Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I.

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6-8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.

Paucity of Online Information About Gender-Affirming Surgery Fellowships in the United States.

BACKGROUND: Despite growing demand for gender-affirming surgery (GAS), there are few formal GAS fellowships in the United States. Paucity of online information about GAS fellowships may discourage potential applicants and decrease the visibility of the field. Thus, it is important to analyze the existing online information about GAS fellowships to improve fellow recruitment and patient outcomes. OBJECTIVE: To identify the number of GAS fellowship websites (GASFWs) and evaluate their robustness. Second, to report the social media presence of GAS fellowships. METHODS: To identify GASFWs, existing databases sponsored by plastic surgery associations and Google query were used between April and May 2023. Thirty-five independent variables based on previously published data were evaluated for presence in a bivariate fashion on GASFWs. Accounts on popular social media websites were also identified by Google query. Website and social media analysis were also done for GAS fellowships that were offered by departments/specialties other than plastic surgery. RESULTS: In total, only 6 GASFWs associated with plastic surgery departments were identified and analyzed. Eight nonplastic surgery GASFWs were included for analysis. Overall, both categories of GASFWs were not robust; key information such as previous fellow listing and selection criteria was often missing. Furthermore, important topics specifically related to GAS such as community engagement and programmatic building are often not found on GASFWs either. In addition, none of the fellowships had any independent Facebook, Instagram, or Twitter. CONCLUSIONS: To ensure patient safety and quality outcomes, it is important to promote GAS by recruiting more applicants for specialized training beyond residency. With increased Internet use, improving GASFWs and social media presence as well as considering the use of a centralized database or match system can foster the growth of the field.

Utilization and Patient-Reported Outcomes of Direct-to-Consumer Telemedicine During the First 6 Weeks of the COVID-19 Pandemic in the Largest Pediatric Ambulatory Network in New York State.

Objective: We aimed to (1) describe telemedicine utilization and usability during the first 6 weeks of the pandemic and (2) determine if usability varied by individual- or visit-level characteristics. Methods: We conducted a retrospective cohort study of ambulatory pediatric telemedicine visits occurring between March 10, 2020, and April 18, 2020, across a large academic health system. We performed manual chart review to assess individual- and visit-level characteristics and invited caregivers to respond to an adapted Telehealth Usability Questionnaire (TUQ). We used multiple logistic regression to determine predictors of high usability. Results: There were 3,197 ambulatory pediatric telemedicine visits, representing 2,967 unique patients. Patients were racially/ethnically diverse (42.5% non-Hispanic White) and primarily English-speaking (89.2%). Surveys were completed by 441 (17%) of those invited. Every item of the TUQ had agreement or strong agreement from the majority of respondents. Compared with non-Hispanic White, non-Hispanic Asian identity was associated with lower usability in three domains and overall, and non-Hispanic Black identity was associated with higher satisfaction and future use. As compared with caregivers of infants younger than 1 year, caregivers of older patients reported lower usability in the three domains. Conclusions: Telemedicine was successfully implemented across 18 ambulatory pediatric specialties in the largest health system in New York State at the onset of COVID-19, and caregivers found it usable and acceptable. Usability scores did not vary by visit-level characteristics but did vary by race/ethnicity and age. Further research is necessary to identify modifiable drivers of the patient experience, particularly in non-Hispanic Asian communities and older adolescents.

What are Board-Certified Plastic Surgeons Posting on Instagram?

BACKGROUND: Plastic surgeons increasingly use social media to market their practices and educate prospective patients. Previous studies have investigated plastic surgery content on Instagram from the angle of hashtags and most popular plastic surgeons. However, very little is understood about what plastic surgeons themselves post on Instagram and what plastic surgery content average users engage with. OBJECTIVES: The aim of this study was to analyze Instagram posts from accounts related to plastic surgeons in the USA to establish suggestions for growing one's practice with this powerful platform to reach patients. METHODS: Board-certified plastic surgeons from all US regions that were active from February 1, 2023 to April 12, 2023 were randomly chosen. Their Instagram accounts were accessed for post analysis. For procedural posts, engagement statistics and multiple variables were collected. Dixon's outlier test was used to determine outliers in the data. ANCOVA and Tukey analysis was used to determine whether procedure type influenced engagement. RESULTS: 120 surgeon accounts were identified with 2157 posts analyzed, yielding notable differences in posts among regions. Most posts were aesthetic procedures (94.4%) and of female patients (90.3%). Surgical procedures were also predominant (86.1%). In addition, Reels had higher engagement than photograph posts. Users engaged with Body procedures at the highest rate. CONCLUSIONS: This cross-sectional analysis shows plastic surgeons tend to overwhelmingly post female patients, aesthetic procedures, and surgical content. These insights may be used to guide social media content and improve the effectiveness of Instagram as a tool for marketing or education. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Disparities in Marijuana and Tobacco Smoke Incursions Among New York City Families During Early Months of the COVID-19 Pandemic.

