The Evolutionary Forest of Pancreatic Cancer.

The genomic features of pancreatic ductal adenocarcinoma (PDAC) have been well described, yet the evolutionary contexts within which those features occur remains unexplored. We studied the genome landscapes, phylogenies and clonal compositions of 91 PDACs in relation to clinicopathologic features. There was no difference in the number of driver mutations or the evolutionary timing that each mutation occurred. High truncal density, a metric of the accumulation of somatic mutations in the lineage that gave rise to each PDAC, was significantly associated with worse overall survival. Polyclonal, monoclonal or mixed polyclonal/monoclonal metastases were identified across the cohort highlighting multiple forms of inter-tumoral heterogeneity. Advanced stage and treated PDACs had higher odds of being polyclonal, whereas oligometastatic PDACs had fewer driver alterations, a lower fractional allelic loss and increased likelihood of being monoclonal. In sum, our findings reveal novel insights into the dynamic nature of the PDAC genome beyond established genetic paradigms.

Emerging and extensive clonal evolution in the pancreas.

Pancreatic cancer is one of the most lethal malignancies, yet much remains to be learned regarding how its precursors develop. In a recent Nature publication, Braxton and Kiemen et al. found that the normal, adult pancreas harbors hundreds to thousands of pancreatic cancer precursors evolving by a variety of routes.

Perceptions of Clinical Clerks and Interns of the University of the Philippines College of Medicine towards Physical and Rehabilitation Medicine as a Medical Specialty.

Objectives: Perception about Physical and Rehabilitation Medicine provides information about awareness on identifying disabilities and managing their impact on activities of daily living; however, misconceptions about the field continue to exist among both students and physicians. This study aims to describe the perceptions of clinical clerks and interns towards the practice and role of Rehabilitation Medicine in management of patients. Methods: This is a descriptive cross-sectional study. Students from the Learning Unit 6 and 7 of UP College of Medicine answered adapted online survey forms from a previous study and participated in online focus group discussions. Qualitative data were used to infer the perception of medical students towards the specialty. The effect of the respondent's profile, background and affiliation on their knowledge, attitudes and perceptions were analyzed using One-Way ANOVA (α = 0.05). Qualitative data were analyzed using thematic analysis. Results: Learning Unit 6 and 7 students were found to have a perceived broad level of knowledge with regards the specialty. The students associated the specialty with focus on holistic care, quality of life, interdisciplinary collaboration, and diversity of cases managed. No statistically significant differences were found between the perception among: 1) Learning Unit 6 and 7, 2) those with or without a previous encounter with the specialty, 3) allied medical and non-allied medical undergraduate courses in terms of: a) confidence in the knowledge (p = 0.489), b) familiarity with conditions managed (p = 0.93) and c) interest towards the specialty (p = 0.693). The Organ System Integrated (OSI) curriculum, which promotes horizontal and vertical integration of concepts, provided a wide understanding of the basic concepts related to physiatry. The students' responses suggest a positive attitude towards Physical and Rehabilitation Medicine, as measured in their level of interest about knowing more regarding the specialty. Most common perceptions were that the specialty was multidisciplinary and holistic. However, the respondents' perceptions regarding the roles of the Rehabilitation team were limited. Conclusion: Learning unit level 6 and 7 students had a broad understanding of the practice and scope of the Physical and Rehabilitation Medicine specialty. Future researches can include other medical students in all year levels, including Learning Units 3, 4 and 5 of UPCM, to observe the development of their perceptions about the specialty throughout medical school.

Acute activation of adipocyte lipolysis reveals dynamic lipid remodeling of the hepatic lipidome.

Adipose tissue is the site of long-term energy storage. During the fasting state, exercise, and cold exposure, the white adipose tissue mobilizes energy for peripheral tissues through lipolysis. The mobilization of lipids from white adipose tissue to the liver can lead to excess triglyceride accumulation and fatty liver disease. Although the white adipose tissue is known to release free fatty acids, a comprehensive analysis of lipids mobilized from white adipocytes in vivo has not been completed. In these studies, we provide a comprehensive quantitative analysis of the adipocyte-secreted lipidome and show that there is interorgan crosstalk with liver. Our analysis identifies multiple lipid classes released by adipocytes in response to activation of lipolysis. Time-dependent analysis of the serum lipidome showed that free fatty acids increase within 30 min of ß3-adrenergic receptor activation and subsequently decrease, followed by a rise in serum triglycerides, liver triglycerides, and several ceramide species. The triglyceride composition of liver is enriched for linoleic acid despite higher concentrations of palmitate in the blood. To further validate that these findings were a specific consequence of lipolysis, we generated mice with conditional deletion of adipose tissue triglyceride lipase exclusively in adipocytes. This loss of in vivo adipocyte lipolysis prevented the rise in serum free fatty acids and hepatic triglycerides. Furthermore, conditioned media from adipocytes promotes lipid remodeling in hepatocytes with concomitant changes in genes/pathways mediating lipid utilization. Together, these data highlight critical role of adipocyte lipolysis in interorgan crosstalk between adipocytes and liver.

