared to satellite imagery, while the reverse was true for agriculture. These differences in interpretation also impacted the appreciation scores assigned to the landscapes in the images. Specifically, if respondents perceived an image to be dominated by a traditionally appreciated land cover (e.g., Native Vegetation), they provided a higher score, even if the image depicted another class (e.g., Plantation Forestry). These findings highlight that considering the influence of satellite imagery in shaping perception is crucial in supporting land management activities. [ABSTRACT FROM AUTHOR]

Nine in 10 road traffic deaths occur in low- and middle-income countries (LMICs). Despite this disproportionate burden, few studies have examined built environment correlates of road traffic injury in these settings, including in Latin America. We examined road traffic collisions in Bogotá, Colombia, occurring between 2015 and 2019, and assessed the association between neighborhood-level built environment features and pedestrian injury and death. We used descriptive statistics to characterize all police-reported road traffic collisions that occurred in Bogotá between 2015 and 2019. Cluster detection was used to identify spatial clustering of pedestrian collisions. Adjusted multivariate Poisson regression models were fit to examine associations between several neighborhood-built environment features and rate of pedestrian road traffic injury and death. A total of 173,443 police-reported traffic collisions occurred in Bogotá between 2015 and 2019. Pedestrians made up about 25% of road traffic injuries and 50% of road traffic deaths in Bogotá between 2015 and 2019. Pedestrian collisions were spatially clustered in the southwestern region of Bogotá. Neighborhoods with more street trees (RR, 0.90; 95% CI, 0.82–0.98), traffic signals (0.89, 0.81–0.99), and bus stops (0.89, 0.82–0.97) were associated with lower pedestrian road traffic deaths. Neighborhoods with greater density of large roads were associated with higher pedestrian injury. Our findings highlight the potential for pedestrian-friendly infrastructure to promote safer interactions between pedestrians and motorists in Bogotá and in similar urban contexts globally. [ABSTRACT FROM AUTHOR]

The evolutionary transition from diffusion-mediated cell-cell communication to faster, targeted synaptic signaling in animal nervous systems is still unclear. Genome sequencing analyses have revealed a widespread distribution of synapse-related genes among early-diverging metazoans, but how synaptic machinery evolved remains largely unknown. Here, we examine the function of neurexins (Nrxns), a family of presynaptic cell adhesion molecules with critical roles in bilaterian chemical synapses, using the cnidarian model, Nematostella vectensis. Delta-Nrxns are expressed mainly in neuronal cell clusters that exhibit both peptidergic and classical neurotransmitter signaling. Knockdown of δ-Nrxn reduces spontaneous peristalsis of N. vectensis polyps. Interestingly, gene knockdown and pharmacological studies suggest that δ-Nrxn is involved in glutamate- and glycine-mediated signaling rather than peptidergic signaling. Knockdown of the epithelial α-Nrxn reveals a major role in cell adhesion between ectodermal and endodermal epithelia. Overall, this study provides molecular, functional, and cellular insights into the pre-neural function of Nrxns, as well as key information for understanding how and why they were recruited to the synaptic machinery.The evolutionary origin of neural synapses is unclear. Analysis of cnidarian neurexins provides clues as to when this synaptic hub molecule, which had an ancestral role in adhesion between heterotypic epithelial cells, acquired a neuronal function. [ABSTRACT FROM AUTHOR]

Density Functional Theory (DFT) is extensively used in theoretical and computational chemistry to study molecular and crystal properties across diverse fields, including quantum chemistry, materials physics, catalysis, biochemistry, and surface science. Despite advances in DFT hardware and software for optimized geometries, achieving consensus in molecular structure comparisons with experimental counterparts remains a challenge. This difficulty is exacerbated by the lack of automated bond length comparison tools, resulting in labor-intensive and error-prone manual processes. To address these challenges, we propose MolGC, a Molecular Geometry Comparator algorithm that automates the comparison of optimized geometries from different theoretical levels. MolGC calculates the mean absolute error (MAE) of bond lengths by integrating data from various DFT software. It provides interactive and customizable visualization of geometries, enabling users to explore different views for enhanced analysis. In addition, it saves MAE computations for further analysis and offers a comprehensive statistical summary of the results. MolGC effectively addresses complex graph labeling challenges, ensuring accurate identification and categorization of bonds in diverse chemical structures. It achieves a 98.91% average rate in correct bond label assignments on an antibiotics dataset, showcasing its effectiveness for comparing molecular bond lengths across geometries of varying complexity and size. The executable file and software resources for running MolGC can be downloaded from https://github.com/AbimaelGP/MolGC/tree/main. [ABSTRACT FROM AUTHOR]