OBJECTIVES: Once the COVID-19 pandemic arrived in New York City (NYC), stay-at-home orders led to more time spent indoors, potentially increasing exposure to secondhand marijuana and tobacco smoke via incursions from common areas or neighbors. The objective of this study was to characterize housing-based disparities in marijuana and tobacco incursions in NYC housing during the pandemic. DESIGN: We surveyed a random sample of families from May to July 2020 and collected sociodemographic data, housing characteristics, and the presence, frequency, and pandemic-related change in incursions. SETTING: Five pediatric practices affiliated with a large NYC health care system. PARTICIPANTS: In total, 230 caregivers of children attending the practices. MAIN OUTCOME MEASURES: Prevalence and change in tobacco and marijuana smoke incursions. RESULTS: Tobacco and marijuana smoke incursions were reported by 22.9% and 30.7%, respectively. Twenty-two percent of families received financial housing support (public housing, Section-8). Compared with families in private housing, families with financial housing support had 3.8 times the odds of tobacco incursions (95% CI, 1.4-10.1) and 3.7 times the odds of worsening incursions during pandemic (95% CI, 1.1-12.5). Families with financially supported housing had 6.9 times the odds of marijuana incursions (95% CI, 2.4-19.5) and 5 times the odds of worsening incursions during pandemic (95% CI, 1.9-12.8). Children in financially supported housing spent more time inside the home during pandemic (median 24 hours vs 21.6 hours, P = .02) and were more likely to have asthma (37% vs 12.9%, P = .001) than children in private housing. CONCLUSIONS: Incursions were higher among families with financially supported housing. Better enforcement of existing regulations (eg, Smoke-Free Public Housing Rule) and implementation of additional policies to limit secondhand tobacco and marijuana exposure in children are needed. Such actions should prioritize equitable access to cessation and mental health services and consider structural systems leading to poverty and health disparities.

Effect of a multidisciplinary ward-based intervention on end-of-life care for general medicine patients.

OBJECTIVE: Providing good end-of-life (EOL) care for noncancer patients has been made a national priority in Singapore. A combined medical and nursing ward-based intervention known as the EOL care plan was piloted in a general medicine ward at our institution, aiming to guide key aspects of EOL care. The aim of this study is to assess the EOL care plan's effect on EOL care for general medicine patients. METHOD: We conducted a retrospective cohort study on inpatients who died in a general ward under the discipline "General Medicine" from May to October 2019. We collected data around symptom management, rationalization of care and communication with families. The primary analysis compared care received by patients who died in the pilot ward with that of a control group of patients who died in other wards. RESULTS: In total, 112 records were included in the analysis. Pain assessment was more common in the pilot ward compared with the control group (35.3% vs. 6.3%, p < 0.001), as were anti-psychotic prescriptions for delirium (64.7% vs. 24.4%, p = 0.001). Fewer patients received blood glucose monitoring in the last 48 h of life in the pilot ward (69.5% vs. 35.3%, p = 0.007). There were also less frequent parameters monitoring in the pilot ward (p < 0.004). SIGNIFICANCE OF RESULTS: The implementation of the EOL care plan was associated with process-level indicators of better EOL care, suggesting that it could have a significant positive impact when implemented on a wider scale.

KRAS and guanine nucleotide-binding protein mutations in pancreatic juice collected from the duodenum of patients at high risk for neoplasia undergoing endoscopic ultrasound.

