Endogenous CD28 drives CAR T cell responses in multiple myeloma.

Recent FDA approvals of chimeric antigen receptor (CAR) T cell therapy for multiple myeloma (MM) have reshaped the therapeutic landscape for this incurable cancer. In pivotal clinical trials B cell maturation antigen (BCMA) targeted, 4-1BB co-stimulated (BBζ) CAR T cells dramatically outperformed standard-of-care chemotherapy, yet most patients experienced MM relapse within two years of therapy, underscoring the need to improve CAR T cell efficacy in MM. We set out to determine if inhibition of MM bone marrow microenvironment (BME) survival signaling could increase sensitivity to CAR T cells. In contrast to expectations, blocking the CD28 MM survival signal with abatacept (CTLA4-Ig) accelerated disease relapse following CAR T therapy in preclinical models, potentially due to blocking CD28 signaling in CAR T cells. Knockout studies confirmed that endogenous CD28 expressed on BBζ CAR T cells drove in vivo anti-MM activity. Mechanistically, CD28 reprogrammed mitochondrial metabolism to maintain redox balance and CAR T cell proliferation in the MM BME. Transient CD28 inhibition with abatacept restrained rapid BBζ CAR T cell expansion and limited inflammatory cytokines in the MM BME without significantly affecting long-term survival of treated mice. Overall, data directly demonstrate a need for CD28 signaling for sustained in vivo function of CAR T cells and indicate that transient CD28 blockade could reduce cytokine release and associated toxicities.

LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic ß cells.

Using 13C6 glucose labeling coupled to gas chromatography-mass spectrometry and 2D 1H-13C heteronuclear single quantum coherence NMR spectroscopy, we have obtained a comparative high-resolution map of glucose fate underpinning ß cell function. In both mouse and human islets, the contribution of glucose to the tricarboxylic acid (TCA) cycle is similar. Pyruvate fueling of the TCA cycle is primarily mediated by the activity of pyruvate dehydrogenase, with lower flux through pyruvate carboxylase. While the conversion of pyruvate to lactate by lactate dehydrogenase (LDH) can be detected in islets of both species, lactate accumulation is 6-fold higher in human islets. Human islets express LDH, with low-moderate LDHA expression and ß cell-specific LDHB expression. LDHB inhibition amplifies LDHA-dependent lactate generation in mouse and human ß cells and increases basal insulin release. Lastly, cis-instrument Mendelian randomization shows that low LDHB expression levels correlate with elevated fasting insulin in humans. Thus, LDHB limits lactate generation in ß cells to maintain appropriate insulin release.

CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity.

Metabolic flexibility has emerged as a critical determinant of CD8+ T-cell antitumor activity, yet the mechanisms driving the metabolic flexibility of T cells have not been determined. In this study, we investigated the influence of the nuclear cap-binding complex (CBC) adaptor protein ARS2 on mature T cells. In doing so, we discovered a novel signaling axis that endows activated CD8+ T cells with flexibility of glucose catabolism. ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events. Among these effects, the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2, a key determinant of CD8+ T-cell glucose utilization, interferon gamma production, and antitumor effector function. Importantly, PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation, revealing a novel means by which costimulation reprograms glucose metabolism in CD8+ T cells.

Perinatal triphenyl phosphate exposure induces metabolic dysfunctions through the EGFR/ERK/AKT signaling pathway: Mechanistic in vitro and in vivo studies.