Recently, there has been a significant increase in the use of deep learning techniques in the molecular sciences, which have shown high performance on datasets and the ability to generalize across data. However, no model has achieved perfect performance in solving all problems, and the pros and cons of each approach remain unclear to those new to the field. Therefore, this paper aims to review deep learning algorithms that have been applied to solve molecular challenges in computational chemistry. We proposed a comprehensive categorization that encompasses two primary approaches; conventional deep learning and geometric deep learning models. This classification takes into account the distinct techniques employed by the algorithms within each approach. We present an up-to-date analysis of these algorithms, emphasizing their key features and open issues. This includes details of input descriptors, datasets used, open-source code availability, task solutions, and actual research applications, focusing on general applications rather than specific ones such as drug discovery. Furthermore, our report discusses trends and future directions in molecular algorithm design, including the input descriptors used for each deep learning model, GPU usage, training and forward processing time, model parameters, the most commonly used datasets, libraries, and optimization schemes. This information aids in identifying the most suitable algorithms for a given task. It also serves as a reference for the datasets and input data frequently used for each algorithm technique. In addition, it provides insights into the benefits and open issues of each technique, and supports the development of novel computational chemistry systems. [ABSTRACT FROM AUTHOR]

Patterns of transcriptional activity are encoded in our genome through regulatory elements such as promoters or enhancers that, paradoxically, contain similar assortments of sequence-specific transcription factor (TF) binding sites1–3. Knowledge of how these sequence motifs encode multiple, often overlapping, gene expression programs is central to understanding gene regulation and how mutations in non-coding DNA manifest in disease4,5. Here, by studying gene regulation from the perspective of individual transcription start sites (TSSs), using natural genetic variation, perturbation of endogenous TF protein levels and massively parallel analysis of natural and synthetic regulatory elements, we show that the effect of TF binding on transcription initiation is position dependent. Analysing TF-binding-site occurrences relative to the TSS, we identified several motifs with highly preferential positioning. We show that these patterns are a combination of a TF’s distinct functional profiles—many TFs, including canonical activators such as NRF1, NFY and Sp1, activate or repress transcription initiation depending on their precise position relative to the TSS. As such, TFs and their spacing collectively guide the site and frequency of transcription initiation. More broadly, these findings reveal how similar assortments of TF binding sites can generate distinct gene regulatory outcomes depending on their spatial configuration and how DNA sequence polymorphisms may contribute to transcription variation and disease and underscore a critical role for TSS data in decoding the regulatory information of our genome.The effect of transcription factor binding on transcription initiation is dependent on the position of the transcription factor binding site. [ABSTRACT FROM AUTHOR]

We propose a method to estimate the household secondary attack rate (hSAR) of COVID-19 in the United Kingdom based on activity on the social media platform X, formerly known as Twitter. Conventional methods of hSAR estimation are resource intensive, requiring regular contact tracing of COVID-19 cases. Our proposed framework provides a complementary method that does not rely on conventional contact tracing or laboratory involvement, including the collection, processing, and analysis of biological samples. We use a text classifier to identify reports of people tweeting about themselves and/or members of their household having COVID-19 infections. A probabilistic analysis is then performed to estimate the hSAR based on the number of self or household, and self and household tweets of COVID-19 infection. The analysis includes adjustments for a reluctance of Twitter users to tweet about household members, and the possibility that the secondary infection was not acquired within the household. Experimental results for the UK, both monthly and weekly, are reported for the period from January 2020 to February 2022. Our results agree with previously reported hSAR estimates, varying with the primary variants of concern, e.g. delta and omicron. The serial interval (SI) is based on the time between the two tweets that indicate a primary and secondary infection. Experimental results, though larger than the consensus, are qualitatively similar. The estimation of hSAR and SI using social media data constitutes a new tool that may help in characterizing, forecasting and managing outbreaks and pandemics in a faster, affordable, and more efficient manner. [ABSTRACT FROM AUTHOR]