BACKGROUND & AIMS: Pancreatic imaging can identify neoplastic cysts but not microscopic neoplasms. Mutation analysis of pancreatic fluid after secretin stimulation might identify microscopic neoplasias in the pancreatic duct system. We determined the prevalence of mutations in KRAS and guanine nucleotide-binding protein α-stimulating genes in pancreatic juice from subjects undergoing endoscopic ultrasound for suspected pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms, or pancreatic adenocarcinoma. METHODS: Secretin-stimulated juice samples were collected from the duodenum of 272 subjects enrolled in Cancer of the Pancreas Screening studies; 194 subjects were screened because of a family history of, or genetic predisposition to, pancreatic cancer, and 78 subjects were evaluated for pancreatic cancer (n = 30) or other disorders (controls: pancreatic cysts, pancreatitis, or normal pancreata, n = 48). Mutations were detected by digital high-resolution melt-curve analysis and pyrosequencing. The number of replicates containing a mutation determined the mutation score. RESULTS: KRAS mutations were detected in pancreatic juice from larger percentages of subjects with pancreatic cancer (73%) or undergoing cancer screening (50%) than controls (19%) (P = .0005). A greater proportion of patients with pancreatic cancer had at least 1 KRAS mutation detected 3 or more times (47%) than screened subjects (21%) or controls (6%, P = .002). Among screened subjects, mutations in KRAS (but not guanine nucleotide-binding protein α-stimulating) were found in similar percentages of patients with or without pancreatic cysts. However, a greater proportion of patients older than age 50 years had KRAS mutations (54.6%) than younger patients (36.3%) (P = .032); the older subjects also had more mutations in KRAS (P = .02). CONCLUSIONS: Mutations in KRAS are detected in pancreatic juice from the duodenum of 73% of patients with pancreatic cancer, and 50% of asymptomatic individuals with a high risk for pancreatic cancer. However, KRAS mutations were detected in pancreatic juice from 19% of controls. Mutations detected in individuals without pancreatic abnormalities, based on imaging analyses, likely arise from small pancreatic intraepithelial neoplasia lesions. ClinicalTrials.gov no: NCT00438906 and NCT00714701.

Antiphospholipid antibodies promote tissue factor-dependent angiogenic switch and tumor progression.

Progression to an angiogenic state is a critical event in tumor development, yet few patient characteristics have been identified that can be mechanistically linked to this transition. Antiphospholipid autoantibodies (aPLs) are prevalent in many human cancers and can elicit proangiogenic expression in several cell types, but their role in tumor biology is unknown. Herein, we observed that the elevation of circulating aPLs among breast cancer patients is specifically associated with invasive-stage tumors. By using multiple in vivo models of breast cancer, we demonstrated that aPL-positive IgG from patients with autoimmune disease rapidly accelerates tumor angiogenesis and consequent tumor progression, particularly in slow-growing avascular tumors. The action of aPLs was local to the tumor site and elicited leukocytic infiltration and tumor invasion. Tumor cells treated with aPL-positive IgG expressed multiple proangiogenic genes, including vascular endothelial growth factor, tissue factor (TF), and colony-stimulating factor 1. Knockdown and neutralization studies demonstrated that the effects of aPLs on tumor angiogenesis and growth were dependent on tumor cell-derived TF. Tumor-derived TF was essential for the development of pericyte coverage of tumor microvessels and aPL-induced tumor cell expression of chemokine ligand 2, a mediator of pericyte recruitment. These findings identify antiphospholipid autoantibodies as a potential patient-specific host factor promoting the transition of indolent tumors to an angiogenic malignant state through a TF-mediated pathogenic mechanism.

Interleukin 1 receptor 1 and interleukin 1ß regulate megakaryocyte maturation, platelet activation, and transcript profile during inflammation in mice and humans.

OBJECTIVE: Interleukin 1 Receptor 1 (IL1R1) and its ligand, IL1ß, are upregulated in cardiovascular disease, obesity, and infection. Previously, we reported a higher level of IL1R1 transcripts in platelets from obese individuals of the Framingham Heart Study (FHS), but its functional effect in platelets has never been described. Additionally, IL1ß levels are increased in atherosclerotic plaques and in bacterial infections. The aim of this work is to determine whether IL1ß, through IL1R1, can activate platelets and megakaryocytes to promote atherothrombosis. APPROACH AND RESULTS: We found that IL1ß-related genes from platelets, as measured in 1819 FHS participants, were associated with increased body mass index, and a direct relationship was shown in wild-type mice fed a high-fat diet. Mechanistically, IL1ß activated nuclear factor-κB and mitogen-activated protein kinase signaling pathways in megakaryocytes. IL1ß, through IL1R1, increased ploidy of megakaryocytes to 64+ N by 2-fold over control. IL1ß increased agonist-induced platelet aggregation by 1.2-fold with thrombin and 4.2-fold with collagen. IL1ß increased adhesion to both collagen and fibrinogen, and heterotypic aggregation by 1.9-fold over resting. High fat diet-enhanced platelet adhesion was absent in IL1R1(-/-) mice. Wild-type mice infected with Porphyromonas gingivalis had circulating heterotypic aggregates (1.5-fold more than control at 24 hours and 6.2-fold more at 6 weeks) that were absent in infected IL1R1(-/-) and IL1ß(-/-) mice. CONCLUSIONS: In summary, IL1R1- and IL1ß-related transcripts are elevated in the setting of obesity. IL1R1/IL1ß augment both megakaryocyte and platelet functions, thereby promoting a prothrombotic environment during infection and obesity; potentially contributing to the development of atherothrombotic disease.