Triphenyl phosphate (TPhP), a widely used organophosphate-flame retardant, is ubiquitously found in household environments and may adversely affect human health. Evidence indicates that TPhP exposure causes metabolic dysfunctions in vivo; however, the underlying mechanism of such adverse effects has not been comprehensively investigated. Herein, we utilized two in vitro models including mouse and human preadipocytes to delineate adipogenic mechanisms of TPhP. The results revealed that both mouse and human preadipocytes exposed to TPhP concentration-dependently accumulated more fat through a significant upregulation of epidermal growth factor receptor (EGFR). We demonstrated that TPhP significantly promoted adipogenesis through the activation of EGFR/ERK/AKT signaling pathway as evident by a drastic reduction in adipogenesis of preadipocytes cotreated with inhibitors of EGFR and its major effectors. Furthermore, we confirmed the mechanism of TPhP-induced metabolic dysfunctions in vivo. We observed that male mice perinatally exposed to TPhP had a significant increase in adiposity, hepatic triglycerides, insulin resistance, plasma insulin levels, hypotension, and phosphorylated EGFR in gonadal fat. Interestingly, an administration of a potent and selective EGFR inhibitor significantly ameliorated the adverse metabolic effects caused by TPhP. Our findings uncovered a potential mechanism of TPhP-induced metabolic dysfunctions and provided implications on toxic metabolic effects posed by environmental chemicals.

The use and costs of same-day surgery versus overnight admission for total thyroidectomy: A multi-state, all-payer analysis.

BACKGROUND: Outpatient thyroidectomy is increasingly favored, given evidence of safety and convenience for selected patients. However, the prevalence of same-day discharge is unclear. We aimed to evaluate temporal trends, hospital characteristics, and costs associated with same-day discharge after total thyroidectomy in an all-payer, multi-state cohort. METHODS: We included patients aged ≥18 years who underwent a total thyroidectomy (2013-2019) using Healthcare Cost and Utilization Project data. Admission type was defined as same-day, overnight, or inpatient based on length of stay. Same-day patients were propensity-score matched 1:1 with overnight patients. Hospital characteristics and costs were compared in the matched cohort. RESULTS: Among 86,187 patients who underwent total thyroidectomy, 16,743 (19.4%) cases were same-day, 59,778 (69.4%) were overnight, and 9,666 (11.2%) were inpatient. The proportion of patients who underwent same-day thyroidectomy increased from 14.8% to 20.8% over the study period (P < .001), whereas overnight admissions decreased from 72.9% to 68.8% (P < .001). In total, 9,571 same-day patients were matched to 9,571 overnight patients. Same-day patients had higher odds of treatment at a certified cancer center (odds ratio 1.77; 95% confidence interval 1.65-1.90), Accreditation Council for Graduate Medical Education-accredited teaching hospital (odds ratio 1.72; 95% confidence interval 1.61-1.85), and high-volume hospital (odds ratio 1.53; 95% confidence interval 1.42-1.65). Pairwise cost differences showed median savings of $974 (interquartile range -1,610 to 3,491) for same-day relative to overnight admission (P < .001). CONCLUSION: Although over two-thirds of patients are admitted overnight, same-day total thyroidectomy is increasingly performed. Same-day thyroidectomy may be a lower-cost option for selected patients, particularly in specialty centers with experience in thyroidectomy.

Response-Adapted Therapy for Newly Diagnosed Multiple Myeloma.

PURPOSE OF REVIEW: The development of potent novel agents has improved outcomes for patients with multiple myeloma (MM). Heterogeneity of response to therapy, an expanding arsenal of treatment options, and cost are however major challenges for physicians making treatment decisions. Response-adapted therapy is hence an attractive strategy for sequencing of therapy in MM. Despite its successful application in other haematologic malignancies, response-adapted therapy is yet to become a standard of care for MM. We provide our perspective on response-adapted therapeutic strategies evaluated thus far and how they may be implemented and improved on in treatment algorithms of the future. RECENT FINDINGS: While older studies suggested that early response based on International Myeloma Working Group response criteria could impact long-term outcomes, recent data have contradicted these findings. The advent of minimal residual disease (MRD) as a powerful prognostic factor in MM has raised the promise of MRD-adapted treatment strategies. The development of more sensitive techniques for paraprotein quantification as well as imaging modalities to detect extramedullary disease is likely to change response assessment in MM. These techniques combined with MRD assessment may provide sensitive and holistic response assessments which could be evaluated in clinical trials. Response-adapted treatment algorithms have the potential to allow an individualised treatment strategy, maximising efficacy, while minimising toxicities and cost. Standardisation of MRD methodology, incorporation of imaging into response assessment, and the optimal management of MRD positive patients are key questions to be addressed in future trials.