There are massive sources of lactic acid bacteria (LAB) in traditional dairy products. Some of these indigenous strains could be novel probiotics with applications in human health and supply the growing needs of the probiotic industry. In this work, were analyzed the probiotic and technological properties of three Lactobacilli strains isolated from traditional Brazilian cheeses. In vitro tests showed that the three strains are safe and have probiotic features. They presented antimicrobial activity against pathogenic bacteria, auto-aggregation values around 60%, high biofilm formation properties, and a survivor of more than 65% to simulated acid conditions and more than 100% to bile salts. The three strains were used as adjunct cultures separately in a pilot-scale production of Prato cheese. After 45 days of ripening, the lactobacilli counts in the cheeses were close to 8 Log CFU/g, and was observed a reduction in the lactococci counts (around -3 Log CFU/g) in a strain-dependent manner. Cheese primary and secondary proteolysis were unaffected by the probiotic candidates during the ripening, and the strains showed no lipolytic effect, as no changes in the fatty acid profile of cheeses were observed. Thus, our findings suggest that the three strains evaluated have probiotic properties and have potential as adjunct non-starter lactic acid bacteria (NSLAB) to improve the quality and functionality of short-aged cheeses. [ABSTRACT FROM AUTHOR]

Background: Artificial Intelligence (AI) offers an approach to predictive modeling. The model learns to determine specific patterns of undesirable outcomes in a dataset. Therefore, a decision-making algorithm can be built based on these patterns to prevent negative results. This systematic review aimed to evaluate the usefulness of AI in breast reconstruction. Methods: A systematic review was conducted in August 2022 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. MEDLINE, EMBASE, SCOPUS, and Google Scholar online databases were queried to capture all publications studying the use of artificial intelligence in breast reconstruction. Results: A total of 23 studies were full text-screened after removing duplicates, and twelve articles fulfilled our inclusion criteria. The Machine Learning algorithms applied for neuropathic pain, lymphedema diagnosis, microvascular abdominal flap failure, donor site complications associated to muscle sparing Transverse Rectus Abdominis flap, surgical complications, financial toxicity, and patient-reported outcomes after breast surgery demonstrated that AI is a helpful tool to accurately predict patient results. In addition, one study used Computer Vision technology to assist in Deep Inferior Epigastric Perforator Artery detection for flap design, considerably reducing the preoperative time compared to manual identification. Conclusions: In breast reconstruction, AI can help the surgeon by optimizing the perioperative patients' counseling to predict negative outcomes, allowing execution of timely interventions and reducing the postoperative burden, which leads to obtaining the most successful results and improving patient satisfaction. [ABSTRACT FROM AUTHOR]

Purpose: External ventricular drain (EVD) is one of the most frequent procedures in neurosurgery and around 15 to 30% of these patients require a permanent cerebrospinal fluid (CSF) diversion. The optimal EVD weaning strategy is still unclear. Whether gradual weaning compared to rapid closure, reduces the rate of permanent CSF diversion remains controversial. The aim of this trial is to compare the rates of permanent CSF diversion between gradual weaning and rapid closure of an EVD. Methods: This was a single-center, retrospective cohort study including patients between 2010 to 2020. Patients were divided into a weaning (WG) and non-weaning (NWG) group. The primary outcome was permanent CSF diversion rates, secondary outcomes included hospitalization time, EVD-related morbidity, and clinical outcome. Results: Out of 412 patients, 123 (29.9%) patients were excluded due to early death or palliative treatment. We registered 178 (61.6%) patients in the WG and 111 (38.4%) in the NWG. Baseline characteristics were comparable between groups. The VPS rate was comparable in both groups (NWG 37.8%; WG 39.9%, p = 0.728). EVD related infection (13.5% vs 1.8%, p < 0.001), as well as non-EVD related infection rates (2.8% vs 0%, p < 0.001), were significantly higher in the WG. Hospitalization time was significantly shorter in the NWG (WG 24.93 ± 9.50 days; NWG 23.66 ± 14.51 days, p = 0.039). Conclusion: Gradual EVD weaning does not seem to reduce the need for permanent CSF diversion, while infection rates and hospitalization time were significantly higher/longer. Therefore, direct closure should be considered in the clinical setting. [ABSTRACT FROM AUTHOR]