Paneth cell marker expression in intestinal villi and colon crypts characterizes dietary induced risk for mouse sporadic intestinal cancer.

Nutritional and genetic risk factors for intestinal tumors are additive on mouse tumor phenotype, establishing that diet and genetic factors impact risk by distinct combinatorial mechanisms. In a mouse model of dietary-induced sporadic small and large intestinal cancer in WT mice in which tumor etiology, lag, incidence, and frequency reflect >90% of intestinal cancer in Western societies, dietary-induced risk altered gene expression profiles predominantly in villus cells of the histologically normal mucosa, in contrast to targeting of crypt cells by inheritance of an Apc(1638N) allele or homozygous inactivation of p21(Waf1/cip1), and profiles induced by each risk factor were distinct at the gene or functional group level. The dietary-induced changes in villus cells encompassed ectopic expression of Paneth cell markers (a lineage normally confined to the bottom of small intestinal crypts), elevated expression of the Wnt receptor Fzd5 and of EphB2 (genes necessary for Paneth cell differentiation and localization to the crypt bottom), and increased Wnt signaling in villus cells. Ectopic elevation of these markers was also present in the colon crypts, which are also sites of sporadic tumors in the nutritional model. Elevating dietary vitamin D(3) and calcium, which prevents tumor development, abrogated these changes in the villus and colon cells. Thus, common intestinal cancer driven by diet involves mechanisms of tumor development distinct from those mechanisms that cause tumors induced by the rare inheritance of a mutant adenomatous polyposis coli (Apc) allele. This is fundamental for understanding how common sporadic tumors arise and in evaluating relative risk in the population.

Global Regulatory Frameworks for the Use of Artificial Intelligence (AI) in the Healthcare Services Sector.

The healthcare sector is faced with challenges due to a shrinking healthcare workforce and a rise in chronic diseases that are worsening with demographic and epidemiological shifts. Digital health interventions that include artificial intelligence (AI) are being identified as some of the potential solutions to these challenges. The ultimate aim of these AI systems is to improve the patient's health outcomes and satisfaction, the overall population's health, and the well-being of healthcare professionals. The applications of AI in healthcare services are vast and are expected to assist, automate, and augment several healthcare services. Like any other emerging innovation, AI in healthcare also comes with its own risks and requires regulatory controls. A review of the literature was undertaken to study the existing regulatory landscape for AI in the healthcare services sector in developed nations. In the global regulatory landscape, most of the regulations for AI revolve around Software as a Medical Device (SaMD) and are regulated under digital health products. However, it is necessary to note that the current regulations may not suffice as AI-based technologies are capable of working autonomously, adapting their algorithms, and improving their performance over time based on the new real-world data that they have encountered. Hence, a global regulatory convergence for AI in healthcare, similar to the voluntary AI code of conduct that is being developed by the US-EU Trade and Technology Council, would be beneficial to all nations, be it developing or developed.

Qualitative feedback from caregivers in a multidisciplinary pediatric neuromuscular clinic.

OBJECTIVE: This study explored family satisfaction and perceived quality of care in a pediatric neuromuscular care clinic to assess the value of the multidisciplinary clinic (MDC) model in delivering coordinated care to children with neuromuscular disorders, such as cerebral palsy. METHODS: Caregivers of 22 patients were administered a qualitative survey assessing their perceptions of clinic efficiency, care coordination, and communication. Surveys were audio-recorded and transcribed. Thematic analysis was completed using both deductive and inductive methods. RESULTS: All caregivers reported that providers adequately communicated next steps in the patient's care, and most reported high confidence in caring for the patient as a result of the clinic. Four major themes were identified from thematic analysis: Care Delivery, Communication, Care Quality, and Family-Centeredness. Caregivers emphasized that the MDC model promoted access to care, enhanced efficiency, promoted provider teamwork, and encouraged shared care planning. Caregivers also valued a physical environment that was suitable for patients with complex needs. CONCLUSION: This study demonstrated that caregivers believed the MDC model was both efficient and convenient for pediatric patients with neuromuscular disorders. This model has the potential to streamline medical care and can be applied more broadly to improve care coordination for children with medical complexity.

