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.

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.

PURPOSE: 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.

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.

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.

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.

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.

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.

Spontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters.

α-ketoglutarate (KG), also referred to as 2-oxoglutarate, is a key intermediate of cellular metabolism with pleiotropic functions. Cell-permeable esterified analogs are widely used to study how KG fuels bioenergetic and amino acid metabolism and DNA, RNA, and protein hydroxylation reactions, as cellular membranes are thought to be impermeable to KG. Here we show that esterified KG analogs rapidly hydrolyze in aqueous media, yielding KG that, in contrast to prevailing assumptions, imports into many cell lines. Esterified KG analogs exhibit spurious KG-independent effects on cellular metabolism, including extracellular acidification, arising from rapid hydrolysis and de-protonation of α-ketoesters, and significant analog-specific inhibitory effects on glycolysis or mitochondrial respiration. We observe that imported KG decarboxylates to succinate in the cytosol and contributes minimally to mitochondrial metabolism in many cell lines cultured in normal conditions. These findings demonstrate that nuclear and cytosolic KG-dependent reactions may derive KG from functionally distinct subcellular pools and sources.

Fc galactosylation follows consecutive reaction kinetics and enhances immunoglobulin G hexamerization for complement activation.

Fc galactosylation is a critical quality attribute for anti-tumor recombinant immunoglobulin G (IgG)-based monoclonal antibody (mAb) therapeutics with complement-dependent cytotoxicity (CDC) as the mechanism of action. Although the correlation between galactosylation and CDC has been known, the underlying structure-function relationship is unclear. Heterogeneity of the Fc N-glycosylation produced by Chinese hamster ovary (CHO) cell culture biomanufacturing process leads to variable CDC potency. Here, we derived a kinetic model of galactose transfer reaction in the Golgi apparatus and used this model to determine the correlation between differently galactosylated species from CHO cell culture process. The model was validated by a retrospective data analysis of more than 800 historical samples from small-scale and large-scale CHO cell cultures. Furthermore, using various analytical technologies, we discovered the molecular basis for Fc glycan terminal galactosylation changing the three-dimensional conformation of the Fc, which facilitates the IgG1 hexamerization, thus enhancing C1q avidity and subsequent complement activation. Our study offers insight into the formation of galactosylated species, as well as a novel three-dimensional understanding of the structure-function relationship of terminal galactose to complement activation in mAb therapeutics.

A Multidisciplinary Home Visiting Program for Children With Medical Complexity.

OBJECTIVES: Given the high needs and costs associated with the care of children with medical complexity (CMC), innovative models of care are needed. Home-visiting care models are effective in subpopulations of pediatrics and medically complex adults, but there is no literature on this model for CMC. We describe the development and outcomes of a multidisciplinary program that provides comprehensive home-based primary care for CMC. METHODS: Medical records from our institution were reviewed for patients enrolled in our program from July 2013 through March 2019. Demographics, clinical characteristics, and health care use were collected. We compared the differences in pre- and postprogram enrollment health care use using Wilcoxon signed rank test. We applied Cox proportional hazard models to examine the association between the time-dependent postenrollment health care use and numbers of home visits. We collected total claims data for a subset of our patients to examine total costs of care. RESULTS: We reviewed data collected from 121 patients. With our findings, we demonstrate that enrollment in our program is associated with reductions in average length of stay. More home visits were associated with decreased emergency department visits and hospitalizations. We also observed in patients with available cost data that total costs of care decreased after enrollment into the program. CONCLUSIONS: Our model has the potential to improve health outcomes and be financially sustainable by providing home-based primary care to CMC.

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.

Biosensors Show the Pharmacokinetics of S-Ketamine in the Endoplasmic Reticulum.