Disparities in Huntington Disease Severity: Analysis Using the ENROLL-HD Dataset.

Background and Objectives: Social and structural determinants of health (SDOH) have been associated with disability in neurologic diseases. However, the association between these factors and disability in Huntington disease (HD) has not been studied. This study aimed to evaluate the association of racial and sociodemographic factors with disease severity in patients with HD in North America. Methods: We conducted a cross-sectional study of genetically confirmed participants with HD (36+ CAG repeats) in the North American region using the ENROLL-HD 2020 periodic dataset. In this analysis, our exposure variable was the participant's race/ethnicity. The main outcome measure was disease severity, as measured by the Total Functional Capacity Score (TFC), which measures the level of disability of patients with HD. We used multivariate regression models to adjust for sociodemographic factors that may mediate or moderate a causal effect between race/ethnicity and disease severity. Results: Among 4,717 gene-positive participants in the North American region, 89.5% identified as White, 3.4% as Hispanic or Latino, and 2.3% as African American/Black. The average TFC score was 10.22 (SD 3.22); 48% of participants completed either secondary education (including college) or a professional degree, and 55% lived in a city and not in a town, village, or rural location. In multivariate regression models, we found that Black participants and those with less than a high school degree entered the ENROLL-HD study with lower TFC scores than White participants. We also found that compared with those with at least a high school degree, those who completed some form of higher education or professional degree had higher TFC scores (p < 0.001). This multivariate analysis did not find an association between geographic location and TFC score. Discussion: Our study found that Black participants in North America presented to ENROLL-HD with more advanced disease than White patients. We also found that higher education was associated with less advanced disease when entering the ENROLL-HD study. The role of race/ethnicity and education in HD symptom severity warrants further investigation. These findings underscore the importance of further studying the role of social and structural determinants of health in patients with HD, particularly those from historically marginalized communities.

Parenteral Nutrition in the Neonatal Intensive Care Unit: Intravenous Lipid Emulsions.

Intravenous lipid emulsions (ILEs) are a source of nonprotein calories and fatty acids and help promote growth in preterm infants and infants with intestinal failure. An ILE dose and oil source determines its fatty acid, phytosterol, and vitamin E delivery. These factors play a role in the infant's risk for essential fatty acid deficiency and cholestasis, and help modulate inflammation, immunity, and organ development. This article reviews different ILEs and their constituents and their relationship with neonatal health.

Home-based telerehabilitation for community-dwelling persons with stroke during the COVID-19 pandemic: A pilot study.

OBJECTIVES: To determine the feasibility and safety of use of asynchronous telerehabilitation for community-dwelling persons with stroke in the Philippines during the COVID-19 (SARS-CoV-2) pandemic, and to evaluate the change in participants' telerehabilitation perceptions, physical activity, and well-being after a 2-week home-based telerehabilitation programme using a common social media application. DESIGN: Pilot study. PARTICIPANTS: Nineteen ambulatory, non-aphasic adult members of a national university hospital stroke support group in the Philippines. METHODS: Pre-participation screening was performed using the Physical Activity Readiness Questionnaire. The participants were medically cleared prior to study enrollment. They then engaged in telerehabilitation by watching original easy-to-follow home exercise videos prepared and posted by the study authors on a private group page on Facebook™ every other day for 2 weeks. Descriptive statistics was performed. RESULTS: All 19 participants (mean age: 54.9 years) completed the programme with no significant adverse events. The majority of subjects improved their telerehabilitation perceptions (based on the Telepractice Questionnaire), physical activity levels (based on the Simple Physical Activity Questionnaire), and perceived well-being (based on the Happiness Scale). CONCLUSION: Asynchronous telerehabilitation using a common low-cost social media application is feasible and safe for community-dwelling persons with chronic stroke in a lower-middle-income country.