A Novel Mobile App to Identify Patients With Multimorbidity in the Emergency Setting: Development of an App and Feasibility Trial.

BACKGROUND: Multimorbidity is associated with an increased risk of poor surgical outcomes among older adults; however, identifying multimorbidity in the clinical setting can be a challenge. OBJECTIVE: We created the Multimorbid Patient Identifier App (MMApp) to easily identify patients with multimorbidity identified by the presence of a Qualifying Comorbidity Set and tested its feasibility for use in future clinical research, validation, and eventually to guide clinical decision-making. METHODS: We adapted the Qualifying Comorbidity Sets' claims-based definition of multimorbidity for clinical use through a modified Delphi approach and developed MMApp. A total of 10 residents input 5 hypothetical emergency general surgery patient scenarios, common among older adults, into the MMApp and examined MMApp test characteristics for a total of 50 trials. For MMApp, comorbidities selected for each scenario were recorded, along with the number of comorbidities correctly chosen, incorrectly chosen, and missed for each scenario. The sensitivity and specificity of identifying a patient as multimorbid using MMApp were calculated using composite data from all scenarios. To assess model feasibility, we compared the mean task completion by scenario to that of the American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator (ACS-NSQIP-SRC) using paired t tests. Usability and satisfaction with MMApp were assessed using an 18-item questionnaire administered immediately after completing all 5 scenarios. RESULTS: There was no significant difference in the task completion time between the MMApp and the ACS-NSQIP-SRC for scenarios A (86.3 seconds vs 74.3 seconds, P=.85) or C (58.4 seconds vs 68.9 seconds,P=.064), MMapp took less time for scenarios B (76.1 seconds vs 87.4 seconds, P=.03) and E (20.7 seconds vs 73 seconds, P<.001), and more time for scenario D (78.8 seconds vs 58.5 seconds, P=.02). The MMApp identified multimorbidity with 96.7% (29/30) sensitivity and 95% (19/20) specificity. User feedback was positive regarding MMApp's usability, efficiency, and usefulness. CONCLUSIONS: The MMApp identified multimorbidity with high sensitivity and specificity and did not require significantly more time to complete than a commonly used web-based risk-stratification tool for most scenarios. Mean user times were well under 2 minutes. Feedback was overall positive from residents regarding the usability and usefulness of this app, even in the emergency general surgery setting. It would be feasible to use MMApp to identify patients with multimorbidity in the emergency general surgery setting for validation, research, and eventual clinical use. This type of mobile app could serve as a template for other research teams to create a tool to easily screen participants for potential enrollment.

Non-English Primary Language: A Growing Population's Access to Cholecystectomy.

OBJECTIVE: To examine access to cholecystectomy and postoperative outcomes among non-English primary-speaking patients. BACKGROUND: The population of U.S. residents with limited English proficiency is growing. Language affects health literacy and is a well-recognized barrier to health care in the United States of America. Historically marginalized communities are at greater risk of requiring emergent gallbladder operations. However, little is known about how primary language affects surgical access and outcomes of common surgical procedures, such as cholecystectomy. METHODS: We conducted a retrospective cohort study of adult patients after receipt of cholecystectomy in Michigan, Maryland, and New Jersey utilizing the Healthcare Cost and Utilization Project State Inpatient Database and State Ambulatory Surgery and Services Database (2016-2018). Patients were classified by primary spoken language: English or non-English. The primary outcome was admission type. Secondary outcomes included operative setting, operative approach, in-hospital mortality, postoperative complications, and length of stay. Multivariable logistics and Poisson regression were used to examine outcomes. RESULTS: Among 122,013 patients who underwent cholecystectomy, 91.6% were primarily English speaking and 8.4% were non-English primary language speaking. Primary non-English speaking patients had a higher likelihood of emergent/urgent admissions (odds ratio: 1.22, 95% CI: 1.04-1.44, P = 0.015) and a lower likelihood of having an outpatient operation (odds ratio: 0.80, 95% CI: 0.70-0.91, P = 0.0008). There was no difference in the use of a minimally invasive approach or postoperative outcomes based on the primary language spoken. CONCLUSIONS: Non-English primary language speakers were more likely to access cholecystectomy through the emergency department and less likely to receive outpatient cholecystectomy. Barriers to elective surgical presentation for this growing patient population need to be further studied.