As age increases, a decline in lower extremity strength leads to reduced mobility and increased fall risks. This decline outpaces the age-related reduction in muscle mass, resulting in mobility limitations. Older adults with varying degrees of mobility-disability use different stepping strategies. However, the link between functional lower extremity strength and stepping strategy is unknown. Therefore, understanding how age-related reductions in functional lower extremity strength influence stepping strategy is vital to unraveling mobility limitations. Twenty participants (17F, 72 ± 6 years) were recruited and tested at a local community event. Participants were outfitted with inertial measurement units (IMU) and walked across a pressurized walkway under single and dual motor task conditions (walking with and without carrying a tray with water) at their usual and fast speeds. Participants were dichotomized into normal (11) or low functional strength groups (9) based on age-specific normative cutoffs using the instrumented 5-repetition Sit-to-Stand test duration. Our study reveals that older adults with normal strength prefer adjusting their step time during walking tasks, while those with reduced strength do not exhibit a preferred stepping strategy. This study provides valuable insights into the influence of functional lower extremity strength on stepping strategy in community-dwelling older adults during simple and complex walking tasks. These findings could aid in diagnosing gait deviations and developing appropriate treatment or management plans for mobility disability in older adults. [ABSTRACT FROM AUTHOR]

In order to become bioactive, proteins must be translated and protected from aggregation during biosynthesis. The ribosome and molecular chaperones play a key role in this process. Ribosome-bound nascent chains (RNCs) of intrinsically disordered proteins and RNCs bearing a signal/arrest sequence are known to interact with ribosomal proteins. However, in the case of RNCs bearing foldable protein sequences, not much information is available on these interactions. Here, via a combination of chemical crosslinking and time-resolved fluorescence-anisotropy, we find that nascent chains of the foldable globin apoHmp1–140 interact with ribosomal protein L23 and have a freely-tumbling non-interacting N-terminal compact region comprising 63–94 residues. Longer RNCs (apoHmp1–189) also interact with an additional yet unidentified ribosomal protein, as well as with chaperones. Surprisingly, the apparent strength of RNC/r-protein interactions does not depend on nascent-chain sequence. Overall, foldable nascent chains establish and expand interactions with selected ribosomal proteins and chaperones, as they get longer. These data are significant because they reveal the interplay between independent conformational sampling and nascent-protein interactions with the ribosomal surface. [ABSTRACT FROM AUTHOR]

Due to the anthropogenic pressures of expansion areas for livestock and agricultural production in the Brazilian Cerrado, it is of paramount importance to understand the dynamics of land use/land cover (LULC) changes in this region. Thus, we investigated LULC changes in two sub-basins of the Tocantins-Araguaia River basin from 1997 to 2015 and consequently projected future changes for the timespan between 2030 and 2050. The Formoso sub-basin experienced significant expansion of agricultural and pasture areas, whereas the Sono sub-basin limited farmland expansion (more stable native vegetation) due to substantial protected areas, trends that were also observed for future projections (2030 and 2050). Pastureland in the Formoso sub-basin increased by 5.8%, while the Sono sub-basin saw significant gains in cultivated land, according to change detection analyses during the 1997–2015 period. High stability probabilities of no change (> 70%) for grassland areas in the Sono River sub-basin and pasturelands in the Formoso River sub-basin were computed. The CA–Markov model demonstrated a high consistency level with actual LULC classes for both sub-basins, as indicated by an overall Kappa coefficient above 0.8. Future projections for 2030 and 2050 show a substantial expansion of agriculture and pasture in both sub-basins, driven by specific factors such as soil organic carbon stocks, distance from rural settlements, and proximity to rivers. Short- and mid-term simulations indicate substantial expansion of agriculture and pasture in both basins, with potential adverse impacts on water erosion. Consequently, developing policies for soil management and sustainable land use planning is essential for agroecosystem sustainability, promoting a balanced approach to economic development while addressing climate change and anthropogenic challenges. [ABSTRACT FROM AUTHOR]

