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Over the past decade, boldine, a naturally occurring alkaloid found in several plant species including the Chilean Boldo tree, has garnered attention for its efficacy in rodent models of human disease. Some of the properties that have been attributed to boldine include antioxidant activities, neuroprotective and analgesic actions, hepatoprotective effects, anti-inflammatory actions, cardioprotective effects and anticancer potential. Compelling data now indicates that boldine blocks connexin (Cx) hemichannels (HCs) and that many if not all of its effects in rodent models of injury and disease are due to CxHC blockade. Here we provide an overview of boldine's pharmacological properties, including its efficacy in rodent models of common human injuries and diseases, and of its absorption, distribution, pharmacokinetics, and metabolism.

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Melanoma, a malignant tumor of melanocytes, poses a significant clinical challenge due to its aggressive nature and high potential for metastasis. The advent of targeted therapy has revolutionized the treatment landscape of melanoma, particularly for tumors harboring specific genetic alterations such as BRAF V600E mutations. Despite the initial success of targeted agents, resistance inevitably arises, underscoring the need for novel therapeutic strategies. This review explores the latest advances in targeted therapy for melanoma, focusing on new molecular targets, combination therapies, and strategies to overcome resistance.

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By August 17, 2021, 4.3 million people had died globally as a result of SARS-CoV-2 infection. While data collection is ongoing, it is abundantly obvious that this is one of the most significant public health crises in modern history. Consequently, global efforts are being made to attain a greater understanding of this disease and to identify risk factors associated with more severe outcomes. The goal of this study is to identify clinical characteristics and risk factors associated with COVID-19 mortality in Mexico. The dataset used in this study was released by Sistema Nacional de Vigilancia Epidemiologica de Enfermedades Respiratorias (SISVER) de la Secretaría de Salud and contains 2.9 million COVID-19 cases. The effects of risk factors on COVID-19 mortality were estimated using multivariable logistic regression models with generalized estimation equation and Kaplan-Meier curves. Case fatality rates, case hospitalization rates are also reported using the Centers for Disease Control and Prevention (CDC) USA death-to-case ratio method. In general, older males with pre-existing conditions had higher odds of death. Age greater than 40, male sex, hypertension, diabetes, and obesity are associated with higher COVID-19 mortality. End-stage renal disease, chronic obstructive pulmonary disease, and immunosuppression are all linked with COVID-19 patient fatalities. Smoking and Asthma are associated with lower COVID-19 mortality which is consistent with findings from the article published in Nature based on National Health Service (NHS) of UK dataset (17 million cases). Intensive care unit (ICU), patient intubation, and pneumonia diagnosis are shown to substantially increase mortality risk for COVID-19 patients.

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Background: The objective outcomes of masseteric nerve transfer in the setting of parotid malignancy are unclear. Objective: To measure objective facial reanimation outcomes of masseteric nerve transfer in patients with parotid malignancy who underwent parotidectomy with facial nerve resection. Materials and Methods: Retrospective review of patients who underwent masseteric nerve transfer for facial paralysis secondary to parotid malignancy was carried out at a tertiary referral hospital from August 2017 to November 2021. Objective facial reanimation outcomes were analyzed using Emotrics. Minimal follow-up of 6 months was required for inclusion. Results: Eight patients (five males) with a median age of 75.5 years (range 53-91) met inclusion criteria. Fifty percent had metastatic squamous cell carcinoma, and 50% had primary parotid malignancy. Five patients underwent concomitant cancer resection with facial nerve reconstruction. Seven patients received postoperative adjuvant radiotherapy. After reinnervation, patients had improved oral commissure excursion (from 1.51 mm ±1.27 to 3.77 mm ±1.81; p < 0.01) and facial symmetry during smile. Conclusion: In this study, masseteric nerve transfer enhanced oral commissure excursion and facial symmetry during smile in patients with parotid malignancy and facial nerve resection.