Development of a Machine Learning Model to Identify Colorectal Cancer Stage in Medicare Claims.

PURPOSE: Staging information is essential for colorectal cancer research. Medicare claims are an important source of population-level data but currently lack oncologic stage. We aimed to develop a claims-based model to identify stage at diagnosis in patients with colorectal cancer. METHODS: We included patients age 66 years or older with colorectal cancer in the SEER-Medicare registry. Using patients diagnosed from 2014 to 2016, we developed models (multinomial logistic regression, elastic net regression, and random forest) to classify patients into stage I-II, III, or IV on the basis of demographics, diagnoses, and treatment utilization identified in Medicare claims. Models developed in a training cohort (2014-2016) were applied to a testing cohort (2017), and performance was evaluated using cancer stage listed in the SEER registry as the reference standard. RESULTS: The cohort of patients with 30,543 colorectal cancer included 14,935 (48.9%) patients with stage I-II, 9,203 (30.1%) with stage III, and 6,405 (21%) with stage IV disease. A claims-based model using elastic net regression had a scaled Brier score (SBS) of 0.45 (95% CI, 0.43 to 0.46). Performance was strongest for classifying stage IV (SBS, 0.62; 95% CI, 0.59 to 0.64; sensitivity, 93%; 95% CI, 91 to 94) followed by stage I-II (SBS, 0.45; 95% CI, 0.44 to 0.47; sensitivity, 86%; 95% CI, 85 to 76) and stage III (SBS, 0.32; 95% CI, 0.30 to 0.33; sensitivity, 62%; 95% CI, 61 to 64). CONCLUSION: Machine learning models effectively classified colorectal cancer stage using Medicare claims. These models extend the ability of claims-based research to risk-adjust and stratify by stage.

Factors Associated With Primary Care Physician Decision-making When Making Medication Recommendations vs Surgical Referrals.

Importance: Although objective data are used routinely in prescription drug recommendations, it is unclear how referring physicians apply evidence when making surgeon or hospital recommendations for surgery. Objective: To compare the factors associated with the hospital or surgeon referral decision-making process with that used for prescription medication recommendations. Design, Setting, and Participants: This qualitative study comprised interviews conducted between April 26 and May 18, 2021, of a purposive sample of 21 primary care physicians from a large primary care network in the Northeast US. Main Outcomes and Measures: Main outcomes were the factors considered when making prescription medication recommendations vs referral recommendations to specific surgeons or hospitals for surgery. Results: All 21 participant primary care physicians (14 women [66.7%]) reported use of evidence-based decision support tools and patient attributes for prescription medication recommendations. In contrast, for surgeon and hospital referral recommendations, primary care physicians relied on professional experience and training, personal beliefs about surgical quality, and perceived convenience. Primary care physicians cited perceived limitations of existing data on surgical quality as a barrier to the use of such data in the process of making surgical referrals. Conclusions and Relevance: As opposed to the widespread use of objective decision support tools for guidance on medication recommendations, primary care physicians relied on subjective factors when making referrals to specific surgeons and hospitals. The findings of this study highlight the potential to improve surgical outcomes by introducing accessible, reliable data as an imperative step in the surgical referral process.

