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Abstract Background Primary progressive aphasia (PPA) is a clinical dementia syndrome. Impairments in language (speaking, reading, writing, and understanding) are the primary and persistent symptoms. These impairments progress insidiously and devastate communication confidence, participation, and quality of life for persons living with PPA. Currently, there are no effective disease modifying treatments for PPA. Speech-language interventions hold promise for mitigating communication challenges and language symptoms. However, evidence regarding their efficacy in PPA is of low quality and there are currently no rigorous randomized trials. Method Communication Bridge™-2 (CB2) is a Stage 2, superiority, single-blind, randomized, parallel group, active-control, behavioral clinical trial delivered virtually within a telehealth service delivery model to individuals with PPA. Ninety carefully characterized participants with clinically confirmed PPA will be randomized to one of two speech-language intervention arms: (1) Communication Bridge™ a dyadic intervention based in communication participation therapy models that incorporates salient training stimuli or (2) the control intervention a non-dyadic intervention based in impairment therapy models addressing word retrieval and language production that incorporates fixed stimuli. The superiority of Communication Bridge™ over the Control arm will be evaluated using primary outcomes of communication confidence and participation. Other outcomes include accuracy for trained words and scripts. Participants complete two therapy blocks over a 12-month period. Outcomes will be measured at baseline, at each therapy block, and at 12 months post enrollment. Discussion The CB2 trial will supply Level 2 evidence regarding the efficacy of the Communication Bridge™ intervention delivered in a telehealth service delivery model for individuals with mild to moderate PPA. An important by-product of the CB2 trial is that these data can be used to evaluate the efficacy of speech-language interventions delivered in both trial arms for persons with PPA. The impact of these data should not be overlooked as they will yield important insights examining why interventions work and for whom, which will advance effectiveness trials for speech-language interventions in PPA. Trial Registration ClinicalTrials.gov NCT03371706 . Registered prospectively on December 13, 2017.

CT visualization of the mandible and dentition of Hadrocodium wui, a stem mammaliaform from the Lower Jurassic Lower Lufeng Formation of Yunnan, China has revealed new features not accessible by previous microscopic study of the fossil. Its mandible shows a postdentary trough with an overhanging medial ridge and a short Meckel’s sulcus. An incomplete part of the ectotympanic and possibly a remnant of Meckel’s element are preserved in the postdentary trough. Thus, Hadrocodium is similar to other mammaliaforms in retaining a mandibular middle ear, contrary to our earlier interpretation. The mandible exhibits a large postcanine diastema from shedding of anterior premolars without replacement, an age-dependent feature better developed in older adults. Another adult feature is the alignment of the ultimate molar to the coronoid process. This is consistent with age-dependent changes in other mammaliaforms where the last molars of the toothrow shift from medial of the coronoid process in the juvenile, to a position in front of the coronoid process in the adult. The mandible has a short mobile symphysis. The dentition consists of I5, C1 (two-rooted), P3 (including P1 position) and M2 (M2 with confluent roots), and i4, c1 (partially two-rooted), p3, and m2 (m2 with partially confluent roots). The two-rooted upper canines are more derived than other Early Jurassic mammaliaforms from the same fauna, although similar to docodontans. Hadrocodium is unique in that the lower m2 cusp a occludes in the embrasure between upper M1–M2, but the posterior part of m2 shows between-cusp occlusion with upper M2 main cusp A. M2 is half the size of the lower m2, and occludes only with the distal half of m2. The upper postcanines show a steep gradient of posteriorly decreasing tooth size, more so than other mammaliaforms. The CT examination corroborates that there are no unerupted teeth in the upper or lower jaws, and the holotype of H. wui is dentally and osteologically mature and capable of independent feeding.

The present research examined the relationship between perceived supervisory autonomy support and counseling self-efficacy (CSE) of counselor trainees. We explored whether this relationship was mediated by autonomous work motivation using the framework of self-determination theory (SDT; Ryan & Deci, 2017) . Participants were master’s level mental health counseling interns (n = 182) enrolled in field internships. Mediational analyses showed that autonomous work motivation partially mediated the relationship between perceived autonomy support from supervisor and counselor trainees’ CSE. Results underscore the importance of adopting autonomy-supportive styles of clinical supervision for enhancing counselor trainees’ counseling self-efficacy. What is the public significance of this article?: This study suggests that when clinical supervisors provide an environment that supports counselor trainees’ autonomy, trainees experience increased autonomous motivation, which further enhances their counseling self-efficacy.