Targeting pancreatic cancer metabolic dependencies through glutamine antagonism.

Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and therapeutic resistance. Here, we demonstrated that treating PDAC cells with a Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), led to a metabolic crisis in vitro. In addition, we observed a profound decrease in tumor growth in several in vivo models using sirpiglenastat (DRP-104), a pro-drug version of DON that was designed to circumvent DON-associated toxicity. We found that extracellular signal-regulated kinase (ERK) signaling is increased as a compensatory mechanism. Combinatorial treatment with DRP-104 and trametinib led to a significant increase in survival in a syngeneic model of PDAC. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. The combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.

A Quality Improvement Project to Improve After-visit Summary Patient Instructions in a Pediatric Multidisciplinary Neuromuscular Program.

Introduction: Multidisciplinary clinics aim to coordinate care between multiple specialties for children with medical complexity yet may result in information overload for caregivers. The after-visit summary (AVS) patient instruction section offers a solution by summarizing visit details and recommendations. No known studies address patient instruction optimization and integration within a multidisciplinary clinic setting. This project aimed to improve the quality of patient instructions to support better postvisit communication between caregivers and providers in a multidisciplinary pediatric neuromuscular program. Methods: A multidisciplinary stakeholder team created a key driver diagram to improve postvisit communication between caregivers and providers in the clinic. The first specific aim was to achieve an 80% completion rate of AVS patient instructions within 6 months. To do so, a standardized electronic medical record "text shortcut" was created for consistent information in each patient's instructions. Feedback on AVS from caregivers was obtained using the Family Experiences with Coordination of Care survey and open-ended interviews. This feedback informed the next specific aim: to reduce medical jargon within patient instructions by 25% over 3 months. Completion rates and jargon use were reviewed using control charts. Results: AVS patient instruction completion rates increased from a mean of 39.4%-85.0%. Provider education reduced mean jargon usage in patient instructions, from 8.2 to 3.9 jargon terms. Conclusions: Provider education and caregiver feedback helped improve patient communication by enhancing AVS compliance and diminishing medical jargon. Interventions to improve AVS patient instructions may enhance patient communication strategies for complex medical visits.

Regulatory effects of TLR2 on megakaryocytic cell function.

TLR2, a functional, inflammatory-related receptor, is known to be expressed on megakaryocytes and platelets and to lead to infection and immune-mediated activation of platelets; however, the role of this receptor in megakaryocytes is not understood. Using Meg-01 cells and mouse megakaryocytes, we found that NFκB, ERK-MAPK, and PI3K/Akt pathways, known downstream pathways of TLRs, are activated by Pam3CSK4, a TLR2-specific ligand. In addition, transcription factors associated with megakaryocyte maturation, GATA-1, NF-E2, and mammalian target of rapamycin (mTOR), are all increased in the presence of Pam3CSK4. The effect of Pam3CSK4 on megakaryocyte maturation was verified by the increase in DNA content and adhesion to extracellular matrix proteins by TLR2-dependent stimulation. In addition, TLR2 stimulation resulted in an increase in reactive oxygen species (ROS) production. Gene expression and protein levels of GP1b, CD41, MCP-1, COX2, NFκB1, and TLR2 were up-regulated in megakaryocytes after TLR2 stimulation through NFκB, PI3K/Akt, and ERK-MAPK pathways. Treatment of wild-type mice with Pam3CSK4 resulted in a return to normal platelet levels and an increase in megakaryocyte maturation, which did not occur in the TLR2(-/-) mice. Therefore, inflammation, through TLR2, can increase maturation and modulate the phenotype of megakaryocytes, contributing to the interrelationship between inflammation and hemostasis.

Risk factors for 90-day readmission and prolonged length of stay after hip surgery in children with cerebral palsy.