Angiotensin II type 1 receptor antibodies and native kidney function in pediatric liver and intestinal transplant recipients.

BACKGROUND: Angiotensin II type-1 receptor antibody (AT1R-Ab) has been associated with vascular injury and kidney dysfunction in pediatric kidney transplant recipients. The role of AT1R-Ab in the development of chronic kidney disease in pediatric liver and intestinal transplant recipients has not been explored. METHODS: Twenty-five pediatric intestinal transplant recipients and 79 pediatric liver transplant recipients had AT1R-Ab levels measured at varying time points in the post-transplant period. Estimated glomerular filtration rate (eGFR) was determined using creatinine based CKiD U25 equation and measured at time of AT1R-Ab measurement, at 1 year post-AT1R-Ab measurement, at 5 years post-AT1R-Ab measurement, and at the most recent routine clinic visit. The prevalence of hypertension and antihypertensive medication use were also evaluated. RESULTS: Younger age at time of AT1R-Ab measurement was associated with AT1R-Ab positivity in liver transplant recipients. There was no association between AT1R-Ab status and change in eGFR, prevalence of hypertension, or use of antihypertensive medications at the described time points. CONCLUSIONS: AT1R-Ab positivity was not associated with a decline in eGFR or hypertension in pediatric liver and intestinal transplant recipients. Further studies are needed using other markers of kidney function, such as cystatin C, to validate this finding. A higher resolution version of the Graphical abstract is available as Supplementary information.

Childhood Cholestatic Liver Diseases that Persist Into Adulthood: Lessons for the Adult Gastroenterologist.

Children with cholestatic liver diseases are increasingly living into adulthood, thanks to innovations in medical and surgical therapies. The excellent outcomes observed in pediatric liver transplantation for diseases, such as biliary atresia, have transformed the life trajectory of children born with once-fatal liver diseases. The evolution of molecular genetic testing, has helped expedite the diagnosis of other cholestatic disorders, improving the clinical management, disease prognosis, and family planning for inherited disorders, such as progressive familial intrahepatic cholestasis and bile acid synthesis disorders. The expanding list of therapeutics, including bile acids and the newer ileal bile acid transport inhibitors, has also helped slow the progression of disease and improve the quality of life for certain diseases, like Alagille syndrome. More and more children with cholestatic disorders are expected to require care from adult providers familiar with the natural history and potential complications of these childhood diseases. The aim of this review is to bridge the gap between pediatric and adult care in children with cholestatic disorders. The present review addresses the epidemiology, clinical features, diagnostic testing, treatment, prognosis, and transplant outcomes of 4 hallmark childhood cholestatic liver diseases: biliary atresia, Alagille syndrome, progressive familial intrahepatic cholestasis, and bile acid synthesis disorders.

Telerehabilitation Readiness, Knowledge, and Acceptance of Future Physiatrists in the Philippines: An Online Survey During the COVID-19 Pandemic.

Background: Clinical, educational, and research interest in telerehabilitation has not been widely explored until the COVID-19 pandemic. Amid the enduring pandemic, telerehabilitation remains part of the daily service, academic, and research responsibilities of residents in various training institutions worldwide. Objective: To determine the Rehabilitation Medicine residents' current levels of telerehabilitation readiness, knowledge, and acceptance, their pattern of beliefs about telerehabilitation, and the factors affecting their readiness. Methods: All bona fide residents from all training institutions in the Philippines were invited to participate in an online survey evaluating the following constructs: technological readiness (using the Technological Readiness Index or TRI 2.0); telerehabilitation knowledge (using an original multiple-choice examination); and telerehabilitation acceptance (using the Unified Theory of Acceptance and Use of Technology questionnaire). A pre-test and pilot test were conducted. The TRI responses were classified according to technology adoption segments to determine the respondents' pattern of beliefs about telerehabilitation. Results: Sixty-two residents participated (86.1% response rate). They had good telerehabilitation readiness (3.3 ± 0.4 out of 5), fair telerehabilitation knowledge (2.1 ± 1.1 out of 5), and excellent telerehabilitation acceptance (4.5 ± 0.6 out of 5). The majority were classified either as telerehabilitation skeptics (38.7%), pioneers (19.4%), or explorers (19.4%). The factors that significantly influenced telerehabilitation readiness were optimism, innovativeness, discomfort, and insecurity (p < 0.05). Conclusion: Despite having favorable levels of telerehabilitation readiness and acceptance, the Rehabilitation Medicine residents showed fair telerehabilitation knowledge. Our results suggest the need for formal education and training on virtual rehabilitation care during residency.