Exploring ethnic differences in post-discharge patterns of surgical care for older adults admitted with diverticulitis.

AIM: We aimed to evaluate ethnic differences in patterns of care following an index nonoperative admission for acute diverticulitis amongst a universally insured patient cohort. METHODS: We identified nationwide Medicare beneficiaries aged 65.5 years or older hospitalized between 1 July 2015 and 1 November 2017 for nonoperative management of an index admission for diverticulitis. Patients were followed for 1 year to examine patterns of care. Primary categorical outcomes included receipt of an elective operation, emergency operation, nonoperative readmission or no further hospitalizations for diverticulitis. Multinomial regression was performed to determine the association between ethnicity and receipt of each primary outcome category whilst adjusting for potential confounders. We examined the use of percutaneous drainage during the index admission to better understand its association with subsequent care patterns. RESULTS: Amongst 22 630 study patients, subsequent operative treatment was less common for Black, Hispanic, Asian and American Indian patients relative to White patients. Multinomial logistic regression noted that Black (relative risk 0.40; 95% CI 0.32-0.50) and Asian (relative risk 0.37; 95% CI 0.15-0.91) patients were associated with the lowest relative risk of undergoing an elective interval operation compared to White patients. Black patients were also associated with a 1.43 (95% CI 1.19-1.73) increased risk of requiring subsequent nonoperative readmissions for disease recurrence compared to White patients. The use of percutaneous drainage was higher amongst White patients relative to Black patients (6.9% vs. 4.0%, P value < 0.001). CONCLUSION: We have identified ongoing inequities in the consumption of medical resources, with White patients being more likely to undergo elective colectomy and percutaneous drainage. Differences in care are not fully alleviated by equal access to insurance.

Chronic Exposure to Low Levels of Parabens Increases Mammary Cancer Growth and Metastasis in Mice.

Methylparaben (MP) and propylparaben (PP) are commonly used as food, cosmetic, and drug preservatives. These parabens are detected in the majority of US women and children, bind and activate estrogen receptors (ER), and stimulate mammary tumor cell growth and invasion in vitro. Hemizygous B6.FVB-Tg (MMTV-PyVT)634Mul/LellJ female mice (n = 20/treatment) were exposed to MP or PP at levels within the US Food and Drug Administration's "human acceptable daily intake." These paraben-exposed mice had increased mammary tumor volume compared with control mice (P < 0.001) and a 28% and 91% increase in the number of pulmonary metastases per week compared with the control mice, respectively (P < 0.0001). MP and PP caused differential expression of 288 and 412 mammary tumor genes, respectively (false discovery rate < 0.05), a subset of which has been associated with human breast cancer metastasis. Molecular docking and luciferase reporter studies affirmed that MP and PP bound and activated human ER, and RNA-sequencing revealed increased ER expression in mammary tumors among paraben-exposed mice. However, ER signaling was not enriched in mammary tumors. Instead, both parabens strongly impaired tumor RNA metabolism (eg, ribosome, spliceosome), as evident from enriched KEGG pathway analysis of differential mammary tumor gene expression common to both paraben treatments (MP, P < 0.001; PP, P < 0.01). Indeed, mammary tumors from PP-exposed mice had an increased retention of introns (P < 0.05). Our data suggest that parabens cause substantial mammary cancer metastasis in mice as a function of their increasing alkyl chain length and highlight the emerging role of aberrant spliceosome activity in breast cancer metastasis.

Health System Structure: An Opportunity to Address Structural Racism and Discrimination.