Despite the global adoption of Content and Language Integrated Learning (CLIL) and extensive research on the effectiveness (product-oriented) and classroom interactions (process-oriented) of CLIL, existing studies have overlooked the motivational beliefs and metacognitive strategies of CLIL students. Hence, there is a need for a participant-oriented approach to better understand students' perspectives and enhance CLIL's success. Drawing on the social cognitive model of self-regulated learning (SRL), this study aimed to explore how students plan, monitor, and evaluate their learning in CLIL contexts by employing a novel vignette-based microanalytic assessment approach to empirically capture students' SRL processes. Participants were 108 junior secondary school students from three schools in Hong Kong. Data were analysed using structuring qualitative content analysis. Findings revealed that students employed diverse strategies to manage the demands of language and content learning, with variations in self-efficacy beliefs influencing their approaches. Furthermore, some learners faced challenges in maintaining effective self-regulation. This study argues that improving self-regulatory processes and enhancing CLIL's success requires prioritising assessment, considering the state of 'others', and fostering deeper learning beyond CLIL. This study contributes to the empirical, methodological, and pedagogical understanding of students' SRL in CLIL settings and informs future research on student-focused aspects in CLIL.

Intratumoural heterogeneity is a feature of liver cancer. Here, the authors demonstrate that heterogeneity exists at the immune cell level in liver cancer and show that tumours with high intratumoural immune heterogeneity demonstrated an immune suppressive microenvironment, which was associated with tumour evolution and a poor prognosis.

Patients undergoing liver transplant (LTX) typically confront a challenging postoperative journey. A dysbiotic gut microbiome is associated with the development of complications, including post-LTX allograft rejection, metabolic diseases and de novo or recurrent cancer. A major explanation of this are the bipartite interactions between the gut microbiota and host immunity, which modulates the alloimmune response towards the liver allograft. Furthermore, bacterial translocation from dysbiosis causes pathogenic changes in the concentrations of microbial metabolites like lipopolysaccharides, short-chain fatty acids (SCFAs) and Trimethylamine-N-Oxide, with links to cardiovascular disease development and diabetes mellitus. Gut dysbiosis also disrupts bile acid metabolism, with implications for various post-LTX metabolic diseases. Certain taxonomy of microbiota such as lactobacilli, F.prausnitzii and Bacteroides appear to be associated with these undesired outcomes. As such, an interesting but as yet unproven hypothesis exists as to whether induction of a “beneficial” composition of gut microbiota may improve prognosis in LTX patients. Additionally, there are roles of the microbiome as predictive and prognostic indicators for clinicians in improving patient care. Hence, the gut microbiome represents an exceptionally exciting avenue for developing novel prognostic, predictive and therapeutic applications.

Background: Organ shortage is still a world-wide problem, resulting in long waiting lists for kidney, liver, and heart transplant candidates across many transplant centers globally. This has resulted in the move toward presumed consent to increase deceased organ donation rates. However, there remains a paucity of literature on public attitude and barriers regarding the opt-out system, with existing studies limited to Western nations. Therefore, this study aimed to understand public sentiment and different barriers toward organ donation from the perspective of Singapore, a highly diverse and multiethnic Asian society.Methods: A cross-sectional community semi-structured interview was conducted in a public housing estate in Singapore. Pilot test was undertaken before participants were interviewed face-to-face by trained personnel. All statistical evaluations were conducted using Stata. The χ2-test compared subgroups based on patient characteristics while multivariable logistic regression identified predictors of willingness to donate/ assent. Effect estimates were quantified using odds ratio (OR).Findings: Out of 799 individuals, 85% were agreeable to organ donation after death and 81% were willing to assent to donations of family members' organs, which declined by 16% (p < 0.001) after a clinical scenario was presented. Demographic factors including ethnicity, education, marital, and employment status affected willingness to donate and assent. Knowledge correlated significantly with willingness to donate and assent. In particular, knowledge regarding brain death irreversibility had the strongest correlation (AOR 2.15; 95% CI 1.60–2.89).Conclusions: Organ donation rates remain low albeit presumed consent legislation, due to patient-level barriers, including but not limited to knowledge gaps, cultural values, religious backgrounds, and emotional impact at relatives' death. To effectively boost donor rates, it is crucial for policy makers to invest in public education and improve transplant provisions and family protocols.