Objective: Spastic hip dysplasia is a common complication of cerebral palsy in children, and surgical intervention is usually warranted. While current literature has primarily analyzed single institution outcomes, this study utilized a national database to describe readmission rates and factors correlated with readmission for children with cerebral palsy undergoing hip surgery in order to treat this population more effectively. Methods: This study queried the Nationwide Readmissions Database (2014-2018) for pediatric patients with cerebral palsy who underwent hip surgery. Patient demographics, pre-operative comorbidities, length of stay (LOS), treatment complications, and readmission data were collected for each patient and analyzed with inferential statistics. Results: Of the 1225 patients included, the average age was 9.3 ± 3.8 years and 42.8% were female. Approximately 26.3% patients had a prolonged LOS (≥5 days) and 14.2% patients required readmission within 90-days of surgery. Medical complications, cardiac arrhythmias, and iron deficiency anemia were all significantly associated with elongated LOS as well as 90-day readmission. Patients with Medicaid were more frequently associated with an inpatient medical complication and the overall complication rate was 5.5%. Conclusions: While current literature has analyzed common risk factors and complications associated with hip surgery in the pediatric cerebral palsy patient, this study identifies a national readmission rate (14.2%) as well as preoperative comorbidities associated with readmission within 90-days and/or elongated LOS. Notably, complications are more frequently associated with patients using Medicaid. These results further exemplify the importance of equitable access to care and thorough selection of pediatric cerebral palsy patients appropriate for hip surgery.

Autophagy supports mitochondrial metabolism through the regulation of iron homeostasis in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) cells maintain a high level of autophagy, allowing them to thrive in an austere microenvironment. However, the processes through which autophagy promotes PDAC growth and survival are still not fully understood. Here, we show that autophagy inhibition in PDAC alters mitochondrial function by losing succinate dehydrogenase complex iron sulfur subunit B expression by limiting the availability of the labile iron pool. PDAC uses autophagy to maintain iron homeostasis, while other tumor types assessed require macropinocytosis, with autophagy being dispensable. We observed that cancer-associated fibroblasts can provide bioavailable iron to PDAC cells, promoting resistance to autophagy ablation. To overcome this cross-talk, we used a low-iron diet and demonstrated that this augmented the response to autophagy inhibition therapy in PDAC-bearing mice. Our work highlights a critical link between autophagy, iron metabolism, and mitochondrial function that may have implications for PDAC progression.

DOCU-CLIM: A global documentary climate dataset for climate reconstructions.

Documentary climate data describe evidence of past climate arising from predominantly written historical documents such as diaries, chronicles, newspapers, or logbooks. Over the past decades, historians and climatologists have generated numerous document-based time series of local and regional climates. However, a global dataset of documentary climate time series has never been compiled, and documentary data are rarely used in large-scale climate reconstructions. Here, we present the first global multi-variable collection of documentary climate records. The dataset DOCU-CLIM comprises 621 time series (both published and hitherto unpublished) providing information on historical variations in temperature, precipitation, and wind regime. The series are evaluated by formulating proxy forward models (i.e., predicting the documentary observations from climate fields) in an overlapping period. Results show strong correlations, particularly for the temperature-sensitive series. Correlations are somewhat lower for precipitation-sensitive series. Overall, we ascribe considerable potential to documentary records as climate data, especially in regions and seasons not well represented by early instrumental data and palaeoclimate proxies.

PediHome: Development of a Family-Reported Measure of Pediatric Home Healthcare Quality.

OBJECTIVE: No validated tools exist to measure pediatric home healthcare quality. The objective of this work was to develop a family-reported survey (PediHome) to measure the quality of home healthcare for children with medical complexity (CMC). METHODS: A national multidisciplinary expert panel (N = 19) was convened to develop survey content domains. Panelist were joined by 3 additional experts to rank candidate survey items for importance and evaluate relevance and structure. Cognitive interviews were conducted with English-speaking (n = 12) and Spanish-speaking (n = 4) family caregivers of CMC to revise problematic items and clarify response options. A cross-sectional survey was then fielded (6/1/20-10/31/20) to parents whose children receive healthcare at 2 regional academic medical centers. RESULTS: The final measure included N = 28 total items with 4 items quantifying access, 1 evaluating overall quality rating, and 21 items assessing provider tasks (11 home nursing only, 2 certified nursing assistant/home health aide only, and 1 dual). Out of 312 caregivers of CMC, 142 (46%) responded and one-half (n = 68, 48%) reported a child receiving home nursing. They received a weekly median of 58.4% (IQR ±31.2%) of approved nursing hours with 55% reporting a missed nursing shift within the last month. Median overall quality was 75-9 (0-10 scale) and median scores on specific quality items ranged from 31-4 to 43-4 (0-4 scale). CONCLUSIONS: PediHome is a new content-valid family-reported measure of home healthcare quality for CMC that is useful for evaluating healthcare quality across several domains. Future work will involve assessing PediHome's construct and predictive validity.