OBJECTIVE: To examine the role of hub-and-spoke systems as a factor in structural racism and discrimination. BACKGROUND: Health systems are often organized in a "hub-and-spoke" manner to centralize complex surgical care to 1 high-volume hospital. Although the surgical health care disparities are well described across health care systems, it is not known how they seem across a single system's hospitals. METHODS: Adult patients who underwent 1 of 10 general surgery operations in 12 geographically diverse states (2016-2018) were identified using the Healthcare Cost and Utilization Project's State Inpatient Databases. System status was assigned using the American Hospital Association dataset. Hub designation was assigned in 2 ways: (1) the hospital performing the most complex operations (general hub) or (2) the hospital performing the most of each specific operation (procedure-specific hub). Independent multivariable logistic regression was used to evaluate the risk-adjusted odds of treatment at hubs by race and ethnicity. RESULTS: We identified 122,236 patients across 133 hospitals in 43 systems. Most patients were White (73.4%), 14.2% were Black, and 12.4% Hispanic. A smaller proportion of Black and Hispanic patient underwent operations at general hubs compared with White patients (B: 59.6% H: 52.0% W: 62.0%, P <0.001). After adjustment, Black and Hispanic patients were less likely to receive care at hub hospitals relative to White patients for common and complex operations (general hub B: odds ratio: 0.88 CI, 0.85, 0.91 H: OR: 0.82 CI, 0.79, 0.85). CONCLUSIONS: When White, Black, and Hispanic patients seek care at hospital systems, Black and Hispanic patients are less likely to receive treatment at hub hospitals. Given the published advantages of high-volume care, this new finding may highlight an opportunity in the pursuit of health equity.

Evaluating Changes in Surgical Outcomes for Patients With Inflammatory Bowel Disease Following Medicaid Expansion.

BACKGROUND: Little is known about the impact of Medicaid expansion on the surgical care of inflammatory bowel disease. We sought to determine whether Medicaid expansion is associated with improved postsurgical outcomes for patients with inflammatory bowel disease undergoing a colorectal resection. METHODS: We performed a risk-adjusted difference-in-difference study examining postsurgical outcomes for patients ages 26 to 64 with Crohn's disease or ulcerative colitis undergoing a colorectal resection across 15 states that did and did not expand Medicaid before (2012-2013) and after (2016-2018) policy reform. Primary study outcomes included 30-day readmission and postoperative complication. RESULTS: Study population included 11 394 patients with inflammatory bowel disease that underwent a colorectal resection. States that underwent Medicaid expansion were associated with a rise in Medicaid enrollment following policy reform (11.8% pre-Medicaid expansion vs 19.7% post-Medicaid expansion). Difference-in-difference analysis revealed a statistically significant lower odds of 30-day readmission in patients undergoing a colorectal resection in expansion states following policy reform relative to patients in nonexpansion states prior to reform (odds ratio, 0.56; 95% confidence interval, 0.36-0.86). No changes in odds of postoperative complication were noted across expansion and nonexpansion states. CONCLUSIONS: Medicaid expansion is associated with a rise in Medicaid enrollment in expansion states following policy reform. There were greater improvements in postoperative outcomes associated with patients in expansion states following policy reform relative to patients in nonexpansion states prior to reform, which may have been related to improved perioperative care and medical management.

Do Post-injury Prophylactic Antibiotics Reduce Infection for Isolated Midface Fractures: A Cohort Study.