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Introduction/Purpose: Virtually supervised, group-based exercise presents an innovative way to expand the reach of exercise-oncology programs and help cancer survivors increase physical activity (PA) and connect with other participants. This study examined the feasibility, acceptability, and preliminary effects of a group-based PA program delivered exclusively using videoconferencing software. Methods: This study used a single-group pre-post design. The 8-wk program consisted of aerobic and resistance exercise sessions once per week and three PA behavior change discussion sessions in groups of four to six. Feasibility was determined by enrollment, retention, safety, and adherence. Postprogram surveys evaluated acceptability using a Likert scale and open-ended responses. Changes in PA (Godin Leisure-Time Exercise Questionnaire), quality of life (QOL; Functional Assessment of Cancer Therapy- General), and upper and lower body muscular endurance (bicep curl and sit-to-stand test) were also evaluated. Results: Enrollment was feasible (n = 61 of 65 who expressed interest in the program), and retention (86.9%) and adherence (88% for exercise, 91% for discussion) were high; no adverse events were reported. Participants (mean age, 59.9 ± 10.1 yr; 96.2% female; 64.2% ovarian cancer, 28.3% breast cancer, 7.5% other cancer) reported they enjoyed the program (median, 7 of 7), and videoconferencing software was easy to use and had good video and audio quality (median, 5 of 5). From preprogram to postprogram, participants increased their weekly minutes of aerobic (mean (SD) change, 82.4 (144.2)) and resistance (mean (SD) change, 31.9 (42.7)) PA; sit-to-stand (mean (SD) change, 1.4 (3.9)) and bicep curl (mean (SD) change, 5.3 (6.8)) repetitions; and emotional (mean (SD) change, 0.82 (2.3) points), functional (mean (SD) change, 1.2 (3.6) points), and total QOL (mean (SD) change, 3 (7.9) points; all P < 0.05). Conclusions: A group-based PA program delivered using videoconference technology is feasible and acceptable for cancer survivors, and may increase PA and improve physical fitness and some aspects of QOL. A larger, controlled intervention is needed to determine efficacy, as well as pragmatic studies to directly compare this approach with conventional strategies (i.e., face-to-face programs).

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Despite general declines in coral reef ecosystems in the tropical western Atlantic, some reefs, including mesophotic reefs (30-150 m), are hypothesized to function as coral refugia due to their relative isolation from anthropogenic stressors. Understanding the connectivity dynamics among these putative refugia and more degraded reefs is critical to develop effective management strategies that promote coral metapopulation persistence and recovery. This study presents a geographically broad assessment of shallow (<30 m) and mesophotic (>30 m) connectivity dynamics of the depth-generalist coral species Montastraea cavernosa. Over 750 coral genets were collected across the Northwest and Southern Gulf of Mexico, Florida, Cuba, and Belize, and ~5000 SNP loci were generated to quantify high-resolution genetic structure and connectivity among these populations. Generally, shallow and mesophotic populations demonstrated higher connectivity to distant populations within the same depth zone than to adjacent populations across depth zones. However, exceptions to this pattern include the Northwest Gulf of Mexico and the Florida Keys which exhibited relatively high vertical genetic connectivity. Furthermore, estimates of recent gene flow emphasize that mesophotic M. cavernosa populations are not significant sources for their local shallow counterparts, except for the Northwest Gulf of Mexico populations. Location-based differences in vertical connectivity are likely a result of diverse oceanographic and environmental conditions that may drive variation in gene flow and depth-dependent selection. These results highlight the need to evaluate connectivity dynamics and refugia potential of mesophotic coral species on a population-by-population basis and to identify stepping-stone populations that warrant incorporation in future international management approaches.

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Immunoglobulin A (IgA) is an important factor in maintaining homeostasis at mucosal surfaces, yet luminal IgA levels vary widely. Total IgA levels are thought to be driven by individual immune responses to specific microbes. Here, we found that the prebiotic, pectin oligosaccharide (pec-oligo), induced high IgA levels in the small intestine in a T cell-dependent manner. Surprisingly, this IgA-high phenotype was retained after cessation of pec-oligo treatment, and microbiome transmission either horizontally or vertically was sufficient to retain high IgA levels in the absence of pec-oligo. Interestingly, the bacterial taxa enriched in the overall pec-oligo bacterial community differed from IgA-coated microbes in this same community. Rather, a group of ethanol-resistant microbes, highly enriched for Lachnospiraceae bacterium A2, drove the IgA-high phenotype. These findings support a model of intestinal adaptive immunity in which a limited number of microbes can promote durable changes in IgA directed to many symbionts.