Telerehabilitation as a Method for Achieving Competencies in Physical and Rehabilitation Medicine Residency Training in a Developing Country: A Protocol for a Pilot Mixed-Methods Study.

Background: In the second year of the COVID-19 pandemic, Physical and Rehabilitation Medicine (PRM) residents in a developing country continue to face a lack of in-person clinical exposure and learning opportunities. With the unprecedented shift to virtual care, it remains uncertain whether residents can achieve PRM competencies using telerehabilitation as a method of instruction. Objective: To determine the PRM residents' ability to achieve competencies through telerehabilitation, as perceived by different stakeholders (residents, chief residents, training officers, and department heads). Methods: This will be a pilot mixed-methods study, employing concurrent triangulation, in the Department of Rehabilitation Medicine in one large private medical center and one large government hospital in Manila, Philippines. There will be two phases of online data collection upon approval by their respective research ethics board. The first phase will involve an online Likert-scale questionnaire to obtain the residents' self-perceived attainment of competencies and learning of PRM topics and skills specified by the International Society of Physical and Rehabilitation Medicine and the Philippine Board of Rehabilitation Medicine. The results of the survey will then be summarized and presented in a focus group discussion (FGD) with the department heads, training officers, and chief residents of the two institutions in an attempt to explain the residents' perceptions on their competencies achieved through virtual care. Afterwards, the qualitative data obtained from the FGD will then be thematically analyzed, and mixed methods integration will be employed to generate knowledge and recommendations. Discussion: It is hypothesized that the majority of the residents had little to no experience with telerehabilitation pre-pandemic. Suddenly telerehabilitation was used to augment clinical training during the pandemic. It is uncertain whether telerehabilitation can help residents achieve competencies in the different domains of training, namely: patient safety and quality patient care; medical knowledge and procedural skills; interpersonal and communication skills; practice- and systems-based learning and improvement; reintegration of people with disabilities into the society; medical ethics and public health; quality assurance; policies of care and prevention for disabled people; and professionalism. The study results can provide insights on the aspects of a PRM curriculum that may have to be modified to ensure the training program is sensitive and appropriate to the changing training needs of the residents amid the pandemic and similar crises that may disrupt in-person clinical encounters in the future.

Hypertriglyceridemia in Preterm Infants.

Preterm and critically ill infants are at risk for hypertriglyceridemia (HTG). Common risk factors for HTG include prematurity, intravenous lipid emulsion dose and oil composition, reduced lipoprotein lipase activity, fetal growth restriction, sepsis, and renal failure. Despite these risk factors, clinicians lack a universally agreed upon definition for HTG and evidence-based approach to HTG management. This review provides a detailed overview of triglyceride and intravenous lipid emulsion metabolism and how this relates to specific HTG risk factors, along with some practical considerations for managing HTG in the neonatal population.

Evidence for reduced BRCA2 functional activity in Homo sapiens after divergence from the chimpanzee-human last common ancestor.

We performed a comparative analysis of human and 12 non-human primates to identify sequence variations in known cancer genes. We identified 395 human-specific fixed non-silent substitutions that emerged during evolution of human. Using bioinformatics analyses for functional consequences, we identified a number of substitutions that are predicted to alter protein function; one of these mutations is located at the most evolutionarily conserved domain of human BRCA2.

Telehealth in surgery: an umbrella review.

BACKGROUND: Telehealth use has increased worldwide during the COVID-19 pandemic. However, hands-on requirements of surgical care may have resulted in slower implementation. This umbrella review (review of systematic reviews) evaluated the perceptions, safety and implementation of telehealth services in surgery, and telehealth usage in Australia between 2020 and 2021. METHODS: PubMed was searched from 2015 to 2021 for systematic reviews evaluating real-time telehealth modalities in surgery. Outcomes of interest were patient and provider satisfaction, safety, and barriers and facilitators associated with its use. Study quality was appraised using the AMSTAR 2 tool. A working group of surgeons provided insights into the clinical relevance to telehealth in surgical practice of the evidence collated. RESULTS: From 2025 identified studies, 17 were included, which were of low to moderate risk of bias. Patient and provider satisfaction with telehealth was high. Time savings, decreased healthcare resource use and lower costs were reported as key advantages of the service. Inability to perform comprehensive examinations was noted as the primary barrier. In Australia, peak telehealth usage coincided with the introduction of temporary telehealth services and increased lockdown measures. CONCLUSIONS: Patients and providers are broadly satisfied with telehealth and its benefits. Barriers may be overcome via multidisciplinary collaboration. Telehealth may benefit surgical care long-term if implemented correctly both during and after the COVID-19 pandemic.