Abstract Background Literature has shown a significant relationship between radiation dose to the larynx and swallowing disorders. We prospectively studied the dose-volume relationship for larynx substructures and aspiration. Methods Forty nine patients with stage III/IV head-and-neck (H&N) squamous cell carcinoma were prospectively enrolled in this IRB-approved, federally funded study. All patients received IMRT-based chemoradiation therapy (CRT) and were scheduled for videofluorography (VFG) prior to CRT and at 3, 6, 9, 12, and 24 months post-CRT. Twelve laryngeal substructures were contoured in each patient: thyroid cartilage, cricoid cartilage, total epiglottis, suprahyoid epiglottis, infrahyoid epiglottis, total larynx, supraglottic larynx, subglottic larynx, glottic larynx, arytenoids, aryepiglottic (AE) folds, and glossoepiglottic fold. After exclusions, 29 patients were included in the final analysis. Incidence of aspiration at 1 year following CRT was correlated with dose-volume data to laryngeal substructures using logistic regression. Results The median age was 54 years with 79% being non-smokers. Tumor sites included oropharynx (22), unknown primary (6), and hypopharynx (1). One year following CRT, 10/29 (34%) showed aspiration on VFG. Dose to the AE folds showed the highest correlation with aspiration at 12 months and was significant on multivariate analysis (p = 0.025). A mean dose cutpoint of 6500 cGy or higher to the AE folds was associated with an increased risk of aspiration at 1 year [positive likelihood ratio (+LR) 2.81, positive predictive value (PPV) 60%, negative predictive value (NPV) 92.9%, relative risk (RR) 8.4]. Conclusions In this analysis, mean dose to the AE folds was associated with an increased risk of aspiration at 1 year. However, these are hypothesis-generating data that require further research and validation in a larger patient subset.

Introduction While the incidence of skin cancers continues to rise, there remains a disproportionate lack of introductory training on skin cancer screening and identification of modifiable behaviors in medical curricula. Trainees and students have cited low confidence in their ability to counsel patients and lack of instruction as barriers. Methods To address this need, we created a 1-hour didactic lecture based on a cognitive teaching framework for third-year medical students during their core primary care clerkship. The session highlighted visual identification of different skin cancers, factors increasing individual risk, and photoprotective behaviors. Session content was based on American Academy of Dermatology recommendations for skin cancer prevention. An assessment of knowledge, behaviors, and attitudes given before, immediately following, and at 6 months after the session was used to determine efficacy. Results One hundred eight students before and immediately after the session demonstrated significantly improved knowledge (mean correct: 71% presession vs. 99% postintervention, p < .0001). Based on 39 participants completing 6-month follow-up, knowledge remained improved (mean answered correctly: 80%, p < .0001). Confidence in patient counseling on preventive behaviors, risk assessment, and reported likelihood of counseling significantly increased across the three time points (p < .0001 for all attitude questions). Specific topics included appropriate referral to a dermatologist, sunscreen application, and dangers of indoor tanning bed usage. Discussion Our session on skin cancer screening and prevention demonstrated improvements in medical student knowledge, confidence, and patient counseling likelihood. This introductory curriculum could be adapted for multiple core clerkships or specialties.

In a search for appropriate theory, this essay inserts drug trafficking, the world’s largest illicit economic activity, within a wider analytical frame called the ‘covert netherworld.’ Through the convergence of three factors—covert operations, illicit commerce, and social milieu—such netherworlds can form at regional, national, and international levels, thereby transforming social margins of crime and illicit commerce into potent sources of political change. By deftly playing upon this netherworld’s politics and illicit commerce along the Burma-Thai borderlands, a regional ‘drug lord’ amassed sufficient local power to dominate the global heroin trade for over a decade and simultaneously sustain an ethnic revolt for nearly 15 years. In the Philippines, the illicit traffic in synthetic drugs developed a parallel power to influence the character of national politics, compromising three presidential administrations and shaping the moral economy of political life. For the past 40 years in Afghanistan, an illicit commodity, opium, has shaped the fate of military intervention by the world’s sole superpower, allowing it an initial success and later contributing to its ongoing failure. Through the sum of these cases, the essay concludes that the covert netherworld can serve as invisible incubator for a range of extralegal activities and has thereby attained sufficient autonomy to be treated as a significant factor in international politics.