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It is usually beneficial for species to restrict activity to a particular phase of the 24-hour cycle as this enables the development of morphological and behavioural adaptations to enhance survival under specific biotic and abiotic conditions. Sloth activity patterns are thought to be strongly related to the environmental conditions due to the metabolic consequences of having a low and highly variable core body temperature. Understanding the drivers of sloth activity and their ability to withstand environmental fluctuations is of growing importance for the development of effective conservation measures, particularly when we consider the vulnerability of tropical ecosystems to climate change and the escalating impacts of anthropogenic activities in South and Central America. Unfortunately, the cryptic nature of sloths makes long term observational research difficult and so there is very little existing literature examining the behavioural ecology of wild sloths. Here, we used micro data loggers to continuously record, for the first time, the behaviour of both Bradypus and Choloepus sloths over periods of days to weeks. We investigate how fluctuations in the environmental conditions affect the activity of sloths inhabiting a lowland rainforest on the Caribbean coast of Costa Rica and examined how this might relate to their low power lifestyle. Both Bradypus and Choloepus sloths were found to be cathemeral in their activity, with high levels of between-individual and within-individual variation in the amounts of time spent active, and in the temporal distribution of activity over the 24-hour cycle. Daily temperature did not affect activity, although Bradypus sloths were found to show increased nocturnal activity on colder nights, and on nights following colder days. Our results demonstrate a distinct lack of synchronicity within the same population, and we suggest that this pattern provides sloths with the flexibility to exploit favourable environmental conditions whilst reducing the threat of predation.

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There is limited literature investigating the association between chronic back pain (CBP) and depression in Brazil. This study evaluates the association between CBP, CBP-related physical limitations (CBP-RPL), and self-reported current depression (SRCD), in a nationally representative sample of Brazilian adults. The data for this cross-sectional study came from the 2019 Brazilian National Health Survey (n = 71,535). The Personal Health Questionnaire depression scale (PHQ-8) was used to measure the SRCD outcome. The exposures of interest were self-reported CBP and CBP-RPL (none, slight, moderate, and high limitation). Multivariable weighted and adjusted logistic regression models were used to investigate these associations. The weighted prevalence of SRCD among CBP was 39.5%. There was a significant weighted and adjusted association between CBP and SRCD (weighted and adjusted odds ratio (WAOR) 2.69 (95% CI: 2.45-2.94). The WAOR of SRCD among individuals with high, moderate, and slight levels of physical limitation was significantly greater than for those without physical limitation due to CBP. Among Brazilian adults with high levels of CBP-RPL, there was over a five-fold increased risk of SRCD compared to those without CBP-RPL. These results are important for increasing awareness of the link between CBP and SRCD and for informing health services policies.

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Shyness, the tendency to be inhibited and uncomfortable in novel social situations, is a consequential personality trait, especially during adolescence. The present study examined the development of shyness from late childhood (age 10) through adolescence (age 16) using data from a large, longitudinal study of Mexican-origin youth (N = 674). Using both self- and mother-reports of shyness assessed via the Early Adolescent Temperament Questionnaire-Revised, we found moderate to high rank-order stabilities across two-year intervals and a mean-level decrease in shyness from age 10 to 16. Anxiety and depression were associated with higher initial levels of shyness, and anxiety was associated with greater decreases in shyness from age 10 to 16. Contrary to predictions, neither nativity (country of birth) nor language proficiency (English, Spanish) was associated with the development of shyness across adolescence. Thus, youth generally decline in shyness during adolescence, although there is substantial individual variability in shyness trajectories.