A Rare Case of Steroid-Resistant Neurosarcoidosis of the Cavernous Sinus With Optic Neuropathy: A Case Report.

Sarcoidosis is an inflammatory disease that presents with nervous system involvement in 5-10% of cases, commonly known as neurosarcoidosis.1 While there are no randomized controlled trials for the treatment of neurosarcoidosis, expert opinion supports initial treatment with corticosteroids and the use of steroid-sparing or anti-TNF agents in refractory or severe cases. We report a case of a 48-year-old African American male with a past medical history of biopsy-proven hepatic and renal sarcoidosis and progressive headache, dizziness, and blurry vision for 5 months, presenting with an acute exacerbation of right-sided vision loss over one day. MRI of the brain revealed a dural-based mass extending into the right cavernous sinus and compressing the right optic nerve. Given the pathological confirmation of systemic granulomatous disease consistent with sarcoidosis, clinical manifestations, bilateral hilar and mediastinal lymphadenopathy, MRI findings typical of central nervous system inflammation, and exclusion of other possible etiologies, the patient was diagnosed with probable neurosarcoidosis. Corticosteroids initially resolved his symptoms; however, he suffered an acute relapse. Combination therapy with corticosteroids plus mycophenolate mofetil (MMF) led to the eventual resolution of his symptoms. Only 8 cases of neurosarcoidosis involving the cavernous sinus have been reported. Our patient represents the only reported case of probable neurosarcoidosis of the cavernous sinus with optic neuropathy successfully treated with corticosteroid plus MMF combination therapy. We highlight the need to consider early, aggressive treatment in cases of neurosarcoidosis with optic neuropathy and to develop criteria to guide treatment strategy based on neurolocalization and the degree of neurological disability.

FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption.

FXR agonists are used to treat non-alcoholic fatty liver disease (NAFLD), in part because they reduce hepatic lipids. Here, we show that FXR activation with the FXR agonist GSK2324 controls hepatic lipids via reduced absorption and selective decreases in fatty acid synthesis. Using comprehensive lipidomic analyses, we show that FXR activation in mice or humans specifically reduces hepatic levels of mono- and polyunsaturated fatty acids (MUFA and PUFA). Decreases in MUFA are due to FXR-dependent repression of Scd1, Dgat2, and Lpin1 expression, which is independent of SHP and SREBP1c. FXR-dependent decreases in PUFAs are mediated by decreases in lipid absorption. Replenishing bile acids in the diet prevented decreased lipid absorption in GSK2324-treated mice, suggesting that FXR reduces absorption via decreased bile acids. We used tissue-specific FXR KO mice to show that hepatic FXR controls lipogenic genes, whereas intestinal FXR controls lipid absorption. Together, our studies establish two distinct pathways by which FXR regulates hepatic lipids.

Role of Telerehabilitation in the Rehabilitation Medicine Training Program of a COVID-19 Referral Center in a Developing Country.

ABSTRACT: This article describes the impact of the pandemic on physical medicine and rehabilitation in a COVID-19 referral center of a developing country. It describes how telerehabilitation can be leveraged to fill in the gaps in service, training, and research arms of the physical medicine and rehabilitation specialty. The ITAWAG ("to call") telerehabilitation program is the response of the Department of Rehabilitation Medicine at Philippine General Hospital, which is the country's national university hospital, to the ongoing COVID-19 crisis that continues to limit face-to-face access to physical medicine and rehabilitation services throughout the country. With the significant decline in the number of patients served since the start of the pandemic, the ITAWAG program aimed to bridge the physical distance between patients and clinicians after a set of eligibility criteria for teleconsultation or teletherapy and a step-by-step process used before, during, and after each virtual encounter. However, because many physical medicine and rehabilitation consultants, residents, and therapists were not trained for the virtual approach to patient care, a telerehabilitation curriculum was developed to help in providing quality and competent services. Finally, despite the growing awareness of telerehabilitation throughout the country, several research gaps about this emerging technology are identified to determine its acceptance, applicability, and cost-effectiveness among others.