The target for the "rapid" (<24 h) antidepressant effects of S-ketamine is unknown, vitiating programs to rationally develop more effective rapid antidepressants. To describe a drug's target, one must first understand the compartments entered by the drug, at all levels-the organ, the cell, and the organelle. We have, therefore, developed molecular tools to measure the subcellular, organellar pharmacokinetics of S-ketamine. The tools are genetically encoded intensity-based S-ketamine-sensing fluorescent reporters, iSKetSnFR1 and iSKetSnFR2. In solution, these biosensors respond to S-ketamine with a sensitivity, S-slope = delta(F/F0)/(delta[S-ketamine]) of 0.23 and 1.9/µM, respectively. The iSKetSnFR2 construct allows measurements at <0.3 µM S-ketamine. The iSKetSnFR1 and iSKetSnFR2 biosensors display >100-fold selectivity over other ligands tested, including R-ketamine. We targeted each of the sensors to either the plasma membrane (PM) or the endoplasmic reticulum (ER). Measurements on these biosensors expressed in Neuro2a cells and in human dopaminergic neurons differentiated from induced pluripotent stem cells (iPSCs) show that S-ketamine enters the ER within a few seconds after appearing in the external solution near the PM, then leaves as rapidly after S-ketamine is removed from the extracellular solution. In cells, S-slopes for the ER and PM-targeted sensors differ by <2-fold, indicating that the ER [S-ketamine] is less than 2-fold different from the extracellular [S-ketamine]. Organelles represent potential compartments for the engagement of S-ketamine with its antidepressant target, and potential S-ketamine targets include organellar ion channels, receptors, and transporters.

Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets.

The roles of tumor-associated macrophages (TAMs) and circulating monocytes in human cancer are poorly understood. Here, we show that monocyte subpopulation distribution and transcriptomes are significantly altered by the presence of endometrial and breast cancer. Furthermore, TAMs from endometrial and breast cancers are transcriptionally distinct from monocytes and their respective tissue-resident macrophages. We identified a breast TAM signature that is highly enriched in aggressive breast cancer subtypes and associated with shorter disease-specific survival. We also identified an auto-regulatory loop between TAMs and cancer cells driven by tumor necrosis factor alpha involving SIGLEC1 and CCL8, which is self-reinforcing through the production of CSF1. Together these data provide direct evidence that monocyte and macrophage transcriptional landscapes are perturbed by cancer, reflecting patient outcomes.

Immunology of Wound Healing.

PURPOSE OF REVIEW: Chronic wounds are a tremendous burden on the healthcare system and lead to significant patient morbidity and mortality. Normal cutaneous wound healing occurs through an intricate and delicate interplay between the immune system, keratinocytes, and dermal cells. Each cell type contributes signals that drive the normal phases of wound healing: hemostasis, inflammation, proliferation, and remodeling. This paper reviews how various immunological cell types and signaling molecules influence the way wounds develop, persist, and heal. RECENT FINDINGS: Concurrent with the achievement of hemostasis, neutrophils are the first cells to migrate to the wound bed, brought in by pro-inflammatory signals including IL-8. Their apoptosis and engulfment by macrophages (efferocytosis) provides a key signal to the local immune milieu, including macrophages, to transition to an anti-inflammatory, pro-repair state, where angiogenesis occurs and granulation tissue is laid down. Myofibroblasts, activated through contractile forces and signaling molecules, then drive remodeling, where granulation tissue becomes scar. Unchecked inflammation at this stage can result in abnormal scar formation. SUMMARY: Although the derangement of immune signals at any stage can result in impaired wound healing, recent research has shown that the key transition point lies between the inflammatory and the proliferative phases. This review summarizes the events that facilitate this transition and discusses how this process can be disrupted, leading to chronic, non-healing wounds.

A review of neurologic complications of biologic therapy in plaque psoriasis.

The use of biologic medications has represented a great advancement in the treatment of moderate to severe plaque psoriasis and has improved patients' quality of life. Despite the increasing popularity of biologics, their neurological side effects have been a constant concern. Reports of demyelinating diseases associated with tumor necrosis factor α (TNF-α) inhibitors continue to accumulate. Additionally, efalizumab was withdrawn from the market in 2009 for causing progressive multifocal leukoencephalopathy (PML). These reports highlight the need for dermatologists to inform patients of the risks and promote informed decision-making with patients prior to starting a biologic agent. Dermatologists also need to recognize early manifestations of neurologic side effects. This review provides an overview of the literature on neurologic diseases that have been found to be associated with biologic agents used for plaque psoriasis. Clinical presentations and diagnostic workups of such diseases are given to aid dermatologists in their early diagnosis and referral.