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BACKGROUND: Although current clinical practice guidelines from the American Academy of Orthopaedic Surgeons suggest that Type II and III supracondylar humerus (SCH) fractures be treated by closed reduction and pin fixation, controversy remains as to whether type IIa fractures with no rotation or angular deformity require surgery. The purpose of our study was to prospectively compare radiographic and functional outcomes of type IIa SCH fractures treated with or without surgery. METHODS: Between 2017 and 2019, 105 patients between 2 and 12 years of age presenting with type IIa SCH fractures and without prior elbow trauma, neuromuscular or metabolic conditions, were prospectively enrolled. Ten orthopaedic surgeons managed the patients with 5 preferring surgical treatment and 5 preferring an initial attempt at nonoperative treatment. Patients in the nonoperative cohort were managed with a long-arm cast and close radiographic follow-up. Patients underwent a standardized protocol, including 3 to 4 weeks of casting, bilateral radiographic follow-up 6 months postinjury, and telephone follow-up at 6, 12, and 24 months. RESULTS: Ninety-nine patients met the inclusion criteria (45 nonoperative and 54 operatives). Of the nonoperative patients, 4 (9%) were converted to surgery up to their first clinical follow-up. No differences were identified between the cohorts with respect to demographic data, but patients undergoing surgery had on average 6 degrees more posterior angulation at the fracture site preoperatively (P<0.05). At the final clinical follow-up (mean=6 mo), the nonoperative group had more radiographic extension (176.9 vs 174.4 degrees, P=0.04) as measured by the hourglass angle, but no other clinical or radiographic differences were appreciated. Complications were similar between the nonoperative and operative groups: refracture (4.4 vs 5.6%), avascular necrosis (2.2 vs 1.9%) and infection (0 vs 1.9%) (P>0.05). Patient-reported outcomes at a mean of 24 months showed no differences between groups. CONCLUSION: Contrary to American Academy of Orthopaedic Surgeons guidelines, about 90% of patients with type IIa supracondylar fractures can be treated nonoperatively and will achieve good radiographic and functional outcomes with mild residual deformity improving over time. Patients treated nonoperatively must be monitored closely to assess for early loss of reduction and the need for surgical intervention.

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MOTIVATION: Next-generation sequencing (NGS) technologies are decisive for discovering disease-causing variants, although their cost limits their utility in a clinical setting. A cost-mitigating alternative is an extremely low coverage whole-genome sequencing (XLC-WGS). We investigated its use to identify causal variants within a multi-generational pedigree of individuals with retinitis pigmentosa (RP). Causing progressive vision loss, RP is a group of genetically heterogeneous eye disorders with approximately 60 known causal genes. RESULTS: We performed XLC-WGS in seventeen members of this pedigree, including three individuals with a confirmed diagnosis of RP. Sequencing data were processed using Illumina's DRAGEN pipeline and filtered using Illumina's genotype quality score metric (GQX). The resulting variants were analyzed using Expert Variant Interpreter (eVai) from enGenome as a prioritization tool. A nonsense known mutation (c.1625C > G; p.Ser542*) in exon 4 of the RP1 gene emerged as the most likely causal variant. We identified two homozygous carriers of this variant among the three sequenced RP cases and three heterozygous individuals with sufficient coverage of the RP1 locus. Our data show the utility of combining pedigree information with XLC-WGS as a cost-effective approach to identify disease-causing variants.

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Adenosine monophosphate-activated kinase (AMPK) functions in a broad spectrum of cellular stress response pathways. Investigation of AMPK activity has been limited to whole-organism analyses in Caenorhabditis elegans which does not allow for observations of cellular heterogeneity, temporal dynamics, or correlation with physiological states in real time. We codon adapted the genetically-coded AMPK biosensor, called AMPKAR-EV, for use in C. elegans . We report heterogeneity of activation in different tissues (intestine, neurons, muscle) and test the biosensor in the context of two missense mutations affecting residues T243 and S244 on the AMPK α subunit, AAK-2, which are predicted regulatory sites.