Concerns about methane (CH4) emissions from rice, a staple sustaining over 3.5 billion people globally, are heightened due to its status as the second-largest contributor to greenhouse gases, driving climate change. Accurate quantification of CH4 emissions from rice fields is crucial for understanding gas concentrations. Leveraging technological advancements, we present a groundbreaking solution that integrates machine learning and remote sensing data, challenging traditional closed chamber methods. To achieve this, our methodology involves extensive data collection using drones equipped with a Micasense Altum camera and ground sensors, effectively reducing reliance on labor-intensive and costly field sampling. In this experimental project, our research delves into the intricate relationship between environmental variables, such as soil conditions and weather patterns, and CH4 emissions. We achieved remarkable results by utilizing unmanned aerial vehicles (UAV) and evaluating over 20 regression models, emphasizing an R2 value of 0.98 and 0.95 for the training and testing data, respectively. This outcome designates the random forest regressor as the most suitable model with superior predictive capabilities. Notably, phosphorus, GRVI median, and cumulative soil and water temperature emerged as the model's fittest variables for predicting these values. Our findings underscore an innovative, cost-effective, and efficient alternative for quantifying CH4 emissions, marking a significant advancement in the technology-driven approach to evaluating rice growth parameters and vegetation indices, providing valuable insights for advancing gas emissions studies in rice paddies. [ABSTRACT FROM AUTHOR]

We summarize the clinical trials (CTs) main characteristics, including members of ethnic minorities from Latin America. We carried out a systematic search in six databases. We made a descriptive synthesis of CTs, summarizing the characteristics, interventions, main findings, results, and conclusions reported. 4411 studies were acquired in search strategy, leaving 24 CTs in the final selection. Of these, ten were randomized, four were non-randomized, and the remainder had other designs. Most of the studies were carried out in the population of infants and children (08), ten of the studies included only women, and two studies included men. Nine studies were conducted in Mexico, with the Mayan ethnic minority being mostly evaluated (05). In only 15 it was mentioned that their research was approved by a research ethics committee. Finally, half of the CTs reported funding from international agencies and third reported funding from government agencies. Our results show that that CTs in ethnic minorities are limited and reduced to a few native peoples of the continent. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review explores the evidence surrounding the efficacy of preventing and treating lymphedema through surgical means. Recent Findings: Sentinel Lymph Node Biopsy (SLNB) has significantly reduced the need for axillary lymph node dissection (ALND), decreasing lymphedema rates. Axillary Reverse Mapping (ARM) techniques offer the opportunity to identify and preserve lymphatics during surgery. Immediate lymphatic reconstruction through lymphatic or lymphatic venous anastomosis and free lymph node transfer attempt to maintain continued post-operative lymphatic flow, further mitigating BCRL risks and optimizing patient outcomes. Summary: A growing body of data is evaluating surgical techniques for lymphedema prevention and treatment. Improvements in patients' quality of life have been reported with these techniques. Further research should focus on randomized controlled trials and prospective studies to investigate patient indications, technique selection, long-term durability, and personalized patient strategies. [ABSTRACT FROM AUTHOR]