PURPOSE: Fractures of the midface are a core component to the practice of contemporary oral and maxillofacial trainees and surgeons. As such, in an era where antibiotic resistance is increasing it is important to investigate if antibiotics are required after midface fractures to prevent infections before follow-up in an outpatient setting. The purpose of this study is to determine whether postinjury prophylactic preoperative antibiotics reduce rates of infection after midface fracture. METHODS: A retrospective multicenter cohort study was conducted in Queensland, Australia. Patients who presented to Royal Brisbane Hospital and Townsville Hospital with isolated midface fractures between January 2017 and January 2019 were included. Clinical and demographic data of patients who received postinjury prophylactic antibiotics were compared to those who did not using the χ2 test. Logistic regression was used to determine factors associated with increased odds of postinjury prophylactic antibiotic prescription. RESULTS: In total, 1,353 patients with midfacial fractures over the 2-year period were included. In addition, 724 (53.5%) patients received postinjury antibiotics and 629 (46.5%) patients did not. The overall rate of infection was very low: 1 patient who received postinjury prophylactic antibiotics (0.1%) developed infection compared to 2 patients (0.3%) who did not receive postinjury prophylactic antibiotics, and this difference was not significant (χ2 = 0.49; P = .48). Male sex (odds ratio 1.4; 95% confidence interval, 1.1 to 1.7; P = .02) and tobacco use (odds ratio 1.4; 95% confidence interval, 1.1 to 1.7; P = .008) were associated with an increased odds of postinjury prophylactic antibiotic prescription in the univariate analyses, but were no longer significant once site, age, and fracture type were adjusted for in the multivariate model. CONCLUSIONS: The rate of infection after midface fracture was low and there was no significant difference in infection rates for patients who received postinjury prophylactic antibiotics compared to those who did not. Use of postinjury prophylactic preoperative antibiotics for midfacial fractures should be reconsidered.

Local activation of focal adhesion kinase orchestrates the positioning of presynaptic scaffold proteins and Ca2+ signalling to control glucose-dependent insulin secretion.

A developing understanding suggests that spatial compartmentalisation in pancreatic ß cells is critical in controlling insulin secretion. To investigate the mechanisms, we have developed live-cell subcellular imaging methods using the mouse organotypic pancreatic slice. We demonstrate that the organotypic pancreatic slice, when compared with isolated islets, preserves intact ß-cell structure, and enhances glucose-dependent Ca2+ responses and insulin secretion. Using the slice technique, we have discovered the essential role of local activation of integrins and the downstream component, focal adhesion kinase (FAK), in regulating ß cells. Integrins and FAK are exclusively activated at the ß-cell capillary interface and using in situ and in vitro models we show their activation both positions presynaptic scaffold proteins, like ELKS and liprin, and regulates glucose-dependent Ca2+ responses and insulin secretion. We conclude that FAK orchestrates the final steps of glucose-dependent insulin secretion within the restricted domain where ß-cell contact the islet capillaries.

How Referring Providers Choose Specialists for Their Patients: a Systematic Review.

BACKGROUND: Physician referrals are a critical step in directing patients to high-quality specialists. Despite efforts to encourage referrals to high-volume hospitals, many patients receive treatment at low-volume centers with worse outcomes. We aimed to determine the most important factors considered by referring providers when selecting specialists for their patients through a systematic review of medical and surgical literature. METHODS: PubMed and Embase were searched from January 2000 to July 2021 using terms related to referrals, specialty, surgery, primary care, and decision-making. We included survey and interview studies reporting the factors considered by healthcare providers as they refer patients to specialists in the USA. Studies were screened by two independent reviewers. Quality was assessed using the CASP Checklist. A qualitative thematic analysis was performed to synthesize common decision factors across studies. RESULTS: We screened 1,972 abstracts and identified 7 studies for inclusion, reporting on 1,575 providers. Thematic analysis showed that referring providers consider factors related to the specialist's clinical expertise (skill, training, outcomes, and assessments), interactions between the patient and specialist (prior experience, rapport, location, scheduling, preference, and insurance), and interactions between the referring physician and specialist (personal relationships, communication, reputation, reciprocity, and practice or system affiliation). Notably, studies did not describe how providers assess clinical or technical skills. CONCLUSIONS: Referring providers rely on subjective factors and assessments to evaluate quality when selecting a specialist. There may be a role for guidelines and objective measures of quality to inform the choice of specialist by referring providers.

Case Report: Hypoglycemia Due to a Novel Activating Glucokinase Variant in an Adult - a Molecular Approach.