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OBJECTIVE: To test associations between parent-reported confidence to avoid hospitalization and caregiving strain, activation, and health-related quality of life (HRQOL). STUDY DESIGN: In this prospective cohort study, enrolled parents of children with medical complexity (n = 75) from 3 complex care programs received text messages (at random times every 2 weeks for 3 months) asking them to rate their confidence to avoid hospitalization in the next month. Low confidence, as measured on a 10-point Likert scale (1 = not confident; 10 = fully confident), was defined as a mean rating <5. Caregiving measures included the Caregiver Strain Questionnaire, Family Caregiver Activation in Transition (FCAT), and caregiver HRQOL (Medical Outcomes Study Short Form 12 [SF12]). Relationships between caregiving and confidence were assessed with a hierarchical logistic regression and classification and regression trees (CART) model. RESULTS: The parents were mostly mothers (77%) and were linguistically diverse (20% spoke Spanish as their primary language), and 18% had low confidence on average. Demographic and clinical variables had weaker associations with confidence. In regression models, low confidence was associated with higher caregiver strain (aOR, 3.52; 95% CI, 1.45-8.54). Better mental HRQOL was associated with lower likelihood of low confidence (aOR, 0.89; 95% CI, 0.80-0.97). In the CART model, higher strain similarly identified parents with lower confidence. In all models, low confidence was not associated with caregiver activation (FCAT) or physical HRQOL (SF12) scores. CONCLUSIONS: Parents of children with medical complexity with high strain and low mental HRQOL had low confidence in the range in which intervention to avoid hospitalization would be warranted. Future work could determine how adaptive interventions to improve confidence and prevent hospitalizations should account for strain and low mental HRQOL.

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BACKGROUND: Obesity is increasingly prevalent in pulmonary arterial hypertension (PAH) but is associated with improved survival, creating an "obesity paradox" in PAH. It is unknown if the improved outcomes could be attributable to obese patients deriving a greater benefit from PAH therapies. RESEARCH QUESTION: Does BMI modify treatment effectiveness in PAH? STUDY DESIGN AND METHODS: Using individual participant data, a meta-analysis was conducted of phase III, randomized, placebo-controlled trials of treatments for PAH submitted for approval to the U.S. Food and Drug Administration from 2000 to 2015. Primary outcomes were change in 6-min walk distance (6MWD) and World Health Organization (WHO) functional class. RESULTS: A total of 5,440 participants from 17 trials were included. Patients with overweight and obesity had lower baseline 6MWD and were more likely to be WHO functional class III or IV. Treatment was associated with a 27.01-m increase in 6MWD (95% CI, 21.58-32.45; P < .001) and lower odds of worse WHO functional class (OR, 0.58; 95% CI, 0.48-0.70; P < .001). For every 1 kg/m2 increase in BMI, 6MWD was reduced by 0.66 m (P = .07); there was no significant effect modification of treatment response in 6MWD according to BMI (P for interaction = .34). Higher BMI was not associated with odds of WHO functional class at end of follow-up; however, higher BMI attenuated the treatment response such that every 1 kg/m2 increase in BMI increased odds of worse WHO functional class by 3% (OR, 1.03; P for interaction = .06). INTERPRETATION: Patients with overweight and obesity had lower baseline 6MWD and worse WHO functional class than patients with normal weight with PAH. Higher BMI did not modify the treatment response for change in 6MWD, but it attenuated the treatment response for WHO functional class. PAH trials should include participants representative of all weight groups to allow for assessment of treatment heterogeneity and mechanisms.

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Um falso reconhecimento de uma pessoa pode levar à condenação de um inocente. Um método efetivo de diminuir o falso reconhecimento é por meio do alinhamento, procedimento no qual o suspeito é apresentado em conjunto com outras pessoas - fillers (não suspeitos similares ao suspeito). Em um experimento foi comparado o desempenho de testemunhas em alinhamentos nos quais fillers apresentavam moderada ou alta similaridade em relação ao suspeito. Independentemente do grau de similaridade, suspeitos foram identificados com maior frequência que suspeitos inocentes e do que fillers, e fillers foram reconhecidos em maior frequência do que suspeitos inocentes. A similaridade entre fillers e suspeito não teve efeito na probabilidade de reconhecimento do suspeito, seja ele culpado ou inocente. Os resultados são discutidos à luz de teorias acerca do efeito de similaridade de fillers e implicações dos resultados para o sistema de justiça brasileiro (AU).