Introduction: Pediatric Neurosurgery as a subspeciality started to emerge during the late 1950s, with only a few dedicated pediatric neurosurgeons in the Western world. Over the last few decades, the awareness that children require subspecialized care by dedicated pediatric neurosurgeons and an interdisciplinary team has been growing worldwide, leading to an increase in pediatric neurosurgeons. Several studies have shown that subspecialized care for pediatric patients improves outcomes and is cost-effective. This survey aims to assess the current setting of pediatric neurosurgery and training of neurosurgical residents in pediatric neurosurgery in Switzerland. Methods: We conducted an online survey by sending e-mail invitations in 2021 to all neurosurgical residents in Switzerland. The survey included questions regarding the participants' demographics, current workplace structures, the care of specific pediatric neurosurgical pathologies, and participants' opinions of the Swiss training program for pediatric neurosurgery and possible improvement. We defined at the beginning of the survey that a pediatric neurosurgeon is a board-certified neurosurgeon with at least one year of dedicated pediatric neurosurgical fellowship training abroad. Results: We received a total of 25 responses from residents, of which 20 (80%) were male. Twenty-two participants (88%) worked in one of seven major hospitals in Switzerland at the time of the survey, and four (16%) were interested in pursuing a fellowship in pediatric neurosurgery. Seven (35%) and five residents (25%) feel comfortable taking care on the ward of a craniosynostosis and hydrocephalus patient younger than 6 months, respectively. Twelve residents (60%) feel comfortable taking care of a pediatric brain tumor patient. The majority (n = 22, 88%) of all residents agree that a fellowship-trained pediatric neurosurgeon should treat children, while two (8%) residents state that any neurosurgeon with an interest in pediatric neurosurgery should be able to treat children. All residents (n = 25, 100%) agree that pediatric neurosurgery training and care in Switzerland needs to be improved. Conclusion: Pediatric neurosurgery training in Switzerland is rather heterogeneous and not very well structured, with varying frequencies of children-specific neurosurgical pathologies. Most residents agreed that a subspecialized pediatric neurosurgeon should oversee the care of children in neurosurgery, while all agree that pediatric neurosurgical training and care should be improved in Switzerland. [ABSTRACT FROM AUTHOR]

Background: Older adults' engagement on social media may be a resource to reduce loneliness and improve mental health. Purpose: This study aimed to examine loneliness and social media use and its association with severe psychological distress among older adults and whether social media use moderated the association of loneliness on severe psychological distress among older adults. Methods: This study is a secondary analysis of the 2019–2020 California Health Interview Survey. The Kessler 6-item Psychological Distress Scale (K6) assessed symptoms of psychological distress, with a K6 score ≥ 13 associated with severe mental illness. Loneliness was measured using a revised Three Item Loneliness Scale (TILS) score. Multiple regression analyses were conducted to examine associations between loneliness and severe psychological distress. Results: Loneliness, health status, and identification as Asian, remained strong predictors of severe psychological distress among older adults when adjusting for other factors. In bivariate analysis, high-frequent social media users, but did not remain significant when accounting for covariates. Social media use did not moderate the association between loneliness and severe psychological distress. Conclusion: This study underscores the significant impact of loneliness on poor mental health among older adults, emphasizing that while frequent social media use correlates with severe psychological distress, it may not alleviate the association of loneliness on poor mental health, thus highlighting the urgent need to address social isolation and promote genuine social connectedness, particularly among Asian older adults. [ABSTRACT FROM AUTHOR]

The utilization of antibody–drug conjugates (ADCs) has gained considerable attention in the field of targeted cancer therapy due to their ability to synergistically combine the specificity of monoclonal antibodies (mAbs) and the potency of small molecular drugs. However, the immunogenic nature of the antibody component within ADCs warrants the need for robust immunogenicity testing, including a neutralizing antibody (NAb) assay. Since the mechanism of action (MOA) of the ADC is to first bind to the target cells and then release the payload intracellularly to kill the cells, the most relevant NAb assay format would be a cell-based killing assay. However, in this paper, we present a case where a cell-based killing assay could not be developed after multiple cell lines and NAb-positive controls (PC) had been tested. Surprisingly, contrary to our expectations, all NAb PCs tested exhibited an increased killing effect on the target cells, instead of the expected protective response. This unexpected phenomenon most likely is due to the non-specific internalization of drug/NAb complexes via FcγRs, as an excessive amount of human IgG1 and mouse IgG2a, but not mouse IgG1, greatly inhibited drug or drug/NAb complexes induced cell death. To overcome this obstacle, we implemented a novel cell-based binding assay utilizing the Meso Scale Discovery (MSD) platform. We also propose that an in vitro cell killing NAb assay is limited to at best monitoring the target binding and internalization induced cell death, but not by-stander killing induced by prematurely released or dead-cell released payload, hence cannot really mimic the in vivo MOA of ADC. [ABSTRACT FROM AUTHOR]

Glucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the mechanisms underlying resistance remain poorly understood. Here, we report that in B-ALL, GC paradoxically induce their own resistance by activating a phospholipase C (PLC)-mediated cell survival pathway through the chemokine receptor, CXCR4. We identify PLC as aberrantly activated in GC-resistant B-ALL and its inhibition is able to induce cell death by compromising several transcriptional programs. Mechanistically, dexamethasone (Dex) provokes CXCR4 signaling, resulting in the activation of PLC-dependent Ca2+ and protein kinase C signaling pathways, which curtail anticancer activity. Treatment with a CXCR4 antagonist or a PLC inhibitor improves survival of Dex-treated NSG mice in vivo. CXCR4/PLC axis inhibition significantly reverses Dex resistance in B-ALL cell lines (in vitro and in vivo) and cells from Dex resistant ALL patients. Our study identifies how activation of the PLC signalosome in B-ALL by Dex limits the upfront efficacy of this chemotherapeutic agent. Resistance to glucocorticoids (GC) is a major obstacle for the treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL). Here, the authors report that GC-triggered CXCR4 internalization promotes a phospholipase C (PLC)-mediated cell survival pathway, driving GC resistance in B-ALL. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 virus that led to COVID-19 is associated with significant and long-lasting neurologic symptoms in many patients, with an increased mortality risk for people with Alzheimer's disease (AD) and/or Down syndrome (DS). However, few studies have evaluated the neuropathological and inflammatory sequelae in postmortem brain tissue obtained from AD and people with DS with severe SARS-CoV-2 infections. We examined tau, beta-amyloid (Aβ), inflammatory markers and SARS-CoV-2 nucleoprotein in DS, AD, and healthy non-demented controls with COVID-19 and compared with non-infected brain tissue from each disease group (total n = 24). A nested ANOVA was used to determine regional effects of the COVID-19 infection on arborization of astrocytes (Sholl analysis) and percent-stained area of Iba-1 and TMEM 119. SARS-CoV-2 antibodies labeled neurons and glial cells in the frontal cortex of all subjects with COVID-19, and in the hippocampus of two of the three DS COVID-19 cases. SARS-CoV-2-related alterations were observed in peri-vascular astrocytes and microglial cells in the gray matter of the frontal cortex, hippocampus, and para-hippocampal gyrus. Bright field microscopy revealed scattered intracellular and diffuse extracellular Aβ deposits in the hippocampus of controls with confirmed SARS-CoV-2 infections. Overall, the present preliminary findings suggest that SARS-CoV-2 infections induce abnormal inflammatory responses in Down syndrome. [ABSTRACT FROM AUTHOR]

Changes in rainfall and temperature patterns can impact water security, mainly in tropical and subtropical regions. This study aimed to assess if climate change in Minas Gerais state, Brazil has impacted groundwater storage. Headwaters of four representative basins with minimum land use change were selected to quantify the effects of atmospheric forcing. Daily streamflow time series were used to assess changes in groundwater storage using the Brutsaert method. The Mann–Kendall and Sen tests were applied to evaluate the trends and determine the rate of change. Most studied sub-basins showed an upward trend in temperature and evapotranspiration, while a nonsignificant trend was found for annual precipitation in some sub-basins. Mean annual streamflow, minimum streamflow over seven consecutive days (Q7, min), and groundwater storage (S) showed downward trends in most sub-basins. The Jequitinhonha sub-basin is the closest hydrological unit to the pristine conditions, indicating that changes in climate have impacted its hydrological response. In contrast, at the Piracicaba sub-basin and Sapucaí sub-basin, it was not clear that climate changes can exclusively explain the decreasing trend in groundwater storage due to the changes in land use from native forest (Atlantic Forest and Cerrado) to pasture. The São Francisco and Grande River sub-basins are the most anthropized and showed the lowest reduction rates, showing that these sub-basins have a relevant resilience to climate change as their geomorphological aspects, i.e., soils, topography, soil-vegetation relationship, and hydrogeology, play a fundamental role in buffering the hydrological impacts. Our results can contribute to water resource management in Minas Gerais state, supporting decision-makers actions to minimize the effects. [ABSTRACT FROM AUTHOR]