We present a case of an obese 22-year-old man with activating GCK variant who had neonatal hypoglycemia, re-emerging with hypoglycemia later in life. We investigated him for asymptomatic hypoglycemia with a family history of hypoglycemia. Genetic testing yielded a novel GCK missense class 3 variant that was subsequently found in his mother, sister and nephew and reclassified as a class 4 likely pathogenic variant. Glucokinase enables phosphorylation of glucose, the rate-limiting step of glycolysis in the liver and pancreatic ß cells. It plays a crucial role in the regulation of insulin secretion. Inactivating variants in GCK cause hyperglycemia and activating variants cause hypoglycemia. Spleen-preserving distal pancreatectomy revealed diffuse hyperplastic islets, nuclear pleomorphism and periductular islets. Glucose stimulated insulin secretion revealed increased insulin secretion in response to glucose. Cytoplasmic calcium, which triggers exocytosis of insulin-containing granules, revealed normal basal but increased glucose-stimulated level. Unbiased gene expression analysis using 10X single cell sequencing revealed upregulated INS and CKB genes and downregulated DLK1 and NPY genes in ß-cells. Further studies are required to see if alteration in expression of these genes plays a role in the metabolic and histological phenotype associated with glucokinase pathogenic variant. There were more large islets in the patient's pancreas than in control subjects but there was no difference in the proportion of ß cells in the islets. His hypoglycemia was persistent after pancreatectomy, was refractory to diazoxide and improved with pasireotide. This case highlights the variable phenotype of GCK mutations. In-depth molecular analyses in the islets have revealed possible mechanisms for hyperplastic islets and insulin hypersecretion.

Reporting of Discrimination by Health Care Consumers Through Online Consumer Reviews.

IMPORTANCE: Little is known about how discrimination in health care relates to inequities in hospital-based care because of limitations in the ability to measure discrimination. Consumer reviews offer a novel source of data to capture experiences of discrimination in health care settings. OBJECTIVE: To examine how health care consumers perceive and report discrimination through public consumer reviews. DESIGN, SETTING, AND PARTICIPANTS: This qualitative study assessed Yelp online reviews from January 1, 2011, to December 31, 2020, of 100 randomly selected acute care hospitals in the US. Word filtering was used to identify reviews potentially related to discrimination by using keywords abstracted from the Everyday Discrimination Scale, a commonly used questionnaire to measure discrimination. A codebook was developed through a modified grounded theory and qualitative content analysis approach to categorize recurrent themes of discrimination, which was then applied to the hospital reviews. EXPOSURES: Reported experiences of discrimination within a health care setting. MAIN OUTCOMES AND MEASURES: Perceptions of how discrimination in health care is experienced and reported by consumers. RESULTS: A total of 10 535 reviews were collected. Reviews were filtered by words commonly associated with discriminatory experiences, which identified 2986 reviews potentially related to discrimination. Using the codebook, the team manually identified 182 reviews that described at least 1 instance of discrimination. Acts of discrimination were categorized by actors of discrimination (individual vs institution), setting (clinical vs nonclinical), and directionality (whether consumers expressed discriminatory beliefs toward health care staff). A total of 53 reviews (29.1%) were coded as examples of institutional racism; 89 reviews (48.9%) mentioned acts of discrimination that occurred in clinical spaces as consumers were waiting for or actively receiving care; 25 reviews (13.7%) mentioned acts of discrimination that occurred in nonclinical spaces, such as lobbies; and 66 reviews (36.3%) documented discrimination by the consumer directed at the health care workforce. Acts of discrimination are described through 6 recurrent themes, including acts of commission, omission, unprofessionalism, disrespect, stereotyping, and dehumanizing. CONCLUSIONS AND RELEVANCE: In this qualitative study, consumer reviews were found to highlight recurrent patterns of discrimination within health care settings. Applying quality improvement tools, such as the Plan-Do-Study-Act cycle, to this source of data and this study's findings may help inform assessments and initiatives directed at reducing discrimination within the health care setting.