Faulty witness identification can lead to the conviction of an innocent person. An effective method to reduce misidentification is using a lineup, a procedure in which the suspect is presented among "fillers" (non-suspects similar to the suspect). In an experiment, we compared the responses of eyewitnesses in lineups where fillers had moderate or high similarity to the suspect. Regardless of the degree of similarity, guilty suspects were identified more often than innocent suspects and fillers, and fillers were identified more often than innocent suspects. The similarity between fillers and suspect did not affect the probability of suspect recognition, whether the suspect was guilty or innocent. The results are discussed in the light of theories about the similarity effect of fillers, and implications for the Brazilian justice system (AU).

Un reconocimiento falso de una persona puede conducir a la condena de un inocente. Un método eficaz para reducir el reconocimiento falso es la alineación, un procedimiento en el que el sospechoso se presenta junto con otras personas - fillers (no sospechosos similares al sospechoso). En un experimento se compara el rendimiento de los testigos en alineaciones en las que los fillers tenían una similitud moderada o alta con el sospechoso. Los resultados mostraron que, independientemente del grado de similitud, en una alineación justa, los sospechosos culpables son más propensos a ser identificados que los inocentes y que los fillers, y cuando el sospechoso es inocente, los fillers tienen más probabilidades de ser reconocidos. La similitud entre filler y sospechoso no tuvo efecto sobre la probabilidad de reconocimiento del sospechoso, tanto si era culpable o inocente. Los resultados se discuten a la luz de las teorías sobre el efecto de similitud de los rellenos y las implicaciones de los resultados para el sistema judicial brasileño (AU).

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OBJECTIVES: Characterize transport medical control education in Pediatric Critical Care Medicine fellowship. DESIGN: Cross-sectional survey study. SETTING: Pediatric Critical Care Medicine fellowship programs in the United States. SUBJECTS: Pediatric Critical Care Medicine fellowship program directors. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We achieved a 74% (53/72) response rate. A majority of programs (85%) require fellows to serve as transport medical control, usually while carrying out other clinical responsibilities and sometimes without supervision. Fellows at most programs (80%) also accompany the transport team on patient retrievals. Most respondents (72%) reported formalized transport medical control teaching, primarily in a didactic format (76%). Few programs (25%) use a standardized assessment tool. Transport medical control was identified as requiring all six Accreditation Council for Graduate Medical Education competencies, with emphasis on professionalism and interpersonal and communication skills. CONCLUSIONS: Transport medical control responsibilities are common for Pediatric Critical Care Medicine fellows, but training is inconsistent, assessment is not standardized, and supervision may be lacking. Fellow performance in transport medical control may help inform assessment in multiple domains of competencies. Further study is needed to identify effective methods for transport medical control education.

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Ezrin, radixin, and moesin (ERM) family proteins regulate cytoskeletal responses by tethering the plasma membrane to the underlying actin cortex. Mutations in ERM proteins lead to severe combined immunodeficiency, but the function of these proteins in T cells remains poorly defined. Using mice in which T cells lack all ERM proteins, we demonstrate a selective role for these proteins in facilitating S1P-dependent egress from lymphoid organs. ERM-deficient T cells display defective S1P-induced migration in vitro, despite normal responses to standard protein chemokines. Analysis of these defects revealed that S1P promotes a fundamentally different mode of migration than chemokines, characterized by intracellular pressurization and bleb-based motility. ERM proteins facilitate this process, controlling directional migration by limiting blebbing to the leading edge. We propose that the distinct modes of motility induced by S1P and chemokines are specialized to allow T cell migration across lymphatic barriers and through tissue stroma, respectively.

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