Abstract Background Patients with prolonged length of hospital stay (LOS) not only increase their risks of nosocomial infections but also deny other patients access to inpatient care. Hepatobiliary (HPB) malignancies have some of highest incidences in East and Southeast Asia and the management of patients undergoing HPB surgeries have yet to be standardized. With improved neurosurgery techniques for intracranial aneurysms and tumors, neurosurgeries (NS) can be expected to increase. Elective surgeries account for far more operations than emergencies surgeries. Thus, with potentially increased numbers of elective HPB and NS, this study seeks to explore perioperative factors associated with prolonged LOS for these patients to improve safety and quality of practice. Methods A retrospective cross-sectional medical record review study from January 2014 to January 2015 was conducted at a 1250-bed tertiary academic hospital in Singapore. All elective HPB and NS patients over 18 years old were included in the study except day and emergency surgeries, resulting in 150 and 166 patients respectively. Prolonged LOS was defined as above median LOS based on the complexity of the surgical procedure. The predictor variables were preoperative, intraoperative, and postoperative factors. Student’s t-test and stepwise logistic regression analyses were conducted to determine which factors were associated with prolonged LOS. Results Factors associated with prolonged LOS for the HPB sample were age and admission after 5 pm but for the NS sample, they were functional status, referral to occupational therapy, and the number of hospital-acquired infections. Conclusion Our findings indicate that preoperative factors had the greatest association with prolonged LOS for HPB and NS elective surgeries even after adjusting for surgical complexity, suggesting that patient safety and quality of care may be improved with better pre-surgery patient preparation and admission practices.

Zika virus infection during pregnancy can result in birth defects, but underlying pathogenesis at the maternal-fetal interface is unclear. Here, the authors use non-invasive in vivo imaging of Zika-infected rhesus macaques and show that infection results in abnormal oxygen transport across the placenta.

Abstract: Sequestering of latent HIV in follicular helper T cells within B-cell follicles that largely exclude cytotoxic T cells is a major barrier to cellular immune-based approaches to eradicate HIV. Here, we show that the clinical-grade human interleukin-15 (IL-15) superagonist ALT-803 activates and redirects simian immunodeficiency virus (SIV)–specific CD8+ T cells from the peripheral blood into B-cell follicles. In agreement with the increased trafficking of SIV-specific cytotoxic T cells to sites of cryptic viral replication, lymph nodes of elite controlling macaques contained fewer cells expressing SIV RNA or harboring SIV DNA post–ALT-803 treatment. These data establish ALT-803 as an immunotherapeutic for HIV and other chronic viral pathogens that evade host immunity by persisting in B-cell follicles.

Hepatitis B virus (HBV) has a limited host range and current animal models can only recapitulate certain aspects of HBV replication. Here, the authors show that expression of the HBV receptor NTCP in macaques supports HBV replication in vivo, suggesting this as animal model for future HBV studies.

Rhesus macaques are not ideal for studying response to allogeneic hematopoietic stem cell transplant (allo-HSCT) owing to complex MHC genetics that prevent full MHC-matching. Here the authors show that inbred Mauritian-origin cynomolgus macaques are a superior preclinical model of allogeneic stem cell transplantation that mimics diverse clinical outcomes of human allo-HSCT.

Advances in computer technology and the human-computer interface have created a wealth of new opportunities for the development of computer-based instruction and intelligent tutoring systems. Unfortunately, much of the material currently available amounts to little more than "electronic books," in which learning is still accomplished by reading text and viewing two dimensional images. This paper describes the features of CyberProf - an interactive, World Wide Web-based teaching system developed at the University of Illinois. Using CyberProf, instructors can create on-line lecture notes that include equations, animations, and graphics; write online interactive homework problems; communicate with students using CyberProf’s Web-based conferencing system; survey students in order to receive feedback on course material; and record student grades in CyberProf’s online gradebook. Students can review lecture notes 24 hours a day; complete homework problems on the Web and receive immediate intelligent feedback to their answers; use the conferencing system to post questions to their instructor, teaching assistants, and peers; and review their grades in the class at any time.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21556-y.